Published online before print March 30, 2009, doi: 10.1161/CIRCULATIONAHA.108.848218
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(Circulation. 2009;119:1853-1866.)
© 2009 American Heart Association, Inc.
Cardiovascular Surgery |
Benefits and Risks of Corticosteroid Prophylaxis in Adult Cardiac Surgery
A Dose-Response Meta-Analysis
From the Department of Intensive Care Medicine, Royal Perth Hospital (K.M.H., J.A.T.), and School of Population Health, University of Western Australia (K.M.H.), Perth, Australia.
Correspondence to Dr K.M. Ho, Intensive Care Specialist and Clinical Associate Professor, Department of Intensive Care Medicine, Royal Perth Hospital, Perth, WA 6000, Australia. E-mail kwok.ho{at}health.wa.gov.au
Received January 13, 2009; accepted February 10, 2009.
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Abstract |
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Background— Cardiopulmonary bypass and cardiac surgery are associated with a significant systemic inflammatory response that may increase postoperative complications. This meta-analysis assessed whether the benefits and risks of corticosteroid use were dose dependent in adult cardiac surgery.
Methods and Results— Randomized controlled trials of the use of corticosteroid prophylaxis in adult cardiac surgery (>18 years of age) requiring cardiopulmonary bypass were selected from MEDLINE (1966 to August 1, 2008), EMBASE (1988 to August 1, 2008), and the Cochrane controlled trials register without any language restrictions. A total of 3323 patients from 50 randomized controlled trials were identified and subject to meta-analysis. Corticosteroid prophylaxis reduced the risk of atrial fibrillation (25.1% versus 35.1%; number needed to treat, 10; relative risk, 0.74; 95% confidence interval [CI], 0.63 to 0.86; P<0.01) and length of stay in the intensive care unit (weighted mean difference, –0.37 days; 95% CI, –0.21 to –0.52; P<0.01) and hospital (weighted mean difference, –0.66 days; 95% CI, –0.77 to –1.25; P=0.03) compared with placebo. The use of corticosteroid was not associated with an increased risk of all-cause infection (relative risk, 0.93; 95% CI, 0.61 to 1.41; P=0.73), but hyperglycemia requiring insulin infusion after corticosteroid prophylaxis was common (28.2%; relative risk, 1.49; 95% CI, 1.11 to 2.01; P<0.01). No additional benefits were found on all outcomes beyond a total dose of 1000 mg hydrocortisone, and very high doses of corticosteroid were associated with prolonged mechanical ventilation.
Conclusions— Evidence suggests that low-dose corticosteroid is as effective as high-dose corticosteroid in reducing the risk of atrial fibrillation and duration of mechanical ventilation but with fewer potential side effects in adult cardiac surgery.
Key Words: arrhythmia • cardiopulmonary bypass • coronary disease • inflammation • steroid • surgery
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Introduction |
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Cardiopulmonary bypass and ischemia/reperfusion injury in cardiac surgery are associated with significant activation of complement, platelets, neutrophils, monocytes, and macrophages.1 Sequestration of neutrophils and activation of coagulation, fibrinolysis, and kallikrein cascades may occur, resulting in a systemic inflammatory response syndrome.1 This systemic inflammatory response syndrome is characterized by elevated concentrations of tumor necrosis factor, C-reactive protein (CRP), interleukin (IL)-6, and IL-8 within the first few days after cardiac surgery.1–3
Clinical Perspective p 1866
Atrial fibrillation after cardiac surgery is very common and is associated with significant morbidities, including prolonged intensive care unit (ICU) and hospital stay.4 Both systemic inflammatory response and local inflammation of the atrium are believed to contribute to the pathogenesis of atrial fibrillation after cardiac surgery.3,5 The link between inflammation and atrial fibrillation after cardiac surgery is further strengthened by studies that showed that corticosteroid prophylaxis can reduce the occurrence of atrial fibrillation after cardiac surgery.4,6 Apart from atrial fibrillation, excessive systemic inflammatory response also may induce myocardial, respiratory, renal, hepatic, and intestinal injury.1,6
Corticosteroid prophylaxis in cardiac surgery has been studied extensively for >30 years,1,2,4,6 but its potential benefits and risks remain controversial and inconclusive. Small sample sizes, a wide range of doses, and different preparations of corticosteroid used in different studies are the major confounders affecting the interpretation of these studies. Although a meta-analysis on this topic exists,7 the wide range of doses of corticosteroid in the included studies was not considered.
