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Ann Thorac Surg 1999;68:1230-1235
© 1999 The Society of Thoracic Surgeons

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Original Articles

Heparin-coated circuits reduce myocardial injury in heart or heart-lung transplantation: a prospective, randomized study

^a Departments of Cardiac Surgery, University Hospital Erasme, Free University of Brussels, Brussels, Belgium
^b Intensive Care, University Hospital Erasme, Free University of Brussels, Brussels, Belgium

Address reprint requests to Dr Wan, Division of Cardiothoracic Surgery, Department of Surgery, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong
e-mail: swan{at}cuhk.edu.hk

	Abstract

Top Abstract Introduction Material and methods Results Comment References

 
Background. The effects of heparin-coated (HC) circuits have been primarily investigated in routine cardiac operations with limited duration of cardiopulmonary bypass (CPB) and ischemia. Their benefits have not been conclusively proven but could be more significant when CPB and ischemic times are longer, such as during heart transplantation (HTx) or heart-lung transplantation (HLTx).

Methods. In a 22-month period, 29 patients undergoing HTx and HLTx were randomly divided into two groups using HC (Duraflo II, n = 14, 10 HTx and 4 HLTx) or uncoated but identical circuits (NHC group, n = 15, 10 HTx and 5 HLTx). All patients received full systemic heparinization (3 mg/kg) during CPB. Plasma endotoxin, interleukin (IL)-6, IL-8, IL-10, IL-12, and cardiac troponin-I were measured before heparin administration, immediately after aortic cross-clamping, 5, 30, 60, 90, 120 minutes, and 12 and 24 hours after aortic declamping. The intensive care unit (ICU) staff and the laboratory technologists were blinded as to the use of HC circuits.

Results. No statistically significant differences between groups were found with respect to all baseline values, duration of CPB and aortic cross-clamping, graft ischemic time, doses of heparin, postoperative blood loss and transfusion, peak lactate and creatine kinase-MB isoenzyme values, duration of mechanical ventilation, or length of ICU stay. One patient in each group died during the hospital stay. Patients in the HC group needed more protamine sulfate after CPB. Although endotoxin levels were similar in the two groups, significantly lower IL-6, IL-8, and IL-10 levels were observed 1 hour after aortic declamping in the HC group. The release of cardiac troponin-I was also significantly reduced in the HC group 12 and 24 hours after reperfusion.

Conclusions. The use of HC circuit limits both pro- and anti-inflammatory responses to CPB. It may also reduce myocardial injury after prolonged duration of CPB and ischemia.

	Introduction

Top Abstract Introduction Material and methods Results Comment References

 
The use of heparin-coated (HC) circuits during cardiopulmonary bypass (CPB) has been shown to improve biocompatibility by reducing complement and granulocyte activation, preserving platelet function, and inhibiting the release of pro-inflammatory cytokines such as tumor necrosis factor (TNF-), interleukin (IL)-6 and IL-8 [1]. Although the release of these pro-inflammatory cytokines may play a key role in postoperative morbidity [2], the clinical benefits of HC circuits have not been conclusively proven [1, 3]. To date, HC circuits have been tested primarily in routine cardiac operations with limited duration of CPB and ischemia. We previously demonstrated that heart transplantation (HTx) and heart-lung transplantation (HLTx) procedures are associated with a much more pronounced production of pro-inflammatory cytokines than routine open heart operations [4]. It is therefore worthwhile to evaluate the use of HC circuits in longer duration of CPB and ischemia, such as during HTx and HLTx.

The purpose of this prospective, randomized study was to compare the degree of release of endotoxin, cytokines (IL-6, IL-8, IL-10, IL-12), and cardiac troponin-I (cTnI), a highly specific marker of myocardial injury [5], in patients undergoing HTx and HLTx using either HC or uncoated but otherwise identical CPB circuits. Postoperative clinical performances, as well as serum levels of creatine kinase-MB isoenzyme (CK-MB) and lactate, were also compared in the two groups of patients.

	Material and methods

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From January 1, 1996, through October 31, 1997, 29 of 40 consecutive patients undergoing HTx or HLTx at the University Hospital Erasme were randomly divided into two groups using HC (n = 14, 10 HTx and 4 HLTx) or conventional bypass circuits (NHC group, n = 15, 10 HTx and 5 HLTx). The type of circuit was determined by opening a sealed envelope prepared in advance. Eleven patients were not included during this period, because the procedure was a retransplantation (n = 4), a left ventricular assist device had been implanted before operation (n = 2), or for logistic reasons (n = 5). The study was approved by the institution review board. All patients gave their informed consent. The preoperative data of the 29 patients studied are shown in Table 1.

