Definitive Answer on Steroids for Infant Heart Surgery Falls Short

Babies given perioperative methylprednisolone to reduce inflammation from cardiopulmonary bypass didn’t do better overall in a randomized trial nestled within a registry, although secondary outcomes and a Bayesian win ratio analysis suggested an advantage.

Infants younger than age 1 year given the glucocorticoid had no lower odds of a ranked set of adverse outcomes including death, heart transplantation, and 13 other major complications than did those who got placebo (adjusted OR 0.86, 95% CI 0.71-1.05, P=0.14), reported Kevin D. Hill, MD, MSCI, of the Duke Pediatric and Congenital Heart Center in Durham, North Carolina.

However, the intervention held a borderline-significant 18% lower odds ratio for a worse outcome in secondary analysis without the adjustment for prespecified risk factors that was used in the primary analysis (HR 0.82, 95% CI 0.67-1.00). And comparing matched pairs of patients suggested that methylprednisolone would have “won” for outcomes 15% more often than placebo, although again a borderline significant finding (win ratio 1.15, 95% CI 1.00-1.32).

Occurrence of bleeding requiring operation came out significantly less common with methylprednisolone (OR 0.34, 95% CI 0.14-0.81, P=0.016) in the STRESS trial that Hill presented at the American Heart Association (AHA) meeting. The findings were simultaneously published in the New England Journal of Medicine.

“Wow,” said Larry Allen, MD, MHS, of the University of Colorado in Aurora, in discussing the results at an AHA press conference. “Such borderline results in medicine are common and can be challenging to implement. But I would suggest that the use of steroids based on the based on this study seems reasonable.”

Without any well-powered evidence and no guidelines to go on, practice has been split. Registry data from 2011-2016 showed pre- or perioperative steroid use in 52% of neonatal surgeries.

Hill agreed with Allen’s take-home message from the trial: “There’s a lot of signal to suggest a small benefit from steroids. So in talking with our surgeons, I suggested that we continue to use them. But I do think that there’s potential to use them in more targeted fashion for patients who have more potential to benefit and less potential for side effects.”

That might mean forgoing steroids in certain infants, “perhaps those who have issues with glycemic control, those who are undergoing shorter bypass time,” Allen noted.

Subgroup analyses showed potential benefit of the steroid in less complex, STAT Mortality Category 1, 2, or 3 procedures (adjusted OR 0.75, 95% CI 0.60-0.94), with a longer duration of cardiopulmonary bypass (aOR for 180 minutes 0.77, 95% CI 0.60-0.99), and patients who were born premature (aOR 0.80, 95% CI 0.64-0.99).

The Steroids to Reduce Systemic Inflammation after Infant Heart Surgery (STRESS) trial included 1,200 patients in a modified intention-to-treat population who received double-blind methylprednisolone (30 mg/kg) or placebo as randomized. The trial was performed at 24 U.S. congenital heart disease centers leveraging the infrastructure of the Society of Thoracic Surgeons Congenital Heart Surgery Database. Eligibility criteria included elective cardiac surgery for congenital heart disease using cardiopulmonary bypass and age younger than 1 year at the time of surgery (median 126 days).

The most common procedures for these infants were ventricular septal defect, atrioventricular septal defect, and tetralogy of fallot.

The primary endpoint assigned patients their worst outcome during hospitalization with higher ranking for events with more clinical impact. In order of descending rank, these were:

• Operative mortality
• Heart transplant during the hospitalization
• Renal failure with permanent dialysis
• Neurologic deficit that persisted at discharge
• Respiratory failure requiring tracheostomy
• Postoperative mechanical circulatory support
• Unplanned cardiac reoperation
• Reoperation for bleeding
• Unplanned delayed sternal closure
• Postop unplanned interventional catheterization
• Postop cardiac arrest
• Multi-system organ failure
• Renal failure with temporary dialysis
• Ventilator support for >7 days
• Postop length of stay >90 days

As expected from the known impact on glucose regulation, methylprednisolone recipients got more postop insulin for hyperglycemia (19.0% vs 6.7%, P<0.001).

“We see a lot of hyperglycemia period as a stress response to surgery,” Hill told MedPage Today at the press conference. “Long story short, it was a transient hyperglycemia in the moderately elevated range. I don’t see it as a factor that is prohibitive to the administration of steroid.”

Glucose levels in the methylprednisolone group were high — in the 200-300 mg/dL range — but not extremely elevated, he said. Prior trials in children with heart surgery investigating whether tight glycemic control would improve outcome didn’t show that to be the case, but did show potentially increased infection risk. No increased infection risk was seen in the STRESS trial with methylprednisolone.

Even so,”another thing we need to explore in the future is lower-dose steroids instead of the high doses we used, which I think would decrease the likelihood of hyperglycemia,” he said.