Citrate anticoagulation for continuous venovenous hemoltration*

Heleen M. Oudemans-van Straaten, MD, PhD; Rob J. Bosman, MD; Matty Koopmans, RN; Peter H. J. van der Voort, MD, PhD, MSc; Jos P. J. Wester, MD, PhD; Johan I. van der Spoel, MD; Lea M. Dijksman, MSc; Durk F. Zandstra, MD, PhD
Objective: Continuous venovenous hemoltration (CVVH) is applied in critically ill patients with acute renal failure for renal replacement. Heparins used to prevent circuit clotting may cause bleeding. Regional anticoagulation with citrate reduces bleeding, but has metabolic risks. The aim was to compare the safety and efcacy of the two. Design: Randomized, nonblinded, controlled single-center trial. Setting: General intensive care unit of a teaching hospital. Patients: Adult critically ill patients needing CVVH for acute renal failure and without an increased bleeding risk. Interventions: Regional anticoagulation with citrate or systemic anticoagulation with the low-molecular weight heparin nadroparin. Measurements and Main Results: End points were adverse events necessitating discontinuation of study anticoagulant, transfusion, metabolic and clinical outcomes, and circuit survival. Of the 215 randomized patients, 200 received CVVH per protocol (97 citrate and 103 nadroparin). Adverse events required discontinuation of citrate in two patients (accumulation and clotting) of nadroparin in 20 (bleeding and thrombocytopenia) (p < 0.001). Bleeding occurred in 6 vs. 16 patients (p 0.08). The median number of red blood cell units transfused per CVVH day was 0.27 (interquartile range, 0.0 0.63) for citrate, 0.36 (interquartile range, 0 0.83) for nadroparin (p 0.31). Citrate conferred less metabolic alkalosis (p 0.001) and lower plasma calcium (p < 0.001). Circuit survival was similar. Threemonth mortality on intention-to-treat was 48% (citrate) and 63% (nadroparin) (p 0.03), per protocol 45% and 62% (p 0.02). Citrate reduced mortality in surgical patients (p 0.007), sepsis (p 0.01), higher Sepsis-Related Organ Failure Assessment score (p 0.006), and lower age (p 0.009). Conclusions: The efcacy of citrate and nadroparin anticoagulation for CVVH was similar, however, citrate was safer. Unexpectedly, citrate reduced mortality. Less bleeding could only partly explain this benet, less clotting could not. Post hoc citrate appeared particularly benecial after surgery, in sepsis and severe multiple organ failure, suggesting interference with inammation. (Crit Care Med 2009; 37:545552) KEY WORDS: citrate; hemoltration; acute renal failure; heparin; nadroparin; anticoagulation; sepsis

cute renal failure (ARF) in critically ill patients represents a strong and an independent risk for mortality (1). Prognosis is especially poor if renal replacement therapy (RRT) is required. Strategies of RRT may inuence outcome. Among these is RRT dose (2, 3). Anticoagulation is required to prevent clotting in extracorporeal circuits. Heparins are the classic choice. Their main drawback is bleeding because of systemic anticoagulation (4). Citrate is an attractive alternative (5). Citrate chelates calcium decreasing ionized calcium in the circuit. Because calcium is a cofactor in the coagula-

*See also p. 764. From the Department of Intensive Care Medicine (HMO-VS, RJB, MK, PHJVDV, JPJW, JIVDS, DFZ); and Teaching Hospital (LMD), Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands. The authors have not disclosed any potential conicts of interest. For information regarding this article, E-mail: h.m.oudemans-vanstraaten@olvg.nl Copyright 2009 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins DOI: 10.1097/CCM.0b013e3181953c5e

tion cascade, thrombin generation is inhibited. Citrate and calcium are partially removed by ltration or dialysis (6, 7). The remaining citrate is rapidly metabolized if liver function and muscle perfusion are sufcient (8). Calcium is replaced. Systemic effects on coagulation are thus avoided. However, because citrate is substrate for buffer as well, its use may cause metabolic derangements (9). The three small randomized controlled studies comparing citrate with heparin in critically ill patients found longer or similar circuit life and less bleeding or transfusion with citrate (10 12). Large randomized studies are not available yet. The aim of this study was to compare the safety and efcacy of regional anticoagulation for continuous venovenous hemoltration (CVVH) with citrate to our standard systemic anticoagulation with the low-molecular weight heparin nadroparin (13, 14). Low-molecular weight heparins are effectively used by others as well (15, 16).

