JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
5, 2019
ª 2019 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
PUBLISHED BY ELSEVIER
EDITORIAL COMMENT
Corticosteroids for
Congenital Heart Surgery
When Is a Negative Trial Not a Negative Trial?*
Steven M. Schwartz, MD
C orticosteroids to prevent cardiopulmonary
bypass (CPB)–related inflammatory injury
have been used for almost one-half century,
and yet, there remains significant debate as to
whether they are helpful (1–3), harmful (4,5), or just
useless (6). There is relatively strong evidence that
steroids reduce inflammation associated with CPB
(1,7), but less consistent evidence that inflammation
is associated with clinical outcomes (8). Furthermore,
there remain concerns about potential risks associ-
ated with steroids including hyperglycemia (9), poor
wound healing, development of infections (4), and
adverse neurodevelopmental outcomes (10). Conflict-
ing clinical outcomes of case series, single-center tri-
als, and studies using administrative or quality
databases have led to significant practice variability
(11) to the point that pleas for a multicenter trial
have become almost a constant refrain in any discus-
sion of mitigation strategies for the effects of CPB.
Unfortunately, such a trial has not been conducted,
primarily because of lack of equipoise between sites,
although there is clearly equipoise within the field.
There are also practical obstacles in studying any
approach to reducing CPB-related injury. It is chal-
lenging to identify a primary outcome that both is
measurable and occurs often enough for the study to
be adequately powered within the realistic confines
of program volumes in pediatric heart surgery.
Choosing patients within the pediatric cardiac
*Editorials published in the Journal of the American College of Cardiology
reflect the views of the authors and do not necessarily represent the
views of JACC or the American College of Cardiology.
From the Departments of Critical Care Medicine and Paediatrics, The
Hospital for Sick Children and The University of Toronto, Toronto,
Ontario, Canada. Dr. Schwartz has reported that he has no relationships
relevant to the contents of this paper to disclose.
ISSN 0735-1097/$36.00
VOL. 74, NO.
surgical population who are at risk of clinical mani-
festations of CPB-related injury is also critical. As the
debate about steroids has occurred, there have been
many changes to the conduct of CPB and pediatric
heart surgery that have led to decreases in mortality,
morbidity, and resource utilization (12). It is now
common for many patients to be extubated in the
operating room or shortly thereafter (13), which was
almost unheard of 15 years ago. It is hard to imagine
that patients who are in the intensive care unit for
only 1 night and are discharged 3 to 5 days after sur-
gery have much opportunity for improved outcomes
by being given high-dose steroids at the time of CPB.
Higher-risk groups, such as neonates, especially those
undergoing staged single-ventricle palliation, have
significant morbidity and mortality (14), but the
number of potential causes of these post-operative
events is large and the inherent variability may
contribute to a high signal-to-noise ratio when trying
to tease out the potential effects of steroids.
SEE PAGE 659
It is within this context that we have anxiously
awaited the results of the study by Graham et al. (15)
in this issue of the Journal. They report the results of
a 2-center, randomized, placebo-controlled trial of
methylprednisolone, administered as a single dose of
30 mg/kg after the induction of anesthesia to
infants #31 days of age undergoing surgery for
congenital heart disease using CPB. The primary
outcome of the trial was a composite of death or
cardiac arrest, extracorporeal membrane oxygena-
tion, renal injury, hepatic injury, or rising lactate.
Overall, this was a negative trial, with no difference in
the primary outcome between those who did and did
not receive steroids. The most interesting findings of
the trial, however, lie in differences in the apparent
effects of steroids at the 2 participating sites. One
https://doi.org/10.1016/j.jacc.2019.06.019
670 Schwartz JACC VOL. 74, NO. 5, 2019

Corticosteroids for Congenital Heart Surgery AUGUST 6, 2019:669–71

site showed a statistically and clinically significant
improvement in outcomes, primarily for
undergoing palliative operations, associated with
administration of pre-operative steroids.
strength of this observation is bolstered by other
secondary outcomes, such as less inotrope use, lower
incidence of low cardiac output, and use of open label
steroids post-operatively. The second site had a much
higher incidence of the primary outcome overall, but
there was no discernable association of that outcome
with steroid use.
There is some irony in the statement by the au-
thors that one reason that the second site was
added was “to improve the generalizability of the
results,” when in fact, the outcomes do quite the
opposite. This report seems more likely to increase
rather than resolve debate about steroid use in this
population; however, it does offer important guid-
ance on future trials in this complex population.
Primarily, we need to consider site-specific differ-
ences that can make a treatment effective at one
site and ineffective, or even adverse, at another. In
the 2010 report of the Pediatric Heart Network and
National Heart, Lung, and Blood Institute Working
Group on the Perioperative Management
Congenital Heart Disease (16), one key area for
study was noted to be practice variation and quality
improvement. The working group noted, “practice
variation in the perioperative care of neonates with
CHD is significant, driven by physician preference,
experience, and uncertainty resulting from the lack
of sound evidence” (16). The current study suggests
caution with regard to standardization across sites
without an understanding of the context in which it
those takes place. It is impossible to know from the study
by Graham et al. (15) exactly why there was such a
The disparity in trial outcomes between the 2 centers.
There were differences in the conduct of CPB be-
tween the 2 sites, or perhaps the higher incidence
of the primary outcome at the second site over-
whelmed any potential benefit of steroids. Of
course, practice variation should not be driven by
the simple preferences of individual clinicians, but
it is conceivable, and even probable, that on an
individual level, different centers might have better
outcomes by approaching things differently. These
types of observations can also drive investigations
around comparative outcomes (17) and collaborative
learning (15), which can be informative and
practice-changing in ways that even the best ran-
domized clinical trials may not.
As medicine moves toward the concept of indi-
vidualized care, studies such as this remind us that
individualization can occur at different strata in the
overall health care system. To maximize outcomes for
our most complex patients, we will need to study
ourselves even as we study others, and avoid the
of temptation to apply quick fixes without understand-
ing the context of our own problems.
ADDRESS FOR CORRESPONDENCE: Dr. Steven M.
Schwartz, Department of Critical Care Medicine, The
Hospital for Sick Children, 555 University Avenue,
Toronto, Ontario M5G 1X8, Canada. E-mail: steven.
schwartz@sickkids.ca. Twitter: @sickkids.

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KEY WORDS cardiopulmonary bypass,
congenital heart disease, pediatric