Sustained low-efficiency dialysis (SLED) with prostacyclin in critically ill patients with acute renal failure.

Prostacyclin is an easy-to-use and safe antihaemostatic drug for continuous renal replacement therapies (RRTs). No study has been performed so far about its use in critically ill patients with acute renal failure (ARF) treated with sustained low-efficiency dialysis (SLED), a hybrid modality between conventional intermittent and continuous RRTs.



We studied 35 consecutive ICU patients with ARF, in whom data on safety and efficacy were prospectively collected in a single-centre experience over 15 months since August 2001. There were 25 males and 10 females; mean age, 72.1 (SD 11.4); mean APACHE II score at ICU admission, 24 (range 14-43); at RRT start, 27.4 (20-43); 28 patients (80%) were on mechanical ventilation and 17 (48.6%) had sepsis. SLED was performed using a conventional dialysis machine, with blood flow at 200 ml/min, bicarbonate-based ultrapure dialysate running at 100 ml/min, dialysate temperature 35 degrees C and low-flux polysulfone filters. Prostacyclin, under the form of its synthetic analogue epoprostenol, was infused at 6 ng/kg/min before the filter.



Out of 185 daily sessions performed (8-10 h, median 4 per patient, range 1-19), 19 (in 11 patients) were prematurely interrupted (10.3%; 95% CI: 5.4-18.6), after an average 58.5% of the prescribed treatment time (nine sessions in six patients for circuit clotting). This finding compared favourably with the experience we had at our unit using SLED with saline flushes. With the use of prostacyclin, two episodes of upper gastrointestinal bleeding were observed in 2/35 patients during SLED (5.7%; 95% CI: 0.7-19.2), corresponding to 1.1 episodes per 100 person-day on SLED. Therapeutic intervention for hypotension (fluids and/or vasopressor increase) was required in 45/185 (in 20 patients) of the sessions monitored (24.3%; 95% CI: 17.4-32.9); two sessions had to be interrupted because of refractory hypotension. Urea reduction ratio was 0.50 (SD 0.12); mean prescribed and obtained net ultrafiltration were 1.96 l (range 0.5-5.0) and 1.99 l (0.5-5.0), respectively. In-hospital mortality was 46%; mortality predicted by the APACHE II model at ICU admission was 42%; at SLED start, 51%.



Prostacyclin is a safe and effective antihaemostatic agent for SLED.

Related papers:

title: Extended daily dialysis: A new approach to renal replacement for acute renal failure in the intensive care unit.
abstract: Continuous venovenous hemofiltration (CVVH) is an effective form of renal replacement therapy for acute renal failure (ARF) that offers greater hemodynamic stability and better volume control than conventional hemodialysis in the critically ill, hypotensive patient. However, the application of CVVH in the intensive care unit (ICU) has several disadvantages, including intensive nursing requirements, continuous anticoagulation, patient immobility, and expense. We describe a new approach to the treatment of ARF in the ICU, which we have termed extended daily dialysis (EDD). In this study, EDD was compared with CVVH in 42 patients: 25 patients were treated with EDD for a total of 367 treatment days, and 17 patients were treated with CVVH for a total of 113 days. Median treatment time per day was 7.5 hours for EDD (range, 6 to 8 hours, 25th to 75th percentile) versus 19.5 hours for CVVH (range, 13.4 to 24 hours; P < 0.001). Mean arterial blood pressures (MAPs) did not differ significantly for patients treated with EDD when measured predialysis (median MAP, 70 versus 67 mm Hg for CVVH; P = 0.078), midway through daily treatment (70 versus 68 mm Hg for CVVH; P = 0.083), or at the end of treatment (71 versus 69 mm Hg for CVVH; P = 0.07). Net daily ultrafiltration was similar for the two treatment modalities (EDD, median, 3,000 mL/d; range, 1,763 to 4,445 mL/d; CVVH, 3,028 mL/d; range, 1,785 to 4,707 mL/d; P = 0.514). Anticoagulation requirements were significantly less for patients treated with EDD (median dose of heparin, 4,000 U/d; range, 0 to 5,800 U/d versus 21,100 U/d; range, 8,825 to 31,275 U/d for patients treated with CVVH; P < 0.001). We found that EDD eliminated the need for constant supervision of the dialysis machine by a subspecialty dialysis nurse, allowing one nurse to manage more than one treatment. Overall, EDD was well tolerated by the majority of patients, offered many of the same benefits provided by CVVH, and was technically easier to perform.

title: Sustained low-efficiency dialysis for critically ill patients requiring renal replacement therapy.
abstract: The replacement of renal function for critically ill patients is procedurally complex and expensive, and none of the available techniques have proven superiority in terms of benefit to patient mortality. In hemodynamically unstable or severely catabolic patients, however, the continuous therapies have practical and theoretical advantages when compared with conventional intermittent hemodialysis (IHD).



We present a single center experience accumulated over 18 months since July 1998 with a hybrid technique named sustained low-efficiency dialysis (SLED), in which standard IHD equipment was used with reduced dialysate and blood flow rates. Twelve-hour treatments were performed nocturnally, allowing unrestricted access to the patient for daytime procedures and tests.



One hundred forty-five SLED treatments were performed in 37 critically ill patients in whom IHD had failed or been withheld. The overall mean SLED treatment duration was 10.4 hours because 51 SLED treatments were prematurely discontinued. Of these discontinuations, 11 were for intractable hypotension, and the majority of the remainder was for extracorporeal blood circuit clotting. Hemodynamic stability was maintained during most SLED treatments, allowing the achievement of prescribed ultrafiltration goals in most cases with an overall mean shortfall of only 240 mL per treatment. Direct dialysis quantification in nine patients showed a mean delivered double-pool Kt/V of 1.36 per (completed) treatment. Mean phosphate removal was 1.5 g per treatment. Mild hypophosphatemia and/or hypokalemia requiring supplementation were observed in 25 treatments. Observed hospital mortality was 62.2%, which was not significantly different from the expected mortality as determined from the APACHE II illness severity scoring system.



