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Single-Dose Application of Antithrombin as a Potential Alternative Anticoagulant During Continuous Renal Replacement Therapy in Critically Ill Patients with Advanced Liver Cirrhosis: A Retrospective Data Analysis

Brunner, Richard MD; Leiss, Waltraud; Madl, Christian MD; Druml, Wilfred MD; Holzinger, Ulrike MD

doi: 10.1213/ANE.0b013e31827ced39
Cardiovascular Anesthesiology

BACKGROUND: Adequate anticoagulation is essential to achieve efficient and cost-effective continuous renal replacement therapy (CRRT). However, in critically ill patients with advanced liver cirrhosis, this goal is challenging because of the concomitant bleeding disorder. Therefore, the evaluation of alternative anticoagulants is necessary.

METHODS: In this retrospective study, we analyzed data of 37 CRRTs in 16 critically ill patients with advanced liver cirrhosis and acute kidney injury admitted to a medical intensive care unit between 2006 and 2008 and included patients undergoing CRRT with either single doses of antithrombin (AT) or continuous low-dose heparin as a sole anticoagulant. The primary outcome measure was lifetime of single CRRT filters.

RESULTS: Data were available for 13 CRRT filters for patients anticoagulated with single doses of AT (n = 6), and 24 CRRT filters for patients anticoagulated continuously with low-dose heparin (n = 10). Means of single-filter lifetimes were significantly higher in the AT group compared with the heparin group (45 ± 29 hours [95% confidence interval 27–62 hours] vs 26 ± 23 hours [95% confidence interval 16–36 hours]; P = 0.03), whereas mean filter lifetimes of individual patients were comparable (median [25th–75th percentile] 30 hours [21–59 hours] vs 28 hours [17–70 hours]; P = 0.79).

CONCLUSIONS: Our data suggest that anticoagulation with single doses of AT may be an alternative to continuously administered low-dose heparin in critically ill patients with advanced liver cirrhosis during CRRT. However, additional controlled trials are necessary to confirm our findings.

From the Department of Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria.

Accepted for publication October 23, 2012.

See Disclosures at end of article for Author Conflicts of Interest.

This report was previously presented, in part, at the ISICEM 2011.

Reprints will not be available from the authors.

Address correspondence to Ulrike Holzinger, MD, Department of Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria. Address e-mail to ulrike.holzinger@meduniwien.ac.at.

Acute kidney injury (AKI) is a serious condition in critically ill patients.1,2 Despite the potential recovery of organ function and the recent advantages in therapy, AKI is still associated with a mortality of 20% to 50%.3 Continuous renal replacement therapy (CRRT) is used as treatment for AKI in critically ill patients.4

Adequate anticoagulation is essential to achieve efficient and cost-effective renal replacement therapy with long filter lifetimes.5 A major problem in critically ill patients is the increased tendency for both coagulation and bleeding.6 Bleeding rates of 5% to 40% and filter clotting rates of more than 50% have been reported, depending on the anticoagulation method.6–8 In critically ill patients with liver cirrhosis, bleeding risk is increased because of the abnormal clotting status, thrombocytopenia, and predisposition for variceal and gastrointestinal (GI) hemorrhage.8 However, a decreased concentration of anticoagulant factors such as antithrombin (AT), fibrinolysis, disseminated intravascular coagulation (DIC), and endothelial dysfunction pose the risk for thrombus formation at the same time.9

In patients with advanced liver cirrhosis, the systemic administration of heparin at a standard dose as anticoagulant should be avoided because of the risk of active hemorrhage.8 Although regional citrate anticoagulation is successfully used in patients at high risk of bleeding, there are several potential hazards in patients with liver dysfunction, because citrate cannot be metabolized adequately.10–12 The accumulation of citrate leads to a progressive increase in total serum calcium and a reduction of ionized calcium concentration.13 Moreover, citrate toxicity may cause prolongation of the QT interval and tetanic symptoms.14 Currently, in critically ill patients with hepatic insufficiency at high risk of bleeding, low-dose heparin, prostacyclins, or low-dose citrate is used as anticoagulant.15,16 An alternative in these patients may be not to use anticoagulation at all,17 with the disadvantage of potential clotting of filter systems.15

