1Department of Anaesthesia and Intensive Care, Amphia Hospital, PO Box 90108, 4800 RA Breda, The Netherlands.Departments of 2Anaesthesiology and 3Intensive Care, Vrije Universiteit Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands. 4Department of Epidemiology and Biostatistics, Erasmus Universiteit Medical School, PO Box 1738, 3000 DR Rotterdam, The Netherlands*Corresponding author
Accepted for publication: December 6, 2001
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Methods. Seventeen patients were studied: nine patients received dexamethasone 100 mg before induction of anaesthesia (group 1) and eight patients acted as controls (group 2). Plasma levels of tumour necrosis factor (TNF)-, interleukin (IL)-6, IL-8, IL-10 and IL-4 were measured perioperatively.
Results. TNF- and IL-8 did not increase significantly in group 1 whereas they increased in group 2 to greater than preoperative values (P<0.05). IL-6 increased in both groups, with lower values in group 1 than in group 2 (P<0.05). IL-10 increased in both groups, with higher values in group 1 (P<0.05). IL-4 did not change in group 1 but decreased in group 2 compared with pre-induction values (P<0.05). After surgery, patients in group 2 had tachycardia, hyperthermia, a greater respiratory rate and higher pulmonary artery pressure, and a longer stay in the intensive care unit.
Conclusion. Dexamethasone given before cardiac surgery changes circulating cytokines in an anti-inflammatory direction. Postoperative outcome may be improved by inhibition of the systemic inflammatory response.
Br J Anaesth 2002; 88: 496501
Keywords: analgesics anti-inflammatory, steroid, dexamethasone; protein, cytokine
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Corticosteroids have been recommended during cardiac surgery to prevent haemodynamic instability after CPB and to inhibit the leucocyte and tissue plasminogen activator activity generated after the release of the aortic cross clamp, and thus improve the postoperative course.8 9 The effect of steroid administration on the cytokine response during cardiac surgery has been described previously.10 11 However, the evidence of steroid effect on the balance between pro-inflammatory and anti-inflammatory cytokines during cardiac surgery is still very limited. We studied the effect of a single dose of dexamethasone given before anaesthesia on the balance between pro-inflammatory and anti-inflammatory cytokines during coronary artery bypass graft (CABG) surgery. We measured circulating concentrations of the pro-inflammatory cytokines tumour necrosis factor (TNF)-, interleukin (IL)-6 and IL-8 and the anti-inflammatory cytokines IL-10 and IL-4 in patients undergoing CABG with CPB, with and without dexamethasone pretreatment.
![]() |
Patients and methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
On the morning of the operation, patients were randomized to receive either dexamethasone 100 mg (group 1, n=9) or a placebo (group 2, n=9). This dosage was masked. Cardiac medication, including beta-adrenergic blocking agents, calcium-channel blocking agents and nitrates, was continued until the morning of surgery. All patients received lorazepam 40 µg kg1 orally on the night before the operation and morphine sulphate 70 µg kg1 i.m. and scopolamine 8 µg kg1 i.m. 1 h before the operation. Anaesthesia was induced with sufentanil 2 µg kg1 and midazolam 0.15 mg kg1 and maintained with sufentanil 1.0 µg kg1 h1 and midazolam 0.12 mg kg1 h1. Tracheal intubation was facilitated with pancuronium bromide 0.1 mg kg1. A bolus dose of sufentanil 0.5 µg kg1 was given before skin incision. Patients were ventilated with oxygen/air (inspired oxygen fraction 0.5) with a tidal volume of 57.5 ml kg1, aiming at normocapnia.
