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Ann Thorac Surg 1996;62:1128-1133
© 1996 The Society of Thoracic Surgeons
Departments of Cardiac Surgery and Anesthesiology, Oslo Heart Center, Oslo, Norway
Accepted for publication May 6, 1996.
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Abstract |
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 TopFootnotes Abstract IntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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Methods. Two hundred seventeen patients having first-time myocardial revascularization were prospectively randomized either to a group in which a completely ("tip-to-tip") heparin-coated circuit (Duraflo II) was used for perfusion (n = 107) or to a control group (n = 110) in which an uncoated, but otherwise identical, circuit was used. Full systemic heparinization was induced in both groups (activated clotting time, >480 seconds). The postoperative blood loss, requirements for homologous blood transfusions, clinical performance, and complications were recorded.
Results. The amount of postoperative mediastinal drainage was nearly identical in the two groups. The mean 18-hour drainage was 694 ± 313 mL in the heparin-coated group and 679 ± 269 mL in the control group (p = not significant). Three patients in the heparin-coated group and 6 patients in the control group received homologous red blood cell transfusions (p = not significant). The incidence of postoperative atrial fibrillation was significantly lower in the heparin-coated group (21.8%) than in the control group (43.1%) (p = 0.002). Otherwise, there were no significant differences in the extubation times, the incidence of perioperative myocardial infarction, the creatinine concentration, the incidence of neurologic dysfunction, the progress in physical rehabilitation, or the hemoglobin concentration at discharge.
Conclusions. The use of completely heparin coated cardiopulmonary bypass circuits and full systemic heparinization in patients undergoing coronary artery bypass procedures did not reduce postoperative bleeding or change clinical performance, except for a significant decrease in the incidence of postoperative atrial fibrillation.
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Introduction |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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The purpose of the present study was to compare the clinical performance in patients undergoing heparin-coated CPB and full systemic heparinization, with that in patients operated on using uncoated, but otherwise identical extracorporeal equipment.
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Material and Methods |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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Initially 220 patients were randomly and prospectively allocated to either the heparin-coated group or a control group. The randomization procedure was done in blocks (six by six in sealed envelopes) of equal numbers for both surgeons. The study protocol was approved by the local ethics commitee. The surgical team, but not the anesthesiologist and the perfusionist, was blinded to the randomization.
Cardiopulmonary Bypass
In the heparin-coated group, CPB was performed using a Duraflo II circuit (Baxter-Bentley Laboratories, Irvine, CA). All surfaces in contact with blood were coated with a water-insoluble heparin complex. The circuit consisted of silicone and polyvinyl chloride tubings connected to a hard-shell cardiotomy reservoir (DII BCR-3500), a soft-shell venous reservoir (DII BMR-1900), a woven, hollow polypropylene–fiber membrane oxygenator (Univox Gold; Baxter-Bentley, Irvine, CA), and a 25-µm arterial filter (DII AF-1025). Heparin (5,000 IU/mL; Nyco Pharma, Oslo, Norway) was used for anticoagulation. A bolus dose of 400 IU/kg was given intravenously. The ACT (HemoTec, Englewood, CO) had to be at least 480 seconds before CPB was started. The bolus dose of protamine (protamine sulfate; Novo Nordisk, Baksverd, Denmark) for neutralization of the heparin effects was 1.3 mg/100 IU of heparin. The extracorporeal bypass was disconnected before the administration of protamine sulfate.
In the control group, CPB was performed with an identical, but uncoated, circuit. Heparin doses, ACT limits, and the protamine-heparin ratio were the same in the two groups.
The ACT was determined preoperatively, after heparin administration and before CPB, 10 minutes after the start of CPB, each 20 minutes during CPB, after protamine administration, and 2 hours postoperatively. Additional heparin was given if the level was below the target level. The administration of supplemental doses of protamine was considered if the postoperative ACT was more than 130 seconds and mediastinal bleeding was above average.
