Erika F Fernandez MD Assistant Professor Department of Pediatrics, Division of Neonatology Adrenal function in critically ill term newborn infants

Background Many intubated late preterm and term newborns will receive fluid boluses & vasopressors for hypotension The etiology of hypotension in many infants is unclear In other critically ill populations: – Hypotension and shock have been linked to : “relative adrenal insufficiency” cortisol < 15 mcg/dl acute stress – Glucocorticoids have significantly ↓ mortality & morbidity in large RCTs Lamberts et al, NEJM 337:1285, 1997 Lamberts et al, NEJM 337:1285, 1997

Evidence for AI in term newborns Small observational studies 10 infants with diaphragmatic hernia: 79% of cortisol values <7mcg/dl Pittinger and Sawin, J Pediatr Surg 35:223, of 6 infants with hypotension refractory to vasopressors had cortisol values < 10mcg/dl, BP improved in assoc. with dexamethasone » Tantivit et al, J Perinatol 19:352, 1999

Prevalence of low cortisol values Retrospective chart review ≥ 35 weeks GA with cortisol values Critically ill: Intubated, mechanically ventilated and on vasopressors for hypotension BW (g) GA (weeks) Postnatalday Cortisol concentration, mcg/dl Number (%) with cortisol <15 mcg/dl Total, n= ± 2 1 (0–3) 11.7 (5–27) 18 (56%) Treated with hydrocortisone n= ± 2 1 (0–2) 7.5 (5–19) 15 (65%) Did not receive hydrocortisonen= ± 3 1 (0–3.5) 23.5 (12–30) 3 (33%) Fernandez and Watterberg et al, J Perinatol 25:114, 2005 Data are mean +_ SD or median (25%-75%) 3 infants died (1 MAS, 1 HLHS, 1 CHD)

Fernandez, Watterberg et al. J Perinatol 25:114, 2005 Physiologic response to hydrocortisone Physiologic response to hydrocortisone Critically ill hypotensive infants treated w/ hydrocortisone, Critically ill hypotensive infants treated w/ hydrocortisone, Cortisol <15mcg/dl (▲) Cortisol <15mcg/dl (▲) compared to compared to Cortisol ≥ 15 mcg/dl (O) Cortisol ≥ 15 mcg/dl (O)  Cortisol <15mcg/dl responded to HC with ↓ dopamine support ↓ dopamine support ↓ heart rate ↓ heart rate ↓ volume expanders ↓ volume expanders

Prospective observational study of term and late preterm critically ill newborns Non- critically ill infants Critically ill infants All NOT receiving vasopressors Receiving vasopressors Gestation (weeks) * 38.8 Birth weight (g) 3240 † * 3221 Postnatal age (days) 2 [1-4] † 1 [0-1] 1 [1-2] 1 [0-1] Median [25%-75% percentile] P-value= critically ill infants not receiving vasopressors vs. those receiving vasopressors * = P < 0.05 Fernandez, Montman, Watterberg. 2008, unpublished data Baseline cortisol (mcg/dl) ACTH-stimulated cortisol (mcg/dl) Baseline cortisol < 15 mcg/dl (n(%)) (74%) 6 (60%) 20 (80%) ACTH pg/ml 11.9

No correlation between measures of severity of illness and cortisol values Fernandez, Montman, Watterberg, 2008, unpublished data

Summary High incidence of Rx for hypotension in mechanically ventilated term and late preterm infants Transitional relative adrenal insufficiency appears to be associated with cardiovascular instability in this population Prospective observational data consistent with this hypothesis There are no randomized controlled trials of hydrocortisone for the treatment of hypotension Plan: multicenter RCT of hydrocortisone for hypotension We have submitted a proposal for a multicenter observational study through NIH/NICHD/NRN ( currently undergoing budget approval ) to collect baseline data for the final design of such as RCT

Mentors and Collaborators Kristi Watterberg, MD Professor Pediatrics, Division of Neonatology, Mentor, Principal Investigator for Neonatal Research Network (NIH/NICHD/NRN)site at UNM Robin Ohls, MD, Professor Pediatrics, Division of Neonatology, Co-Principal Investigator for NRN site at UNM Rebecca Montman, RN, GCRC Research Nurse Conra Backstrom, RN, GCRC Research Nurse GCRC statistics, Ronald Schrader, PhD Administrative support, Green Carlson