Alteration of the CPB Circuit When Using Direct Thrombin Inhibitors
Robert C. Groom, MS, CCP
Director of Cardiovascular Perfusion
Maine Medical Center
Portland, Maine Medical Center
groomr@mmc.org
Introduction
Thrombocytopenia is one of the most common laboratory abnormalities found
among hospitalized patients.i Serologically proven Heparin Induced
Thrombocytopenia (HIT) is a severe thrombotic disorder that occurs in 1.5 -3%
of patients with heparin exposure. Do to the intense activation of the hemostasis
mechanism that occurs with cardiopulmonary bypass (CPB), substantial levels of
anticoagulation with heparin is requisite to prevent thrombosis within the CPB
circuit and within the patient.ii,iii However, re-exposure of HIT patients to heparin
results in catastrophic complications and death. Heart surgery patients with HIT
may be managed safely using a direct thrombin inhibitor (DTIs) for
anticoagulation. However, some modification of the CPB circuit and perfusion
techniques is necessary.
The aim of this lecture is to:
1) Review alteration of the CPB circuit that are necessary when direct thrombin
inhibitors are used in place of heparin
2) Describe patient management strategies and monitoring of anticoagulation
during CPB when DTIs are used
3) Discuss challenges that may arise during such procedures .
While, none of the currently available anti-coagulants are ideal, according to
Poetzsch and Madlener the ideal drug should have the following characteristics:
1). The agent should be effective in minimizing activation of coagulation
during CPB.
2) A rapid and simple method of monitoring its anti-coagulating effects
should be available to avoid inappropriate under- or over anticoagulation.
3) Rapid and complete reversibility of the anti-coagulating effects is
important to minimize postoperative bleeding complications.iv
Currently, the most common heparin alternative anticoagulation strategy involves
the use of DTIs as a substitute for unfractionated heparin. Bivalrudin and
Argatroban are most common agents. Bivalrudin is more frequently used
because of its shorter half-life.
Of note, an alternative method of managing anticoagulation is the administration
of a platelet inhibitor (ie. iloprost or tirofiban) at a dose sufficient to block platelet
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Alteration of the CPB Circuit When Using Direct Thrombin Inhibitors
aggregation prior to administration of a full dose of unfractionated heparin with
continuous infusion of the platelet inhibitor until the heparin has been reversed.
CPB Circuit Alterations/Management
A CPB circuit comprised of tubing or components that are coated with heparin
(ie. Carmeda coating Medtronic, Minneapolis, MN) should not be used. While
closed circuits may have a theoretic advantage, both open (hard shell venous
reservoir) or closed (collapsible venous reservoir) circuit have been used with
success.v Of major concern are the areas of stasis within the circuit that are
exposed to blood where the flow of blood is intermittent. These areas must be
identified and steps should be taken to prevent prolonged stasis (for more than
15 minutes) in these areas.
Common areas where this may occur and strategies to mitigate the stasis are
shown in the table below:
Area
Cardiotomy Reservoir
Venous Reservoir
Oxygenator shunts
Arterial Filter Purge line
Arterial Filter bypass bridge
Strategy
Avoid holding blood in the cardiotomy reservoir
Maintain minimum safe level (600-800mls). Remove excess
Blood and store in transfer bags with citrate anticoagulant)
Open shunts briefly every 10-15 minutes for 3 sec.
Keep filter purge open during CPB
Remove clamp to bridge for 1 sec every 10-15 minutes
Blood Cardioplegia System
Cardioplegia Delivery Line
Flush continuously / or dose @15min intervals / or flush
between doses. Administer dose @15min/or flush between doses
Arterial Line and Cannulae
Post CPB
Flush cannulae by infusion of 50ml of blood every 3 minutes
Not uncommon to see clotted pooled blood. Use a pericardial sum
Blood in the pericardial well or To keep blood evacuate from these areas.