The surgical procedure was median sternotomy and placement of internal mammary artery or saphenous vein grafts. Cardiopulmonary bypass was with a Cobe hollow-fibre membrane oxygenator. The circuit was primed with 1100 ml (500 ml gelofusine plus 500 ml Ringers solution plus 100 ml mannitol). The CPB flow was maintained at 2.4 litre min1 m2, and mild hypothermia of 32°C was accomplished. Cold cardioplegic solution was given after cross-clamping for myocardial protection (8001000 ml initially and 200300 ml after every 30 min through the aortic root and 100 ml after each distal anastomosis through the vein graft). Blood was sampled for measurement of TNF-, IL-6, IL-8, IL-10 and IL-4 at the following times: before induction of anaesthesia (T0), after induction of anaesthesia and before skin incision (T1), before starting cardiopulmonary bypass (T2), after aortic declamping (T3), at the end of CBP (T4), 2 h after skin closure (T5), and 24 h after skin closure (T6). Samples were collected in tubes containing lithium heparin (VenoJect®, Terumo, Europe NV, Leuven, Belgium). The samples were immediately centrifuged at 1000 g, and the plasma was stored at 70°C until assays were performed. Enzyme-linked immunosorbent assays (ELISA; Immulite®, DPC, Los Angeles, USA) were used to measure TNF-
, IL-6, IL-8, IL-10 and IL-4. All assays were performed according to the manufacturers instructions.
After completion of surgery, patients were transferred to the ICU, where standard care and processes were followed until discharge. The physicians and nurses in the ICU did not know which patients had received dexamethasone. Patients were weaned from mechanical ventilation when they were haemodynamically stable, responded to verbal stimulation, were completely rewarmed and when blood loss did not exceed 100 ml h1. Postoperative pain management was with piritramide 510 mg i.v., given as necessary. Cardiovascular and respiratory values and temperature were recorded every 15 min before extubation and then hourly until discharge from the ICU. Length of stay in the ICU was also recorded. Patients were discharged from the ICU on the first morning that they were haemodynamically stable, had normal blood gases during spontaneous breathing and had satisfactory renal function. We reviewed each patients records after discharge from the ICU and noted the minimum and maximum values of mean arterial pressure, heart rate, cardiac index, mean pulmonary artery pressure, respiratory rate, and temperature.
Statistical analysis
Calculations were performed on a personal computer using SPSS version 10.0. Data are presented as mean (SD) and cytokine concentrations as median (interquartile range). The groups were tested for differences using Students t-test for continuous variables and Fishers exact test for categorical variables. The MannWhitney U test was used to compare cytokine levels between the two groups at each time point. Repeated measures analysis of variance together with Bonferroni adjustment was used for multiple within-group comparisons. In all cases a P value less than 0.05 was considered to indicate statistical significance.
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
|
|
|
|
|
|
|
|
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
IL-8 affects ischaemia-reperfusion injury through an effect on neutrophil activation and adherence to the vascular endothelium.13 Treatment with anti-IL-8 antibodies prevents lung ischaemia-reperfusion injury in rabbits.14 This could explain the higher mean pulmonary artery pressure we noticed in the control group, who had high IL-8 concentrations.
Our results confirm those of others10 11 that corticosteroid administration inhibits but does not abolish the IL-6 response. This is because the production of IL-6 is affected by the degree of surgical trauma and tissue damage, as well as the effect of CPB.15 Hennein and colleagues suggested that IL-6 may be a sensitive indicator of myocardial damage, and reported an association between the IL-6 response and cardiac morbidity.3 Cruickshanks and colleagues reported that high concentrations of IL-6 had a negative inotropic effect, possibly by impairing entry of calcium into myocardial cells.16
IL-10 has been described as a cytokine synthesis inhibitory factor, and the most potent inhibitor of IL-8.17 This may explain the abolished TNF- and IL-8 response and the weak IL-6 response in the dexamethasone-treated group, in whom the IL-10 response was greater.
IL-4 inhibits the differentiation and action of Th 1 cytokines. It can antagonize these inflammatory responses, which can cause excessive tissue destruction.18 In our study IL-4 decreased in the control group before skin incision. Thereafter, the pro-inflammatory cytokines increased after aortic declamping. Thus, low concentrations of IL-4 may be another reason for the greater pro-inflammatory cytokine response in this group.
