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Endotoxin induces an inflammatory response, with secondary release of cytokines, which can progress to shock and multiple organ failure. We explored whether continuous renal replacement therapy (CRRT) using a modified membrane (oXiris) capable of adsorption could reduce endotoxin and cytokine levels in septic patients. Sixteen patients requiring CRRT for septic shock-associated acute renal failure and who had endotoxin levels >0.03 EU/ml were prospectively randomized in a crossover double-blind design to receive CRRT with an oXiris filter or with a standard filter. Endotoxin and cytokine levels were measured at baseline and 1, 3, 8, 16 and 24 hours after the start of CRRT. Norepinephrine infusion rate and blood lactate levels were monitored. During the first filter treatment period, endotoxin levels decreased in 7 of 9 (77.8%) oXiris filter patients, but in only 1 of 6 (16.7%) standard filter patients (P = 0.02). Levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-8 and interferon (IFN)γ decreased more with the oXiris filter than with the standard filter. Lactate concentration decreased with oXiris (-1.3[-2.2 to -1.1] mmol/l, P = 0.02), but not with the standard filter (+0.15[-0.95 to 0.6]). The norepinephrine infusion rate was reduced during oXiris CRRT, but not during standard filter CRRT. In the second filter treatment period, there was no significant reduction in endotoxin or cytokine levels in either group. CRRT with the oXiris filter seemed to allow effective removal of endotoxin and TNF-α, IL-6, IL-8 and IFNγ in patients with septic shock-associated acute renal failure. This may be associated with beneficial hemodynamic effects.

PurposeNet ultrafiltration (UFNET) during continuous renal replacement therapy (CRRT) can control fluid balance (FB), but is usually 0 ml·h−1 in patients with vasopressors due to the risk of hemodynamic instability associated with CRRT (HIRRT). We evaluated a UFNET strategy adjusted by functional hemodynamics to control the FB of patients with vasopressors, compared to the standard of care.MethodsIn this randomized, controlled, open-label, parallel-group, multicenter, proof-of-concept trial, adults receiving vasopressors, CRRT since ≤ 24 h and cardiac output monitoring were randomized (ratio 1:1) to receive during 72 h a UFNET ≥ 100 ml·h−1, adjusted using a functional hemodynamic protocol (intervention), or a UFNET ≤ 25 ml·h−1 (control). The primary outcome was the cumulative FB at 72 h and was analyzed in patients alive at 72 h and in whom monitoring and CRRT were continuously provided (modified intention-to-treat population [mITT]). Secondary outcomes were analyzed in the intention-to-treat (ITT) population.ResultsBetween June 2021 and April 2023, 55 patients (age 69 [interquartile range, IQR: 62; 74], 35% female, Sequential Organ Failure Assessment (SOFA) 13 [11; 15]) were randomized (25 interventions, 30 controls). In the mITT population, (21 interventions, 24 controls), the 72 h FB was −2650 [−4574; −309] ml in the intervention arm, and 1841 [821; 5327] ml in controls (difference: 4942 [95% confidence interval: 2736–6902] ml, P < 0.01). Hemodynamics, oxygenation and the number of HIRRT at 72 h, and day-90 mortality did not statistically differ between arms.ConclusionIn patients with vasopressors, a UFNET fluid removal strategy secured by a hemodynamic protocol allowed active fluid balance control, compared to the standard of care.