For immunosuppression, all patients received methylprednisolone (Solu-Medrol; Pharmacia & Upjohn, Kalamazoo, MI) at a dose of 500 mg/ 1 hr before surgery as previously proposed [6], and 125 mg every 8 hours thereafter during the first postoperative day. Patients also received azathioprine (Imuran; Wellcome, Dartford, UK) at a dose of 3 to 4 mg/kg after induction of anesthesia, and human anti-T-lymphocyte immunoglobulin (ATG; Fresenius AG, Bad Homburg, Germany) at a dose of 3 mg/kg 3 to 4 hours after aortic declamping.

The extracorporeal circuit consisted of a roller pump (Stockert Instrumente GmbH, Munich, Germany) and a membrane oxygenator (Duraflo II for the HC group, and Univox-IC for the NHC group; Baxter Healthcare Co, Bentley Division, Irvine, CA). The circuits used in the HC group were "from cannula to cannula" heparin-treated. Full systemic heparinization (3 mg/kg) was accomplished and an activated clotting time (ACT) of more than 480 seconds was maintained during CPB. The pump flow was set at 2.4 L/min/m². All patients were cooled to between 27 and 29°C, with the rewarming started during the aortic anastomosis. On discontinuation of CPB, heparin was neutralized with protamine sulfate. Supplemental dose of protamine sulfate was given after operation when ACT was still beyond normal range.

Serial blood samples were drawn from a peripheral arterial catheter at the following time points: (1) before heparin administration; (2) immediately after aortic cross-clamping; (3) 5 minutes after aortic declamping, and (4) 30 minutes, (5) 60 minutes, (6) 90 minutes, (7) 2 hours, (8) 12 hours, and (9) 24 hours after aortic declamping. Samples for endotoxin measurements were collected in endotoxin-free tubes (EndoTube ET, with sodium heparin 120 IU, Chromogenix AB, Mölndal, Sweden). Other samples were anticoagulated with ethylenediaminetetraacetic acid. All samples were immediately cooled down to 4°C and centrifuged (2,800 g for 6 minutes at 4°C). Plasma was stored at -70°C until assay.

Postoperative serum CK-MB and lactate values were measured every 12 hours within 48 hours. Duration of mechanical ventilation and intensive care unit (ICU) stay, postoperative blood loss, and requirements for homologous blood transfusions, as well as clinical complications and outcome (including the results of the first three endomyocardial biopsies in every HTx recipient) were also recorded. The ICU staffs were blinded as to the use of HC circuits.

Plasma endotoxin levels were measured using the Limulus amebocyte lysate (LAL) test (Coatest Plasma-Endotoxin, Endosafe Inc, Charleston, SC). The principle of this assay is that endotoxin activates a proenzyme in the LAL. The activated enzyme split off para-nitro aniline from the chromogenic substrate S-2423 to produce a yellow color, which can be determined photometrically at 405 nm. The end-point method was applied for endotoxin measurement and each sample was tested in duplicate. The endotoxin concentration is presented as picograms (pg) per milliliter plasma, with 1 pg corresponding to 0.012 units endotoxin. No adjustment was made for hemodilution.

IL-6, IL-8, IL-10, and IL-12 were determined in plasma by the same technologist, using commercially available enzyme-linked immunosorbent assays (Medgenix Diagnostics, Fleurus, Belgium) as in our previous studies [4,6]. The sensitivity was 15 pg/mL for IL-6 and IL-12, 7 pg/mL for IL-8, and 11 pg/mL for IL-10.

Plasma cTnI was quantified using an immunoenzymometric assay (Access, Sanofi Diagnostics Pasteur SA, Marnes-la-Coquette, France). The cut-off value (above which a sample will be considered as positive) was 0.1 ng/mL for cTnI. Technologists were not aware of the clinical data.

Data were stored and analyzed using standard computer software (StatView Software, Brainpower Inc, Calabasas, CA). Values are presented as mean ± standard error of the mean unless otherwise indicated. A two-way analysis of variance for repeated measures was used for comparison of endotoxin, cytokines and cTnI between two groups at each time point. Unpaired two-tailed t test was also used for comparing clinical variables between groups. A p value less than 0.05 was considered to be statistical significant.

