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Methylprednisolone Use is Associated with Endothelial Cell Activation Following Cardiac Surgery
ORIGINAL ARTICLE
Original Article
Methylprednisolone Use is Associated with Endothelial Cell Activation Following Cardiac Surgery Vladimir V. Lomivorotov, M.D., Ph.D., Sergey M. Efremov, M.D., Ph.D. ∗ , Andrey P. Kalinichenko, M.D., Ph.D., Igor A. Kornilov, M.D., Ph.D., Lubov G. Knazkova, M.D., Ph.D. 1 , Alexandr M. Chernyavskiy, M.D., Ph.D., Vladimir N. Lomivorotov, M.D., Ph.D. and Alexander M. Karaskov, M.D., Ph.D. Research Institute of Circulation Pathology, Rechkunovskaya Street 15, Novosibirsk 630055, Russia
Background: The objective of this study was to investigate the effect of the perioperative use of methylprednisolone in medium doses on markers of endothelial cell activation in patients with coronary artery disease undergoing cardiopulmonary bypass. Methods: In this prospective, double-blinded, placebo-controlled, randomised study, 44 patients, undergoing a coronary artery bypass graft surgery received either methylprednisolone 20 mg/kg or a placebo intraoperatively after anaesthesia induction. The primary endpoint was endothelin-1, and secondary endpoints were E-selectin, interleukin (IL)-6 and IL-10, PaO2 /FiO2 coefficient, and microalbuminuria. Results: Endothelin-1 was higher in the study group postoperatively at 10 min (p = 0.0008), 2 h (p = 0.02), 4 h (p = 0.005), and 24 h (p = 0.004). IL-6 was lower in the study group postoperatively at 2 h (p = 0.03), 4 h (p = 0.04), and 24 h (p < 0.0001). IL-10 was higher in the study group postoperatively at 10 min (p < 0.0001), 2 h (p = 0.009), and 4 h (p = 0.001). PaO2 /FiO2 was lower in the study group at 24 h after surgery (p = 0.03). Microalbuminuria was similar in both groups. Conclusion: Despite an obvious anti-inflammatory effect, methylprednisolone causes endothelial cell activation in patients undergoing cardiopulmonary bypass. (Heart, Lung and Circulation 2013;22:25–30) © 2012 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier Inc. All rights reserved. Keywords. Methylprednisolone; Cardiopulmonary bypass; Endothelin-1; E-selectin; Endothelial cell
Introduction
T
he systemic inflammatory response syndrome (SIRS) is an inevitable consequence of cardiopulmonary bypass (CPB). The severity of SIRS is strongly correlated with the duration of CPB and affects the development of postoperative complications [1]. Corticosteroids remain a promising strategy for the correction of SIRS in cardiac patients undergoing CPB. The perioperative use of corticosteroids modulates plasma and cell inflammatory responses [2] and reduces pro-inflammatory cytokine concentrations, thus increasing anti-inflammatory responses [3]. This favourable effect may underlie the reduction of capillary leak syndrome [4], which contributes to the development of organ dysfunction [5]. However, a recent meta-analysis demonstrated no clinical benefit Received 2 February 2012; received in revised form 1 May 2012; accepted 1 August 2012; available online 28 August 2012 ∗
Corresponding author. Tel.: +7 9833088415. E-mail address: [email protected] (S.M. Efremov). 1 Deceased.
derived from perioperative administration of corticosteroids [6]. The ongoing SIRS Trial (NCT00427388) is currently recruiting participants in a large prospective study [7]. Furthermore, there is some evidence that corticosteroids negatively impact lung function [8]. Endothelial dysfunction due to endothelial damage is one of the principal causes of postoperative respiratory failure [9]. It is well known that hypercorticism is associated with endothelial dysfunction and is a significant risk factor for cardiovascular disease [10,11]. Corticosteroids have been shown to cause endothelial dysfunction [12] and sensitise the endothelium to pro-inflammatory cytokines [13]. Endothelin-1 (ET-1) and E-selectin are extensively used markers of endothelial cell activation. Released predominantly from endothelial cells, ET-1 is perhaps the most potent vasoconstrictor substance known [14]. Increased release of the ET-1 has been documented in the early post-CPB period and can affect important determinants of postoperative recovery such as systemic, pulmonary, and coronary conduit vascular tone [15,16]. Eselectin is specifically localised on endothelial cells and
© 2012 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier Inc. All rights reserved.
1443-9506/04/$36.00 http://dx.doi.org/10.1016/j.hlc.2012.08.001
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Lomivorotov et al. Endothelial Cell Activation
hence is a more sensitive marker of endothelial activation compared to other adhesion molecules that have a wider tissue distribution [17]. We hypothesised that short-term use of methylprednisolone (MP) may modulate endothelial function, thereby influencing capillary permeability and lung function. The aim of this study was to investigate the effect of the perioperative use of MP in medium doses on endothelial cell activation in patients with coronary artery disease undergoing CPB.