MATERIALS AND METHODS

Study Design and Setting. This nonblinded single-center randomized controlled trial

comparing the safety and efcacy of two anticoagulant strategies for CVVH was conducted in an 18-bed closed format general intensive care unit of a teaching hospital. CVVH is the only modality of RRT in the unit and is performed under responsibility of the intensivists. The Institutional Review Board approved the study according to European and Dutch legislation. At that time, the need for informed consent was waived because the two modalities were standard practice in the unit, and patients with an increased risk of adverse events to either intervention were not included (13, 14, 17). All patients or their legal representatives received written information explaining that data collected in the patient data management system were used to evaluate treatment. Patients and Randomization. All adult critically ill patients with ARF requiring RRT in the unit were eligible for inclusion. CVVH was initiated when after resuscitation of the circulation oliguria persisted and was accompanied by a steep rise in serum creatinine, or at a nondeclining rise in creatinine in nonoliguric patients. Exclusion criteria were liver cirrhosis Child-Pugh C, (suspicion) of bleeding necessitating transfusion or fall in hemoglobin 0.5 mmol/L within 24 hours, surgery within 24 hours before CVVH, need of therapeutic anticoagulation, (suspected) heparin-

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induced thrombocytopenia, chronic dialysis, and do-not-resuscitate orders. Shock-related hepatitis and low-dose heparin for thromboprophylaxis were no exclusion criteria. Randomization was computer based in two blocks of 100 patients and an additional block of 20 patients to compensate for dropouts. When inclusion and exclusion criteria were checked in the patient data management system, the system automatically randomized the patient. Study Protocol. In the nadroparin group, 2850 IU of nadroparin (Sano-Synthelabo, Maassluis, The Netherlands) were added to the 1 L priming solution. Patients received an intravenous bolus of 2850 IU at initiation of CVVH, or 3800 IU when body weight exceeded 100 kg, followed by a continuous infusion in the extracorporeal circuit of 380 or 456 IU/hr, respectively, without anti-Xa monitoring (14, 15). The hospital pharmacy prepared the citrate solution in 500 mL bags, containing 500 mmol/L citrate, 1352 mmol/L sodium, and 148 mmol/L hydrogen. Citrate dose was 3 mmol/L blood ow (17). Citrate patients received standard thromboprophylaxis (unfractionated heparin up to 10,000 IU/day or nadroparin up to 3800 IU/day). If adverse advents needed discontinuation of nadroparin or citrate, CVVH was continued using citrate respectively, nadroparin or no anticoagulation according to clinical judgment. CVVH Protocol. We performed postdilution CVVH targeting a blood ow of 220 mL/min, ltrate ow of 4000 mL/hr for each new circuit and a ltration fraction below 32%. As long as the patient needed vasopressors, a new circuit was connected if the ltrate ow decreased below 4000 mL/hr to maintain transmembranous pressure below 300 mm Hg. In nonvasodepressor-dependent patients, ltrate ow could be decreased after 24 hours to 2000 mL/hr minimally. Circuits were disconnected at high prelter or transmembrane pressure (both more than 300 mm Hg), if vascular access failed, routinely after 72 hours or for clinical reasons (renal recovery, transport). After disconnection, a new circuit was initiated immediately if the patient remained vasopressor dependent. If not, CVVH was postponed for 24 hours awaiting renal recovery (13). We used a 1.9 m2 cellulose triacetate hollow ber membrane (UF 205, Nipro, Osaka, Japan) and in the rst half of this study the Diapact continuous RRT (CRRT) device (B-Braun, Melsungen, Germany), thereafter we used the Aquarius device (Edwards LifeSciences SA, Switzerland). Replacement uids were heated to 39C. In the nadroparin group, we used commercial uids, bicarbonate buffered (35 mmol/L) in case of metabolic acidosis and/or hyperlactatemia, and lactate buffered (42 mmol/L), if acidosis was corrected and plasma lactate remained below 5 mmol/L (SH 53 HEP and BH 504, Dirinco, Rosmalen, The Netherlands). In the citrate patients, a combination of buffer free (SH 44 HEP part I, Dirinco, Rosmalen,

