Extracorporeal life support (ECLS) is a form of respiratory or cardiac support used in patients who have temporary and reversible respiratory with or without cardiac failure. The inflammatory and coagulation response because of contact of circulating blood with the nonbiologic surface of the ECLS circuit is responsible for the high risk of hemorrhagic and thrombotic complications of ECLS. To prevent thrombotic events as a result of this procoagulant state, systemic anticoagulation is the standard of care.1
Conventionally, continuous infusion unfractionated heparin has been the mainstay of anticoagulation during ECLS. Limitations to using heparin include acquired antithrombin deficiency, unpredictable pharmacokinetics and pharmacodynamics, heparin allergies, and heparin-induced thrombocytopenia. Heparin relies on the presence of antithrombin to exert its anticoagulant effect. Acquired antithrombin deficiency can occur in critically ill patients and may result in heparin resistance.1 In the setting of ECLS, however, antithrombin supplementation has not influenced the measured or clinical response to heparin.2–4 Additionally, significant inter-and intrapatient variability in heparin dosing exists because of various levels of heparin-binding proteins and potential enhanced clearance in pediatrics.5 Finally, heparin-induced thrombocytopenia (HIT) is an immune-mediated adverse drug reaction with a reported incidence of 1–5% that can result in arterial and venous thrombosis in patients treated with heparin.6,7
Bivalirudin is a direct thrombin inhibitor (DTI) with the ability to bind both circulating and clot-bound thrombin independent of antithrombin activity. It is Food and Drug Administration–approved for use during percutaneous coronary intervention and angioplasty.8 Bivalirudin has been studied in a variety of cardiac populations and has been used for the treatment of HIT.7 However, the optimal dosing and monitoring of bivalirudin in adult ECLS patients is still not well defined and use is variable.9,10 Given this limited published evidence, we sought to assess the dosing and outcomes associated with bivalirudin use in an adult ECLS population.
Materials and Methods
This was a single-center, retrospective, observational analysis of adult ECLS patients conducted at the University of California, Davis Medical Center (UCDMC). This study was approved by the UCDMC Investigational Review Board. Adult patients who received bivalirudin between July 2006 and September 2016 during ECLS were identified from UCDMC ECLS program records and included for analysis. Data extracted from ECLS program, electronic, and written medical records included demographic information, ECLS indication and duration, bivalirudin dosing and monitoring, thrombosis and bleeding events, and survival. Descriptive statistics were used to analyze the data.
Institution Extracorporeal Life Support Protocols
Extracorporeal life support circuit designs used in adult patients during the study period included either Biomedius Bio-Pump BP 80 with an Affinity NT oxygenator (Medtronic, Minneapolis, MN) or after 2009, Jostra Rotaflow Centrifugal Pump with Quadrox iD Adult Bioline-coated oxygenator (MAQUET GmbH & Co. KG, Rastatt, Germany). Adult circuits included Medtronic Carmeda Coating Tubing in 3/8″ (Medtronic) and incorporated the Cincinnati Sub-Zero Hemotherm (Cincinnati, OH).
Unless a contraindication was present, heparin was the first-line anticoagulation during ECLS. Antithrombin supplementation was not used during the study period because of lack of evidence regarding the optimal maintenance of antithrombin levels during ECLS. For patients experiencing HIT, heparin resistance, or evidence of clinically concerning thrombosis while on heparin, bivalirudin was the alternate anticoagulant used. Each patient receiving bivalirudin was evaluated and monitored by a clinical pharmacist working with the primary medical team; no standardized bivalirudin dosing protocol existed during the study period. The heparin infusion was stopped at the same time the new bivalirudin infusion was started. Bivalirudin bolus doses were not routinely administered.
While on bivalirudin, activated partial thromboplastin time (aPTT) values were initially measured every 2 to 6 hours, and infusions were adjusted to maintain individualized aPTT target ranges. Individualized aPTT targets were generally in the range of 1.5–2.5 times the patient’s baseline aPTT. However, this target range could be modified by the medical team based on each patient’s relative risk of bleeding versus thrombosis (i.e., a patient with bleeding concerns may target an aPTT range of 1.5–2.0 times baseline). The aPTT value was based on a bivalirudin response curve done with each aPTT reagent lot. The laboratory used Actin FS (Siemens) for the aPTT reagent and the BCSXP analyzer (Siemens) before 2009. From 2009 to 2016, the laboratory used SynthASil (Instrumentation Laboratories) for the aPTT reagent with the ACL TOP700 analyzer (Instrumentation Laboratories).
