Prophylactic corticosteroids for paediatric heart surgery with cardiopulmonary bypass

Ben Gibbison, José Carlos Villalobos Lizardi, Karla Isis Avilés Martínez, Daniel P Fudulu, Miguel Angel Medina Andrade, Giordano Pérez-Gaxiola, Alvin Wl Schadenberg, Serban C Stoica, Stafford L Lightman, Gianni D Angelini, Barnaby C Reeves, Ben Gibbison, José Carlos Villalobos Lizardi, Karla Isis Avilés Martínez, Daniel P Fudulu, Miguel Angel Medina Andrade, Giordano Pérez-Gaxiola, Alvin Wl Schadenberg, Serban C Stoica, Stafford L Lightman, Gianni D Angelini, Barnaby C Reeves

Abstract

Background: Corticosteroids are routinely given to children undergoing cardiac surgery with cardiopulmonary bypass (CPB) in an attempt to ameliorate the inflammatory response. Their use is still controversial and the decision to administer the intervention can vary by centre and/or by individual doctors within that centre.

Objectives: This review is designed to assess the benefits and harms of prophylactic corticosteroids in children between birth and 18 years of age undergoing cardiac surgery with CPB.

Search methods: We searched CENTRAL, MEDLINE, Embase and Conference Proceedings Citation Index-Science in June 2020. We also searched four clinical trials registers and conducted backward and forward citation searching of relevant articles.

Selection criteria: We included studies of prophylactic administration of corticosteroids, including single and multiple doses, and all types of corticosteroids administered via any route and at any time-point in the perioperative period. We excluded studies if steroids were administered therapeutically. We included individually randomised controlled trials (RCTs), with two or more groups (e.g. multi-drug or dose comparisons with a control group) but not 'head-to-head' trials without a placebo or a group that did not receive corticosteroids. We included studies in children, from birth up to 18 years of age, including preterm infants, undergoing cardiac surgery with the use of CPB. We also excluded studies in patients undergoing heart or lung transplantation, or both; studies in patients already receiving corticosteroids; in patients with abnormalities of the hypothalamic-pituitary-adrenal axis; and in patients given steroids at the time of cardiac surgery for indications other than cardiac surgery.

Data collection and analysis: We used the Covidence systematic review manager to extract and manage data for the review. Two review authors independently assessed studies for inclusion, extracted data, and assessed risks of bias. We resolved disagreements by consensus or by consultation with a third review author. We assessed the certainty of evidence with GRADE.

Main results: We found 3748 studies, of which 888 were duplicate records. Two studies had the same clinical trial registration number, but reported different populations and interventions. We therefore included them as separate studies. We screened titles and abstracts of 2868 records and reviewed full text reports for 84 studies to determine eligibility. We extracted data for 13 studies. Pooled analyses are based on eight studies. We reported the remaining five studies narratively due to zero events for both intervention and placebo in the outcomes of interest. Therefore, the final meta-analysis included eight studies with a combined population of 478 participants. There was a low or unclear risk of bias across the domains. There was moderate certainty of evidence that corticosteroids do not change the risk of in-hospital mortality (five RCTs; 313 participants; risk ratio (RR) 0.83, 95% confidence interval (CI) 0.33 to 2.07) for children undergoing cardiac surgery with CPB. There was high certainty of evidence that corticosteroids reduce the duration of mechanical ventilation (six RCTs; 421 participants; mean difference (MD) 11.37 hours lower, 95% CI -20.29 to -2.45) after the surgery. There was high-certainty evidence that the intervention probably made little to no difference to the length of postoperative intensive care unit (ICU) stay (six RCTs; 421 participants; MD 0.28 days lower, 95% CI -0.79 to 0.24) and moderate-certainty evidence that the intervention probably made little to no difference to the length of the postoperative hospital stay (one RCT; 176 participants; mean length of stay 22 days; MD -0.70 days, 95% CI -2.62 to 1.22). There was moderate certainty of evidence for no effect of the intervention on all-cause mortality at the longest follow-up (five RCTs; 313 participants; RR 0.83, 95% CI 0.33 to 2.07) or cardiovascular mortality at the longest follow-up (three RCTs; 109 participants; RR 0.40, 95% CI 0.07 to 2.46). There was low certainty of evidence that corticosteroids probably make little to no difference to children separating from CPB (one RCT; 40 participants; RR 0.20, 95% CI 0.01 to 3.92). We were unable to report information regarding adverse events of the intervention due to the heterogeneity of reporting of outcomes. We downgraded the certainty of evidence for several reasons, including imprecision due to small sample sizes, a single study providing data for an individual outcome, the inclusion of both appreciable benefit and harm in the confidence interval, and publication bias.

Authors' conclusions: Corticosteroids probably do not change the risk of mortality for children having heart surgery using CPB at any time point. They probably reduce the duration of postoperative ventilation in this context, but have little or no effect on the total length of postoperative ICU stay or total postoperative hospital stay. There was inconsistency in the adverse event outcomes reported which, consequently, could not be pooled. It is therefore impossible to provide any implications and policy-makers will be unable to make any recommendations for practice without evidence about adverse effects. The review highlighted the need for well-conducted RCTs powered for clinical outcomes to confirm or refute the effect of corticosteroids versus placebo in children having cardiac surgery with CPB. A core outcome set for adverse event reporting in the paediatric major surgery and intensive care setting is required.

Trial registration: ClinicalTrials.gov NCT00490828 NCT00590018 NCT02615262 NCT03229538.

Conflict of interest statement

BG: Dr Gibbison's institution is in receipt of project grants from the UK National Institute of Health Research and the British Heart Foundation to carry out research surrounding the topics of cardiac surgery, perioperative care and perioperative hypothalamic‐pituitary‐adrenal function including corticosteroids.

JCVL: none known.

KIAM: none known.

DPF: none known.

MAMA: none known.

GPG: none known.

AWLS: none known.

SCS: none known.

SLL: none known.

GDA: none known.

BCR: Prof Barnaby Reeves is funded (both part salary and research consumables) in part by the Cardiovascular theme of the NIHR Bristol Biomedical Research Centre.