plural spaces
Bivalirudin has a 25 minute half-live with 80% of it being eliminated by circulating
proteases and approximately 20% of the drug by the kidneys. It may be
necessary to reduce the continuous infusion rate in patients with renal
dysfunction. It is important to note that elimination of the drug is slower at lower
temperatures. Approximately 15 to 20 minutes before separation from bypass,
the continuous infusion of the drug should be discontinued. Immediately
following bypass, ultrafiltration with a 65,000 Dalton filter has been successfully
used to increase the removal rate of direct thrombin inhibitors followingvi,vii Use of
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Alteration of the CPB Circuit When Using Direct Thrombin Inhibitors
hypothermia will prolong the half-life of bivalirudin and must be considered in
managing the continuous infusion. Furthermore, it is important to rewarm
completely before separation from bypass to allow more rapid elimination of the
drug. Argatroban has a half-life of 39-51 minutes which may result in more loss of
blood following CPB due to the longer elimination period.v Argatroban is
eliminated by the liver and may the drug of choice for patients with compromised
renal function. Following separation from bypass the arterial and venous lines
should be connected and blood should be circulated and a continuous infusion of
the DTI should be administered in the circuit to prevent thrombus formation. The
blood in the pump should be processed with a cell saver within fifteen minutes of
stopping the continuous infusion to the pump and cessation of circulation of the
blood in the circuit.
Anticoagulation Monitoring
Careful monitoring of anticoagulation is critical when DTIs are used. The type of
point of care test used will depend which DTI is used. Optimal anticoagulation
tests for various drugs are as follows;
Argatroban –ACT
Danaparoid-Antifactor Xa level
Lepirudin – ECT
Bivalirudin- ECT preferred (ACT has been reported).
Murphy and Marymount have reported the following recommendations from the
ACCP.viii,ix
Clotting time must be monitoring during CPB to determine adequate
anticoagulation and it is used following CPB to evaluate the elimination of the DTI
and the return of hemostasis. Several studies have shown that the ecarin
clotting time (ECT) has better correlation than Activated Clotting Time (ACT)
with actual drug levels particularly at higher plasma concentrations (r = 0.71 for
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Alteration of the CPB Circuit When Using Direct Thrombin Inhibitors
Hemochron ACT vs. r = 0.90 for the TIM-ECT) and inhibition of coagulation. The
ECT can be performed with the TIM-ECT test card, designed for use with the
Thrombolytic Assessment System (TAS, Bayer Diagnostics; Rapidpoint Coag
Analyzer, Morrisville, North Carolina).x ECT tests may also be carried out using
an ecarin clot activator with the Thromboelastographxi,xii or with the Rotational
Thromboelastometry (ROTEM)xiii. However, many centers use a standard ACT
point of care test. A clotting time of 2.5 times the baseline ACT value is the
widely accepted target.
Challenges
Management of coagulation during CPB with a direct thrombin inhibitor must be
carried out with the utmost precision xiv,xv,xvi. The patient’s sensitivity to heparin
must be clearly communicated to all members of the team and vials of heparin
should be removed from medication trays in the operating room and care units
to prevent inadvertent administration. A continuous infusion of the DTI must be
maintained during CPB and be discontinued prior to the planned separation from
CPB. It is not uncommon to see clots forming in the pericardial and plural
spaces during CPB. The CPB circuit should be frequently inspected for
formation of clot in the cardiotomy reservoir, venous reservoir, oxygenator and
arterial filter. The perfusion team should anticipate the possible need to replace
some or all of these components However catastrophic hemorrhage and
associated massive transfusion has been reportedxvii and is likely more common
that thromboembolism in the cardiac surgery setting. An autotransfusion device
with a calcium chelating anticoagulant (CPDA or ACD) should be available for
blood loss following separation from CPB. The team should anticipate excessive
bleeding after separation from bypass and have appropriate topical hemostatic
agents, sufficient replacement blood components, point of care testing to
determine platelet, plasma, and red cell replacement requirements and rapid
volume infusion capability.
i
Warkentin T, Levine MN, Horsewood P, Roberts RS, et al. Heparin-induced thrombocytopenia in
patients treated with low molecular weight or unfractionated heparin. N Engl J Med
1995;332:1330-5.
ii
Edmunds LH Jr. Blood-surface interactions during cardiopulmonary bypass. J Cardiovasc
Surg 1993; 8:404–410.
iii
Slaughter TF, LeBleu TH, Douglas JM Jr, Leslie JB, Parker JK, Greenberg CS.