SLED is a viable alternative to traditional continuous renal replacement therapies for critically ill patients in whom IHD has failed or been withheld, although prospective studies directly comparing two modalities are required to define the exact role for SLED in this setting.

title: Sustained low-efficiency daily diafiltration (SLEDD-f) for critically ill patients requiring renal replacement therapy: towards an adequate therapy.
abstract: Sustained low-efficiency daily dialysis (SLEDD) is an increasingly popular renal replacement therapy for intensive care unit (ICU) patients. SLEDD has been previously reported to provide good solute control and haemodynamic stability. However, continuous renal replacement therapy (CRRT) is considered superior by many ICU practitioners, due first to the large amounts of convective clearance achieved and second to the ability to deliver treatment independently of nephrology services. We report on a program of sustained low-efficiency daily diafiltration (SLEDD-f) delivered autonomously by ICU nursing personnel, and benchmark solute clearance data with recently published reports that have provided dose-outcome relationships for renal replacement therapy in this population.



SLEDD-f treatments were delivered using countercurrent dialysate flow at 200 ml/min and on-line haemofiltration at 100 ml/min for 8 h on a daily or at least alternate day basis. All aspects of SLEDD-f were managed by ICU nursing personnel. Clinical parameters, patient outcomes and solute levels were monitored. Kt/V, corrected equivalent renal urea clearance (EKRc) and theoretical Kt/V(B12) were calculated.



Fifty-six SLEDD-f treatments in 24 critically ill acute renal failure patients were studied. There were no episodes of intradialytic hypotension or other complications. Observed hospital mortality was 46%, not significantly different from the expected mortality as determined from the APACHE II illness severity scoring system. Electrolyte control was excellent. Kt/V per completed treatment was 1.43+/-0.28 (0.96-2.0). Kt/V(B12) per completed treatment was 1.02+/-0.21 (0.6-1.38). EKRc for patients was 35.7+/-6.4 ml/min (25.0-48.2).



SLEDD-f provides stable renal replacement therapy and good clinical outcomes. Logistic elements of SLEDD-f delivery by ICU nursing personnel are satisfactory. Small solute clearance is adequate by available standards for CRRT and intermittent haemodialysis, and larger solute clearance considerable. SLEDD-f is a viable alternative to CRRT in this setting.

title: Efficacy and cardiovascular tolerability of extended dialysis in critically ill patients: a randomized controlled study.
abstract: Extended dialysis is an increasingly used modality of renal replacement therapy that theoretically offers advantages of both intermittent and continuous therapies in the intensive care unit (ICU).



We randomly treated 39 ventilated critically ill patients with oliguric acute renal failure with either continuous venovenous hemofiltration (CVVH; n = 19; age, 50.1 +/- 3.2 years; Acute Physiology and Chronic Health Assessment II [APACHE II] score, 32.3 +/- 1.2; 79% sepsis) and a substitution fluid rate of at least 30 mL/kg/h for 24 hours or with extended dialysis for 12 hours (n = 20; age, 50.8 +/- 3.6 years; APACHE II score, 33.6 +/- 1.0; 85% sepsis). The latter was performed using an easy-to-handle, single-pass, batch dialysis system. All hemodynamic parameters were monitored invasively by means of an indwelling arterial catheter.



Average mean arterial blood pressure, heart rate, cardiac output, systemic vascular resistance, and catecholamine dose were not significantly different in both therapies. Urea reduction rate was similar with extended dialysis compared with CVVH therapy (53% +/- 2% versus 52% +/- 3%; P = not significant) despite an average rate of substitution fluid with the latter of 3.2 +/- 0.1 L/h. This was corroborated by the finding of similar amounts of urea eliminated in the collected spent total hemofiltration and dialysis fluid. Correction of acidosis was accomplished faster with extended dialysis than CVVH, and the amount of heparin used was significantly lower with extended dialysis (P < 0.01).



Extended dialysis combines excellent detoxification with cardiovascular tolerability, even in severely ill patients in the ICU. The technically simple dialysis system used offers flexibility of treatment time.

title: Sustained low-efficiency dialysis in the ICU: cost, anticoagulation, and solute removal.
abstract: Hemodialysis (HD) for critically ill patients with acute renal failure has been provided as intermittent hemodialysis (IHD) or continuous renal replacement therapy (CRRT). IHD is often complicated by hypotension and inadequate fluid removal, and CRRT by high cost of solutions and problems with anticoagulation. Sustained low-efficiency daily dialysis (SLED) has been suggested as an alternative treatment. This is an observational, prospective pilot study describing the introduction of SLED at our institution. We compared SLED (23 patients, 165 treatments) with CRRT (11 patients, 209 days), focusing on cost, anticoagulation, and small solute removal. SLED consisted of 8 h of HD 6 days a week, with blood flow of 200 ml/min, dialysate flows of 350 ml/min, and hemofiltration with 1 l of saline/h. CRRT patients were anticoagulated with either heparin or citrate, and SLED patients with either heparin or saline flushes. The weekly costs to the hospital were $1431 for SLED, $2607 for CRRT with heparin, and $3089 for CRRT with citrate. Sixty-five percent of SLED treatments were heparin-free; filter clotting occurred in 18% of heparin treatments and 29% of heparin-free treatments (NS). Weekly Kt/V was significantly higher for SLED (8.4+/-1.8) and time-averaged serum creatinine was lower; equivalent renal clearance (EKRjc) was 29+/-6 ml/min for SLED, similar to that for CRRT. In summary, SLED may be routinely performed without anticoagulation; it provides solute removal equivalent to CRRT at significantly lower cost.

title: Technology Insight: treatment of renal failure in the intensive care unit with extended dialysis
abstract: Sustained low-efficiency dialysis (SLED) is an increasingly popular extracorporeal renal replacement therapy for patients with renal failure in the intensive care unit (ICU). Several centers across the world employ this 'hybrid' technique, which has advantages of both intermittent and continuous methods. The goal of these centers is to provide an easy-to-perform treatment with reduced solute clearances for prolonged periods. Many centers use standard, sophisticated dialysis equipment for SLED. An increasing number of hospitals in Europe and South America employ a single-pass batch dialysis system, the procedural simplicity of which makes it an ideal modality for SLED in the ICU. All systems offer the advantages of flexible timing of treatment and reduced costs; their ease of handling means that SLED is readily accepted by ICU staff. Prospective controlled studies have shown that SLED clears small solutes with an efficacy comparable to that of intermittent hemodialysis and continuous venovenous hemofiltration (even when the latter employs high rates of fluid substitution). Cardiovascular tolerability associated with SLED is similar to that associated with continuous renal replacement therapy, even in severely ill patients. Nocturnal dialysis—a special form of SLED—has all the advantages outlined above, with the added benefit of unrestricted physician access to the patient during the day, minimizing the interference of renal replacement therapy with other ICU activities.