Materials and Methods This prospective, double-blinded, placebo-controlled, randomised study was approved by the local hospital Ethics Committee. Patients undergoing a coronary artery bypass graft (CABG) in 2009 were included in the study. Written informed consent was obtained from all patients prior to randomisation. Exclusion criteria were age >70 years, left ventricular ejection fraction <40%, diabetes mellitus, chronic obstructive pulmonary disease, and chronic renal disease. Randomisation was performed using opaque sealed envelopes. Twenty-four patients were allocated to the MP group, of which 23 patients received allocated intervention and one patient was excluded due to cancellation of surgery. Another group of 26 patients was allocated to the placebo group; of these, 24 patients received allocated intervention and two patients withdrew from the study. Upon study completion, 3 patients were excluded from the study: one patient in the MP group due to mitral valve surgery, and two patients in placebo group, as one patient underwent an off-pump surgery and another patient developed severe surgical perioperative bleeding. Thus, a total of 44 patients comprising 22 in the study group and 22 in the placebo group were included for the final statistical analyses. Patients in the study group received MP (Orion Corporation, Espoo, Finland) at a dose of 20 mg/kg intraoperatively immediately after anaesthesia induction. Patients in the control group were given a placebo (20 mL of 0.9% NaCl). The solution for injections was prepared in a nontransparent syringe by an independent pharmacist. Serum ET-1 was the primary endpoint. The secondary endpoints included E-selectin, pro- and antiinflammatory markers [interleukin (IL)-6 and IL-10], oxygenation index (PaO2 /FiO2 ), and serum glucose. Microalbuminuria was measured to assess capillary leak syndrome. These parameters were measured at the following stages: (1) immediately prior to anaesthesia induction; (2) 10 min after CPB; (3) 2 h after CPB; (4) 4 h after CPB; and (5) 24 h after surgery. We also assessed hospital mortality, ventilation time after surgery, frequency of inotropic support, frequency of atrial fibrillation during the first 24 h after surgery, infectious complications, intensive care unit (ICU) and hospital stay durations, and ICU readmission. Based on the data from the pilot study, a sample size of 20 patients per group was chosen to provide 80%
Heart, Lung and Circulation 2013;22:25–30
power to detect a reduction in ET-1 to 0.16 fmol/mL (SD 0.18 fmol/mL) by using a two-sided type I error of 5%. All patients were operated under normothermic CPB (35.5–36.5 ◦ C). Surgeries were performed using standard anaesthetic and surgical techniques. Patients received beta-blockers until the day of the surgery and preoperative benzodiazepines. Induction was performed using midazolam, fentanyl, and pipecuronium bromide. Anaesthesia was maintained by sevoflurane inhalation in combination with fentanyl. Midazolam or propofol were used during CPB. All patients underwent a full median sternotomy. An S3 heart–lung machine with roller pumps and heater–cooler device were used for CPB (Stöckert Instrumente GMBH, Munich, Germany). The extracorporeal circuit consisted of a tubing system with a hollow fibre oxygenator, hard shell venous reservoir, and arterial line filter (Affinity, Medtronic, Minneapolis, MN, USA). Flow rate during CPB was aimed at 2.5 l/min/m2 , and mean systemic pressure was maintained between 60 and 90 mmHg. Myocardial protection was achieved by 4 ◦ C antegrade crystalloid cardioplegia solution. All patients were admitted to the ICU immediately after surgery. Ventilator weaning was performed in the presence of stable haemodynamic parameters, no signs of haemorrhage, adequate blood gases, and appropriate acid–base values. Blood samples were obtained from a central venous catheter using BD Vacutainer® Plus plastic K3EDTA tubes (BD, Franklin Lakes, NJ, USA). The samples were then centrifuged immediately after collection to obtain plasma samples (Hettich Universal 320R, DJB Labcare Ltd., Newport Pagnell, England). Plasma samples were stored under −80 ◦ C (Snijders Ultra Low Temperature freezer, Snijders Scientific b.v., Tilburg, Netherlands), for a maximum of 10 months. Plasma samples were analysed in two steps using two batches of the same assay. A microalbuminuria test of urine samples, concentrations of soluble E-selectin in plasma, and levels of IL-6 and IL-10 were evaluated using an enzyme-linked immunosorbent assay (ELISA, Bender Medsystems, Vienna, Austria) on an automatic Reader Model PW-40 (BIO-RAD, Hercules, CA, USA). ELISAs were also used to determine ET-1 concentrations (Biomedica, USA). Blood oxygen and glucose levels were evaluated on a Gas Analyzer Model Rapidlab-865 (Bayer, Germany). The independent samples t-test was used to compare parametric variables, the Mann–Whitney test used for nonparametric variables, and the Chi-square test used for qualitative variables. Comparative analysis of repeated measurements variables was performed with repeated measures ANOVA for parametric data and Friedman test for nonparametric data. Multiple comparisons were carried out with introduction of Bonferroni correction. Spearman’s rank correlation coefficient (rs ) was used to find correlations between variables with abnormal distribution. A p value < 0.05 was considered statistically significant. The statistical data analysis was conducted according to the standard methods [18] using MedCalc Statistical Software v11.3.3 (MedCalc Software, Belgium) [19].
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Table 1. Baseline Characteristics of Patients. MP (n = 22)
Control (n = 22)
p
Age
57.8 (7.7)
57.3 (6.8)
0.804
Female
6
1
0.099
Body mass index
29.2 (3.8)
29.6 (4.5)
0.752
NYHA class II/III
4/18
8/14
0.151
Logistic EuroScore
3 (2–5)
2 (1–3)
0.013
Coronary grafts
2.6 (0.6)
2.5 (0.7)
0.721
Peripheral vascular disease
9
5
0.811
Cardiopulmonary bypass (min)
66 (26)
57 (23)
0.272
Aortic Cross-Clamp (min)
41 (15)
35 (15)
0.151
Results are presented as mean (SDs) or median (25–75 percentile) or number of patients.
