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Ann Thorac Surg 2007;84:110-119
© 2007 The Society of Thoracic Surgeons
a Department of Thoracic and Cardiovascular Surgery, Emergency and Intensive Care Medicine, University of Göttingen, Göttingen, Germany
b Department of Anesthesiology, Emergency and Intensive Care Medicine, University of Göttingen, Göttingen, Germany
Accepted for publication January 3, 2007.
* Address correspondence to Dr Liakopoulos, Klinik für Thorax-, Herz- und Gefäßchirurgie, Georg-August-Universität Göttingen, Robert-Koch-Strasse 40; 37099 Göttingen, Germany (Email: oliver{at}liakopoulos.de).
Presented at the Forty-third Annual Meeting of The Society of Thoracic Surgeons, San Diego, CA, Jan 29–31, 2007.
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Abstract |
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Methods: Eighty patients undergoing elective coronary artery bypass grafting were randomly assigned to receive a single shot of methylprednisolone (15 mg/kg) or placebo before CPB. Variables of myocardial and pulmonary function and systemic hemodynamics were measured before and 1, 4, 10, and 24 hours after CPB. Blood was sampled for measurement of proinflammatory (tumor necrosis factor-
, interleukin 6, interleukin 8) and antiinflammatory (interleukin 10) cytokines (by enzyme-linked immunoassay), troponin T, and C-reactive protein. Phosphorylation of inhibitory kappa-B alpha and p38 mitogen-activated protein kinase was determined in right atrial biopsies before and after CPB (phosphoprotein assay).
Results: Preoperative and intraoperative characteristics of patients were not different between groups. Methylprednisolone attenuated postoperative tumor necrosis factor-, interleukin 6, interleukin 8, and C-reactive protein levels while increasing interleukin 10 release. Myocardial inhibitory kappa-B alpha was preserved with methylprednisolone (p < 0.05 versus placebo), but p38 mitogen-activated protein kinase activation occurred in both groups after CPB (p < 0.05 versus before CPB). Methylprednisolone improved postoperative cardiac index and was associated with decreased troponin T when compared with placebo (p < 0.05). Postoperative blood glucose, oxygen delivery index, and pulmonary shunt flow were increased in the methylprednisolone group (p < 0.05). There was no difference in postoperative oxygenation index, ventilation time, and clinical outcome between treatment groups.
Conclusions: Glucocorticoid treatment before CPB attenuates perioperative release of systemic and myocardial inflammatory mediators and improves myocardial function, suggesting potential cardioprotective effects in patients undergoing cardiac surgery.
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Introduction |
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The concept of a systemic inflammatory response related to CPB is well established, and numerous studies have demonstrated an association between the systemic release of proinflammatory cytokines (tumor necrosis factor- [TNF], interleukin [IL] 6, and IL-8) and postoperative morbidity with adverse clinical outcome and increased mortality [2]. Beyond systemic inflammation, various reports suggest that local induction of inflammatory cytokines in the heart [3–5], lung, and remote organs [6] may substantially contribute to postoperative organ dysfunction. A key role for the transcriptional regulation of proinflammatory cytokines has been attributed to the ubiquitous transcription factor nuclear factor-kappa B (NF
B) and p38 mitogen-activated protein kinase (MAPK) signaling pathway [7–10]. Triggered by ischemia–reperfusion and proinflammatory cytokines themselves, phosphorylation of the inhibitory protein of NFB (inhibitory kappa-B alpha [IB]), and p38 MAPK promotes gene expression of potential myocardial damaging mediators such as TNF, IL-1ß, and IL-6 [7–9].
