IMPORTANCEAlthough current guidelines suggest the use of regional citrate anticoagulation (which involves the addition of a citrate solution to the blood before the filter of the extracorporeal dialysis circuit) as first-line treatment for continuous kidney replacement therapy in critically ill patients, the evidence for this recommendation is based on few clinical trials and meta-analyses.OBJECTIVE To determine the effect of regional citrate anticoagulation, compared with systemic heparin anticoagulation, on filter life span and mortality. DESIGN, SETTING, AND PARTICIPANTSA parallel-group, randomized multicenter clinical trial in 26 centers across Germany was conducted between March 2016 and December 2018 (final date of follow-up, January 21, 2020). The trial was terminated early after 596 critically ill patients with severe acute kidney injury or clinical indications for initiation of kidney replacement therapy had been enrolled. INTERVENTIONSPatients were randomized to receive either regional citrate anticoagulation (n = 300), which consisted of a target ionized calcium level of 1.0 to 1.40 mg/dL, or systemic heparin anticoagulation (n = 296), which consisted of a target activated partial thromboplastin time of 45 to 60 seconds, for continuous kidney replacement therapy. MAIN OUTCOMES AND MEASURESCoprimary outcomes were filter life span and 90-day mortality. Secondary end points included bleeding complications and new infections. RESULTS Among 638 patients randomized, 596 (93.4%) (mean age, 67.5 years; 183 [30.7%] women) completed the trial. In the regional citrate group vs systemic heparin group, median filter life span was 47 hours (interquartile range [IQR], 19-70 hours) vs 26 hours (IQR, 12-51 hours) (difference, 15 hours [95% CI, 11 to 20 hours]; P < .001). Ninety-day all-cause mortality occurred in 150 of 300 patients vs 156 of 296 patients (Kaplan-Meier estimator percentages, 51.2% vs 53.6%; unadjusted difference, -2.4% [95% CI, -10.5% to 5.8%]; unadjusted hazard ratio, 0.91 [95% CI, 0.72 to 1.13]; unadjusted P = .38; adjusted difference, -6.1% [95% CI, -12.6% to 0.4%]; primary adjusted hazard ratio, 0.79 [95% CI, 0.63 to 1.004]; primary adjusted P = .054). Of 38 prespecified secondary end points, 34 showed no significant difference. Compared with the systemic heparin group, the regional citrate group had significantly fewer bleeding complications (15/300 [5.1%] vs 49/296 [16.9%]; difference, -11.8% [95% CI, -16.8% to -6.8%]; P < .001) and significantly more new infections (204/300 [68.0%] vs 164/296 [55.4%]; difference, 12.6% [95% CI, 4.9% to 20.3%]; P = .002).CONCLUSIONS AND RELEVANCE Among critically ill patients with acute kidney injury receiving continuous kidney replacement therapy, anticoagulation with regional citrate, compared with systemic heparin anticoagulation, resulted in significantly longer filter life span. The trial was terminated early and was therefore underpowered to reach conclusions about the effect of anticoagulation strategy on mortality.

Purpose of review The delivery of an effective dialysis dose in continuous renal replacement therapy (CRRT) depends on adequate anticoagulation of the extracorporeal circuit. In most patients, either systemic heparin anticoagulation (SHA) or regional citrate anticoagulation (RCA) is used. This review will outline the basics and rationale of RCA and summarize data on safety and efficacy of both techniques. Recent findings The basic principle of RCA is to reduce the level of ionized calcium in the extracorporeal circuit via infusion of citrate. This way, effective anticoagulation restricted to the extracorporeal circuit is achieved. SHA and RCA were compared in a variety of studies. RCA significantly prolonged filter lifetime, reduced bleeding complications and provided excellent control of uremia and acid-base status. RCA was also safe in the majority of patients with impaired liver function, whereas caution must be exerted in those with severe multiorgan failure and persistent hyperlactatemia. Summary RCA per se is safe and effective for anticoagulation of CRRT. Compared to SHA, efficacy of anticoagulation is improved and adverse effects are reduced. RCA can be recommended as the anticoagulation mode of choice for CRRT in most ICU patients.

