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The history of continuous renal replacement therapy (CRRT) is marked by technological advances linked to improvements in the knowledge of the mechanisms and kinetics of extracorporeal removal of solutes, and the pathophysiology of acute kidney injury (AKI) and other critical illnesses. In the present article, we review the main steps in the history of CRRT, from the discovery of continuous arteriovenous hemofiltration to its evolution into the current treatments and its early use in the treatment of AKI, to the novel sequential extracorporeal therapy. Beyond the technological advances, we describe the development of new medical specialties and a shared nomenclature to support clinicians and researchers in the broad and still evolving field of CRRT.

Uber zwei Millionen Menschen in Deutschland leiden an einer Niereninsuffizienz. Untersuchungen legen nahe, dass der Nachweis von COVID-19-RNA im Nierengewebe mit einer hoheren Rate an akutem Nierenversagen und einer hoheren Sterblichkeit korreliert. Der Ausfall eines Organsystems fuhrt in der Regel zur Beeintrachtigung anderer Organsysteme. Bei einer ganz oder teilweise ausgefallenen Nierenfunktion kommen als Therapie intra- oder extrakorporale Blutreinigungsverfahren wie Peritoneal- oder Hamodialyse zum Einsatz. Hamodialyse ist hierbei das weitaus haufiger angewandte Verfahren und das Mittel der Wahl in akuten Situationen. Die Therapieziele sind die Elimination von Giftstoffen, die Regulation des Flussigkeitshaushaltes, eine Korrektur der Serumlektrolyte sowie ein Azidoseausgleich.

Objective: To evaluate the transmembrane clearance (CLTM) of apixaban during modeled in vitro continuous renal replacement therapy (CRRT), assess protein binding and circuit adsorption, and provide initial dosing recommendations. Design: In vitro pharmacokinetic (PK) study.Setting: University research laboratory.Subjects: Not applicable. Interventions: Apixaban was added to the CRRT circuit and serial, undiluted pre-filter bovine blood samples were collected along with analogous post-filter blood and effluent samples. All experiments were performed in duplicate using continuous veno-venous hemofiltration (CVVH) and hemodialysis (CVVHD) modes, with varying filter types (M150 and HF1400), flow rates (2 and 4 L/h), and point of CVVH replacement fluid dilution (pre, post, and pre/post filter). Concentrations of apixaban and urea were quantified via liquid chromatography-tandem mass spectrometry. Plasma PK parameters for apixaban were estimated via noncompartmental analysis in WinNonlin. CLTM was calculated via the estimated area under the curve (AUC) and by the product of the sieving/saturation coefficient (SC/SA) and flow rate. Two and three-way ANOVA models were built to assess the effects of mode, filter type, flow rate, and point of dilution on CLTM by each method. Optimal doses were suggested by matching the AUC observed in vitro to the systemic exposure demonstrated in Phase 2/3 studies of apixaban. Linear regression was then utilized to provide dosing estimations for flow rates from 0.5-5 L/h. Measurements and Main Results: Mean adsorption to the HF1400 and M150 filters differed significantly at 38% and 13%, respectively, while mean (±SD) percent protein binding was 70.81±0.01%. Effect of CVVH point of replacement fluid dilution did not differ across filter types, although CLTM was consistently significantly higher during CRRT with the HF1400 filter compared to the M150. The three-way ANOVA demonstrated improved fit when CLTM values calculated by AUC were used (adjusted R2 0.87 vs. 0.52), and therefore, these values were used to generate optimal dosing recommendations. Linear regression revealed significant effects of filter type and flow rate on CLTM by AUC, suggesting doses of 5-10 mg BID may be needed for flow rates ranging from 0.5-5 L/h respectively. Conclusion: CLTM of apixaban during CRRT resulted in estimated dosing recommendations ranging from 5 mg BID for flow rates ≤3 L/h up to 7.5-10 mg BID for rates >3 L/h, depending on filter type, in order to match target systemic exposure thresholds. The safety and efficacy of these proposed dosing regimens warrants further investigation in clinical studies.