Results Patient demographics are presented in Table 1. The logistic EuroScore number was significantly higher for the study group than for the control group (p = 0.01). There was no significant difference in the mortality rates, ventilation period, frequency of inotropic support, frequency of atrial fibrillation, infectious complications, and ICU and hospital stay between the two groups (Table 2). One patient in the control group died on postoperative day 47 from sepsis secondary to a stroke. One patient in the study group died on postoperative day 17 from the development of multiorgan failure following perioperative myocardial infarction. Another patient in the study group died on postoperative day 2 from the development of multiorgan failure secondary to an acute arterial thrombosis in the legs. Serum ET-1 was significantly higher in the study group compared to the control group at 10 min after CPB [0.24 (0.13–0.35) vs. 0.09 (0.06–0.13) fmol/mL; p = 0.0008], 2 h after CPB (0.47 ± 0.2 vs. 0.31 ± 0.18 fmol/mL; p = 0.02), 4 h after CPB [0.57 (0.39–0.77) vs. 0.28 (0.19–0.54) fmol/mL; p = 0.005], and 24 h after surgery [0.47 (0.36–0.64) vs. 0.25 (0.18–0.4) fmol/mL; p = 0.004] (Fig. 1). We found no difference between the groups in serum E-selectin (Table 3), However, in the placebo group, this parameter changed significantly within one day after CPB. Further analysis of multiple comparisons in the placebo group
showed a significant increase in E-selectin at 4 h after CPB compared to the preoperative level (p = 0.017). Furthermore, serum E-selectin was significantly lower on postoperative day 1 than at 2 h (p = 0.049) and 4 h after CPB (p = 0.002). Although microalbuminuria changed significantly within one day after CPB in both groups, no significant differences were noted in the microalbuminuria levels between the groups. The study group had worse gas exchange rates compared to the control group. At 24 h after surgery, PaO2 /FiO2 was significantly lower in the study group relative to the control group (p = 0.03). There was no correlation between PaO2 /FiO2 and ET-1 (r = −0.085; p = 0.27). The study group had higher blood glucose levels compared to the control group, which were significantly different at 10 min after CPB (p = 0.0006) and 24 h after surgery (p = 0.02). Serum IL-6, a pro-inflammatory marker, was significantly lower in the study group compared to the control group at 2 h after CPB (25.9 ± 18.7 pkg/mL vs. 40.9 ± 22 pkg/mL; p = 0.03), 4 h after CPB [22.9 (10.7–32) pkg/mL vs. 49.4 (23.8–57.3) pkg/mL; p = 0.04], and 24 h after surgery [3.9 (1.7–6.2) pkg/mL vs. 24.8 (16.8–37.6)
Table 2. Postoperative Complications and Clinical Course. MP (n = 22)
Control (n = 22)
p
Mortality
2
1
0.951
Ventilation (h)
6.7 (1.9)
5.7 (1.7)
0.073
Inotropic support
4
1
0.316
Atrial fibrillation
5
2
0.392
Infectious complications
2
1
0.951
Readmission to ICU
3
0
0.219
ICU stay, days
1 (1–1.5)
1 (1–1.2)
0.907
Results are presented as mean (SDs) or median (25–75 percentile) or number of patients. ICU, intensive care unit.
Figure 1. Medians (error bars: 95% CI for median). Methylprednisolone is associated with significantly higher concentration of serum endothelin-1 at all postbypass phases of study.
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Heart, Lung and Circulation 2013;22:25–30
Table 3. Perioperative Serum E-selectin, Microalbuminuria, Gas Exchange Parameters and Blood Glucose. N
Induction
10 min Postbypass
2 h Postbypass
4 h Postbypass
1 Postop. Day
p-Value*
E-selectin, ng/mL MP
22
27.4 (10.3)
26.1 (7.1)
30.7 (10.4)
31.5 (8)
26.6 (11.8)
0.1
Control
22
25.7 (12.5)
22.2 (11.1)
25.4 (13.1)
25.1 (12.1)
20.6 (10.4)
0.001
Microalbuminuria, mkg/min MP
22
26.4 (17.6–37.5)
154 (92.9–191.2)
64 (40.5–121.6)
23.7 (13.1–39.5)
13.6 (11.7–29.2)
<0.001
Control
22
24 (20–31.1)
160 (132.3–211.4)
56 (34–115.7)
20.3 (16–38.7)
15 (10.6–24.4)
<0.001
PaO2 /FiO2 MP
22
407 (118)
286 (106)
264 (76)
302 (89)
302 (46)
<0.001
Control
22
420 (114)
266 (101)
307 (81)
341 (79)
337 (47)
<0.001
p = 0.03∧ Blood glucose, Mmol/L MP
22
5.3 (0.7)
9.7 (8.7–11.1)
Control
22
5.3 (0.8)
7.2 (6.8–8.6) p = 0.0006∧
10 (2.2) 8.8 (1.7)
10.4 (2.6)
8.2 (1.1)
<0.001
9.4 (1.8)
7.4 (0.9)
<0.001
p = 0.02∧
Results are presented as mean (SDs) or median (25–75 percentile). Significance level accordingly to repeated measures (ANOVA for parametric data and Friedman ANOVA for non-parametric data). ∧ Significance level of difference between groups accordingly to independent samples t-test or Mann–Whitney tests results (distinctions are statistically significant at p < 0.05). ∗
Figure 2. Medians (error bars: 95% CI for median). Dynamics of IL-6. Methylprednisolone causes significant decreasing of IL-6 concentration on 2nd, 4th hours after cardiopulmonary bypass and on 1 postoperative day.
pkg/mL; p < 0.0001] (Fig. 2). However, serum IL-10, an antiinflammatory marker, was significantly higher in the study group compared to the control group at 10 min after CPB (339 ± 213 pkg/mL vs. 97.1 ± 80.4 pkg/mL; p < 0.0001), 2 h after CPB [109.5 (34.2–135.5) pkg/mL vs. 28.3 (12.2–44.3) pkg/mL; p = 0.009], and 4 h after CPB [12.2 (5.8–22.8) pkg/mL vs. 4.4 (3.1–7.7) pkg/mL; p = 0.001] (Fig. 3).