Introduction During continuous renal replacement therapy (CRRT), preload-independent patients risk of becoming preload-dependent in case of excessive net ultrafiltration (UF NET ). We aimed to evaluate the ability of a UF NET challenge to identify de novo preload-dependence in preload-independent patients undergoing CRRT. Materials and methods We conducted a single-center, randomized, cross-over trial, enrolling adult patients with CRRT, calibrated continuous cardiac index (CCI) monitoring, and preload-independent at time of enrolment. The diagnostic test consisted of 250-ml UF NET removal over 15 (fast challenge) or 30 min (slow challenge), preceded and followed by a postural maneuver (PM) evaluating preload-dependence using CCI relative variations. Patients underwent both types of challenges, starting with either fast or slow challenges as determined by randomization, separated by a wash-out period of 24 h. We evaluated the performance of UF NET challenges to diagnose de novo preload-dependence using the area under the receiver operating curve (AUROC) of the relative change in calibrated cardiac index between before and after the challenge (∆CI UFC ), based on the result of the PM performed after the challenge (responder if positive, non-responder if negative). NCT05214729. Results We included 20 patients, comprising 36 UF NET challenges (19 fast and 17 slow challenges). In intention-to-treat (ITT), the rate of preload-dependence after the challenge was 33% (12/36, 95% confidence interval: 19% to 51%). In ITT, the AUROC of ∆CI UFC to identify de novo preload-dependence was 0.74 (95% confidence interval: 0.58–0.88), with the respective AUROCs of fast and slow challenges not reaching statistical significance. After exclusion of 5 challenges a posteriori identified as being preload-dependent before challenge start (modified intention-to-treat [mITT], N = 31), the AUROC of ∆CI UFC was 0.83 (0.66–0.99), with ∆CI UFC not significantly differing between fast and slow challenges. In mITT, CCI variation during the PM preceding the challenge predicted de novo preload-dependence with an AUROC of 0.82 (0.65–0.98), at an optimal threshold of + 5%. Conclusions A 250-ml UF NET challenge had acceptable diagnostic performance to identify preload-independent patients becoming preload-dependent during CRRT, with no detectable difference between fast and slow challenges. A CCI variation ≥ 5% during a PM in preload-independent patients may help identify those at risk of becoming preload-dependent.

Background Current continuous kidney replacement therapy (CKRT) protocols ignore physiological renal compensation for hypercapnia. This study aimed to explore feasibility, safety, and clinical benefits of pCO2-adapted CKRT for hypercapnic acute respiratory distress syndrome (ARDS) patients with indication for CKRT. Methods We enrolled mechanically ventilated hypercapnic ARDS patients (pCO2 > 7.33 kPa) receiving regional citrate anticoagulation (RCA) based CKRT in a prospective, randomized-controlled pilot-study across five intensive care units at the Charité—Universitätsmedizin Berlin, Germany. Patients were randomly assigned 1:1 to the control group with bicarbonate targeted to 24 mmol/l or pCO 2 -adapted-CKRT with target bicarbonate corresponding to physiological renal compensation. Study duration was six days. Primary outcome was bicarbonate after 72 h. Secondary endpoints included safety and clinical endpoints. Endpoints were assessed in all patients receiving treatment. Results From September 2021 to May 2023 40 patients (80% male) were enrolled. 19 patients were randomized to the control group, 21 patients were randomized to pCO 2 -adapted-CKRT. Five patients were excluded before receiving treatment: three in the control group (consent withdrawal, lack of inclusion criteria fulfillment (n = 2)) and two in the intervention group (lack of inclusion criteria fulfillment, sudden unexpected death) and were therefore not included in the analysis. Median plasma bicarbonate 72 h after randomization was significantly higher in the intervention group (30.70 mmol/l (IQR 29.48; 31.93)) than in the control group (26.40 mmol/l (IQR 25.63; 26.88); p  < 0.0001). More patients in the intervention group received lung protective ventilation defined as tidal volume < 8 ml/kg predicted body weight. Thirty-day mortality was 10/16 (63%) in the control group vs. 8/19 (42%) in the intervention group ( p  = 0.26). Conclusion Tailoring CKRT to physiological renal compensation of respiratory acidosis appears feasible and safe with the potential to improve patient care in hypercapnic ARDS. Trial registration The trial was registered in the German Clinical Trials Register (DRKS00026177) on September 9, 2021 and is now closed.

