Impact of Pre-operative Steroids on Adrenal Insufficiency

Cardiopulmonary bypass (CPB) induces systemic inflammatory response syndrome (SIRS), which may contribute to postoperative morbidity. Neonates experience an exaggerated inflammatory response and may be at a higher risk for the deleterious effects of CPB. SIRS may disrupt the hypothalamic-pituitary-adrenal (HPA) axis leading to a relative adrenal insufficiency (AI) after neonatal CPB. There is some emerging evidence supporting an association of AI with morbidity in neonates after cardiac surgery. Postoperative steroids may offer hemodynamic benefits to neonates suffering from low cardiac output syndrome (LCOS) following CPB. Benefit of postoperative steroids is multifactorial including: suppression of inflammatory cytokines, direct actions on the heart and vascular smooth muscle, and treatment of AI in a subset of patients.

Little is known regarding the incidence and clinical impact of AI in neonates during the acute postoperative period following separation from CPB. In a randomized control pilot study performed by the UAB CVICU research team, prophylactic post-CPB hydrocortisone infusions improved some postoperative outcomes, especially in those that acquired AI. In an attempt to further explore post-CPB AI, a retrospective analysis of data from this study was performed. Of the 40 neonates included in the study, one-third (32.5%) developed AI following CPB (as determined by low-dose, 1 µg, cosyntropin stimulation test). Almost all of these subjects had normal response to cosyntropin stimulation pre-CPB. Subjects that developed AI demonstrated more hemodynamic instability, increased serum lactate and required more colloid resuscitation in the immediate post-CPB period in the operating room.

In this retrospective analysis by Crawford et al.8 ACTH levels were found to be significantly lower post-CPB compared to preoperative levels. This may be secondary to a blunted HPA axis caused by preoperative methylprednisolone (all patients received), which could result in transient, iatrogenic AI. Serum cytokines were not significantly different in patients exhibiting AI compared to those with a normal adrenal response indicating that increased inflammation was not primarily responsible for the development of AI. Higher methylprednisolone levels result in higher cortisol levels due to cross-reactivity of the assays; patients with higher baseline postoperative cortisol levels demonstrated a blunted response to cosyntropin suggesting that these patients may have higher blood concentrations of methylprednisolone and its metabolites, thereby leading to more inhibition of the HPA axis. Taken together, these two studies demonstrate that AI occurs at high frequency after neonatal CPB and that AI is associated with deleterious outcomes. While postoperative hydrocortisone improves outcomes in neonates with AI, the investigator cannot exclude preoperative methylprednisolone as a cause of iatrogenic AI. Other investigators have shown in children treated with dexamethasone prior to surgery, that higher measured levels of dexamethasone were associated with postoperative AI9.

The majority of congenital heart surgery centers utilize perioperative steroids in neonates undergoing cardiac surgery with the rationale that it modulates post-CPB SIRS and treats/prevents AI; studies have inconsistently demonstrated benefit of this approach. Additionally, recent evidence has begun to highlight potential morbidity associated with perioperative steroid administration. Our cardiac surgery program is changing clinical practice and ceasing to give preoperative steroids to all patients (previously only neonatal CPB patients received preoperative methylprednisolone). With the possibility that preoperative steroid administration, and not CPB, primarily causes the high incidence of AI, it is prudent to further investigate the benefit and/or harm of perioperative steroid administration.

With these facts in mind, the investigator designed this study to determine the impact of preoperative steroid administration on development of AI and other outcomes after neonatal cardiac surgery.

B. Herein the investigator proposes to test the following HYPOTHESES and address these SPECIFIC AIMS:

HYPOTHESES: Preoperative steroid (methylprednisolone) administration is associated with development of iatrogenic AI; AI leads to increased postoperative morbidity. Preoperative steroids do not have important impact on other postoperative clinical outcomes.

SPECIFIC AIM# 1: Determine the incidence of AI (as diagnosed by 1µg cosyntropin stimulation testing) following CPB in neonates who do not receive preoperative steroids; compare to the previous cohort that received preoperative steroids.

SPECIFIC AIM# 2: Compare ACTH and cortisol levels between the two cohorts of neonates (those who do and those who do not receive preoperative steroids).

SPECIFIC AIM# 3: Compare secondary clinical outcomes including volume of crystalloid/colloid administered in the CVOR, hemodynamic parameters, laboratory values, vasoactive-inotrope score (VIS), duration of mechanical ventilation, fluid overload and mortality of the two cohorts of neonates.

Inclusion criteria

40 consecutive neonates (≤30 days of age) with complex congenital heart disease undergoing cardiac surgery with CPB who will not be given preoperative steroids.

• Controls: 40 neonates with complex congenital heart disease undergoing cardiac surgery with CPB who received two doses of preoperative methylprednisolone (10mg/kg at eight hours and one hour prior to their operation). Data from this cohort has already been prospectively collected during the original pilot randomized control trial. Based on our clinical data over the past 8 years, the demographic and risk factors of the two cohorts will be very similar.

Exclusion criteria

Neonates who do not require CPB during cardiac surgery or fail to separate from CPB in the operating room.

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