1 Department of Pediatric Anesthesia and Intensive Care, University Hospital, Lund, Sweden. 2 Pediatric Cardiac Surgery, University Hospital, Lund, Sweden
Corresponding author: Department of Pediatric Anesthesia and Intensive Care, University Hospital Lund, S-221 85 Lund, Sweden. Email: larsolavlindberg@hotmail.com
Accepted for publication: January 27, 2003
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Methods. We studied the effects of dexamethasone on clinical course, C-reactive protein, von Willebrand factor antigen (vWf:Ag) and S100B in a randomized masked study of children after open cardiac surgery. Twenty children weighing >10 kg received dexamethasone (1 mg kg1) and 20 controls received saline after induction of anaesthesia. We measured vWf:Ag as a marker of endothelial activation, S100B as a marker of cerebral protein release and C-reactive protein as a marker of inflammatory activity. Oxygenation, body temperature, fluid balance, leucocyte and platelet counts, days in the intensive care unit (ICU) and days on mechanical ventilation were noted.
Results. Dexamethasone decreased C-reactive protein concentration on the first postoperative day (P<0.05), but did not affect the release of vWf:Ag or S100B. There was no significant difference in oxygenation, body temperature, fluid balance, leucocyte and platelet counts, days in the ICU or days on mechanical ventilation between the placebo and dexamethasone-treated groups.
Conclusion. Administration of dexamethasone before cardiopulmonary bypass for paediatric cardiac surgery decreased the inflammatory response, but did not affect the immediate features after surgery or changes in vWf:Ag or S100B.
Br J Anaesth 2003; 90: 72832
Keywords: heart, cardiopulmonary bypass; hormones, corticosteroid; surgery, cardiovascular
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Glucocorticoids given before CPB can reduce the inflammatory response by several mechanisms. They reduce endotoxin release and decrease several proinflammatory cytokines, including interleukin 6, which regulates the release of C-reactive-protein (CRP).57 The effect of glucocorticoids on the activation of the complement system is disputed.811 The inflammatory cascade activates endothelial cells and may be a central link between the inflammatory response and clinical changes. Although the inhibition of proinflammatory mediator release by glucocorticoids has been shown, the effects of glucocorticoids on clinical outcome are still controversial.9 12 13
In a randomized, prospective study we measured the effects of dexamethasone given before paediatric cardiac surgery on immediate postoperative clinical features. We also studied activation of the endothelium and the release of a marker for cerebral damage, S100B.14
![]() |
Materials and methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Forty children (>10 kg) about to have open heart surgery were randomized to i.v. treatment with dexamethasone 1 mg kg1 (group A, n=20) or placebo (sodium chloride 0.9% w/v; group B, n=20) The nature of the agent was masked. Administration was immediately after induction of anaesthesia and the placement of the central venous catheter. Patient data, diagnosis and operative procedures are presented in Tables 1 and 2. In our institution it is clinical practice to give dexamethasone to smaller children (<10 kg). Omitting dexamethasone in these children was considered unethical and thus only patients weighing >10 kg were studied. The code was broken after data collection and analysis. One child randomized to receive dexamethasone (group A) was excluded because the operation was cancelled after induction of anaesthesia and drug administration.
|
|
CPB was with non-pulsatile perfusion under hypothermia with a lowest perfusate temperature of 20°C. A membrane oxygenator (Cobe VPCML; Gambro, Lund, Sweden) and arterial line filters (D733 or D736; Dideco, Täby, Sweden) were used. The circuit was primed with a mixture of crystalloids, mannitol, buffer solution (THAM) and erythrocyte concentrate if needed to keep the haemoglobin concentration around 70 g litre1. Autotransfusion was not used after operation. The pump flow was adjusted to the childs body surface area and body temperature. Bolus injections of norepinephrine 0.11 µg kg1 were given to stabilize arterial pressure if necessary. Cold, crystalloid cardioplegic solution was given in the aortic root and repeated every 20 min. Peroperatively, fluid administration and fluid losses were recorded and total fluid balance was calculated.