Non-anticoagulation is a commonly used strategy in continuous renal replacement therapy (CRRT) among patients with high-bleeding risk. However, the optimal blood flow rate (BFR) to maximize filter and circuit life remains uncertain. This study is designed to elucidate the impact of different BFRs on the durability of filters and circuits in CRRT without anticoagulation. This single-center, prospective, three-arm, single-blind, randomized controlled trial (RCT) will involve adult patients requiring non-anticoagulation continuous veno-venous hemodiafiltration (CVVHDF). A total of 486 filters and circuits will be enrolled and randomly assigned to one of three BFR groups: low (150 mL/min), medium (200 mL/min), or high (250 mL/min) BFR group. The outcomes will be analyzed by both intention-to-treat analysis and per-protocol analysis. The primary outcome is filter and circuit life, which is defined as the time from CRRT initiation to CRRT termination due to extracorporeal circuit clotting or other reasons, alongside the proportion of patent circuits at 24, 48, and 72 hours. Secondary outcomes encompass clinical outcomes and potential adverse events such as bleeding and hemodynamic alterations. This study is aiming at comparing the filter and circuit life under different BFR levels during CVVHDF without anti-coagulation. The results may add knowledge to the optimal BFR to prevent extracorporeal circulation clotting and prolong filter and circuit life in non-anticoagulation CRRT. The study has been registered at https://www.chictr.org.cn (ChiCTR2400087819).

Background The tip design and length of catheter impact catheter function. Two types of catheters with different tips, side-hole catheters and step-tip catheters, are commonly used during continuous renal replacement therapy (CRRT). However, there is insufficient evidence comparing their efficacy and safety in CRRT. In addition, whether the insertion of a longer catheter could enhance catheter function remains poorly studied and controversial. Methods In this open-label, three-arm, randomized trial, critically ill patients receiving CRRT were randomized to three groups. Group A received 20 cm side-hole catheters (GDHK‐1120), group B received 20 cm step-tip catheters (GDHK‐1320) and group C received 25 cm step-tip catheters (GDHK‐1325). The primary outcomes were the incidence of catheter dysfunction and catheter survival time. Results A total of 351 patients were enrolled, with 116 in group A, 117 in group B, and 118 in group C. The incidence of catheter dysfunction in group A (35.7%, 51/143) was significantly higher than that in group B (17.7%, 22/124) ( P  = 0.001). However, there was no difference between group B and group C (15.6%, 23/147) ( P  = 0.744). The catheter survival time was comparable between group A (5.5 days, IQR 2.5–9.3) and group B (5.0 days, IQR 3.0–10.0) ( P  = 0.626). In contrast, group C (6.4 days, IQR 3.9–12.0) demonstrated a significantly longer catheter survival time compared to group B ( P  = 0.019). Cox regression analysis identified BMI (HR 1.052, 95% CI 1.003–1.103, P  = 0.036) as an independent risk factor for catheter dysfunction. Results were not consistent across BMI tertiles, with similar results observed only in patients with a lower BMI (BMI < 24.2) (chi-square 13.65, P  = 0.001). There was also a trend that patients in group C have a longer filter lifespan (36.5 h, IQR 16.9–68.1, P  = 0.001) and a lower incidence of catheter-related thrombosis (10.40 per 1000 catheter-days, 95% CI 5.93, 17.83, P  = 0.019). Other secondary outcomes were not significantly different among groups. Conclusions Step-tip catheters may be preferable for CRRT, particularly for patients in the lower BMI tercile. Longer femoral vein catheterization demonstrated enhanced benefits in CRRT, especially among obese patients. Further high-quality, multicenter RCTs are essential to strengthen the evidence guiding catheter selection during CRRT. Trial registration : ChiCTR2300075107. Registered 25 August 2023.