Discussion The use of CPB in cardiac surgery potentiates the development of SIRS and endothelial activation [20,21]. Endothelial dysfunction and capillary leak are basic characteristics of several pathogenic pathways induced
Figure 3. Medians (error bars: 95% CI for median). Dynamics of IL-10. Methylprednisolone causes significant increasing of IL-10 concentration on 10 min, 2nd and 4th hours after cardiopulmonary bypass.
by CPB. Activation of complement, leukocytes, adhesion molecules, and output of cytokines and other inflammatory mediators, which accompany cardiac surgeries with CPB, is also responsible for the development of pulmonary dysfunction [22]. Despite limited evidence, the use of corticosteroids continues to be a cornerstone of treatment aimed at optimising recovery in some institutions [1], with the goal of regulating the inflammatory response. However, we found that the study group demonstrated significantly higher concentrations of ET-1 in the post-CPB period, suggesting that MP 20 mg/kg causes endothelial cell activation in patients undergoing CPB.
Another mechanism whereby corticosteroids can affect an endothelial cell is well known. Corticosteroids can inhibit production of the nitric oxide (NO) synthase by inducing the hyperglycaemia [23]. This enzyme is responsible for NO production, one of the main regulators of vascular tone. Corroborating other studies, we showed an association between the use of MP and significantly higher rates of hyperglycaemia at 10 min after CPB and at 24 h after surgery. Increased serum ET-1 level is observed in various clinical conditions, such as pulmonary artery hypertension (PAH), acute and chronic heart failure, essential hypertension, chronic kidney disease, and atherosclerosis. The benefits of ET-1 receptor blockade have been demonstrated for these diseases [14]. Furthermore, ET-1 is a prognostic factor for mortality in patients with chronic heart failure [22]. Activation of the ET-1 system has been shown in both plasma and lung tissues of patients with PAH. Although it is not unknown whether increased ET-1 plasma levels cause or are a result of PAH, studies have supported its prominent role in the development of PAH [24]. Ventilation/perfusion mismatch as a consequence of intrapulmonary right to left shunting is one of the principal causes of hypoxaemia associated with the PAH [25]. Chaney et al. have described MP administration leading to an increase in the volume of an arteriovenous bypass in the lungs as well as prolonged ventilation [26]. In this study, increased serum ET-1 was associated with a decrease of PaO2 /FiO2 on postoperative day 1. Although there is no direct dependence between this oxygenation index and serum ET-1, the increase of ET-1 due to MP administration may be clinically relevant. We also observed that perioperative MP did not significantly blunt the capillary leak syndrome, which was assessed by microalbuminuria. These results prove that both medium and small doses of corticosteroids [27] do not influence the manifestation of capillary leak syndrome in low-risk patients. Furthermore, considering the significant differences found in serum ET-1 between the groups, but no differences in microalbuminuria, we suggest that a reduction of pulmonary function is likely associated with endothelial cell activation but not with capillary leak. The use of MP significantly lowered the levels of IL-6 and at the same time increased the levels of IL-10. Thus, MP modulated the inflammatory response towards antiinflammation. Our findings support the existing data. Despite randomisation, the initial differences between the groups in EuroScore may be due to a relatively greater number of women and patients with peripheral vascular pathologies in the study group. There are several limitations in our study. First, a SwanGanz catheter was not employed and there are therefore no haemodynamic data available. Thus, we could not evaluate the correlation among serum ET-1, the rates of peripheral vascular resistance, pressure in the pulmonary artery, and intrapulmonary venous shunting. Second, this study does not elucidate the mechanism(s) of the increased serum ET-1, i.e., whether it is caused by increased
Lomivorotov et al. Endothelial Cell Activation
29
production or decreased elimination of this molecule. Third, the overall rate of mortality observed in this study was most likely accidental and does not reflect the overall rate of mortality in our institution, which is 2.3% among the low-risk patients. Finally, our study consisted of a small sample size, low-risk patients, and relatively short CPB duration. No differences in postoperative complication rates were observed. Thus, further research involving high-risk patients is required to determine the clinical effects of increased serum ET-1 caused by MP.
Conclusion Despite an obvious anti-inflammatory effect, the use of MP in medium doses is associated with increased levels of serum ET-1. However, increased levels of ET-1 were not associated with capillary leak syndrome. The mechanism and the clinical relevance of these findings remain unknown, but it may help explain the contradictory clinical effects of steroid administration in patients undergoing CPB and the postoperative development of respiratory dysfunction.