Laboratory tests
Plasma von Willebrand factor antigen (vWf:Ag) was used to assess endothelial cell activation15 and S100B was used as a marker of cerebral and/or bloodbrain barrier dysfunction.16 Plasma vWf:Ag and serum S100B were determined after induction of anaesthesia, immediately after CPB and 5 and 15 h after CPB.
Measurement of vWf:Ag was with a commercially available latex immunoassay (STA®Liatest® vWF, Triolab AB, Gothenburg, Sweden) according to the manufacturers instructions.
Whole blood samples were taken from the arterial catheter and immediately sent for centrifugation at 5000 r.p.m. for 20 min. The plasma supernatant was frozen at 80°C and batch analysis for soluble vWf:Ag was done. Soluble antigens were captured using latex particles coated with antibodies against vWf:Ag. The vWf:Ag forms a complex with the antibodylatex particles, and light absorption increases when this complex is formed. Light absorption was determined with a spectrophotometer at 570 nm; light absorption is directly proportional to the concentration of vWf:Ag in plasma. A control was made from the light absorption of a known concentration of vWf:Ag in reference plasma solutions (ORKE 65 and OUPZ 21; Dade-Behring, Stockholm, Sweden). The method has been validated and had a coefficient of variation of 2.2% at a level of 0.36 IU ml1 and sensitivity a lower limit of 0.04 IU ml1.
S100B was measured with a commercially available monoclonal immunoluminometric assay (LIA-mat® Sangtec® 100; Sangtec Medical, Bromma, Sweden) according to the manufacturers instructions. Blood samples from the arterial catheter were sent immediately for centrifugation to separate the serum, and frozen at 20°C to preserve the samples until bench analysis was done the next day. Samples were diluted with phosphate buffer and incubated with plastic tubes coated with the monoclonal antibodies SMST 12, SMSK 25 and SMSK 28. During incubation, S100B binds to the antibody-coated tubes. The tubes were washed after 1 h of incubation, and incubated with tracer anti-S100B antibody, which has a covalently bound isoluminol derivative. After 2 h incubation and subsequent washing, alkaline peroxide solution and catalyst solution were added and fluorescence was measured. The coefficient of variation was 7% and the sensitivity defined by the manufacturer was 0.02 µg litre1. However, to keep the coefficient of variation at 7% in all samples, a functional detection limit of 0.1 µg litre1 has been recommended.
CRP was measured with an immunoturbidimetric assay (Roche Diagnostics, Mannheim, Germany), in which the sample was added to buffer and anti-CRP antibodybuffer solutions. Anti-CRP antibodies react with antigen in the sample to form an antigenantibody complex. After agglutination, this is measured turbidimetrically. The CRP method was standardized against a reference preparation in human serum. The lower detection limit of this method is 0.003 g litre1, but was set to 0.005 g litre1 for practical reasons. CRP was measured before operation and on the first day after operation.
Samples were taken for arterial and venous blood gas analysis after induction of anaesthesia, 5 min after going on CPB, before rewarming, 5 min before coming off CPB, immediately after CPB, on arrival in the ICU and then after 1, 2, 3 and 5 h. Arterial oxygen tension (PaO2), carbon dioxide tension (PaCO2), central venous oxygen tension (PvO2), and carbon dioxide tension (PvCO2), pH and base excess (BE) were analysed directly after the sample was obtained (ABL 505; Radiometer, Copenhagen, Denmark). Arterial and central venous oxygen saturation and haemoglobin concentration were analysed by a multi-wavelength oximeter (OSM3; Radiometer, Copenhagen, Denmark). The ratio of arterial oxygen tension to inhaled oxygen fraction (PaO2/FIO2) was calculated. Rectal temperature was taken at the same time as blood gas analysis.
