The objective of this study was to determine whether ICPtcd can be considered a reliable screening test compared to the reference standard method, invasive ICP monitoring (ICPi), in excluding the presence of intracranial hypertension.Alternative noninvasive methods capable of excluding intracranial hypertension through use of transcranial Doppler (ICPtcd) with a reference standard (ICPi), defined as the best available method for establishing the presence or absence of the condition of interest . Acute brain-injured patients pertaining to one of four categories: traumatic brain injury (TBI), subarachnoid hemorrhage (SAH), intracerebral hemorrhage (ICH) or ischemic stroke (IS) requiring ICPi monitoring, were enrolled in 16 international intensive care units. ICPi measurements (reference test) were compared to simultaneous ICPtcd measurements (index test) at three different timepoints: before, immediately after and 2 to 3 h following ICPi catheter insertion. Sensitivity, specificity, positive (PPV) and negative predictive values (NPV) were calculated at three different ICPi thresholds  to assess ICPtcd as a bedside real-practice screening method. A receiver operating characteristic (ROC) curve analysis with the area under the curve (AUC) was used to evaluate the discriminative accuracy and predictive capability of ICPtcd.This was a prospective, international, multicenter, unblinded, diagnostic accuracy study comparing the index test , indicating high discriminant accuracy of ICPtcd in excluding intracranial hypertension. Concordance correlation between ICPtcd and ICPi was 33.3% (95% CI 25.6–40.5%), and Bland–Altman showed a mean bias of -3.3 mmHg. The optimal ICPtcd threshold for ruling out intracranial hypertension was 20.5 mmHg, corresponding to a sensitivity of 70% (95% CI 40.7–92.6%) and a specificity of 72% (95% CI 51.9–94.0%) with an AUC of 76% (95% CI 65.6–85.5%).Two hundred and sixty-two patients were recruited for final analysis. Intracranial hypertension (> 22 mmHg) occurred in 87 patients (33.2%). The total number of paired comparisons between ICPtcd has a high NPV in ruling out intracranial hypertension and may be useful to clinicians in situations where invasive methods cannot be used or not available.ICPTrial registration: NCT02322970.The online version contains supplementary material available at 10.1186/s13054-022-03978-2. If diag20 years , 14. In 20 mmHg) . Based otcd, with a reference standard , defined as the best available method for establishing the presence or absence of the condition of interest . The study was unblinded, and the reference standard results were available to the performers of the index test.This prospective, international, multicenter, diagnostic accuracy study is reported according to the Standards for Reporting of Diagnostic Accuracy Studies (STARD) guidelines . We used a method based on a mathematical model which comprises parameters derived from TCD flow velocities and arterial blood pressure, which is described in detail elsewhere [diastolic and mean blood flow velocities derived from the TCD measurements. ICPtcd is then calculated as: MAP–CPPe.lsewhere –15. Briei placement was preferred. Cerebral blood flow velocities were assessed by using either of two technologies, TCD or transcranial color-coded Doppler (TCCD). Regarding the various ultrasound machine companies, no limitations nor specifications were requested by the protocol since the ICPtcd method is based on a calculated formula derived from standard TCD parameters [The insonation technique of the middle cerebral artery (MCA) was standardized across all sites: A low-frequency pulsed 2 MHz ultrasound probe was placed over the acoustic temporal window for insonation of the M1/M2 section of MCA at a depth ranging from 45 to 55 mm. The acoustic window ipsilateral to the side of the ICPrameters , 14.For each patient enrolled into the study, a total of three comparisons of ICPi and ICPtcd were made in three different time frames, as described previously in the IMPRESSIT pilot study Fig. .Fig. 1Thtcd was obtained shortly before performing the burr hole procedure and was compared to the first ICPi reading once the invasive probe was positioned. An effort was made to limit the cerebrospinal fluid leakage during intraventricular catheter placement which may cause changes in ICP. At TIME 2 and TIME 3, paired ICPtcd and ICPi were obtained immediately after TIME 1 and 2 to 3 h following the second reading. This later time lapse was chosen for two reasons: First, it was deemed necessary to permit any variations of cerebral hemodynamics induced by the ICPi device insertion maneuver to stabilize to a steady state; second, once the invasive device is inserted, a specific physiologically based time lapse becomes less relevant since any further variations in cerebral hemodynamics would automatically influence both the invasive and noninvasive measurement.At TIME 1, ICPThe decision to insert invasive ICP monitoring was independent from the study protocol and was made by the physician in charge of the patient based on the international guidelines for TBI patients, and neurological signs , clinical course  and neuroradiological findings  for SAH, ICH and IS patients. Arterial blood pressure (ABP) was invasively monitored in order to obtain mean arterial pressure (MAP), and cerebral perfusion pressure (CPP) was calculated with the transducer placed at the tragus level.ICPi was measured by means of either an intraparenchymal fiberoptic transducer  placed in the non-dominant frontal lobe, or a catheter inserted into the brain ventricles and connected to an external pressure transducer and drainage system .Sixteen centers in seven countries, chosen for their high volume of brain-injured patients and for their expertise in the field of TCD monitoring, enrolled a convenience sample of adult (≥ 18 years) critically ill neurological patients who required invasive ICP monitoring, either using intraventricular, intraparenchymal or post-craniotomy/postsurgical catheters, for any of the following diagnostic categories: traumatic brain injury (TBI), subarachnoid hemorrhage (SAH), intracerebral hemorrhage (ICH) and ischemic stroke (IS).tcd estimation and immediately before or during the first ICPi measurements in TIME 1.Patients were excluded if they had an inaccessible or poor acoustic ultrasound window, cardiac or vascular disease which had the potential of causing hemodynamic variations affecting the TCD measurement , or a craniotomy or craniectomy performed prior to the first time frame readings. Patients were also excluded if they required treatment for suspected intracranial hypertension or manipulation of arterial blood pressure between the first ICPFor the coordinating center of Brescia, Italy, the ethics committee approval was obtained on July 17, 2017 (NP-2762). The study approval was also obtained at each site from local regulatory boards before the study started. Written informed consent was obtained by family representatives. In the Italian centers, the requirement of informed consent was waived, because relatives are not regarded as legal representatives of the patient in the absence of a formal designation. Written informed consent was requested from all surviving patients if, and as soon as, they regained their mental competency.i above 22 mmHg and lasting for at least 10 min. Since definition of intracranial hypertension is not well established in SAH, ICH and IS, we also assessed the accuracy of ICPtcd with ICPi above 20 mmHg and above 25 mmHg [Intracranial hypertension in TBI patients was defined as ICP 25 mmHg .Given the focused nature of the study on diagnostic TCD accuracy, we collected a minimum number of parameters for parsimony, including demographic characteristics, cause of admission, neurological  and neuroradiological severity , and type of device used to measure invasive ICP. De-identified data were extracted from electronic medical records and stored within the main database located at the coordinating center .tcd of 90% with lower acceptable confidence limit of 10%, resulting in a requirement of 147 cases. Assuming a prevalence of intracranial hypertension equal to 30%, the total sample size was 490 patients [Sample size was calculated using an exact method, assuming a true sensitivity of ICPpatients .tcd and ICPi was calculated using variance components, estimated through linear mixed model to account for repeated measurements [tcd) relative to the reference standard (ICPi) was determined by calculating sensitivity, specificity, and the areas under a curve (AUC), for each ICPi threshold at each time frame  and averaged over all three time points . 95% confidence intervals (CI) were computed using bootstrapping (B = 2000). The best ICP thresholds were computed using the Youden criterion [p value of 0.05 was considered as the threshold for significance. The R software was used for statistical analysis  [Continuous variables are presented as mean  or median and interquartile range (IQR), and discrete variables as counts and percentages. Concordance correlation coefficient between ICPurements . A Blandurements . Descripriterion . In caseMA, USA) . Negativtcd and ICPi measurements performed  and the reference standard (ICPi) with no protocol violation  mmHg and intracranial hypertension (> 22 mmHg) occurred in 87 patients (33.2%). ICPtcd was higher than ICPi in 412 measurements (60%); details regarding intracranial hypertension according to different ICP thresholds  are reported in Additional file i threshold, respectively, of 20 mmHg, 22 mmHg and 25 mmHg, and 1-NPV was low, ranging from 9 to 2%, indicating high discriminant accuracy of ICPtcd in excluding intracranial hypertension with few model misclassifications of events. Data regarding the PPV, NPV, 1-NPV, sensitivity, specificity, accuracy, the positive and negative likelihood ratios and AUC for the three different ICPi thresholds during each separate and averaged time frame are reported in Table The mean ICPension > 2 mmHg octcd).Regarding negative likelihood ratio (LR-), this has a constant value of 0.3 across time, corresponding to a moderate performance in ruling out the condition, with an approximate 25% reduction in condition probability after a negative test  and a specificity of 0.76 (0.70–0.81) with an AUC of 0.76 (95% CI 0.66–0.85) to predict intracranial hypertension.The best measured ICPT1,2,3) at the same thresholds are presented in Fig. The percentage of patients with ICP above and below the given thresholds of 20, 22 and 25 mmHg and NPVs and PPVs of the averaged time frames T1,2, at the stcd compared to ICPi at three different ICPi thresholds  in TBI versus non-TBI non-TBI patients, and found no substantial differences   of -3.3 mmHg with limits of agreement comprised between −26.1 mmHg and + 19.5 mmHg  in patients with concordant or discordant ICPi and ICPtcd readings, we found that CPP showed a significant trend, with lower values in false negative and higher values in false positives, compared to concordant readings. All measurements were considering the average value over the three timings  and a PPV of 56% (95% CI 34%-75%) for the detection of concurrent ICPi > 20 mmHg. [tcd may in fact be most useful as a screening tool to exclude intracranial hypertension. Two recent prospective studies found contrasting results in terms of diagnostic accuracy of TCD, with one study reporting good diagnostic test accuracy with 81% sensitivity and 70% specificity and the other reporting 0% sensitivity and 74.4% specificity for ICPtcd to detect ICPi > 20 mm Hg mmHg [To date, this study is the first to demonstrate the value of ICP studies –26, of w studies –26 and o studies . A recen studies  found a  studies . Accurac20 mmHg.  