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Ann Thorac Surg 2001;72:1316-1320
© 2001 The Society of Thoracic Surgeons

Original article: cardiovascular

Preoperative administration of steroids: influence on adhesion molecules and cytokines after cardiopulmonary bypass

Ulrich P. Schurr, MDa, Gregor Zünd, MDb, Simon P. Hoerstrup, MDb, Jürg Grünenfelder, MDa, Friedrich E. Maly, MDc, Paul R. Vogt, MDa, Marko I. Turina, MDa

a Clinic for Cardiovascular Surgery, University Hospital Zurich, Zurich, Switzerland
b Division of Cardiovascular Research, University Hospital Zurich, Zurich, Switzerland
c Institute of Clinical Chemistry, University Hospital Zurich, Zurich, Switzerland

Address reprint requests to Dr Zünd, Clinic for Cardiovascular Surgery, University Hospital Zurich, Raemistrasse 100, CH 8091 Zurich, Switzerland
e-mail: gregor.zund{at}chi.usz.ch

Presented at the Poster Session of the Thirty-seventh Annual Meeting of The Society of Thoracic Surgeons, New Orleans, LA, Jan 29–31, 2001.


   Abstract
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 Abstract
Introduction
 Material and methods
 Results
 Comment
 References
 
Background. Cardiopulmonary bypass (CPB) is associated with tissue damage mediated by adhesion molecules and cytokines. Prebypass steroid administration may modulate the inflammatory response, resulting in improved postoperative recovery.

Methods. Fifty patients undergoing elective coronary operations under normothermic CPB were randomized into two groups: group A (n = 24) received intravenous methylprednisolone (10 mg/kg) 4 hours preoperatively, and group B (n = 26) served as controls. Cytokines (tumor necrosis factor-{alpha} [TNF-{alpha}], interleukin-2R [IL-2R], IL-6, IL-8), soluble adhesion molecules (sE-selectin, sICAM-1), C-reactive protein, and leukocytes were measured before steroid application, then 24 and 48 hours, and 6 days postoperatively. Adhesion molecules were measured by enzyme-linked immunosorbent assay, cytokines by chemiluminescent immunoassay. Postoperatively, hemodynamic measurements, inotropic agent requirements, blood loss, duration of mechanical ventilation, and intensive care unit stay were compared.

Results. Aortic cross-clamp and CPB time was similar in both groups. Prednisolone administration reduced postoperative levels of IL-6 (611 versus 92.7 pg/mL; p = 0.003), TNF-{alpha} (24.4 versus 11.0 pg/L, p = 0.02), and E-selectin (327 versus 107 ng/mL, p = 0.02). Postoperative recovery did not differ between groups.

Conclusions. Preoperative administration of methylprednisolone blunted the increase of IL-6, TNF-{alpha}, and E-selectin levels after CPB but had no measurable effect on postoperative recovery.


   Introduction
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 Abstract
 Introduction
Material and methods
 Results
 Comment
 References
 
Systemic inflammation as an abnormal response to severe injuries was first recognized by the British surgeon John Hunter in 1794. A similar pattern was noticed after cardiopulmonary bypass (CPB) in the early times of cardiac operations, and was supposed to result from exposure of blood to artificial surfaces in the bypass circuit, initiating a "whole body inflammatory response" [1].

The use of CPB techniques may cause capillary leak syndrome and tissue damage caused mainly by leukocyte–endothelial interactions mediated by cytokine and adhesion molecules. Cytokine levels are increased after CBP and are associated with an increased morbidity and mortality rate [2, 3] In addition, the induction of adhesion molecules (sE-selectin, sICAM-1) on the surface of hypoxic coronary endothelial cells has been shown to result in myocardial injury after reoxygenation [4].

