Clinical benefit of steroid use in patients
undergoing cardiopulmonary bypass: a
meta-analysis of randomized trials
Richard P. Whitlock1,2*, Simon Chan3, P.J. Devereaux4,5, Jack Sun1,
Fraser D. Rubens6, Kristian Thorlund7, and Kevin H.T. Teoh1
1Division of Cardiac Surgery, McMaster University, 202-304 Victoria Avenue North, Hamilton, Ontario, Canada L8L 5G4;2Division of Critical Care Medicine, McMaster University,
Hamilton, Ontario, Canada;3McMaster University, Hamilton, Ontario, Canada;4Department of Medicine, McMaster University, Hamilton, Ontario, Canada;5Department of Clinical
Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada;6Division of Cardiac Surgery, University of Ottawa Heart Institute, Ottawa, Ontario, Canada;
and7Copenhagen Trial Unit, Copenhagen University Hospital, Copenhagen, Denmark
Received 14 January 2008; revised 29 May 2008; accepted 25 June 2008; online publish-ahead-of-print 28 July 2008
We sought to establish the efficacy and safety of prophylactic steroids in adult patients undergoing cardiopulmonary bypass (CPB). We per-
formed a meta-analysis of randomized trials reporting the effects of prophylactic steroids on clinical outcomes after CPB. Outcomes exam-
ined were mortality, myocardial infarction, neurological events, new onset atrial fibrillation, transfusion requirements, postoperative bleeding,
duration of ventilation, intensive care unit (ICU) stay, hospital stay, wound complications, gastrointestinal complications, and infectious com-
plications. We included 44 trials randomizing 3205 patients. Steroids reduced new onset atrial fibrillation [relative risk (RR) 0.71, 95% con-
fidence interval (CI) 0.59 to 0.87], postoperative bleeding [weighted mean difference (WMD) 299.6 mL, 95% CI 2149.8 to 249.3], and
duration of ICU stay (WMD 20.23 days, 95% CI 20.40 to 20.07). Length of hospital stay was also reduced (WMD 20.59 days, 95%
CI 21.17 to 20.02), but this result was less robust. A trend towards reduction in mortality was observed (RR 0.73, 95% CI 0.45 to
1.18). Randomized trials suggest that perioperative steroids have significant clinical benefit in CPB patients by decreasing the risk of new
onset atrial fibrillation, while results are encouraging for reducing bleeding, length of stay, and mortality. These data do not raise major
safety concerns, however, a sufficiently powered trial is warranted to confirm or refute these findings.
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Steroids † Cardiac surgery † Meta-analysis † Cardiopulmonary bypass † Inflammatory response † Clinical
Cardiopulmonary bypass (CPB) exposes the body to foreign
surfaces and non-physiologic blood flow. This initiates a systematic
inflammatory response that is intensified by the ischaemia-
reperfusion injury that can occur when weaning from CPB.1–3
The increased endothelial permeability and free radical damage
to vessels and parenchyma that results is due to a complex inter-
play between platelets, neutrophils, monocytes, macrophages,
coagulation, fibrinolytic cascades, and kallikrein cascades.1–5This
inflammatory reaction may contribute to postoperative compli-
cations including ventricular dysfunction and multiorgan failure.
Studies demonstrate steroids are effective in attenuating the
inflammation secondary to CPB.5Despite this, many surgeons
remain unenthusiastic about the routine use of perioperative
steroids in patients undergoing CPB. This may be because many
of the existing studies are underpowered to assess clinically
important outcomes, focusing on surrogate outcomes such as
markers of inflammation. Further, physicians fear potential
adverse effects associated with their use.
Accurate understanding of the impact of steroid therapy in
patients undergoing CPB requires a systematic, comprehensive,
and unbiased accumulation and summary of the available evidence.
We therefore undertook a systematic review and meta-analysis of
randomized controlled trials (RCT) to address the following ques-
tion: What is the efficacy and safety of perioperative steroids in
patients undergoing CPB?
* Corresponding author. Tel: þ1 905 527 4322, Fax: þ1 905 523 4885, Email: firstname.lastname@example.org
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2008. For permissions please email: email@example.com.
European Heart Journal (2008) 29, 2592–2600
by guest on September 13, 2015
A protocol was prospectively developed outlining the criteria for trial
selection, outcomes of interest, approach to assessing trial quality, and
the statistical methodology.