Clinical variables
We noted body temperature, fluid balance, duration of mechanical ventilation and duration of stay in the ICU.
Statistical analysis
Data were analysed with Statistica for Windows (Statsoft, Tulsa, OK, USA). The groups were compared using the MannWhitney U-test. Within-group comparisons were made using the Wilcoxon signed rank test. The Bonferroni method was used to correct for multiple comparisons. P<0.05 was considered statistically significant.
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Plasma vWf:Ag was detected in all children before operation. Values were similar immediately after CPB. vWf:Ag increased 5 h after CPB (P<0.001) and remained increased 15 h after CPB (P<0.001). There was no difference between children who received dexamethasone and placebo (Fig. 1).
|
|
|
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
It is possible that a larger dose of dexamethasone, different timing of the dose or repeated administration could have influenced the clinical course. We believe that the dose was sufficient, in agreement with doses in other studies, and it is a potent inhibitor of the inflammatory response, with a long duration of action. The time between steroid administration and the start of surgery is usually quite short (1 h). Perhaps if a longer time had been allowed for the glucocorticoid to work, the inhibitory effect on cytokine production would have been greater. Earlier administration and repeated doses after CPB could allow more effective inhibition of the inflammatory response.
Another factor that may have influenced the findings is the degree of surgical trauma and the duration of CPB. Extensive cardiac surgery in small and severely sick children may activate the inflammatory system more intensively and result in more severe clinical deterioration. It is possible that dexamethasone could improve outcome in such patients.
Exactly how the proinflammatory cytokines, coagulation factors, complement factors and leucocytes after CPB impair the clinical course is unknown. We considered that activation of the endothelium influenced the clinical course after cardiac surgery, as both fluid retention and oedema formation, which are early signs of endothelial dysfunction, may be related to it. Because increased serum concentrations of vWf:Ag can indicate endothelial cell activation15 17 and increased vWf:Ag activity has been shown after CPB operations for congenital heart disease,18 we wanted to observe if dexamethasone could inhibit this release and protect the endothelial cells and if this would be correlated to any improvement in clinical course. We confirmed a marked increase in vWf:Ag after CPB, but found no effect of dexamethasone. This indicated that the endothelial cells were activated, but that the release of vWf:Ag from endothelial cells is not directly and solely regulated by mechanisms that are affected by dexamethasone.
S100B release 5 and 15 h after operation has been used as a marker of cerebral damage during cardiac surgery and is correlated with the duration of CPB and circulatory arrest.19 However, S100B is not specific for brain tissue and extracerebral sources of S100B have been identified.16 The bloodbrain barrier is normally not permeable to proteins. The finding of S100B protein release in children without overt neurological dysfunction could show that the permeability of the bloodbrain barrier increased during cardiac surgery and CPB without irreversible cerebral damage.14 Magnetic resonance imaging shows that cardiac surgical patients have cerebral oedema within 1 h of surgery without overt neurological dysfunction.20 We considered that dexamethasone could protect endothelial cells and prevent cerebral endothelial cell activation and greater permeability of the bloodbrain barrier, and thus inhibit release of S100B. We confirmed a transient increase in S100B, but dexamethasone did not change this response.
In conclusion, we found an anti-inflammatory effect of dexamethasone given before CPB in children weighing >10 kg, but the postoperative clinical course did not change. Dexamethasone did not prevent or change the activation of endothelial cells, indicated by release of vWf:Ag and S100B.