title: What is the renal replacement method of first choice for intensive care patients?
abstract: Renal replacement therapy for the patient with acute renal failure on the intensive care unit can be offered in several different formats: intermittent hemodialysis (IHD), continuous renal replacement therapy (CRRT), and slow low-efficient daily dialysis (SLEDD). It is frequently claimed that CRRT offers several advantages over IHD, but most of these, such as correction of metabolic acidosis, better recovery of renal function, better clinical outcome due to application of biocompatible dialysis membranes, correction of malnutrition, and better removal of cytokines, are not corroborated by the results of controlled prospective studies. There is also no evidence that CRRT results in a better survival, compared with IHD. The only potential advantages of CRRT that stood the test of clinical evaluation (hemodynamic stability, correction of hypervolemia, better solute removal) can be offered as well by SLEDD. In addition, the latter strategy is less expensive because the same infrastructure is used as for IHD, while the patient is not immobilized continuously, which leaves time free for other activities such as nursing care and technical investigations. SLEDD is a relatively young technique, so thorough clinical studies are lacking. Nevertheless, the hypothesis is proposed that SLEDD offers a valuable alternative to the classical dialysis strategies, applied in the intensive care patient.

title: Continuous is not continuous: the incidence and impact of circuit "down-time" on uraemic control during continuous veno-venous haemofiltration
abstract: ObjectiveThere is little information on the duration of time that patients spend off therapy (down-time) during continuous veno-venous haemofiltration (CVVH) and the effect of this treatment free time on azotaemic control.Design and settingProspective observational study in the ICU of tertiary hospital.Patients and participants48 critically ill patients treated with CVVH at 2 l/h of ultrafiltration.InterventionsProspective collection of demographic and biochemical data.Measurements and resultsTwo hundred and sixty-six filters were observed. Start and end times were collected for each filter. Creatinine and urea were measured daily and percentage of reduction of these two solutes was calculated (%Δ creatinine and urea). The median period when CVVH was not applied to a patient (down-time) was 3 h per day. There was a significant inverse correlation between down-time and %Δ creatinine and urea over each 24-h time cycle. On average at least 16 h per day of CVVH was required to maintain creatinine and urea concentration for each 24-h cycle.Conclusions"Continuous" therapy is not truly continuous. Down-time adversely affects azotaemic control. Physicians prescribing CRRT should be aware of the consequences of such down-time on the quality and quantity of renal replacement therapy delivered.

title: The first international consensus conference on continuous renal replacement therapy.
abstract: Management of acute renal failure (ARF) in the critically ill is extremely variable and there are no published standards for the provision of renal replacement therapy in this population. We sought to review the available evidence, make evidence-based practice recommendations, and delineate key questions for future study.



We undertook an evidence-based review of the literature on continuous renal replacement therapy (CRRT) using MEDLINE searches. We determined a list of key questions and convened a 2-day consensus conference to develop summary statements via a series of alternating breakout and plenary sessions. In these sessions, we identified supporting evidence and generated practice guidelines and/or directions for future research.



Of the 46 questions considered, we found consensus for 20. We found inadequate evidence for 21 questions and for the remaining five we found data but no consensus. Full versions of workgroup findings are available on the Internet at http://www.ADQI.net.



Despite limited data, broad areas of consensus exist for use of CRRT and guideline development appears feasible. Equally broad areas of disagreement also exist and additional basic and applied research in acute renal failure is needed.

title: Regional citrate anticoagulation during simulated treatments of sustained low efficiency diafiltration
abstract: Renal replacement therapy is frequently required for critically ill patients with a high risk of bleeding. Conventional heparinization strategies to prevent extracorporeal blood circuit clotting can cause significant haemorrhage in such patients because of systemic anticoagulation. Regional citrate anticoagulation (RCA) is a well‐established technique that minimizes this complication by the decalcification of blood in the extracorporeal circuit such that it is incapable of clotting. To date, there are no reports on the use of RCA for sustained low‐efficiency dialysis/diafiltration (SLED), a hybrid therapy that involves the use of conventional haemodialysis machinery to deliver lower solute clearances over prolonged periods of time. In preparation for clinical study, an in vitro simulation of SLED was devised (blood substitute flow 250 mL/min, dialysate flow 200 mL/min, predilution haemofiltration 100 mL/min). Blood substitute was decalcified by an infusion of 4% trisodium citrate (TSC) proximally into the extracorporeal blood circuit, with partial restoration of calcium homeostasis from dialysate containing ionized [Ca2+] at 0.9 mmol/L. This simulation was used to establish first the 4% TSC requirement for therapeutic decalcification, and second the associated changes in ionized [Ca2+] and [Mg2+] within the blood substitute from chelation with citrate and subsequent removal of the resulting divalent cation‐citrate complex. Serial measurements of blood substitute [Ca2+] from strategic points along the extracorporeal circuit showed therapeutic decalcification was not achieved with 4% TSC infusion rates up to 400 mL/h, and extrapolation of experimental results suggests that 450 mL/h will be required. Under these conditions, ionized [Ca2+] and [Mg2+] in the blood substitute venous return and would be 0.42 and 0.2 mmol/L, respectively, with 0.35 mmol of citrate being returned per minute via the blood substitute venous return. These results were modelled for various changes in SLED operating parameters, and discussed in detail. An appropriate regimen for 4% TSC infusion and divalent cation replacement is proposed for clinical study in the future.

title: A Simple, Safe and Effective Citrate Anticoagulation Protocol for the Genius® Dialysis System in Acute Renal Failure
abstract: The Genius® dialysis system is a close loop dialysis batch system increasingly used as an intermittent hemodialysis device in intensive care units. The aim of this study was to test the safety and feasibility of a regional citrate anticoagulation protocol with respect to acid-base and electrolyte disarrangements in critically ill patients with acute renal failure. A standard heparin anticoagulation protocol served as control.  In a cross-over study design, 27 acute renal failure patients were allocated to a citrate- and heparin-anticoagulated dialysis sessions (4–6 h). For citrate anticoagulation, a 4% sodium-citrate solution was infused into the arterial line of the extracorporeal circuit. A low calcium dialysate (1 mmol/l) was used for all dialysis sessions. Citrate dosing was adjusted according to the post-filter ionized calcium concentration (targeted values 0.5–0.7 mmol/l). There was no routine calcium substitution. Heparin anticoagulation was started with a heparin-loading dose followed by an individual, patient-adjusted continuous heparin infusion. Electrolyte disarrangements, namely hypernatremia, hypo- and hypercalcemia did not occur in either group. Although the highest bicarbonate levels were achieved during citrate anticoagulation (p = 0.021 versus heparin) the acid base values remained equilibrated in both groups. Filter longevity was excellent and the targeted dialysis time was achieved in all but 1 patient. Citrate anticoagulation was well tolerated with respect to cardiovascular hemodynamics.  Citrate anticoagulation can be safely and effectively performed during intermittent Genius® dialysis. Calcium supplementation is not routinely required.