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[20] Vallely MP, Bannon PG, Bayfield MS, Hughes CF, Kritharides L. Endothelial activation after coronary artery bypass surgery: comparison between on-pump and off-pump techniques. Heart Lung Circ 2010;19:445–52. [21] Onorati F, Rubino AS, Nucera S, Foti D, Sica V, Santini F, et al. Off-pump coronary artery bypass surgery versus standard linear or pulsatile cardiopulmonary bypass: endothelial activation and inflammatory response. Eur J Cardiothorac Surg 2010;37:897–904. [22] Asimakopoulos G, Smith PL, Ratnatunga CP, Taylor KM. Lung injury and acute respiratory distress syndrome after cardiopulmonary bypass. Ann Thorac Surg 1999;68:1107–15. [23] Rodeberg DA, Chaet MS, Bass RC, Arkovitz MS, Garcia VF. Nitric oxide: an overview. Am J Surg 1995;170:292–303. [24] Tuteja N, Chandra M, Tuteja R, Misra MK. Nitric oxide as a unique bioactive signaling messenger in physiology and pathophysiology. J Biomed Biotechnol 2004;4:227–37. [25] Vodoz JF, Cottin V, Glérant JC, Derumeaux G, Khouatra C, Blanchet AS, et al. Right-to-left shunt with hypoxemia in pulmonary hypertension. BMC Cardiovasc Disord 2009;31:9–15. [26] Chaney MA, Nikolov MP, Blakeman B, Bakhos M, Slogoff S. Pulmonary effects of methylprednisolone in patients undergoing coronary artery bypass grafting and early tracheal extubation. Anesth Analg 1998;87:27–33. [27] Loef BG, Henning RH, Epema AH, Rietman GW, van Oeveren W, Navis GJ, et al. Effect of dexamethasone on perioperative renal function impairment during cardiac surgery with cardiopulmonary bypass. Br J Anaesth 2004;93:793–8.
Original Article
Methylprednisolone Use is Associated with Endothelial Cell Activation Following Cardiac Surgery Vladimir V. Lomivorotov, M.D., Ph.D., Sergey M. Efremov, M.D., Ph.D. ∗ , Andrey P. Kalinichenko, M.D., Ph.D., Igor A. Kornilov, M.D., Ph.D., Lubov G. Knazkova, M.D., Ph.D. 1 , Alexandr M. Chernyavskiy, M.D., Ph.D., Vladimir N. Lomivorotov, M.D., Ph.D. and Alexander M. Karaskov, M.D., Ph.D. Research Institute of Circulation Pathology, Rechkunovskaya Street 15, Novosibirsk 630055, Russia
Background: The objective of this study was to investigate the effect of the perioperative use of methylprednisolone in medium doses on markers of endothelial cell activation in patients with coronary artery disease undergoing cardiopulmonary bypass. Methods: In this prospective, double-blinded, placebo-controlled, randomised study, 44 patients, undergoing a coronary artery bypass graft surgery received either methylprednisolone 20 mg/kg or a placebo intraoperatively after anaesthesia induction. The primary endpoint was endothelin-1, and secondary endpoints were E-selectin, interleukin (IL)-6 and IL-10, PaO2 /FiO2 coefficient, and microalbuminuria. Results: Endothelin-1 was higher in the study group postoperatively at 10 min (p = 0.0008), 2 h (p = 0.02), 4 h (p = 0.005), and 24 h (p = 0.004). IL-6 was lower in the study group postoperatively at 2 h (p = 0.03), 4 h (p = 0.04), and 24 h (p < 0.0001). IL-10 was higher in the study group postoperatively at 10 min (p < 0.0001), 2 h (p = 0.009), and 4 h (p = 0.001). PaO2 /FiO2 was lower in the study group at 24 h after surgery (p = 0.03). Microalbuminuria was similar in both groups. Conclusion: Despite an obvious anti-inflammatory effect, methylprednisolone causes endothelial cell activation in patients undergoing cardiopulmonary bypass. (Heart, Lung and Circulation 2013;22:25–30) © 2012 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier Inc. All rights reserved. Keywords. Methylprednisolone; Cardiopulmonary bypass; Endothelin-1; E-selectin; Endothelial cell
Introduction
T
he systemic inflammatory response syndrome (SIRS) is an inevitable consequence of cardiopulmonary bypass (CPB). The severity of SIRS is strongly correlated with the duration of CPB and affects the development of postoperative complications [1]. Corticosteroids remain a promising strategy for the correction of SIRS in cardiac patients undergoing CPB. The perioperative use of corticosteroids modulates plasma and cell inflammatory responses [2] and reduces pro-inflammatory cytokine concentrations, thus increasing anti-inflammatory responses [3]. This favourable effect may underlie the reduction of capillary leak syndrome [4], which contributes to the development of organ dysfunction [5]. However, a recent meta-analysis demonstrated no clinical benefit Received 2 February 2012; received in revised form 1 May 2012; accepted 1 August 2012; available online 28 August 2012 ∗
Corresponding author. Tel.: +7 9833088415. E-mail address: [email protected] (S.M. Efremov). 1 Deceased.
derived from perioperative administration of corticosteroids [6]. The ongoing SIRS Trial (NCT00427388) is currently recruiting participants in a large prospective study [7]. Furthermore, there is some evidence that corticosteroids negatively impact lung function [8]. Endothelial dysfunction due to endothelial damage is one of the principal causes of postoperative respiratory failure [9]. It is well known that hypercorticism is associated with endothelial dysfunction and is a significant risk factor for cardiovascular disease [10,11]. Corticosteroids have been shown to cause endothelial dysfunction [12] and sensitise the endothelium to pro-inflammatory cytokines [13]. Endothelin-1 (ET-1) and E-selectin are extensively used markers of endothelial cell activation. Released predominantly from endothelial cells, ET-1 is perhaps the most potent vasoconstrictor substance known [14]. Increased release of the ET-1 has been documented in the early post-CPB period and can affect important determinants of postoperative recovery such as systemic, pulmonary, and coronary conduit vascular tone [15,16]. Eselectin is specifically localised on endothelial cells and
© 2012 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier Inc. All rights reserved.
