Ann Thorac Surg 2000;69:743-749
© 2000 The Society of Thoracic Surgeons
Original Articles
No benefit of reduced heparinization in thoracic aortic operation with heparin-coated bypass circuits
Christian Olsson, MDa,
Agneta Siegbahn, MD, PhDb,
Eric Haldén, MD, PhDc,
Bo Nilsson, MD, PhDd,
Per Venge, MD, PhDb,
Stefan Thelin, MD, PhDa
a Department of Cardiothoracic Surgery, Uppsala University Hospital, Uppsala, Sweden
b Department of Clinical Chemistry, Uppsala University Hospital, Uppsala, Sweden
c Department of Cardiothoracic Anesthesia, Uppsala University Hospital, Uppsala, Sweden
d Department of Clinical Immunology, Uppsala University Hospital, Uppsala, Sweden
Address reprint requests to Dr Thelin, Department of Cardiothoracic Surgery, Uppsala University Hospital, S-751 85 Uppsala, Sweden
e-mail: stefan.thelin{at}thorax.uas.lul.se
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Abstract
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Background. Heparin coating of the cardiopulmonary bypass circuit attenuates inflammatory response and confer clinical benefits in cardiac operations. The positive effects may be amplified with reduced systemic heparin dosage. We studied markers of inflammation and coagulation in thoracic aortic operations with heparin-coated circuits and standard vs reduced systemic heparinization.
Methods. Thirty patients were randomized to standard (group S; 300 IU/kg initially; activated clotting times [ACT] > 480 seconds; 5,000 IU in prime; n = 16) or reduced (group R; 100 IU/kg initially; ACT > 250 seconds; 2,500 IU in prime; n = 14) dose systemic heparin. The following markers were analyzed perioperatively: (a) inflammatory response; acute phase cytokine interleukin-6, and granulocytic proteins myeloperoxidase and lactoferrin; (b) complement activation; factor C3a and the C5a-9 terminal complement complex [TCC]; and (c) coagulation; thrombin-antithrombin III complex.
Results. The clinical outcome did not differ between groups. Four (29%) patients in group R had a perioperative thromboembolic event. All studied markers were significantly elevated during and throughout cardiopulmonary bypass in both groups. Maximal values were higher in group R for all variables except for TCC. There were no statistically significant intergroup differences regarding markers of inflammation, complement activation, or coagulation activation.
Conclusions. The blood trauma in thoracic aortic operation is extensive, as reflected by the elevation of the studied biochemical markers, even when heparin-coated cardiopulmonary bypass circuits are used. In this study, we did not detect any benefits, either biochemical or clinical, of reducing the dose of systemic heparin.
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Introduction
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Cardiopulmonary bypass (CPB) exposes the body to a foreign surface, which induces activation of several cascade systems: inflammation including acute-phase reactants and various subsets of leukocytes, complement, and coagulation. This response is detrimental to the patient, and contributes to postoperative morbidity and mortality [1–3]. Attempts have been made to attenuate the activation of these cascades to reduce the negative effects of CPB. Heparin-coating of the CPB circuits has shown beneficial effects on markers of inflammation and complement activation [4, 5], and has also been correlated with improved clinical results, less bleeding and need for blood transfusions, shorter duration of assisted ventilation, and shorter stay in the intensive care unit and hospital [6, 7]. Heparin-coated CPB circuits allow for reduction of the dose of systemic heparin administered during CPB. Recent studies have indicated additional benefits of combining reduced heparinization and heparin-coated circuits [7–9].
In thoracic aortic operations, reduction of systemic heparin dosage has been shown to be feasible and a potential improvement to the clinical outcome [10], but comprehensive studies on the inflammatory response, complement activation, and coagulation activation are, to the best of our knowledge, lacking. Other authors have reported adverse effects on coagulation and fibrinolysis with reduced systemic heparinization [11], and a growing body of literature supports the view that reduced anticoagulation allows for extensive thrombin formation with its associated risks [12, 13].
Our main objective was to study the effect on biochemical markers of systemic response under the circumstances of the substantial surgical and blood trauma of operations on the thoracic aorta, CPB with heparin-coated circuits, and standard vs reduced systemic heparinization. Several markers were measured: (a) inflammatory mediators: interleukin-6 (IL-6), a potent proinflammatory cytokine; lactoferrin (LF) and myeloperoxidase (MPO), markers of neutrophil degranulation; (b) complement factors: factor C3a and C5a-9 terminal complement complex (TCC); and (c) coagulation activation as reflected by thrombin-generation: thrombin-antithrombin III complex (TAT).