title: Safety of Regional Citrate Anticoagulation for Continuous Sustained Low Efficiency Dialysis (C-SLED) in Critically Ill Patients
abstract: Sustained low efficiency dialysis (SLED) is a hybrid therapy that uses a conventional hemodialysis machine to deliver lower solute clearance over prolonged periods of time, typically 8 to 12 hours per treatment, and utilizes the same sodium and bicarbonate concentrations as intermittent hemodialysis. The therapy has been shown to be an effective dialysis mode for the critically ill patient with acute renal failure and hemodynamic instability. At our institution, critically ill patients requiring renal replacement therapy receive SLED on a continuous, 24-hour schedule (C-SLED). The higher dialysis dose with C-SLED compared to continuous venovenous hemodiafiltration (CVVHDF) or traditional SLED would likely alter the prescription needed to provide regional citrate anticoagulation and the incidence of hypernatremia and metabolic alkalosis.  To evaluate the safety of utilizing regional citrate anticoagulation with continuous SLED in critically ill patients who frequently clot the hemofilter and have contraindications to systemic anticoagulation with heparin. We hypothesized that the higher dialysis dose with C-SLED would affect the prescription of citrate anticoagulation and the development of hypernatremia and metabolic alkalosis.  We prospectively followed the first 20 patients who received regional citrate anticoagulation on C-SLED for acute renal failure in the intensive care unit. Important outcomes measured included serum sodium, bicarbonate, ionized calcium concentration, serum pH, and PCO2. The number of clotting episodes for each patient while on regional citrate anticoagulation was recorded.  Surgical and medical intensive care units at The University of Texas MD Anderson Cancer Center.  In over 2200 hours of continuous dialysis with citrate anticoagulation none of the 20 patients had derangements in the serum sodium or acid base status requiring cessation of regional citrate anticoagulation. In 14 patients, no clotting occurred during 1500 hours of SLED with the citrate infusion. There were eight episodes of hemofilter clotting in six patients during 750 hours of C-SLED.  Regional citrate anticoagulation is a safe method of anticoagulation in critically ill patients on continuous SLED.

title: Prostacyclin (PGI2): new aspects of an old substance in the treatment of critically ill patients
abstract: It is now 20 years since Moncada and Vane discovered prostaglandin I2 (PGI2)  and named it “prostacyclin”. Since then, interest in the theoretical background and clinical application of this natural agent has increased continuously. This review summarizes the pharmacological properties and endogenous role of PGI2. Furthermore, clinical applications (in particular of its analogue epoprostenol) are discussed, with special emphasis on the treatment of critically ill patients suffering from sepsis and/or pulmonary hypertension, either associated with the acute respiratory distress syndrome (ARDS) or of other origin (e. g., after cardiac surgery). In this context we also point out recent advances concerning the transbronchial delivery route as opposed to intravenous infusion and compare its effects to that of nitric oxide (NO) inhalation.

title: Continuous haemofiltration in acute renal failure with prostacyclin as the sole anti-haemostatic agent
abstract: To investigate the safety and efficacy of a synthetic prostacyclin analogue (epoprostenol) for circuit maintenance during continuous veno-venous haemofiltration (CVVH) in patients with acute renal failure (ARF).  Observational case study.  University-affiliated six-bed intermediate renal care unit in a nephrology and internal medicine department of a 1300-bed teaching hospital.  A consecutive series of critically ill ARF patients in whom prostacyclin was the sole anti-haemostatic agent used for CVVH.  Bicarbonate-based CVVH in pre-dilution (1.5 l/h); blood flow rate at 200 ml/min; prostacyclin at 4 ng/kg per min infusion in the extracorporeal circuit before the haemofilter.  Fifty-one ARF patients (mean APACHE II 27.2, SD 7.8; acute tubular necrosis in 44/51, 83%; mechanical ventilation 14/51, 21%; in-hospital mortality 28/51, 54%) underwent CVVH for a total of 4040 h (230 circuits, median number 4 circuits per patient, range 1–13). Four patients out of 51 (7.8%) experienced major bleeding during CVVH (1.0 episode per 1000 patient-hours of treatment; 95%CI, 0.4–2.6); no death could be attributed to haemorrhage. Therapeutic intervention for hypotension (fluids and/or vasopressors) was required in 15.5% of the CVVH sessions monitored. The median duration of the circuit was 15.0 h (95% CI, 13.0–16.5).  The use of prostacyclin as the sole anti-haemostatic agent for CVVH entails a low risk of haemorrhagic complications, while maintaining the patency of the circuit long enough to allow the delivery of an adequate dose of renal replacement therapy. Further studies are needed to compare this technique to other anti-haemostatic strategies for CVVH.

title: Anticoagulation for continuous arteriovenous hemofiltration in children.
abstract: Continuous arteriovenous hemofiltration requires continuous anticoagulation to prevent early hemofilter clotting. We used heparin given continuously in the arterial line of the extracorporeal circuit as anticoagulant in children with initially normal coagulation status, and heparin and/or prostacyclin in high-risk bleeding patients with preexisting coagulopathy. Heparin infusion enabled a mean running time of 22.2 +/- 9.6 h, with the 0.1-m2 hemofilter and of 26.6 +/- 4.7 h with the 0.25-m2 hemofilter. The mean filter running time with combined heparin/prostacyclin infusion was 31 +/- 8.8 h. Prostacyclin as the sole antithrombotic agent provided good filter function only in 1 patient with preexisting coagulopathy. No adverse effects such as bleeding thrombosis, or hypotension were observed.