Although various pharmacologic, mechanistic and operative strategies to attenuate CPB-induced systemic inflammatory response have been investigated [1], randomized trials have consistently demonstrated that perioperative administration of corticosteroids in patients undergoing cardiac surgery with CPB inhibits the systemic release of proinflammatory cytokines and decreases the ratio between proinflammatory and antiinflammatory interleukins [11–15]. Resulting clinical benefits include improvement of postoperative hemodynamics [14], myocardial function and protection [11, 13, 15], and pulmonary function [11, 14], and reduced length of stay in the intensive care unit (ICU). However, studies addressing the role of local, antiinflammatory myocardial actions of glucocorticoids in patients undergoing cardiac surgery are still lacking. Proposed mechanisms for the local antiinflammatory glucocorticoid’s actions are inhibition of IB degradation resulting in decreased NFB activation [16] and inhibition of p38 MAPK through induction of the mitogen-activated protein kinase phosphatase-1 [17].
In the present study the effect of a single-dose corticosteroid application before CPB on (1) activation of myocardial transcriptional proteins of inflammation (IB, p38 MAPK) and (2) systemic cytokine response (TNF, IL-6, IL-8, and IL-10) was investigated in patients undergoing cardiac surgery and linked to variables of postoperative hemodynamic, myocardial, and pulmonary function.
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Patients and Methods |
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Following a computer-generated sequence, patients were randomly assigned to receive either a single intravenous bolus of 15 mg/kg methylprednisolone (Urbason, Sanofi-Aventis, Frankfurt, Germany; MP group) or placebo (NaCl 0.9%; PLA group) 30 minutes before CPB was instituted.
Perioperative Management
After premedication with 1 to 2 mg of flunitrazepam orally, general anesthesia was induced with sufentanil 2 µg/kg and etomidate 0.3 mg/kg, and pancuronium 0.1 mg/kg was administered to facilitate tracheal intubation. Anesthesia was maintained by continuous intravenous infusion of sufentanil (1 to 2 µg/kg per hour) and isoflurane (0.3 to 1.0 vol%). Coronary artery bypass grafting was performed in a standardized fashion through a median sternotomy, and moderate hypothermic CPB (32°C) was established through cannulation of the right atrium and ascending aorta. Cardiopulmonary bypass equipment consisted of a nonocclusive centrifugal pump (Sarns Delphin System, Terumo Europe, Eschborn, Germany), a membrane oxygenator (Quadrox, Jostra AG, Hirrlingen, Germany), a 40-µm arterial filter (Quart, Jostra AG), a hard-shell cardiotomy reservoir (MC-4030, Medos Medizintechnik, Stolberg, Germany), and an extracorporeal circuit (ME H2–1551, Medos Medizintechnik). The circuit was primed with 500 mL of hydroxyethyl starch 6%, 500 mL of Ringer’s lactate solution, 500 mL of saline solution 0.9%, and 7500 IU of heparin. Nonpulsatile flow was set between 2.2 and 2.4 L · min–1
· m–2, and perfusion pressure was maintained between 50 and 70 mm Hg. During aortic clamping, cardioplegic cardiac arrest was achieved by intermittent antegrade and retrograde infusion of blood cardioplegia (Köhler Chemie GmbH, Alsbach-Hähnlein, Germany), and the left ventricle was decompressed using a vent. After rewarming to greater than 36°C, patients were weaned from CPB, and systemic anticoagulation was reversed by protamine sulfate administration. If required, weaning from CPB was supported with epinephrine or norepinephrine at the discretion of the attending surgeon and anesthesiologist.
After surgery, patients were transferred to the ICU where postoperative therapy was performed at the discretion of the attending ICU team. Postoperative sedation and analgesia was achieved by intravenous administration of propofol (1 to 2 mg · kg–1 · h–1), midazolam (0.1 to 0.2 mg · kg–1 · h–1), or piritramide (maximal 7 mg/h). No glucose infusions were used perioperatively, and insulin (bolus or continuous infusion) was given when blood glucose levels exceeded 200 to 210 mg/dL. Inotropic and vasoactive drug therapy was managed on the basis of patients’ hemodynamics, and extubation was accomplished after the following criteria were met: adequate level of consciousness and muscle strength, stable hemodynamics, normothermic body temperature (>36°C), adequate oxygenation (arterial oxygen tension >80 mm Hg at an inspired oxygen fraction <0.4 and positive end-expiratory pressure <8 mm Hg), adequate renal function (urine output >1 mL · kg–1 · h–1), and minimal blood loss through chest tubes (<150 mL/2 h).