1443-9506/04/$36.00 http://dx.doi.org/10.1016/j.hlc.2012.08.001
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hence is a more sensitive marker of endothelial activation compared to other adhesion molecules that have a wider tissue distribution [17]. We hypothesised that short-term use of methylprednisolone (MP) may modulate endothelial function, thereby influencing capillary permeability and lung function. The aim of this study was to investigate the effect of the perioperative use of MP in medium doses on endothelial cell activation in patients with coronary artery disease undergoing CPB.
Materials and Methods This prospective, double-blinded, placebo-controlled, randomised study was approved by the local hospital Ethics Committee. Patients undergoing a coronary artery bypass graft (CABG) in 2009 were included in the study. Written informed consent was obtained from all patients prior to randomisation. Exclusion criteria were age >70 years, left ventricular ejection fraction <40%, diabetes mellitus, chronic obstructive pulmonary disease, and chronic renal disease. Randomisation was performed using opaque sealed envelopes. Twenty-four patients were allocated to the MP group, of which 23 patients received allocated intervention and one patient was excluded due to cancellation of surgery. Another group of 26 patients was allocated to the placebo group; of these, 24 patients received allocated intervention and two patients withdrew from the study. Upon study completion, 3 patients were excluded from the study: one patient in the MP group due to mitral valve surgery, and two patients in placebo group, as one patient underwent an off-pump surgery and another patient developed severe surgical perioperative bleeding. Thus, a total of 44 patients comprising 22 in the study group and 22 in the placebo group were included for the final statistical analyses. Patients in the study group received MP (Orion Corporation, Espoo, Finland) at a dose of 20 mg/kg intraoperatively immediately after anaesthesia induction. Patients in the control group were given a placebo (20 mL of 0.9% NaCl). The solution for injections was prepared in a nontransparent syringe by an independent pharmacist. Serum ET-1 was the primary endpoint. The secondary endpoints included E-selectin, pro- and antiinflammatory markers [interleukin (IL)-6 and IL-10], oxygenation index (PaO2 /FiO2 ), and serum glucose. Microalbuminuria was measured to assess capillary leak syndrome. These parameters were measured at the following stages: (1) immediately prior to anaesthesia induction; (2) 10 min after CPB; (3) 2 h after CPB; (4) 4 h after CPB; and (5) 24 h after surgery. We also assessed hospital mortality, ventilation time after surgery, frequency of inotropic support, frequency of atrial fibrillation during the first 24 h after surgery, infectious complications, intensive care unit (ICU) and hospital stay durations, and ICU readmission. Based on the data from the pilot study, a sample size of 20 patients per group was chosen to provide 80%
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power to detect a reduction in ET-1 to 0.16 fmol/mL (SD 0.18 fmol/mL) by using a two-sided type I error of 5%. All patients were operated under normothermic CPB (35.5–36.5 ◦ C). Surgeries were performed using standard anaesthetic and surgical techniques. Patients received beta-blockers until the day of the surgery and preoperative benzodiazepines. Induction was performed using midazolam, fentanyl, and pipecuronium bromide. Anaesthesia was maintained by sevoflurane inhalation in combination with fentanyl. Midazolam or propofol were used during CPB. All patients underwent a full median sternotomy. An S3 heart–lung machine with roller pumps and heater–cooler device were used for CPB (Stöckert Instrumente GMBH, Munich, Germany). The extracorporeal circuit consisted of a tubing system with a hollow fibre oxygenator, hard shell venous reservoir, and arterial line filter (Affinity, Medtronic, Minneapolis, MN, USA). Flow rate during CPB was aimed at 2.5 l/min/m2 , and mean systemic pressure was maintained between 60 and 90 mmHg. Myocardial protection was achieved by 4 ◦ C antegrade crystalloid cardioplegia solution. All patients were admitted to the ICU immediately after surgery. Ventilator weaning was performed in the presence of stable haemodynamic parameters, no signs of haemorrhage, adequate blood gases, and appropriate acid–base values. Blood samples were obtained from a central venous catheter using BD Vacutainer® Plus plastic K3EDTA tubes (BD, Franklin Lakes, NJ, USA). The samples were then centrifuged immediately after collection to obtain plasma samples (Hettich Universal 320R, DJB Labcare Ltd., Newport Pagnell, England). Plasma samples were stored under −80 ◦ C (Snijders Ultra Low Temperature freezer, Snijders Scientific b.v., Tilburg, Netherlands), for a maximum of 10 months. Plasma samples were analysed in two steps using two batches of the same assay. A microalbuminuria test of urine samples, concentrations of soluble E-selectin in plasma, and levels of IL-6 and IL-10 were evaluated using an enzyme-linked immunosorbent assay (ELISA, Bender Medsystems, Vienna, Austria) on an automatic Reader Model PW-40 (BIO-RAD, Hercules, CA, USA). ELISAs were also used to determine ET-1 concentrations (Biomedica, USA). Blood oxygen and glucose levels were evaluated on a Gas Analyzer Model Rapidlab-865 (Bayer, Germany). The independent samples t-test was used to compare parametric variables, the Mann–Whitney test used for nonparametric variables, and the Chi-square test used for qualitative variables. Comparative analysis of repeated measurements variables was performed with repeated measures ANOVA for parametric data and Friedman test for nonparametric data. Multiple comparisons were carried out with introduction of Bonferroni correction. Spearman’s rank correlation coefficient (rs ) was used to find correlations between variables with abnormal distribution. A p value < 0.05 was considered statistically significant. The statistical data analysis was conducted according to the standard methods [18] using MedCalc Statistical Software v11.3.3 (MedCalc Software, Belgium) [19].
