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Ann Thorac Surg 1996;61:674-678
© 1996 The Society of Thoracic Surgeons

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Original Article: Cardiovascular

Steroid Administration in Heart and Heart–Lung Transplantation: Is the Timing Adequate?

Departments of Cardiac Surgery, Immunology and Intensive Care, University Hospital Erasme, Free University of Brussels, Brussels, Belgium

Accepted for publication October 14, 1995.

	Abstract

Top Footnotes Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 
Background. The release of cytokines after cardiopulmonary bypass may play an important role in postoperative morbidity. The release of proinflammatory cytokines, such as tumor necrosis factor , interleukin (IL)-6 and IL-8, is even greater in patients undergoing heart transplantation (HTx) than coronary artery grafting. We tested the hypothesis that in HTx patients the earlier administration of steroids, before rather than after cardiopulmonary bypass as usual, can reduce the inflammatory response.

Methods.In 20 consecutive patients who underwent HTx or heart–lung transplantation (HLTx), plasma levels of tumor necrosis factor , IL-6, IL-8, and anti-inflammatory cytokine IL-10 were measured before heparin administration, at aortic cross-clamping and declamping, and 0.5, 1, 1.5, 2, 4, 12, and 24 hours after aortic declamping. In 10 patients (group I, 6 HTx and 4 HLTx), 500 mg of methylprednisolone was first given as usual at 1.5 hours after aortic declamping (at the end of cardiopulmonary bypass). In the next 10 patients (group II, 6 HTx and 4 HLTx), the first doses of methylprednisolone were given 1 hour before operation. In both groups, 125 mg of methylprednisolone were given every 8 hours thereafter during the first postoperative day.

Results. The ischemic time and cardiopulmonary bypass time were similar in the two groups (166 ± 16 minutes versus 157 ± 13 minutes, and 192 ± 21 minutes versus 186 ± 20 minutes, respectively, mean ± standard error of the mean). At 30 minutes after aortic declamping and throughout the next 4 hours, tumor necrosis factor levels were significantly lower in group II than in group I (all p < 0.03). Interleukin-8 values 1 hour after declamping were also lower in group II than in group I (49 ± 15 pg/mL versus 130 ± 38 pg/mL, p < 0.02). Interleukin-10 levels were significantly higher in group II than in group I from 30 minutes after declamping through 2 hours after (all p < 0.03). Interleukin-6 levels were similar in the two groups.

Conclusions. Earlier steroid administration in the immunosuppressive protocol for HTx or HLTx may be preferable to reduce the inflammatory response to cardiopulmonary bypass, as reflected by a lower production of tumor necrosis factor and IL-8, and a greater release of IL-10.

	Introduction

Top Footnotes Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 
Although heart transplantation (HTx) has been successfully performed for more than one and a half decades, the long-term outcome is still far from ideal. The 12-year actuarial survival is less than 40% for HTx , and less than 20% for heart–lung transplantation (HLTx) [1]. It is beyond doubt that efforts to improve immunosuppressive therapy are of the utmost importance as acute rejection remains the most common cause of death [2, 3]. Induction of immune suppression is particularly crucial as it is a major determinant of hospital survival after HTx [4], and steroid administration has been a mainstay of induction therapy. The first dose of steroids is usually administered shortly after the transplant procedure [2, 5–8], but an earlier administration could also be considered.

Over the past few years, much attention has been turned to the involvement of the cytokine network after transplantation [9, 10]. A number of studies have shown cytokine expression after HTx or lung transplantation [11–15] and suggested some correlation between cytokines levels and rejection or infection [12–14]. In a recent study, we [15] observed that the production of proinflammatory cytokines, such as tumor necrosis factor (TNF-), interleukin (IL)-6 and IL-8, was more striking in the early phase (within 24 hours) after HTx than after coronary artery bypass grafting. We also found a significant release of antiinflammatory cytokine IL-10, but the magnitude of the release was not clearly related to the duration of ischemia [15].

Routine administration of corticosteroids before cardiopulmonary bypass (CPB) has been used for many years [16], although the beneficial effect of this intervention has not been proven. Recent studies have indicated that steroid administration before CPB may prevent the release of TNF- [17] and IL-8 [18, 19], or increase the production of IL-10 [19]. This cytokine response may be involved in the development of complications after CPB, and may also play a role in acute rejection of cardiac allografts early after transplantation [9, 20]. Between March 1982 and May 1995, 346 HTxs in 341 recipients and 58 HLTxs have been performed at the University Hospital Erasme, Free University of Brussels. The immunosuppressive protocol changed several times during this period, but the first doses of steroids were always administered at the end of CPB [6]. We tested the hypothesis that pretreatment with steroids (methylprednisolone), as opposed to administration at the end of CPB as usual, can reduce the inflammatory response to CPB in HTx patients.