Data Collection
Preoperative and operative characteristics of patients were recorded. After induction of anesthesia a pulmonary artery catheter (HANDS-OFF Thermodilution Catheter, Arrow International, Inc, Reading, PA) was inserted and hemodynamic measurements were performed before CPB (pre-CPB) and at 1, 4, 10, and 24 hours after CPB. Hemodynamic monitoring comprised heart rate, mean arterial pressure, central venous pressure, mean pulmonary artery pressure, pulmonary capillary wedge pressure, and cardiac output. Cardiac index, systemic vascular resistance index, pulmonary vascular resistance index, and left ventricular stroke work index were calculated from standard equations. At all time points perioperative body temperature (temperature probe from pulmonary artery catheter) and catecholamine support was recorded. Oxygenation index (arterial oxygen tension divided by fraction of inspired oxygen), pulmonary shunt, oxygen delivery index, and extraction rate index were calculated after analysis of arterial and mixed venous blood gas samples using standard formulas [14].
Corresponding to the above-mentioned time points, arterial blood samples were obtained for measurement of pH and glucose and lactate concentrations, and venous blood was sampled for measurement of troponin T, white blood cell count, C-reactive protein, and cytokine levels (IL-6, IL-8, IL-10, and TNF).
For cytokine determination, blood samples were immediately centrifuged (3,000 rpm for 10 minutes at 4°C), plasma was separated, and samples were stored at –80°C until assay. Cytokine concentration was determined by a human multiplex bead enzyme-linked immunosorbent assay using the Bioplex suspension array systems (Bio-Rad Laboratories Inc, Munich, Germany) with less than 10% interassay and intraassay coefficients of variation. For measurement of total and phosphorylated IB- and p38 MAPK, right atrial biopsies were taken before cannulation of the right atrium and after CPB was discontinued. Sterile biopsies were snap-frozen in liquid nitrogen and stored at –80°C. Total and phosphorylated IB- and p38 MAPK were determined in 40 patients (20 per group) using a human single-plex total target and phosphoprotein assay (Bio-Rad Laboratories Inc) according to the manufacturer’s recommendations.
Postoperative data recording included variables of renal function (maximal creatinine), renal failure (creatinine > 2.0 mg/dL; need for hemofiltration), and average insulin dose (international units per hour) during the first 24 hours in the ICU. Additionally time on mechanical ventilation, need for reintubation, in-hospital mortality, and length of stay in the ICU and at hospital were recorded. Fluid balance was calculated from total intravenous fluid input (crystalloid, colloid, and blood products) and total fluid output (urine output and blood loss through chest tubes) as documented at the operating room and the first 24 hours in the ICU. Postoperative infections were recorded if patients met one of the following criteria: any signs of wound infection, superficial and deep mediastinitis, and receiving antibiotic therapy after the second postoperative day (fever > 38.5° C, bacteremia, persistent leukocytosis > 15 x 103/µL). Additionally, pneumonia was diagnosed when two of the following criteria were present: fever, chest radiography with infiltrates, tracheal secretion with cultured pathogenic bacteria, abnormal lung auscultation, and leukocytosis or leukopenia (<4 x 103/µL).
Statistical Analysis
Data are expressed as mean ± standard deviation. Preoperative, intraoperative, and postoperative characteristics of groups were compared by unpaired Student’s t test for continuous data or Fisher’s exact test for categorical data. Intergroup and intragroup differences for hemodynamic and pulmonary data, catecholamine support, body temperature, and biochemical variables were assessed by two-way analysis of variance with the Fisher’s least significant difference procedure for post hoc repeated measurements. Correlation analysis between cytokines and perioperative variables was performed using Spearman correlation test. All data were analyzed with Statistica 6.1 (Statsoft GmbH, Hamburg, Germany), and p values of 0.05 or less were considered statistically significant.