COVID-19 often leads to acute respiratory distress syndrome complicated by acute kidney injury (AKI). The indications for renal replacement therapy for these patients are those commonly accepted to treat AKI. We describe a continuous veno-venous haemodialysis (CVVHD) protocol for AKI, which aims to provide the best treatment according to the particular patient&rsquo, s and medical personnels&rsquo, needs in biohazard settings with limited human and technological resources. We designed a CVVHD protocol with a high cut-off (HCO) filter in regional citrate anticoagulation (RCA). The HCO filter in diffusion determines the enhanced cytokines clearance with less filter clotting due to a lower filtration fraction. In our hospital, at the beginning of the pandemic outbreak, we treated seven COVID-19 patients with AKI stage 2 and 3 and recorded the circuit lifespan and the number of interventions on monitors. CVVHD in RCA appears to be safe, effective and easy to be performed in a biohazard scenario using lower blood flows and less bag changes with fluid savings, a biohazard reduction and sparing of resources. Although the data come from a very small cohort, our protocol seems related to a low mortality.

Rationale & Objective Since 1994, the Nephrology and Hypertension Department at the Cleveland Clinic has prepared and used bicarbonate-based solution for continuous venovenous hemodialysis (CVVHD) using a standard volumetric hemodialysis machine rather than purchasing from a commercial vendor. This report describes the process of producing Cleveland Clinic UltraPure Solution (CCUPS), quality and safety monitoring, economic costs, and clinical outcomes. Study Design Retrospective study. Setting & Participants CVVHD experience at Cleveland Clinic, focusing on dialysate production, institutional factors, and patients requiring continuous kidney replacement therapy. Production is shown at www.youtube.com/watch?v=WGQgephMEwA. Outcomes Feasibility, safety , and cost. Results Of 6,426 patients treated between 2011 and 2019 with continuous kidney replacement therapy, 59% were men, 71% were White, 40% had diabetes mellitus, and 74% presented with acute kidney injury. 98% of patients were treated with CVVHD using CCUPS, while the remaining 2% were treated with either continuous venovenous hemofiltration or continuous venovenous hemodiafiltration using commercial solution. The prescribed and delivered effluent doses were 24.8 (IQR) versus 20.7 mL/kg/h (IQR), respectively. CCUPS was as effective in restoring electrolyte and serum bicarbonate levels and reducing phosphate, creatinine, and serum urea nitrogen levels as compared with packaged commercial solution over a 3-day period following initiation of dialysis, with a comparable effluent dose. Among those with acute kidney injury, mortality was similar to that predicted with the 60-day acute kidney injury predicted mortality score (r = 0.997; CI: 0.989-0.999). At our institution, the cost of production for 1 L of CCUPS is $0.67, which is considerably less than the cost of commercially purchased fluid. Limitations Observational design without a rigorous control group. Conclusions CVVHD using locally generated dialysate is safe and cost-effective., Graphical abstract

Background Tigecycline is a vital antibiotic treatment option for infections caused by multiresistant bacteria in the intensive care unit (ICU). Acute kidney injury (AKI) is a common complication in the ICU requiring continuous renal replacement therapy (CRRT), but pharmacokinetic data for tigecycline in patients receiving CRRT are lacking. Methods Eleven patients mainly with intra-abdominal infections receiving either continuous veno-venous hemodialysis (CVVHD, n = 8) or hemodiafiltration (CVVHDF, n = 3) were enrolled, and plasma as well as effluent samples were collected according to a rich sampling schedule. Total and free tigecycline was determined by ultrafiltration and high-performance liquid chromatography (HPLC)-UV. Population pharmacokinetic modeling using NONMEM® 7.4 was used to determine the pharmacokinetic parameters as well as the clearance of CVVHD and CVVHDF. Pharmacokinetic/pharmacodynamic target attainment analyses were performed to explore the potential need for dose adjustments of tigecycline in CRRT. Results A two-compartment population pharmacokinetic (PK) model was suitable to simultaneously describe the plasma PK and effluent measurements of tigecycline. Tigecycline dialysability was high, as indicated by the high mean saturation coefficients of 0.79 and 0.90 for CVVHD and CVVHDF, respectively, and in range of the concentration-dependent unbound fraction of tigecycline (45–94%). However, the contribution of CRRT to tigecycline clearance (CL) was only moderate (CLCVVHD: 1.69 L/h, CLCVVHDF: 2.71 L/h) in comparison with CLbody (physiological part of the total clearance) of 18.3 L/h. Bilirubin was identified as a covariate on CLbody in our collective, reducing the observed interindividual variability on CLbody from 58.6% to 43.6%. The probability of target attainment under CRRT for abdominal infections was ≥ 0.88 for minimal inhibitory concentration (MIC) values ≤ 0.5 mg/L and similar to patients without AKI. Conclusions Despite high dialysability, dialysis clearance displayed only a minor contribution to tigecycline elimination, being in the range of renal elimination in patients without AKI. No dose adjustment of tigecycline seems necessary in CRRT. Trial registration EudraCT, 2012–005617-39. Registered on 7 August 2013. Electronic supplementary material The online version of this article (10.1186/s13054-018-2278-4) contains supplementary material, which is available to authorized users.