AT has been proposed as an alternative anticoagulant in patients at high risk of bleeding.18 AT is a natural anticoagulant that is decreased in patients with liver cirrhosis. At AT levels below 30%, DIC is common in these patients, contributing to the procoagulatory state.19,20 AT supplementation inhibits the coagulation cascade by multiple mechanisms including inhibiting thrombin and potentially DIC.21 Thereby, single-dose administration of AT may improve filter lifetimes in critically ill patients with advanced liver cirrhosis during CRRT. Moreover, continuous AT supplementation in AT-deficient, critically ill patients led to prolonged filter lifetimes in 2 small studies.18,22

Thus, the aim of this retrospective data analysis was to evaluate the single-dose administration of AT as alternative anticoagulation in critically ill patients with liver cirrhosis requiring CRRT.

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METHODS

Study Hypotheses

The primary focus of this analysis was to determine whether filter lifetimes in critically ill patients with advanced liver cirrhosis requiring CRRT are longer using single doses of AT as anticoagulation compared with anticoagulation with continuously administered low-dose heparin. Additionally, we sought to determine whether complications of bleeding and clotting rates of CRRT filters are lower in patients who were anticoagulated with single doses of AT compared with anticoagulation with continuously administered low-dose heparin.

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Patients’ Characteristics

In this retrospective analysis, data of subjects admitted to the medical intensive care unit (ICU) of the Department of Medicine III–Division of Gastroenterology and Hepatology at the Medical University of Vienna, Austria, between 2006 and 2008 were analyzed. Data collection and analysis were performed in 2010 and 2011 based on data from the hospital’s digital patient file archive. Patients older than 18 years with advanced liver cirrhosis (Child-Pugh class C)23 and marked clotting disorder (AT levels and prothrombin time below 50%) requiring CRRT with either single doses of AT or continuously administered low-dose heparin as the sole anticoagulant were included.

Patients in the AT group received a single dose of 2000 IU AT (Kybernin® P; CSL Behring, Vienna, Austria) immediately before each CRRT. After 24, 48, and/or 72 hours, AT levels were determined and subsequent doses of 1000 or 2000 IU AT were administered. We aimed to increase initial AT values by 20 to 30 percentage points and to keep AT levels stable during CRRT.

Patients in the heparin group received continuous infusions of heparin at low doses (Ebewe Pharma GmbH, Vienna, Austria) as anticoagulant via a central venous catheter. Heparin dosing was based on the ASSENT III trial scheme with an activated partial thromboplastin time (aPTT) target between 50 and 70 seconds.24 Because of the impaired coagulation variables in the study patients, no initial heparin bolus was given and the recommended starting dose of heparin was 6 IU/kg/h. However, heparin dosing could be modified by the doctor in charge based on clinical factors. Besides AT (AT group) or heparin (heparin group), no additional coagulation-inhibiting drugs including low-molecular-weight heparin were administered during CRRT.

CRRT was performed using the multiFiltrate® renal replacement device (Fresenius, Bad Homburg, Germany) with Ultraflux® Polysulfone CVVHD filters (AV 600; Fresenius). For venous access, high-flow, double-lumen catheters (length 17.5 or 20 cm; diameter 4.3 mm) were inserted in one of the internal jugular veins.

Allocation of the patients to the treatment groups was not randomized, but based on the personal decision of the doctor in charge. In one patient, anticoagulation was switched from heparin to AT after several circuit clotting episodes. Data of this patient are included in the heparin group (CRRT periods on heparin anticoagulation) and in the AT group (CRRT periods after switch to AT anticoagulation).