The auth Hg mmHg , 29. Nontcd may be helpful in these cases, because coagulopathy, which is always present, increases the risk of intracranial hemorrhage following monitor insertion [tcd may be helpful in prioritizing treatment when extracerebral lesions are also involved. In the general ICU population, especially in cardiac arrest patients or in metabolic coma and liver failure, ICPtcd can be an important tool for the early diagnosis and treatment of cerebral complications [tcd remains low. If ICPtcd indicates intracranial hypertension, further diagnostic modalities, including a prompt decision for invasive ICP monitoring, should be considered. A simple algorithm for application of ICPtcd is provided in Fig. There is general agreement that sensitivity and specificity, which are important descriptors of the accuracy of a diagnostic test, should be applied only in the context of describing the screening test’s attributes relative to a reference standard . With sensertion . During ications . Anotherications , 34. Fintcd, an excellent screening test to exclude intracranial hypertension and a poor screening test to confirm it, remain speculative. Unlike a pressure transducer, TCD is a measurement of blood flow velocity and not a direct measurement of pressure and is greatly influenced by the ratio between FVd and FVm: the lower the ratio, the higher the ICPtcd value. A low ratio may occur in the presence of true intracranial hypertension due to external vessel compression and increased resistance, but also in the case of normal ICPi with decreased MAP and altered cerebrovascular autoregulation. In both cases, the transmural pressure  increases with a disproportionate reduction in FVd compared to FVm and, hence, a reduction in their ratio.Of those measurements identified as having intracranial hypertension at ICPtcd, 67.4% (53.7–77.3) had intracranial hypertension at ICPi using a threshold of > 20 mmHg, 77.0% (50.0–83.8) using a threshold > 22 and 76.9% (51.7–86.9) using a threshold of > 25 mmHg. Reasons for this duality of ICPi and ICPtcd leading to a probable disassociation between the two; and finally, as per study design, the patients’ outcome was not assessed, and hence, the impact of using TCD in reducing morbidity and mortality remains unanswered.Some study limitations are worth considering: First, as mentioned previously, recruitment stopped after 266 patients were enrolled; therefore, we did not reach the target sample size of 490 patients. Nevertheless, we believe that the number of patients recruited was sufficient enough to perform an adequate statistical analysis of our study aim; second, we do not have an exact number of patients screened among the 16 centers who took part in this study; third, we enrolled patients with different types of brain injury, including IS, SAH and ICH, for which ICP thresholds are not as well defined as for TBI; fourth, the study was unblinded and therefore correct reporting of paired ICPi and ICPtcd may have been imprecise; fifth, the incidence of intracranial hypertension was lower than in other series, which may limit the generalizability of results to other populations with more severe disease; sixth, hemodynamic instability during critical illness due to extracranial causes  may influence the correlation between true ICPDespite the study limitations, the results in this study confirm the results obtained from our previous multicenter pilot IMPRESSIT-1 study, which showed a NPV of 100% in excluding intracranial hypertension at ICP thresholds of > 20 and > 22 mmHg, and at the best threshold value of 24.8 mmHg.  TCD screNevertheless, TCD retained excellent screening performances, suggesting that its use to exclude intracranial hypertension in everyday clinical practice, where the presence of multiple sonographers represents a common situation, is feasible.tcd has a high NPV compared to ICPi in a variety of acute neurological conditions. As such, TCD may prove useful to exclude intracranial hypertension in situations where invasive methods cannot be used or are not available, and to screen at-risk patients for potential invasive ICP monitoring.This study demonstrates that ICPAdditional file 1. STARD checklist.Additional file 2.Figure S1. Total number of patients recruited per center.Additional file 3. Study Protocol.Additional file 4.Table S1. Number of measurements of invasive intracranial pressure (ICPi) and trans-cranial Doppler (TCD)-estimated ICP (ICPtcd) at the three time-frames  in relation to the three ICP different thresholds . Additional file 5.Figure S2. Forest plot indicating the areas under a curve (AUC), sensitivity and specificity for each time frame .Additional file 6.Table S2. Descriptors of diagnostic accuracy of intracranial pressure measured with transcranial doppler (ICPtcd) compared to invasive ICP measurement (ICPi) at three different ICPi thresholds  in Traumatic (TBI) vs non-TBI (non-TBI) brain injury. PPV = positive predictive value. NPV = negative predictive value. LR = Likelihood Ratio. AUC = area under the curve.Additional file 7.Figure S3. Bland-Altman analysis for each time frame.Additional file 8.Table S3. Comparison of relevant clinical variables  in patients with concordant or discordant ICPi and ICPtcd readings at the three ICPi thresholds, .CPP showed lower values in the False Negatives and higher values in False Positives compared to Concordant readings. All measurements considered the average value over the the three time-frames (T1–3).


Patients with cirrhosis and portal hypertension are at high risk of developing complications such as variceal hemorrhage, ascites, and cardiac dysfunction, the latter of which is known as cirrhotic cardiomyopathy. Since non-selective beta-blockers (NSBB) may aggravate hemodynamic complications we investigated the effect of real-time propranolol infusion on cardiac function in patients with varying degrees of cirrhosis.Thirty-eight patients with Child-Pugh A (n = 17), B (n = 17) and C (n = 4) underwent liver vein catheterization and cardiac magnetic resonance imaging. We assessed the effect of real-time propranolol infusion on the hepatic venous pressure gradient, cardiac index, stroke volume, ejection fraction, heart rate, and contractility.p = 0.043). The effect of NSBB on portal pressure was inversely correlated to changes in the left atrium where the left atrial volume changed by 4 mL±18 in responders compared to 15 mL±11 in non-responders (p = 0.03). Finally, the baseline ejection fraction correlated inversely with the reduction in portal pressure .Nineteen patients were classified as responders to beta-blocker therapy. In pooling Child-Pugh B and C patients, the reduction in cardiac index by beta-blockade was weaker than in Child-Pugh A patients (-8.5% vs. -20.5%, We found the effect of beta-blockade on cardiac index in patients with advanced cirrhosis to be less potent than in patients with early cirrhosis, indicating that underlying cirrhotic cardiomyopathy increases, and the cardiac compensatory reserve becomes more compromised, with disease progression. The differential effects of beta-blockade in the left atrium may be used to predict the effect of beta-blockers on portal pressure, but further studies are needed to investigate this possibility. Patients with advanced cirrhosis are at high risk of developing complications from multiple organ systems, leading to increased morbidity and mortality . CardiacThe exact prevalence of CCM is not known, but estimates range from 50–60% depending on the definition used . It is tUntil now, cardiac changes have primarily been assessed using echocardiography and under strain . InvestiIn this cross-sectional intervention study, we recruited 38 patients with cirrhosis with a mean age of 59.8±9 years. Seventeen healthy controls with a mean age of 54.2±7 years were included for acquisition of baseline values. The diagnosis of cirrhosis was based on clinical, biochemical, and ultrasonographic indicators. All patients underwent endoscopy that revealed esophageal varices and signs of portal hypertension, with an indication for treatment with NSBB, according to the EASL guidelines  in the responders vs. 5.9%  in the non-responders (p<0.001). There were no differences found in the cardiac parameters, apart from a higher peak diastolic strain rate in the responders (0.89±0 per. sec) than in non-responders (0.77±0 per. sec) (p = 0.04).Nineteen patients were classified as responders to NSBB, eight patients of whom were Child-Pugh class A, with an average MELD-Na score of 12.5±3; the average MELD-Na of non-responders was 13.4±5 (p = 0.03), equivalent to a relative change of 6%  vs. 22%  (p = 0.011) . The nominal changes in MAP and HVPG are illustrated in r = -0.39, p = 0.02, The left atrial volume changed by 4 mL±18 in the responders, compared to 15 mL±11 in the non-responders (= 0.011) . The decIn this study, we aimed to investigate the acute effects of beta-blockade on cardiac function using CMRI in patients with varying degrees of cirrhosis. There were two main findings of our study: first, the impact of NSBB on cardiac index was blunted in patients with more severe cirrhosis compared to patients with mild cirrhosis, suggesting that cardiac reserve becomes increasingly compromised as the disease progresses.Second, in addition to the weaker effect of NSBB on portal pressure, we found that the response to NSBB was inversely correlated with the left atrial volume, which dilated significantly more in non-responders. Both of these findings are most likely the result of an underlying cirrhotic cardiomyopathy (CCM).A first attempt at defining CCM was made at the World Congress of Gastroenterology in Montreal in 2005, and it continues to be revised as our understanding advances . The adrIn a pharmacological study of seventy-one cirrhotic patients with normal left ventricular systolic function at baseline, Kim et al. found that 25% of the patients had blunted left ventricular response during dobutamine infusion . Two stuThe results of previous studies of exercise undertaken by cirrhotic patients indicate that cardiac chronotropic incompetence as part of the cirrhotic cardiac dysfunction and CCM , 33. We Our findings of an inadequate response to the increased sympathetic nervous activity, in terms of a blunted response to NSBB, favors the hypothesis of an autonomic dysfunction as an imposing part of CCM rather than a general deconditioning; however, a full understanding of the mechanisms of cardiac chronotropic incompetence will depend on future research.Interestingly, the cardiac index of some patients increased after beta-blockage. Paradoxical effects of NSBB have previously been observed and described in patients with increased sympathetic drive and emotional stress , 41. SinIn patients with advanced disease, such as refractory ascites, low cardiac index and a dilated left atrium have proved to be strong prognostic indicators of poor survival , 43, 44.p = 0.060). Yet interestingly, the change in arterial blood pressure did correlate with the change in portal pressure . Furthermore, we observed that a high ejection fraction at baseline was associated with a smaller decrease in portal pressure . One possible explanation for this is that NSSB responders exhibit less desensitization to beta-2 receptors than non-responders [Arterial blood pressure is regulated by several physiological mechanisms, which in cirrhosis counteract arterial vasodilatation. It is therefore unsurprising that there was no significant difference in arterial blood pressure between NSBB responders and non-responders , Hepatic venous pressure gradient (HVGP), Non-selective betablockers (NSBB).(PDF)Click here for additional data file.S2 TableData are presented as mean ±SD or medians and interquartile ranges. Abbreviations: Mean Arterial pressure (MAP), Hepatic venous pressure gradient (HVGP).(PDF)Click here for additional data file.S3 TableData are presented as mean ±SD or medians and interquartile ranges as appropriate. Abbreviations: Mean Arterial pressure (MAP), Hepatic venous pressure gradient (HVGP).(PDF)Click here for additional data file.