title: Anticoagulation with prostacyclin and heparin during continuous venovenous hemofiltration
abstract: To investigate anticoagulation with prostacyclin (prostaglandin I2 [PGI2]) and/or heparin during continuous venovenous hemofiltration, and the role of in vitro tests of primary hemostasis in controlling anticoagulation.  Prospective, randomized, controlled trial.  Intensive care unit.  Forty‐six consecutive, critically ill, mechanically ventilated patients with postoperative acute renal failure.  Anticoagulation of the patient's blood was accomplished using heparin (6.0 ± 0.3 IU/kg/hr for group 1), PGI2 (7.7 ± 0.7 ng/kg/min for group 2), or both PGI2 and heparin (6.4 ± 0.3 ng/kg/min, 5.0 ± 0.4 IU/kg/hr, respectively, for group 3), administered into the extracorporeal line before the hemofilter during continuous venovenous hemofiltration.  After Ethics Committee approval and informed consent were obtained, tests of primary and secondary hemostasis, plasma concentrations of 6‐ketoprostaglandin F1&agr; (by radioimmunoassay), and hemodynamic measurements were performed before hemofiltration and 24 hrs after hemofiltration. In groups 1 and 3, hemodynamic parameters remained stable, whereas in group 2 (the PGI2 group), there were significant reductions in systemic and pulmonary vascular resistances and mean arterial pressure. Platelet function was unchanged in group 1, and was inhibited in groups 2 and 3. Corresponding with the prolongation of in vitro bleeding time, the 6‐ketoprostaglandin F1&agr; concentration was increased, indicating an effective inhibition of platelet aggregation within the hemofilter. Platelet counts remained stable in all patients. Plasma coagulation tests were stable in groups 2 and 3, and were prolonged in group 1. In all patients, no major bleeding complications were observed and there was no clinically important bleeding. Mean hemofilter duration lasted longest in group 3. Blood urea nitrogen and circulating creatinine concentrations decreased significantly in groups 2 and 3 within the study period.  Patients receiving both PGI2 and heparin showed better hemodynamic profiles and enhanced hemofilter duration compared with the other groups and no bleeding complications were observed. Therefore, we recommend anticoagulation with PGI2 and heparin during continuous venovenous hemofiltration with close monitoring of platelet function, coagulation profile, and overall hemodynamics.

title: Anticoagulation with prostaglandins and unfractionated heparin during continuous venovenous haemofiltration: a randomized controlled trial.
abstract: The objective of this prospective, randomized, controlled clinical study was to compare efficacy, safety, and costs of fixed-dose prostaglandins with adjusted-dose unfractionated heparin as anticoagulants for continuous venovenous haemofiltration.



Perioperative critically ill patients requiring continuous haemofiltration for acute renal failure received unfractionated heparin anticoagulation titrated to achieve an activated clotting time in the extracorporeal system of > 120 s. Patients were randomly assigned to receive a test infusion containing either prostaglandin I2 (5 ng/kg/min; group I; n = 15; 75 filters), prostaglandin E1 (5 ng/kg/min; group E; n = 18; 72 filters), or placebo (group H; n = 17; 63 filters). Heparin and test solutions were infused into the extracorporeal circuit before the haemofilter. All AN69-surface hollow fiber filters were primed with normal saline containing 5.000 IU heparin.



The primary outcome measure--adequate haemofilter life span > 24 h--was compared by using Cochran's Q test. There was a significant difference in the frequencies of adequate haemofilter life span between the groups (36% group H, 65% group I, 59% group E; P < 0.05 versus group H). There were 6 bleeding episodes in group H, 2 in group E, and only 1 trivial bleeding episode in group I (P < 0.05 versus group H). Daily costs of haemofiltration were 61% higher in group I and 23% higher in group E than in group H (P < 0.05 versus group H). A heparin-sparing effect of prostaglandins was observed.



Fixed-dose prostaglandins I2 and E1 reduced the incidence of haemofilter failure and bleeding when compared with adjusted-dose unfractionated heparin. There was no significant difference between the two prostaglandin groups. The increase in daily costs for haemofiltration treatment under prostaglandins is not clinically relevant.

title: Prevalence and clinical outcome associated with preexisting malnutrition in acute renal failure: a prospective cohort study.
abstract: Malnutrition is a frequent finding in hospitalized patients and is associated with an increased risk of subsequent in-hospital morbidity and mortality. Both prevalence and prognostic relevance of preexisting malnutrition in patients referred to nephrology wards for acute renal failure (ARF) are still unknown. This study tests the hypothesis that malnutrition is frequent in such clinical setting, and is associated with excess in-hospital morbidity and mortality. A prospective cohort of 309 patients admitted to a renal intermediate care unit during a 42-mo period with ARF diagnosis was studied. Patients with malnutrition were identified at admission by the Subjective Global Assessment of nutritional status method (SGA); nutritional status was also evaluated by anthropometric, biochemical, and immunologic parameters. Outcome measures included in-hospital mortality and morbidity, and use of health care resources. In-hospital mortality was 39% (120 of 309); renal replacement therapies (hemodialysis or continuous hemofiltration) were performed in 67% of patients (206 of 309); APACHE II score was 23.1+/-8.2 (range, 10 to 52). Severe malnutrition by SGA was found in 42% of patients with ARF; anthropometric, biochemical, and immunologic nutritional indexes were significantly reduced in this group compared with patients with normal nutritional status. Severely malnourished patients, as compared to patients with normal nutritional status, had significantly increased morbidity for sepsis (odds ratio [OR] 2.88; 95% confidence interval [CI], 1.53 to 5.42, P < 0.001), septic shock (OR 4.05; 95% CI, 1.46 to 11.28, P < 0.01), hemorrhage (OR 2.98; 95% CI, 1.45 to 6.13, P < 0.01), intestinal occlusion (OR 5.57; 95% CI, 1.57 to 19.74, P < 0.01), cardiac dysrhythmia (OR 2.29; 95% CI, 1.36 to 3.85, P < 0.01), cardiogenic shock (OR 4.39; 95% CI, 1.83 to 10.55, P < .001), and acute respiratory failure with mechanical ventilation need (OR 3.35; 95% CI, 3.35 to 8.74, P < 0.05). Hospital length of stay was significantly increased (P < 0.01), and the presence of severe malnutrition was associated with a significant increase of in-hospital mortality (OR 7.21; 95% CI, 4.08 to 12.73, P < 0.001). Preexisting malnutrition was a statistically significant, independent predictor of in-hospital mortality at multivariable logistic regression analysis both with comorbidities (OR 2.02; 95% CI, 1.50 to 2.71, P < 0.001), and with comorbidities and complications (OR 2.12; 95% CI, 1.61 to 2.89, P < 0.001). Malnutrition is highly prevalent among ARF patients and increases the likelihood of in-hospital death, complications, and use of health care resources.

title: Predicting patient outcome from acute renal failure comparing three general severity of illness scoring systems.
abstract: A major problem of studies on acute renal failure (ARF) arises from a lack of prognostic tools able to express the medical complexity of the syndrome adequately and to predict patient outcome accurately. Our study was thus aimed at evaluating the predictive ability of three general prognostic models [version II of the Acute Physiology and Chronic Health Evaluation (APACHE II), version II of the Simplified Acute Physiology Score (SAPS II), and version II of the Mortality Probability Model at 24 hours (MPM24 II)] in a prospective, single-center cohort of patients with ARF in an intermediate nephrology care unit.



