Circuit lifespan during continuous renal replacement therapy for combined liver and kidney failure

Journal of Critical Care (2012) 27, 744.e7–744.e15

Circuit lifespan during continuous renal replacement therapy for combined liver and kidney failure☆,☆☆,★ Horng-Ruey Chua MBBS a,d , Ian Baldwin PhD a,b , Michael Bailey MD c , Ashwin Subramaniam MBBS a , Rinaldo Bellomo MD a,c,⁎ a

Department of Intensive Care, Austin Hospital, Melbourne, Australia RMIT University, School of Nursing and Health Sciences, Melbourne, Australia c Australian and New Zealand Intensive Care Research Committee (ANZIC-RC), Monash University, School of Public Health and Preventive Medicine, Melbourne, Australia d Division of Nephrology, University Medicine Cluster, National University Hospital, National University Health System, Singapore b

Keywords: Acute liver failure; Acute kidney injury; Bleeding risk; Circuit life; Cirrhosis; Continuous renal replacement therapy; Decompensated chronic liver disease; No anticoagulation; Thrombocytopenia

Abstract Purpose: To evaluate circuit lifespan (CL) and bleeding risk during continuous renal replacement therapy (CRRT), in combined liver and renal failure. Methods: Single-center retrospective analysis of adults with acute liver failure or decompensated cirrhosis who received CRRT, without anticoagulation or with heparinization in intensive care unit. Results: Seventy-one patients with 539 CRRT circuits were evaluated. Median overall CL was 9 (6–16) hours. CL was 12 (7-24) hours in 51 patients never anticoagulated for CRRT. In 20 patients who subsequently received heparinization, CL was 7 (5-11) hours without anticoagulation, which did not improve with systemic or regional heparinization (P = .231), despite higher peri-circuit activated partial thromboplastin time (APTT) and heparin dose. Using multivariate linear regression, patients with higher baseline APTT or serum bilirubin, or who were not mechanically ventilated, had longer CL (P b .05). Additionally, peri-circuit thrombocytopenia (P b .0001) or higher international normalized ratio (P b .05) predicted longer CL. Of 71 patients, 33 had significant bleeding events. Using multivariate logistic regression, patients with higher baseline APTT, vasoactive drug use N24 hours, or thrombocytopenia, had more bleeding complications (P b .05). Decreasing platelet counts (especially b50 × 109/mm3) had an incremental effect on CL (P b .0001). Conclusion: CRRT CL is short in patients with liver failure despite apparent coagulopathy. Thrombocytopenia predicts longer CL and bleeding complications. © 2012 Elsevier Inc. All rights reserved.

☆

The authors confirm that the results presented in this paper have not been published previously in whole or part, except in abstract form. Disclosures/Conflicts of Interest. The authors have no conflicts of interest to declare. ★ Contributions: HRC, IB, and RB conceived the study idea and proposal, and developed the study design. HRC, IB, and AS collected the data. HRC, MB, and RB analyzed the data. HRC and RB wrote the manuscript. All authors were involved in the revision of the manuscript, and take responsibility of the data and the contents of the article. ⁎ Corresponding author. Australian and New Zealand Intensive Care Research Centre (ANZIC-RC), Melbourne, Victoria 3181, Australia. Tel.: +61 3 9496 5992; fax: +61 3 9496 3932. E-mail address: [email protected] (R. Bellomo). ☆☆

0883-9441/$ – see front matter © 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jcrc.2012.08.016

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H.R. Chua et al.