	Results

Top Abstract Introduction Material and methods Results Comment References

 
Patients
The operative and postoperative data are summarized in Tables 1 and 2 . Cell saving devices were used when patients had previously undergone open heart surgery (2 patients in each group). Although heparin doses were similar in the two groups, patients in the HC group needed more protamine sulfate after CPB. No patient required re-exploration for bleeding after surgery. There were no statistically significant differences between groups in terms of the duration of CPB and aortic cross-clamping, peak postoperative CK-MB or lactate values, total amount of chest tube drainage, duration of mechanical ventilation, and ICU stay. Graft ischemic times were somewhat longer in the NHC group, which could be due to chance (p = 0.08). In addition, no new-onset Q-waves on the electrocardiogram were observed after surgery in all patients.

No differences were noted between groups with respect to the results of first three postoperative endomyocardial biopsies in each HTx recipient. The biopsies were performed 7 days after HTx and once per week thereafter during the hospital stay. The histological scores were mainly 1A or 1B in both groups, according to the criteria of the International Society for Heart and Lung Transplantation [7].

Endotoxin and cytokines
Endotoxin levels increased after the onset of CPB to reach their peak value of 30 to 40 pg/mL 5 minutes after aortic declamping (Fig 1). The degree of endotoxin release was similar in the two groups. IL-6, IL-8, and IL-10 levels increased after aortic declamping in both groups, but to a lesser extent in the HC group (Fig 2). IL-12 levels were detectable in all patients even before the start of CPB without significant intergroup differences, and decreased during the first postoperative day (Fig 2).

View larger version (23K): [in this window] [in a new window]   Fig 1. Plasma levels of endotoxin in patients undergoing heart and heart-lung transplantation with heparin-coated (HC) or noncoated (NHC) extracorporeal circuits. Data are mean ± SEM. (BH = before heparin administration; CC = immediately after aortic cross-clamping; DC = 5 minutes after aortic declamping; 0.5h, 1h, 1.5h, 2h, 12h, 24h = time points after declamping.)

View larger version (28K): [in this window] [in a new window]   Fig 2. Plasma levels of interleukin (IL)-6 (A), IL-8 (B), IL-10 (C) and IL-12 (D) in patients undergoing heart and heart-lung transplantation with heparin-coated (HC) or noncoated (NHC) extracorporeal circuits. (Sampling time points: see legend of Fig 1.)

View larger version (21K): [in this window] [in a new window]   Fig 3. Plasma levels of cardiac troponin-I (cTnI) in patients undergoing heart and heart-lung transplantation with heparin-coated (HC) or noncoated (NHC) extracorporeal circuits. (Sampling time points: see legend of Fig 1.)

	Comment

Top Abstract Introduction Material and methods Results Comment References

Many factors during CPB, either material-dependent (ie, the extensive contact between blood and the nonphysiological surfaces) or material-independent (ie, ischemia-reperfusion to the organs), can induce a complex inflammatory response involving complement and cellular activation, along with the production of various mediators including endotoxin and cytokines [1]. The application of HC circuits during routine CPB has been suggested to improve biocompatibility, as reflected by reduced complement and granulocyte activation, preserved platelet function [1], and reduced production of pro-inflammatory cytokines including TNF- [8], IL-6 and IL-8 [9, 10]. The use of HC circuits can also inhibit contact activation during CPB [11]. However, it was still unclear whether it can also influence the release of endotoxin and IL-10.

Our current data suggest that the use of HC circuits has no effect on the release of endotoxin during CPB. Although transient endotoxemia during CPB has long been recognized, the exact mechanism involved as well as its clinical relevance remains a subject of debate [1]. It was speculated that the gut is the major source of endotoxin during CPB since non-pulsatile perfusion may lead to gut mucosal ischemia, increase gut permeability, and result in endotoxin translocation into portal and systemic circulation [1]. Therefore, it is not surprising that the degree of endotoxemia during CPB is not influenced by the type of circuit. Bouma and colleagues [12] found that the release of bactericidal/permeability-increasing protein can be significantly attenuated by the use of HC circuits, but this reduction may simply be a marker of reduced leukocyte activation. On the other hand, circulating endotoxin is not the only trigger for increased pro-inflammatory cytokine production or systemic inflammatory response [13]. The longer duration of CPB and cardiac or cardiopulmonary ischemia during HTx and HLTx can induce greater release of pro-inflammatory cytokines [4], but endotoxin levels during HTx and HLTx were not greater in the present study than during routine CPB [14]. These elements illustrate that factors other than endotoxin are involved in cytokine production during CPB.