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Table 1. Baseline Characteristics of Patients. MP (n = 22)
Control (n = 22)
p
Age
57.8 (7.7)
57.3 (6.8)
0.804
Female
6
1
0.099
Body mass index
29.2 (3.8)
29.6 (4.5)
0.752
NYHA class II/III
4/18
8/14
0.151
Logistic EuroScore
3 (2–5)
2 (1–3)
0.013
Coronary grafts
2.6 (0.6)
2.5 (0.7)
0.721
Peripheral vascular disease
9
5
0.811
Cardiopulmonary bypass (min)
66 (26)
57 (23)
0.272
Aortic Cross-Clamp (min)
41 (15)
35 (15)
0.151
Results are presented as mean (SDs) or median (25–75 percentile) or number of patients.
Results Patient demographics are presented in Table 1. The logistic EuroScore number was significantly higher for the study group than for the control group (p = 0.01). There was no significant difference in the mortality rates, ventilation period, frequency of inotropic support, frequency of atrial fibrillation, infectious complications, and ICU and hospital stay between the two groups (Table 2). One patient in the control group died on postoperative day 47 from sepsis secondary to a stroke. One patient in the study group died on postoperative day 17 from the development of multiorgan failure following perioperative myocardial infarction. Another patient in the study group died on postoperative day 2 from the development of multiorgan failure secondary to an acute arterial thrombosis in the legs. Serum ET-1 was significantly higher in the study group compared to the control group at 10 min after CPB [0.24 (0.13–0.35) vs. 0.09 (0.06–0.13) fmol/mL; p = 0.0008], 2 h after CPB (0.47 ± 0.2 vs. 0.31 ± 0.18 fmol/mL; p = 0.02), 4 h after CPB [0.57 (0.39–0.77) vs. 0.28 (0.19–0.54) fmol/mL; p = 0.005], and 24 h after surgery [0.47 (0.36–0.64) vs. 0.25 (0.18–0.4) fmol/mL; p = 0.004] (Fig. 1). We found no difference between the groups in serum E-selectin (Table 3), However, in the placebo group, this parameter changed significantly within one day after CPB. Further analysis of multiple comparisons in the placebo group
showed a significant increase in E-selectin at 4 h after CPB compared to the preoperative level (p = 0.017). Furthermore, serum E-selectin was significantly lower on postoperative day 1 than at 2 h (p = 0.049) and 4 h after CPB (p = 0.002). Although microalbuminuria changed significantly within one day after CPB in both groups, no significant differences were noted in the microalbuminuria levels between the groups. The study group had worse gas exchange rates compared to the control group. At 24 h after surgery, PaO2 /FiO2 was significantly lower in the study group relative to the control group (p = 0.03). There was no correlation between PaO2 /FiO2 and ET-1 (r = −0.085; p = 0.27). The study group had higher blood glucose levels compared to the control group, which were significantly different at 10 min after CPB (p = 0.0006) and 24 h after surgery (p = 0.02). Serum IL-6, a pro-inflammatory marker, was significantly lower in the study group compared to the control group at 2 h after CPB (25.9 ± 18.7 pkg/mL vs. 40.9 ± 22 pkg/mL; p = 0.03), 4 h after CPB [22.9 (10.7–32) pkg/mL vs. 49.4 (23.8–57.3) pkg/mL; p = 0.04], and 24 h after surgery [3.9 (1.7–6.2) pkg/mL vs. 24.8 (16.8–37.6)
Table 2. Postoperative Complications and Clinical Course. MP (n = 22)
Control (n = 22)
p
Mortality
2
1
0.951
Ventilation (h)
6.7 (1.9)
5.7 (1.7)
0.073
Inotropic support
4
1
0.316
Atrial fibrillation
5
2
0.392
Infectious complications
2
1
0.951
Readmission to ICU
3
0
0.219
ICU stay, days
1 (1–1.5)
1 (1–1.2)
0.907
Results are presented as mean (SDs) or median (25–75 percentile) or number of patients. ICU, intensive care unit.
Figure 1. Medians (error bars: 95% CI for median). Methylprednisolone is associated with significantly higher concentration of serum endothelin-1 at all postbypass phases of study.
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Table 3. Perioperative Serum E-selectin, Microalbuminuria, Gas Exchange Parameters and Blood Glucose. N
Induction
10 min Postbypass
2 h Postbypass
4 h Postbypass
1 Postop. Day
p-Value*
E-selectin, ng/mL MP
22
27.4 (10.3)
26.1 (7.1)
30.7 (10.4)
31.5 (8)
26.6 (11.8)
0.1
Control
22
25.7 (12.5)
22.2 (11.1)
25.4 (13.1)
25.1 (12.1)
20.6 (10.4)
0.001
Microalbuminuria, mkg/min MP
22
26.4 (17.6–37.5)
154 (92.9–191.2)
64 (40.5–121.6)
23.7 (13.1–39.5)
13.6 (11.7–29.2)
<0.001
Control
22
24 (20–31.1)
160 (132.3–211.4)
56 (34–115.7)
20.3 (16–38.7)
15 (10.6–24.4)
<0.001
PaO2 /FiO2 MP
22
407 (118)
286 (106)
264 (76)
302 (89)
302 (46)
<0.001
Control
22
420 (114)
266 (101)
307 (81)
341 (79)
337 (47)
<0.001
p = 0.03∧ Blood glucose, Mmol/L MP
22
5.3 (0.7)
9.7 (8.7–11.1)
Control
22
5.3 (0.8)
7.2 (6.8–8.6) p = 0.0006∧
10 (2.2) 8.8 (1.7)
10.4 (2.6)
8.2 (1.1)
<0.001
9.4 (1.8)
7.4 (0.9)
<0.001
p = 0.02∧
Results are presented as mean (SDs) or median (25–75 percentile). Significance level accordingly to repeated measures (ANOVA for parametric data and Friedman ANOVA for non-parametric data). ∧ Significance level of difference between groups accordingly to independent samples t-test or Mann–Whitney tests results (distinctions are statistically significant at p < 0.05). ∗
Figure 2. Medians (error bars: 95% CI for median). Dynamics of IL-6. Methylprednisolone causes significant decreasing of IL-6 concentration on 2nd, 4th hours after cardiopulmonary bypass and on 1 postoperative day.
