Impact of Pre-operative Steroids on Adrenal Insufficiency
Condition: Adrenal Insufficiency Neonatal
MeSH terms: Adrenal Insufficiency
Study type: Observational

Summary: 
      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 AI7. 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. 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
    

Detailed description: 
      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.
    

Intervention name(s): No pre-operative steroids
Intervention type(s): Other
Intervention description(s): Due to new information provide from previous studies at our center the investigator instituted a clinical practice change remove steroid administration in the pre-operative period for all neonates undergoing surgery with cardiopulmonary bypass. This study is to evaluate this change.
Observational model: Cohort
Time perspective: Prospective
Sampling method: Probability Sample
Study population: 
        Neonates less than 30 days old undergoing cardiac surgery with cardiopulmonary bypass who
        do not receive pre-operative steroid administration as part of their standard of care
        medical management.
      
Biospecimen description: 
      As a separate portion to this study consenting subject's legally authorized representative
      can provide consent to allow specimens to be stored for future research related to heart
      disease. These specimens include: blood (cell pellet and plasma), urine, and peritoneal
      dialysis fluid (if applicable).
    
Keywords: neonates; cardiopulmonary bypass; adrenal insufficiency; congenital heart disease