We discovered that the use of HC circuits could also reduce the release of IL-10, an important anti-inflammatory cytokine, which can inhibit the release of TNF-, IL-6 and IL-8 [2]. Previous observations indicated that the myocardium is a major source of IL-6 and IL-8, while the liver is a major source of IL-10 during CPB [2]. We recently documented that steroid administration prior to HTx procedures can not only inhibit the release of TNF- but also greatly increase the production of IL-10 [6]. Nevertheless, the release of IL-6 and IL-8 has not been significantly influenced by the timing of steroid administration in patients undergoing HLTx who suffer from even longer duration of CPB and ischemia [6]. Thus, by limiting material-dependent blood activation and the subsequent reactions on the different target organs, heparin coating of CPB circuits may help to keep balance between pro- and anti-inflammatory responses rather than just inhibiting the production of some individual pro-inflammatory mediators.

IL-12 is another important cytokine in immune regulation [15]. We found that IL-12 levels can be detected before operation in almost all patients, slightly increased during CPB (if corrected for hemodilution), but decreased on the first postoperative day. The type of circuit appears to have little effect on the release of IL-12 during and after CPB.

The inflammatory cascade may contribute to the development of postoperative complications including myocardial dysfunction [1]. Although the increased release of IL-6 and IL-8 has been linked with myocardial injury after CPB [2], whether the reduction in the levels of these cytokines during CPB could result in improved myocardial preservation was unknown. Lazar and colleagues [16] recently observed in a pig model of ischemia-reperfusion with CPB that HC circuits may better preserve ventricular wall motion scores, decrease tissue acidosis or lung water accumulation, and reduce infarct size. However, supportive evidence for a real clinical advantage has yet to be given. Since the release of IL-8 can induce leukocyte and endothelial cell activation, which play a central role in myocardial ischemia-reperfusion injury [17], less IL-8 production with reduced cellular activation might therefore reduce the degree of injury. For a quantitative determination of myocardial damage, we measured cTnI, which is probably the most sensitive and specific marker of cardiac injury [5]. After CPB, cTnI levels were correlated with the duration of aortic cross-clamping in patients with normal coronary arteries, although cTnI levels in these patients were much lower than those in patients undergoing CABG [18]. It has been found that the risk of mortality is proportional to cTnI levels in acute coronary syndrome [19]. We [20] recently also observed that IL-8 levels were correlated strongly with postoperative cTnI levels. Moreover, Grant and coworkers [21] noted that elevated donor cTnI values (above 3.1 ng/mL) were likely to predict acute graft failure after infant HTx. Hence, the finding of significantly reduced release of cTnI 12 and 24 hours after reperfusion in the HC group may reflect clinical implications. In the current study, two groups showed similarity in variables such as postoperative blood loss or transfusion, peak lactate and CK-MB values, time on ventilator, and length of ICU stay. Obviously, our study sample was too small to document the ultimate outcome. A larger trial would be required to address this issue.

Finally, a controversial issue relating to the use of HC circuits is heparin dosage to be applied during CPB [1]. In spite of the encouraging results from some previous clinical trials indicating that a reduced systemic heparinization may be safe and even beneficial [22, 23], we have chosen to use standard full systemic heparinization in all patients. There are two reasons to do so. First, some recent studies revealed, both in vitro [24] and in vivo [25, 26], that the reduction in systemic heparinization may predispose to intravascular and CPB circuit clotting simply because HC circuits produce no anticoagulant effect. Second, in the study design, we preferred to change only one parameter. It is known that heparin leaching may occur when ionic coating technique is used such as with the Duraflo II HC circuit [27]. Therefore, it was not surprising in our study that more protamine sulfate was needed after CPB in the HC group. However, there were no intergroup differences in terms of total amount of blood loss or transfusion requirements.

Our data indicated that the use of HC circuits with full systemic heparinization is safe in patients suffering from prolonged duration of CPB and ischemia. By limiting both pro- and anti-inflammatory reactions under these conditions, HC circuit may contribute significantly to the reduction in myocardial ischemia-reperfusion injury as suggested by a lower cTnI release following CPB.

	Acknowledgments

 
This study was supported by Foundation pour la Chirurgie Cardiaque, Belgium. We acknowledge the contributions made to this project by all members of the transplant team, especially the perfusion staff, at the University Hospital Erasme.

	Footnotes

 
This article has been selected for the open discussion forum on the STS Web site: http://www.sts.org/section/atsdiscussion/

	References

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This Article Abstract Full Text (PDF) 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 Author home page(s): Song Wan Martine Antoine Anthony P.C. Yim Jean-Louis Vincent Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wan, S. Articles by Vincent, J.-L. Search for Related Content PubMed PubMed Citation Articles by Wan, S. Articles by Vincent, J.-L.