1. Introduction

2.2. Definitions and data collection

Liver failure is associated with bleeding, sepsis, vasodilatory shock, multi-organ dysfunction [1], and acute kidney injury (AKI). The incidence of AKI is 29% in advanced cirrhosis and 33% in liver failure needing transplantation [2,3]. AKI is also a predictor of short and long-term mortality in this cohort [2,4,5]. The dual impact of renal and hepatic dysfunction is especially significant, due to frequent need for blood products and difficulties with metabolic and volume control. Thus, renal replacement therapy (RRT) is often indicated. Continuous RRT (CRRT) is the preferred option for RRT in these patients because it reduces the risk of cerebral edema [6,7]. However, frequent circuit clotting may compromise treatment efficacy [8] and lead to blood loss, which increases the need for transfusion [9]. The use of systemic or regional anticoagulation is restricted by bleeding tendencies, lack of safety data in liver failure, and concerns about impaired hepatic clearance of citrate [10,11]. Accordingly, in many patients, CRRT is managed with no anticoagulation. The impact of this approach on circuit lifespan (CL) has not been well studied. Therefore, we aimed to investigate CRRT circuit longevity in critically ill patients with liver failure and AKI, and the incidence of bleeding complications during therapy. Additionally, we evaluated the ability of hematological and coagulation parameters to predict either bleeding or longer CL. We hypothesized that CL would be short and bleeding events frequent and that both would be predicted by thrombocytopenia and coagulation tests.

We included patients diagnosed with ALF, with an international normalized ratio (INR) of at least 1.5 during hospitalization and any degree of hepatic encephalopathy [13,14]. Chronic liver disease was defined as presence of histologic or ultrasonographic evidence of hepatic cirrhosis. DCLD was inferred by presence of related complications including variceal bleeding, symptomatic ascites, encephalopathy, or bacterial peritonitis, which required hospitalization [15]. The ICU admission diagnosis was the acute condition that precipitated need for intensive care. Patients’ profile, laboratory investigation results, and illness severity indices on ICU admission were collected. Specifically, we computed the model for end-stage liver disease (MELD) score to reflect the severity of liver disease [16,17]. Clinically significant bleeding complications that warranted medical intervention and blood transfusions were identified. In addition, patients’ hemoglobin levels, platelet counts, INR and activated partial thromboplastin time (APTT) were obtained from levels performed just prior to, or within 12 hours of each circuit commencement; so as to reflect the current hematological profile peri-CRRT circuit. If unavailable, corresponding results on the day of every circuit commencement were used.

2. Methods 2.1. Study design and population The study was conducted in a regional tertiary referral center for patients with liver failure in possible need for emergent transplantation. We retrospectively studied critically ill patients aged N18 years, diagnosed with acute liver failure (ALF) or decompensated chronic liver disease (DCLD) complicated by AKI (class “failure” by RIFLE classification) [12], who were admitted to the intensive care unit (ICU) and received CRRT from January 2006 till July 2011. Patients were identified using the ICU admission database. CRRT circuits were studied until cessation of therapy, patient death, ICU discharge, or liver transplantation. CRRT circuits used during and after liver transplant were excluded. In addition, we excluded circuits terminated prematurely due to elective indications (patient transports for scans or procedures, planned cessation, renal recovery, and withdrawal of artificial life support). The study was approved by the Human Research Ethics Committee, which waived the need for informed consent.

2.3. CRRT details All patients received either continuous venovenous hemofiltration or hemodiafiltration (CVVH or CVVHDF). Hemodiafilter membranes were of AN69 polyacrylonitrile or polyamide with surface area of 1.2 m2 or greater (Gambro, Lund, Sweden). Blood pump rate was set at 200 mL/min routinely. Replacement fluid was administered as 50% to 50% or 70% to 30% in pre- and post-dilutional modes for CVVH, respectively; and 100% post-dilution for CVVHDF. Replacement fluid and dialysate flow were divided in equal proportions for CVVHDF. Systemic heparinization for CRRT was achieved by pre-filter heparin infusion with no reversal, while regional heparinization included post-filter infusion of protamine, with ratio of heparin 100 IU to protamine 1 mg. The prescribed CRRT dose was calculated for individual circuits using the documented effluent rate and estimated body weight. Details on anticoagulation (including dose) were collected.