The Netherlands), containing 109.5 mmol/L Na , 2.0 mmol/L K , 1.81 mmol/L Ca , 0.52 mmol/L Mg , 116.2 mmol/L Cl , 3 mmol/L lactate, 1 g/L glucose, and bicarbonatebuffered uids were used, guided by plasma bicarbonate and pH according to a computerdriven algorithm (www.nvic.nl). To maintain plasma-ionized calcium between 0.9 and 1.0 mmol/L, calcium-magnesium-chloride (0 0.4 mmol/hr of calcium and 0 0.24 mmol/hr magnesium) was administered via a separate line or if not available into the venous chamber. Vascular access was obtained via a 1214F double-lumen catheter. Study End Points. Primary outcomes were safety and efcacy. We dened safety as the absence of adverse events necessitating discontinuation of study anticoagulant: e.g., accumulation of citrate in the citrate group (dened as calciumtotal/calciumionized 2.25) (17), and bleeding (requiring 2 red blood cells [RBCs] units or causing a 0.5 mmol/L fall in hemoglobin within 24 hours) or suspected heparin-induced thrombocytopenia in the nadroparin group (18). Bleeding was

quantied by transfusion rate. Trigger hemoglobins for transfusion were 4.0 or 4.5 mmol/L in patients 40 years or between 40 and 60 years without cardiopulmonary limitations, and 5.0 or 5.5 mmol/L in patients 60 years without cardiopulmonary limitation or bleeding. Clinicians adhered to these triggers with support of the patient data management system. Efcacy was dened as circuit survival. Secondary outcomes were hospital and 3-month mortality. Of the patients discharged alive, we queried outcome in the other hospital or at home. Follow-up time was 3 months for all patients. Concomitant Treatment. Concomitant vasoactive treatment consisted of uids (crystalloids and gelatins; starches were not used), inotropics, vasopressors, and/or vasodilators to optimize circulation targeting mean arterial pressure above 60 mm Hg, cardiac index above 2.5 L/min/m2, and a central minus peripheral temperature 4C. Patients in shock received dexamethasone 1 mg/kg once (19), followed, after 24 hours, by a 4-day tapering scheme with prednisolon if the circulation re-

Figure 1. Enrollment, exclusion, and randomization of study patients. ICU, intensive care unit; CVVH, continuous venovenous hemoltration; HIT, heparin-induced thrombocytopenia.

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mained vasopressor dependent. All patients received enteral nutrition and selective decontamination of the digestive tract (20). Data Collection. Severity of illness and organ failure were scored using the Acute Physiology and Chronic Health Evaluation II and III systems, the Simplied Acute Physiology Score II system, and the Sepsis-Related Organ Failure Assessment (SOFA) score as dened by the Dutch National Intensive Care Evaluation

(www.stichting-nice.nl) (2124). Renal function was classied according to the RIFLE (Risk, Injury, Failure, Loss, End stage kidney disease) System (25). All data were prospectively collected in the patient data management system of the unit. A research nurse (M. K.), who did not participate in patient care, was responsible for the database. Denitions. (Cardiac) surgical was dened as (cardiac) surgery within the week

before intensive care unit admission, medical as no surgery in this period, sepsis according to the International Sepsis Denition (26), duration of CVVH as the time from initiation of the rst session to disconnection of the last, duration of ARF as the time from initiation to the end of RRT (including temporary intermittent hemodialysis after discharge), renal recovery as independence from RRT.