What is the difference in 10-year restricted mean survival time when receiving a kidney transplant versus remaining on the wait list and continuing dialysis for transplant-eligible patients with kidney failure across different ages?In this cohort study including 4445 adults on the wait list for their first single-organ deceased donor kidney transplant, application of target trial emulation methods showed a difference in terms of restricted mean survival times. Kidney transplant prolonged life expectancy across patient ages compared with continuing dialysis.The findings of this study suggest that transplant-eligible patients with kidney failure should not be excluded from transplant programs based on their age. Kidney transplant is considered beneficial in terms of survival compared with continued dialysis for patients with kidney failure. However, randomized clinical trials are infeasible, and available evidence from cohort studies is at high risk of bias.To compare restricted mean survival times (RMSTs) between patients who underwent transplant and patients continuing dialysis across transplant candidate ages and depending on waiting time, applying target trial emulation methods.In this retrospective cohort study, patients aged 18 years or older appearing on the wait list for their first single-organ deceased donor kidney transplant between January 1, 2000, and December 31, 2018, in Austria were evaluated. Available data were obtained from the Austrian Dialysis and Transplant Registry and Eurotransplant and included repeated updates on wait-listing status and relevant covariates. Data were analyzed between August 1, 2019, and December 23, 2021.A target trial was emulated in which patients were randomized to either receive the transplant immediately (treatment group) or to continue dialysis and never receive a transplant (control group) at each time an organ became available.The primary outcome was time from transplant allocation to death. Effect sizes in terms of RMSTs were obtained using a sequential Cox approach.Among the 4445 included patients , transplant was associated with increased survival time across all considered ages compared with continuing dialysis and remaining on the wait list within a 10-year follow-up. The estimated RMST differences were 0.57 years  at age 20 years, 3.01 years  at age 60 years, and 2.48 years  at age 70 years. The survival benefit for patients who underwent transplant across ages was independent of waiting time.The findings of this study suggest that kidney transplant prolongs the survival time of persons with kidney failure across all candidate ages and waiting times. This cohort study uses target trial emulation to examine survival time in patients with kidney failure who undergo kidney transplant vs those who receive dialysis across ages and waiting time to transplant. Numerous studies have shown that transplant is cost-effective and improves survival compared with long-term dialysis.Well-designed and well-conducted randomized clinical trials constitute the standard for establishing causality. Randomized treatment allocation to kidney replacement therapy, however, is not feasible. Hence, quantifying the survival benefit achieved from kidney transplant in terms of differences in 10-year restricted mean survival times (RMSTs) must rely on observational studies.6 A target trial is an idealized randomized clinical trial that is not feasible and is therefore mimicked through the application of design principles from randomized clinical trials to the analysis of observational data.7In attempts to mitigate bias in causal estimates from observational research, the concept of target trial emulation was introduced.10Given the scarcity of robust evidence to underpin the anticipated survival advantage for kidney transplant recipients, it remains unclear whether kidney transplant improves survival for patients eligible for transplant of all ages and whether the duration of pretransplant dialysis reduces anticipated survival benefits for transplant recipients compared with their peers remaining on a wait list while receiving long-term dialysis.Our hypotheses were that survival benefits achieved with kidney transplant diminish with increasing recipient age and as waiting time with maintenance dialysis lengthens owing to an increasing frailty of the patient population. The primary aim of our study therefore was to investigate survival benefit between kidney transplant and long-term dialysis for transplant-eligible patients across different candidate ages. Our secondary aim was to investigate survival benefit depending on waiting time with dialysis across ages of transplant candidates.6 using the Austrian (Oesterreichische) Dialysis and Transplant Registry (OEDTR), which was established in 1965 by the Austrian Society of Nephrology and has almost complete follow-up data. The contained information was thoroughly extracted from medical records originally documented by the responsible physician at the follow-up visits. The study was approved by the Ethics Committee of the Medical University Vienna, performed in accordance with the Declaration of Helsinki,11 and reported in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.12 Patients consented to data collection in the OEDTR at the time of initiation of kidney replacement therapy.We conducted a retrospective cohort study that emulated a target trial evaluation approach described by Hernán and RobinsWe retrieved data from the OEDTR on demographic characteristics , type of kidney disease , comorbidities , and number of blood pressure–lowering drugs. The data were supplemented by information from the Eurotransplant database, including the wait-listing status , the first wait-listing date, transplant date, and death date. Information on various patient characteristics, comorbidities, blood pressure–lowering medication, and wait-listing status were updated approximately yearly throughout the follow-up period.We included all transplant-eligible patients who started receiving dialysis between January 1, 2000, and December 31, 2018. Transplant eligibility was determined by wait-listing status after January 1, 2000. Patients were followed up until their date of death, loss to follow-up, or end of follow-up on June 30, 2019, whichever came first. We included all transplants from deceased donors occurring between January 1, 2000, and the end of follow-up. We excluded patients younger than 18 years at the time of first wait-listing; patients registered for multiorgan transplant; those with implausible dates regarding wait-listing status, death, or transplant; and patients with missing measurements at first wait-listing. Because only a minimal proportion of values were missing in the follow-up recordings, we decided to use last observation carried forward or backward, assuming that comorbidities  do not recede. More details are available in eMethods 2 in the The characteristics of patients at the time of their first wait-listing are described by means (SDs) for continuous variables and frequencies and percentages for categorical variables. Data analysis was conducted between August 1, 2019, and December 23, 2021.We developed a protocol for a hypothetical target trial that applies design principles from randomized clinical trials to the analysis of observational data. The target trial was then emulated using the observed data mimicking patient selection by applying appropriate inclusion criteria, randomization by confounder adjustment, and treatment adherence by adjustments for informative censoring. Herein, we describe the target estimand and the corresponding estimation procedure. eMethods 1 in the 13 Secondarily, we were interested in differences in RMST conditional on different durations of wait-listing before treatment allocation. To allow comparison with the literature, we additionally report the results of our main analysis in terms of survival curves and hazard ratios.The primary end point of interest in our study was the time from transplant allocation to death from any cause. Particularly, we aimed to compare the 2 treatment strategies—receive a transplant from a nonliving donor vs remain waitlisted while undergoing dialysis and never receive a transplant—across different ages and quantify the contrast in terms of differences in RMSTs. The RMST has the interpretation of a mean survival time of a population within a prespecified time horizon; hence, differences in RMST indicate gain or loss in the mean survival time within the specified period.15 creating a series of auxiliary trials. Auxiliary trials started each time a transplant occurred . For each auxiliary trial, the trial population consisted of patients actively waitlisted who had survived for at least the same amount of time since being waitlisted. At each transplant allocation time, patients who underwent transplant were classified as treated, and patients who continued dialysis were classified as controls. Patients in the control group who underwent transplant during follow-up of an auxiliary trial were artificially censored at the time of transplant because their treatment did not adhere to the assigned strategy from this point onward (remain on wait list and never undergo transplant). These patients were subsequently assigned to the treated group in a later auxiliary trial of the series. Data from all auxiliary trials were stacked into a single data set, and the outcome models to address the main research questions were applied to this data set.To assess the target estimand, we followed a sequential Cox approach16 Inverse probability of treatment weights were estimated for each patient at each transplant allocation time based on a multivariable logistic regression model including sex, the year of first appearance on the wait list, dialysis use before wait-listing (yes/no), and the most recent updates of age, body mass index, comorbidities , number of blood pressure–lowering medications, time from wait-listing to transplant allocation, and episodes of nontransplantable status before transplant allocation (yes/no) as covariates, which were selected based on the common cause criterion.17To deal with confounding and nonadherence to the assigned treatment strategy, we estimated stabilized inverse probability of treatment weights (IPTWs) as well as annual stabilized inverse probability of censoring weights (IPCWs).The annual stabilized IPCWs for the control groups were estimated using the same covariates in separate Cox models per auxiliary trial. In the treated groups, the IPCWs were set to 1. Final weights were computed as the product of stabilized IPTWs and IPCWs, and subsequently winsorized at the 0.1st and 99.9th percentile of their distribution. Different cutoffs were applied in sensitivity analyses.We fit a weighted Cox proportional hazards model for all-cause survival, with our main exposure of interest  as the only independent variable. By incorporating the final weights, the Cox model was dynamically adjusted for measured confounders selected based on the common cause