All included blood variables were routinely measured in the central laboratory of the hospital, which is validated by the Austrian Society of Quality Control and Standardisation of Medical-Diagnostic Analyses. For every patient, the following variables were assessed: age, sex, height, weight, body mass index (BMI), admission reason, sequential organ failure assessment score, simplified acute physiology score (SAPS) II, acute physiology and chronic health evaluation II score, filter lifetime of CRRT, clotting rate, complications, outcome, medication, and daily routine blood chemistry. Complications (significant bleeding defined as bleeding requiring a blood transfusion), filter lifetime, and clotting rates of CRRT filters were used as outcome measures. The study and data analysis were approved by the ethics committee and IRB of the Medical University of Vienna.

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Statistics

The primary outcome measure (single CRRT filter lifetime) was compared between the 2 groups using the Student t test with logarithmic values to gain normal distribution. The secondary outcome measure, mean filter lifetime of individual patients, was compared using the Mann Whitney U test, and clotting rates and bleeding complications were compared using the Fisher exact test. Further comparisons between the groups described in Tables 1–3 were done using Student t test (values shown as mean ± SD), the Mann Whitney U test (values shown as median [25th–75th percentile]), or Fisher exact test (binary data).

We conducted a multivariate linear regression with the filter lifetime as the dependent variable, and age, gender, BMI, SAPS II, and anticoagulation (AT or low-dose heparin) as cofactors to account for possible confounders. The relation of the cofactors to the dependent variable “CRRT filter lifetime” can be described with a linear function. Residuals meet an approximate normal distribution by visual inspection. Homogeneity of variance was considered equal in both groups by visual inspection of a scattered diagram with residuals plotted against the fitted values. No major interactions among cofactors were found by calculating the variance inflation factor.

We calculated the Pearson correlation coefficient to measure the association between the mean filter lifetime and AT levels using the software PASW/SPSS (version 18.0 for Windows). A 2-sided P value ≤0.05 was generally considered statistically significant. Data are shown as mean ± SD or as median (25th–75th percentile), unless otherwise stated.

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RESULTS

The 16 patients reported in our study were admitted to a medical ICU between 2006 and 2008 for decompensated liver cirrhosis (n = 5), sepsis/septic shock (n = 4), respiratory insufficiency (n = 3), hemorrhagic shock (n = 2), intracerebral bleeding (n = 1), and renal insufficiency (n = 1).

The primary end point, filter lifetime of individual filter periods, was significantly higher in the AT group compared with the heparin group, whereas mean filter lifetimes of individual patients were comparable (Table 3). In a multivariate linear regression model with the filter lifetime as the dependent variable and age, gender, BMI, SAPS II, and anticoagulation (AT or low-dose heparin) as cofactors, only anticoagulation (AT; P = 0.002) and gender (male; P = 0.046) had a significant positive influence on the dependent variable filter lifetime.

Table 3

Table 3

Data were available for 13 CRRT filters with total filter lifetimes of 581 hours for patients anticoagulated with single doses of AT, and 24 CRRT filters with total filter lifetimes of 631 hours for patients anticoagulated continuously with low-dose heparin, respectively.

Baseline characteristics are given in Table 1; laboratory variables and survival data are shown in Table 2. All included patients had advanced liver cirrhosis equivalent to Child-Pugh class C and were undergoing CRRT. On average, 84 ± 59 IU (mean ± SD) of AT (AT group) or 471 ± 207 IU (mean ± SD) of heparin (heparin group) were given per hour of filter lifetime during CRRT, respectively.

Table 2

Table 2

Table 1

Table 1

Coagulation at the start of first CRRT was impaired in both groups including low AT levels, prolonged global clotting tests, and decreased platelets. However, D-dimer levels were elevated in all patients (Table 2).25 Two patients in the heparin group and 1 patient in the AT group presented with pronounced DIC, represented by markedly elevated D-dimer levels (51–120 µg/mL), low platelets, low fibrinogen, and minor bleeding from their mouth, nose, and/or venipuncture sites.