To perform a post-hoc reanalysis of the Standard versus Accelerated Initiation of Renal-Replacement Therapy in Acute Kidney Injury (STARRT-AKI) and the Intensity of Continuous Renal-Replacement Therapy in Critically Ill Patients (RENAL) trials through hierarchical composite endpoint analysis using win ratio (WR). All patients with complete information from the STARRT-AKI (which compared accelerated versus standard approaches for renal replacement therapy – RRT initiation) and RENAL (which compared two different RRT doses in critically ill patients) trials were selected. WR was defined as a hierarchical composite endpoint using 90-day mortality, RRT dependency at 90-days, intensive care unit (ICU) length-of-stay (LOS), and hospital LOS (primary analysis); values above the unit represent a benefit of the intervention for the hierarchical composite endpoint. A secondary analysis replacing LOS by days alive and free of RRT was performed. Stratified analyses were performed according to illness severity score, surgical status, and the presence of sepsis. The WR analysis produced 2,141,830 pairs for the STARRT-AKI trial and 536,446 pairs for the RENAL trial, respectively. The WR results for STARRT-AKI and RENAL were 1.04 (95% confidence interval [CI] 0.96–1.13; p = 0.33) and 1.02 (95% CI; 0.90–1.15; p = 0.75) for the primary analysis, and 0.88 (95% CI; 0.79–0.99; p = 0.03) and 1.02 (95% CI; 0.87–1.21; p = 0.77) for the secondary analysis, respectively. The stratified analysis of the primary suggested possible benefit of the accelerated-strategy in the STARRT-AKI trial for non-surgical patients with sepsis, while the secondary analysis suggested possible harm of the accelerated-strategy for surgical patients without sepsis. There was no evidence of heterogeneity in treatment effects in stratified analyses in the RENAL trial. WR approach using a hierarchical composite endpoint is feasible for trials in critical care nephrology. The primary re-analyses of the STARRT-AKI and RENAL trials both yielded neutral results; however, there was suggestion of heterogeneity in treatment effect in stratified analyses of the STARRT-AKI trial by surgical status and sepsis. Selection of the endpoints and hierarchical ordering before trial design using the WR approach can have important implications for trial interpretation. Trial Registry: ClinicalTrials.gov number NCT02568722 (STARRT-AKI) and NCT00076219 (RENAL). •Hierarchical endpoints can be assessed using win ratio (WR), which provides pairwise comparisons among trial participants according to a defined hierarchy.•WR is an alternative to endpoint assessment in trials with competing risks•In this post-hoc reanalysis of the STARRT-AKI and RENAL trials, WR showed overall neutral results for both trials; however, in the STARRT-AKI trial, there was evidence of heterogeneity in treatment effect according to surgical status and the presence of sepsis.

Background and Objective Renal replacement therapy (RRT) plays a critical role in antimicrobial removal, particularly for low-molecular-weight drugs with low plasma protein binding, low distribution volume and hydrophilicity. Medium cut-off (MCO) membranes represent a new generation in dialysis technology, enhancing diffusive modality efficacy and increasing the cut-off from 30 to 45 kDa, crucial for middle molecule removal. This monocentric randomized crossover pilot study aimed to evaluate the impact of continuous haemodialysis with MCO membrane (MCO-CVVHD) on the removal of piperacillin, tazobactam and meropenem compared with continuous veno-venous hemodiafiltration with standard high-flux membrane (HFM-CVVHDF). Methods Twenty patients were randomized to undergo MCO-CVVHD followed by HFM-CVVHDF or vice versa. Extraction ratio (ER), effluent clearance (Cl eff ) and treatment efficiency were assessed at various intervals. Antibiotic nadir plasma levels were measured for both treatment days. Results HFM-CVVHDF showed greater ER compared with MCO-CVVHD for meropenem ( β = − 8.90 (95% CI − 12.9 to − 4.87), p < 0.001) and tazobactam ( β = − 8.29 (95% CI − 13.5 to − 3.08), p = 0.002) and Cl eff for each antibiotic (meropenem β = − 10,206 (95% CI − 14,787 to − 5787), p = 0.001); tazobactam ( β = − 4551 (95% CI − 7781 to − 1322), p = 0.012); piperacillin ( β = − 3913 (95% CI − 6388 to − 1437), p = 0.002), even if the carryover effect influenced the Cl eff for meropenem and tazobactam. No difference was observed in nadir plasma concentrations or efficiency for any antibiotic. Piperacillin ( β = − 38.1 (95% CI − 47.9 to − 28.3), p < 0.001) and tazobactam ( β = − 4.45 (95% CI − 6.17 to − 2.72), p < 0.001) showed lower nadir plasma concentrations the second day compared with the first day, regardless the filter type. Conclusion MCO demonstrated comparable in vivo removal of piperacillin, tazobactam and meropenem to HFM.