Extracorporeal circulation was accomplished using a Stöckert roller pump with the pulsatile flow control (PFC III; Stöckert Instrumente GmbH, Munich, Germany). Mild hypothermia (blood temperature, 32°C) was instituted immediately after the start of bypass. The heart-lung machine was primed with 2,000 mL of Ringer's acetate solution. Hemodilution was further accentuated (and standardized) by autologous blood removal for blood conservation, which aimed at an intraoperative hematocrit of more than 22%.
Operation and Blood Conservation
The anesthesia protocol was designed to permit early extubation and mainly consisted of a combination of diazepam (0 to 0.2 mg/kg), midazolam hydrochloride (0 to 0.2 mg/kg), fentanyl (6 to 8 µg/kg), and pancuronium bromide supplemented with isoflurane and nitrous oxide.
At least one internal mammary artery anastomosis was constructed in all patients, supplemented with saphenous vein grafts. The aorta was cross-clamped during performance of the distal anastomoses. Myocardial protection for high-risk patients (age >70 years; emergency procedure; ejection fraction <0.50, insulin-dependent diabetes) was accomplished by the antegrade administration of blood cardioplegia, delivered by heparin-coated equipment (DII HE-30 Gold; Baxter-Bentley). Otherwise, crystalloid cardioplegia (St. Thomas' Hospital solution No. 2) was given. Topical cooling with ice slush was used in all patients. The proximal anastomoses were sutured during partial occlusion of the ascending aorta while the patient was being rewarmed. A cardiotomy suction device was used during the entire period of heparinization. The blood conservation protocol of the institution has already been described in detail [12] and includes autologous blood removal before CPB with later retransfusion, returning all contents of the extracorporeal circuit to the patient, as well as autotransfusion of the shed mediastinal blood up to 18 hours after the operation. To further minimize the need for banked blood transfusions, a low threshold for reexploration for postoperative bleeding was adopted. Apart from obvious surgical reasons for bleeding, a mediastinal drainage amount of more than 300 mL/h for 2 subsequent hours was the indication for resternotomy. No patients received aprotinin or any other antifibrinolytic agents.
The amount of postoperative bleeding was recorded from the time of sternal closure until 18 hours after the operation. Normovolemic anemia was accepted to a hematocrit of 0.25 postoperatively; a level below this was considered an indication for homologous red blood cell transfusion. The hemoglobin concentrations were determined preoperatively, at 3 and 18 hours postoperatively, and at discharge on the fifth to seventh day. Kidney function was monitored by repeated measurements of the serum creatinine level before and after the operation. Platelet counts were also routinely performed before and after the operation.
Postoperative Arrhythmias
After continuous electrocardiographic monitoring the day of operation, all patients were monitored with continuous telemetry for 48 hours postoperatively. In the event of arrhythmias, telemetry was prolonged or reinstituted. All patients having one or more episodes of arrhythmias were prospectively registered. Treatment with preoperative medication (ß-blockers, Ca2+-channel blockers, and digitalis) was resumed the first day after the operation. In those patients not receiving ß-blockers preoperatively, such treatment was instituted on the first postoperative day.
Statistical Analysis
Comparison of the two groups was done using the Mann-Whitney U test for continuous variables. Discrete variables were treated by means of contingency tables, with Yates' correction and Fisher's test performed when one of the expected cell values was less than 5. The data are presented as the mean ± standard deviation. A p value of less than 0.05 was considered significant. All data were recorded prospectively and stored in a database.
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Results |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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The two groups did not differ significantly in terms of any major preoperative variables (Table 1
). Most patients underwent their procedures on an elective basis. There were no significant intergroup differences in terms of the preoperative ingestion of ß-receptor blockers (heparin-coated group, 88.5%; control group, 93.6%), Ca2+-channel blockers (heparin-coated group, 32.0%; control group, 39.1%), or digitalis (heparin-coated group, 1.9%; control group, 4.5%). Operative characteristics such as the number of distal anastomoses, the aortic cross-clamping times, and the extracorporeal bypass times were similar, as was the distribution of high-risk patients (those given blood cardioplegia). Sinus rhythm returned spontaneously after declamping of the aorta in an equal proportion of patients in the two groups.