criterion and corrected for treatment nonadherence .18To address the primary aim of our study and evaluate whether the differences in RMSTs achieved by transplant vary by age at transplant allocation, we fit a Cox model including interaction terms between treatment and age. Age was flexibly modeled using a restricted cubic spline with knots at the 1st, 25th, 50th, 75th, and 99th percentiles of the age distribution.To investigate our secondary aim of whether the difference in RMSTs achieved by transplant depended on the time spent on wait list before transplant allocation we estimated separate models among patients who had been on the wait list up to 1 year, between 1 and 2 years, or more than 2 years. We included interaction terms for treatment and age as described above in all 3 models.13 comparing transplant with remaining on the wait list. Effect size estimates are reported with 95% CIs based on the 2.5th and 97.5th percentiles from the distribution of 1000 bootstrap resamples of all patients.From the fitted Cox models, we computed the marginal differences in restricted mean survival timesData preparation and analyses were conducted using R statistical software, version 4.0.1 . Further information about data management, handling of missing data, and details on the analyses steps outlined in this section can be found in eMethods 2 in the The study cohort comprised 4445 patients who met the eligibility criteria . The popIn total, 3621 of 4445 patients (81.5%) received a kidney transplant and 1392 patients (31.3%) died. Transplants were performed between September 16, 2000, and May 23, 2019. The median time from wait-listing to kidney transplant was 1.7 years, from wait-listing to date-last-seen was 8.0 years, and from wait-listing to death was 13.4 years. The median time from beginning of dialysis to kidney transplant was 3.2 years. The follow-up was not long enough to determine the IQRs.15 Characteristics of the study population at treatment allocation of the auxiliary trials can be found in eTable 1 in the Target trial emulation resulted in 1367 auxiliary trials, comprising a total of 2 067 620 person-trials.Our analysis based on target trial emulation revealed a marginal increase in RMST for patients who underwent transplant compared with those who remained on the wait list for 0.53 years  over a follow-up of 5 years and an increase of 2.40 years  over a follow-up of 10 years. eFigure 1A in the To allow comparison with the previous studies, we report estimated survival curves  important confounders were not adjusted for dynamically throughout follow-up, ignoring the development of illness while patients were on the wait list; (2) periods of temporary ineligibility for transplant were not taken into account; (3) outcomes of transplant recipients were compared with those of patients continuing dialysis ineligible for transplant; (4) outcomes of transplant recipients after graft failure were attributed to dialysis; (5) survival time until transplant was artificially guaranteed for those who eventually received a transplant vs patients who continued dialysis may have died at any time during follow-up; or (6) kidney transplant was modeled as a time-dependent variable using standard survival methods shown to be inferior when the efficacy of an intervention is evaluated in the presence of time-dependent confounding by dynamic treatment allocation.19A large systematic review published in 2011 concluded that kidney transplant was associated with reduced mortality, but findings were at high risk for bias.4 other studies reported advantageous survival for kidney transplant recipients.21 In a national registry study from Denmark, kidney transplant was associated with survival benefit despite severe comorbidities and older age.21 However, the study did not take temporary withdrawal from the wait list into account and comorbidities were not updated dynamically. Another northern European registry analysis found a very large survival advantage of almost 14 years for kidney transplant recipients compared with patients on the wait list who were receiving dialysis, classifying patients into treatment groups at the start of kidney replacement therapy.20 Classifying individuals as transplant recipients at the start of kidney replacement therapy, however, introduces immortal time bias.22Since the aforementioned systematic review was published,23 This study applied an interesting approach to trial emulation with propensity score–matched comparison groups. The chosen approach makes results for the marginal effect size comparable to the reports described in our study. However, in our study, patients in the control group were required to never undergo transplant, but the French registry study allowed for later transplant in the control group. This variation could in part explain any differences in the marginal effect estimates. Unlike the French registry study, in addition to estimating marginal effects, we investigated the survival benefit across transplant candidate ages as well as conditional on different durations patients receiving dialysis were on the wait list before transplant allocation.A recent French registry study reported a 6.8-month gain in life expectancy for patients who undergo transplant compared with transplant-eligible patients receiving dialysis at 10-year follow-up.26 These studies, however, described outcomes among patients who actually received a kidney transplant and compared dialysis vintage characteristics, but do not allow conclusions about the effectiveness of transplant in those who are eligible and may receive a transplant at a particular dialysis vintage. We believe our results noting greater survival benefit with increased dialysis vintage is a signal that cohorts of transplant-eligible patients receiving dialysis change over time. During the first 2 years of dialysis, transplant-eligible patients are well enough to survive while receiving dialysis, which results in a smaller net benefit from transplant. As dialysis vintage accumulates, mortality increases, resulting in a greater survival benefit of transplant . Our study does not contradict knowledge about increasing mortality rates as dialysis vintage accumulates, but rather is, to our knowledge, the first study to use target trial emulation methods to quantify the survival benefit of kidney transplant in terms of restricted mean survival time in patients who are eligible to receive such a treatment given a particular dialysis vintage.Multiple studies reported worsening of survival in kidney transplant recipients as dialysis vintage accumulates.Strengths of our approach include a clearly defined target estimand and accompanying target trial protocol that defines time 0 for the outcome estimand of interest. Building a series of auxiliary trials allowed us to dynamically adjust for repeatedly measured confounders and ensured the inclusion of only patients eligible for transplant, thus taking the development of disease and temporal withdrawal from the wait list into account. In addition, considering only patients who survived equally long while on the wait list at the start of an auxiliary trial further mitigated the risk of immortal time bias.The study has limitations. Although the long-term follow-up with a reported observation period of 10 years is a strength of our registry data, it is difficult to determine the survival benefit of kidney transplant in younger patients with kidney failure who have a life expectancy longer than 10 years. Therefore, the findings showing only a small survival benefit in younger patients should not be interpreted as ineffectiveness of kidney transplant, but rather as a limitation of follow-up in this subgroup. Furthermore, the relatively small sample size, resulting in wide 95% CIs, implies some caution is needed when interpreting the results for younger patients.Deriving estimates from target trial emulation methods involves strong structural assumptions. Specifically, we assumed that we had sufficient information on confounders to ensure exchangeability of our treatment groups after adjusting by means of IPTWs. The OEDTR is a closely monitored national registry with a negligible number of patients lost to follow-up and long-term data periodically updated information by the responsible physician. The registry offered high-quality data with information on a rich set of potential confounders that were incorporated by a careful covariate selection and modeling approach. Nevertheless, as for any observational study, there is still a risk for bias owing to unmeasured confounding. Furthermore, we assumed that each participant had a positive probability to receive either treatment at each transplant allocation time (positivity assumption). Because we only considered patients on the wait list and hence eligible for transplant, we can rule out any structural violation of the positivity assumption. Any sampling-related violations would have been detected during the inverse probability of treatment weight calculations, for example, by running into divergence or separation problems.In addition, our approach based on sequential Cox models implies the proportional hazards assumption, but it is well known that hazards are nonproportional shortly after transplant because the mortality rate within the first year after transplant is higher than the rate for patients undergoing dialysis. However, the main focus of our study was long-term life expectancy after kidney transplant when the differences from early follow-up are mitigated. Furthermore, missing data in the registry were a concern. Because only 2.6% of the observations were incomplete, we decided to use last observation carried forward or backward, assuming that comorbidities  do not recede.Our study population is representative for a Central European, primarily White, population, and our findings may not be generalizable to populations in other regions of the world or with different racial and ethnic backgrounds. Because glomerulonephritis was the leading cause of kidney disease in our cohort, external validity our findings is limited in populations dominated by other types of underlying kidney diseases, such as diabetes. When assessing applicability of our findings in terms of dialysis vintage, one needs to recognize that median time from beginning of dialysis to kidney transplant was 3.2 years.Randomization to kidney replacement therapy modalities is infeasible, and studies on comparative effectiveness of kidney transplant vs long-term dialysis are at high risk of bias. Our study followed target trial emulation methods to quantify life expectancy gain for kidney transplant recipients compared with patients eligible for transplant who were receiving long-term dialysis across all ages and conditional on time on wait list. We found a survival benefit for patients who receive a kidney transplant regardless of time spent on the wait list and for all ages of adults who are candidates for kidney transplant. However, data for older transplant candidates are still sparse.