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Patients and methods
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From January 1995 through May 1996 a total of 30 patients were entered into the study. Those eligible were adult patients accepted for operation under the diagnoses thoracic or thoracoabdominal aortic aneurysm or aortic dissection of any type. Emergency night-time operations were not included. Informed consent was obtained from all participants. The study was approved by the local ethical committee of the medical faculty. Well-established surgical procedures were performed in all patients. Patients were randomly assigned a standard dose (group S, n = 16) or a reduced dose (group R, n = 14) systemic heparin regimen. Heparin dosage was 300 IU/kg with 5,000 IU in the CPB priming solution in group S, and 100 IU/kg with 2,500 IU in prime in group R, respectively. Activated clotting times (ACT) were maintained above 480 seconds and 250 seconds, respectively. After inclusion, 1 patient was excluded because of difficulties with weaning from CPB and the subsequent use of an extracorporeal life support device, another because of uncontrolled hemorrhage requiring restoration of CPB with a different, noncoated circuit. Thus, data from 28 patients (14 in each group) are presented in this study.
Anesthesia
Patients were premedicated with intramuscular morphine (0.10 to 0.15 mg/kg). General anesthesia was inducted with thiopenthal (2 to 4 mg/kg) and alfentanil (10 to 30 µg/kg). Pancuronium (0.1 mg/kg) was used for muscle relaxation. Anesthesia was maintained with fentanyl and isoflurane (0.3 to 1.0 MAC in expired concentration). During CPB, volatile isoflurane in the bypass circuit was used for maintenance. Commencing at rewarming, a continuous intravenous infusion of propofol (0.8 to 1.3 mg/kg/hour) was used for sedation. The patients were ventilated to normocapnia. Monitoring included arterial lines in the radial arteries bilaterally, and a central venous line. Central hemodynamics and cardiac performance were monitored by transesophageal echocardiography.
Cardiopulmonary bypass
CPB equipment was identical in both groups. A Stöckert heart-lung machine (Stöckert Instrumente GmBH, Munich, Germany) was used. The Univox membrane oxygenator, soft venous reservoir, cardiotomy reservoir, and polyvinyl chloride tubing were heparin-coated with the Duraflo II surface (Baxter Healthcare Corp, Irvine, CA). Aortic and venous cannulas were not heparin-coated. The extracorporeal circuit was primed with 2,000 mL asanguineous fluid added with low-dose (1 to 2 x 106 KIU) aprotinin (Trasylol; Bayer AG, Leverkusen, Germany). Aprotinin was administered as a single dose, and used postoperatively only in selected cases as an adjunct to counteract excessive bleeding. CPB bloodflow was nonpulsatile, initially at 2.5 L/min/m2 body surface and reduced proportionally to core temperature. Procedures involving the descending aorta were managed with partial distal bypass including a roller pump and oxygenator, if possible. Several cases were managed with alternating periods of total and partial bypass. In cases of partial distal bypass, flow was adjusted to maintain distal arterial pressure above 50 mm Hg. Initial heparin dose was administered as an intravenous bolus. ACT was monitored throughout operation and kept at prespecified values for the S and R groups, respectively, with additional doses of heparin if necessary. After discontinuation of CPB, heparin was reversed with protamine sulphate, dose ratio 1 to 1.
Cold cardioplegia, when used, was employed using 500 to 1,500 mL of a modified St Thomas’ solution delivered antegradely or retrogradely. Deep hypothermia (18° to 20°C core temperature) with circulatory arrest was employed as needed, otherwise the operation was performed at moderate (28°C to 33°C) hypothermia. Retrograde cerebral perfusion when used was established through reversed flow in a snared one-stage superior vena cava cannula. Internal jugular vein pressure was kept below 25 mm Hg. Cardiotomy suction was used throughout the operation.
Sampling and biochemistry measurements
Baseline samples were collected after the induction of anesthesia. Samples for analysis of IL-6, LF, MPO, TAT, C3a, and TCC were taken at 60 minutes on CPB, at the end of CPB, 3 hours after protaminization, and 20 hours postoperatively. For C3a, TCC, and TAT, additional sampling was performed 30 minutes after protamine administration. When on CPB, samples were collected from the venous reservoir of the heart-lung machine. In every other instance, blood was sampled from the radial arterial line. Samples were collected after discarding 10 mL blood, iced and centrifuged. Plasma was aliquoted and frozen without delay and stored at -70°C until analysis. Routine hematologic parameters were measured automatically with a cell counter (Coulter, FL). Plasma levels of MPO and LF were determined with I125 radioimmunoassay (RIA) methods, MPO with a commercial kit (Pharmacia, Uppsala, Sweden) and LF with a previously described modified technique [14]. IL-6 was measured using a commercial enzyme-linked immunosorbent assay (ELISA) kit (Quantikine IL-6, R&D Systems, Abingdon, UK), carefully adhering to the manufacturers instructions for use. Modified enzyme-linked immunosorbent assays were used to determine C3a and TCC [15, 16]. TAT was determined with a sandwich ELISA method (Enzygnost TAT, Behringwerke, Marburg, Germany).