pkg/mL; p < 0.0001] (Fig. 2). However, serum IL-10, an antiinflammatory marker, was significantly higher in the study group compared to the control group at 10 min after CPB (339 ± 213 pkg/mL vs. 97.1 ± 80.4 pkg/mL; p < 0.0001), 2 h after CPB [109.5 (34.2–135.5) pkg/mL vs. 28.3 (12.2–44.3) pkg/mL; p = 0.009], and 4 h after CPB [12.2 (5.8–22.8) pkg/mL vs. 4.4 (3.1–7.7) pkg/mL; p = 0.001] (Fig. 3).
Discussion The use of CPB in cardiac surgery potentiates the development of SIRS and endothelial activation [20,21]. Endothelial dysfunction and capillary leak are basic characteristics of several pathogenic pathways induced
Figure 3. Medians (error bars: 95% CI for median). Dynamics of IL-10. Methylprednisolone causes significant increasing of IL-10 concentration on 10 min, 2nd and 4th hours after cardiopulmonary bypass.
by CPB. Activation of complement, leukocytes, adhesion molecules, and output of cytokines and other inflammatory mediators, which accompany cardiac surgeries with CPB, is also responsible for the development of pulmonary dysfunction [22]. Despite limited evidence, the use of corticosteroids continues to be a cornerstone of treatment aimed at optimising recovery in some institutions [1], with the goal of regulating the inflammatory response. However, we found that the study group demonstrated significantly higher concentrations of ET-1 in the post-CPB period, suggesting that MP 20 mg/kg causes endothelial cell activation in patients undergoing CPB.
Another mechanism whereby corticosteroids can affect an endothelial cell is well known. Corticosteroids can inhibit production of the nitric oxide (NO) synthase by inducing the hyperglycaemia [23]. This enzyme is responsible for NO production, one of the main regulators of vascular tone. Corroborating other studies, we showed an association between the use of MP and significantly higher rates of hyperglycaemia at 10 min after CPB and at 24 h after surgery. Increased serum ET-1 level is observed in various clinical conditions, such as pulmonary artery hypertension (PAH), acute and chronic heart failure, essential hypertension, chronic kidney disease, and atherosclerosis. The benefits of ET-1 receptor blockade have been demonstrated for these diseases [14]. Furthermore, ET-1 is a prognostic factor for mortality in patients with chronic heart failure [22]. Activation of the ET-1 system has been shown in both plasma and lung tissues of patients with PAH. Although it is not unknown whether increased ET-1 plasma levels cause or are a result of PAH, studies have supported its prominent role in the development of PAH [24]. Ventilation/perfusion mismatch as a consequence of intrapulmonary right to left shunting is one of the principal causes of hypoxaemia associated with the PAH [25]. Chaney et al. have described MP administration leading to an increase in the volume of an arteriovenous bypass in the lungs as well as prolonged ventilation [26]. In this study, increased serum ET-1 was associated with a decrease of PaO2 /FiO2 on postoperative day 1. Although there is no direct dependence between this oxygenation index and serum ET-1, the increase of ET-1 due to MP administration may be clinically relevant. We also observed that perioperative MP did not significantly blunt the capillary leak syndrome, which was assessed by microalbuminuria. These results prove that both medium and small doses of corticosteroids [27] do not influence the manifestation of capillary leak syndrome in low-risk patients. Furthermore, considering the significant differences found in serum ET-1 between the groups, but no differences in microalbuminuria, we suggest that a reduction of pulmonary function is likely associated with endothelial cell activation but not with capillary leak. The use of MP significantly lowered the levels of IL-6 and at the same time increased the levels of IL-10. Thus, MP modulated the inflammatory response towards antiinflammation. Our findings support the existing data. Despite randomisation, the initial differences between the groups in EuroScore may be due to a relatively greater number of women and patients with peripheral vascular pathologies in the study group. There are several limitations in our study. First, a SwanGanz catheter was not employed and there are therefore no haemodynamic data available. Thus, we could not evaluate the correlation among serum ET-1, the rates of peripheral vascular resistance, pressure in the pulmonary artery, and intrapulmonary venous shunting. Second, this study does not elucidate the mechanism(s) of the increased serum ET-1, i.e., whether it is caused by increased
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production or decreased elimination of this molecule. Third, the overall rate of mortality observed in this study was most likely accidental and does not reflect the overall rate of mortality in our institution, which is 2.3% among the low-risk patients. Finally, our study consisted of a small sample size, low-risk patients, and relatively short CPB duration. No differences in postoperative complication rates were observed. Thus, further research involving high-risk patients is required to determine the clinical effects of increased serum ET-1 caused by MP.
Conclusion Despite an obvious anti-inflammatory effect, the use of MP in medium doses is associated with increased levels of serum ET-1. However, increased levels of ET-1 were not associated with capillary leak syndrome. The mechanism and the clinical relevance of these findings remain unknown, but it may help explain the contradictory clinical effects of steroid administration in patients undergoing CPB and the postoperative development of respiratory dysfunction.
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