Optimal strategy for volume control and the clinical implication of achieved volume control are unknown in patients with sepsis-associated acute kidney injury (AKI) receiving continuous renal replacement therapy (CRRT). This randomized controlled trial aimed to compare the survival according to conventional or bioelectrical impedance analysis (BIA)-guided volume control strategy in patients with sepsis-associated AKI receiving CRRT. We also compared patient survival according to achieved volume accumulation rate ([cumulative fluid balance during 3 days × 100]/fluid overload measured by BIA at enrollment) as a post-hoc analysis. We randomly assigned patients to conventional volume control strategy (n = 39) or to BIA-guided volume control strategy (n = 34). There were no differences in 28-day mortality (HR, 1.19; 95% CI, 0.63–2.23) or 90-day mortality (HR, 0.99; 95% CI 0.57–1.75) between conventional and BIA-guided volume control group. In the secondary analysis, achieved volume accumulation rate was significantly associated with patient survival. Compared with the achieved volume accumulation rate of ≤  − 50%, the HRs (95% CIs) for the risk of 90-day mortality were 1.21 (0.29–5.01), 0.55 (0.12–2.48), and 7.18 (1.58–32.51) in that of  − 50–0%, 1–50%, and > 50%, respectively. Hence, BIA-guided volume control in patients with sepsis-associated AKI receiving CRRT did not improve patient outcomes. In the secondary analysis, achieved volume accumulation rate was associated with patient survival.

IntroductionThe only supportive therapy for patients with severe acute kidney injury (AKI), a common complication among the critically ill, is dialysis. Based on the literature and current guidelines, continuous renal replacement therapy (CRRT) with a total effluent dose of 20–25 mL/kg/hour and adjustments to ensure such dose is delivered despite down time (eg, due to surgical procedures) is recommended. However, experimental and clinical studies suggest that azotaemia, which can be induced by lowering the effluent dose, may accelerate renal recovery. This clinical study investigates whether a lower effluent dose (10–15 mL/kg/hour) for a maximum of 7 days or until successful (>24 hours) liberation of CRRT in critically ill patients with a dialysis-dependent AKI accelerates renal recovery and reduces time on CRRT compared with guideline-directed standard dose (25–30 mL/kg/hour).Methods and analysisThe Ketzerei trial is an international, multicentre randomised, controlled trial, designed to investigate if a lower effluent dose (10–15 mL/kg/hour) accelerates renal recovery and reduces the time on CRRT compared with the guideline directed standard effluent dose (25–30 mL/kg/hour). The study aims to enrol 150 critically ill patients with a dialysis-dependent AKI. Eligible patients will be randomised to receive either a standard effluent dose (control group, 25–30 mL/kg/hour) or lower effluent dose (interventional group, 10–15 mL/kg/hour). The primary endpoint is the number of days free from CRRT and alive (from randomisation through day 28). Key secondary endpoints include the number of (serious) adverse events due to potential uremia, the duration of RRT and intensive care unit survival.Ethics and disseminationThe Ketzerei trial has been approved by the Ethics Committee of the Chamber of Physicians Westfalen-Lippe (2023–343 f-s), the University of Muenster and subsequently by the corresponding Ethics Committee of the participating sites. Results will be disseminated widely and published in peer-reviewed journals, presented at conferences and will guide patient care and further research.Trial registration numberclinicaltrials.gov (NCT06021288).