Several therapeutic aspects have been proposed to modulate ischemia–reperfusion injury, such as modified ultrafiltration [5] or the use of various pharmacological agents, eg, steroids [6], nonsteroidal antiphlogistica, thymomimetic agents [7], pentoxyphylline [8], aprotinin, antioxidants, or complement receptor or adhesion molecule-blocking agents [9]. Modification of the CPB equipment using pulsatile flow patterns, integration of leukocyte filters [10], and heparin-coated circuits [11] has also been applied to limit postbypass systemic inflammation.

The aim of the present prospective, randomized study was to measure adhesion molecule and cytokine expression after preoperative administration of steroids in patients undergoing primary isolated coronary artery bypass grafting (CABG) using normothermic CPB.


   Material and methods
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 Abstract
 Introduction
 Material and methods
Results
 Comment
 References
 
Patient selection
Between August 1999 and November 2000, 50 patients, mean age 64 ± 9 years (Table 1) undergoing primary isolated CABG were prospectively enrolled and randomized into two groups: group A (n = 24) received 10 mg/kg methylprednisolone sodium succinate (Solu-Medrol; Pharmacia & Upjohn AG, Duebendorf, Switzerland) intravenously 4 hours before the operation; group B (n = 26) served as a control. Patients with insulin-dependent diabetes mellitus, peptic ulcer history, malignant tumors, immunologic deficiencies, renal or hepatic insufficiency, and chronic pulmonary obstructive disease were excluded from the study. Each patient gave his or her informed consent to participate in this trial according to the protocol of the Ethics Committee of the University Hospital Zurich, Switzerland (date of approval 13 May 1999).


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  		Table 1. Perioperative Data

 
Operative technique
Myocardial revascularization was performed under normothermic CPB using a roller pump system (Stöckert Instrumente GmbH, Munich, Germany) and a Shiley–Dideco Maxima hollow fiber oxygenator (Dideco, Mirandola, Italy), by the senior surgeon. Myocardial protection was accomplished using intermittent antegrade warm potassium blood cardioplegia. The perioperative anesthesia management and medication treatment were identical in both groups.

Blood sampling and analysis
Preoperative blood samples (10 mL) were taken before the administration of 10 mg/kg body weight methylprednisolone, delivered 4 hours before induction of anesthesia. Postoperatively, blood samples were collected after 24 hours, 48 hours, and on the sixth postoperative day. The following measurements were taken: interleukin-2 (IL-2R), IL-6, IL-8, tumor necrosis factor-{alpha} (TNF-{alpha}), and the soluble adhesion molecules sE-selectin and sICAM-1.

The blood samples were allowed to coagulate, then centrifuged for 20 minutes at 4°C, and the serum was aliquoted and stored at -70°C. Soluble adhesion molecules in the serum were measured using commercially available enzyme-linked immunosorbent assay kits (R&D Systems, Abingdon, UK). Standards of known concentration were run in parallel together with a control serum. The optical density was read at 450 nm with a correction wavelength set to 630 nm. The absorbency was plotted against a standard curve of known concentrations (and expressed as ng/mL). The values were corrected by hemodilution using hematocrit. Cytokines (TNF-{alpha}, IL-2, IL-6, and IL-8) were analyzed by solid-phase, two-site chemiluminescent enzyme immunometric assay (Immunlite, EURO/DPC Ltd, Gwynedd, UK).

Clinical variables
Medical history, demographic data, and the clinical course were analyzed for each patient. Postoperatively, fluid balance; hemodynamic measurements; time on respirator; blood loss; occurrence of atrial fibrillation; renal, hepatic and coagulation disorders; and pulmonary infection requiring antibiotic treatment were registered, as well as the duration of intensive care unit stay and hospitalization.

Statistics
Data were processed with Statview software (Abacus Concepts Inc, Berkeley, CA). All data were expressed as mean with one standard deviation and were graphically presented as bar charts. Intergroup comparison was performed with the Mann–Whitney unpaired test. The Wilcoxon test has been used for the paired data of the intragroup comparison. Groups with normally distributed values were compared by the Student’s t test. Unnormally distributed data were compared either with the Fisher exact test or the Mann–Whitney U test with Bonferroni correction; p values less than 0.05 were considered statistically significant.