We hypothesized that corticosteroid prophylaxis may have a dose-dependent effect on outcomes after cardiac surgery and performed a dose-response meta-analysis to assess the clinical benefits and risks of corticosteroid use in adult cardiac surgery.
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Methods |
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Search Strategy
Two researchers searched the Cochrane controlled trials register (2008, issue 2) and the EMBASE (January 1988 to August 1, 2008) and MEDLINE (1966 to August 1, 2008) databases independently. During the electronic database search, the following exploded Medical Subject Heading (MeSH) terms were used: "steroid," "corticosteroid," "glucocorticoid," "dexamethasone," "prednisolone," "prednisone," "methylprednisolone," "hydrocortisone" with "cardiac surgery," "cardiopulmonary bypass," or "heart surgery." The search was limited to clinical trials, letters, editorial, reviews, or randomized controlled trials. The reference lists of related editorials, reviews, and original articles identified were searched for relevant trials. Finally, the Websites of the International Network of Agencies of Health Technology Assessment and International Society of Technology Assessment in Health Care were searched to ensure that all suitable trials were included. No language restrictions existed for inclusion in this meta-analysis.
Selection Criteria and Validity Assessment
Only randomized controlled clinical trials comparing corticosteroid with placebo or equal volume of normal saline, initiated either before or at the time of cardiopulmonary bypass, in adult (>18 years of age) cardiac surgery were included. Studies that used unequal concurrent medical therapies or studies that evaluated corticosteroid in off-pump cardiac surgery were excluded. Two independent reviewers examined all identified trials to confirm that they fulfilled the inclusion criteria. They examined and recorded the trial characteristics and outcomes independently using a predesigned data abstraction form. This abstraction form was used to record information regarding the quality of the trial such as allocation concealment, randomization method, blinding of treatment, and inclusion and exclusion criteria. The grading of allocation concealment was based on the Cochrane approach, ie, adequate, uncertain, or clearly inadequate. The 2 independent reviewers had no disagreements on the data extracted.
Outcomes of Interest
The proportion of patients with new-onset atrial fibrillation in the postoperative period was chosen as the main outcome of interest because atrial fibrillation is common and associated with other significant morbidities after cardiac surgery.4 The other outcomes assessed included the proportion of patients who developed infections after cardiac surgery, hyperglycemia requiring insulin infusion, hospital mortality, CRP/IL-6/IL-8 concentrations at 24 hours after cardiopulmonary bypass or surgery, duration of mechanical ventilation, and length of ICU and hospital stay.
Statistical Analysis
The differences in categorical outcomes were reported as relative risk (RR) with 95% confidence interval (CI) using a random-effects model. The differences in continuous outcomes were reported as weighted mean difference (WMD) also using a random-effects model.
The dose response of corticosteroid was assessed by two methods. First, the trials were stratified into 3 broad dose strata. They were classified as low dose if the total dose of corticosteroid used was <1000 mg hydrocortisone or equivalent, as medium dose if the total dose used was between 1000 and 10 000 mg hydrocortisone or equivalent, and as high dose if the total dose used was >10 000 mg hydrocortisone or equivalent. These cut points were chosen so that the doses of corticosteroid used in high-dose stratum were at least 10 times higher than those in the low-dose stratum. For studies that used prednisolone/prednisone, methylprednisolone, or dexamethasone, the total dose of corticosteroid used was converted to an equivalent dose of hydrocortisone with similar glucocorticoid effect. The dose conversion factors for prednisolone/prednisone, methylprednisolone, and dexamethasone to hydrocortisone were 4, 5, and 26.7, respectively (http://www.globalrph.com/steroid.cgi). To interpret subtle dose-response pattern, individual studies were listed sequentially according to the total dose of corticosteroid used in all forest plots, with the studies using the smallest dose of corticosteroid at the top. The interactions among the 3 dose strata were then tested by ratio of RRs for categorical outcomes and mean difference for continuous outcomes.8,9 Second, the dose of corticosteroid was used as a continuous "predictor" in meta-regression to assess whether the dose of corticosteroid affected the RRs of atrial fibrillation between the studies.