Statistics
Data are presented as medians with interquartile ranges (IQR), ie the difference between the 75th and 25th percentiles, as measurement of distribution. The Mann-Whitney U-test and the 
2 test were used for intergroup statistical comparisons as appropriate. The Wilcoxon signed rank test was used to determine changes over time in each group. Values of p less than 0.05 were considered statistically significant.
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Results
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Patient characteristics and surgical data are presented in Tables 1 to 3. As anticipated, the total dosages of heparin (180 [40] IU/kg vs 355 [90] IU/kg; p < 0.001) and protamine (187.5 [75] mg vs 300 [100] mg; p < 0.001) were significantly lower in group R. ACTs were also significantly lower in group R. Median values at peaks were 592 (180) seconds and 357 (107) seconds in group S and R, respectively; p less than 0.001.
Clinical outcomes
Postoperative complications were equally distributed between groups. There were no nonfatal myocardial infarctions, and no patient needed hemodialysis postoperatively. The median (IQR) hospital stay was 9 (4.5) days in group S and 8 (8) days in group R. Overall 30 day mortality as well as in-hospital mortality was 7% (2 of 28). One death resulted from a myocardial infarction 15 days postoperatively, the other from cardiac tamponade two days after operation. Five of 28 (18%; 3 in group R and 2 in group S) experienced a neurologic complication perioperatively; 1 patient had a cerebrovascular insult resulting in a permanent hemiparesis (verified radiologically), 1 had a transitory ischemic attack with transient blindness in one eye, the other 3 had varying degrees of single-extremity paralysis, which all resolved gradually up to discharge from hospital (not possible to verify radiologically). No patient suffered from paraplegia or paraparesis. One patient in group R had a femoral artery thrombosis the first postoperative day, which was successfully treated with a femoro-popliteal bypass procedure. Apart from the latter, all thromboebolic events occurred in patients managed with deep hypothermic circulatory arrest.
Inflammatory markers (LF, MPO, and IL-6)
Lactoferrin and MPO both reacted promptly to CPB and were significantly elevated throughout CPB (p < 0.001 for both). Values peaked at the end of CPB (Fig 1, 2). Myeloperoxidase values did not reach baseline within 20 hours. Myeloperoxidase median values were consistently somewhat lower in group R, whereas the intergroup relation of LF-values was ambiguous. Figure 3 illustrates IL-6 measurements. The initial response during CPB was significant (p = 0.005) in both groups, and the peak value was reached at 3 hours after protamine administration. In neither group R nor group S, were baseline values reached on postoperative morning 1. In Table 4, baseline, peak, and maximum values are listed. There were no statistically significant differences between the groups.
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Table 4. Baseline Levels, Peak Levels, and Maximal Encountered Values of the Biochemical Markers With Reduced (Group R) or Standard (Group S) Dose Systemic Heparin
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Complement factors (C3a and TCC)
C5a-9 terminal complement complex rose during CPB (p = 0.001), peaking at end of CPB, and regained baseline values the first postoperative morning (Fig 4). C3a displayed a similar pattern of significant elevation (p = 0.001), culminating at the end of CPB and reaching baseline level for group S but not group R the first postoperative day (Fig 5).
Coagulation activation (TAT)
Thrombin-antithrombin III complex levels increased markedly (p = 0.002), reaching a maximum at the end of CPB in group S, but earlier, after 1 hour on CPB, in group R (Fig 6). Baseline levels were reached the first postoperative morning. The maximal value of group R was 40% higher than that in group S (Table 4). The tendency for coagulation parameters was opposite that for inflammatory markers and complement factors, with median values somewhat higher in group R.