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. The fluid balance at the end of operation and during the first 18 hours postoperatively was not significantly different between the two groups. Patients in both groups were extubated early. Fewer patients in the heparin-coated group than in the control group who were in normal sinus rhythm preoperatively had one or more episodes of atrial fibrillation in the postoperative period (n = 22/101 [21.8%] in the heparin-coated group; n = 47/109 [43.1%] in the control group; p = 0.002). This difference was even more evident in patients younger than 65 years of age (p = 0.001) (Table 2). The progress made in physical rehabilitation was similar in both groups. No differences in kidney function were seen (Fig 1). One patient in the heparin-coated group and 2 patients in the control group (p = not significant) sustained a perioperative myocardial infarction. In the control group, 1 patient experienced a definite stroke and 4 more patients had transient neurologic disturbances, compared with one stroke and one minor neurologic event in the heparin-coated group. The differences did not reach statistical significance (p = 0.3), however. The patient with stroke in the heparin-coated group died; this was the only death in the study.
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The doses of heparin and protamine administered are shown in Table 3 and reflect the fact that some patients were given additional heparin and protamine so that the target ACT was reached before, during, and after CPB. Thirteen patients in the heparin-coated group were given an additional 4,231 ± 1,201 IU of heparin, and 18 patients in the control group received an additional 5,278 ± 2,081 IU of heparin during CPB (p = not significant). Supplemental protamine doses were given to 11 patients in the heparin-coated group and 9 patients in the control group (p = not significant). The protamine-to-heparin ratio remained similar for the two groups. The ACTs in the two groups are shown in Figure 2. The ACT was significantly higher in the heparin-coated group 30 minutes after the start of CPB (p = 0.007).
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). In both groups, more than 95% of the shed mediastinal blood was autotransfused without any pretreatment. Three patients in the heparin-coated group received a total of 1,800 mL of homologous red blood cells, and 6 patients in the control group were given 4,500 mL of red blood cells. Neither the difference in the number of patients receiving transfusions nor the difference in the volumes of red blood cells administered was statistically significant. The rate of reexploration for postoperative bleeding (5.6% in the heparin-coated group and 3.6% in the control group) was higher than the average for the institution (97/3,659; 2.7% in the period 1989–1995) and reflects the strategy of performing early resternotomy in the study to reduce the requirement for homologous blood transfusions and to exclude eventual bias stemming from mechanical bleeding. The maximal amount of postoperative mediastinal bleeding recorded in the study was 2,065 mL. The hemoglobin concentrations in the perioperative period were similar in the groups (Fig 3), as were the platelet counts (Fig 4). The lowest hematocrit value during CBP did not differ between the two groups, indicating the same extent of intraoperative hemodilution.
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Comment |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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The use of extracorporeal circuits coated with surface-bound heparin has been found to lead to a significant reduction in complement and granulocyte activation [3–7], as well as a reduced release of various cytokines [8, 13, 14]. These effects have generally been regarded as resulting from the improved biocompatibility of the heparin-treated surfaces, because the activation of biologic cascades plays an important role in the pathogenesis of organ dysfunction after CPB [14–16]. In the present study, we were not able to demonstrate any clinical improvements with respect to organ functions. There were no changes in the total fluid balance, indicating unaffected capillary permeability during and after CPB. For the lungs, neither the blood gas values nor the time required for ventilatory support after the operation were different between the groups. Similarly, there were no differences in kidney function postoperatively, as shown by the creatinine concentration. The progress made in physical rehabilitation was identical in the groups. These facts may largely be due to the relatively low operative risk profile of most of the patients, in combination with short ischemic and CPB times. Under these circumstances, severe postoperative complications were not anticipated in either groups. However, analysis of the subset of patients at higher operative risk (one third of the patients) revealed no significant intergroup differences in terms of organ function. This compares well with the findings from a recent study of 30 patients undergoing a similar clinical and CPB protocol [17], in whom no significant differences were demonstrated with respect to the fluid balance, postoperative intubation time, and difference between rectal temperature and skin temperature, although a summary score composed of these variables showed a slight improvement for the heparin-coated group.