	Patients and Methods

Top Footnotes Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 
The study was approved by the ethical committee of the University Hospital Erasme, Free University of Brussels. Informed verbal consent was obtained from each patient. Twenty patients undergoing HTx or HLTx were studied consecutively. Clinical characteristics of both groups of patients are shown in Table 1.

The patients were included in two consecutive groups. The group I patients (n = 10, 6 HTx and 4 HLTx) received methylprednisolone (Solu-Medrol; Upjohn, Kalamazoo, MI) 90 minutes after aortic declamping (500 mg, intravenously), at the end of CPB. The group II patients (n = 10, 6 HTx and 4 HLTx) received the same doses of methylprednisolone 1 hour before operation. In both groups, 125 mg of methylprednisolone was also administered every 8 hours thereafter during the first postoperative day.

The extracorporeal circuit consisted of a roller pump (Stockert Instrumente Gmbh, Munich, Germany) and a membrane oxygenator (Univox-IC; Baxter Bentley Lab, Irvine, CA). Pump flow was kept at 2.4 L • min^-1 • m^-2. Heparin (loading dose, 3 mg/kg) was infused to maintain an activated clotting time of more than 480 seconds during CPB. All patients were cooled to between 26 and 28°C and rewarming began during the aortic anastomosis. On discontinuation of CPB, heparin was neutralized with protamine sulfate in a 2:3 ratio of total dose of heparin. Inotropic support with dobutamine as well as temporary pacing were provided at the end of operation in all patients.

Blood was collected from peripheral arterial lines or the arterial side of the pump circuit on an event-based schedule as follows: (1) just before heparin administration; (2) immediately after aortic cross-clamping; (3) 1 minute after aortic declamping, and (4) 30 minutes, (5) 60 minutes, (6) 90 minutes, (7) 2 hours, (8) 4 hours, (9) 12 hours, and (10) 24 hours after aortic declamping. All samples were anticoagulated with ethylenediaminetetraacetic acid, immediately cooled to 4°C and centrifuged within 30 minutes (3,000 g for 10 minutes at 4°C). Plasma was stored at -20°C until assayed.

Tumor necrosis factor , IL-6, IL-8, and IL-10 levels were determined in plasma by using commercially available enzyme-linked immunosorbent assays (Medgenix Diagnostics, Fleurus, Belgium). No adjustment was made for hemodilution. The sensitivity was 20 pg/mL for TNF-, 15 pg/mL for IL-6, 7.8 pg/mL for IL-8, and 14 pg/mL for IL-10.

Data were expressed as mean ± standard error of the mean unless otherwise indicated. Because the data were normally distributed, a two-way analysis of variance for repeated measures was used, followed by a modified t test. A p value less than 0.05 was considered to be significant.

	Results

Top Footnotes Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 
Table 1 summarizes the details of patients studied. There were no significant differences between groups in CPB time, cross-clamping time, or ischemic time. Within each group, the duration of CPB, cross-clamping, and ischemia were longer in HLTx patients than in HTx patients (Table 1).

No patient required reexploration for bleeding after operation. All patients survived the hospital stay except one 45-year-old male patient in group II, who had an acute dissection of descending aorta, underwent an emergency vascular operation, and died 1 week later of multiple organ failure.

The cytokines levels are shown in Figures 1 and 2. Tumor necrosis factor levels were significantly lower in group II than in group I from 30 minutes after aortic declamping and for another 4 hours after. Interleukin-6 levels were similar in the two groups. One hour after declamping the IL-8 levels were also significantly lower in group II than in group I (p < 0.02). Interleukin-10 levels increased in both groups during the 2 hours after aortic declamping but this increase was far more pronounced in group II than in group I (Fig 1).

View larger version (18K): [in this window] [in a new window]   Fig 1. . Plasma tumor necrosis factor (TNF-), interleukin-6, -8, -10 (IL-6, IL-8, and IL-10) levels in group I (open circles, dotted lines) and group II (closed circles, solid lines) of patients. *p < 0.01, p < 0.05 between groups. Data are mean ± standard error of the mean. (BH — before heparin administration; CC — cross-clamping; DC — 1 minute after declamping; 0.5h, 1h, 1.5h, 2h, 4h, 12h, and 24h — time points after declamping.)

View larger version (16K): [in this window] [in a new window]   Fig 2. . Plasma interleukin-8 (IL-8) levels in heart transplant (HTx) patients (A) and in heart–lung transplant (HLTx) patients (B). See legend of Figure 1 for details.

	Comment

Top Footnotes Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 
Corticosteroids have a variety of antiinflammatory and immunosuppressive effects that place them as fundamental agents in the induction protocol for HTx and HLTx. In this context, steroids are usually given at the end of CPB [2, 5, 6], a little earlier (just before aortic declamping) [7], or even later (immediately after operation) [8]. The present study demonstrates that earlier administration of steroids before operation can significantly inhibit the release of proinflammatory cytokines, such as TNF- and IL-8, and also increase the production of antiinflammatory cytokine IL-10 during CPB.

