Barriers to Enrollment in a Randomized Controlled Trial of Hydrocortisone for Cardiovascular Insufficiency in Term and Late Preterm Newborn Infants

Overview

Journal J Perinatol

Specialty Gynecology & Obstetrics

Date 2017 Sep 8

PMID 28880260

Citations 8

Authors

K L Watterberg

E Fernandez

M C Walsh

W E Truog

B J Stoll

G M Sokol

K A Kennedy

M V Fraga

S S Beauman

B Carper

A Das

A F Duncan

W F Buss

C Gauldin

C B Lacy

P J Sanchez

S Chawla

S Lakshminrusimha

C M Cotten

K P Van Meurs

B B Poindexter

E F Bell

W A Carlo

U Devaskar

M H Wyckoff

R D Higgins

Affiliations

Soon will be listed here.

Abstract

Objective: To analyze reasons for low enrollment in a randomized controlled trial (RCT) of the effect of hydrocortisone for cardiovascular insufficiency on survival without neurodevelopmental impairment (NDI) in term/late preterm newborns.

Study Design: The original study was a multicenter RCT. Eligibility: ⩾34 weeks' gestation, <72 h old, mechanically ventilated, receiving inotrope. Primary outcome was NDI at 2 years; infants with diagnoses at high risk for NDI were excluded. This paper presents an analysis of reasons for low patient enrollment.

Results: Two hundred and fifty-seven of the 932 otherwise eligible infants received inotropes; however, 207 (81%) had exclusionary diagnoses. Only 12 infants were randomized over 10 months; therefore, the study was terminated. Contributing factors included few eligible infants after exclusions, open-label steroid therapy and a narrow enrollment window.

Conclusion: Despite an observational study to estimate the population, very few infants were enrolled. Successful RCTs of emergent therapy may require fewer exclusions, a short-term primary outcome, waiver of consent and/or other alternatives.

Citing Articles

Eligible Infants Included in Neonatal Clinical Trials and Reasons for Noninclusion: A Systematic Review.

Shaikh H, Lyle A, Oslin E, Gray M, Weiss E JAMA Netw Open. 2024; 7(10):e2441372.

PMID: 39453652 PMC: 11581680. DOI: 10.1001/jamanetworkopen.2024.41372.

An Update on Pharmacologic Management of Neonatal Hypotension: When, Why, and Which Medication.

Agakidou E, Chatziioannidis I, Kontou A, Stathopoulou T, Chotas W, Sarafidis K Children (Basel). 2024; 11(4).

PMID: 38671707 PMC: 11049273. DOI: 10.3390/children11040490.

The use of milrinone in neonates with persistent pulmonary hypertension of the newborn - a randomised controlled trial pilot study (MINT 1).

El-Khuffash A, McNamara P, Breatnach C, Bussmann N, Smith A, Feeney O J Perinatol. 2022; 43(2):168-173.

PMID: 36385642 PMC: 9666925. DOI: 10.1038/s41372-022-01562-8.

Overview of the neonatal research network: History, contributions, challenges, and future.

Watterberg K, Carlo W, Brion L, Cotten C, Higgins R Semin Perinatol. 2022; 46(7):151634.

PMID: 35786518 PMC: 10996928. DOI: 10.1016/j.semperi.2022.151634.

Hypotension in Preterm Infants (HIP) randomised trial.

Dempsey E, Barrington K, Marlow N, ODonnell C, Miletin J, Naulaers G Arch Dis Child Fetal Neonatal Ed. 2021; 106(4):398-403.

PMID: 33627329 PMC: 8237176. DOI: 10.1136/archdischild-2020-320241.

References

Sood B, Keszler M, Garg M, Klein J, Ohls R, Ambalavanan N . Inhaled PGE1 in neonates with hypoxemic respiratory failure: two pilot feasibility randomized clinical trials. Trials. 2014; 15:486. PMC: 4414424. DOI: 10.1186/1745-6215-15-486. View

Fernandez E, Watterberg K, Faix R, Yoder B, Walsh M, Lacy C . Definitions of cardiovascular insufficiency and relation to outcomes in critically ill newborn infants. Am J Perinatol. 2015; 32(11):1024-30. PMC: 4689139. DOI: 10.1055/s-0035-1547321. View

Suominen P, Dickerson H, Moffett B, Ranta S, Mott A, Price J . Hemodynamic effects of rescue protocol hydrocortisone in neonates with low cardiac output syndrome after cardiac surgery. Pediatr Crit Care Med. 2005; 6(6):655-9. DOI: 10.1097/01.pcc.0000185487.69215.29. View