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Results |
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Blood glucose (Fig 1C) and lactate concentrations were elevated in both groups after surgery, but MP resulted in higher blood glucose concentrations at 1 and 4 hours, and increased lactate levels at 4 hours when compared with PLA. Consistent to this, MP-treated patients received more insulin during the postoperative period than the PLA group (p < 0.05; Table 4). Acidosis was present at 1 hour after CPB in both groups, with lower pH values in MP (p < 0.05).
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Baseline cytokine concentrations were similar in both groups. Postoperative TNF concentrations remained unchanged in MP, but increased at 1 and 4 hours after CPB in PLA (Fig 2A) and were higher at 4 hours compared with MP. Postoperative IL-8 levels increased in both groups after CPB (Fig 2B). Compared with PLA, MP treatment attenuated IL-8 release at 1 and 4 hours. Similarly, IL-6 concentrations were increased during the entire postoperative period in PLA and at 1 and 4 hours in MP compared with baseline (Fig 2C). Compared with PLA, IL-6 increase was attenuated in MP at 4 and 10 hours after surgery. In contrast, MP treatment accentuated the release of antiinflammatory IL-10, which was significantly higher in MP at 1 and 4 hours compared with PLA (Fig 2D). Ratio of phosphorylated IB- to total IB- in atrial biopsies was not different between groups before CPB (Fig 3A) and increased after CPB only in PLA. In MP, IB- ratio remained unchanged after CPB and was decreased compared with PLA. In contrast to this, MP had no effect on observed activation of p38 MAPK after CPB, resulting in similar increases of the phosphorylated p38 MAPK to total p38 MAPK ratio in both groups (Fig 3b).
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Correlations
Peak cytokine (IL-6 and IL-8) concentrations correlated positively to maximal postoperative body temperature (r = 0.45, 0.44, respectively; p < 0.001), troponin T (r = 0.39, 0.42, respectively; p < 0.001), and C-reactive protein (r = 0.32, 0.034, respectively; p < 0.01), and negatively with cardiac index (r = –0.26, –0.39, respectively; p < 0.05). In contrast to that, peak IL-10 correlated positively to cardiac index (r = 0.34; p = 0.002), and inversely to maximal postoperative body temperature (r = –0.38; p < 0.001), troponin T (r = –0.27; p < 0.015) and C-reactive protein (r = –0.43; p < 0.001) concentrations. No correlations were found between cytokines and postoperative clinical outcome of patients.
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Comment |
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, IL-6, and IL-8) and induces antiinflammatory cytokine release (IL-10), (2) inhibits myocardial inflammation by stabilization of NFB inhibitory protein IB-, (3) reduces markers of myocardial injury and general inflammation, and (4) is associated with improved cardiac index, oxygen delivery, and oxygen extraction rate in the postoperative period after cardiac surgery. Adverse effects of glucocorticoid treatment included increases in pulmonary shunt flow and alterations in glucose metabolism with postoperative hyperglycemia, acidosis, and hyperlactatemia.
Comparable inhibition of the systemic release of proinflammatory cytokines such as TNF, IL-6, and IL-8, augmentation of antiinflammatory IL-10 release, and decrease of C-reactive protein levels by glucocorticoid treatment after cardiac surgery has been reported in numerous studies [11–15]. Although this report did not investigate the exact inhibitory mechanisms of methylprednisolone on the CPB-related systemic cytokine generation, our results demonstrate a sustained systemic antiinflammatory effect of the 15-mg/kg dose used in this study. Elevated blood levels of TNF, IL-6, and IL-8 are associated with postoperative hemodynamic instability, myocardial and pulmonary dysfunction, and major perioperative complications [2]. In agreement with other studies [14, 18], we report a catecholamine-independent improvement in postoperative systemic vascular resistance index and cardiac index, inversely related to proinflammatory and directly related to antiinflammatory cytokine levels. The favorable effect of glucocorticoid treatment on cardiac index is also mirrored by increased oxygen delivery and lower oxygen extraction rate, a finding that has also been confirmed by other clinical studies [14]. Moreover, the lower body temperature in the MP group during the postoperative course might have contributed to reduced oxygen consumption and has been related to decreased generation of proinflammatory cytokines [6].
