STeroids to REduce Systemic Inflammation After Neonatal Heart Surgery

Overview:

Congenital heart diseases (CHD) are the most common birth defects, occurring in nearly 1% of
live births. Every year, an estimated 40,000 infants born in the U.S. suffer from CHD.
Despite advances in surgical management, CHD requiring neonatal surgery is associated with
poor outcomes; national registry data demonstrates post-operative major morbidity in 23% and
10% do not survive to hospital discharge.

Poor outcomes after neonatal heart surgery are often attributable to a severe systemic
inflammatory response to cardiopulmonary bypass (CPB). CPB is necessary for most neonatal CHD
surgeries. Therefore, to reduce the post-CPB inflammatory reaction, many surgeons administer
pre-or intra-operative steroids. Steroids have been shown to reduce inflammatory markers
after neonatal heart surgery. However, steroids also have potential harmful effects including
an increased risk of post-operative infection. The recent SIRS trial evaluated the safety and
efficacy of steroids after CPB in adults and demonstrated no beneficial effect of steroids
but increased risk of post-CPB myocardial infarction and other major adverse events.

Adult trial results cannot be reliably extrapolated to neonates because the neonatal response
to CPB is markedly different to that seen in adults; neonates demonstrate both a more
pronounced inflammatory reaction and a different post-operative complication profile. For
these reasons approximately 2/3rds of congenital heart surgeons continue to administer
perioperative steroids to neonates undergoing heart surgery. Yet this practice is not
evidence based as no safety/efficacy trial has ever evaluated steroids in neonates undergoing
heart surgery with CPB. Several smaller steroid trials (all enrolling < 75 patients) have
focused on surrogate outcome measures, but none have provided conclusive data.

The major barrier to performing a steroid trial in neonates with CHD has been the high cost
associated with trial conduct for these relatively rare defects. To overcome this barrier,
the investigators will use a novel approach leveraging existing registry infrastructure at
CHD surgical sites that participate in the Society of Thoracic Surgeons Congenital Heart
Surgery Database (STS-CHSD). Sites participating in the STS-CHSD collect data into their
institutional databases using standardized case report forms so that the data can be exported
to the STS-CHSD. These sites already employ data coordinating specialists to capture patient
demographics, procedural variables, and post-operative outcomes (including a list of over 60
complication variables) using strict and consistent data element definitions. By leveraging
these site-specific resources the investigators project that the investigators can reduce
trial costs by >75%.

Background:

Some surgeons/centers currently administer perioperative high dose (20mg to 60mg) intravenous
methylprednisolone before neonatal heart surgery with CPB. In a national registry study of >
3000 neonates with data capture spanning 2004 to 2008, 62% of neonates undergoing surgery
with CPB received perioperative methylprednisolone while 38% did not. Of those receiving
methylprednisolone, 22% received methylprednisolone on both the day before, and day of
surgery, 12% on the day before surgery only, and 28% on the day of surgery only. Results of a
survey of surgeons from the Congenital Heart Surgeon's Society were similar; 28% did not
routinely use steroids for neonatal heart surgery. Of the 72% that did routinely use
steroids, ~1/3rd administered steroids pre-operatively and intra-operatively and the
remainder gave intra-operative steroids only.

Several previous small translationally focused clinical trials have evaluated the safety and
efficacy of methylprednisolone. In the largest contemporary trial, neonates scheduled for
cardiac surgery were prospectively randomized to receive either 2-dose (8 hours
preoperatively and operatively, n = 39) or single-dose (operatively, n = 37)
methylprednisolone at 30 mg/kg IV per dose in a prospective double-blind trial. Neonates
receiving pre-operative methylprednisolone therapy demonstrated significantly reduced
pre-operative pro-inflammatory cytokines including interleukin-6 and 8. There were no
differences between the two groups in post-operative pro-inflammatory markers and no
differences in the incidence of post-operative low cardiac output syndrome.
Methylprednisolone was well tolerated with no adverse drug reactions. The overall incidence
of post-operative infection was 13% (10/76) and 4% (3/76) received a post-operative insulin
infusion for hyperglycemia.

A meta-analysis evaluated six previous steroid trials in children undergoing heart surgery
with CPB. The combined enrollment of these six trials was 232 participants including 116
receiving peri-operative steroids; two of these studies used methylprednisolone at doses of
30mg/kg IV per dose (n=67 patients). The results of this meta-analysis demonstrated a
nonsignificant trend of reduced mortality in steroid-treated patients (11 [4.7%] vs 4 [1.7%]
patients; odds ratio, 0.41; 95% CI, 0.14-1.15; p = 0.089). Steroids had no effects on
mechanical ventilation time (117.4 ± 95.9 hr vs 137.3 ± 102.4 hr; p = 0.43) and ICU length of
stay (9.6 ± 4.6 d vs 9.9 ± 5.9 d; p = 0.8). Perioperative steroid administration reduced the
prevalence of renal dysfunction (13 [54.2%] vs 2 [8%] patients; odds ratio, 0.07; 95% CI,
0.01-0.38; p = 0.002). There were no significant differences in the adverse event profiles
for patients receiving steroids versus placebo.

The conclusions of the aforementioned studies, as well as several associated editorials have
all been that a large, randomized, controlled trial is needed to evaluate the safety and
efficacy of perioperative steroids for neonatal heart surgery with CPB.

Design:

This study is a prospective, double-blind, multi-center, placebo-controlled safety and
efficacy study of methylprednisolone in neonates undergoing heart surgery with CPB. The study
will enroll up to 1500 neonates (< 30 days of age) and the total study duration is expected
to be approximately 48 months. An ancillary PK/PD/Biomarker study will enroll subjects at
select centers. This study is unique in that it is designed to leverage existing registry
infrastructure at participating sites so as to reduce trial costs. Participants will be
randomized and will receive a randomization ID. This ID will also serve as a unique patient
identifier allowing us to crosslink datasets. Participants will then receive two doses of
study drug/placebo. The first dose will be administered 8 to 12 hours before anticipated
heart surgery and the second dose will be administered into the pump prime during
cardiopulmonary bypass. All study participants will then receive routine post-operative care.
Participating centers will enter all demographic, preoperative, operative and outcomes data
into their existing institutional databases for submission to the STS-CHSD as they currently
do. These data will be used to evaluate trial outcomes.

Inclusion Criteria:

- Age < 1 year at the time of surgery

- Undergoing heart surgery with CPB as part of standard clinical care

- Availability and willingness of the parent/legally authorized representative to
provide written informed consent

Exclusion Criteria:

- < 37 weeks adjusted gestational age at time of surgery

- Any oral or intravenous steroid treatment within two days of surgery

- Any patient receiving any of the following medications within 2 days of surgery:

Amphoteracin B, aminoglutethimide, anticholesterases, warfarin, P450 3A4 inducers including
(but not limited to) carbamazepine, phenobarbital, phenytoin, rifampin, bosentan and
nafcillin or P450 3A4 inhibitors including (but not limited to) clarithromycin,
voriconazole, itraconazole, ketoconazole, ciprofloxacin, diltiazem, fluconazole,
erythromycin and verapamil.

- Infection contraindicating steroid use

- Preoperative mechanical circulatory support or active resuscitation at the time of
randomization

- Emergent surgery precluding steroid administration 8-12 hours before surgery