Transfusion thresholds were based on clinical experience and compared with recommendations within the ELSO Anticoagulation Guidelines.11 Packed red blood cells were transfused to maintain hematocrit greater than 25–30% depending on the underlying diagnosis. Platelets and cryoprecipitate were transfused to maintain platelet counts greater than 100,000/m3 and fibrinogen greater than 100 mg/dL, respectively. Fresh frozen plasma was transfused to maintain an international normalized ratio (INR) less than 1.3. However, since a laboratory interaction with DTIs causes a prolongation of the INR, fresh frozen plasma was only transfused in patients receiving bivalirudin in the setting of an elevated INR and bleeding.
Fourteen adult patients met inclusion criteria. Demographic and ECLS information is displayed in Table 1. The median patient age was 36 years (range 18–78 years), and 64% were male. The primary indication for ECLS was acute respiratory distress syndrome in 12 patients, and two patients required ECLS for cardiogenic shock after cardiac surgery. Most patients (n = 11, 79%) were maintained on venovenous ECLS. Median duration of ECLS was 189 hours (range 42–675 hours).
Indications for bivalirudin are displayed in Table 2 and included confirmed or suspected HIT, heparin resistance, persistent clotting while on heparin, or significant bleeding on heparin. HIT was suspected in 11 patients; of those, two had a confirmed HIT diagnosis before ECLS cannulation. Nine patients developed a suspicion for HIT during their ECLS course, and of those, six had positive HIT enzyme-linked immunosorbent assays. Of the three patients with negative HIT enzyme-linked immunosorbent assays, two had experienced a 50% decrease in platelets without thrombosis noted and one had persistent thrombocytopenia associated with circuit and right internal jugular thromboses while on appropriate heparin therapy. Heparin resistance was suspected in one patient whose aPTT and anti-Factor Xa activity levels remained subtherapeutic despite heparin infusion rates up to 50 units/kg/h. One patient had persistent clotting of the ECLS circuit despite therapeutic aPTT values and anti-Factor Xa activity levels on heparin. One patient was transitioned to bivalirudin for persistent hematuria and cannulation site oozing. In this patient, activated clotting time measurements were in goal range but aPTT and anti-Factor Xa activity were elevated while on heparin.
A bivalirudin bolus dose of 0.2 mg/kg was used in only one patient to facilitate ECLS cannulation. The remainder of patients had the bolus dose omitted before initiating the bivalirudin infusion. The initial infusion rate ranged from 0.02 to 0.26 mg/kg/h. The median time to target aPTT was 3.9 hours (range 0.4–16.5 hours), and the time to 90–110% target aPTT was 3 hours (range 0.4–13.7 hours).
The initial target aPTT range was achieved with maintenance bivalirudin doses ranging from 0.04 to 0.26 mg/kg/h with a median rate of 0.15 mg/kg/h. Patients who received continuous renal replacement therapy (CRRT) were observed to have higher maintenance bivalirudin dosing requirements than those not on CRRT, with a median dose of 0.21 mg/kg/h. Four patients were transitioned onto CRRT during their bivalirudin ECLS course. Three of these patients required an increase in their bivalirudin maintenance dose to maintain target aPTT values. One patient (case 9) had a decrease in their bivalirudin maintenance dose upon transition to CRRT, likely as a result of a reduction in their aPTT target.
Additionally, of the nine total patients who received CRRT while on bivalirudin, dosing requirements were observed to increase for a period of time after CRRT initiation as displayed in Figures 1 and 2. Excluding case 9 because of reduced aPTT goals, the median maximum rate patients were titrated to in order to maintain aPTT target range was 0.36 mg/kg/h from the initial median rate of 0.21 mg/kg/h. Individual patients required between 75% and 125% bivalirudin rate increases over the first 48–120 hours on CRRT. For seven of those patients, once they reached their maximum maintenance rate, they remained on that rate for the remainder of their ECLS course, which ranged from 2 to 8.5 days.