Four hundred twenty-five patients consecutively admitted for ARF to the Nephrology and Internal Medicine Department over a five-year period were studied (272 males and 153 females, median age 71 years, interquartile range 61 to 78, median APACHE II score 23, interquartile range 18 to 28). Acute tubular necrosis (ATN) accounted for 68.7% (292 out of 425) of patients. Renal replacement therapies (hemodialysis or continuous hemofiltration) were used in 64% (272 out of 425) of ARF patients.



Observed mortality was 39.1% (166 out of 425). The mean predicted mortality was 36.2% with APACHE II (P = 0.571 vs. observed mortality), 39.3% with SAPS II (P = 0.232), and 45.1% with MPM24 II (P < 0.0001). Lemeshow-Hosmer goodness-of-fit C and H statistics were 15.67 (P = 0.047) and 12.05 (P = 0.15) with APACHE II, 32.53 (P = 0.0001), 39.8 (P = 0.0001) with SAPS II, 21.86 (P = 0.005), and 20. 24 (P = 0.009) with MPM24 II, respectively. Areas under the receiver operating characteristic (ROC) curve were 0.75, 0.77, and 0.85, respectively.



The APACHE II model was a slightly better calibrated predictor of group outcome in ARF patients, as compared with the SAPS II and MPM24 II outcome prediction models. The MPM24 II model showed the best discrimination capacity, in comparison with both APACHE II and SAPS II models, but it constantly and significantly overestimated mean predicted mortality in ARF patients. None of the models provided sufficient confidence for the prediction of outcome in individual patients. A high degree of caution must be exerted in the application of existing general prognostic models for outcome prediction in ARF patients.

title: Incidence, risk factors, and prognosis of gastrointestinal hemorrhage complicating acute renal failure.
abstract: Few prospective data are currently available on acute gastrointestinal hemorrhage (AGIH) as a complication of acute renal failure (ARF). The aim of the present study was to define incidence, sources, risk factors, and outcome of AGIH in patients with ARF.



We performed a prospective study on an inception cohort of 514 patients admitted for ARF to a nephrology intermediate care unit. Data on clinical risk factors for bleeding, frequency of occurrence of AGIH, length of hospital stay, and in-hospital mortality were collected. Independent predictors of AGIH were identified. The relative odds of death and the relative increase in length of hospital stay associated with AGIH were calculated after adjusting for baseline comorbidities.



Sixty-nine patients out of 514 [13.4% (95% CI, 10.6 to 16.7)] had AGIH as a complication of ARF; 59 were upper AGIH. Forty patients had clinically important bleeding. Erosions and/or ulcers accounted for 71% of cases of upper AGIH. Independent baseline predictors of AGIH were represented by severity of illness [odds ratio 1.45 (95% CI, 1.05 to 2.01) for every 10 point increase in APACHE II score], low platelet count [<50,000 mm3; 3.71 (1.70 to 8.11)], noncirrhotic chronic hepatic disease [2.22 (1.09 to 4.55)], liver cirrhosis [3.38 (1.50 to 7.60)], de novo ARF [2.77 (1.30 to 5.90)], and severe ARF [2.07 (1.10 to 3.88)]. In-hospital mortality was 63.8% in patients with AGIH and 34.2% in the other patients; after adjusting for baseline confounders, AGIH remained significantly associated with an increase in both mortality [2.57 (1.30 to 5.09), P = 0.006] and length of hospital stay [37% (1 to 87%), P = 0.047].



AGIH and clinically important bleeding are frequent complications of ARF. In this clinical condition, AGIH is more often due to upper gastrointestinal bleeding and is associated with a significantly increased risk of death and length of hospital stay. Both renal and extrarenal risk factors are related to the occurrence of AGIH.

title: APACHE II: a severity of disease classification system.
abstract: This paper presents the form and validation results of APACHE II, a severity of disease classification system. APACHE II uses a point score based upon initial values of 12 routine physiologic measurements, age, and previous health status to provide a general measure of severity of disease.

title: Prognosis of patients with acute renal failure requiring dialysis: results of a multicenter study.
abstract: Despite several decades of clinical experience, the mortality rate for patients with acute renal failure (ARF) requiring dialysis remains high, and the evaluation of the patients prognosis has been difficult. To date, the Acute Physiology and Chronic Health Evaluation II (APACHE II) scoring system has been used more frequently for prediction in studies of ARF than any other scoring system, but has not been prospectively validated in controlled multicenter studies of this entity. In a multicenter, prospective, controlled trial evaluating the use of biocompatible hemodialysis membranes (BCMs) in patients with ARF, we evaluated the extent to which the APACHE II scoring system, based on the physiological variables in the 24 hours before the onset of dialysis and the presence or absence of oliguria, is predictive of outcome. Analysis of survival and recovery of renal function for the 153 patients treated in this study show that APACHE II scores are predictive both of survival and recovery of renal function, whether analyzed separately by type of dialysis membrane used (BCM or bioincompatible [BICM]) or for both groups combined (all P < 0.01). There was no evidence of a significant center effect or interaction of APACHE II score with dialysis membrane in our study. After adjusting for the APACHE II score, there was a positive effect of the BCM on both probability of survival (P < 0.05) and recovery of renal function (P < 0.01). In patients dialyzed with BCMs, oliguria at onset of dialysis had an adverse effect on both survival and recovery of renal function (both P < 0.01). Receiver operator curves (ROCs) using APACHE II score and the use of BCMs in nonoliguric patients yielded a statistically significant improvement versus the use of APACHE II score alone in the area under the curve (AUC) for survival (0.747 to 0.801; P < 0.05) and recovery of renal function (0.712 to 0.775; P < 0.05). We conclude that the use of the APACHE II score determined at the time of initiation of dialysis for patients with ARF is a statistically significant predictor of patient survival and recovery of renal function. The use of the APACHE II score measured at the time of dialysis initiation, especially when modified by the presence or absence of oliguria, should help in predicting outcome when evaluating interventions for patients with ARF.