We included RCTs that compared perioperative steroid treatment
with a control group (i.e. standard care or placebo) among adults
undergoing CPB reporting at least one of the a priori defined out-
comes, having at least one event occur in the treatment or control
group. RCTs were eligible regardless of their primary objective or
language of publication. We excluded trials only published in abstract
We undertook an electronic search of Embase, Medline, Cochrane,
CINAHL, and OVID using the search terms cardiac surgery, cardiac
surgical procedure, open heart surgery, coronary artery bypass,
mitral valve, aortic valve, heart valve, cardiopulmonary bypass, extra-
corporeal circulation, preoperative, and prophylactic, in combination
with generic and trade names of steroid preparations. We hand-
searched the reference lists from eligible trials. Finally, we used the
‘see related articles’ feature for key publications in Pubmed.
All title and abstracts from the electronic search were uploaded into
TrialStat SRS version 3.0 and were evaluated by two independent
investigators (k ¼ 0.96). The consensus process to resolve disagree-
ments required researchers to discuss the decision; in all cases one
person recognized an error.
Data extraction and quality assessment
We abstracted descriptive data (e.g. patient population, intervention)
and markers of validity (e.g. blinding) from all trials. Outcomes of inte-
rest were mortality, myocardial infarction (MI), neurological events,
new onset atrial fibrillation, transfusion requirements, postoperative
bleeding, duration of ventilation, intensive care unit (ICU) stay, and
hospital stay, wound, gastrointestinal (GI), and infectious compli-
cations. We accepted the authors’ definitions for clinical outcomes.
Postoperative bleeding was defined as 24 h chest tube output or
total chest tube output, which ever was reported.
Two independent investigators abstracted data and resolved differ-
ences using the consensus process mentioned earlier. We attempted
to obtain all missing data from the corresponding author. We used
the Jadad criteria to evaluate the trials included in our meta-analysis
(?3 points was considered high quality).6
For each trial we calculated the relative risk (RR) of each binary
outcome and the weighted mean difference (WMD) for continuous
variables and their 95% confidence intervals (CI), comparing patients
receiving perioperative steroid therapy with patients receiving
control therapy. We pooled the effect estimate of the outcomes
using the DerSimonian and Liard random effects model.
The I2value was calculated as a measure of heterogeneity for each
outcome analysis. An I2of ,25% was considered low.7A priori
hypotheses related to blinding status, surgery type [i.e. isolated coron-
ary artery bypass graft (CABG) surgery vs. other (valve or combined)],
steroid used (i.e. methylprednisolone vs. other), and steroid dose (i.e.
(1.5gm methylprednisolone or equivalent in 24 h or repeated dosing
for .24 h vs. ,1.5 gm in 24 h) were explored to explain potential
heterogeneity (I2value (25%).
In studies reporting the median and quartiles, the median was
assumed to most accurately represent the central tendency and was
treated as the mean. The distribution was assumed to be normal
with a z-value of +0.68 corresponding to the reported 25th and
75th percentiles. In this manner, the standard deviation was calculated.
The variances for three data points were imputed by using the mean of
the other studies. In studies reporting multiple steroid treatment
groups, the results of the groups were pooled.
We conducted a sensitivity analysis to examine the robustness of
the results. The analyses were repeated after (i) removing those
studies with imputed data and (ii) including only the high-quality
studies. To evaluate potential publication bias we constructed a
funnel plot for the outcomes and visually inspected it for asymmetry.
All statistical calculations were performed using RevMan 4.2.8
(Cochrane Collaboration, Oxford).
The sample size required for a meta-analysis is at least as large as
that of a single optimally powered RCT and can be determined
using the heterogeneity-corrected optimal information size. If the
meta-analysis does not surpass its heterogeneity-corrected optimal
information size then it is essentially similar to an interim analysis of
a single RCT. Because statistically significant findings in this situation
are prone to false positive findings, we used methods adapted from
meta-analysis to assess the reliability and conclusiveness of the avail-
able evidence. We used the optimal information size to construct a
Lan DeMets sequential monitoring boundary, analogous to interim
monitoring in an RCT.8The sequential ordering of the studies was
based on the publication date of the manuscript. In this way, we
assessed whether the evidence for significant outcomes that had not
surpassed their optimal information size were reliable and conclusive.
