Diagnostic performance of a 250-ml net ultrafiltration challenge to identify risk of preload-dependence in critically ill patients undergoing continuous renal replacement therapy: a randomized, cross-over trial

Biscarrat et al. Critical Care (2025) 29:446 https://doi.org/10.1186/s13054-025-05674-3 Critical Care Open Access RESEARCH Diagnostic performance of a 250-ml net ultrafiltration challenge to identify risk of preload-dependence in critically ill patients undergoing continuous renal replacement therapy: a randomized, cross-over trial Charlotte Biscarrat1, Guillaume Deniel1,2,3, Matthieu Chivot1, Hodane Yonis1, Louis Chauvelot1, Mehdi Mezidi1, Jean-Christophe Richard1,2,3 and Laurent Bitker1,2,3* Abstract Introduction During continuous renal replacement therapy (CRRT), preload-independent patients risk of becoming preload-dependent in case of excessive net ultrafiltration (UFNET ). We aimed to evaluate the ability of a UFNET 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 UFNET 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 UFNET 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 (∆CIUFC), 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 UFNET challenges (19 fast and 17 slow challenges). In intention-totreat (ITT), the rate of preload-dependence after the challenge was 33% (12/36, 95% confidence interval: 19% to 51%). In ITT, the AUROC of ∆CIUFC 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 ∆CIUFC was 0.83 (0.66–0.99), with ∆CIUFC not significantly differing between fast and slow *Correspondence: Laurent Bitker Full list of author information is available at the end of the article © The Author(s) 2025. 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To view a copy of this licence, visit http://creati vecommons.org/licenses/by-nc-nd/4.0/. Biscarrat et al. Critical Care (2025) 29:446 Page 2 of 13 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 UFNET 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. Keywords Renal replacement therapy, Acute circulatory failure, Preload-dependence, Cardiac output, Pulse contour analysis, Passive leg raising, Net ultrafiltration Introduction During renal replacement therapy (RRT), net fluid removal by mean of net ultrafiltration (UFNET) may help control fluid balance and prevent fluid overload. Nevertheless, uncertainty exists about the optimal rate of UFNET. Indeed, while a lower rate of fluid removal may be associated with prolonged exposure to tissue edema and organ dysfunction, a faster rate may lead to hemodynamic instability associated with renal replacement therapy (HIRRT) [1, 2]. As a consequence, HIRRT commonly leads to discontinuation of UFNET by clinicians, fueling the vicious circle of fluid overload [3]. However, HIRRT by hypovolemia may only occur if UFNET rate exceeds plasma inputs (from IV medications and interstitial transfer) in a preload-dependent patient in whom cardiac output falls. The prevalence of HIRRT associated with preload-dependence reaches 50% during continuous RRT (CRRT), suggesting that some HIRRT episodes may not be related to a state of RRT-induced hypovolemia [4, 5]. Also, preload-dependence outside a HIRRT episode is associated with the incidence of preload-dependent HIRRT [4]. On the other hand, patients who are preload-independent, although deemed at lower risk of presenting with preload-dependent HIRRT, may fall into a preloaddependent state if their heart function is situated close to the tipping point of the Frank-Starling curve [6, 7]. This situation is not clinically detectable by passive leg raising or other dynamic evaluations which increase cardiac preload, leaving the clinician blind to the patient’s risk of developing preload-dependent HIRRT. We hence hypothesized that the fast removal of a small ultrafiltrate volume – a UFNET challenge – would stress the cardiac preload reserve, and would help detect preload-independent patients who would fall into a preloaddependent state in case of excessive fluid removal. The primary objective of our study was to evaluate the diagnostic performance of the UFNET challenge to identify de novo preload-dependence appearing after the challenge in preload-independent patients undergoing CRRT. Methods Study design We conducted a single-center, randomized, open-label, cross-over, proof-of-concept trial in a 15-bed intensive care unit in Lyon, France. The study protocol (Additional File 1) complied with the Declaration of Helsinki, was approved by an ethics committee (CPP Sud-Est VI Clermont Ferrand 2021-A02939-32) and was registered on ClinicalTrials.gov (NCT05214729). Informed consent was obtained from all participants or their representative. 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