The presence of heterogeneity between trials was assessed by the 
2 statistics, and the extent of inconsistency was assessed using I2 statistics.10 An I2>40% was regarded as significant heterogeneity in this study. Sensitivity analyses were conducted by restricting the analysis to trials that were double blinded and with adequate allocation concealment, were published after 1997, did not use routine postoperative β-blockers, or included only coronary artery bypass graft surgery. Publication bias was assessed by funnel plot with the risk of atrial fibrillation used as an end point. The "trim and fill" method was used to adjust for any potential publication bias.11 Data were analyzed by Review Manager (version 4.2.6 for Windows, The Cochrane Collaboration, Oxford, UK, 2003), and meta-regression and trim and fill adjustment were performed by Comprehensive Meta Analysis (version 2.2.034, 2006; Biostat). A value of P<0.05 was regarded as significant in this meta-analysis.
The authors have full access to and take responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.
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Results |
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Characteristics of the Included Studies
A total of 3323 patients from 50 randomized controlled trials in 16 countries were identified and subject to meta-analysis (Figure 1).1,2,4,6,12–57 All studies except 1 were published in English.17 The total dose of corticosteroid used was quite variable and ranged between 214 and 72 000 mg hydrocortisone. Routine postoperative β-blocker therapy to prevent atrial fibrillation was used in only 2 studies.4,51 Seventeen studies had adequate allocation concealment; 26 studies used double or triple blinding; and 14 studies had both adequate allocation concealment and double blinding.4,15,20,28,37,38,41–43,49–52,57 The characteristics of the included trial are described in the Table
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Effects of Corticosteroid Prophylaxis on Inflammatory Markers
Corticosteroid prophylaxis was associated with a reduction in concentrations of some inflammatory markers 24 hours after surgery. CRP concentrations (WMD, –44.2 mg/L; 95% CI, –15.4 to –72.9; P<0.01; I2=90.7%) and IL-6 concentrations (WMD, –148.0 pg/mL; 95% CI, –114.8 to –181.1; P<0.01; I2=98.1%) were significantly reduced after corticosteroid prophylaxis. Also, a suggestion was found that IL-8 was mildly reduced after corticosteroid (WMD, –8.2 pg/mL; 95% CI, –17.0 to 0.60; P=0.07; I2=97.0%). Significant heterogeneity was present in the concentrations of these inflammatory markers between the included studies, but no significant differences between different dose strata were observed.
Effects of Corticosteroid Prophylaxis on Atrial Fibrillation, Mortality, All-Cause Infection, and Hyperglycemia
Corticosteroid prophylaxis was associated with a significant reduction in the risk of atrial fibrillation (25.1% versus 35.1%; number needed to treat, 10; 95% CI, 7 to 19; RR, 0.74; 95% CI, 0.63 to 0.86; P<0.01; I2=0.1%; Figure 2). Meta-regression showed that the doses of corticosteroid were not significantly related to the variations in the RR of atrial fibrillation in the pooled studies (Figure 3). The RR ratios between the low-dose or moderate-dose stratum and the high-dose stratum were 0.86 (95% CI, 0.53 to 1.37) and 0.72 (95% CI, 0.43 to 1.21), respectively, suggesting that the RR reduction in atrial fibrillation was not significantly different between the 3 dose strata.
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Hyperglycemia requiring insulin infusion was common (28.2%) after corticosteroid prophylaxis (RR, 1.49; 95% CI, 1.11 to 2.01; P<0.01; I2=36.1%; Figure 4), but corticosteroid did not appear to increase the risk of all-cause infection (RR, 0.93; 95% CI, 0.61 to 1.41; P=0.73; I2=0%; Figure 5) or mortality (RR, 0.72; 95% CI, 0.45 to 1.14; P=0.16; I2=0; Figure 6). Meta-regression showed that the doses of corticosteroid were not significantly related to the variations in the RR of infections in the pooled studies (slope of the regression line, 1.00; 95% CI, 0.99 to 1.01; P=0.89). No significant heterogeneity in these clinical outcomes was found between the studies.