Selection of included studies
The process of trial selection is presented in Figure 1. Forty-four
RCTs published between the years 1977 and 2007 fulfilled our eli-
gibility criteria. Table 1 summarizes the characteristics of the
included trials. The median sample size of the RCTs was 51
patients (range 13–295). Twenty-eight trials focused on isolated
CABG patients, three on isolated valve patients, seven on CABG
and valve patients, and six on all CPB patients. Treatment proto-
cols varied in duration and formulation including dexamethasone,
methylprednisolone, hydrocortisone, and prednisolone.
Twenty-nine of the trials reported a double-blind design. Twenty-
six of the trials were of high quality by the criteria of Jadad et al.
(score ?3). The mean Jadad score for all the trials was 2.7+
1.4. The Jadad scores are presented in Table 1.
Table 2 presents the results of the meta-analysis for each outcome.
There were few events reported for most outcomes, limiting infer-
ences possible about whether steroids affect outcomes.
Clinical benefit of steroid use in patients undergoing CPB
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28. Harig F, Feyrer R, Mahmoud FO, Blum U, von der Emde J. Reducing the post-
pump syndrome by using heparin-coated circuits, steroid, or aprotonin. Thorac
Cardiovasc Surg 1999;47:111–118.
29. Jansen NJ, van Oeveren W, van den BL, Oudemans-van Straaten HM,
Stoutenbeek CP, Joen MC, Roosendaal KJ, Eysman L, Wildevuur CR. Inhibition
by dexamethasone of the reperfusion phenomena in cardiopulmonary bypass.
J Thorac Cardiovasc Surg 1991;102:515–525.
30. Kilger E, Weis F, Briegel J, Frey L, Goetz AE, Reuter D, Nagy A, Schuetz A,
Lamm P, Knoll A, Peter K. Stress doses of hydrocortisone reduce severe systemic
inflammatory response syndrome and improve early outcome in a risk group of
patients after cardiac surgery. Crit Care Med 2003;31:1068–1074.
Effect of dexamethasone on peri-operative renal function impairment during
cardiac surgery with cardiopulmonary bypass. Br J Anaesth 2004;93:793–798.
32. Liakopolous OJ, Schmitto JD, Kazmaier S, Brauer A, Quintel M, Schoendube FA,
Dorge H. Cardiopulmonary and systemic effects of methylprednisolone in
patients undergoing cardiac surgery. Ann Thorac Surg 2007;84:110–119.
33. Mayumi H, Zhang QW, Nakashima A, Masuda M, Kohno H, Kawachi Y, Tasui H.
Synergistic immunosuppression caused by high-dose methylprednisolone and car-
diopulmonary bypass. Ann Thorac Surg 1997;63:129–137.
34. McBride WT, Allen S, Gormley SM, Young IS, McClean E, MacGowan SW,
Elliott P, McMurray TJ, Armstrong MA. Methylprednisolone favourably alters
plasma and urinary cytokine homeostasis and subclinical renal injury at cardiac
surgery. Cytokine 2004;27:81–89.
35. Morton JR, Hiebert CA, Lutes CA, White RL. Effect of methylprednisolone on
myocardial preservation during coronary artery surgery. Am J Surg 1976;131:
36. Niazi Z, Flodin P, Joyce L, Smith J, Mauer H, Lillehei RC. Effects of glucocorticos-
teroids in patients undergoing coronary artery bypass surgery. Chest 1979;76:
37. Oliver WC Jr, Nuttall GA, Orsulak TA, Bamlet WR, Abel MD, Ereth MH,
Schaff HV. Hemofiltration but not steroids results in earlier tracheal extubation
following cardiopulmonary bypass: a prospective, randomized double-blind trial.
38. Prasongsukarn K, Abel JG, Jamieson WRE, Cheung A, Russell JA, Walley KR,
Lichtenstein SV. The effects of steroids on the occurrence of post-operative
atrial fibrillation after coronary artery bypass grafting surgery: a prospective ran-
domized trial. J Thorac Cardiovasc Surg 2005;130:93–98.
39. Rao G, King J, Ford W, King G. The effects of methylprednisolone on the com-
plications of coronary artery surgery. Vasc Surg 1977;11:1–7.