Table 1. Baseline characteristics of study patients and delivered continuous venovenous hemoltration Citratea (n 97) Demographics Age (yrs) (IQR) Weight (kg) (IQR) Male sex, n (%) Type of admission Medical, n (%) Cardiac surgical, n (%) Other surgical, n (%) Severity of illness at ICU admission Acute Physiology and Chronic Health Evaluation II Score, points (95% CI) Predicted mortality (%) (95% CI) Simplied Acute Physiology Score II Score, points (95% CI) Predicted mortality (%) (95% CI) Acute Physiology and Chronic Health Evaluation III score, points (95% CI) Plasma creatinine (mg/dL) (IQR) Severity of illness at start CVVH Sequential Organ Failure Assessment score, points (IQR) C-reactive protein (mg/L) (IQR) Plasma lactate (mmol/L) (IQR) Mean arterial pressure (mm Hg) (IQR) Cumulative uid balance from ICU admission (L) (IQR) Dopamine dose ( g/kg/min) (IQR) Noradrenalin dose ( g/kg/min) (IQR) PaO2/FIO2 ratio (mm Hg/fraction) (IQR) Mechanical ventilation, n (%) Diuresis 6 hrs before (mL) (IQR) Plasma creatinine (mg/dL) (IQR) Plasma urea (mg/dL) (IQR) RIFLE score, points (CI)h Hemoglobin (mmol/L) (IQR) Platelet count (109/L) (IQR) Prothrombin time (sec) (IQR) Activated partial thromboplastin time (sec) (IQR) Causes of acute renal failurek Sepsis, n (%) Cardiac failure, n (%) Absolute hypovolemia, n (%) Major surgery, n (%) Toxic, n (%) Delivered CVVH Time ICU admission to start CVVH (days) (IQR) Duration of CVVH period (days) (IQR) Hours on CVVH device (IQR) Duration of acute renal failure (days) (IQR)l Ultraltrate ow CVVH period (mL/kg/hr) (IQR)m Ultraltrate ow on CVVH (mL/kg/hr) (IQR)n Nadroparina (n 103)

73 (6479) 84 (8087) 66 (68) 46 (47) 27 (28) 24 (25) 28 (2730) 57 (5162) 59 (5562) 61 (5666) 105 (98111) 2.3 (1.03.4)b 11 (1013) 111 (60229) 1.8 (1.22.3) 60 (5370) 6.2 (2.210.3) 6.1 (3.510.3) 0.000 (0.0000.019) 195 (153246) 86 (89) 130 (34370) 3.8 (2.74.8)d 78 (56106)f 3 (23) 5.8 (5.26.2)i 144 (97181) 12 (1115) 34 (2842) 42 (43) 57 (59) 20 (21) 43 (44) 5 (5) 1.9 (0.243.2) 2.7 (1.66.8) 58 (36105) 2.8 (1.67.3) 36 (3239) 41 (4043)

73 (6779) 85 (8288) 70 (68) 50 (49) 30 (29) 23 (22) 28 (2729) 57 (5362) 61 (5864) 63 (5968) 105 (100111) 2.3 (1.53.6)c 11 (1014) 113 (45181) 1.7 (1.33.6) 60 (5368) 6.5 (2.312.1) 6.5 (3.09.7) 0.000 (0.0000.032) 184 (149245) 94 (91) 150 (30350) 3.7 (2.85.1)e 78 (56112)g 3 (23) 5.6 (5.26.2)j 125 (78193) 13 (1116) 34 (3042) 50 (49) 49 (48) 13 (13) 43 (42) 5 (5) 1.8 (0.283.4) 3.2 (1.77.6) 63 (31109) 3.2 (1.47.9) 33 (3035) 40 (3842)

IQR, interquartile range; ICU, intensive care unit; CI, condence interval; CVVH, continuous venovenous hemoltration; RIFLE, acute renal failure classication score, Risk 1, Injury 2, Failure 3. a Differences between randomized groups were not statistically signicant; b203 (117301) mol/L; c198 (132318) mol/L; d332 (240 420) mol/L; e 326 (247 448) mol/L; f28 (20 38) mmol/L; g28 (20 40) mmol/L; hWe scored RIFLE-risk as 1, injury as 2, and failure as 3; i9.2 (8.4 10) g/dL; j9.0 (8.4 10) g/dL; kMost patients had more than one cause, toxic was never the sole cause of acute renal failure; lIncluding intermittent hemodialysis after ICU discharge; mIncluding lter down-time; nConnected to CVVH device.

