Tantalizing Therapeutics in Bronchopulmonary Dysplasia

Tantalizing Therapeutics in Bronchopulmonary Dysplasia is a concise reference that provides an overview of emerging concepts in the understanding of lung development and injury from a molecular and cellular point-of-view, including exciting pathways that are paving the way for new options to prevent or treat Bronchopulmonary Dysplasia (BPD). The book's chapters are written by experts who are at the forefront of BPD research. Coverage includes chapters on exosomes, stem cells and miRs, as well as a section on new discoveries in BPD research with translational potential. This is a must-have reference for researchers, physicians and trainees working on BPD, lung developmental biology, and more.

• Includes discussions on which aspects of the bench research in Bronchopulmonary Dysplasia are the most promising areas
• Offers insights into the latest research being conducted that could potentially move to the bassinet (in the NICU)
• Contains evidence-based summaries and informed opinions about existing therapies

• Language: English
• Publisher: Academic Press
• Release date: Jun 2, 2020
• ISBN: 9780128189917

Book preview

Tantalizing Therapeutics in Bronchopulmonary Dysplasia

Editor

Vineet Bhandari

Department of Pediatrics, Division of Neonatal-Perinatal Medicine, Drexel University College of Medicine, Philadelphia, PA, United States

Department of Pediatrics, Division of Neonatology, The Children’s Regional Hospital at Cooper, Cooper Medical School of Rowan University, Camden, NJ, United States

Table of Contents

Cover image

Title page

Copyright

Dedication

Contributors

Preface

Section 1. Current therapeutics: State of the art

Chapter 1. Systemic and topical glucocorticoids to prevent BPD

Introduction

Dexamethasone

Dexamethasone and hydrocortisone in the brain: different actions, different outcomes?

Hydrocortisone

Other systemic steroids

Topical steroids (inhaled and instilled)

Conclusion

Chapter 2. Use of caffeine for prevention of bronchopulmonary dysplasia

Brief history of caffeine use in premature neonates

Epidemiology of caffeine use

Pharmacology of caffeine in premature neonates

Cellular mechanism of action of caffeine

Mechanism of action of caffeine for prevention of BPD

Dosing and route of caffeine administration

Drug interactions with caffeine

Serum drug monitoring for caffeine

Timing of caffeine use – early vs. late

Evidence for the use of late caffeine for prevention of BPD

Evidence for the use of early caffeine for prevention of BPD

Adverse effects of caffeine

Caffeine and neurodevelopmental outcomes

Caffeine controversies

Conclusions

Recommendations

Chapter 3. Next generation ventilation strategies to prevent and manage bronchopulmonary dysplasia

Introduction

Pathophysiology of ventilator-associated lung injury

General strategies to prevent PBD

Respiratory support at birth and lung injury

Positive end-expiratory pressure in the delivery room

Sustained inflation (SI)

Non-invasive respiratory support

Less invasive surfactant administration

Lung-protective strategies of mechanical ventilation

Volume-controlled and volume-targeted ventilation

Volume-controlled versus volume-targeted ventilation

How does VTV work?

Documented benefits of volume-controlled and volume-targeted ventilation

General guidelines for clinical application of VTV in preterm infants

Importance of the open lung strategy

High-frequency ventilation

Neurally adjusted ventilatory assist (NAVA)

Airway pressure release ventilation (APRV)

Respiratory support of infants with established BPD

Conclusion

Section 2. Ongoing therapeutic studies with translational potential

Chapter 4. End points for therapeutic trials for BPD: lessons learned from clinical trials

Introduction

Limitations of common BPD definitions as clinical trials endpoints

Does a BPD diagnosis predict important long-term outcomes with high sensitivity and specificity?

Is 36 weeks PMA the optimal timing for a BPD endpoint?

Is 40 weeks PMA a better endpoint than 36 weeks?

Should a diagnosis of BPD be based on respiratory status on a single day of a protracted hospital stay?

Should BPD be based on use of oxygen, positive pressure or both?

Are there advantages to a graded severity score over a dichotomous BPD endpoint?

Respiratory death as an outcome

Considerations when defining clinical trials endpoints after NICU discharge

Long-term clinical trials endpoints; how long is too long?

Conclusions

Chapter 5. What can exogenous surfactant provide in the fight against BPD?