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Effects of Corticosteroid Prophylaxis on Duration of Mechanical Ventilation, Length of ICU, and Hospital Stay
Corticosteroid prophylaxis was associated with a reduction in duration of mechanical ventilation when all trials were pooled together (WMD, –0.68 hours; 95% CI, –0.03 to –1.33; P=0.04; Figure 7). However, the effect of high-dose corticosteroid on duration of mechanical ventilation was very different from the effect of lower doses of corticosteroid. The high-dose stratum was associated with an increased duration of mechanical ventilation without significant heterogeneity (WMD, 2.1 hours; 95% CI, 1.76 to 2.52; P<0.01; I2=0%). Further analysis of this dose-response relationship showed that the effect of high-dose corticosteroid was significantly different from either the low-dose (mean difference, 4.9 hours; 95% CI, 0.59 to 9.25; P=0.03) or medium-dose (mean difference, 3.09 hours; 95% CI, 2.17 to 3.92; P<0.01) corticosteroid stratum. No significant difference was found, however, between the low- and medium-dose strata in this outcome.
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Corticosteroid prophylaxis was associated with a reduction in length of ICU (WMD, –0.37 days; 95% CI, –0.21 to –0.52; P<0.01; I2=89.1%) and hospital stay (WMD, –0.66 days; 95% CI, –0.77 to –1.25; P=0.03; I2=77.2%) with no significant difference between the dose strata. Heterogeneity in these 2 outcomes between the pooled studies was significant.
Sensitivity Analyses and Publication Bias
After the analysis was restricted to studies that both were double blinded and had adequate allocation concealment, the effect of corticosteroid on atrial fibrillation remained unchanged (RR, 0.69; 95% CI, 0.57 to 0.84; P<0.01; I2=0%). Restricting the analysis to studies that did not use routine postoperative β-blocker therapy, were published after 1997, or recruited only coronary artery bypass graft surgery also did not change the effects of corticosteroid on risk of atrial fibrillation and all-cause infection. The funnel plot suggested the possibility of a small publication bias (Figure 8). With the trim and fill method, the adjusted effect of corticosteroid on atrial fibrillation was slightly more conservative but remained significant (RR, 0.75; 95% CI, 0.63 to 0.89; P<0.01).
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Discussion |
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This meta-analysis showed that corticosteroid prophylaxis was effective in reducing the risk of atrial fibrillation and that this benefit was not significantly different between different doses of corticosteroid. Corticosteroid prophylaxis was associated with an increased risk of hyperglycemia requiring insulin infusion, and at high doses (equivalent to >10 000 mg hydrocortisone), it was also associated with an increased duration of mechanical ventilation.
The systemic inflammatory response after cardiopulmonary bypass and cardiac surgery is usually short-lived, but it can be severe and prolonged in some patients.1 The clinical effects of corticosteroid are known to be dose dependent; thus, different doses are often used for different medical conditions and titrated to the magnitude of antiinflammatory action required. Although corticosteroid prophylaxis in adult cardiac surgery has been studied extensively for >30 years, its role remains controversial, and the optimal dose remains uncertain. To the best of our knowledge, this is the first meta-analysis that assessed the dose-response relationship of corticosteroid in adult cardiac surgery. Our results showed that corticosteroid had no adverse effect on mortality and was effective in reducing atrial fibrillation. This latter beneficial effect of corticosteroid was not significantly different between different doses. Previous studies have shown that corticosteroid prophylaxis may offer some beneficial effects to patients who require cardiopulmonary bypass through a number of different mechanisms. These may include an improvement in myocardial or pulmonary cell integrity, a reduction in the expression of endothelial adhesion molecules, complement activation, and cytokine release.58 It is highly possible that only low doses of corticosteroid are required to activate these protective mechanisms to attenuate the systemic and atrial inflammation associated with cardiopulmonary bypass. Our results also showed that very high doses of corticosteroid did not offer any additional benefits and might hinder weaning of mechanical ventilation after surgery. The potential adverse effects of high-dose corticosteroid on sodium and water clearance, risk of respiratory tract infections, and intrapulmonary shunt may explain our results.12,13
Corticosteroid can induce hyperglycemia, and our results confirmed that corticosteroid prophylaxis was associated with an increased risk of hyperglycemia requiring insulin infusion. None of the studies in the low-dose stratum reported this outcome; thus, whether lower doses of corticosteroid (<1000 mg hydrocortisone) will have less adverse effect on glucose hemostasis remains uncertain. Recent evidence suggests that tight blood glucose control by an insulin clamp technique can have significant antiinflammatory effect during cardiopulmonary bypass.59 Whether the benefits of corticosteroid can be further enhanced with this new technique remains uncertain but merits further investigation.