Intraoperative myocardial damage is a major determinant of postoperative cardiac dysfunction, and troponin T is well documented to reflect myocardial damage and clinical outcome after adult and pediatric cardiac surgery [19, 20]. In the present study, methylprednisolone treatment was linked to decreased levels of troponin T, suggesting reduced myocardial injury when compared with nontreated patients. The potential cardioprotective effects might be explained by the improved balance of systemic proinflammatory and antiinflammatory cytokine release, which is known to directly correlate with perioperative myocardial markers of injury [13, 15]. These findings are consistent with recent reports [13, 15] that documented a decreased cytokine-related postoperative myocardial injury in glucocorticoid-treated patients undergoing cardiac surgery, but in contrast to our results failed to show beneficial effects on postoperative myocardial performance.
Beyond inhibition of the systemic inflammation, the impact of glucocorticoid treatment on local myocardial inflammation after cardiac surgery and its sequelae has been investigated less extensively. Recent studies have demonstrated that intramyocardial activation of NFB by degradation of IB- and induction of p38 MAPK occur after cardiac surgery [8, 9, 21]. This promotes the expression of proinflammatory cytokines such as IL-1ß, TNF, and IL-6, which in turn substantially contribute to postoperative myocardial depression and injury [7, 8, 16]. An important finding of our study is that a single dose of methylprednisolone before CPB was effective in preventing myocardial degradation of NFB inhibitory protein IB-. Thus, the observed attenuation of myocardial injury and the improvement of postoperative myocardial function may be related not exclusively to the systemic but also intramyocardial antiinflammatory effects of methylprednisolone. In agreement with this, methylprednisolone treatment prevented myocardial inflammation and TNF-associated myocardial contractile dysfunction in animals subjected to CPB with 1 hour of cardioplegic cardiac arrest [22]. In a piglet model of deep hypothermic circulatory arrest, methylprednisolone preserved postoperative myocardial function and reduced cardiac NFB protein levels, while attenuating myocardial IL-6 and increasing antiinflammatory IL-10 expression [16]. Surprising, however, was the finding that glucocorticoid treatment had no effect on intramyocardial activation of p38 MAPK after CPB. Although the exact crosstalk between the glucocorticoid receptor, NFB, and MAPK signaling pathway remains to be further elucidated [17, 23], it might be speculated that methylprednisolone failed to induce mitogen-activated protein kinase phosphatase-1, an inhibitor of p38 MAPK [17, 24]. Thus, more-specific therapeutic approaches toward inhibition of the p38 MAPK signaling pathway might prove beneficial to further limit postoperative myocardial and vasomotor dysfunction [10]. Consistent with this, application of the serine protease inhibitor aprotinin has been reported to inhibit p38 activity after CPB, resulting in decreased myocardial endothelial dysfunction and tissue edema [24].
