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Ann Thorac Surg 1999;67:446-449
© 1999 The Society of Thoracic Surgeons
a Department of Cardiothoracic Surgery, The Boston Medical Center and Boston University School of Medicine, Boston, Massachusetts, USA
Accepted for publication July 8, 1998.
Address reprint requests to Dr Lazar, Department of Cardiothoracic Surgery, The Boston Medical Center, 88 East Newton St, Suite B404, Boston, MA 02118
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Abstract |
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Methods. In 25 adult pigs, a 9F, 40-mL IAB was inserted into the femoral artery and positioned just below the takeoff of the left subclavian artery for 9 hours. Five animals received systemic heparin, 10 animals had no heparin, and another 10 animals received no heparin but the IAB was heparin-bonded (Duraflo II). Thrombus formation was assessed using a numerical scoring system (0 = no thrombosis to 3 = thrombus >5 cm or evidence of luminal compromise).
Results. Animals receiving heparin and heparin-bonded IAB had no thrombus formation around the IAB (mean ± SE; 0 ± 0.00 heparin versus 1.55 ± 0.29 no heparin versus 0 ± 0.00 heparin-bonded; p < 0.005), at the insertion site (0 ± 0.00 heparin versus 1.55 ± 0.29 no heparin versus 0 ± 0.0 heparin-bonded; p < 0.005), and in the distal femoral artery (0 ± 0.00 heparin versus 2.00 ± 0.23 no heparin versus 0 ± 0.00 heparin-bonded; p < 0.005).
Conclusions. Heparin-bonding of the IAB significantly decreases thrombus formation in the absence of systemic heparinization.
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Introduction |
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In 1971, a heparin-coating process was developed (Carmeda) that resulted in an antithrombogenic surface [11]. This process was applied to extracorporeal tubing in addition to hollow-fiber microporous oxygenator surfaces [12]. Subsequent clinical and experimental studies have shown that heparin-bonded cardiopulmonary bypass circuits significantly decrease complement and white blood cell activation and result in markedly decreased cellular and platelet adhesion to extracorporeal surfaces [12–15]. This experimental study was, therefore, undertaken to determine whether heparin-bonding of the IAB would decrease the incidence of arterial thrombosis in the absence of systemic heparinization.
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Material and methods |
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-chloralose (75 mg/kg), and placed on positive-pressure endotracheal ventilation. Catheters were inserted into the right femoral artery and vein for monitoring systemic pressure and administering drugs and fluids. A cutdown was performed in the left groin to expose the common femoral artery. A 9F, 40-mL IAB (Arrow International, Reading, PA) was inserted through the left common femoral artery without the use of a sheath, and positioned just below the takeoff of the left subclavian artery for 9 hours at a cycle of 1:1 using an IAB pump console (Arrow International). Transthoracic echocardiography was used to determine that the IAB was properly positioned and functioning well.
Experimental groups
Animals were randomly allocated to one of three groups.
Heparin group
In 5 animals intravenous heparin (3 mg/kg) was given during the period of IAB support to achieve an activated clotting time (ACT) greater than 200 seconds. The ACT was determined before IAB insertion, 20 minutes after the initiation of systemic heparinization, and every hour during IAB support. The ACT averaged 220 ± 4 seconds during the 9 hours of IAB support.
No heparin group
In 10 animals, no systemic heparin was given during the 9 hours of IAB support. The ACT averaged 128 ± 3 seconds in these animals.
Heparin-bonded group
In another 10 animals, no systemic heparin was given. However, these animals received a heparin-bonded IAB. A 1.5% (weight to volume) Duraflo II coating solution (Baxter Laboratories, Irvine, CA) was prepared by dissolving Duraflo II in a mixture of dichlorofluorethane and methanol [16]. The IAB and its catheter were then coated by dipping in the solution with the balloon inflated and subsequently dried under ambient conditions. Both the entire IAB and its catheter were completely heparin-bonded using this technique. The ACT averaged 125 ± 2 seconds during the 9 hours of IAB pumping.
Measurements and data analysis
Electrocardiographic leads were placed to monitor heart rate. Balloon-augmented diastolic pressure was determined from IAB arterial tracings. Balloon-augmented diastolic pressure was recorded each hour. A mean pressure was calculated for each experiment and then averaged for each of the three groups.
After 9 hours of IAB support, animals were sacrificed with an injection of Succumb (10 mL/kg), a high-dose pentobarbital derivative, and exsanguinated. A thoracoabdominal incision was performed, exposing the descending and abdominal aorta as well as the iliac and femoral arteries. The aorta was then opened longitudinally with the IAB still in situ. Thrombus formation around the IAB, at the femoral artery insertion site, and in the femoral artery distal to the IAB was assessed using a numerical scoring system in which 0 = no thrombus; 1 = adherent thrombus between 0 and 2 cm; 2 = adherent thrombus between 2 and 5 cm; and 3 = adherent thrombus greater than 5 cm or evidence of luminal compromise. The scores were recorded for each experiment and then averaged for each group.
All values represent the mean ± standard error. Differences in measurements between the three groups and across time were assessed using analysis of variance techniques. Differences were considered significant at a p value less than 0.05.
All animals received humane care in compliance with the "Principles of Laboratory Animal Care" formulated by the National Society for Medical Research and the "Guide for the Care and Use of Laboratory Animals" prepared by the Institute of Laboratory Animal Resources and published by the National Institutes of Health (NIH publication 86-23, revised 1985).