For many years, steroids have been administered before CPB to reduce the inflammatory response and prevent hemodynamic instability [16]. Recent studies have shown that steroid administration before CPB can inhibit effectively the release of proinflammatory cytokines [17–19, 22]. Our observation that steroids can inhibit the release of TNF- during CPB has been reported [17]. Jorens and co-workers [18] found that methylprednisolone administration before CPB can inhibit the subsequent IL-8 release and other investigators confirmed their finding [19, 22]. In HLTx patients, steroid pretreatment did not influence IL-8 levels but the IL-8 release was much more significant in these patients. This may be attributable to the longer duration of CPB as well as the longer ischemic time associated with HLTx. The lungs may also be an important organ source of IL-8. Whether a higher dose of steroids could have prevented the IL-8 release in HLTx patients may require further study. Through its antiinflammatory properties, IL-10 can play an important role in regulation of this cytokine response [23, 24]. Tabardel and colleagues [19] recently showed that steroid administration before CPB can also markedly increase IL-10 production during and after CPB. Tumor necrosis factor can trigger the synthesis of other cytokines including IL-10 [25], and in turn, IL-10 is a potent inhibitor of the production of proinflammatory cytokines [24]. In the present study, a greater IL-10 release was the likely cause of lower levels of TNF- and IL-8 in the steroid pretreatment group. Interestingly, the IL-6 levels were similar in the two groups suggesting that this cytokine, whose levels are thought to reflect the degree of inflammatory injury after CPB [26], is not significantly influenced by the timing of steroid administration.

The duration of CPB and ischemia in HTx and HLTx patients is much longer than in routine open heart operation. Although some reports indicated that a cardiac allograft ischemic time of 4 to 6 hours was not a significant risk factor for mortality [5, 27], a longer ischemic time is still among the major risk factors for death within the first postoperative year [1]. Proinflammatory cytokines, especially TNF- and IL-8, can induce harmful effects by their multiple effects on adhesion molecules, endothelial cells, and white blood cells [10, 20]. In a previous study [15], we documented that the degree of expression of proinflammatory cytokines, but not of IL-10, is strongly related to the duration of ischemia in patients undergoing CPB. It has been suggested that CPB itself may be detrimental to early graft function [28], resulting in myocardial injury and capillary leak [29–31] and prolonged ischemia can jeopardize graft survival. These deleterious effects are largely mediated by a proinflammatory response with increased release of cytokines (such as IL-8) and expression of adhesion molecules [9]. On the basis of this reasoning, inhibiting the release of TNF- and IL-8 as well as increasing the production of IL-10 with earlier steroid administration may reduce complications after HTx and HLTx.

Earlier steroid administration may also improve the induction of tolerance. It has been suggested that ischemia–reperfusion injury plays a key role in the development of acute and chronic rejection [32]. Cytokines can also alter the host immune responses and participate in the complex process of rejection [20]. Monitoring the cytokine levels after transplantation may have some prognostic value in organ transplantation [13, 33]. Although the relationship between the cytokine network and the allograft response is complex and still unraveled, a lesser TNF response and especially a greater IL-10 response may improve tolerance to allografts [20].

In summary, earlier steroid administration can reduce the inflammatory response to CPB in patients undergoing HTx or HLTx, as reflected by a lower production of TNF- and IL-8, but a greater release of IL-10. Earlier administration of steroids in HTx or HLTx patients may be preferable to reduce the postoperative complications and to improve the immune response to transplantation. Our study included only one dose regimen of steroids before CPB. Higher doses of steroids may have better inhibitory effects. Further investigation is certainly warranted.

	Acknowledgments

Top Footnotes Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 
This study was supported by Fondation pour la Chirurgie Cardiaque , Belgium. We thank Drs Jean-Luc Vachiery, Didier De Canniere, and Chi-Hoang Huynh in our transplant team for their continued support. We are particularly grateful to Drs Arnaud Marchant and Haibo Zhang for their help. The technical assistance of Eric Quertinmont is also sincerely acknowledged.

	Footnotes

Top Footnotes Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 
Address reprint requests to Dr LeClerc, Department of Cardiac Surgery, University Hospital Erasme, Free University of Brussels, Route de Lennik 808, B-1070, Brussels, Belgium.

	References

Top Footnotes Abstract Introduction Patients 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 Author home page(s): Song Wan Martine Antoine Jean-Louis Vincent Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wan, S. Articles by LeClerc, J.-L. Search for Related Content PubMed PubMed Citation Articles by Wan, S. Articles by LeClerc, J.-L.