Median time on bivalirudin infusion was 5.2 days with a maximum of 28 days. The average time spent within target aPTT range and 90–110% target aPTT range was 76% and 95%, respectively. Five patients (36%) required a circuit change while on bivalirudin because of clotting or failing oxygenation. The first case required a total of 7 circuit changes over the 28 day time span on ECLS. For the remaining cases, two circuit changes occurred within 24 hours of the switch to bivalirudin (at 3 and 22 hours) because of previously developed clots within the circuit and the other two occurred between 4.5 and 5.3 days after bivalirudin initiation.
Four patients (28.6%) had bleeding significant enough to require either reduction in aPTT goals or temporary hold of bivalirudin infusion. No rescue recombinant activated factor VII or activated prothrombin complex concentrates were given. One patient (case 1) developed a gastrointestinal bleed and had bloody output from chest tubes which required surgical intervention and repeat thoracotomies. Two patients, who initially had bleeding complications (hematuria for case 5 and alveolar hemorrhage for case 7) on heparin, had recurrence of their bleeding event while on bivalirudin, and aPTT goals were reduced to compensate. The patient with recurrent alveolar hemorrhage additionally received aminocaproic acid during this time. No other patients in the study period received aminocaproic acid. Case 14 initially had high aPTT goals on bivalirudin given high concern for ECLS circuit clotting. After developing hematuria, continued oozing from ECLS cannulation sites, and limited aPTT response to increased bivalirudin infusion rates, no further up-titrations were allowed.
Median hospital length of stay was 36 days (range 15–107). Nine patients (64%) survived to successful ECLS decannulation, and seven patients (50%) survived to hospital discharge.
The use of nonheparin anticoagulants is uncommon during ECLS; however, DTIs (i.e., argatroban, bivalirudin, lepirudin) have been used when clinically indicated by some centers.9 Among the DTIs, bivalirudin has an advantageous pharmacological profile including a shorter half-life and limited reliance on organ function for clearance.8,12,13 Experience with bivalirudin in cardiac surgery, cardiopulmonary bypass, and HIT also lends a level of familiarity with the agent.7 However, optimal dosing strategies within the ECLS population have not been well defined.
A systematic review conducted by Sanfilippo et al.10 identified two retrospective case–control studies, one case series, and five case reports reporting on bivalirudin use in patients maintained on ECLS. A total of 21 adult patients received bivalirudin with infusion rates ranging from 0.028 to 0.2 mg/kg/h with or without initial bolus doses.10 This wide variability in dosing requirements was also observed in our present analysis with maintenance rates achieving target aPTT ranges of 0.04 to 0.26 mg/kg/h. Individualized aPTT goals and variable renal function in our sample likely contributed to the observed variability in dosing requirements.
At UCDMC, aPTT goals for bivalirudin were determined based on anecdotal experiences with the first few patient cases. This experience resulted in the selection of an initial aPTT goal of 1.5 to 2.5 times the mean baseline aPTT. All aPTT goals were set by the attending physician and were adjusted based on each patient’s clinical presentation. Depending on clinical concern for bleeding or thrombotic events, aPTT goals may change over time for an individual patient, which can contribute to changing bivalirudin requirements over time. This variability in coagulation goals and monitoring has previously been reported in systematic reviews and surveys of Extracorporeal Life Support Organization centers.9,10
Second, the heterogeneity of the current analysis in regards to renal function likely impacted dosing requirements. Bivalirudin dose reductions in the setting of impaired renal function have previously been described. In patients receiving treatment for HIT, reductions of approximately 40% and 60% for CrCl 30–60 mL/min and CrCl <30 mL/min were required.14 Bivalirudin can also be removed during hemofiltration.15 Doses were lower in patients receiving renal replacement therapy than observed for patients with normal renal function (CrCl >60 mL/min), but greater than those in patients with impaired function but not receiving dialysis.14 Similarly, in the case–control study conducted by Pieri et al.16 in adult ECLS patients, patients undergoing hemofiltration required higher doses than those without. Although this trend appeared to be consistent in the current analysis, drawing conclusions from the data is limited because of the small sample size and number of patients within different CrCl ranges.