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Comment |
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It was hoped that the incidence of IAB-related vascular complications would be significantly reduced by the wire-guided Seldinger technique. However, several studies have reported similar or higher complication rates with percutaneous insertion compared with surgical insertion techniques [2, 5–7, 9]. The vascular complications associated with IAB insertion are caused by mechanical trauma to the vessel wall during catheter insertion [2], flow obstruction by the catheter [4], and low cardiac output and vasoconstriction seen in patients with low ejection fractions. Although systemic heparinization may help to decrease the incidence of arterial thrombosis before operation, it is often not started until 24 to 48 hours after surgery to avoid bleeding complications [5]. Thus, postoperative patients requiring IAB support are more susceptible to arterial thrombosis.
Because the IAB represents a potential site for cellular and fibrin deposition, we postulated that heparin-bonding the IAB surface would decrease the incidence of thrombus formation on the IAB surface as well as at the insertion site and in the distal femoral artery. Recent advances in heparin bonding and coating techniques have resulted in more biocompatible surfaces, which minimize complement activation and platelet aggregation [12, 16]. In a clinical study involving patients undergoing coronary artery bypass graft operation, Borowiec and coworkers [13] demonstrated that heparin-coated arterial filters diminished cellular adhesion to the filter surface. Using scanning electron microscopy techniques, they were able to show that heparin-bonding prevented the deposition of red blood cells, leukocytes, platelets, and fibrin deposits seen on non–heparin-bonded surfaces, which occurred despite the use of heparin. In our study, animals treated with heparin-bonded IABs had no evidence of arterial thrombosis (Fig 1). In contrast, animals receiving nonbonded IABs without systemic heparin had evidence of significant arterial thrombosis and deposition of clot on the IAB surface (Fig 2).
Although our initial results with heparin-bonded IABs are encouraging, longer periods of IAB support in conditions simulating cardiac operations will be necessary to determine whether systemic heparinization can be completely avoided in postoperative IAB patients. Muehrcke and coworkers [18], working with heparin-bonded extracorporeal membrane oxygenator circuits, found that the absence of systemic heparinization postoperatively resulted in intramyocardial thrombus formation. Although Magovern and coworkers [19] reported excellent hemodynamic data in postcardiotomy cardiogenic shock patients using a heparin-coated extracorporeal membrane oxygenator circuit and no systemic heparinization, intramyocardial thrombus developed in 3 of 21 patients. It is postulated that the administration of protamine at the conclusion of cardiopulmonary bypass to reverse the heparin after the extracorporeal membrane oxygenator has been inserted may have promoted thrombin generation. von Segesser and coworkers [20] demonstrated that reversing systemic heparinization with protamine in animals supported by a heparin-coated extracorporeal membrane oxygenator circuit markedly increased fibrin formation within the circuit and promoted platelet and red blood cell deposition. They postulated that protamine administration might effectively neutralize the heparin surface coating. It is unknown whether the administration of protamine might have a similar effect on the heparin-bonded surface of the IAB. Future studies using models of cardiopulmonary bypass are currently being designed to determine whether the reversal of heparin with protamine may negate the beneficial effects of heparin-bonded IABs.
The favorable effects of heparin-bonding on the surfaces of cardiopulmonary bypass circuits and the IAB have also been seen in pulmonary artery catheters. Doherty and Lanteigne [21] showed that heparin-bonded pulmonary artery catheters placed in animals remained thrombus-free for at least several days after placement. Hoar and colleagues [22] demonstrated no thrombus formation on the surface of heparin-bonded pulmonary artery catheters in 10 patients undergoing cardiac surgical procedures.
Our experimental study has demonstrated that heparin-bonded IABs significantly decrease the incidence of thrombus formation in the absence of systemic heparinization within 9 hours. There are, however, several limitations to our study. Although no macroscopic thrombus formation could be detected on the surface of the IAB and its catheters, we did not perform microscopic studies to determine whether platelet thrombi were present. Pigs have a marked predisposition to platelet thrombi, and it is possible that platelet thrombi may have been present on the heparin-bonded surface. The influence of protamine on the heparin-bonded IAB will also need to be studied. It is possible that when protamine is administered after cardiopulmonary bypass to reverse the effects of heparin, the IAB surface may be altered and made more susceptible to thrombus formation. It is unknown whether the Duraflo coating will eventually wear off or have an adverse effect on IAB function over time. Studies are currently being designed to answer these questions in preparation for clinical trials.
Although 9 hours of IAB support is significantly shorter than would be encountered in clinical practice, the absence of any macroscopic thrombus formation on the heparin-bonded IABs compared with nonbonded IABs without systemic heparinization is encouraging. Heparin-bonded IABs may ultimately become a valuable method of mechanical support for postoperative patients who require longer periods of IAB support and in whom systemic heparinization may be associated with a higher risk for bleeding complications.
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Acknowledgments |
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This work was supported in part by grants from the Baxter Healthcare Corporation, Irvine, CA, and the Arrow International Corporation, Reading, PA.
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This article has been cited by other articles:
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  M. N. Helmus, D. F. Gibbons, and D. Cebon Biocompatibility: Meeting a Key Functional Requirement of Next-Generation Medical Devices Toxicol Pathol, January 1, 2008; 36(1): 70 - 80. [Abstract] [Full Text] [PDF]
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