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Statistical Analysis. We based the power of the study on adverse events necessitating discontinuation of study medication (safety). On account of a 12.3% incidence of bleeding during heparin-based CVVH (27) and a 1.5% incidence of heparin-induced thrombocytopenia (18, 28), we hypothesized that, given the exclusion criteria, discontinuation of nadroparin

would be necessary in 12.5% of the patients whereas citrate accumulation would develop in 2% (9). A sample size of 200 patients would give the study 80% power with a two-sided level 0.05 to detect this difference. Although we did not anticipate a mortality difference, the study would be large enough to detect a trend to whatever side. Analysis was per-

formed using per protocol approach, excluding the patients who did not receive CVVH or were erroneously randomized, because the primary end points could not be (reliably) evaluated in these patients. We additionally performed an intention-to-treat analysis for hospital and 3-month mortality, avoiding any bias. Patients needing discontinuation of

Table 2. Prevalence of metabolic derangements before start of hemoltration and at the end of individual hemoltration sessions Before Hemoltrationa Citrate (%) Metabolic event Plasma sodium 130 (mmol/L) Plasma sodium 150 (mmol/L) Plasma bicarbonate 20 (mmol/L) Plasma bicarbonate 30 (mmol/L) Plasma pH 7.30 Plasma pH 7.50 Plasma lactate 2 (mmol/L) Plasma ionized calcium (mmol/L) 0.9 0.91.19 1.191.31 1.31
a

End of Hemoltration Sessions Citrate (%) Nadroparin (%) pb

Nadroparin (%)

1 2 45 3 31 2 48 13 67 18 3

5 0 49 7 30 4 47 9 75 16 0

1 0.4 3 9 5 9 35 6 80 11 2

8 0 5 26 5 19 64 2 54 33 11

0.001 0.50 0.50 0.001 0.84 0.001 0.001 0.001

Differences between randomized groups before start of hemoltration were not signicant. Values are presented as % of the sessions; bp values represent the difference between randomized groups at the end of the sessions. Table 3. Safety, efcacy, and clinical outcomes Citrate (n Safety Adverse events needing discontinuation of study anticoagulant, n (%) Bleeding, n (%) Heparin-induced thrombocytopenia, n (%) Transfusion Red blood cells During CVVH period, number of patients (%) Per CVVH day, number of units (IQR) Quarantaine plasma, number of patients (%) Platelets, number of patients (%) Hemoglobin start-end CVVH (mmol/L) (IQR) Platelet count start-end CVVH (109/L) (IQR) Efcacy Circuit survival time (hr) (IQR) Total ltrate volume per session (L) (IQR) Total ltrate volume per hour (mL/kg/hr) (IQR) Reasons of circuit disconnection (%) Circuit failure/catheter failure/otherc Renal recovery Renal recovery (all patients), n (%) Renal recovery (surviving patients), n (%) Recovery in the intensive care unit/after intensive care unit discharge (n) Nonrecovery (surviving patients), n (%) Creatinine hospital discharge (mg/dL) (IQR) Mortality All randomized patients Mortality hospital (%) (95% CI) Mortality 3-month (%) (95% CI) Per protocol patients Mortality hospital (%) (95% CI) Mortality 3-month (%) (95% CI) 97) Nadroparin (n 103) p

2 (2) 6 (6) 3 (3) 56 (58) 0.27 (0.00.63) 8 (8) 6 (6) 0.10 ( 0.06 to 0.05)a 6 ( 32 to 13) 27 (1347) 90 (48158) 41 (3450) 46/8/46 67 (69) 55 (97) 50/5 2 (2) 1.4 (1.02.3)d 42 (3151) 48 (3858) 41 (3151) 45 (3555)

20 (19) 16 (16) 4 (3) 62 (60) 0.36 (0.00.83) 11 (11) 9 (9) 0.20 ( 0.07 to 0.07)b 8 ( 32 to 9) 26 (1543) 86 (52141) 39 (3446) 49/7/44 54 (52) 38 (86) 31/7 6 (6) 1.4 (1.12.5)e 57 (4867) 63 (5372) 57 (4867) 62 (5372)

0.001 0.08 0.90 0.89 0.31 0.63 0.59 0.36 0.46 0.68 0.55 0.27 0.77 0.02 0.08

0.70 0.02 0.03 0.03 0.02

CVVH, continuous venovenous hemoltration; IQR, interquartile range; CI, condence interval. a 0.16 ( 0.097 to 0.081) g/dL; b0.32 ( 0.11 to 0.11) g/dL; cOther: transport, death, 72 hr, or clinical decision for interruption anticipating recovery of renal function; d127 (88 200) mol/L; e124 (100 221) mol/L.