2.4. Data analysis Statistical analysis was performed using SAS version 9.2 (SAS Institute Inc, Cary, NC). Parametric variables were presented as mean (±S.D.) and compared using Student t test, whereas non-parametric variables were presented as median (interquartile range) and compared using MannWhitney or Kruskal-Wallis test. Categorical variables were presented as frequency (percentage) and compared using

CRRT circuit life in liver failure

744.e9

χ2 or Fisher exact test. The CL was found to be well approximated by a log-normal distribution and was logtransformed prior to analysis. Univariate and multivariate analysis of CL were performed using mixed linear modeling with individual patients treated as random effects. All available variables were considered for inclusion into the multivariate model for CL life (see Table 3), with the final model developed using both stepwise selection and backwards elimination techniques with the P value for inclusion into the final model being .05. The final model was assessed for collinearity and plausibility using correlation coefficients and the difference in parameter estimates and standard errors

Table 1

between univariate and multivariate models. Multivariate analysis of bleeding complications was performed using logistic regression with both stepwise selection and backwards elimination techniques considering all plausible variables (see Table 4). The criteria for inclusion into the final model was P = .05. Goodness of fit was determined using a Hosmer and Lemeshow Goodness-of-Fit Test while discrimination was determined using area under the curve. Kaplan-Meier plots and log-rank test were used to further assess differential effects of peri-circuit variable(s) on circuit lifespan. A 2-sided P value of .05 was considered to be statistically significant.

Profile of study population

Patient characteristics

All patients

ALF

DCLD

n = 71

n = 41

n = 30

Age, mean (SD), y 45.9 Male sex, no. (%) 26 Primary etiology of liver disease Alcohol-induced, no. (%) 10 Hepatitis virus, no. (%) 15 Drug-induced, no. (%) 26 Metabolic disease, no. (%) 7 Autoimmune/biliary disease, no. (%) 5 Others, no. (%) 8 Reason for ICU admission, no. (%) Severe encephalopathy 37 Hepatorenal syndrome 13 Septic shock 12 Acute pulmonary edema 5 Other hemodynamic shock 4 Illness severity scores on ICU admission APACHE III score, mean (SD) 100 MELD score, mean (SD) 37 Admission serum laboratory results Hemoglobin, mean (SD), g/dL 10.3 Platelet count, mean (SD) 132 INR, median (IQR) 2.7 APTT, mean (SD) 58 Albumin, mean (SD), g/L 29 Bilirubin, median (IQR), μmol/L 160 Renal function upon CRRT commencement Urea, median (IQR), mmol/L 11.8 Creatinine, mean (SD), μmol/L 296 Progression in ICU and hospital Mechanical ventilation, no. (%) 56 MV duration, median (IQR), h 75 Vasoactive drugs N24 h, no. (%) 49 CRRT duration, median (IQR), d 5 Bleeding complications, no. (%) 33 ICU LOS, median (IQR), d 8 Hospital LOS, median (IQR), d 17 Liver transplant, no. (%) 13 ICU mortality, no. (%) 30 Hospital mortality, no. (%) 34

P

(11.2) (36.6)

44.2 11

(11.6) (26.8)

48.3 15

(10.3) (50.0)

.93 .045

(14.1) (21.1) (36.6) (9.9) (7.0) (11.3)

1 9 26 0 1 4

(2.4) (22.0) (63.4) (0) (2.4) (9.8)

9 6 0 7 4 4

(30.0) (20.0) (0) (23.3) (13.3) (13.3)

.001 .84 b.001 .002 .16 .71

(52.1) (18.3) (16.9) (7.0) (5.6)

26 9 5 1 0

(63.4) (22.0) (12.2) (2.4) (0)

11 4 7 4 4

(36.7) (13.3) (23.3) (13.3) (13.3)

.03 .54 .22 .16 .03 .55 .70

(30) (8)

100 37

(34) (9)

101 38

(24) (8)

(2.5) (76) (2.0-4.2) (30) (13) (82-385)

