Argatroban for anticoagulation in continuous renal replacement therapy* Andreas Link, MD; Matthias Girndt, MD; Simina Selejan, MD; Alexander Mathes, MD; Michael Bo¨hm, MD; Hauke Rensing, MD Objective: Argatroban, a direct thrombin inhibitor, was evalu- during CRRT could be determined: a loading dose of 100 ␮g/kg ated for anticoagulation in continuous renal replacement therapy followed by a maintenance infusion rate (␮g/kg/min), which (CRRT) in critically ill patients with heparin-induced thrombocy- can be calculated from the scores as follows: for APACHE II: 2.15– ؊.81, p < 0.001); for SAPS II: 2.06–0.03 ؋؍ topenia type II and acute renal failure. The investigation focused 0.06 ؋ APACHE II (r ؊.8, p < 0.001); and for ICG-PDR: ؊0.35 ؉ 0.08 ؋؍ on predictors for the maintenance doses of argatroban with SAPS II (r -p < 0.001). The efficacy and safety of anticoag ,89. ؍ efficacy and safety of argatroban being secondary outcomes. ICG-PDR (r Design: Prospective, dose finding study. ulation during CRRT were determined by the steady state of blood Setting: Two intensive care units (medical and surgical) of a urea nitrogen (32.16 ؎ 18.02 mg/dL), mean filter patency at 24 hrs university hospital. (98%), and the rate of bleeding episodes. Only two patients devel- .with acute or oped minor bleeding; no patient developed severe bleeding episodes (30 ؍ Patients: Medical and surgical patients (n histories of heparin-induced thrombocytopenia type II and acute Conclusion: In critically ill patients with heparin-induced renal failure with necessity for CRRT. thrombocytopenia type II and necessity for CRRT critical illness Intervention: CRRT with argatroban for anticoagulation. scores (APACHE II, SAPS II) or ICG-PDR can help to predict the Measurements and Main Results: Critical illness severity required argatroban maintenance dose for anticoagulation. These scores Acute Physiology and Chronic Health Evaluation (APACHE)- predictors identify decreased argatroban dosing requirements II, Simplified Acute Physiology Score (SAPS) II, and the indocya- resulting in effective and safe CRRT. (Crit Care Med 2009; 37: nine green plasma disappearance rate (ICG-PDR) were correlated 105–110) to the argatroban maintenance doses. These diagnostic tools can KEY WORDS: continuous renal replacement therapy; heparin- help to identify patients with the necessity for decreased argatro- induced thrombocytopenia II syndrome; argatroban; multiple ban doses. The following recommendations for argatroban dosing organ failure ontinuous renal replacement inhibitors. Although danaparoid has on argatroban under hemodialysis in- therapy (CRRT) is proven ef- been used in HIT-II for a long time sev- clude case reports and small studies only fective for critically ill pa- eral major drawbacks have been reported. in patients on intermittent hemodialysis tients with (acute) renal fail- Cross-reactivity with heparin/platelet fac- (12–14) or in patients after cardiovascu- Cure (1, 2). In patients with heparin- lar surgery with cardiopulmonary by- tor 4 antibodies in 15% of cases (5), pro- induced thrombocytopenia type II longation of half-life in renal failure up to passes (15). (HIT-II) requiring CRRT effective anti- 36–48 hours (6), and an increased risk In our study, critically ill patients with coagulation, it is necessary to avoid for bleeding events in 46% (7) have been HIT-II-syndromes or histories of HIT-II thrombembolic complications (3, 4). described. Direct thrombin inhibitors, in- and necessity for CRRT were assigned to The options for anticoagulant treat- cluding argatroban and lepirudin, differ an argatroban treatment. The investiga- ment in critically ill patients with in their mode of elimination. The major tion focused on predictors for the main- HIT-II requiring CRRT are limited and route of elimination of lepirudin is renal tenance doses of argatroban with efficacy include danaparoid and direct thrombin clearance. In anuria prolonged half-lives and safety of argatroban being secondary up to 50 hrs have been reported (8). Fur- outcomes. thermore, after 5 days 44% of the pa- *See also p. 342. tients developed lepirudin antibodies that METHODS From the Klinik fu¨r Innere Medizin III (AL, SS, MB,); decrease renal clearance, increase activ- Patients and Registration Klinik fu¨r Innere Medizin IV (MG); Klinik fu¨r Ana¨sthesi- ity, and thus, augment the risk of bleed- ologie und Intensivmedizin (AM, HR), Universita¨tsklini- With approval of the Institutional Review ing (9) contributing to major bleeding kum des Saarlandes; D-66421Homburg/Saar, Board, we evaluated all critically ill patients Germany. complications (10, 11). with necessity for CRRT and clinical signs or The authors have not disclosed any potential con- In contrast, argatroban is mainly elim- history of HIT-II syndromes on the medical flicts of interest. inated by hepatic metabolism. As such, For information regarding this article, E-mail: and surgical intensive care units of the Uni- [email protected] argatroban may be the more appropriate versity Hospital of the