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study anticoagulant were analyzed in the initially randomized group. The data are presented as means (95% condence interval) or medians (interquartile ranges [IQRs]). We compared variables using the Students t test, chi-square (two-sided), or Mann-Whitney U test, as appropriate. The effect of study anticoagulant on circuit survival time and (time to) death at 3 months was assessed using Kaplan-Meier estimates with log-rank testing. For 3-month mortality, we additionally performed a Coxs proportional hazard regression analysis, using stepwise forward inclusion of all variables signicantly related to 3-month mortality in univariate analysis (p 0.05). Variables were removed when not signicantly improving the model. To explain the unexpected difference in mortality, we stratied post hoc for complementary subgroups: medical vs. surgical, sepsis vs. nonsepsis, SOFA score (higher vs. lower than median), and age (higher vs. lower than median). A p value 0.05 was considered statistically signicant. Because of the explorative nature of the study, we did not correct for multiple testing. We used SPSS 13.0 (SPSS, Chicago, IL) for analysis.

Figure 2. Graphs represent circuit survival. Dotted lines represent the citrate patients; continuous lines represent the nadroparin patients. In the right graph, circuits disconnected for catheter failure, recovery of renal function, (impending) death or logistic reasons are censored. p values (log rank) for both populations are 0.92.

RESULTS
From March 2003 until November 2006, 5712 patients were admitted to the intensive care unit, 365 had an indication for RRT. Of these, 170 met the exclusion criteria leaving 215 patients for randomization. Fifteen patients were subsequently censored from per protocol analysis because they fullled the exclusion criteria or did not receive CVVH (Fig. 1). Baseline characteristics, timing of initiation of CVVH, delivered CVVH dose (ltrate ow), and duration of the RRT were similar between groups (Table 1). Metabolic Control. Nadroparin patients more frequently developed metabolic alkalosis and hyperlactatemia, whereas initial hypocalcemia was less often corrected in the citrate patients (Table 2). Mean, lowest and highest glucose concentrations, and insulin dose were not signicantly different between groups, neither was C-reactive protein (data not shown). Safety and Efcacy. Citrate was prematurely discontinued in two patients because of accumulation and early clotting (protocol violation), and nadroparin in 20 on account of bleeding (16 patients), severe thrombocytopenia (6 patients) or both (Table 3). Six patients had bleeding in the citrate group. Sites of bleeding were not different. The difference in transfusion rate was nonsignicant. Circuit survival and the total amount of lCrit Care Med 2009 Vol. 37, No. 2

trate per circuit were similar (Table 3, Fig. 2), also when adjusted for different reasons of circuit disconnection or ltrate ow at disconnection. Of the 20 patients requiring premature discontinuation of nadroparin, 12 continued CVVH with citrate, 5 without anticoagulation, and 3 with fondaparinux or lepirudin. In these 20 patients, the median number of RBC per CVVH day was signicantly higher than that in the other nadroparin patients (0.65 [IQR 0.221.38] vs. 0.27 [IQR 0 0.65] [p 0.01]) or in the citrate patients. They had higher SOFA scores (13.0, IQR 11.715.0) than all other patients (p 0.005) and a hospital mortality of 80%. Acute Physiology and Chronic Health Evaluation and Simplied Acute Physiology scores, body weight, and urinary output were not different. Secondary Outcomes. Citrate patients had a higher rate of renal recovery (Table 3). Length of mechanical ventilation, intensive care unit, and hospital stay were not different between groups. Among the 215 randomized patients, hospital and 3-month mortality rates were 15% lower in the citrate than in the nadroparin group (Table 3); among the 200 per protocol patients, hospital and 3-month mortality rates were 16% and 17% lower (Table 3, Fig. 3). To explore whether the survival benet had been consistent in time, we retrospectively calculated mortality for each sequential cohort of 50 patients. Over the entire study period the absolute survival benet for citrate varied between 10% and 23%. Post hoc analysis showed that mortality was lower with citrate in all subgroups (Fig. 3). The difference was signicant for