11.4 142 3.9 57 29 112

(2.4) (84) (2.4-5.2) (31) (16) (74-193)

8.8 117 2.2 59 30 428

(1.9) (63) (1.8-2.8) (30) (7) (160-595)

b.0001 .08 .0001 .62 .63 b.0001

(6.5-25.6) (162)

7.8 284

(5.3-10.3) (176)

25.4 313

(14.2-37.4) (142)

b.0001 .77

(78.9) (20-240) (69.0) (3-8) (46.5) (5-17) (9-36) (18.3) (42.3) (47.9)

33 131 26 4 17 8 14 6 20 20

(80.5) (24-308) (63.4) (3-8) (41.5) (4-16) (8-22) (14.6) (48.8) (48.8)

23 38 23 5 16 8 22 7 10 14

(76.7) (10-117) (76.7) (3-12) (53.3) (6-19) (13-54) (23.3) (33.3) (46.7)

APACHE, Acute Physiology and Chronic Health Evaluation; IQR, interquartile range; LOS, length of stay; MV, mechanical ventilation.

.70 .05 .23 .77 .32 .47 .02 .35 .19 .86

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3. Results We studied 71 patients, of whom 41(57.7%) had ALF and 30 (42.3%) had DCLD (Table 1). For patients with ALF, the admission platelet counts, INR, and APTT were 142(±84) × 109/mm3, 3.9 (2.4-5.2) and 57(±31) seconds, respectively, while corresponding levels for patients with DCLD were 117(±63) × 109/mm3, 2.2 (1.8-2.8), and 59 (±30) seconds. A significantly higher proportion of patients with ALF were women with drug-related hepatotoxicity as predominant disease etiology. Patients with ALF were also more likely to present with severe encephalopathy and higher INR on ICU admission, whereas patients with DCLD had lower admission hemoglobin, higher initial serum bilirubin levels, and longer hospitalization. Their illness severity indices such as Acute Physiology and Chronic Health Evaluation (APACHE) III and MELD scores were comparable (Table 1). Data were collected on 631 circuits. Ninety-two circuits were terminated due to elective indications and were excluded. Analysis was performed on the remaining 539 (85.4%) circuits. The overall median CL was 9 (6-16) hours; 503 of 539 circuits (93%) were performed via femoral venous access. In patients never anticoagulated for CRRT (n = 51), median CL was 12 (7-24) hours, with median 1.0 (0.6-1.4) circuit change per CRRT day. In patients who subsequently received heparinization for CRRT (n = 20), median circuit change was Table 2

more frequent at 1.5 (1.1-1.9) per CRRT day compared to the former (P = .001); and median CL was 7 (5-11) hours without anticoagulation; which did not improve significantly with systemic or regional heparinization (P = .231). This was despite significantly elevated systemic APTT with systemic heparinization, higher intravenous heparin dose with regional heparinization, and greater proportion of circuits performed using hemodiafiltration versus hemofiltration (Table 2). No patients received regional citrate anticoagulation. Fifty-one patients never anticoagulated during CRRT were transfused a median of 0.63 (0.20-1.20) U of packed red blood cell (PRBC) per CRRT day, or 1 unit PRBC every 1.6 days; as compared to 0.38 (0-0.74) U of PRBC per CRRT day or 1 unit every 2.6 days, in patients subsequently anticoagulated during CRRT (P = .10). Among the latter 20 patients, the respective amounts of PRBC per CRRT day received during anticoagulation-free versus heparinized CRRT, were 0.40 (0-0.93) versus 0.17 (0-0.61) U; with median difference of zero (95% confidence interval [CI] 0-0.40) U. On multivariate linear regression analysis, longer CL was associated with higher APTT and serum bilirubin levels on ICU admission, as well as lower peri-CRRT circuit platelet counts. The absence of mechanical ventilation during ICU stay and higher INR were not significantly associated with longer CL on univariate comparison but became statistically