Background Tigecycline is a vital antibiotic treatment option for infections caused by multiresistant bacteria in the intensive care unit (ICU). Acute kidney injury (AKI) is a common complication in the ICU requiring continuous renal replacement therapy (CRRT), but pharmacokinetic data for tigecycline in patients receiving CRRT are lacking. Methods Eleven patients mainly with intra-abdominal infections receiving either continuous veno-venous hemodialysis (CVVHD, n = 8) or hemodiafiltration (CVVHDF, n = 3) were enrolled, and plasma as well as effluent samples were collected according to a rich sampling schedule. Total and free tigecycline was determined by ultrafiltration and high-performance liquid chromatography (HPLC)-UV. Population pharmacokinetic modeling using NONMEM® 7.4 was used to determine the pharmacokinetic parameters as well as the clearance of CVVHD and CVVHDF. Pharmacokinetic/pharmacodynamic target attainment analyses were performed to explore the potential need for dose adjustments of tigecycline in CRRT. Results A two-compartment population pharmacokinetic (PK) model was suitable to simultaneously describe the plasma PK and effluent measurements of tigecycline. Tigecycline dialysability was high, as indicated by the high mean saturation coefficients of 0.79 and 0.90 for CVVHD and CVVHDF, respectively, and in range of the concentration-dependent unbound fraction of tigecycline (45–94%). However, the contribution of CRRT to tigecycline clearance (CL) was only moderate (CLCVVHD: 1.69 L/h, CLCVVHDF: 2.71 L/h) in comparison with CLbody (physiological part of the total clearance) of 18.3 L/h. Bilirubin was identified as a covariate on CLbody in our collective, reducing the observed interindividual variability on CLbody from 58.6% to 43.6%. The probability of target attainment under CRRT for abdominal infections was ≥ 0.88 for minimal inhibitory concentration (MIC) values ≤ 0.5 mg/L and similar to patients without AKI. Conclusions Despite high dialysability, dialysis clearance displayed only a minor contribution to tigecycline elimination, being in the range of renal elimination in patients without AKI. No dose adjustment of tigecycline seems necessary in CRRT. Trial registration EudraCT, 2012–005617-39. Registered on 7 August 2013.

Aim The objective of this population pharmacokinetic (PK) analysis was to provide guidance for the dosing interval of daptomycin in patients undergoing continuous renal replacement therapy (CRRT). Methods A previously published population PK model for daptomycin was updated with data from patients undergoing continuous veno‐venous haemodialysis (CVVHD; n = 9) and continuous veno‐venous haemodiafiltration (CVVHDF; n = 8). Model‐based simulations were performed to compare the 24 h AUC, C max and C min of daptomycin following various dosing regimens (4, 6, 8, 10, and 12 mg kg−1 every [Q] 24 h and Q48 h), with the safety and efficacy exposure references for Staphylococcus aureus bacteraemia/right‐sided infective endocarditis. Results The previously developed daptomycin structural population PK model could reasonably describe data from the patients on CRRT. The clearance in patients undergoing CVVHDF and CVVHD was estimated at 0.53 and 0.94 l h−1, respectively, as compared with 0.75 l h−1 in patients with creatinine clearance (CrCl) ≥ 30 ml min−1. Daptomycin Q24 h dosing in patients undergoing CRRT resulted in optimal exposure for efficacy, with AUC comparable to that in patients with CrCl ≥ 30 ml min−1. In contrast, Q48 h dosing was associated with considerably lower AUC24–48h in all patients for doses up to 12 mg kg−1 and is therefore inappropriate. Conclusions Q24 h dosing of daptomycin up to 12 mg kg−1 provides comparable drug exposure in patients on CVVHD and in those with CrCl ≥ 30 ml min−1. Daily daptomycin use up to 8 mg kg−1 doses are appropriate for patients on CVVHDF, but higher doses may increase the risk of toxicity.