Pulmonary injury and impairment of lung function in states of systemic inflammatory response is well documented [1]. Glucocorticoids are known to decrease vascular resistance and capillary permeability of the lungs, thereby improving pulmonary functional variables in adults with acute respiratory distress syndrome [25]. Numerous well-designed studies demonstrate a beneficial effect of glucocorticoids on variables of pulmonary function [11, 14, 15], fluid balance [11, 14, 15], and decreased time on mechanical ventilation [14, 26] after cardiac surgery. Conversely, others report absent [12] or even detrimental effects on pulmonary function with decreased oxygenation indices [13], increased pulmonary shunt flow [18], and increased extravascular lung water and delayed extubation [13, 18]. In agreement with observations showing that steroids inhibit hypoxia-related changes of pulmonary vascular resistance [25], we demonstrate a significant increase of pulmonary shunt flow in methylprednisolone-treated subjects. These findings might have further been promoted by increased postoperative cardiac index at comparable amount of atelectasis formation in the study groups. No other detrimental glucocorticoid effects on postoperative pulmonary function or infections related to hyperglycemia [13, 14, 18, 26] and immunosuppression [12] could be demonstrated by the current and a larger randomized study [26]. However, hyperglycemia is associated with increased morbidity and mortality in critically ill patients [27] and has been found to be a strong predictor of organ injury in patients undergoing elective coronary artery bypass grafting [13]. Thus, the authors suggest that a tighter glucose control should be used for every patient receiving glucocorticoids during cardiac surgery to avoid postoperative hyperglycemia, as also indicated by the hyperlactatemia of the methylprednisolone group in this study.
We acknowledge the limitations of a randomized and controlled but not blinded study. However, the fact that most clinical decisions in the operating room and on the ICU (CPB, anesthetic, hemodynamic and respiratory management) are guided by standard algorithms may somehow attenuate the resulting bias. Moreover, it might be speculated that measurement of inflammatory markers in atrial tissue might not reflect ventricular changes. However, beyond ethical restrictions for ventricular tissue sampling, prior data on myocardial inflammatory markers have suggested a similar protein expression in atrial and ventricular biopsies after CPB [4].
Our study demonstrates that a single-shot treatment of MP before CPB effectively attenuates the release of systemic and myocardial inflammatory mediators after cardiac surgery. Inhibition of inflammatory mediators was associated with improved postoperative myocardial function and reduced myocardial injury, suggesting potential cardioprotective effects. Adverse effects of glucocorticoid treatment are mainly attributed to alterations in glucose metabolism and should be controlled by a tight glucose control regimen. Future studies, especially addressing high-risk patients, will have to show whether the beneficial hemodynamic and myocardial effects of glucocorticoid treatment will stand a critical risk-benefit evaluation.
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Discussion |
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DR LIAKOPOULOS: Yes, based on the results of the study the majority of the surgeons at our department are currently giving a single methylprednisolone bolus before cardiopulmonary bypass.
DR TURKI ALBACKER (Montreal, Quebec, Canada): I congratulate you on the nice work that you guys have done.
We have conducted a recent study about the effect of high dose insulin on the inflammatory markers post cardiopulmonary bypass. And as you showed here in the group in which you used methyleprednisone, you used higher doses of insulin. Did you study the correlation between the insulin dose and inflammatory markers?
Question No. 2, you showed that patients who received methyleprednisone had higher glucose levels? And we know that hyperglycemia is detrimental in cardiac surgery patients, so how do you defend this point?
DR LIAKOPOULOS: Thank you very much for these good questions.
Regarding the first question, no, we did not look at the correlation between postoperative blood glucose levels or insulin therapy and inflammatory markers. But, since methylprednisolone was associated with hyperglycemia resulting in higher insulin therapy, I would suspect that statistically this would lead to an inverse relation to pro-inflammatory cytokine release. Thus, this might not be the perfect setting to investigate this question.
Regarding your second question, it is well known that hyperglycemia, especially in diabetic patients, is a predictor of postoperative morbidity and mortality. When we conducted this study several years ago we did not employ a strict perioperative glucose control protocol. Now, of course, our strategy at the intensive care unit has changed and we target much lower glucose levels, than the ones we showed here. However, neither our study nor any larger randomized trials using a single shot of glucocorticoids have shown that steroid related hyperglycemia contributes to an increased morbidity or mortality. However, the number of patients investigated in our study is certainly too small to reliably detect any differences in outcome.