CRRT circuit profile

Circuit characteristics

Circuit lifespan, median (IQR), h CVVH/CVVHDF, No. Vascular access, No. (%) Femoral vein Internal jugular/subclavian vein Prescribed intensity, median (IQR), mL/kg per h Heparin dose, median (IQR), U/kg per h Circuit hematology profile c Hemoglobin, median (IQR), g/dL Platelet count, median (IQR) INR, median (IQR) APTT, median (IQR), seconds

ALL circuits

Circuits of patients with Circuits of patients with no AC initially, no AC throughout a but with subsequent AC b Initial AC free

Systemic heparin

Regional heparin

Pd

n = 539

n = 230

n = 188

n = 29

n = 92

9.0 (6.0-15.5)

12.0 (7.0-24.0)

7.0 (5.0-10.5)

7.5 (5.0-13.0)

8.0 (5.8-12.0)

.23

330/209

160/70

112/76

10/19

48/44

.03

503 (93.3) 36 (6.7)

196 (85.2) 34 (14.8)

186 (98.9) 2 (1.1)

29 (100.0) 0 (0)

92 (100.0) 0 (0)

NA

32.8 (22.250.0) NA

30.8 (24.1-40.0)

40.0 (22.2-50.0) 28.6 (22.2-50.0) 31.0 (22.2-51.7) .66

0 (0)

0 (0)

6.4 (5.8-8.3)

13.9 (11.1-17.2) 0.0001

8.1 (7.4-9.3)

8.1 (7.3-9.1)

8.3 (7.6-9.4)

7.6 (7.4-8.6)

8.0 (7.3-9.9)

.20

49 (32-84) 2.3 (1.8-3.0) 46 (38-57)

51 (34-97) 2.3 (1.9-3.0) 48 (40-61)

45 (29-67) 2.2 (1.7-2.9) 43 (37-52)

58 (45-76) 2.5 (1.6-2.9) 64 (40-87)

47 (30-84) 2.2 (1.8-3.1) 47 (37-56)

.04 .59 .001

AC, anticoagulation; IQR, interquartile range; NA, not applicable. a Circuits of patients who were never anticoagulated throughout for CRRT (51 patients). b Circuits of patients who were not anticoagulated initially, but subsequently received heparin for CRRT (20 patients). c Hematology results obtained before each circuit or during initial hours from each circuit commencement. d Comparing only results of last 3 columns.

CRRT circuit life in liver failure

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significant on multivariate analysis (Table 3). ALF/DCLD was removed from the multivariate model due to collinearity with other more significant variables, namely admission bilirubin (ρ = 0.5), vasoactive drugs N24 hours (ρ = 0.3), and mechanical ventilation (ρ = 0.4). Decreasing platelet count had an incremental effect on CL (P b .0001, log-rank test). Median CLs for platelet count of b50, versus 50 to b80, versus ≥80 × 109/mm3; were 11.0 (7.0-21.0) versus 8.0 (5.5-13.5) versus 7.0 (5.0-11.0) hours, respectively (Fig. 1). Of 71 patients, 33 (46.5%) had bleeding complications, including 27 who were never anticoagulated for CRRT. Of these 33 patients, 18 (54.6%) had gastrointestinal bleeding with 11 who underwent urgent endoscopy. Etiologies include variceal bleed, portal gastropathy, and hemorrhoids; 13 (39.4%) patients had severe bleeding from line sites including 3 with arterial bleed; 9 had severe orifice bleeding such as epistaxis or mucosal bleed; and 3 had intraabdominal bleeding. On multivariate logistic regression analysis, patients with higher APTT at ICU admission, prolonged use of vasoactive drugs N24 hours, and lower median peri-circuit platelet counts had more bleeding complications during ICU stay (Table 4). The respective amounts of PRBC per CRRT day received by patients who had bleeding complications versus none were 0.88 (0.63-1.25) versus 0.08 (0-0.50) U (P b .0001).