Characterization of prothrombin activation during cardiac surgery by hemostatic
molecular markers. Anesthesiology 1994; 80:520–526.
iv
Poetzsch and Madlener Management of Cardiopulmonary Bypass Anticoagulation in Patients
with Heparin-Induced. Thrombocytopenia chapter in Heparin Induced Thrombocytopenia 3 rd
Edition Warkentin TE and Greinacher A ISBN: 0-8247-5625-8. Marcel Dekker, Inc., Cimarron
Road, Monticello, New York 12701, U.S.A. 2004.
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Alteration of the CPB Circuit When Using Direct Thrombin Inhibitors
v
Veale JJ, McCarthy HM, Palmer G, and Dyke CM. Use of Bivalirudin as an Anticoagulant During
Cardiopulmonary Bypass. JECT. 2005;37:296–302.
vi
Saravanan P, Rege K, and Falter F. Use of continuous venovenous hemofiltrationfor reversal of
anticoagulation with Lepirudin Post Cardiopulmonary bypass in a patient with HIT. J Card Vasc
Anes 21;2007:269- 72.
vii
Koster A, Merkle F Hansen R et al. Elimination of recombinant hurudin by modified
ultrafilteration during subbing simulated CPB Asssessing different filter systems Anesth Analg
2000: 91;265-269.
viii Murphy GS and Marymont JH. Alternative Anticoagulation Management Strategies for the
patient with Heparin-Induced Thrombocytopenia undergoing cardiac surgery. J thorac Cardiovasc
Anes 2007;21:113-26.
ix
Warkentin T , GreinacherA HIT Recognition, treat and prevention. The seventh ACCP
Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004: 126:311S-37S.
x
Cho L, Kottke-Marchant K, Lincoff AM etal. Correlation of Point-of-Care Ecarin Clotting Time
Versus Activated Clotting Time With Bivalirudin Concentrations. The American Journal of
Cardiology 2003;91: 1110-1012.
xi
Carroll RC, Chavez JJ, Simmons JW, Snider CC, Wortham DC, Bresee SJ, Cohen E.
Measurement of patients' bivalirudin plasma levels by a thrombelastograph ecarin clotting time
assay: a comparison to a standard activated clotting time. Anesth Analg. 2006 May;102(5):13169.
xii
Koster A,Buz S, Krabatsch T, Dehmel F, Hetzer R, Kuppe H and Dyke C.
Monitoring of Bivalirudin Anticoagulation During and After Cardiopulmonary Bypass Using an
Ecarin-Activated TEG® System. Journal of Cardiac SurgeryVolume 23, Issue 4, pages 321–
323, July/August 2008
xiii
Schaden E, Schober A, Hacker S, Kozek- Langenecker S. Ecarin modified rotational
thromboelastometry a point of care alternative to monitor the direct thrombin inhibitor argatroban.
Central European Journal of Medicine Wien Klin Wochenschr DOI 10.1007/s00508-013-0327-1
xiv
Dyke CM, Koster A, Veale JJ, Maier GW, McNiff T , Levy G. Preemptive use of bivalrudin for
urgent on-pump coronary artery bypass grafting in patients with potential HIT. Ann Thorac Surg
2005;80:299-303
xv
Koster A, Spiess B, Chew D. Effectivenesss of bivalirudin as a replacement for heparin during
CPB in patients undergoing CABG . Am J Cardiol 2044;93:356-9.
xvi
Koster A, Yeter A, Buz S etal. Hemostatic activation during normothermic CPB with Bivalirudin;
results of the second pilot study to assess”on-pump” CABG with bivalirudin J Thorac Cardiovasc
Surg 2005;129:1391-4.
xvii
Gasparovic H, Natahan NS, Fitzgerald D, and Aranki SF. Servere Argatroban induced
coagulatopathy in a patient with a history of HIT. Ann Thorac Surg 2004;78e89-91.
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