The effect of steroids on the cytokine balance during cardiac surgery has been previously studied by Kawamura and colleagues.19 They gave methylprednisolone 30 µg kg1 before CPB and declamping, and investigated IL-6, IL-8, IL-10 and IL1ra, whereas we investigated TNF-, IL-6, IL-8, IL-4 and IL-10. In their patients, methylprednisolone did not abolish the IL-8 response as the dexamethasone did in our patients, but the response was inhibited. They found a balanced pro-inflammatory and anti-inflammatory response. In our study, the balance was shifted towards the anti-inflammatory responses. These differences may be the result of the different times of steroid injection or the different doses of steroid. The finding that the pre-induction dose of dexamethasone in our patients was associated with unbalanced cytokine response may be relevant, because wound healing and resistance to infection may depend on this balance. A perioperative pro-inflammatory cytokine response, held in balance by a concomitant anti-inflammatory response could be important.20
The mechanisms involved are far from clear. In non-cardiac-surgery patients, immunosupression has often been associated with exaggerated production of IL-10 and a high ratio of IL-10 to TNF-.21 22 Although the dexamethasone group in our study had a high ratio of IL-10 to TNF-
, no patients had adverse events such as infectious complications or sepsis in the postoperative period. These patients were discharged earlier than those in the control group, which could suggest reduced morbidity in the dexamethasone group.
In our study the clinical effects of dexamethasone in the postoperative period were shown by normothermia, lower heart rate and lower respiratory rate, which may indicate a smaller systemic inflammatory response.
Inhibition of TNF- and IL-6 by dexamethasone might explain the greater cardiac index and arterial blood pressure in group 1. Reduced temperature in the immediate postoperative period can be advantageous in cardiac surgery patients, because oxygen consumption is directly related to temperature.23 However, Chaney and colleagues showed that methylprednisolone had no clinical benefits in patients undergoing elective CABG and possibly hindered early postoperative tracheal extubation.24 This contrasts with our finding that the dexamethasone-treated patients were extubated earlier than the control patients (albeit statistically insignificant).
The small size of our study is not sufficient to assess clinical outcomes. The main purpose of the present study was to investigate the effect of steroid on the cytokine balance. Our results can only partly confirm the improvements of clinical outcome found in previous investigations,8 19 25 26 which may explain the shorter stay in the ICU in our study and in that of Jansen and colleagues.8 We conclude that dexamethasone before cardiac surgery shifts the circulating cytokine profile towards the anti-inflammatory responses and may improve the postoperative course by inhibition of the systemic inflammatory response. Future studies should consider the correlation between circulating cytokines and clinical course.
![]() |
Acknowledgements |
---|
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
2 Ohri SK. Systemic inflammatory response and the splanchnic bed in cardiopulmonary bypass. Perfusion 1996; 11: 20012[Medline]
3
Hennein HA, Ebba H, Rodriguez JL, et al. Relationship of the proinflammatory cytokines to myocardial ischaemia and dysfunction after uncomplicated coronary revascularization. J Thorac Cardiovasc Surg 1994; 108: 62635
4 Finkle MS, Oddis CV, Jacob TD, Watkins SC, Hattler BG, Simmons RL. Negative inotropic effects of cytokines on the heart mediated by nitric oxide. Science 1992; 257: 3879[ISI][Medline]
5 Partrick DA, Moore FA, Moore EE, et al. The inflammatory profile of interleukin-6, interleukin-8 and soluble intercellular adhesion molecule-1in postinjury multiple organ failure. Am J Surg 1996; 112: 13016