Table 3

Fig. 1 Kaplan-Meier analysis of circuit lifespan by differential circuit platelet count and INR. Platelet counts are expressed as ×109/mm3.

Predictors of longer circuit lifespan—linear regression models

Variables

Admission hemoglobin Admission platelet count Admission INR Admission APTT Admission albumin Admission bilirubin MELD score Pre-CRRT urea Pre-CRRT creatinine Vasoactive drugs N24 h Mechanical ventilation APACHE III score MV duration Modality (CVVH/CVVHDF) Femoral vascular access Prescribed CRRT dose Heparinization Heparin dose Circuit hemoglobin Circuit platelet count Circuit INR Circuit APTT MV, mechanical ventilation.

Univariate analysis

Multivariate analysis

Estimate

SE

Probability

−0.032 −0.001 −0.007 0.008 −0.021 0.001 0.007 0.003 0.00002 0.318 −0.167 −0.004 0.0004 −0.150 −0.186 −0.007 0.065 0.002 −0.040 −0.004 0.044 0.004

0.026 0.001 0.036 0.002 0.012 0.0003 0.009 0.005 0.0005 0.151 0.175 0.003 0.0003 0.105 0.165 0.004 0.048 0.007 0.024 0.001 0.028 0.001

.22 .12 .84 .001 .08 .009 .43 .58 .96 .04 .34 .15 .17 .15 .26 .12 .17 .78 .10 b.0001 .12 .006

Estimate

SE

Probability

0.005

0.002

.03

0.001

0.0003

.006

−0.447

0.149

.003

−0.005 0.068

0.001 0.027

b.0001 .01

744.e12 Table 4

H.R. Chua et al. Predictors of bleeding complications—logistic regression model ⁎

Variables

ALF vs DCLD Admission hemoglobin Admission platelet count Admission INR Admission APTT Admission albumin Admission bilirubin MELD score Pre-CRRT urea Pre-CRRT creatinine Vasoactive drugs N24 h Mechanical ventilation APACHE III score % Circuits with heparinization % Circuits with CVVHDF vs CVVH Median circuit platelet count Median circuit INR Median circuit APTT

Univariate analysis

Multivariate analysis

Odds ratio

(95% CI)

Probability

1.61 0.92 0.98 1.11 1.06 0.96 1.00 1.11 0.99 1.00 17.22 2.95 1.01 0.14 0.77 0.98 1.26 1.04

(0.62-4.17) (0.76-1.11) (0.97-0.99) (0.87-1.40) (1.02-1.10) (0.89-1.04) (1.00-1.01) (1.04-1.20) (0.96-1.03) (1.00-1.00) (3.60-82.39) (0.84-10.40) (1.00-1.03) (0.02-1.05) (0.26-2.27) (0.96-0.99) (0.87-1.82) (1.01-1.08)

.32 .40 .0004 .40 .002 .33 .008 .002 .66 .51 .0004 .09 .11 .06 .64 .001 .23 .02

Odds ratio

(95% CI)

Probability

1.06

(1.01-1.11)

.02

8.48

(1.41-51.00)

.02

0.98

(0.97-1.00)

.02

⁎ Hosmer Lemeshow goodness of fit test: P = .77; area under the curve = 0.87.

4. Discussion 4.1. Statement of key findings We studied CRRT circuit longevity and bleeding risk in patients with AKI associated with ALF or DCLD, in whom most circuits were not anticoagulated due to coagulopathy. We found that overall CL was short, and did not improve significantly with heparinization. Thrombocytopenia was a key predictor of both longer CL and bleeding complications, whereas conventional coagulation parameters such as deranged INR had only a weak association with longer CL, but not bleeding risk. Other patient-specific predictors of longer CL include higher admission APTT and serum bilirubin levels, and absence of mechanical ventilation; while higher admission APTT and prolonged vasoactive drug use predicted bleeding complications. As expected, patients who suffered bleeding complications had significantly more PRBC transfusions, compared to those who had no bleeding issues.