   Results
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 Material and methods
 Results
Comment
 References
 
These comparable patients demonstrated no differences in duration of ischemia or bypass time. All the clinical variables, listed in Tables 1 and 2,were essentially identical in both groups.


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  		Table 2. Postoperative Course

 
For the prednisolone group, the mean CPB time was 76 minutes (range 56 to 105 minutes), and the mean aortic cross-clamping time was 42 minutes (range 28 to 73 minutes). No statistical difference was detected when these values were compared with those from the control group (Table 1). White blood cell counts, C-reactive protein values, and body temperature also did not show any significant differences between the two groups.

Statistically significant differences were not found for preoperative or postoperative ejection fraction (estimated by transesophageal echocardiography), cardiac index, or peripheral systemic resistance. The postoperative inotropic support contained only a low-dose administration of either dopamine or dobutamine (maximum 300 µg/min) to keep the mean arterial pressure above 70 mm Hg in 85% of the patients for the first 4 to 8 hours. Three patients from the prednisolone group and 6 patients from the control group needed intermittent support with low-dose noradrenaline in the early postoperative period. The steroid group had no less mean weight on the third postoperative day.

During the postoperative period the two groups experienced an uneventful course without apparent organ dysfunction or severe infection. However, the fluid balance from the CPB was slightly reduced by 13%, also not significant. Intermittent administration of antibiotic agents was required for 2 patients from the control group for pneumonia and 1 patient from the prednisolone group for a urinary infection.

In all patients postoperative levels of sICAM-1, sE-selectin, IL-6, IL-8, IL-2R, and TNF-{alpha} were significantly higher compared with preoperative values. However, prednisolone administration (group A) significantly (p < 0.05) reduced expression of IL-6, TNF-{alpha}, and E-selectin compared with group B (Figs 1–3). For example, IL-6 showed a maximum peak of 611 pg/mL after 24 hours and decreased to 92.7 pg/mL in patients receiving preoperative prednisolone (p = 0.003). Similarly, prednisolone administration decreased the serum levels of TNF-{alpha} significantly after 24 (p = 0.02) and 48 hours (p = 0.003).



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  		Fig 1. Expression of adhesion molecule sE-selectin after normothermic cardiopulmonary bypass operation pretreated with methylprednisolone compared with the control group at different time intervals. Values are mean ± standard deviation.

 


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  		Fig 2. Expression of cytokine interleukin-6 (IL-6) after normothermic cardiopulmonary bypass operation pretreated with methylprednisolone compared with the control group at different time intervals. Values are mean ± standard deviation.

 


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  		Fig 3. Expression of cytokine tumor necrosis factor-{alpha} (TNF-{alpha}) after normothermic cardiopulmonary bypass operation pretreated with methylprednisolone compared with the control group at different time intervals. Values are mean ± standard deviation.

 
The adhesion molecule sE-selectin (Fig 3) reached a maximum after 24 hours (327 ng/mL), but a significant reduction to 107 ng/mL in the steroid group (p = 0.02) was measured after 48 hours. Other measurements such as IL-8 (neutrophil-activating factor), IL-2, and sICAM-1 were also reduced, but again the difference did not reach statistical significance.


   Comment
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 Abstract
 Introduction
 Material and methods
 Results
 Comment
References
 
Despite the inflammatory response after open heart operations, most patients recover uneventfully from CPB. Therefore, it may be assumed that individual responses to the inflammatory stimuli vary substantially demonstrating the physiologic reserve and sophisticated inhibitory pathways preventing extended organ dysfunction. Unfortunately, the patient population requiring cardiac surgical procedures is changing. At our institution, the number of patients between 70 and 80 years of age has more than doubled in the last 10 years; they now represent more than 30% of our patients. For those older patients, the rate of concomitant diseases may increase and therefore it is important to minimize perioperative risk factors such as high cytokine and adhesion molecule levels. The release of inflammatory mediators and adhesion molecules is caused by the exposure of blood cells to extracorporeal circulation and is the result of ischemia–reperfusion injury during cardiac operations. This reaction may cause postoperative arrhythmia, ventricular dysfunction, and a higher tendency for infections and bleeding.