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
2 Boyle EM Jr, Pohlman TH, Cornejo CJ, Verrier ED. Endothelial cell injury in cardiovascular surgery: ischemiareperfusion. Ann Thorac Surg 1996; 62: 186875
3 Wan S, Leclerc JL, Vincent JL. Inflammatory response to cardiopulmonary bypass: mechanisms involved and possible therapeutic strategies. Chest 1997; 112: 67692
4 Millar AB, Armstrong L, Van der LJ, et al. Cytokine production and hemofiltration in children undergoing cardiopulmonary bypass. Ann Thorac Surg 1993; 56: 1499502[Abstract]
5 El Azab SR, Rosseel PM, de Lange JJ, et al. Dexamethasone decreases the pro- to anti-inflammatory cytokine ratio during cardiac surgery. Br J Anaesth 2002; 88: 496501
6 Mayumi H, Zhang QW, Nakashima A, et al. Synergistic immunosuppression caused by high-dose methylprednisolone and cardiopulmonary bypass. Ann Thorac Surg 1997; 63: 12937
7 Butler J, Pathi VL, Paton RD, et al. Acute-phase responses to cardiopulmonary bypass in children weighing less than 10 kilograms. Ann Thorac Surg 1996; 62: 53842
8 Engelman RM, Rousou JA, Flack JE III, Deaton DW, Kalfin R, Das DK. Influence of steroids on complement and cytokine generation after cardiopulmonary bypass. Ann Thorac Surg 1995; 60: 8014
9 Jansen NJ, van Oeveren W, van den BL, et al. Inhibition by dexamethasone of the reperfusion phenomena in cardiopulmonary bypass. J Thorac Cardiovasc Surg 1991; 102: 51525[Abstract]
10 Bronicki RA, Backer CL, Baden HP, Mavroudis C, Crawford SE, Green TP. Dexamethasone reduces the inflammatory response to cardiopulmonary bypass in children. Ann Thorac Surg 2000; 69: 14905
11 Kawamura T, Inada K, Nara N, Wakusawa R, Endo S. Influence of methylprednisolone on cytokine balance during cardiac surgery. Crit Care Med 1999; 27: 5458[ISI][Medline]
12 Chaney MA, Nikolov MP, Blakeman BP, Bakhos M, Slogoff S. Hemodynamic effects of methylprednisolone in patients undergoing cardiac operation and early extubation. Ann Thorac Surg 1999; 67: 100611
13 Chaney MA, Durazo-Arvizu RA, Nikolov MP, Blakeman BP, Bakhos M. Methylprednisolone does not benefit patients undergoing coronary artery bypass grafting and early tracheal extubation. J Thorac Cardiovasc Surg 2001; 121: 5619
14 Ali MS, Harmer M, Vaughan R. Serum S100 protein as a marker of cerebral damage during cardiac surgery. Br J Anaesth 2000; 85: 28798
15 McGill SN, Ahmed NA, Christou NV. Increased plasma von Willebrand factor in the systemic inflammatory response syndrome is derived from generalized endothelial cell activation. Crit Care Med 1998; 26: 296300[CrossRef][ISI][Medline]
16 Jonsson H, Johnsson P, Alling C, Backstrom M, Bergh C, Blomquist S. S100beta after coronary artery surgery: release pattern, source of contamination, and relation to neuropsychological outcome. Ann Thorac Surg 1999; 68: 22028
17 Holdright DR, Hunt BJ, Parratt R, et al. The effects of cardiopulmonary bypass on systemic and coronary levels of von Willebrand factor. Eur J Cardiothorac Surg 1995; 9: 1821[Abstract]
18 Turner-Gomes SO, Andrew M, Coles J, Trusler GA, Williams WG, Rabinovitch M. Abnormalities in von Willebrand factor and antithrombin III after cardiopulmonary bypass operations for congenital heart disease. J Thorac Cardiovasc Surg 1992; 103: 8797[Abstract]
19 Lindberg L, Olsson AK, Anderson K, Jogi P. Serum S-100 protein levels after pediatric cardiac operations: a possible new marker for postperfusion cerebral injury. J Thorac Cardiovasc Surg 1998; 116: 2815
20 Harris DN, Oatridge A, Dob D, Smith PL, Taylor KM, Bydder GM. Cerebral swelling after normothermic cardiopulmonary bypass. Anesthesiology 1998; 88: 3405[ISI][Medline]