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J Thorac Cardiovasc Surg 1998;115:729-731
© 1998 Mosby, Inc.

BRIEF COMMUNICATIONS

Application of a heparin removal device in patients with knownprotamine hypersensitivity

Joseph B. Zwischenberger, MD, Roger A. Vertrees, BA, CCP, Robert L. Brunston, Jr., MD, Weike Tao, MD, Scott K. Alpard, MD, Paul S. Brown, Jr., MD

Galveston, Tex.

From the Department of Surgery, Division of CardiothoracicSurgery, The University of Texas Medical Branch, Galveston, Tex.

Address for reprints: Joseph B. Zwischenberger, MD, Division ofCardiothoracic Surgery, 301 University Blvd., University of Texas MedicalBranch, Galveston, TX 77555-0528.

Severe life-threatening reactions have been reported in association withprotamine use, including pulmonary hypertension, systemic hypotension, andanaphylactic shock, as well as thrombocytopenia, granulocytopenia, complementactivation, and cytokine release.Go 1As an alternative to protamine administration, a heparin removal device (HRD,Research Medical Inc., Midvale, Utah) uses a venovenous extracorporeal circuitwith plasma separation and poly-L-lysineaffinity adsorption to remove heparin from the blood.Go 2 WeGo 3 previously reported the firstcompassionate clinical use of the HRD to decrease life-threatening bleeding in apatient who could not tolerate protamine. Through large animal studies, weGo Go 4-6have since characterized the performance of the HRD and developed a heparinclearance mathematical model to determine the HRD run time needed for a targeted90% heparin removal based on first-order exponential depletion. Variablesaffecting the HRD efficiency, such as extracorporeal blood flow, sorbent amount,and cannula placement, have likewise been improved. The HRD returns activatedclotting time (ACT) and other measured coagulation variables to near baselinevalues in approximately 30 minutes in adult-sized subjects at the venovenousextracorporeal blood flow rate of 1400 ml/min without any apparent adverseeffects on hemodynamics.Go Go 4-6

From May 6 to May 27, 1997, two patients scheduled for elective coronaryartery bypass grafting had documented "hypersensitivity" toprotamine, and the HRD was used as an alternative to reverse systemic heparinanticoagulation. Since the HRD has not been approved by the Food and DrugAdministration, approval for compassionate use was obtained from theInstitutional Review Board of the University of Texas Medical Branch, Galveston,Texas, and informed consent was obtained from each patient before the operation.

Because of persistent angina after a recent myocardial infarction, a58-year-old woman underwent cardiac catheterization demonstrating severethree-vessel disease. On completion of her cardiac catheterization she was givenprotamine (4 mg), resulting in dizziness, an urticarial eruption, andhypotension (74/50 mm Hg). She was treated with intravenous antihistamines(Benadryl 100 mg) and steroids (Solu-Medrol 125 mg) for a presumed protaminereaction. She continued to be hypotensive, despite treatment, and received 1.5 Lof crystalloid solution and inotropic support. She recovered over 4 to 5 hoursand was referred for revascularization. After three-vessel coronary arterybypass grafting, the patient had good hemodynamics and was weaned fromcardiopulmonary bypass (CPB). To avoid protamine, we used the HRD. The rightatrial venous cannula was removed and the HRD dual-lumen venovenous cannula wasinserted through the same atriotomy. The distal port was positioned into theinferior vena cava for drainage and the proximal port at the level of the rightatrium for reinfusion, oriented toward the tricuspid valve to minimize bloodrecirculation. Blood flow was controlled by a roller pump that drained bloodfrom the inferior vena cava and pumped it through the plasma separator, whosehollow fibers allow for plasmapheresis. The strongly negatively charged heparinbinds with the strongly positively charged poly-L-lysine–agaroseto remove heparin from the blood. The heparin-depleted plasma then reenters thehollow fibers to recombine with the formed elements of the blood and return tothe patient's right atrium.