Cardiovascular disease (CVD) is a major contributor to morbidity and mortality causing global economic burden to the health care system. Chronic kidney disease (CKD) is an important risk factor for the progression of CVD. CVD and CKD are interrelated diseases with reciprocated dysfunction that can ultimately lead to organ failure.Hypertension can be classified as salt‐sensitive and non–salt‐sensitive hypertension, with an estimated 50% of patients being salt sensitive. Sodium‐glucose cotransporter‐2 inhibitors (SGLT2i) are a unique class of drugs that improve glucose metabolism, decrease blood pressure, and have cardiorenal benefits in patients with diabetes.2+ influx, vasoconstriction, and blood pressure, and play significant roles in the cardiovascular system, neurons, pancreatic β‐cells, bone, and the immune system.Journal of the American Heart Association (JAHA) includes a study by Zhao et al that demonstrates the mechanisms underlying how SGLT2i canagliflozin improves hypertension in the Dahl salt‐sensitive rat hypertensive model.Canonical transient receptor potential channels (TRPCs) are distributed in all major tissues and regulate Caclinical inertia.In the past decade, the awareness and number of treatment alternatives for patients with hypertension have increased in developed countries; however, ≈50% of known patients with hypertension have uncontrolled blood pressure in the United States. Similar findings have been observed in other countries, even in patients who are already under medication.Increasing evidence from multiple clinical trials suggests a strong association between SGLT2i and their protection in patients with heart failure.Overall, Zhao et alThis work was supported by the Pilot grant to Dr Kolluru from Institutional Development Award from the National Institutes of General Medical Sciences of the National Institutes of Health (NIH) under grant number P20GM121307None.


Blood pressure in the days following endovascular thrombectomy (EVT) can influence functional outcomes of patients who have suffered an acute ischemic stroke, but whether the same is true of blood pressure during the first few hours after EVT is unclear.Several blood pressure parameters were retrospectively analyzed in acute ischemic stroke patients who underwent EVT at West China Hospital from March 2016 to December 2019. Baseline blood pressure, speed of blood pressure reduction, postoperative blood pressure, degree of blood pressure reduction, and quality of blood pressure management were evaluated during the first 24 h after EVT. We explored whether these parameters during different time windows correlated significantly with patients' modified Rankin Scale (mRS) score at 90 days.p = 0.006), and systolic pressure >136 mmHg at this time point was associated with a significantly higher risk of poor outcome, before and after adjusting for other risk factors .Analysis of 163 patients showed that poor functional outcome (mRS scores 3–6) correlated significantly with higher postoperative blood pressure and worse blood pressure management during the first 6 h after EVT. Postoperative systolic blood pressure at 37 min after EVT was significantly higher in patients with poor outcome (141 mmHg) than in those with good outcome (mRS scores 0–2; 122 mmHg, Among acute ischemic patients who successfully undergo recanalization, adequate blood pressure management during the first 30–40 min after EVT may be important for ensuring good 90-day functional outcomes. Since its description in 2015, endovascular thrombectomy (EVT) has become a standard method for treating large-vessel acute ischemic stroke within 6 h of onset . How bloSeveral studies have suggested that lower blood pressure during 24 h after EVT is associated with a better prognosis , but we Therefore, we performed a retrospective observational study to explore whether blood pressure parameters during the first 6 h after EVT significantly influence functional outcomes.Medical records were retrospectively examined for acute ischemic stroke patients who underwent EVT at West China Hospital from March 2016 to December 2019. Follow-up information was derived from a database we set up prospectively since 2016 for all ischemic stroke patients admitted to West China Hospital and underwent reperfusion. Patients were considered eligible for the present study if they were older than 18 years, underwent emergency EVT for acute ischemic stroke affecting the anterior circulation , and underwent successful recanalization after EVT [defined as the modified Thrombolysis in Cerebral Infarction score (mTICI) ≥2b]. Patients were excluded if blood pressure data were missing for any of the following time points: on admission, every hour during the first 6 h after EVT, and every 2 h until 24 h after EVT. Patients were also excluded if computed tomography (CT) data were unavailable within 24 h after EVT, or if the modified Rankin Scale (mRS) score at 90 days after EVT was unknown.This study was approved by the Institutional Review Board of West China Hospital, which waived the requirement for written informed consent because, at the time of treatment, patients or their legal guardians gave informed oral consent for the patient's anonymized medical data to be analyzed and published for research purposes.Patient eligibility for EVT was determined based on established clinical guidelines . VasopreBP values at set points were measured non-invasively. Based on the blood pressure information, we calculated parameters reflecting 5 aspects of blood pressure profiles: (1) baseline BP level: including admission SBP and the first postoperative SBP (FPO SBP). FPO SBP was the SBP value patients on their first measurement when they returned to the ward after EVT; (2) postoperative BP level: including mean SBP and minimum SBP; (3) degree of BP reduction: including FPO SBP-mean SBP, FPO SBP-minimum SBP (FPO SBP-mean SBP)/FPO SBP and (FPO SBP-minimum SBP)/FPO SBP; (4) velocity of BP reduction: indicated by the time from FPO SBP to the minimum SBP record during the first 6 h after EVT; (5) BP management quality: including maximum SBP and the time below 120 and 140 mmHg. The threshold of 140 mmHg was chosen because several studies have proposed it as a target blood pressure during the first 24 h after EVT for patients with successful recanalization –11.Time points of measurements were divided into intervals of 0.5 h. Measurements for the abovementioned parameters, excluding baseline blood pressure and speed of BP reduction, were categorized into the following four intervals after EVT: 1–6, 7–12, 13–18, and 19–24 h.The primary study outcome was the mRS score at 90 days, which was determined through telephone interviews with patients or their legal guardians. Good outcome was defined as mRS scores 0–2, while poor outcome was defined as mRS scores 3–6. The secondary study outcome was intracerebral hemorrhage (ICH) which may have occurred during hospitalization and malignant cerebral edema , accompanied by prominent imaging evidence of brain swelling .We collected data on numerous covariates to adjust for their potential influence in our analyses and thereby isolate the influence of blood pressure at different times after EVT. Covariates included age; sex; history of hypertension, diabetes, coronary heart disease, cardiac dysfunction, and atrial fibrillation; pre-EVT laboratory findings, such as fasting blood glucose, low-density lipoprotein, prothrombin time, and international normalized ratio; Alberta Stroke Program Early Computed Tomography Score (ASPECTS) on pre-EVT computed tomography; score on the National Institutes of Health Stroke Scale (NIHSS) at admission; occluded segment; prior treatment with intravenous alteplase; time from onset to puncture (OTP); postoperative hypotension, underwent decompressive craniectomy and postoperative residual moderate to severe stenosis.t test in the case of normally distributed continuous data, or the Mann-Whitney U test in the case of skewed continuous data.Continuous data were expressed as mean ± standard deviation if normally distributed, or as median  otherwise. Categorical data were expressed as n (%). The normality of data distribution was assessed using the Shapiro-Wilk test. Analyses were conducted initially across all patients for whom covariate data were complete. Differences between patients with poor or good outcome and between patients with or without intracerebral hemorrhage were assessed for significance using a chi-squared test in the case of categorical data, Student's p < 0.1 in univariate analysis were entered into two logistic regression models: Model 1 adjusted for gender, fasting blood glucose, and NIHSS; Model 2 adjusted for age and ASPECTS. Multiple imputation was used to fill in missing values. Stratified analysis was performed based on whether systolic blood pressure at admission was <140 or ≥140 mmHg, patients had ICA occlusion or not, time from onset to thrombectomy was ≤6h, and patients had cardiac dysfunction or not. We set the systolic blood pressure threshold at 140 mmHg because a previous study found that systolic pressures higher than this value were associated with higher mRS score . Data were plotted and Student tests were performed using GraphPad Prism for Windows . Generalized additive modeling was conducted using R (version 4.1). Differences were considered significant at a level of α = 0.05.Of the 206 consecutive patients reviewed for enrollment, 163 were included in the final analysis . The medJust over half of patients  had poor functional outcome at 90 days. These patients were older and showed more severe infarction reflected in a lower rate of ASPECTS > 6 and higher NIHSS score than patients with good functional outcome.p = 0.072, p = 0.006), which was taken an average of 37 min (95%CI 34–40) after EVT.Patients who experienced good or poor functional outcomes did not differ significantly in systolic blood pressure at admission  and minimum SBP (p = 0.011) (p = 0.005) and shorter time when SBP was below 140 mmHg (p = 0.025). During the other time windows analyzed during the first 24 h after EVT, patients who experienced good or poor functional outcomes did not differ significantly in any of the blood pressure parameters except the degree of blood pressure reduction  . Those peduction .Consistent with these results, logistic regression Model 1 showed significant correlations of functional outcome with the first postoperative measurement of systolic blood pressure as well as minimum and maximum values of systolic blood pressure during the first 6 h after EVT. However, the significance did not remain when adjusted for age and ASPECT in Model 2 .When we dichotomized patients based on whether the first postoperative measurement of systolic blood pressure was <140 or ≥140 mmHg, we found that none of the other blood pressure parameters correlated significantly with the functional outcome in both subgroups (data not shown). Among the subgroups of patients with ICA occlusion, time from onset to puncture (<6h), or without cardiac dysfunction, good functional outcome significantly correlated with lower FPO BP, lower postoperative blood pressure, and better quality of blood pressure management during the first 6 h. Among patients without ICA occlusion, functional outcome correlated significantly with maximum and minimum systolic blood pressures during the first 6 h. Among patients with admission SBP ≥140 mmHg, good functional outcome correlated significantly with lower FPO BP and lower maximum SBP during the first 6 h . Our addp = 0.004, R2 = 0.91; p = 0.006), sensitivity was 57%, and specificity was 67%.A generalized additive model showed that an increase in the first postoperative measurement of systolic blood pressure was associated with poor functional outcomes . In factp = 0.004; OR 2.55; 95%CI 1.34–4.85) and logistic regression   . Patient32–1.46) . Their sOf the 163 patients we included, 61 patients (37%) had ICH during hospitalization. These patients were more likely to suffer malignant cerebral edema and have lower ASPECTS, higher NIHSS score and higher fasting blood glucose than patients without ICH . As dataOur analysis of acute ischemic stroke patients who underwent EVT found that higher blood pressure within 6 h after the procedure correlated with worse functional outcomes at 90 days, particularly in patients with ICA occlusion or without cardiac dysfunction. In particular, using various approaches, we demonstrated an association between blood pressure within 30–40 min after EVT and functional outcome. Increasing blood pressure at this early time point correlated with increasing mRS score at 90 days, and blood pressure of 136 mmHg at this time point predicted reasonably well which patients later experienced poor or good functional outcome. Our study suggests that blood pressure should be adequately managed early after EVT to ensure good outcomes.Differences in blood pressure parameters, especially postoperative blood pressure, between patients with good or poor functional outcomes were larger during the first 6 h after EVT than during other time windows within the first 24 h. Our results are consistent with previous studies reporting that clinical outcomes were significantly associated with mean blood pressure  or maximTo the best of our knowledge, this is the first study to report a potential association between blood pressure at 30–40 min after EVT and clinical outcomes. When patients were stratified according to whether systolic blood pressure at this time point was above or below 130 or 140 mmHg, no other blood pressure parameters showed significant associations with functional outcome. This implies that the various correlations of other blood pressure parameters with functional outcome reflect the influence of systolic blood pressure at 30–40 min. Consistent with this idea, we found that pressures at this time point that was below 160 mm were linearly associated with the risk of poor functional outcome. In our sample, a pressure of 136 mmHg predicted well whether our patients experienced good or poor outcomes at 90 days.In our study, patients with higher systolic blood pressure at the first postoperative measurement had higher mean, minimum and maximum blood pressures, and they were at higher risk of poor mRS score at 90 days. This is consistent with previous reports that higher blood pressure can lead to poor functional outcomes in acute ischemic stroke patients , 17, 18.Our subgroup analyses revealed that blood pressure parameters correlated significantly with functional outcomes in patients with ICA occlusion, but not in those without such occlusion. We originally thought that this result might reflect that ICA occlusion correlates with higher blood pressure at admission, but we did not detect such a correlation when we compared blood pressure between subgroups with or without occlusion. Therefore, other mechanisms may be responsible. One possibility is that ICA occlusion is associated with poor collateral circulation . Poor coGiven the retrospective design of our study, we didn't collect blood pressure data 30–40 mins after EVT, which made it difficult to analyze and demonstrate the accuracy of the blood pressure profile at the early stage. Besides, we did we have data on NIHSS after EVT, so we could not explore the potential influence of symptomatic intracerebral hemorrhage on functional outcomes. All our patients underwent EVT while under general anesthesia, so our results may not be generalizable to those who undergo the procedure with local anesthesia, with or without conscious sedation. The type of anesthesia is known to affect blood pressure –22.Blood pressure of acute ischemic stroke patients during the first 6 h after EVT can significantly influence functional outcomes at 90 days. In fact, blood pressure at 30–40 min after the procedure may be independently associated with outcomes, highlighting the need to carefully manage blood pressure early after EVT.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 Ethics Committee on Biomedical Research, West China Hospital of Sichuan University. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.XZ: design of the study, methodology, data analysis, and article writing. TC: data collection and trimming. QZ: literature search and data collection. CW: data analysis direction. AW, YY, and SL: data collection. FH: direction of the study. BW: direction of the study and funding. All authors contributed to the article and approved the submitted version.This study was supported by National Natural Science Foundation of China (82071320 and 81870937) and 1.3.5 Project for Disciplines of Excellence, West China Hospital, Sichuan University (No. ZYGD18009).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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Chronic kidney disease (CKD) is a serious condition whose incidence is steadily rising, particularly in the Western world, due to the increasing prevalence of diabetes, hypertension, and obesity, which are nowadays the major causes of CKD in the Western population, as well as the aging of the population . CurrentCurrently, regardless of the underlying etiology, CKD is a slowly progressive disease and leads to irreversible loss of nephrons, with a consequent progressive silent deterioration of renal function to end-stage kidney disease (ESKD) ,4. This 2 and appears to be a main determinant of ESKD in individuals whose original disease is inactive or resolved [Initial kidney injury can present in a wide range of severity, from asymptomatic hematuria to more complex and severe clinical pictures . These dresolved .2, symptoms and signs related to uremia appear, such as gastrointestinal manifestations , systemic complication , and central nervous system abnormalities  ,9. In moand coma ,13).The rate of CKD progression depends on the underlying disease, presence of comorbidities, treatments, socioeconomic status, genetic background, ethnicity, and other factors .Currently, the identification of patients at risk for progression to CKD/ESKD and of the rate of worsening GFR is achieved through clinical monitoring and risk stratification, such as the CGA system  proposed in 2012 by the KDIGO guidelines . HoweverOther methods to investigate kidney function were made available by sonography that may estimate intrarenal and systemic atherosclerotic vascular dysfunction through the measurement of the intrarenal resistive index. After its first evaluation in proteinuric and atherosclerotic patients , recent Indeed, it is now clear that to prevent the progression of CKD into ESKD, it is not enough to identify the etiology of the underlying kidney disease or to control the well-known risk factors, but the identification of new prognostic factors that can predict progression and lead to a more specific and early therapy is essential. Moreover, it has to be emphasized that, nowadays, no current therapy can prevent AKI or the AKI-to-CKD transition. Also in this case, a maladaptive repair after AKI is strongly associated with the development of CKD and long-term consequences. The prompt identification of patients at higher risk for late CKD progression and the development of new therapeutic interventions remain critical research goals.Present-day therapy also has many shortcomings. Current treatments are mostly based on general nutritional interventions and lifestyle modification, blood pressure control, blood sugar control, and reduction in albuminuria. Although fully agreeable and of critical importance in controlling associated CV risk, current treatments may only delay disease progression, underscoring the need to develop new therapeutic approaches to stop or reverse CKD progression. Adopting measures to help prevent this process may slow down the disease’s evolution and even preserve long-term renal function. If these modalities are truly effective, their benefits are greater the earlier such therapy may start.The current mainstay of CKD therapy is renin–angiotensin system (RAS) blockade using angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin receptor blockers (ARBs) and, recently, sodium-glucose transporter 2 (SGLT2) inhibitors have been introduced. However, RAS blockade is indicated only in proteinuric or hypertensive nephropathies and delays, but does not prevent, CKD progression . SGLT2 iIn addition to pharmacological treatment, the low-protein diet is now considered as an integral part of therapy in CKD patients at pre-dialysis stages as it is effective in delaying ESKD and improving metabolic control and quality of life . ManagemIn our opinion, starting from all this evidence, it should be clear that one of the main challenges that the nephrologist will face in the near future will be the early detection of markers of progression of kidney damage and the development of increasingly targeted therapies able to stop such progression or even allowing the kidney to regenerate.In this regard, developments in knowledge about the ability of SGLT2 inhibitors to prevent or delay kidney fibrosis and cardiac damage will certainly be of primary interest. Moreover, clinical use of non-steroidal mineralocorticoid receptor antagonists should open a new field to reduce the risk of kidney function decline, kidney failure, cardiovascular death, non-fatal heart attacks, and hospitalization for heart failure in adults with CKD ,30. FinaIn addition to therapy, there is certainly the necessity, as mentioned above, for earlier and more accurate identification of patients at high risk of CKD progression. From this premise, new technologies that allow a better study of real renal residual “vitality” (such as more sophisticated imaging)  and idenThe challenge for the future in the treatment of CKD lies in our ability to understand more deeply its underlying pathophysiological mechanisms, to identify patients at risk early, and to propose increasingly effective and personalized therapies to interrupt that “slippery slope” that, in these days, inevitably leads from CKD to ERKD.