To our knowledge, this is the first report to describe increasing dosing requirements over the 48 to 120 hours after initiation of CRRT. It should be noted that in some patients, the expected aPTT response is not observed despite notable increases in the bivalirudin infusion rates. For two patients in this analysis, despite increasing bivalirudin rates to 0.5 mg/kg/h, the aPTT response was very limited. Although no thrombotic events were observed in these patients, bleeding events prompted the ordering of a dose-cap on the infusion rate to prevent further uptitrations. Downward dose titrations were kept in place as it was observed that at some point in therapy, the aPTT would begin to respond. Although it is known that there is a flattening of the dose response curve for the aPTT with parenteral DTIs, the observation of little response for a period of time followed by a robust response is unique.17,18 In addition to potential dose capping, if this phenomenon is suspected, alternative laboratory tests, such as thrombin time, low-range cartridge activated clotting time, ecarin clotting time, or dilute thrombin time may be used to monitor DTI effect if they are readily available.18
The results of this analysis are unable to provide guidance regarding bolus dosing of bivalirudin in this patient population. Only one patient received a bolus loading dose of 0.2 mg/kg bivalirudin at the time of ECLS cannulation. Given the relatively short-half of bivalirudin (25 minutes), onset of anticoagulation effect and achievement of steady state is rapid, and a bolus loading dose may not be necessary outside of acute thrombus or subtherapeutic anticoagulation levels.8 This limited use of bivalirudin bolus doses appears to be consistent with current literature in this population as the majority of investigators did not see a need to administer a bolus dose.10 However, in the adult cases of a patient with arterial thrombus by Pollak et al.19 and a patient with a mechanical aortic valve conduit by Koster et al.,20 bolus loading doses of bivalirudin up to 0.5 mg/kg appear appropriate given the clinical indications.
The duration of bivalirudin use in this analysis accounts for a substantial time period that patients would be at risk for bleeding and thrombotic complications. Registry data report hemorrhagic and thrombotic complications in 10–33% of patients on ECLS.9 Although the current study had limited ability to identify and classify these outcomes because of limitations with retrospectively available documentation, the identified rate of 29% of patients experiencing a bleeding event is consistent with previous literature. Additionally, the rate of thrombotic complications leading to circuit changes in this analysis is similar to rates reported in the literature of 23–26%,21 and average circuit oxygenator life spans range from 2.5 to 5.8 days22,23 depending on type of oxygenators used.
Finally, this study was not designed to compare bivalirudin to heparin in this population. In the comparison study conducted in postcardiotomy veno-arterial extracorporeal membrane oxygenation patients, bivalirudin appeared to limit bleeding and amount of allogenic blood product administration as compared with heparin therapy.24 Additionally in an adult ECLS population, Pieri et al.16 observed less aPTT variation with bivalirudin and a nonsignificant decrease in bleeding and mortality with bivalirudin as compared with heparin. Given the limited sample sizes (n = 21 and 20, respectively) and additional retrospective study limitations in these two case–control studies, definitive conclusions regarding superiority of bivalirudin over heparin are unable to be made. A pharmacoeconomic analysis including clinical outcomes, such as circuit life span, bleeding events, and blood product transfusions, is needed to define the potential role of bivalirudin in the general ECLS population.
To our knowledge, this is the largest case series of bivalirudin use in adult ECLS patients who develop HIT, heparin resistance, or significant clotting while on heparin. Significant intra- and interpatient variability, along with renal replacement therapy, contributed to variable dosing requirements within this population. A lack of aPTT response was also noted in a few cases. This should be taken into consideration along with capping the maximum infusion rate when a substantial dosing increase without aPTT response is observed. Although experience has been favorable, relatively high rates of thrombotic and hemorrhagic complications in the ECLS population warrant further studies to examine the safety and efficacy of bivalirudin use in adult ECLS.
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Keywords:Copyright © 2019 by the American Society for Artificial Internal Organs
anticoagulation; bivalirudin; extracorporeal life support; extracorporeal membrane oxygenation; renal replacement therapy