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Ann Thorac Surg 1997;63:663-668
© 1997 The Society of Thoracic Surgeons

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Original Article: Cardiovascular

Low Heparinization With Heparin-Bonded Bypass Circuits: Is It a Safe Strategy?

Department of Cardiothoracic Surgery, Killingbeck Hospital, and Research School of Medicine, University of Leeds, Leeds, United Kingdom

Accepted for publication September 30, 1996.

	Abstract

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Background. The use of heparin-bonded cardiopulmonary bypass circuits with reduced doses of heparin sodium has been shown to give hemostatic benefits to the patient. However, fears persist that the use of less heparin may put the patient at risk for thrombotic events. This work tested the hypothesis that heparin-bonded circuits per se are effective in preserving cells and reducing thrombin generation when a reduced dose of heparin is used in vitro.

Methods. Simulated extracorporeal circulation was carried out using the same unit of fresh heparinized (1.1 U/mL) human blood to simultaneously perfuse a heparin-bonded circuit and a nonbonded circuit. Samples were taken at 30, 60, 120, and 360 minutes and analyzed for markers of cell activation and thrombin generation.

Results. The concentrations of platelet and white blood cell activation markers were found to be significantly lower in the heparin-bonded circuits compared with the nonbonded circuits. In addition, markers of thrombin generation were significantly lower in bonded circuits. Scanning electron microscopy revealed fewer adherent cells and less debris on the bonded surface compared with the nonbonded surface.

Conclusions. Cell activation and thrombin generation were significantly reduced as a result of the presence of immobilized heparin in a system of cardiopulmonary bypass with reduced plasma heparin. However, evidence of contact activation in the bonded circuits was found after 120 minutes, indicating that anticoagulation in the system was not adequate. This becomes more important clinically where the extrinsic pathway of coagulation is also involved.

	Introduction

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Biocompatibility has become an increasingly more important aspect of cardiopulmonary bypass (CPB) in recent years. To date, the most successful type of biocompatible surface has been the end-point–attached heparin surface manufactured by Carmeda (Medtronic Cardiopulmonary, Kerkrade, the Netherlands). It has proved to be effective in reducing both the inflammatory response associated with CPB [1, 2] and the activation of blood cells [3] and has been used in conjunction with reduced levels of heparinization to achieve hemostatic benefits [4].

Conflicting opinions exist as to the wisdom of reducing systemic heparinization in conjunction with heparin-bonded (HB) circuitry. It has been argued that the use of less systemic heparin may reduce the potential for bleeding problems postoperatively in patients undergoing routine CPB. Benefits may also arise from using smaller quantities of the heparin-neutralizing agent protamine sulfate, which, in excess, is known to induce deleterious effects [5]. Further, the observed adverse effects that heparin has on platelets [6] and in stimulating the complement cascade [7] may be minimized. Conversely, it is argued that full heparinization must be given to CPB patients to prevent thrombin generation [8] leading to potentially fatal thrombus formation in either the circuit or the patient.

On the basis of the lowest doses of heparin that have been used with success clinically in adults [9], the efficacy of immobilized heparin in relation to cell preservation and reduced thrombin generation was assessed in a novel, controlled in vitro study design.

	Material and Methods

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Approval for this study was given by the local ethics committee, and informed consent was obtained from the blood donors, healthy adult volunteers who had not used aspirin.

Blood Collection
Blood (450 mL) was drawn from the volunteers into 1 L bags (Baxter Healthcare, Thetford, Norfolk, UK) to which heparin (Leo Laboratories, Cleveland, Middlesborough, UK) (1.1 U/mL) had previously been added. Within 30 minutes of collection, the blood was diluted to approximate bypass hematocrit (about 20%) with 150 mL each of Hartmann's solution (Baxter Healthcare) and Gelofusin (B. Braun Medical Ltd, Emmenbruke, Switzerland). A sample was taken from the bag (final volume, 750 mL) before perfusion to obtain baseline activated coagulation time (ACT) (HemoTec; Medtronic, Anaheim, CA) and full blood count (blood cell counts, hemoglobin, hematocrit, and derivatives) values [in 1.6 mg/mL of EDTA (ethylenediaminetetraacetic acid)].