Saarland from January Copyright © 2008 by the Society of Critical Care direct thrombin inhibitor in critically ill 2006 to June 2007. HIT-II was defined clini- Medicine and Lippincott Williams & Wilkins patients with renal impairment and with cally as an unexplained decrease of more than DOI: 10.1097/CCM.0b013e3181932394 the necessity for CRRT. Prospective data 50% in platelet count from the patients base- Crit Care Med 2009 Vol. 37, No. 1 105 line, or a platelet count lower than 100 ϫ Management and Monitoring of many) was injected central venously (0.5 mg/ 109/L while on heparin therapy, or by positive Anticoagulation kg). ICG is nearly exclusively eliminated in an local laboratory tests. HIT-II screening tests unconjugated form by the liver into the bile were performed at the University Hospital At the beginning of CRRT, all patients re- and does not undergo enterohepatic recircu- Laboratory using the particle gel immunoas- ceived argatroban at a dose of 100 ␮g/kg as a lation. Its elimination may be expressed as say (ID-HPF-4, DiaMed, Switzerland) for rapid bolus injection followed by a continuous infu- plasma disappearance rate (ICG-PDR) and can detection and the enzyme-linked immunosor- sion of 1 ␮g/kg/min. Argatroban was applied be measured noninvasively at the bedside by bent assay for discovering antibodies (IgG, into the extracorporeal circulation (prefilter transcutaneous pulse densitometry with a IgA, IgM) to heparin-platelet factor 4 com- injection/infusion). The monitoring of antico- finger clip (LiMON monitoring, Pulsion Med- plexes. Both HIT-II tests were done for all agulation was performed by repetitive mea- ical Systems, Germany). Normal values for patients. Critical illness was defined by com- surements of the systemic activated partial ICG-PDR are considered to be over 18%/min. monly used scores in intensive care medicine: thromboplastin time (aPTT) according to In general, ICG removal from the blood de- Acute Physiology and Chronic Health Evalua- standard methods. The anticoagulation regi- pends on liver blood flow, parenchymal cellu- tion II (APACHE-II, 16) and Simplified Acute men was designed to result in a 1.5- to 3-fold lar function, and biliary excretion (18, 19). Physiology Score II (SAPS-II, 17). Thus, crit- elevation of aPTT. The first measurement of ical illness and multiple organ dysfunction aPTT was done 30 minutes after starting syndromes were defined as a minimum CRRT, followed by further controls every 60 Statistical Analysis SAPS-II score of 30 points. minutes until a 1.5- to 3-fold elevated aPTT Demographical data and data on efficacy was reached. If aPTT was below the therapeu- and safety were summarized and descriptive tic range, the argatroban dose was increased statistics were computed (means Ϯ SD). For all Inclusion and Exclusion Criteria stepwise (in steps of 0.25 ␮g/kg/min). If aPTT patients the individual argatroban mainte- was more than 3-fold elevated, argatroban was Critically ill patients with manifestation or nance infusion rates were correlated to the discontinued for 2 consecutive hours and step- history of HIT-II and necessity for CRRT were initial cholinesterase levels, ICG-PDR, SAPS wise reduced (0.25 ␮g/kg/min). When the he- treated with argatroban after exclusion of clin- II, and APACHE II score (Pearson). Further- mofilter systems were routinely changed, the ically relevant bleeding signs, transient more a regression analysis was performed. A argatroban infusion was continued and no fur- thrombocytopenia, disseminated intravasal ␣-error of less than 0.05 was considered sta- ther boluses were given. In all surgical cases, coagulopathy, and preexisting chronic hepatic tistically significant. dysfunction (Child-Pugh C). Concomitant CRRT with argatroban started 24–48 hrs after treatment was performed according to best the surgical procedure. medical practice. The decision to anticoagu- RESULTS late with argatroban was made by the physi- Assessments for Anticoagulation, cian in charge according to clinical needs and Efficacy, and Safety Within 18 months, 34 critically ill pa- the inclusion and exclusion criteria. tients with clinical signs or history of Anticoagulation. For argatroban dose ti- HIT-II and necessity for CRRT were stud- tration, plasma aPTT was measured before, 30 ied. The incidence for the acute manifes- Continuous Renal Replacement minutes after starting CRRT, and every hour tation or history of HIT-II of our critically Therapy until a 1.5- to 3-fold aPTT was reached. In ill patients on medical and surgical inten- cases of a steady state, aPTT was measured sive care units during the study period Continuous venovenous hemodialysis was twice daily. All hemodialysis tubes and filters performed with a polysulfone high-flux hemo- were visually inspected for blood flow and ev- was 1.3%. A manifest HIT-II syndrome dialyzer using a roller-pump-driven hemofil- idence of clot formation. was diagnosed in 28 cases; a history of tration device manufactured by Fresenius AG Hemodialysis Efficacy. The hemodialysis HIT-II in 2 cases.