The only advantage of clinical importance demonstrated in the present study was the remarkably low incidence of atrial fibrillation in the heparin-coated group compared with that in the control group. The heart rhythm was recorded throughout the postoperative hospital stay (5–7 days), and the overall incidence of atrial fibrillation was 21.8% in the heparin-coated group and 43.1% in the control group (p = 0.002). The explanation for this difference remains unclear, and it could not be correlated with confounding variables. Preoperative medication regimens were similar in the two groups, and treatment for postoperative hypertension was equally distributed across the groups. Because high age is known to be a risk factor for atrial fibrillation [18], the trend toward a higher age in the control group, although not statistically significant, could explain some of this effect. Even more surprising was the finding that no intergroup difference with respect to supraventricular arrhythmias was observed for patients older than 65 years of age (see Table 2
). Consequently, the difference was even more evident in patients younger than 65 years (p = 0.001). Whether this observation is related to the beneficial effects of heparin-coated surfaces on the inflammatory response to CPB [3–8] remains speculative. However, the fact that a reduced incidence of arrhythmias was only noted for younger patients may implicate immunologic mechanisms, as older patients are known to have a reduced immunologic response [19]. Nevertheless, the reduced incidence of arrhythmias should be emphasized as postoperative atrial fibrillation constitutes a risk factor for stroke, prolonged hospital stay, and increased hospital cost [18].
Heparin can be attached to polymers with various ionic preparations or by covalent binding to the surface [1, 2]. The Duraflo II process is based on the concept of modifying the physiochemical properties of unfractionated heparin with a proprietary binding agent that has a high affinity for a variety of synthetic surfaces [2]. A smaller proportion of the attached heparin has been demonstrated to leak from the surfaces into the circulation [2, 20]. Evidence of leaking heparin could also be demonstrated in the present study, as the ACT was significantly higher 30 minutes after the start of CPB in the heparin-coated group, despite the fact that more heparin tended to be given to the control group. The protamine requirement was similar in both groups, however, as was postoperative bleeding, making the clinical consequences of heparin leakage negligible.
The main advantage of heparin-coated CPB circuits appears to be the increased thromboresistance that results, which allows systemic heparin volumes to be reduced. As already pointed out, several studies have shown that reduced systemic heparinization is safe in combination with heparin-coated CPB and leads to less perioperative blood loss [9–11]. The reason for this may be that heparin itself causes platelet dysfunction and induces fibrinolysis even before the institution of CPB [21]. The fear that thrombin formation will increase in response to a reduction in the systemic heparin level could not be confirmed in a previous study comparing the full heparin dose (ACT, >480 seconds) with the low heparin dose (ACT, >250 seconds) used in combination with heparinized CPB circuits [22]. Furthermore, there is evidence that circulating heparin is an important agonist for granulocyte activation [23] and that lower levels of circulating heparin seem essential for reducing the activation of both polymorphonuclear and eosinophilic leukocytes seen during heparin-coated CPB [24]. Consequently, a moderate reduction in the systemic level of heparin appears to be an advantage with regard to reducing postoperative bleeding and the requirement for protamine, as well as further improving the biocompatibility of heparin-coated surfaces.
In conclusion, the use of completely "tip-to-tip" heparin-coated circuits for extracorporeal circulation during coronary artery bypass operations, in combination with full systemic heparinization, except for being associated with a lower incidence of postoperative atrial fibrillation, had a minor influence on clinical performance. This is in contrast to several beneficial effects seen when the amount of circulating heparin is reduced.
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Acknowledgments |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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Footnotes |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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