Simulated Cardiopulmonary Bypass
Twenty-four circuits were used in this study, 12 of which were Carmeda HB and 12, nonbonded (NB). The two circuit types were perfused simultaneously in each experiment using the same unit of blood. The circuit consisted of a Minimax (Medtronic) pediatric membrane oxygenator and a Bio-Pump (Medtronic) centrifugal pump connected by polyvinyl chloride tubing. The volume of each circuit was approximately 300 mL, with an inner surface area of around 1 m².

The circuits were primed according to the manufacturers' instructions. Flow was adjusted to maintain 1 L/min over a 6-hour perfusion period. Temperature was kept at 28°C for 4 hours and then increased to 37°C for the rest of the perfusion time to mimic a rewarming period. Physiologic pH was maintained with a flow of a calibrated gas mixture (5% carbon dioxide, 12% oxygen, and 83% nitrogen) through the oxygenator at 1 mL/min.

Blood samples were drawn from the circuits at 30, 60, 120, and 360 minutes and replaced with an equivalent volume of Hartmann's solution to prevent creation of negative pressure. Whole blood was used for the measurement of ACT and heparinase ACT (HemoTec) as well as platelet and white blood cell (WBC) counts. The heparinase ACT channel of the cartridge contained a purified bacterial heparinase, which destroyed heparin present in the sample to produce a clotting time indicative of the baseline unheparinized clotting time of the sample. The remaining blood was collected into citrate (0.3 wt/vol, 1:9) and centrifuged at 1,500 g for 10 minutes at 4°C, and 0.5-mL aliquots of plasma were stored immediately in a -80°C freezer for batch analysis.

Commercial enzyme immunoassay kits were used to measure the plasma levels of soluble P-selectin, a sensitive marker of platelet activation (R and D Systems, Oxon, UK); leukocyte elastase as a marker of WBC activation (E. Merck, Darmstadt, Germany); thrombin-antithrombin complex, a specific marker of thrombin formation (Behring, Marburg, Germany); and interleukin-8 (IL-8), a neutrophil chemoattractant (R and D Systems). Hemoglobin concentration was measured spectrophotometrically by a modification of the method of Harboe [10] using reduced volumes.

At the conclusion of the perfusion period, samples of tubing were taken from both circuits and rinsed with Hartmann's solution to remove any excess red blood cells. The samples were then fixed in 2.5% glutaraldehyde for 15 minutes before they were dehydrated in ascending concentrations of ethanol up to absolute ethanol. They were subsequently air-dried in a desiccator and sputter-coated with gold for viewing on a Jeol T20 scanning electron microscope (Jeol, Tokyo, Japan) at 20 kV.

Statistical Analysis
Sample size calculations for detecting a difference between two medians were carried out using expected values. It was established that a sample size of 10 for each group would be sufficient to demonstrate differences with a power value of 0.85 and a significance of 0.05. Friedman's analysis of variance was applied to detect differences between the two circuit types. Analysis was subsequently carried out by means of Wilcoxon matched-pairs tests.

	Results

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
The baseline ACT values were greater than 250 seconds with a great degree of intersample variability. Figure 1 shows the ACT and heparinase ACT data throughout the course of the experiments. The heparinase ACTs remained within normal ranges up to 120 minutes, after which time they generally became extended beyond the capacity of the instrument (999 seconds). The ACTs themselves became extended after 30 minutes of perfusion, with greater variability in the NB circuits. By 360 minutes, the ACTs were extended beyond the capacity of the instrument.

View larger version (39K): [in this window] [in a new window]   Fig 1. . Activated coagulation times (ACTs) and heparinase (h) ACTs throughout the course of the experiments. A considerable amount of intersample variability was noted in the ACTs, which was not evident in the heparinase ACTs until the final measurement. At 360 minutes, the ACTs for both circuit types had extended considerably, which indicates consumptive coagulopathy. (HB = heparin-bonded circuit; NB = nonbonded circuit.)

Platelet numbers fell considerably in the NB circuits after 30 minutes of perfusion and were significantly lower (p < 0.005) than in the HB circuits up to 120 minutes (Fig 2). However, at 360 minutes, overt clotting of the NB circuits rendered the platelet counts invalid, whereas in the HB circuits, the counts were significantly lower than the precirculation baseline (p < 0.01). The WBC counts fell significantly lower than baseline from 30 minutes in the NB circuits (p < 0.01) and from 120 minutes in the HB circuits (p < 0.05) until the end of the perfusion period. The counts were lower in the NB circuits compared with the HB circuits at 30, 60, 120 (all, p < 0.005), and 360 minutes (p < 0.01) (Fig 3). Scanning electron microscopic observations supported the cell count findings (Fig 4).