4.2. Relationship to other studies CRRT CL with and without anticoagulation in high-risk patients had been evaluated in limited studies. Only one dealt specifically with liver failure. In that study, mean CL for patients with ALF and DCLD was only 10 to 11 hours, despite seemingly lower baseline platelet counts and worse coagulation profile than in our study cohort [18]. Decreasing platelet count also did not predict circuit survival in that study. However, only the baseline hematology results

(before initiation of CRRT) and not respective levels with every circuit were examined; and only the first three circuits were assessed. By factoring every platelet count during circuit commencement, we have highlighted the independent association of thrombocytopenia with prolonged CL. Thrombocytopenia in liver disease is multifactorial [19,20]. Reduced and dysfunctional platelets may lead to less aggregation and subsequent impaired coagulation; consistent with our findings that thrombocytopenia predicts longer CL and bleeding risk. However, high levels of von Willebrand factor and its reduced inhibition from ADAMTS 13 deficiency can restore platelet function [21,22], which may explain our observation that CL was only more significantly increased with platelet counts b50 × 109/mm3. The improved CL from 7 to 11 hours with severe thrombocytopenia implies a 50% increase in circuit life. However, in patients never anticoagulated for CRRT, CL of 12 hours is still low compared to similar high-risk cohorts, who reportedly achieved life spans of 19 to 32 hours without anticoagulation [23-26]. “High risk for anticoagulation” during CRRT is conventionally identified by elevated INR, APTT, or thrombocytopenia. Patients with liver disease frequently meet these criteria. Our study, however, demonstrates that CL is poor in such patients and challenges the paradigm that CRRT circuits should run efficiently in patients with liver failure, who are deemed to be “auto-anticoagulated”. In contrast, conventional baseline and peri-circuit coagulation profiles were not consistent in predicting both longer CL and bleeding risk (with exception of higher baseline APTT, which probably reflected underlying illness severity). These findings are in agreement with recent evidence that patients with liver disease have a parallel decrease in both

CRRT circuit life in liver failure procoagulant and anticoagulant factors, but elevated factor VIII and von Willebrand factor, leading to imbalance in hemostasis, which can tip towards either a hypo- or hypercoagulable situation [27-31]. Furthermore, such reduction in circulating coagulants is more severe in ALF than cirrhosis [31] and is worsened by a hypofibrinolytic state from increased plasminogen-activator inhibitor levels [32]. Rebalanced hemostasis in these patients makes it extremely difficult to have a predictable or consistent bleeding risk [29]. Moreover, INR is standardized based on a different reference population receiving a vitamin K antagonist but not validated in liver disease [30]. Routine prothrombin time and APTT assays do not incorporate the action of thrombomodulin, which otherwise down-regulates thrombin generation through activated protein C and, thus, provide a biased assessment of procoagulant deficiency, and not anticoagulant deficiency [30,33]. These tests also do not assess effect of fibrinolytic factors. These observations explain the inconsistent performance of such tests in predicting CL and bleeding complications in our study. In addition to the above considerations, CL in our patients was not improved with heparinization, despite heparin dose up to 14 IU/kg per hour for regional heparinization and optimal to high systemic APTT of 64 seconds with systemic heparinization [34]. The paradoxical finding that patients with circuits anticoagulated tend to instead have shorter CLs probably reflected higher clotting tendencies, which prompted clinicians to initiate heparinization (Table 2). Yet, this further demonstrates the limited effect of heparinization in prolonging circuits in these patients. As the systemic APTT was prolonged with heparinization, such poor efficacy cannot be solely attributed to anti-thrombin III deficiency. Instead, these results might suggest that in-vitro thrombin inhibition with standard test reagents may not reflect actual in-vivo anticoagulant deficiency (such as protein C) in liver disease. More importantly, heparin can cause thrombocytopenia through reduction in platelet activation threshold, increased platelet aggregation and splenic sequestration, and more uncommonly, immunemediated thrombocytopenia [35]. Given that thrombocytopenia is prevalent in our patients and is an independent predictor of bleeding complications, heparinization for CRRT in this cohort may not be justifiable. Higher baseline serum bilirubin inferred more severe underlying hepatic failure, which explains the link to better CL and bleeding risk. The significance of mechanical ventilation on shorter CL is unclear, and may signify the impact of severe critical illness on a more procoagulant state, mediated by surge in proinflammatory cytokines, platelet activation and enhanced tissue factor expression [36]. It may also affect vascular catheter blood flows due to variations in intrathoracic pressure, though majority of our cohort used femoral venous access. On the other hand, prolonged vasoactive drug use, hemodynamic shock, and bleeding/ hemorrhage are likely inter-related as cause or effect, thus explaining the link between the former and latter.