The CARdiorenal PEDIatric EMergency (CARPEDIEM) machine was originally designed to perform only continuous venovenous hemofiltration (CVVH) in neonatal and pediatric patients. In some cases, adequate convective clearance may not be reached because of a limited blood flow. In such conditions, the application of diffusive clearance [continuous venovenous hemodialysis (CVVHD)] would help optimize blood purification. In this study, the CARPEDIEM™ machine was modified to enable the circulation of dialysis through the filter allowing testing of the performance of CARPEDIEM™ machine in CVVHD.Three different polyethersulfone hemodialyzers (surface area = 0.1 m(2), 0.2 m(2), and 0.35 m(2), respectively) were tested in vitro with a scheduled combination of plasma flow rates (Qp = 10-20-30 ml/min) and dialysis fluid flow rate (Qd = 5-10-15 ml/min). Three sessions were performed in co-current and one in counter-current configuration (as control) for each filter size. Clearance was measured from the blood and dialysate sides and results with mass balance error greater than 5 % were discarded.Urea and creatinine clearances for each plasma/dialysate combination are reported: clearance increase progressively for every filter proportionally to plasma flow rates. Similarly, clearances increase progressively with dialysate flow rates at a given plasma flow. The clearance curve tends to present a steep increase for small increases in plasma flow in the range below 10 ml/min, while the curve tends to plateau for values averaging 30 ml/min. As expected, the plateau is reached earlier with the smaller filter showing the effect of membrane surface-area limitation. At every plasma flow, the effect of dialysate flow increase is evident and well defined, showing that saturation of effluent was not achieved completely in any of the experimental conditions explored. No differences (p 0.05 for all values) were obtained in experiments using whole blood instead of plasma or using co-current versus counter-current dialysate flow configuration.Although plasma flow and filter surface give an important contribution to the level of clearance urea and creatinine, it appears evident that dialysate flow plays an essential role in the blood purification process, justifying the use of CVVHD versus CVVH in case of high dialysis dose requirement and/or limited blood flow rate.

Saad Al Qahtani Intensive Care Department, Critical Care Response Team, King Abdulaziz Medical City (KAMC), National Guard Health Affairs; King Saud Bin Abdulaziz University for Health Sciences, College of Medicine, Riyadh, Kingdom of Saudi Arabia Abstract: Thrombotic thrombocytopenic purpura (TTP) is a rare, life-threatening disorder. This paper describes the case of a 39-year-old Sudanese male who presented to the emergency room with fever, jaundice, decreased level of consciousness, and worsening kidney function for 7 days, a high lactate dehydrogenase level (1947), severe thrombocytopenia (platelets 8), and numerous schistocytes in the peripheral blood smear. The patient was admitted with a diagnosis of TTP for plasma exchange. Fourteen days later, his creatinine kinase (CK) level rose to >50,000 IU; rhabdomyolysis was suggested. Continuous venovenous hemodialysis (CVVHD) was started. The patient's CK level remained high, despite CVVHD, until the 6th day, after which this parameter gradually started to decrease. This report highlights a resistant case of TTP that presented with concomitant severe rhabdomyolysis, which demanded aggressive, continuous intervention. Keywords: TTP, CVVHD, continuous venovenous hemodialysis

The acu-men;™ : A new device for continuous renal replacement therapy in acute renal failure. Background We sought to design a simple machine to safely provide continuous veno-venous hemofiltration to acute renal failure patients. Results The acu-men™ device uses a pneumatic blood pump with tidal blood flow as the driving force. A volumetric balancing system balances the filtrate with the replacement fluid, and the blood—air interface is eliminated by replacing the conventional venous drip chamber with two air-separating membranes. The extracorporeal circuit is integrated in a disposable cartridge, which is inserted into the machine at the beginning of treatment. The priming and rinsing is done automatically. Conclusion While preliminary data from an ongoing clinical trial on the efficacy of this device are encouraging, further longer-term studies are necessary to evaluate its potential to decrease morbidity and mortality in acute renal failure patients.

Some of ICU patients with Acute Renal Failure (ARF) require dialysis. Conventional or intermittent hemodialysis (HD) may cause hypotension and insufficient loss of fluids and toxins from blood. Peritoneal dialysis also my cause peritonitis and has lower efficiency than HD. We did continuous Venovenous Hemodialysis (CVVHD) for three ICU patients with ARF in Saint-Zahra Medical Center for the first time in our country. Method and Material: With a polysulfone membrane, blood pump, peritoneal dialysis solution, heparin, and a fix nurse, HD was done for 12-24 hours. Results: 1) Urea clearance was 18-50 ml/h. 2) Ultrafiltration was 160-1000 ml/h. 3) With dialysis, hemorrhage, coagulation disorder, and oxygenation recovered. 4) All of patients developed hyperglycemia and hypothermia. 5) All of patients died (two with septicemia and one with hypotension). Conclusion: In the absence of hemodialysis or peritoneal dialysis, CVVHD with present preliminary equipments is suitable and can excrete more toxins and fluids.