View larger version (27K): [in this window] [in a new window]   Fig 2. . Platelet counts fell from baseline levels at 30 minutes in the nonbonded ( NB) circuits and at 360 minutes in the heparin-bonded (HB) circuits and were significantly higher in the HB circuits until 360 minutes. (***p < 0.005.)

View larger version (27K): [in this window] [in a new window]   Fig 3. . White blood cell counts dropped significantly lower than baseline from 30 minutes onward in the nonbonded ( NB) circuits but not in the heparin-bonded (HB) circuits and were significantly lower in the NB circuits throughout the course of the experiments. (**p < 0.01; ***p < 0.005.)

View larger version (154K): [in this window] [in a new window]   Fig 4. . (A) Scanning electron micrograph of heparin-bonded tubing surface after 360 minutes of perfusion. The bumpy appearance is an artifact resulting from exposure of the coated polyvinyl chloride to a vacuum. Scattered fibrin strands have formed. (B) Scanning electron micrograft of nonbonded tubing surface at 360 minutes. It is almost completely obscured by clusters of cells and a dense fibrin network. ( Bar = 5 µm).

View larger version (22K): [in this window] [in a new window]   Fig 5. . The concentration of soluble P-selectin increased in a time-dependent fashion but was significantly higher in the nonbonded ( NB) circuits at all times. (HB = heparin-bonded; ***p < 0.01; ***p < 0.005.)

View larger version (29K): [in this window] [in a new window]   Fig 6. . Plasma leukocyte elastase levels rose after 30 minutes of perfusion in both circuit types but significantly more so in the nonbonded ( NB) circuits at 30 and 120 minutes. (HB = heparin- bonded; *p < 0.05; **p < 0.01.)

View larger version (20K): [in this window] [in a new window]   Fig 7. . Interleukin-8 (IL-8) levels did not differ until 120 minutes of perfusion. Then significantly more IL-8 was measured in the nonbonded ( NB) samples until the end of the experiment. (HB = heparin-bonded; *p < 0.05; **p < 0.005.)

View larger version (29K): [in this window] [in a new window]   Fig 8. . Levels of thrombin-antithrombin complex were elevated in the baseline bag sample and reduced on initiation of blood circulation. Then they rose in a time-dependent fashion and were significantly higher in the nonbonded ( NB) circuit until 120 minutes. (HB = heparin-bonded; ***p < 0.005.)

	Comment

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

Cell Activation
It is generally agreed that the adsorption of fibrinogen correlates with the ability of a surface to promote cell adhesion and activation [15]. Once adsorbed, fibrinogen can be replaced by high molecular weight kininogen [16], which is involved in the intrinsic pathway of coagulation. The conditions are thus created for cell adhesion, which is followed by activation reactions such as the platelet release reaction. Substances released by blood cells on activation, or by damage induced by shear stress, are capable of interacting with other blood elements, thereby producing a complex network of interactions between blood cells and their components [17].

Platelet and WBC counts fell immediately on initiation of perfusion in the NB circuits, indicating cell adhesion to the surfaces of the circuit. This observation is in accordance with that made by others [18, 19] in models of CPB even with full heparinization. The fact that such a fall was not observed in the HB circuits until after 120 minutes suggests that the conditions necessary for cell adhesion were not present as a result of the immobilized heparin. This finding is consistent with early work with the HB surface by Thelin and associates [20], who concluded that perfusion with heparin-treated surfaces reduces blood cell trauma.

The platelet release reaction occurs after their adsorption onto the foreign surface. The substances released play a part in the progression of thrombus formation and inflammatory reactions. As a consequence, blood cells and coagulation factors are consumed. P-selectin is stored in the -granules of platelets and is transported to the surface on activation where it plays a key role in the interaction of platelets with surfaces and other cell constituents. Measurement of the soluble form of this protein provides an indication as to the release reaction and state of activation of platelets. The P-selectin concentration indicated that there was considerably less activation of platelets in the HB circuits during the entire perfusion period.