Preventing, diagnosing, and controlling high blood pressure is a global health priority. The self-measurement of blood pressure is therefore fundamental and should be done with devices validated by recognized protocols, although most are not. The most widely used and current protocols are the 2010 European Society of Hypertension (ESH) revision and the 2018 Association for the Advancement of Medical Instrumentation (AAMI)/ ESH/ the International Organization for Standardization (ISO) universal standard, respectively. The aim of this study was to find out which blood pressure measuring devices have been adequately validated by the above protocols. A narrative review of blood pressure device validations was conducted by searching the PubMed database. From 52 records identified, 37 studies were included. Most validations follow the 2010 revision and only six follow the 2018 protocol, which is more demanding. Almost all validated sphygmomanometers are automated oscillometric sphygmomanometers in the general population. Wrist devices and devices combining new technologies are also validated, as well as in specific populations, such as the obese, pregnant women, or children. There is sufficient evidence to confirm that the universal AAMI/ ESH/ISO standard is considered the protocol of the century. However, it is necessary to increase the number of validations following it and, above all, validations of the new technologies that are invading the current market. After obesity, arterial hypertension (HBP) is the second most common cause of cardiovascular disease (CVD) . If we aTherefore, one of the main objectives of health systems is to identify people with AHT and ensure that they have good control of their blood pressure (BP), since the higher the blood pressure levels, the greater the risk and morbidity and mortality from CV events ,9,10. ThThe detection and diagnosis of hypertension must be done by measuring BP. BP measurement is considered as one of the most frequently performed procedures at the clinical level, in primary or specialized care .The first time BP was recorded in a consultation was in 1896, and since the end of the last century, out-of-office measurement has been established in two versions: ambulatory BP monitoring (ABPM) and home blood pressure monitoring (HBPM). The major advantage of these two methods is that by allowing BP to be measured on multiple occasions outside the healthcare environment, it provides a more reliable BP reading and has a higher prognostic value than doing it in the office ,17,18.If we focus on HBPM, it has become a very beneficial and increasingly used simple procedure, for highly consistent reasons ,20,21. TWith regard to blood pressure validations, in the last 30 years, there have been several protocols for this purpose, such as the British Society of Hypertension (BSH)  protocolGiven the relevance of HBPM and the need for increased monitoring of BP devices, according to the literature, the results of the present study will mainly serve to find out which devices can be validly used by subjects to measure and monitor their blood pressure, according to the most used and/or current protocols ,29.A narrative review was carried out following the applicable recommendations of the Scale for the Assessment of Narrative Review Articles (SANRA) . This scThe database search was carried out during November–January 2021. Pubmed was the database used for this process.The advanced search strategy was as follows, combining the terms with the Boolean and grouping operators that follow: (European Society of Hypertension [Title]) OR AAMI/ESH/ISO[Title]) AND validation [Title].As for the search filters, only one of the publication dates is applied: Last 5 years.The search strategy has been filtered by title because, by regulation, all validations following the “the revised 2010 European Society of Hypertension international protocol” and “the 2018 AAMI/ESH/ISO universal standard” should be named in a standardized way and, consequently, the titles of these publications should also be named in the same way.Inclusion criteria comprised blood pressure device validation studies that followed the 2010 European Society of Hypertension international protocol review and/or the 2018 AAMI/ESH/ISO universal standard, conducted within the last 5 years.Exclusion criteria included studies with a publication date prior to 2017, and those that were not device validations or did not follow the revised 2010 European Society of Hypertension international protocol and/or the 2018 AAMI/ESH/ISO universal standard.The data obtained were divided according to the validation protocol used. The common methodology governing the validation conditions was recorded, such as sample size, blood pressure range, and other variables, in accordance with the protocol used.Study characteristics were also recorded, such as citation year and place of validation, types of devices used, population characteristics and origin, and validation conclusions.Additional information was provided where necessary.From 52 records identified through the searching process, 15 were removed due to exclusion, and finally, 37 studies were included in narrative synthesis .− 7 articles discussed the validation standard itself and/or revisions of the validation standard− 2 studies commented with the proper use of validation protocols− 4 publications were corrections of previously included articles.− 1 paper was about validation but only followed the ESH 2002 protocol.− 1 study did not analyze validity but reproducibility.15 studies were excluded for the following reasons:The studies of the last five years on blood pressure measuring devices mainly apply two validation protocols for BP devices, which are the review of the international ESH protocol  and the Thus, 31 articles following the ESH review  and six Both protocols use a similar sequential BP measurement procedure by alternating two devices (reference and test). Validated devices are already used as a reference, but the 2010 ESH prefers these to be two mercury sphygmomanometers with stethoscopes and the AAMI/ESH/ISO standard indicates that the reference can be as stated above, but can also be non-mercury sphygmomanometers, aneroid manometers, or other types. The measurement conditions are similar, where the subject being measured must remain relaxed and calm in a certain position. Also, the human validation equipment is almost identical, and it has a similar tolerable BP measurement error. In both protocols, Bland–Altman charts are required.On the other hand, they vary substantially in the range of BP recruitment, sample characteristics and size, and validation criteria.For a device to pass the ESH , it mustTo pass the universal standard , the devIn terms of specific populations, the standards proposed by the three societies as a whole are more explicit.Thus, although the ESH  protocolAll the studies collected have the same quality in terms of study type, as they all follow the same standards and have the same design: prospective cross-sectional observational studies .Having analyzed the common and different aspects in terms of the validation conditions governing the respective protocols , we now We found positive results in most studies, exceeding the protocol in question and validating the test devices for their recommended use, as well as in the population analyzed, with the exception of two studies with four test devices, Omron RS6 (hem-6221-E), Microlife WatchBP O3 , Yuwell The validated devices are different depending on the measurement method, the area of the body where they are applied, their characteristics, or their function: self-measurement, BP monitoring, or professional use, among others. Only one study has validated a device that uses the auscultatory method to measure BP . TypicalThe cuff used by most authors in their test device is usually the standard or medium size (22–32 cm), except for some who have tested more than one cuff, such as small (18–22 cm) , or largThere are authors who opt for other wrist devices of the same type ,44,50,61Of the above, many are recommended devices for HBPM but some are designed for ABPM ,46,48,53Among those used for HBPM, other validated devices differ more from the above. The Inbody BPBIO320  and the Therefore, of all the validations, only one device without a cuff to measure BP is attempted to be validated , and theIt should be noted that the use of new technologies for health promotion and disease prevention is booming and, in particular, BP control using these has gained importance, adding additional advantages to HBPM, which results in a more active subject with better adherence and follow-up ,69,70,71As for the parameters assessed in the populations, all studies include recruitment SBP and DBP, age (in years), and circumference of the upper arm ,65,66,67These measured characteristics are generally similar as they all meet the recruitment criteria of the protocols ,29, exceMost of these studies are conducted in the general population, which are healthy adults over 25 years of age for one protocol , and 12 Some studies look at other specific populations prone to HBP, such as the obese ,47,61, cAs for the validation team, it also follows the rules of the protocols ,29, reflAlthough the universal standard is considered the protocol of the century , only seFor example, it was recommended to the journals that, from November 2019 onward, they no longer accept articles following the ESH to validate the devices  and onlyTo conclude this section, it is worth mentioning that one of the main limitations of our study is that we have only used one database, Pubmed. We were guided by a study that analysed optimal database combinations for literature searches and found that “Sixteen percent of the included references (291 articles) were only found in a single database” .Since 2017, 37 devices have been attempted to be validated to measure BP with reputable protocols, with most obtaining positive results. It is necessary to increase the number of studies according to what is considered the protocol of the century, the universal AAMI/ESH/ISO standard (ISO 81160-2:2018), and especially using new technologies, as few validations have been found on them.