title: Urea kinetics during sustained low-efficiency dialysis in critically ill patients requiring renal replacement therapy.
abstract: Continuous renal replacement therapies have practical and theoretical advantages compared with conventional intermittent hemodialysis in hemodynamically unstable or severely catabolic patients with acute renal failure (ARF). Sustained low-efficiency dialysis (SLED) is a hybrid modality introduced July 1998 at the University of Arkansas for Medical Sciences that involves the application of a conventional hemodialysis machine with reduced dialysate and blood flow rates for 12-hour nocturnal treatments. Nine critically ill patients with ARF were studied during a single SLED treatment to determine delivered dialysis dose and the most appropriate model for the description of urea kinetics during treatment. Five patients were men, mean Acute Physiology and Chronic Health Evaluation (APACHE) II score was 28.9 and mean weight was 92.5 kg. Kt/V was determined by the reference method of direct dialysate quantification (DDQ) combined with an equilibrated postdialysis plasma water urea nitrogen (PUN) concentration and four other methods that were either blood or dialysate based, single or double pool, or model independent (whole-body kinetic method). Solute removal indices (SRIs) were determined from net urea removal and urea distribution volume supplied from DDQ (reference method) and by mass balance using variables supplied from blood-based formal variable-volume single-pool (VVSP) urea kinetic modeling. Equivalent renal urea clearances (EKRs) were calculated from urea generation rates and time-averaged concentrations for PUN based on weekly mass balance with kinetic variables supplied by either DDQ (reference method) or formal blood-based VVSP modeling. Mean Kt/V determined by the reference method was 1.40 and not significantly different when determined by formal VVSP modeling, DDQ using an immediate postdialysis PUN, or the whole-body kinetic method. Correction of single-pool Kt/V by a Daugirdas rate equation did not yield plausible results. Mean SRI and EKR by the reference methods were 0.61 and 24.8 mL/min, respectively, and not significantly different when determined by blood-based methods. A single-pool urea kinetic model adequately described intradialytic PUN profiles, indicating that SLED was associated with minimal urea disequilibrium. This was supported by the parity between hemodialyzer and whole-body urea clearances, and the mean postdialytic urea rebound of 4.1% (P = 0.13 versus zero). Additional prospective studies are needed in this setting to define the optimal method for dialysis quantification, targets for azotemic control, and optimal modality of renal replacement therapy. In conclusion, SLED delivers a high dose of dialysis with minimal associated urea disequilibrium and can be quantified by Kt/V, SRI, and EKR from blood-based methods using single-pool urea kinetic models.

title: Regression standard errors in clustered samples
abstract: We first sort the residuals and locate the observation in the residuals corresponding to the quantile in question, taking into account weights if they are applied. We then calculate wn, the square root of the sum of the weights. Unweighted data is equivalent to weighted data where each observation has weight 1, resulting in wn p n. For analytically weighted data, the weights are rescaled so that the sum of the weights is the sum of the observations, resulting in p n again. For frequency weighted data, wn literally is the square of the sum of the weights.

title: Comparison of the use of standard heparin and prostacyclin anticoagulation in spontaneous and pump-driven extracorporeal circuits in patients with combined acute renal and hepatic failure.
abstract: Although prostacyclin has been reported to be an effective extracorporeal anticoagulant for intermittent haemofiltration and dialysis treatments, it has been suggested that it is inferior to heparin in preventing clotting in spontaneously driven continuous haemofiltration and/or dialysis circuits. We studied the effectiveness of both heparin and prostacyclin as anticoagulants in a variety of extracorporeal circuits in 17 patients with combined acute hepatic and renal failure who were at risk of haemorrhage. Although there were no differences in the pump-assisted extracorporeal circuits, prostacyclin was found superior to heparin during spontaneously driven continuous arteriovenous haemofiltration and/or dialysis. During some 2,600 h of prostacyclin therapy, there were only 3 episodes of haemorrhage that required blood transfusion compared to 8 major haemorrhages and 2 deaths from intracerebral haemorrhage during 600 h of anticoagulation with heparin. The median filter life was greater with prostacyclin, 60 h (42-72), compared to heparin, 8 h (4-16), p < 0.01. This study suggests that prostacyclin is superior to heparin in maintaining the integrity of a spontaneous arteriovenous extracorporeal circuit in patients at risk of major haemorrhage.

title: Anticoagulation in patients treated by continuous venovenous hemofiltration: a retrospective study.
abstract: The most adequate anticoagulation regimen during extracorporeal renal replacement therapy can be difficult to define. Two hundred fifty-five critically ill patients with a mean age (+/- SD) of 58.2 +/- 16.3 years were treated by continuous venovenous hemofiltration (CVVH) between 1986 and 1992 in our intensive care units. Blood was circulated through hemofilters, either polyacrylonitrile (AN 69; Hospal, Lyon, France) or polyamide (FH 66; Gambro, Lund, Sweden), using a roller pump and an air safety system. The patients were classified into three subgroups according to the amount of heparin needed to achieve an adequate anticoagulation (ie, prevention of extracorporeal circuit clotting without inducing a patient's bleeding tendency): group 1, 37 patients who received no heparin (14.5%); group 2, 189 patients who received 100 to 700 IU/hr of heparin (74.1%); and group 3: 29 patients who received more than 700 IU/hr of heparin (11.4%). We analyzed the filter survival, the routine coagulation parameters, and the evolution of the patients for each group. Median duration of treatment was 144 hours (range, 4 to 1,152 hours). There were no differences in requirement of heparin among the two types of membrane: AN 69 (mean +/- SD), 393 +/- 106 IU/hr v FH 66, 374 +/- 35.3 IU/hr (range, 0 to 2,000 IU/hr). There were no relationships between the amount of heparin the patients received and the mean survival of the filters (group 1, 22.1 +/- 14.8 hr; group 2, 24.7 +/- 13.2 hr; group 3, 23 +/- 9.6 hr).(ABSTRACT TRUNCATED AT 250 WORDS)