6
Wan S, LeClerc JL, Vincent JL. Cytokine response to cardiopulmonary bypass: Lessons learned from cardiac transplantation. Ann Thorac Surg 1997; 63: 26976
7
Eppinger MJ, Ward PA, Bolling SF, Deeb GM. Regulatory effects of interleukin-10 on lung ischaemia-reperfusion injury. J Thorac Cardiovasc Surg 1996; 112: 80611
8 Jansen NJG, van Oeveren W, v.d. Broek L, et al. Inhibition by dexamethasone of the reperfusion phenomena in cardiopulmonary bypass. J Thorac Cardiovasc Surg 1991; 102: 51525[Abstract]
9 Miranda DR, Stoutenbeek C, Karliczek G, Rating W. Effect of dexamethasone on the early postoperative course after coronary artery bypass surgery. Thorac Cardiovasc Surg 1982; 30: 217[Medline]
10
Teoh KHT, Bradley CA, Gauldie J, Burrows H. Steroid inhibition of cytokine-mediated vasodilatation after warm heart surgery. Circulation 1995; 92: II 34753
11 Yilmaz M, Ener S, Akalin H, Sagdik K, Serdar OA, Cengiz M. Effect of low-dose methylprednisolone on serum cytokine levels following extracorporeal circulation. Perfusion 1999; 14: 2016[Medline]
12 Squadrito F, Altavilla D, Zingarelli B, et al. Tumour necrosis factor involvement in myocardial ischaemia-reperfusion injury. Eur J Pharmacol 1993; 237: 22330[ISI][Medline]
13 Finn A, Naik S, Klein N, Levinsky RJ, Strobel S, Elliot M. Interleukin-8 release and neutrophil degranulation after paediatric cardiopulmonary bypass. J Thorac Cardiovasc Surg 1993; 105: 23441[Abstract]
14 Sekido N, Mukaida N, Harada A, et al. Prevention of lung reperfusion injury in rabbits by a monoclonal antibody against interleukin-8. Nature 1993; 365: 65457[ISI][Medline]
15
Wan S, Izzat MB, Lee TW, Wan IWP, Tang NLS, Yim APC. Avoiding cardiopulmonary bypass in multivessel CABG reduces cytokine response and myocardial injury. Ann Thorac Surg 1999; 68: 527
16 Cruickshanks AM, Oldroyd KG, Cobbe SM. Serum interleukin-6 in suspected myocardial infarction. Lancet 1994; 343: 974
17 Marie C, Fitting C, Muret J, Payen D, Cavaillon JM. Interleukin-8 production in whole blood assays: Is interleukin-10 responsible for the downregulation observed in sepsis? Cytokine 2000; 12: 5561[ISI][Medline]
18 Boothby M, Mora AL, Aronica MA, et al. IL-4 signaling, gene transcription regulation, and the control of effector T cells. Immunol Res 2001; 23: 17991[ISI][Medline]
19 Kawamura T, Inada K, Nara N, Wakusawa R, Endo S. Influence of methylprednisolone on cytokine balance during cardiac surgery. Crit Care Med 1999; 27: 54548[ISI][Medline]
20 Hubner G, Brauchle M, Samola H, Madlener M, Fassler R, Werner S. Differential regulation of pro-inflammatory cytokines during wound healing in normal and glucocorticoid treated mice. Cytokine 1996; 8: 54856[ISI][Medline]
21 VanDissel J, Van Langevelde P, Westendorp RGJ, Kwappenberg K, Frollich M. Anti-inflammatory cytokine profile and mortality in febrile patients. Lancet 1998; 351: 9503[ISI][Medline]
22 Giannoudis PV, Smith RM, Perry SL, Windsor AJ, Dickson RA, Bellamy MC. Immediate IL-10 expression following major orthopaedic trauma: relationship to anti-inflammatory response and subsequent development of sepsis. Intensive Care Med 2000; 26: 107681[ISI][Medline]
23 Frank SM, Fleisher LA, Olson KF, et al. Multivariate determinants of early postoperative oxygen consumption in elderly patients. Anesthesiology 1995; 83: 2419[ISI][Medline]
24
Chaney MA, Durazo-Arvizu RA, Nicolov MP, Bakhos M. Methylprednisolone does not benefit patients undergoing coronary artery bypass grafting and early tracheal extubation. J Thorac Cardiovasc Surg 2001; 121: 5619
25 Toft P, Christiansen K, Tonnesen E, Nielsen CH, Lillevang S. Effect of methylprednisolone on the oxidative burst activity, adhesion molecules and clinical outcome following open heart surgery. Scand Cardiovasc J 1997; 31: 2838[ISI][Medline]
26
Yared JP, Starr VJ, Torres FK, et al. Effect of single dose, postinduction dexamethasone on recovery after cardiac surgery. Ann Thorac Surg 2000; 69: 14204