40. Rubens FD, Nathan H, Labow R, Williams KS, Wozny D, Karsh J, Ruel M,
Mesana T. Effects of Methylprednisolone and a biocompatible copolymer circuit
on blood activation during cardiopulmonary bypass. Ann Thorac Surg 2005;79:
41. Rumalla V, Calvano SE, Spotnitz AJ, Krause TJ, Lin E, Lowry SF. The effects of glu-
cocorticoid therapy on inflammatory responses to coronary artery bypass graft
surgery. Arch Surg 2001;136:1039–1044.
42. Sano T, Morita S, Masuda M, Yasui H. Minor infection encouraged by steroid
administration during cardiac surgery. Asian Cardiovasc Thorac Ann 2006;14:
43. Schurr UP, Zund G, Hoerstrup SP, Grunerfelder J, Maly FE, Vogt PR, Turina MI.
Preoperative administration of steroids: influence on adhesion molecules and
cytokines after cardiopulmonary bypass. Ann Thorac Surg 2001;72:1316–1320.
44. Tassani P, Richter JA, Barankay A, Braun SL, Haehnel C, Spaeth P, Schad H,
Meisner H. Does high-dose methylprednisolone in aprotinin-treated patients
attenuate the systemic inflammatory response during coronary artery bypass
grafting procedures? J Cardiothorac Vasc Anesth 1999;13:165–172.
45. Toft P, Christiansen K, Tonnesen E, Nielsen CH, Lillevang S. Effect of methylpred-
nisolone on the oxidative burst activity, adhesion molecules and clinical outcome
following open heart surgery. Scand Cardiovasc J 1997;31:283–288.
46. Turkoz A, Cigli A, But K, Sezgin N, Turkoz R, Gulcan O, Ersoy MO. The effects of
aprotinin and steroids on generation of cytokines during coronary artery surgery.
J Cardiothorac Vasc Anesth 2001;15:603–610.
47. Vallejo Jl, Gimenez-Fernandez R, Mainer JL, Rivera R. Clinical analysis of the pro-
tective effect of methylprednisolone on the heart. Rev Esp Cardiol 1977;30:
48. Volk T, Schmutzler M, Engelhardt L, Docke WD, Volk HD, Konertz W, Kox WJ.
Influence of aminosteroid and glucocorticoid treatment on inflammation and
immune function during cardiopulmonary bypass. Crit Care Med 2002;29:
49. Volk T, Schmutzler M, Engelhardt L, Pantke U, Stangl K, Grune T, Wernecke KD,
Konertz W, Kox WJ. Effects of different steroid treatment on reperfusion-
associated production of reactive oxygen species and arrythmias during coronary
surgery. Acta Anaesthesiol Scand 2003;47:667–674.
50. Wan S, LeClerc JL, Huynh CH, Schmartz D, DeSmet JM, Yim APC, Vincent JL.
Does steroid pretreatment increase endotoxin release during clinical cardiopul-
monary bypass. J Thorac Cardiovasc Surg 1999;117:1004–1008.
51. Weis F, Kilger E, Roozendaal B, de Quervain DJF, Lamm P, Schmidt M, Schmolz M,
Briegel J, Schelling G. Stress doses of hydrocortisone reduce chronic stress
symptoms and improve health-related quality of life in high-risk patients
after cardiac surgery: a randomized study. J Thorac Cardiovasc Surg 2006;131:
52. Yared JP, Starr NJ, Torres FK, Bashour CA, Bourdakos G, Piedmonte M,
Michener JA, Davis JA, Rosenberger TE. Effects of single dose, postinduction
dexamethasone on recovery after cardiac surgery. Ann Thorac Surg 2000;69:
53. Yared JP, Bakri MH, Erzurum SC, Moravec CS, Laskowski DM, Van Wagoner DR,
Mascha E, Thornton J. Effect of dexamethasone on atrial fibrillation after cardiac
surgery: prospective, randomized, double-blind, placebo controlled trial.
J Cardiothorac Vasc Anesth 2007;21:68–75.
54. Yilmaz M, Ener S, Akalin H, Sagdic K, Serdar OA, Cengiz M. Effect of low-dose
methyl prednisolone on serum cytokine levels following extracorporeal circula-
tion. Perfusion 1999;14:201–206.
R.P. Whitlock et al.
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