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Comment
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Alongside with improvements in surgical, anesthetic, and perfusion management, technical and pharmacologic approaches are explored to ameliorate the damages associated with CPB. The advent of the membrane oxygenators [17] and the use of pharmacologic substances, such as aprotinin [18] and methylprednisolone [19], have contributed to the attenuation of the postperfusion syndrome. Coating the foreign surfaces with heparin have shown promising results in clinical as well as in biochemical studies [4, 5, 6–8]. Clarifying the diverse effects of heparin, foremost its proinflammatory properties and the risk of bleeding associated with its use, led to the concept of reduced systemic heparin dosage, which is possible in conjunction with heparin-coated circuits.
In this study, important markers of activated humoral cascades were studied: C3a, TCC, IL-6, LF, MPO, and TAT. They were all significantly elevated throughout CPB, and in two instances, IL-6 and C3a (group R), preoperative values were not regained within 20 hours. Levels of TAT and IL-6 were higher than previously reported [4, 12], with outliers displaying extremely high levels of these potent substances (Table 4). We interpret these findings as reflecting a very profound response because of the extensive surgical procedure performed. We could not detect any statistically significant differences between the groups for any of the substances studied.
In clinical parameters (mortality, neurologic complications, postoperative bleeding, autotransfusion volumes, mechanical ventilation, and stay in intensive care unit and hospital) no differences between the groups were observed. This could in part result from a relatively small patient sample. Notably, in group R, 4 patients (29%) were subjected to some form of thromboembolic event: in 3 cases a cerebral insult and in 1 a peripheral artery thrombosis requiring operation (a patient with documented arteriosclerotic disease in both legs). These findings could at least in part result from suboptimal anticoagulation when systemic heparin dosage was reduced. All patients received low-dose aprotinin preoperatively. At the time of the study, data on properties, safety, and efficacy of aprotinin were conflicting [20, 21], and the decision to use aprotinin was based on shown benefits regarding reduced requirements of allogenous blood products (of special interest in thoracic aortic operations, with high risk of perioperative bleeding) and possible antiinflammatory properties. The decision was a clinical one, and the effect of aprotinin on inflammatory markers was not intended to be investigated. To counteract potential hypercoagulation, and minimize influence on studied parameters, a low dose was used. Reported incidence of thromboembolic events varies widely. Cohn and colleagues [22] reported 2% strokes in operation of the ascending aorta, and Svensson and associates [23] found 9% of patients with strokes or embolic events in a large series of aortic dissections, in which 17% were discharged from hospital with paraplegia or paraparesis after distal aortic dissection, as compared to 11% (3 of 28) with permanent sequele because of thromboembolism in our series, 21% (6 of 28) with temporary neurologic states in both groups included. Figures should be interpreted with great caution because of differences in reporting, case mix, surgical techniques, etc, but clinical endpoints seem to be comparable.
The rationale of coating CPB circuits with heparin is rendering the surfaces more biocompatible, which has been shown convincingly in several reports. This improved biocompatibility leans on the assumption that the intrinsic pathway of coagulation, with activation of factor XII being the initiating step, is responsible for thrombin-formation during CPB [24, 25]. Recent studies have suggested that the extrinsic pathway, depending on tissue factor, is at least as important in this detrimental process [3, 25]. Perhaps heparin-coating and attenuation of the intrinsic pathway is not enough under circumstances were the blood trauma is very severe, as in aortic operations or other complex heart operations [12]. The absence of intergroup differences in this report could reflect the inability of heparin-coated surfaces to blunt the inflammatory and coagulation response more than in part, with the same effect in both groups and thus nivellating the levels of biochemical markers in both groups. Perhaps, the most common clinical manifestation of the inflammatory response to CPB is prolonged need for mechanical ventilation because of complement-mediated lung injury. Requirements of mechanical ventilation were equal, the median time being longer with standard heparin dosage, but with the extremes found in the group managed with reduced heparinization. Whether or not this is a potential benefit concealed by a few extreme outliers remains speculative, but it could be consistent with the trends towards lower levels of complement and degranulation proteins in group R.
This study could not with certainty detect any benefit, clinical or biochemical, of lowering the dose of systemic heparin when heparin-coated CPB circuits are used in operation for thoracic aortic aneurysm or dissection. Neither does it supply statistical evidence for the proposed proinflammatory effects of heparin. In contrast, a notable incidence of various degree thromboembolic events (29%) occurred when the systemic heparin dosage was lowered. From these findings, no recommendations concerning the routine use of reduced systemic heparinization with heparin-coated circuitry in aortic operation can be made.
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Accepted for publication August 11, 1999.
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Top
Abstract
Introduction
) or standard (group S, open squares 
) doses of systemic heparin. Error bars represent interquartile ranges. (Baseline = at anesthesia; CPB = on cardiopulmonary bypass, Prot = after protamine.)