Die Citrate-CVVHD (kontinuierliche venovenöse Hämodialyse mit Citratantikoagulation) stellt heut zu Tage eine wichtige Therapiemaßnahme bei der Behandlung der akuten Nierenschädigung, insbesondere auf Intensivstationen, dar. Ziel der Studie war es, die Dialysebehandlung assoziierten nutritiven Verluste zu quantifizieren und einen Zusammenhang mit der Filterstandzeit und der Dialysedosis zu untersuchen. Die prospektive klinische Studie wurde auf einer operativen Intensivstation eines deutschen Universitätsklinikums durchgeführt. Dabei wurden 40 kritisch kranke Patienten mit Zustimmung und nach positivem Votum einer Ethikkommission in der Studie untersucht. Nach Diagnosestellung einer akuten Nierenschädigung und der Indikationsstellung einer Nierenersatztherapie wurden alle Patienten in einem Zeitraum von 11 Monaten (12/2009 bis 10/2010) in die Studie aufgenommen. Daraufhin wurde eine Citrate-CVVHD-Therapie mit der multifiltrate CiCa® der Firma Fresenius (Fresenius Medical Care AG & Co. KGaA, 61346 Bad Homburg, Deutschland) eingeleitet. Der erste Behandlungszyklus bei jedem Patienten wurde mit einer Dosierung von 100 ml/h mit 2000 ml/h Blut /Dialysatfluss durchgeführt, anschließend weitere Zyklen mit 80 ml/min mit 1500 ml/h und/oder 120 ml/min mit 2500 ml/h Blut-/Dialysatfluss. Die Zyklen von in der Regel 72 h Dauer wurden in Behandlungsintervalle à 24 h unterteilt und für jedes Behandlungsintervall eine repräsentative Dialysatprobe gemischt und eingefroren. Die gesammelten Proben wurden dann auf die entsprechenden Parameter laborchemisch untersucht. Parallel dazu wurden die Patientendaten, die Patientenkurven und die Dialyseprotokolle dokumentiert und anschließend ausgewertet. Die Analyse wurde in Zusammenschau aller Daten und Messergebnisse durchgeführt.

Titelblatt und Inhaltsverzeichnis Einleitung Material und Methoden Ergebnisse Diskussion Zusammenfassung Literaturverzeichnis, In dieser prospektiven Beobachtungsstudie wurden Filterlaufzeiten unter Heparin-, Zitrat- und Zitrat-Heparin-Antikoagulation sowie die Inzidenz metabolischer Entgleisungen während der Zitrat-Antikoagulation bei der kontinuierlichen veno-venösen Hämodialyse untersucht. In dieser Studie wurden 209 Patienten mit akutem Nierenversagen aufgenommen. Es wurden 33 Behandlungszyklen mit der Zitrat-Antikoagulation, 84 Behandlungszyklen mit der Zitrat-Heparin-Antikoagulation und 184 Behandlungszyklen mit der Heparin- Antikoagulation durchgeführt. Die Dialysatlösung für die regionale Zitrat- Antikoagulation wurde auf Sonderanforderung von der Universitätsapotheke erstellt. Diese Dialysatlösung war pufferfrei, enthielt kein Kalzium und wieß eine deutlich niedrigere Natriumkonzentration auf. Die Filterlaufzeit bei der Zitrat-Antikoagulation (80,27 ± 64,04 h) lag signifikant länger als unter Heparin-Antikoagulation (30,22  32,31 h) (p, In a prospective observational study was compared a regional citrate anticoagulation protocol versus a standard heparin anticoagulation protocol in critically ill patients on continuous venovenous hemodialysis. We mainly focused on acid-base and electrolyte derangements as well as on filter life. 209 patients were included in study. In 33 patients citrate was used as the only anticoagalant, in 84 patients citrate was used in combination with low- dose heparin, and in 184 patiens only heparin was used. A customized dialysate solution was used for citrate-anticoagulated continuous renal replacement therapy (no buffer, no calcium, reduced sodium concentration). Filter life was significant higher during citrate anticoagulation compared to heparin anticoagulation (80,27 64 vs. 30,2 32 h, p