Strategies through the years attempting to interfere with the inflammatory response have included the administration of pharmacological agents such as nonsteroidal antiphlogistica, thymomimetic agents [7], pentoxyphylline [8], aprotinin, antioxidants, and complement receptor or adhesion molecule-blocking agents [9]. Moreover, modification of CPB equipment such as pulsatile flow patterns, integration of leukocyte filters [10], heparin-coated circuits [11], and performance of minimally invasive coronary artery operations [12] have been applied. Modified ultrafiltration significantly lowers the levels of soluble adhesion molecules and cytokines after elective coronary bypass operations in adults, but has failed to demonstrate any significant clinical benefit [5].

In adult cardiac operations, the preoperative administration of corticosteroids has been investigated by many authors, although significant suppressive effects on cytokines, complement system, complemented mediated activation of neutrophils, and adhesion molecules has been demonstrated, its influence on the postoperative course remains controversial [12–14].

High cytokine levels observed after massive injuries are associated with high mortality rates [14, 15] and IL-6 has been found to profoundly inhibit myocardial contractility through the production of nitric oxide [16], causing stunned myocardium. Casey [2] observed a 30-day mortality rate of 75% in patients with postoperative IL-6 level above 500 pg/mL and increased expression of IL-6 was associated with postoperative hyperdynamic circulatory instability [17].

Several trials with steroid administrations suggest a clinical benefit for cardiac surgical patients undergoing CPB [18]. However, an improved clinical outcome in adults has not been proved, although significantly reduced expression of several proinflammatory mediators after steroid administration has been reported. Engelman and coworkers [19] recommended preoperative high-dose methylprednisolone (1 g) combined with prolonged postoperative dexamethasone treatment. This combination of two steroids seems interesting, especially because of the significant inhibition of leukotriene B4 and the tissue plasminogen-activator activity by dexamethasone. However, synergistic negative effects of high doses of corticosteroids (40 mg/kg) and CPB on T-cell function (eg, stimulation of phythemagglutinin and IL-2 production) were demonstrated by Mayumi and colleagues [13], suggesting the possibility of increased infectious complications after preoperative steroid administration. This finding was not confirmed by our study or other clinical trials with either high-dose or low-dose application of steroids [6, 20].

Although preoperative steroid administration significantly reduced expression of proinflammatory mediators in our patients, the postoperative clinical course was similar in both groups. Postoperative hemodynamic instability associated with increased IL-6 levels [6] and cytokine-mediated vasodilation after normothermic CBP [18] has not been observed in our patients. In this study, significant clinical changes were not observed in patients with and without preoperative steroid administration. However, a long-term negative effect through high levels of proinflammatory mediators on, for example, the endothelium of the grafts, cannot be excluded yet. The present study confirmed that the pretreatment with steroids in cardiac operations with CPB shows significant inhibition of cytokines and adhesion molecules. However, the clinical benefit of this therapy remains unproved.