Esophageal pressure (Pes) can be used as a reliable surrogate for pleural pressure, especially in critically ill patients requiring personalized mechanical ventilation strategies. How to choose the proper esophageal balloon filling volume and then find the optimal value of esophageal pressure remains a challenge. The study aimed to assess the feasibility of catheters for Pes monitoring in mechanically ventilated patients.WORK was the intermediate linear section on the end-expiratory P-V curve, and VBEST was the filling volume providing the maximum difference between Pes at end-inspiration and end-expiration. The raw value of Pes was recorded, and the calibrated values of Pes were calculated by calculating the esophageal wall pressure (Pew) and esophageal elastance (Ees).Twelve patients under pressure-controlled mechanical ventilation were included in this study. Raw esophageal pressure was recorded at different balloon filling volumes. Then, the P-V curves were determined. VMIN and VMAX were 2.17 ± 0.49 ml  and 6.79 ± 0.83 ml , respectively, whereas VBEST was 4.69 ± 0.16 ml . Ees was 1.35 ± 0.51 cm H2O/ml . The estimated Pew at VBEST was 3.16 ± 2.19 cm H2O . Patients with a body mass index (BMI) ≥ 25 kg/m2 had a significantly lower VMAX  and a significantly lower VBEST  than patients with a BMI < 25 kg/m2. Patients with positive end-expiratory pressure (PEEP) ≥ 10 cm H2O had a lower VMIN and VBEST than patients with PEEP < 10 cm H2O, P > 0.05. Patients in the supine position had a higher esophageal pressure than those in the prone position with the same balloon filling volume.Twenty-four series of Pes measurements were performed. The mean VCalibration of esophageal pressure to identify the best filling volume of esophageal balloon catheters is feasible. The esophageal pressure can be influenced by BMI, PEEP, and position. It is necessary to titrate the optimal inflation volume again when the PEEP values or the positions change. L), which is the distending pressure of the lungs. In the past 20 years, this technique has been used in critically ill patients, especially patients with acute respiratory failure (ARF).An increasing number of clinicians have been focusing on esophageal pressure (Pes) manometry because of its vital role in understanding pulmonary pathophysiology since the end of the 19th century. Due to the impossibility of directly measuring pleural pressure in clinical practice, esophageal pressure has been proposed as a reliable surrogate for pleural pressure (Ppl) . We can L). Second, it can be used to monitor patients’ respiratory muscle activity during assisted ventilation. Last, it contributes to assessing patient-ventilator interaction  at bedside. Therefore, esophageal pressure can be monitored during the entire process of mechanical ventilation, especially personalized mechanical ventilation strategies  , 5. Firsrategies . The esorategies , howeverrategies , 8. It irategies . In recen volume –13. HoweThe study was approved by the Institutional Research and Ethics Committee of the Peking Union Medical College Hospital (NO. ZS-2458). Informed consent was obtained as required before data were included in the study.We enrolled heavily sedated ICU patients  with ARF under controlled mechanical ventilation. ARF was by a ratio of partial pressure of arterial oxygen to fraction of inspired oxygen less than 300 mmHg. Exclusion criteria were as follows: (1) age under 18 years; (2) any contraindication for esophageal balloon catheter insertion ; (3) evidence of active air leakage from the lung, including bronchopleural fistula, and pneumomediastinum; and (4) lack of informed consent.Supplementary Video 1).While undergoing treatment, the included patients remained in the supine position without elevating the head of the bed. The esophageal balloon had a length of 10 cm and a nominal volume of 10 ml. The tube with esophageal and gastric balloon  was inserted in the mid-lower third of the thoracic esophagus for clinical purposes. Appropriate catheter position was confirmed by cardiac oscillations on Pes tracing and radiopaque markers on chest X-ray. A positive pressure occlusion test was performed at end-expiratory occlusion, and the ratio of changes in Pes to changes in Paw (ΔPes/ΔPaw) during the compression of the chest wall was calculated and maintained at 0.8∼1.2. To obtain esophageal balloon pressure-volume curves, we filled the Mindray esophageal balloon with air in 1 ml increments from 0 to 10 ml unless the esophageal pressure clearly rose. At each volume step, the balloon was completely deflated by applying a negative pressure, fully inflated with 10 ml of air, and finally deflated. Then dynamic pressures were obtained at end-inspiration or end-expiration . The filling volume providing the maximum difference between PesEI and PesEE was identified as VBEST. The slope of the intermediate linear section on the end-expiratory P-V curve obtained by least square fitting was defined as the elastance of the esophagus (Ees) (X) above VMIN, was calculated as: Pew = (VX–VMIN) × Ees. The calibrated values of Pes (PesCAL) were obtained by measuring the end-expiration Pes of the best filling volume and PesCAL = Pes-Pew (We recorded the Pes at end-inspiration (PesEI) and end-expiration (PesEE) for each filling volume in each patient. From those data, we obtained two curves to express the patient pressure-volume (P-V) relationship between balloon filling volume and esophageal balloon pressure of end-inspiration and end-expiration. On the end-expiratory P-V curve, the intermediate linear section was identified as Vus (Ees) . As Milius (Ees)  and Franus (Ees)  said, th Pes-Pew , 14.To obtain gastric balloon pressure (Pga), the Mindray gastric balloon was completely deflated by applying a negative pressure, fully inflated with 10 ml of air, and finally withdrawn by 5 ml. Then, the Pga of end-inspiration and end-expiration was recorded.t-test or the Wilcoxon signed-rank test where appropriate. Bland-Altman analysis was used to verify the consistency of PesVBEST and PesCAL at VBEST. Upper and lower limits of agreement were defined as bias ± 1.96 SD of the mean. Statistical analyses were computed using GraphPad Prism 8.0.2 software .Patient demographics and relevant clinical data are expressed as the mean and standard deviation (SD) or median (25th–75th percentile) for continuous, variables, and numbers (percentages) for categorical variables. Differences between body mass index (BMI), position, and PEEP groups were compared by using the 2/FiO2 of 228.6 ± 86.6 mmHg, a tidal volume/predicted body weight of 5.9 ± 1.1 ml/kg, Pplat of 21.0 ± 3.9 cm H2O, Pdriv of 11.5 ± 2.8 cm H2O, and Crs of 34.1 ± 12.2 ml/cm H2O.Twenty-four series of measurements were collected from 12 patients  under pressure-controlled mechanical ventilation. The baseline characteristics are reported in MIN and VMAX were 2.17 ± 0.49  and 6.79 ± 0.83 ml , respectively, while the best filling volume was 4.69 ± 0.16 ml . The slope of the linear section of the curve, i.e., Ees, was 1.35 ± 0.51 cm H2O/ml (range 0.26–2.38 cm H2O/ml). The estimated Pew at VBEST was 3.16 ± 2.19 cm H2O . Four different patients’ end-inspiratory and end-expiratory P-V curves are shown in End-expiratory and end-inspiratory raw esophageal balloon P-V curves were obtained in all patients . An inteThe calibration procedure is shown in 2 had a lower VMIN , a significantly lower VMAX , and a significantly lower VBEST  than patients with BMI < 25 kg/m2 , VMAX , and VBEST  than patients with PEEP < 10 cm H2O  can be quickly confirmed by the maximum esophageal pressure swing (ΔPes) of the intermediate linear section on the balloon P-V curve; (2) VBEST varies widely in different patients or in different PEEPs, BMIs, and positions; and (3) Mindray catheters are suitable for esophageal manometry in critically ill patients. The gastric pressure was stable when the esophageal balloon filling volume increased.We performed esophageal pressure monitoring in patients with ARF under invasive passive mechanical ventilation. We had three main findings: (1) The best filling volume (Vin vitro and in vivo), when pressure generated by the esophageal wall was subtracted from Pes. Although the in vitro study showed that Pes is stable within the VWORK on the P-V curve, the Pes in vivo linearly increased because of esophageal elastance (Ees) , which was larger than the traditional recommended small inflation volume. The study also found that the inflation volume that can pass the validation occlusion test is greater than 0.5 ml, so 0.5 ml may not be able to accurately assess the accurate value of the patient’s esophageal pressure. Sun et al showed that the VBEST for smaller balloons (geometric volume of 2.8 ml) is 1.0 ml  and was highly variable among different patients and conditions , which was larger than that reported by Mojoli et al’s. Our study enrolled patients with lower PEEP and lower BMI compared with Mojoli’s research  , 10, 12.ce (Ees) . The metce (Ees) . Comparei et al.  showed tnditions . In thisresearch .The intrathoracic pressure in critically ill patients can be affected by many factors, such as the accurate measurement of esophageal pressure. Therefore, the following factors may cause different measurement results. The first is body position. Previous studies have suggested that esophageal pressure when patients are in the supine position is higher than that in other positions due to the influence of mediastinal organs and tissues , 17. WasBEST values ranging from 3 to 6 ml. Finally, the VBEST was catheter-specific, such as in NutriVent and Marquat catheters, even at the same catheter volume, in an in vitro study  can be used to assess breathing, respiratory muscle function, and the presence of diaphragm paralysis . It is wIn this study, the supine and prone positions were used to measure esophageal pressure, and the effect of different body positions on esophageal pressure is still inconclusive. This study, based on the method of Mojoli et al. , used thIn summary, the method to identify the best filling volume of esophageal balloon catheters is feasible. This approach is well validated in Mindary’s intercropping. It might aid in developing personalized mechanical ventilation at bedside, such as different body positions and different intervention methods. Further study is required to validate the clinical applicability of this method.The datasets used or analyzed in this study are available from the corresponding authors on reasonable request.The studies involving human participants were reviewed and approved by the Institutional Research and Ethics Committee of the Peking Union Medical College Hospital (NO. ZS-2458). The patients/participants provided their written informed consent to participate in this study.YL and HH took responsibility for the integrity of the study as a whole. JJ was responsible for the collection of data, data management, statistical analysis, and drafted the manuscript. LS was responsible for the study design, conception, data management, and statistical analysis. WC and CW participated in the collection of data and data management. XR, BT, and HZ took responsibility for the study design and conception. All authors revised the manuscript for content and contributed to the article and approved the submitted version.