Corticosteroid can suppress the normal immune response and may potentially increase the risk of infection after surgery.54 Our results are reassuring, albeit still limited, that a short course of corticosteroid prophylaxis (<24 to 72 hours) did not appear to increase the risk of perioperative infection. However, the sample size of our data on this outcome (n=1608) has a power of only 80% to exclude a 3.5% absolute increase in risk of all-cause infections if the baseline infection rate of the control group is 5%.
If corticosteroid prophylaxis is truly effective in reducing complications related to the inflammatory response of cardiopulmonary bypass, corticosteroid prophylaxis may in fact represent a very cost-effective preventive strategy in adult cardiac surgery. Because low-dose corticosteroid was less likely to have an adverse effect on the duration of mechanical ventilation than higher doses, low-dose corticosteroid (<1000 mg hydrocortisone or equivalent) is likely to be the most cost-effective option. Intravenous hydrocortisone is inexpensive (US $2 per 100 mg), and the estimated cost of preventing 1 atrial fibrillation is less than US $200 if we use less than a total dose of 1000 mg hydrocortisone. Accurate cost-effective analysis from our data, however, is not possible because of the significant heterogeneity in the duration of mechanical ventilation and length of ICU and hospital stay among the pooled trials.
This study has some limitations. First, meta-analysis is prone to bias inherited from the original studies and to publication bias. However, the direction and magnitude of our results were not significantly different after we restricted the analysis to higher-quality studies (n=14) and adjusted for the potential publication bias with the trim and fill method. Second, different studies used different doses, preparations, and durations of corticosteroid prophylaxis during the perioperative period. Although we have adjusted for the different doses of corticosteroid between the studies, the optimal duration of therapy remains uncertain. Furthermore, the variable duration of follow-up and incomplete monitoring for atrial fibrillation in some of the pooled studies may have affected the accuracy of the incidence of atrial fibrillation reported in this study. Third, significant heterogeneity limits the generalizability of the effects of corticosteroid on duration of ICU and hospital stay reported in this meta-analysis. Fourth, detailed cost-effectiveness was not reported in any of the pooled studies. Corticosteroid is inexpensive, but accurate cost-effective analysis should also include other indirect costs such as insulin for hyperglycemia, stress ulcer prophylaxis, use of amiodarone for atrial fibrillation, blood glucose monitoring, and other adverse outcomes, including bleeding, stroke, and altered mental function. Evidence suggests that corticosteroid also may offer some benefits on these patient-centered outcomes.7,52 Finally, almost all the pooled studies excluded patients undergoing emergency cardiac surgery and patients with diabetes mellitus or other organ failure. Thus, the benefits and risks of corticosteroid prophylaxis reported in this study may not be generalizable to these patients.
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Conclusions |
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Current evidence suggests that low-dose corticosteroid is as effective as high-dose corticosteroid in reducing the risk of atrial fibrillation but with fewer potential side effects in adult cardiac surgery. Large randomized controlled trials are needed to confirm the cost-effectiveness of low-dose corticosteroid prophylaxis in adult cardiac surgery.
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Acknowledgments |
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We would like to thank Professor Waleed Hamimy for his assistance in retrieving 2 Egyptian references included in this study.
Source of Funding
The study was solely funded by Department of Intensive Care Medicine, Royal Perth Hospital. The funding source had no role in the collection, analysis, and interpretation of the data or in the decision to submit the manuscript for publication.
Disclosures
None.
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  W. L. Baker, C. M. White, and C. I. Coleman Letter by Baker et al Regarding Article, "Benefits and Risks of Corticosteroid Prophylaxis in Adult Cardiac Surgery: A Dose-Response Meta-Analysis" Circulation, November 17, 2009; 120(20): e163 - e163. [Full Text] [PDF]
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 Corticosteroid Prophylaxis in Cardiac Surgery Journal Watch Cardiology, May 13, 2009; 2009(513): 3 - 3. [Full Text]
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