744.e13

4.3. Significance of study findings Our study suggests the need to reconsider strategies to improve CRRT CL in patients with significant liver impairment. It is reasonable to start with anticoagulationfree circuits for safety concern, especially with severe thrombocytopenia, which predicts bleeding complications and longer CL. On the other hand, deranged coagulation assays alone do not necessarily imply severe bleeding diathesis. Regional heparinization appears to add little clinical benefit. Alternatives such as prostacyclin enhances CL compared to heparin [37] but may induce more hypotension, may reduce cerebral perfusion pressure in patients with fulminant hepatic failure [38], and is expensive. Citrate metabolism is impaired in liver disease, and there appears to be a stepwise increase in citrate toxicity risk in patients with higher MELD scores [39]. Yet, there is emerging data of acceptable safety profile for up to 60 hours of regional citrate anticoagulation in liver patients on extracorporeal circulation, and this may be a viable option in selected patients [40]. In essence, the need for anticoagulation must be reviewed regularly, in view of progressive decrease in platelet count with consecutive circuits and bleeding risk. Finally, thromboelastography may provide a better assessment of hemostasis during extracorporeal circulation in liver failure [41].

4.4. Strengths and limitations We have analyzed 539 CRRT circuits, the majority of which were not anticoagulated, making this the largest study so far of circuit characteristics in high-risk patients with liver failure. We accounted for the effect of changing hematology profile on circuit life by studying the respective indices for every circuit. The findings appear logical, plausible, and consistent with recent literature. Despite the retrospective design, elapsed hours of circuit and downtime were clearly documented routinely in our nursing charts. However, circuit APTT was not measured for regional heparinization, and we cannot exclude inadequate anticoagulation as reason for poor efficacy, though the systemic APTT was already 47 seconds in these patients. There may be interpretation bias in assessing reasons for premature circuit termination. The vast majority of patients had femoral venous access, and hence, these results are less applicable for patients with alternative vascular access. The CRRT circuit profiles of patients with ALF and DCLD were pooled and analyzed together, despite likely differences in their thrombogenic milieu. We cannot comment on the effect of diffusive or convective therapies on CL as the respective CRRT intensity was not controlled for. We are also unable to account for effects of plasma or platelet transfusion on circuit clotting. Our study is single center in nature and requires confirmation in other healthcare systems.

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5. Conclusions [11]

In conclusion, CRRT CL without anticoagulation in highrisk patients with significant liver impairment is generally short despite apparent coagulopathy and is not improved significantly by circuit heparinization. Severe thrombocytopenia is strongly associated with longer CL and bleeding complications, while conventional coagulation assays are inconsistent in predicting impaired hemostasis. This highlights the need for further studies to determine improved techniques to assess hemostasis in this unique patient cohort, and alternative strategies to optimize CRRT circuit longevity without compromising patient safety.

[12]

[13] [14] [15] [16]

Acknowledgments Dr Horng-Ruey Chua was a recipient of the Singapore Healthcare Manpower Development Program award in 2010, which was co-funded by the Ministry of Health Singapore, and National University Health System Singapore. The funds were utilized for his clinical and research training in Austin Health, Melbourne, Australia.

[17]

[18]

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