DR EDWARD B. SAVAGE (St. Louis, MO): Those of us who have been around long enough remember that a gram of Solu-Medrol was given to try and prevent bad things happening from the bypass machine; so it’s interesting to see it come back again but in a different format.
What’s interesting is that you did see a discrete measurable response, but your markers of outcome really were not different. Part of the problem is that like so many studies done in our field, this was done on elective CABG patients, not on the patients who might actually benefit from this therapy more. For example, can you identify in advance patients who might be at risk for lung injury and treat them? So I would encourage you to take this concept and advance this more in these types of patients.
The second question is, how does this compare to the responses related to aprotinin?
DR LIAKOPOULOS: Thank you very much for the very good questions.
Indeed, we conducted this study intentionally enrolling low-risk patients to identify any beneficial or adverse effects of anti-inflammatory steroid pretreatment on cardiopulmonary function, and I believe that the low-risk profile of patients investigated in previous randomized trials is the main reason for the failure to show any beneficial effects on clinical outcome. Encouraged by the current results, we are planning to investigate in a next step whether higher risk patients (i.e preoperative LV-dysfunction or lung disease etc.) might benefit the most, in terms of better clinical outcome, from the cardioprotective and anti-inflammatory effects of steroids.
And sorry, I missed the second question.
DR SAVAGE: How do these results compare to the results shown for anti-inflammatory effects of aprotinin?
DR LIAKOPOULOS: That is a very good question. We intentionally avoided aprotinin use in our study. The reason for this was to exclude the known anti-inflammatory actions of aprotinin, which might affect the accurate interpretation of our glucocorticoid therapy. Interestingly, Dr. Sellke’s group recently published a paper showing that aprotinin has its own anti-inflammatory effects, especially on myocardial p38-MAPK activation. Thus, a combined approach using low-dose glucocorticoids with aprotinin might lead to additive perioperative myocardial anti-inflammatory effects by inhibiting both the p38-MAPK and NFkB signaling pathways.
DR SAVAGE: One last thing I did remember, I would just comment, that about 20 years ago a paper was published by a surgeon named Jonathan Bromberg about renal transplant patients where they compared stress steroids to maintenance steroids (5 to 10 mg of prednisone), and the stress patients had a significantly higher incidence of infections and mortality rates.
DR LIAKOPOULOS: Of course, hyperglycemia and immunosuppression due to glucocorticoids, which potentially might contribute to a higher infection rate and mortality, is always of concern. However, as I mentioned before, no randomized trials in this field have shown these adverse effects, even when using higher steroid doses than applied in our study. Thus, the current evidence suggests that a single, preoperative low-dose methylprednisolone bolus is well tolerated by the patient and considered to be safe.
DR MARC RUEL (Ottawa, Ontario, Canada): I have 2 questions regarding your study’s design. First, why did you not blind the intervention? Second, what was the primary outcome of your study and what was your sample size calculation? The relevance of this latter point is that you have showed pathophysiological differences between the two groups with, however, a lack of difference in clinical outcome.
DR LIAKOPOULOS: Thank you very much for your excellent questions.
Initially, we planned a blinded study design. Unfortunately, this was not possible due to restrictions from our local ethic committee and we acknowledge the limitation and possible bias of a non-blinded trial.
Regarding your second question, our primary endpoint was cardiac function (i.e. cardiac index). Our power analysis revealed that, to detect a minimum cardiac index difference of 0.5 L/min/m2 between groups, up to 25–30 patients had to be enrolled per group. However, as aforementioned, our group size is certainly large enough to show differences in hemodynamic and biochemical parameters, but underpowered to detect any differences in clinical outcome.
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) or placebo-treated patients (PLA group; 
); data are mean ± standard deviation (*p < 0.05 compared with pre-CPB; #p < 0.05 between treatment groups). (CPB = cardiopulmonary bypass.)
