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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Fernandez E, Watterberg KL, Faix RG, Yoder BA, Walsh MC, Lacy CB et al. Definitions of cardiovascular insufficiency and relation to outcomes in critically ill newborn infants. Am J Perinatol 2015; 32 (11): 1024–1030.
Fernandez E, Watterberg KL, Faix RG, Yoder BA, Walsh MC, Lacy CB et al. Incidence, management, and outcomes of cardiovascular insufficiency in critically ill term and late preterm newborn infants. Am J Perinatol 2014; 31 (11): 947–956.
Kamath BD, Fashaw L, Kinsella JP . Adrenal insufficiency in newborns with congenital diaphragmatic hernia. J Pediatr 156 (3): 495–7 e1.
Soliman AT, Taman KH, Rizk MM, Nasr IS, Alrimawy H, Hamido MS . 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): 209–214.
Fernandez EF, Montman R, Watterberg KL . ACTH and cortisol response to critical illness in term and late preterm newborns. J Perinatol 2008; 28 (12): 797–802.
Fernandez E, Schrader R, Watterberg K . Prevalence of low cortisol values in term and near- term infants with vasopressor-resistant hypotension. J Perinatol 2005; 25 (2): 114–118.
Baker CF, Barks JD, Engmann C, Vazquez DM, Neal CR Jr, Schumacher RE et al. Hydrocortisone administration for the treatment of refractory hypotension in critically ill newborns. J Perinatol 2008; 28 (6): 412–419.
Suominen PK, Dickerson HA, Moffett BS, Ranta SO, Mott AR, Price JF et al. Hemodynamic effects of rescue protocol hydrocortisone in neonates with low cardiac output syndrome after cardiac surgery. Pediatr Crit Care Med 2005; 6 (6): 655–659.
Tantavit P, Subramanian N, Garg M, Ramanathan R, deLemos RA . Low serum cortisol in term newborns with refractory hypotension. J Perinatol 1999; 19 (5): 352–357.
Watterberg KL . Hydrocortisone dosing for hypotension in the newborn infant: less is more. J Pediatr 2016; 174: 23–26. e1.
Attridge JT, Clark R, Walker MW, Gordon PV . New insights into spontaneous intestinal perforation using a national data set: (2) two populations of patients with perforations. J Perinatol 2006; 26 (3): 185–188.
Konduri GG, Vohr B, Robertson C, Sokol GM, Solimano A, Singer J et al. 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.
Schmidt B, Roberts RS, Davis P, Doyle LW, Barrington KJ, Ohlsson A et al. Caffeine therapy for apnea of prematurity. N Engl J Med 2006; 354: 2112–2121.
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): 383–388.
Sood BG, Keszler M, Garg M, Klein JM, Ohls R, Ambalavanan N et al. Inhaled PGE1 in neonates with hypoxemic respiratory failure: two pilot feasibility randomized clinical trials. Trials 2014; 15: 486.
Steinhorn RH, Fineman J, Kusic-Pajic A, Cornelisse P, Gehin M, Nowbakht P et al. 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.
Konduri GG, Solimano A, Sokol GM, Singer J, Ehrenkranz RA, Singhal N et al. 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: 559–564.
Acknowledgements
Acknowledgments and funding sources are contained in Supplementary Information.
Author information
Authors and Affiliations
Consortia
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Additional information
Supplementary Information accompanies the paper on the Journal of Perinatology website
Supplementary information
Rights and permissions
About this article
Cite this article
Watterberg, K., Fernandez, E., Walsh, M. et al. Barriers to enrollment in a randomized controlled trial of hydrocortisone for cardiovascular insufficiency in term and late preterm newborn infants. J Perinatol 37, 1220–1223 (2017). https://doi.org/10.1038/jp.2017.131
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/jp.2017.131
This article is cited by
-
When perfection is the enemy of good: EBM lessons from the HIP trial
Journal of Perinatology (2023)
-
The use of milrinone in neonates with persistent pulmonary hypertension of the newborn - a randomised controlled trial pilot study (MINT 1)
Journal of Perinatology (2023)
-
Neurodevelopmental outcomes at 2 years in term and late preterm newborns enrolled in a trial of hydrocortisone for cardiovascular insufficiency
Journal of Perinatology (2020)