patients after surgery, with sepsis, higher than median SOFA score (11 points), or lower than median age (73 years). In none of these subgroups, transfusion rates were different between randomized groups. Septic patients had higher RBC transfusion rates, but rates were not different between other complementary subgroups. Septic patients had higher SOFA scores than nonseptic patients: 11 (IQR 9 14) vs. 10 (IQR 9 12) (p 0.01). Medical patients had more often sepsis than surgical patients: 55% vs. 38% (p 0.02). Higher age, severity of illness scores, SOFA score and dopamine dose, more positive uid balance, lower creatinine and diuresis, later initiation, and higher RBC transfusion rate were related to mortality at univariate analysis (Table 4), whereas CVVH dose, metabolic alkalosis during CVVH, type of admission, and the presence of sepsis, or cardiac failure were not. The signicant variables were included in a Coxs proportional regression analysis for 3-month mortality. The best model showed that nadroparin anticoagulation, age, SOFAstart CVVH, and RBC transfusion rate were independent predictors of mortality (Table 4).

DISCUSSION
The present single-center randomized controlled trial in critically ill patients with ARF without an increased bleeding risk found that regional anticoagulation with citrate for CVVH is safer, better tolerated than, and as effective as anticoagulation with nadroparin. Unexpectedly, the study shows a survival benet for citrate. An effect of anticoagulation for CRRT on sur549

Figure 3. Three-month survival of the study patients. Graphs represent survival curves of the per protocol study patients, and of the post hoc complementary subgroups surgical vs. medical, Sepsisrelated Organ Failure Assessment (SOFA) score lower or equal to vs. higher than median (11 points), no sepsis vs. sepsis, age lower or equal to vs. higher than median (73 years). Dotted lines represent the citrate patients; continuous lines represent the nadroparin patients. Log-rank testing was used to calculate p values for comparison of survival between groups.

vival is novel and may confer new insight in the pathophysiology of citrate for CRRT. Although our primary concern was whether citrate would be safe, the study indicates that nadroparin was less safe than citrate even though we excluded four times more patients from study enrollment for nadroparin-related than for citrate-related anticipated adverse events. Nevertheless, nadroparin patients tended to bleed more and nadroparin had to be discontinued more frequently for adverse events. Only one patient had signs of citrate accumulation. The difference in transfusion between randomized groups was, however, not signicant. This may be because nadroparin was discontinued
550

if bleeding developed. Transfusion additionally reects blood loss from sampling and circuit clotting, which was not different between groups. There is some concern in the literature about the use of low-molecular weight heparins in CRRT (29). However, RBC transfusion in our nadroparin group was lower than in heparin groups of other controlled studies (10, 30), possibly because we did not enroll patients with a bleeding risk and discontinued nadroparin if bleeding developed. Although low-molecular weight heparins accumulate in renal failure, they are removed with CRRT (31). Whether anti-Xa monitoring would decrease the risk of bleeding is not known.

Contrary to expectation, citrate patients had less metabolic alkalosis than nadroparin patients. This may be because citrate was administered in a xed relation to blood ow and two replacement uids were used targeting normal pH. Citrate patients had lower-ionized calcium, which was a deliberate choice of the protocol. In this study, efcacy of citrate in terms of circuit survival was similar to nadroparin. Although reasons for circuit disconnections were different between patients, criteria were preset and equal between groups. In several (10, 11) but not all (12, 32) previous studies, citrate conferred a longer circuit survival than heparin (summarized in Ref. 33). Factors negatively inuencing circuit life in our study were the use of postdilution hemoltration with relatively high ltration fractions and routine disconnection after 72 hours. Also, citrate dose was relatively low and not titrated to postlter calcium (33). Finally, calcium replacement in the venous chamber counteracts citrate anticoagulation facilitating clotting at this site. An unexpected nding is the survival benet and higher rate of renal recovery in patients randomized to citrate, present throughout the entire study period. The survival benet was independent from factors known to affect survival such as age, severity of illness, and even transfusion rate. CVVH dose and timing, and uid balance were not different between study groups. Citrate appeared particularly benecial in surgical patients, patients with sepsis, severe organ failure, and in relatively younger patients. There are several hypothetical explanations. Citrate may be favorable, nadroparin unfavorable, or both. Explanations for the survival benet may be related to bleeding, biocompatibility, antiinammatory effects, and mitochondrial fuelling. Less bleeding may be a factor, but can at most partially explain the benet. The difference in bleeding between randomized groups was not signicant, transfusion rates were not different, neither in the entire population nor in any subgroup, and transfusion rate was an independent predictor of mortality in addition to study anticoagulant. Patients with bleeding during nadroparin had more severe organ failure, higher transfusion rates, and an extremely high mortality. Biocompatibility may be an additional factor. In intermittent hemodialysis, citrate anticoagulation (compared with heparin or dalteparin) almost completely abolishes both polymorphonuclear and platelet degranulation and lowers plasma
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oxidized-low density lipoprotein indicating less cellular activation and lipid peroxidation (34). It may be hypothesized that hypocalcemia in the lter downregulates inammation (35, 36). In our setting, about 13 L of blood per hour sustain hypocalcemia while passing the lter. Therefore, hypocalcemia in the lter may not only mitigate membrane induced, but also systemic inammation. An alternative explanation may be that citrate is readily available mitochondrial fuel, about 20 g/day. Substrate availability is a crucial regulator of the citric acid cycle, a central pathway recovering energy and maintaining redox state (37). In