The HRD was used at a target flow rate of 1400 ml/min for 35 minutes aspredicted by our mathematical model of first-order exponential depletion for atargeted 90% heparin removal. No changes in hemodynamics occurred duringthe use of the HRD. Heparinized pump blood (700 ml) was infused via the aorticcannula to replace cardiotomy suction during the HRD run. Fig. 1 (patient A)shows the ACT time course at baseline, during the HRD run, and after theoperation. Before and after the HRD run, fibrindegradation products were less than 5 µg/ml, activated partialthromboplastin time greater than 150 seconds, and d-dimer less than 0.5 ng/ml.Platelet count was 225,000 µl immediately after CPB, 167,000 µlafter the HRD run, and 272,000 µl 3 hours after the operation. The plasmafree hemoglobin concentration was 19 mg/dl immediately after CPB, 25 mg/dl afterthe HRD run, and 3 mg/dl 3 hours after the operation. The hematocrit valueshowed typical changes related to CPB with hemodilution. The patient wastransferred to the intensive care unit with chest tube drainage of only 300 mlover the first 6 hours. No blood products including red blood cells, freshfrozen plasma, platelets, or clotting factors were given, and there was noevidence of significant bleeding or identifiable complications. She wasambulatory on postoperative day 3, discharged day 5, and is doing well 3 monthsafter the operation.



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  		Fig. 1. ACT time course atbaseline, during HRD, and after the operation.

 
A 63-year-old (136 kg) woman with a history of hypertension andinsulin-dependent diabetes had left carotid endarterectomy and three-vesselcoronary artery bypass grafting 7 years ago when profound hypotension andelevated pulmonary pressures developed immediately after protamineadministration, requiring a right ventricular injection of 300 mg ofepinephrine. The patient recently began having symptoms of congestive heartfailure resulting from critical aortic stenosis and recurrent coronary arterydisease. She underwent aortic valve replacement, a single coronary artery bypassgraft, and intraaortic balloon pump placement. She was weaned from CPB after twoattempts. The HRD dual-lumen venovenous cannula was inserted as described, andHRD at a flow rate of 1400 ml/min was used for 68 minutes. A 42-minute HRD runtime at 1400 ml/min was initially predicted by the mathematical model and inretrospect was sufficient; however, the HRD run was extended because of aperceived increase in ACT at 40 to 50 minutes. A total of 1800 ml of heparinizedpump blood was infused via the aortic cannula to replace cardiotomy suction.Fig. 1 (patient B) shows the time courses for ACT at baseline, during the HRDrun, and after the operation. Before and after the HRD run, fibrin degradationproducts were < 5 µg/ml and > 5 < 20 µg/ml,activated partial thromboplastin time was greater than 150 seconds, and d-dimerwas less than 0.5 ng/ml. Platelet count was 138,000 µl immediately afterCPB, 111,000 µl after the HRD run, and 105,000 µl 24 hours after theoperation. Plasma free hemoglobin concentration was 48 mg/dl immediately afterCPB and 52 mg/dl after the HRD run. The patient was transferred to the intensivecare unit with chest tube drainage of 1930 ml over the first 24 hours after theoperation (1425 ml/6 hr). She required 5 units of red blood cells, 75 ml ofplatelets, and 4 units of fresh frozen plasma. She recovered and has returned tofull activity at 3 months' follow-up.

The HRD achieves predictable systemic heparin removal, without causingadditional blood cell damage, in clinical situations in which protamine may becontraindicated. The HRD awaits clinical trials for approval as aninvestigational device.

References

  1. Weiler JM, Gellhaus MA, Carter JG, et al. Aprospective study of the risk of an immediate adverse reaction to protaminesulfate during cardiopulmonary bypass surgery. J Allergy Clin Immunol 1990;85:713-9.[Medline]
  2. Vertrees RA, Zwischenberger JB, McRea JC, TaoW, Kurusz M, Conti VR. Reversal of anticoagulation without protamine using aheparin removal device after cardiopulmonary bypass. ASAIO J 1994;40:M560-4.[Medline]
  3. Conti VR, Vertrees RA, Zwischenberger JB,Kurusz M. First clinical use of a heparin removal device: an alternative toprotamine. J Thorac Cardiovasc Surg 1995;109:1015-7.[Medline]
  4. Tao W, Callahan JD, Vertrees RA, Brunston RLJr, Deyo DJ, McRea JC, et al. Heparin clearance profiles following systemicanticoagulation using a heparin removal device system. ASAIO J  1997;43:922-6.[Medline]
  5. Tao W, Deyo DJ, Brunston RL Jr, Vertrees RA,Grochoske TL, Zwischenberger JB. Extracorporeal heparin adsorption followingcardiopulmonary bypass with a heparin removal device: an alternative toprotamine. Crit Care Med. In press.
  6. Tao W, Deyo DJ, Brunston RL Jr, Vertrees RA,Grochoske TL, Zweischenberger JB. Efficacy of a heparin removal device incomparison with protamine after hypothermic cardiopulmonary bypass. ASAIO J 1997;43:M825-30. [Medline]



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