In the AT group, AT levels could be significantly increased by single doses of AT (P ≤ 0.001; Table 2 and Fig. 1A). Likewise, aPTT could be prolonged significantly in the heparin group (P ≤ 0.001; Fig. 1B). There was no significant correlation between mean filter lifetime and AT levels.

Figure 1

Figure 1

Clotting rates of single filters were significantly decreased in the AT group, whereas the number of patients with one or more clotted filters was similar between the 2 groups (Table 3). Significant bleeding complications were similar in both groups and seen in 2 patients anticoagulated with AT and in 3 patients receiving low-dose heparin. The 2 patients in the AT group and 2 patients in the low-dose heparin group were already presenting with bleeding complications before CRRT. Thus, new onset of significant bleeding was seen only in 1 patient in the low-dose heparin group.

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DISCUSSION

Anticoagulation during CRRT in critically ill patients with advanced liver cirrhosis and a concomitant bleeding disorder is challenging because both conditions are associated with procoagulant and anticoagulant states at the same time.26,27 As expected, we found elevated D-dimer levels and abnormal coagulation tests in all included patients.25 Three patients presented with pronounced DIC manifested by markedly increased D-dimer levels, low platelets and fibrinogen, as well as minor bleeding from their mouths, noses, and/or venipuncture sites. Although diagnosis of DIC in patients with severe liver cirrhosis is challenging, we regarded markedly elevated D-dimer levels (≥50 µg/mL) and active bleeding as the decisive factors. DIC in these patients was likely caused by sepsis.

Based on our findings, we believe heparin at therapeutic doses as derived from the ASSENT III trial24 should be avoided because of the increased risk of systemic hemorrhage. Moreover, regional citrate anticoagulation is challenging because citrate may be metabolized inadequately.8,10–12 Although there are reports of CRRT without any anticoagulation in this patient group, only filter lifetimes of approximately 10 hours were achieved.8 Critical illness is associated with reduced AT levels,28 which are linked to shorter filter lifetimes.18 AT concomitantly administered with heparin led to prolonged filter lifetimes.18 Similarly, AT levels in patients with liver cirrhosis are decreased by approximately 40%.29 Therefore, and because of the high risk of bleeding, in the present analysis, only a single-dose administration of AT as the sole anticoagulant in critically ill patients with advanced liver cirrhosis was evaluated.

In the AT group, we did not aim to supplement AT levels to 80% to 100% as in patients with hereditary AT deficiency because of the increased bleeding risk of patients with advanced liver cirrhosis. However, our target was a 20 to 30 percentage point increase in AT activity, similar to the increase achieved in critically ill patients with sepsis and septic shock.18,22

In the AT group, we observed mean single-filter lifetimes of 45 ± 29 hours, which was significantly longer than filter lifetimes in the control group receiving low-dose heparin (26 ± 23 hours). Probably based on the lower number of cases and the distribution of filter periods among patients, this difference lost statistical significance when comparing means of individual patients (Table 3). The improved lifetime of single filters was confirmed in a multivariate linear regression model where only anticoagulation (AT) and gender (male) had a significant positive influence on the dependent variable filter lifetime. The influence of gender on filter lifetime in this statistical model cannot be explained from the present data and should be evaluated in future prospective trials.

Bleeding rates of 30% to 40% are reported when not using anticoagulation in patients with liver disease,8 which is comparable to the present study (Table 3). The 2 patients in the AT group presenting with active bleeding and 2 of 3 patients in the low-dose heparin group were already presenting with lower GI or pharyngeal bleeding requiring blood transfusions before CRRT. Thus, new onset of significant bleeding episodes was seen in only 1 patient in the low-dose heparin group.

Our evaluation suggests that bleeding might not be increased by AT administration. One of the patients in the AT group presented with cutaneous bleeding around the CRRT catheter (11 hours after AT application) and pronounced DIC manifested by markedly increased D-dimer levels and low platelets and fibrinogen; the other patient had skin bleeding around the arterial line (30 hours after AT application) and upper GI bleeding from a visible vessel at the anastomosis of a Billroth II operation (4 days after AT administration). In our opinion, these events were unlikely to be caused by the administration of AT single doses because the time difference between the respective AT administration and the bleeding events was rather long. AT half-life is reported to be approximately 20 hours in ICU patients and is decreased to 4.4 hours in patients with pronounced DIC.30 However, a causal relationship cannot be fully excluded.