Fernandez E, Montman R, Watterberg K . ACTH and cortisol response to critical illness in term and late preterm newborns. J Perinatol. 2008; 28(12):797-802. PMC: 2729502. DOI: 10.1038/jp.2008.190. View

Hofer N, Jank K, Resch E, Urlesberger B, Reiterer F, Resch B . Meconium aspiration syndrome--a 21-years' experience from a tertiary care center and analysis of risk factors for predicting disease severity. Klin Padiatr. 2013; 225(7):383-8. DOI: 10.1055/s-0033-1361105. View

Kamath B, Fashaw L, Kinsella J . Adrenal insufficiency in newborns with congenital diaphragmatic hernia. J Pediatr. 2010; 156(3):495-497.e1. PMC: 3594092. DOI: 10.1016/j.jpeds.2009.10.044. View

Tantivit P, Subramanian N, Garg M, Ramanathan R, deLemos R . Low serum cortisol in term newborns with refractory hypotension. J Perinatol. 2000; 19(5):352-7. DOI: 10.1038/sj.jp.7200202. View

Konduri G, Vohr B, Robertson C, Sokol G, Solimano A, Singer J . Early inhaled nitric oxide therapy for term and near-term newborn infants with hypoxic respiratory failure: neurodevelopmental follow-up. J Pediatr. 2007; 150(3):235-40, 240.e1. PMC: 1906720. DOI: 10.1016/j.jpeds.2006.11.065. View

Schmidt B, Roberts R, Davis P, Doyle L, Barrington K, Ohlsson A . Caffeine therapy for apnea of prematurity. N Engl J Med. 2006; 354(20):2112-21. DOI: 10.1056/NEJMoa054065. View

10.

Konduri G, Solimano A, Sokol G, Singer J, Ehrenkranz R, Singhal N . A randomized trial of early versus standard inhaled nitric oxide therapy in term and near-term newborn infants with hypoxic respiratory failure. Pediatrics. 2004; 113(3 Pt 1):559-64. DOI: 10.1542/peds.113.3.559. View

11.

Fernandez E, Watterberg K, Faix R, Yoder B, Walsh M, Lacy C . Incidence, management, and outcomes of cardiovascular insufficiency in critically ill term and late preterm newborn infants. Am J Perinatol. 2014; 31(11):947-56. PMC: 4127379. DOI: 10.1055/s-0034-1368089. View

12.

Watterberg K . Hydrocortisone Dosing for Hypotension in Newborn Infants: Less Is More. J Pediatr. 2016; 174:23-26.e1. DOI: 10.1016/j.jpeds.2016.04.005. View

13.

Fernandez E, Schrader R, Watterberg K . Prevalence of low cortisol values in term and near-term infants with vasopressor-resistant hypotension. J Perinatol. 2004; 25(2):114-8. DOI: 10.1038/sj.jp.7211211. View

14.

Baker C, Barks J, Engmann C, Vazquez D, Neal Jr C, Schumacher R . Hydrocortisone administration for the treatment of refractory hypotension in critically ill newborns. J Perinatol. 2008; 28(6):412-9. DOI: 10.1038/jp.2008.16. View

15.

Steinhorn R, Fineman J, Kusic-Pajic A, Cornelisse P, Gehin M, Nowbakht P . Bosentan as Adjunctive Therapy for Persistent Pulmonary Hypertension of the Newborn: Results of the Randomized Multicenter Placebo-Controlled Exploratory Trial. J Pediatr. 2016; 177:90-96.e3. DOI: 10.1016/j.jpeds.2016.06.078. View

16.

Attridge J, Clark R, Walker M, Gordon P . New insights into spontaneous intestinal perforation using a national data set: (2) two populations of patients with perforations. J Perinatol. 2006; 26(3):185-8. DOI: 10.1038/sj.jp.7211439. View

17.

Soliman A, Taman K, Rizk M, Nasr I, Alrimawy H, Hamido M . Circulating adrenocorticotropic hormone (ACTH) and cortisol concentrations in normal, appropriate-for-gestational-age newborns versus those with sepsis and respiratory distress: Cortisol response to low-dose and standard-dose ACTH tests. Metabolism. 2004; 53(2):209-14. DOI: 10.1016/j.metabol.2003.09.005. View