   References
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 References
 

  1. Kirklin J.K. Prospects for understanding and eliminating the deleterious effects of cardiopulmonary bypass. Ann Thorac Surg 1991;51:529-531.[Medline]
  2. Casey L.C. Role of cytokines in the pathogenesis of cardiopulmonary-induced multisystem organ failure. Ann Thorac Surg 1993;56:92-96.[Abstract]
  3. Verrier E.D. The microvascular cell and ischemia–reperfusion injury. J Cardiovasc Pharmacol 1996;27:26-30.
  4. Schreeniwas R., Koga S., Karakurum M., et al. Hypoxia-mediated induction of endothelial cell interleukin-1 alpha. An autocrine mechanism promoting expression of leukocyte adhesion molecules on the vessel surface. J Clin Invest 1992;90:2333-2339.
  5. Grünenfelder J., Zünd G., Schoeberlein A., et al. Modified ultrafiltration lowers adhesion molecule and cytokine levels after cardiopulmonary bypass without clinical relevance in adults. Eur J Cardiothorac Surg 2000;17:77-83.[Abstract/Free Full Text]
  6. Jansen N.J., van Oeveren W., van den Broek L., et al. Inhibition by dexamethasone of the reperfusion phenomena in cardiopulmonary bypass. J Thorac Cardiovasc Surg 1991;102:515-525.[Abstract]
  7. Zünd G., Dzus A.L., Pretre R., Niederhäuser U., Vogt P., Turina M. Endothelial cell injury in cardiac surgery: salicylate may be protective by reducing expression of endothelial adhesion molecules. Eur J Cardiothorac Surg 1998;13:293-297.[Abstract/Free Full Text]
  8. Coe D.A., Freischlag J.A., Johnson D., et al. Pentoxifylline prevents endothelial damage due to ischemia and reperfusion injury. J Surg Res 1997;67:21-25.[Medline]
  9. Gillinov A.M., De Valeria P.A., Winkelstein J.A., Wilson I., Curtis W.E., Cameron D.E. Complement inhibition with soluble complement receptor type 1 in cardiopulmonary bypass. Ann Thorac Surg 1993;55:619-624.[Abstract]
  10. Mihaljevic T., Tonz M., von Segesser L.K., et al. The influence of leukocyte filtration during cardiopulmonary bypass on postoperative lung function. J Thorac Cardiovasc Surg 1995;109:1138-1145.
  11. Steinberg B.M., Grossi E., Schwartz D., et al. Heparin-bonding of bypass circuits reduces cytokine release during cardiopulmonary bypass. Ann Thorac Surg 1995;60:525-529.[Abstract/Free Full Text]
  12. Gu Y.J., Mariani M.A., van Oeveren W., Grandjean J.G., Boonstra P.W. Reduction of inflammatory response in patients undergoing minimally invasive coronary artery bypass grafting. Ann Thorac Surg 1998;65:420-424.[Abstract/Free Full Text]
  13. Mayumi H., Zhang Q.W., Nakashima A., et al. Synergistic immunosuppression caused by high dose methylprednisolone and cardiopulmonary bypass. Ann Thorac Surg 1997;63:129-137.[Abstract/Free Full Text]
  14. Biffl W.L., Moore E.E., Peterson V.M. Interleukin-6 in the injured patient. Marker of injury or mediator of inflammation?. Ann Surg 1996;224:647-664.[Medline]
  15. Antonelli M., Raponi G.M., Gasparetto A., et al. High IL-6 serum levels are associated with septic shock, and mortality in septic patients with severe leukopenia due to hematological malignancies. Scand J Infect Dis 1995;27:381-384.[Medline]
  16. Finkel M.S., Oddis C., Jacob T., Simmons R.L. Negative inotropic effects of cytokines on the heart mediated by nitric oxide. Science 1992;257:387-389.[Abstract/Free Full Text]
  17. Cremer J., Haverich A., Borst H.G., et al. Systemic inflammatory response after cardiac operations. Ann Thorac Surg 1996;61:1714-1720.[Abstract/Free Full Text]
  18. Teoh K.H., Bradley C.A., Gauldie J., Burrows H. Steroid inhibition of cytokine mediated vasodilation after warm heart surgery. Circulation 1995;92(Suppl):II347-II353.
  19. Engelman R.M., Rousou J.A., Flack J.E., 3rd, Deaton D.W., Kalfin R., Das D.K. Influence of steroids on complement and cytokine generation after cardiopulmonary bypass. Ann Thorac Surg 1995;60:801-804.[Abstract/Free Full Text]
  20. Inaba H., Kochi A., Yorozu S. Suppression by methylprednisolone of augmented plasma endotoxine-like activity and interleukin-6 during cardiopulmonary bypass. Br J Anaesth 1994;72:348-350.[Abstract/Free Full Text]



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