Of note is that clotting rates of single CRRT filters were significantly lower in the AT group compared with the heparin group, whereas statistical significance was lost when comparing number of patients with 1 or more clotted filters (Table 3). AT was administered as a single dose with subsequent determination of respective serum levels every 24 hours.

An important cause for the hypercoagulability in critically ill patients with advanced liver cirrhosis is the underlying DIC, which is especially present when AT levels are below 30%.19 AT is a potent inhibitor of the coagulation cascade by stabilizing thrombin21 and has been in clinical use for many years to treat DIC.31,32 Furthermore, AT showed inhibition of platelet aggregation in experimental settings via the following mechanisms: AT binds syndecan-4, an AT-binding cell-surface heparan sulfate proteoglycan present on platelets,33 decreases the release of tissue factor and proinflammatory cytokines,34 and increases endothelial prostacyclin synthesis.35 Thus, we believe that the beneficial effects of AT anticoagulation in our study patients were based on AT attenuating DIC by antiinflammatory effects and by direct inhibition of platelet aggregation.

Lafargue et al.18 found that continuous administration of AT may be superior to bolus administration in filter lifetime during CRRT in septic patients with hereditary AT deficiency. However, our patients were treated in 2006–2008 when these data were not yet available to us. The present study has certain limitations that need to be considered. Although the study hypothesis had been proposed before data collection, the retrospective design per se is prone to bias. The second major limitation is the small sample size.

Furthermore, anticoagulation with AT is compared with only low-dose heparin, and not with heparin at a standard dose. Nevertheless, in the present patient group, low-dose heparin significantly increased aPTT levels, comparable to the effect of standard-dose heparin in healthy patients. Improved filter lifetimes with low complication rates compared with controls were observed, even in severely ill patients prone to extremely high complication rates during CRRT. Therefore, our data suggest that single-dose administration of AT may be feasible as an alternative anticoagulant to continuously administered low-dose heparin in critically ill patients with advanced liver cirrhosis during CRRT.

The limitations of our investigation include the small sample size, the heterogeneous population of critically ill patients, and the retrospective analysis. Furthermore, because of the small sample size, sufficient safety information cannot be obtained from our analysis. Additional prospective, randomized, controlled trials are necessary to confirm our observations.

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DISCLOSURES

Name: Richard Brunner, MD.

Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.

Attestation: Richard Brunner has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.

Conflicts of Interest: Richard Brunner received a travel grant (EUR 500) by CSL Behring (manufacturer of the study drug Kybernin® P/AT) in March 2011 to pay the congress fee of the International Symposium on Intensive Care and Emergency Medicine in Brussels, Belgium, where he presented preliminary data in abstract form of the present study.

Name: Waltraud Leiss.

Contribution: This author helped analyze the data.

Attestation: Waltraud Leiss has seen the original study data and approved the final manuscript.

Conflicts of Interest: The author has no conflicts of interest to declare.

Name: Christian Madl, MD.

Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.

Attestation: Christian Madl approved the final manuscript.

Conflicts of Interest: The author has no conflicts of interest to declare.

Name: Wilfred Druml, MD.

Contribution: This author helped write the manuscript.

Attestation: Wilfred Druml approved the final manuscript.

Conflicts of Interest: The author has no conflicts of interest to declare.

Name: Ulrike Holzinger, MD.

Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.

Attestation: Ulrike Holzinger has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.

Conflicts of Interest: The author has no conflicts of interest to declare.

This manuscript was handled by: Jerrold H. Levy, MD, FAHA.

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ACKNOWLEDGMENTS

We thank Dr. Reinhard Kitzberger, Dr. Wolfgang Miehsler, and Prof. Harald Herkner for their commitment to the study.

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