In this multicenter observational analysis, we did not find a significant benefit associated with any regimen of methylprednisolone examined in neonates undergoing heart surgery. Corticosteroids are administered to patients undergoing heart surgery with the aim of attenuating the systemic inflammatory response and capillary leak syndrome that can be triggered by cardiopulmonary bypass.1,16,17
Although numerous studies have reported that corticosteroids are effective at reducing levels of certain inflammatory markers in this setting, mounting evidence questions the benefit of corticosteroids in relation to clinical outcomes.5,6,8
In a recent meta-analysis, corticosteroids were not associated with any difference in duration of ventilation or LOS.5
However, data from only 4 trials (127 patients) could be analyzed because of heterogeneity between studies.5
There were too few deaths to evaluate mortality and or other safety outcomes.5
An observational analysis performed by our group supported the findings of the meta-analysis in a large cohort of >45
We found no benefit of corticosteroids in relation to duration of ventilation or LOS.6
The large sample size permitted analysis of mortality, which did not differ between groups.6
This analysis grouped all corticosteroids used in clinical practice together and did not differentiate outcomes according to specific regimens.6
Previous studies have suggested that corticosteroid regimens involving more than 1 dose may be more effective.4,7,18
Lodge et al found that a 2-dose regimen was more effective in reducing alveolar-arterial gradient, pulmonary vascular resistance, and extracellular fluid accumulation in piglets exposed to cardiopulmonary bypass.7
Clarizia et al4
retrospectively evaluated 221 children undergoing high-risk cardiac operations at their institution and found that a 2-dose regimen was associated with a greater reduction in the duration of ventilation and LOS. Evaluation of mortality was limited because of the small number of events. However, the results of these studies differ from a recent clinical trial. Graham et al8
randomly assigned 76 neonates to 2-dose versus single-dose methylprednisolone. There was no difference in the primary end point of low cardiac output syndrome, or any difference in LOS or duration of ventilation. The 2-dose regimen was associated with higher postoperative serum creatinine and reduced diuresis.8
There were too few deaths to assess mortality, and the study did not include a placebo control group.8
Thus, it unclear whether both regimens examined were equally effective in comparison with control or whether neither was effective.
The current study builds upon these recent analyses through analyzing a large multicenter cohort of neonates undergoing heart surgery, which enables evaluation of more rare end points. In addition, the inclusion of a control or “no-steroid” group also permits the assessment of outcome associated with various methylprednisolone regimens in relation to no treatment. We did not detect a significant benefit associated with any of the regimens of methylprednisolone examined. It has been previously hypothesized that corticosteroids may not completely address the multifaceted inflammatory response after cardiopulmonary bypass. Several studies have shown that, whereas corticosteroids can reduce levels of certain inflammatory markers, this effect is not universal, and other markers of inflammation may not be impacted.2,19
In addition, consistent with our previous analysis of a larger cohort of patients, we found that methylprednisolone was associated with increased postoperative infection.6
This effect was seen only in the lower-risk surgical group. These lower-risk operations are generally associated with shorter cardiopulmonary bypass times and reduced inflammatory response such that little benefit from the anti-inflammatory properties of corticosteroids may be expected, and the potential risks of therapy may have a relatively greater impact on outcome.6
Finally, this study demonstrates the power of linkage and analysis of large pediatric data sets to answer questions not able to be evaluated by using single-center data, or individual data sets alone.9
Multicenter databases can provide adequate power to overcome the rarity and heterogeneity of disease. These data sources also allow analysis of practice variation from center to center, and how practice variation impacts outcome. Many types of outcomes and comparative effectiveness studies can be conducted (with additional analyses possible when databases are linked), and these databases can also provide information that may aid in better planning future studies. In particular, the study of perioperative corticosteroids highlights many of the difficulties in conducting pediatric clinical research and the limitations of available methodologies, including the heterogeneity of disease, the limitations of single-center studies, and need for multicenter data to provide adequate power. It is also often true, as in this case, that new therapies become widely adopted into routine pediatric practice, based on extrapolation from adults or small pediatric studies, making conducting more rigorous large-scale studies difficult due to the lack of clinical equipoise.20
However, more recent analyses of large data sets have shown that there is in fact widespread variation in the way corticosteroids are used in this setting, and have questioned the clinical benefit associated with corticosteroids.1,6
These data support the feasibility and necessity of a large randomized trial.
This study is subject to the limitations of any observational analysis, including selection bias and the potential impact of confounders. We attempted to account for known patient and center confounders, but there may be other unmeasured factors that impact methylprednisolone receipt and/or outcome. Because of the limitations of the data sources, we were not able to evaluate the specific dose or timing of methylprednisolone in relation to surgery, other than assessment of the day of administration. It is possible that some patients may receive two doses on the day of surgery. If 2 doses were more effective than 1, this could bias our results toward finding a spurious association of regimens involving administration on the day of surgery alone with clinical benefit. However, we found that none of the corticosteroid regimens examined were associated with benefit, and the results of the primary analysis were unchanged when we restricted the cohort to patients who were first cases in the operating room. We were also not able to investigate certain outcomes not collected in detail in the databases, including fluid balance, renal function, blood loss, details and precise duration of mechanical ventilation, and dosage of inotropic agents. In addition, while this represents the largest study of corticosteroids in this population to date, not all US centers were included; and thus the generalizability of these findings requires further study. We did perform a sensitivity analysis within our study cohort and found that our results did not appear to be sensitive to the inclusion of certain patients/centers. In this analysis we also chose to focus on neonates, and our results may not be generalizable to all children undergoing heart surgery. Finally, we were not able to assess the impact of methylprednisolone on longer-term outcomes because these data are not currently captured in the databases used in this study.