Reduced WBC activation can be expected to accompany reduced platelet activation. Evidence of this was provided in the significant differences between the two circuit types in the levels of plasma leukocyte elastase and IL-8. The protease elastase is a constituent of the primary granules of leukocytes [21] and is known to enhance platelet activation [17] in addition to playing a role in organ dysfunction [22]. In terms of contact activation, elastase has been seen to be released concomitant with plasma kallikrein [18]. Interleukin-8 is instrumental in the function of neutrophils and is known to be a neutrophil chemoattractant. As WBCs are the sole source of IL-8 in a closed system of CPB, the detection of IL-8 in plasma is indicative of WBC release. The leukocyte elastase and IL-8 levels suggest that the HB surface reduced the activation of WBCs in the perfusion system.

Thrombin Generation
Initial evidence of the state of thrombin generation was provided by the ACTs and heparinase ACTs. During perfusion, the ACTs fluctuated more markedly in the NB circuits, thus suggesting activation of coagulation. The extended ACTs are consistent with the phenomenon of consumptive coagulopathy, which was evident at 360 minutes in both circuit types. Scanning electron microscopic observations of fibrin strand formation on the surface of the tubing support this notion. However, the fibrin network appeared to be at a more advanced stage on the NB surface.

The level of thrombin-antithrombin complex was measured. This gives an indication of the amount of thrombin generated because antithrombin reacts with thrombin once it has been formed. The complex exists transiently in plasma (around 10 minutes), thus indicating the current state of activation of the coagulation cascade. The baseline sample showed elevated levels because of preformed thrombin-antithrombin complex in the bag. Significantly lower levels of thrombin-antithrombin complex were seen in both circuit types after 30 minutes of perfusion (p < 0.05), a result demonstrating a possible effect of flow on the thrombotic state of the blood. Gorman and co-workers [12] showed significantly more binding of antithrombin III to HB surfaces; it is possible that this may also have contributed to the reduction in the HB circuits, which was greater than that in the NB circuits until 120 minutes. This contradicts the findings of others [14] in a similar in vitro model, although it differed in that it used undiluted blood and contained a venous reservoir. The final measurement showed a considerable elevation in the HB circuits because of a combination of time and temperature effects with possible desorption from the surface or saturation of the binding sites. The diminishing effectiveness of the HB circuits may also be a result of shear-stress damage or denaturation of circulating antithrombin III, which is required for the surface to function.

The level of heparinization used in these experiments was approximately one third of the "full" dose routinely used in CPB for open heart operations. With standard circuitry, such a low level of heparin provides inadequate protection against the activation of platelets and WBCs and the stimulation of thrombin generation caused by the foreign surface. The presence of end-point–attached heparin on the surfaces of the circuits was found to confer protection to platelets and WBCs in addition to preventing thrombin generation up to 120 minutes of perfusion. The advantage of using an in vitro model of CPB is that it allowed the analysis over time of a fixed amount of blood in the absence of metabolism and clearing mechanisms. However, it is impossible to completely mimic the clinical situation with a laboratory model. Fibrinolysis and the intrinsic pathway of coagulation contribute to the deleterious reactions of CPB in the clinical setting. Some studies [23] have shown that the extrinsic pathway of coagulation is more important than the intrinsic pathway in terms of thrombin generation during CPB, thus contradicting the established view that contact activation resulting from blood-surface contact is the major procoagulant stimulus of CPB. Taking this into account, we think it is important to recommend caution with the use of low levels of heparin in conjunction with HB circuits, especially for longer perfusion periods. This is particularly true in pediatric patients, who tend to be more resistant to heparin and metabolize it more quickly [24].

	Acknowledgments

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
We acknowledge the Children's Heart Surgery Fund at Killingbeck Hospital for providing the funding to carry out this work, Medtronic Cardiopulmonary for providing the circuits, and the Blood Transfusion Service for their assistance with blood collection.

	Footnotes

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Address reprint requests to Ms Bannan, Department of Cardiothoracic Surgery, Killingbeck Hospital, York Rd, Leeds LS14 6UQ, UK.

	References

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 

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This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bannan, S. Articles by Martin, P. G. Search for Related Content PubMed PubMed Citation Articles by Bannan, S. Articles by Martin, P. G.