sepsis, inhibition of pyruvate dehydrogenase limits pyruvate conversion to acetylcoenzyme-A, the main substrate of the cycle. Finally, heparins may be harmful by reducing the anti-inammatory effects of antithrombin (38, 39) and mobilizing myeloperoxidase from circulating and adhering inammation-primed leukocytes (40). These explanations need further investigation. This study has the limitation that it is single centered. A typical patient population may bias single-center studies. The age of our patients is remarkably high and this may explain that mortality in this study is higher than in previous studies (2, 3, 27). Single-center studies may

Figure 3. Continued.

on the other hand be a better test situation because cointerventions are standardized, avoiding the confounding effect of nonuniform cointerventions. Although hemoltration prohibits blinding, randomization was free from bias, transfusion targets were strictly followed, and the end point mortality is objective. However, the primary end points could have been biased despite using a protocol. It should further be noted that 12 of the 20 patients needing discontinuation of nadroparin continued CVVH with citrate. These nadroparin patients may have beneted from citrate but not after having experienced a severe adverse event possibly related to nadroparin. However, all citrate patients received low-dose nadroparin for thrombosis prophylaxis. This study has the strength that we did not change daily practice for study purpose and that more than half of the patients needing RRT were randomized. Improving survival in this population with high mortality is clinically relevant. Furthermore, this is the rst large study evaluating the safety of citrate and although the mortality benet was not anticipated, the sample is large enough to show the present difference. The benet of citrate existed throughout the entire study period, which strengthens the results. Safe performance of citrate anticoagulation requires the implementation of a local protocol and training. Safety will further improve as a citrate module is incorporated in the CRRT device. In conclusion, this randomized controlled trial in critically ill patients with ARF without an increased bleeding risk

Table 4. Variables signicant at univariate analysis and at multivariate Coxs proportional-hazard analysis for 3-mo mortality Univariate Variable Anticoagulant strategya Age (yrs)b Sepsis-Related (later Sequential) Organ Failure Assessment start CVVHc Number of red blood cell units per CVVH dayb Acute Physiology and Chronic Health Evaluation II scoreb Simplied Acute Physiology II scoreb Dopamine dose start CVVHb Fluid balanced Creatininestart CVVHc Diuresisstart CVVHe Timing of CVVHf R 0.17 0.28 0.31 0.23 0.17 0.27 0.21 0.18 0.17 0.15 0.17 p 0.02 0.001 0.001 0.001 0.001 0.001 0.003 0.01 0.02 0.03 0.02 Hazard Ratio 0.7 1.06 1.3 1.5 Multivariate 95% Condence Interval (0.450.98) (1.041.08) (1.171.34) (1.191.96) p 0.04 0.001 0.001 0.001

CVVH, continuous venovenous hemoltration. a The hazard is lower with citrate; bLower in survivors; cLower in survivors; dLess positive in survivors; eHigher in survivors; fEarlier in survivors.

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shows that regional anticoagulation with citrate for CVVH is safer than anticoagulation with nadroparin. Citrate was better tolerated and provided better acid-base control. Citrate anticoagulation reduced mortality, which can at most partially be attributed to less bleeding, and not to less clotting. Post hoc analysis suggests that citrate may be particularly benecial in patients after surgery, with sepsis, a high degree of organ failure, or younger age, suggesting a role of citrate in the metabolism of inammation.

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