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Sepsis and septic shock are characterized by a release of cytokines into the circulation. These mediators contribute to the detrimental hemodynamic and metabolic effects in the early phase of septic shock. Recently, a new polystyrene-based hemoadsorption device was introduced into clinical practice (CytoSorb®). The adsorber binds a variety of molecules including cytokines and removes them from the circulation. Studies in septic patients have shown an improved clinical course following hemoadsorption but no increased survival. We hypothesize that not only cytokines but also antibiotics may be removed which potentially may negate any beneficial effect of the adsorber. To test this hypothesis, we performed polystyrene-based hemoadsorption in three patients in septic shock and analysed glycopeptide elimination by measuring serum levels pre- and post-adsorber. We administered both teicoplanin and vancomycin via a 60-min infusion and vancomycin via continuous infusion, additionally. When applied as 60 min infusion, vancomycin and teicoplanin were removed immediately by the adsorber. However, the adsorptive capacity of the device was saturable. Serum levels of vancomycin, but not teicoplanin, decreased to subtherapeutic levels. With continuous infusion of vancomycin, removal was less and serum levels remained in the therapeutic range. In conclusion, we show effective glycopeptide adsorption using a polystyrene-based hemoadsorber in septic patients. The dose of these antibiotics should be adjusted appropriately and early therapeutic drug monitoring is highly recommended.

Continuous renal replacement therapy is a standard treatment in critically ill patients with acute kidney injury. All CRRT techniques provide a high low-molecular weight clearance but even with hemofiltration, clearance of middle molecules is low. We investigated whether a new super high-flux hemofilter provides effective and sustained middle molecule clearance during citrate-anticoagulated continuous venovenous hemodialysis for up to 72 h. We included 14 critically ill patients with AKI-KDIGO-III in a prospective observational trial. We measured/calculated blood and urine concentrations, clearances and sieving coefficients of eight molecules with molecular weights from 60 to 66 kDa, hemodynamic parameters and SAPS-II scores. All filters were patent at 72 h. Clearance and sieving coefficients of small solutes were high and sustained over time, those for larger solutes decreased over 72 h but remained high enough to decrease blood concentrations of solutes up to 25 kDa. Albumin serum levels remained unaffected. Catecholamine doses and SAPS-II scores decreased significantly. This new hemofilter may improve blood purification in critically ill patients with AKI.

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Introduction: Septic shock is characterized by severe metabolic and hemodynamic alterations. It is often accompanied by acute kidney injury. A new adjunct treatment is hemoadsorption using a cytokine adsorber in line with continuous veno-venous renal replacement therapy. We studied the feasibility, efficacy, and safety of cytokine adsorption with citrate-anticoagulated continuous veno-venous hemodialysis (regional citrate anticoagulation–continuous veno-venous hemodialysis). Methods: In 11 patients with septic shock and acute kidney injury stage 3, we studied 12 cycles of cytokine adsorption and regional citrate anticoagulation–continuous veno-venous hemodialysis. We monitored parameters of citrate anticoagulation, circuit lifetime, laboratory parameters, hemodynamics, and vasopressor demand. Results: Ten out of 12 adsorber/continuous veno-venous hemodialysis circuits reached the target lifetime of 24 h for the adsorber. One system clotted and one was stopped for non-device-related reasons. Nine of the remaining continuous renal replacement therapy circuits reached 72 h lifetime. With default settings for regional citrate anticoagulation, serum ionized calcium and pH were in the normal range. Urea and creatinine were reduced significantly, and norepinephrine dose decreased from 0.47 (±0.09) to 0.16 (±0.04) µg/kg/min ( p = 0.016) after 24 h. Discussion: We show that combined cytokine adsorption/continuous veno-venous hemodialysis is effective to control pH, to reduce urea and creatinine, and to improve hemodynamics by reducing norepinephrine doses in patients with septic shock. It can be applied safely with standard settings of regional citrate anticoagulation rendering sufficiently long filter lifetimes for the adsorber and the continuous veno-venous hemodialysis circuit. Further studies are on the way to investigate whether these effects translate into improved outcomes in septic shock patients.