title: Heparin use in continuous renal replacement procedures: the struggle between filter coagulation and patient hemorrhage.
abstract: Heparin is the most widely used anticoagulant in continuous renal replacement procedures but little is known about the balance between filter coagulation and patient hemorrhage during treatment. Filter survival and hemorrhagic complications during 240 filter periods in 78 critically ill patients, treated with continuous arteriovenous hemofiltration and hemodiafiltration, were studied for this article. The crude incidence of filter coagulation was 17.7 +/- 2.5 (mean +/- SE) per 1000 h at an activated partial thromboplastin time (APTT) of 15 to 35 s, as determined in systemic blood samples. The incidence of filter coagulation gradually decreased to 9.0 +/- 2.7 per 1000 h at an APTT of 45 to 55 s (P = 0.031). The crude incidence of patient hemorrhage was 2.9 +/- 1.0 per 1000 h at an APTT of 15 to 35 s and increased almost threefold to 7.4 +/- 2.4 per 1000 h when the APTT was 45 to 55 s (P = 0.009). There was no difference in filter survival between treatment with hemofiltration only and hemodiafiltration. Mean survival of acrylonitrile filters (33.8 +/- 4.3) was significantly lower compared with the survival of polyamide filters (104.1 +/- 14.4 h, P = 0.003). After adjustment for the type of the filter, mean arterial blood pressure, and platelet count, the risk for filter coagulation decreased 25% (relative risk, 0.77; 95% confidence interval [CI], 0.62 to 0.96) for every 10-s increase in APTT. At the same time, the risk for patient hemorrhage increased 50% (relative risk, 1.57; 95% CI, 1.43 to 1.72). The occurrence of filter coagulation or hemorrhages were not correlated with the administered dose of heparin. Concurrent use of coumarin derivatives had a positive effect on filter survival, without increasing the overall incidence of hemorrhages. It was concluded that the systemic APTT is a good predictor of the risk for filter coagulation and patient hemorrhage. Safety and efficacy of heparin therapy seems optimal at an APTT between 35 and 45 s.

title: Extracorporeal management of acute renal failure patients at high risk of bleeding.
abstract: The incidence of systemic bleeding events and extracorporeal clotting was studied in 57 critically ill acute renal failure patients treated with intermittent hemodialysis (IHD) and/or continuous arteriovenous hemodialysis (CAVHD), using heparin (Hep), saline-flush (Sal, no anticoagulant), and citrate (Cit) anticoagulation protocols. Thirty-seven patients received a single dialysis modality, and 20 changed modalities one or more times, each change of dialysis type (IHD or CAVHD) or anticoagulant protocol being considered as a new course of treatment. The study was non-randomized, with a demonstrable bias towards using Hep for patients at lower risk of bleeding, and Sal or Cit for higher risk patients. Despite this bias, new bleeding events occurred during 26% of 35 courses of HepIHD and HepCAVHD, and during 0% of 24 courses of CitIHD and CitCAVHD (P < 0.009). Troublesome dialyzer/filter clotting occurred during one course of HepCAVHD, and during 12% of 129 SalIHD procedures; 28% of 29 courses of SalIHD were terminated for this reason. CitCAVHD was well tolerated and proved superior to other modalities in freedom from bleeding events and clotting problems. Alternatives to heparin anticoagulation should be made available for high risk patients requiring acute extracorporeal therapy.

title: Hemodynamic tolerance of intermittent hemodialysis in critically ill patients: usefulness of practice guidelines.
abstract: Poor hemodynamic tolerance of intermittent hemodialysis (IHD) is a common problem for patients in an intensive care unit (ICU). New dialysis strategies have been adapted to chronic hemodialysis patients with cardiovascular insufficiency. To improve hemodynamic tolerance of IHD, specific guidelines were progressively implemented into practice through the year 1996 in our 26-bed medical ICU. To evaluate the efficiency of these guidelines we retrospectively compared all IHD performed during the years before (1995) and after (1997) implementation of these recommendations. Forty-five patients underwent 248 IHD sessions in 1995 and 76 patients underwent 289 IHD sessions in 1997. The two populations were similar for age, sex, chronic hemodialysis (26% versus 17%), and secondary acute renal failure. In 1997, patients were more severely ill with a higher SAPS II (50 +/- 17 versus 59 +/- 24; p = 0.036), and more patients required epinephrine or norepinephrine infusion before dialysis sessions (16% versus 34%; p < 0.0001). The compliance to guidelines was high, inducing a significant change in IHD modalities. As a result, hemodynamic tolerance was significantly better in 1997, with less systolic blood pressure drop at onset (33% versus 21%, p = 0. 002) and during the sessions (68% versus 56%, p = 0.002). IHD with hypotensive episode or need for therapeutic interventions were less frequent in 1997 (71% versus 61%, p = 0.015). The ICU mortality was similar (53.3% in 1995 versus 47.3% in 1997; p = 0.52) but death rate in 1997, but not in 1995, was significantly less than predicted from SAPS II (47.3% versus 65.6%; p = 0.02). Length of ICU stay was also reduced for survivors in 1997 (p = 0.04). Implementation of practice guidelines for intermittent hemodialysis in ICU patients lessens hemodynamic instability and may improve outcome.

title: Anticoagulation strategies in continuous renal replacement therapy: can the choice be evidence based?
abstract: ObjectivesCritical illness increases the tendency to both coagulation and bleeding, complicating anticoagulation for continuous renal replacement therapy (CRRT). We analyzed strategies for anticoagulation in CRRT concerning implementation, efficacy and safety to provide evidence-based recommendations for clinical practice.MethodsWe carried out a systematic review of the literature published before June 2005. Studies were rated at five levels to create recommendation grades from A to E, A being the highest. Grades are labeled with minus if the study design was limited by size or comparability of groups. Data extracted were those on implementation, efficacy (circuit survival), safety (bleeding) and monitoring of anticoagulation.ResultsDue to the quality of the studies recommendation grades are low. If bleeding risk is not increased, unfractionated heparin (activated partial thromboplastin time, APTT, 1–1.4 times normal) or low molecular weight heparin (anti-Xa 0.25–0.35 IU/l) are recommended (grade E). If facilities are adequate, regional anticoagulation with citrate may be preferred (grade C). If bleeding risk is increased, anticoagulation with citrate is recommended (grade D−). CRRT without anticoagulation can be considered when coagulopathy is present (grade D−). If clotting tendency is increased predilution or the addition of prostaglandins to heparin may be helpful (grade C−).ConclusionAnticoagulation for CRRT must be tailored to patient characteristics and local facilities. The implementation of regional anticoagulation with citrate is worthwhile to reduce bleeding risk. Future trials should be randomized and should have sufficient power and well defined endpoints to compensate for the complexity of critical illness-related pro- and anticoagulant forces. An international consensus to define clinical endpoints is advocated.