Introduction

Conventional surfactant therapy and BPD

Late surfactant therapy and BPD

New modes of exogenous surfactant administration

Anti-inflammatory and immunomodulatory effects of surfactant

Surfactant proteins A and D

Surfactant as a vehicle for anti-inflammatory therapy

Known effects of surfactant on the potency/bioactivity of therapies targeting BPD

Conclusion

Chapter 6. Stem cells in the treatment of bronchopulmonary dysplasia

Introduction

Prospects and challenges for successful clinical translation

Long-term outcomes and safety of MSCs transplantation

Conclusions

Section 3. Future therapeutic directions

Chapter 7. Extracellular vesicles in the therapy of BPD

Bronchopulmonary dysplasia (BPD) and the rationale for stem cell-based therapies

EVs: Intro and nomenclature

EV isolation methods

EV characterization methods

EVs as therapeutic vectors

EVs in BPD

Chapter 8. Growth factors in the therapy of bronchopulmonary dyplasia

Introduction

Summary and conclusions

Chapter 9. Antenatal approaches in the therapy of BPD

Introduction

Antenatal treatment to prevent BPD

Maternal factors influencing lung fetal lung development

The fetal environment

Conclusions

Chapter 10. miRs – Mere hype or master regulators in the therapy of BPD?

Introduction

MicroRNA and early lung development

MicroRNA and late lung development

MicroRNAs for BPD risk prediction and therapeutic targets

miRs and BPD sex predilection

miRs and the lung microbiome

Conclusions

Chapter 11. Immune modulators for the therapy of BPD

Introduction

Antenatal corticosteroids

Macrophage migration inhibitory factor (MIF)

MIF and BPD

Complexity of MIF signaling pathways

Development of MIF modulating agents

Future possibilities for MIF research in BPD

IL-1β

Impact of IL-1β and the NLRP3 inflammasome on lung development

Use of the recombinant IL-1RA anakinra in BPD

NLRP3 inflammasome as a potential therapeutic target in BPD

Surfactant protein D in the treatment of neonatal lung disease

Conclusion

Index

Copyright

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Dedication

This book is dedicated first and foremost to my wife,

Anita Bhandari, MD,

for always being there.

Secondly, to our daughters, who are on-track to become physicians who will continue the family tradition to care for those who most need help,

Shreya Bhandari, MSIII

and

Esha Bhandari, Pre-Med

To treat, teach, and test

Contributors

So Yoon Ahn,     Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea

Namasivayam Ambalavanan,     Department of Pediatrics, University of Alabama, Birmingham, AL, United States

Judy L. Aschner

Hackensack Meridian School of Medicine at Seaton Hall, Nutley, NJ, United States

Joseph M. Sanzari Children’s Hospital at Hackensack University Medical Center, Hackensack, NJ, United States

Olivier Baud

Division of Neonatology, Department of Pediatrics, Gynecology and Obstetrics, School of Medicine, University of Geneva, Geneva, Switzerland

Robert Debré Children's Hospital Inserm U1141, Paris, France

Vineet Bhandari

Department of Pediatrics, Division of Neonatal-Perinatal Medicine, Drexel University College of Medicine, Philadelphia, PA, United States

Department of Pediatrics, Division of Neonatology, The Children’s Regional Hospital at Cooper, Cooper Medical School of Rowan University, Camden, NJ, United States

Yun Sil Chang

Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea

Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, South Korea

Stem Cell and Regenerative Medicine Institute, Samsung Medical Center, Seoul, South Korea

Anne Chetty,     Department of Pediatrics, Tufts Medical Center, Tufts University, Boston, MA, United States

Peter A. Dargaville

Department of Paediatrics, Royal Hobart Hospital, Hobart, TAS, Australia

Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia

Jan Deprest

Department of Development and Regeneration, KU Leuven, Leuven, Belgium

Institute for Women's Health, University College London Hospital, London, United Kingdom

Stefani Doucette,     Department of Pediatrics, Section of Neonatology, University of Calgary, Calgary, AB, Canada

Andre Gie,     Department of Development and Regeneration, KU Leuven, Leuven, Belgium

Margaret Gilfillan

Department of Pediatrics, Division of Neonatal-Perinatal Medicine, Drexel University College of Medicine, Philadelphia, PA, United States

St. Christopher's Hospital for Children, Philadelphia, PA, United States

Ashish Gupta,     Department of Pediatrics, Mercy Hospital, Grand Rapids, MI, United States

Martin Keszler,     Department of Pediatrics, Alpert Medical School of Brown University, Women and Infants Hospital of Rhode Island, Providence, RI, United States

Charitharth Vivek Lal,     Department of Pediatrics, University of Alabama, Birmingham, AL, United States

Flore Lesage

Ottawa Hospital Research Institute, Sinclair Centre for Regenerative Medicine, Ottawa, ON, Canada

Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada

University of Ottawa, Department of Cellular and Molecular Medicine, Ottawa, ON, Canada

Abhay Lodha,     Department of Pediatrics, Section of Neonatology, University of Calgary, Calgary, AB, Canada

Cynthia (Cindy) T. McEvoy,     Oregon Health & Science University, Doernbecher Children's Hospital, Portland, OR, United States

Heber C. Nielsen,     Department of Pediatrics, Tufts Medical Center, Tufts University, Boston, MA, United States

Won Soon Park

Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea

Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, South Korea

Stem Cell and Regenerative Medicine Institute, Samsung Medical Center, Seoul, South Korea

Thomas Salaets,     Department of Development and Regeneration, KU Leuven, Leuven, Belgium

Vivek Shukla,     Department of Pediatrics, University of Alabama, Birmingham, AL, United States

Bernard Thébaud

Ottawa Hospital Research Institute, Sinclair Centre for Regenerative Medicine, Ottawa, ON, Canada

Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada

University of Ottawa, Department of Cellular and Molecular Medicine, Ottawa, ON, Canada

Division of Neonatology, Department of Pediatrics, Children's Hospital of Eastern Ontario, Ottawa, ON, Canada

Jaan Toelen,     Department of Development and Regeneration, KU Leuven, Leuven, Belgium

Ignacio Valenzuela,     Department of Development and Regeneration, KU Leuven, Leuven, Belgium

Kristi L. Watterberg,     Pediatrics, Division of Neonatology, University of New Mexico, Albuquerque, NM, United States

Preface

For the last 35 years, I have been lucky enough to follow my dream of being a physician- scientist: (1) taking care of the most vulnerable of patients, the babies, (2) teaching the scientific methods to the high school students, medical students, scientists, residents, fellows, peers, and (3) testing clinical strategies and constantly asking questions at the bassinet and moving to the bench and vice versa to improve the health of the babies.

This has spurred me to undertake my third book, and as with the others, has been a true labor of love for me. Bronchopulmonary dysplasia (BPD) is a difficult disease, and while a wealth of experimental and clinical information is available, I felt a single source that contained the current and upcoming potential therapeutics to combat this condition would be of value to many people.

I am extremely grateful to the contributors for giving me a glimpse of their expertise and amazing ability to give a succinct, yet comprehensive, description of therapeutic strategies to beat BPD. Section 1 contains 3 chapters on "Current Therapeutics: State of the Art." Drs. Kristi Watterberg and Olivier Baud distill out the salient aspects of steroid use when managing the at-risk infants for developing BPD, in Chapter 1. Caffeine (Chapter 2) has become the standard-of-care in the neonatal intensive care unit (NICU), and Drs. Abhay Lodha, Stefani Doucette, and Vineet Bhandari detail out the science behind the data, and provide practical guidelines on using the drug to prevent BPD. Chapter 3 by Drs. Martin Keszler and Ashish Gupta covers the current invasive and non-invasive ventilator strategies over the early, evolving and established phases of BPD. Section 2 focuses on "Ongoing Therapeutics Studies with Translational Potential." A major reason for the lack of progress in developing new drugs or approaches to prevent/treat BPD, has been convincing the regulatory agencies of when a drug/approach for BPD would be considered effective i.e. what should be the defined end-point to show efficacy. Drs. Judy Aschner and Cindy McEvoy tackle this conundrum and provide us with guidance to progress faster on this path in Chapter 4. Surfactant (one of the very few drugs that was actually developed for and is officially approved for use in neonates) has been the mainstay of NICUs worldwide to treat respiratory distress syndrome. Dr. Peter Dargaville, in Chapter 5, tells us about the novel approaches of utilizing exogenous surfactant in the continued battle against BPD. Stem cells have shown some promise and Drs. So Yoon Ahn, Yun Sil Chang, and Won Soon Park provide us with the latest update on this topic in relation to BPD in Chapter 6. Section 3 is entitled "Future Therapeutic Directions," and is probably the most exciting part of the book. Drs. Flore Lesage and Bernard Thebaud explore the world of extracellular vesicles and the potential of their cargo to impact the therapy of BPD in the future in Chapter 7. In Chapter 8, Drs. Heber Nielsen, Anne Chetty and Vineet Bhandari provide us with a comprehensive summary of a variety of growth factors, and the experimental data that speaks to their potential to be tested in future clinical trials for BPD. Prematurity, of course, is a prime factor in the evolution of BPD, but it also provides us with an opportunity to intervene in the prenatal period, if preterm delivery cannot be prevented. The exciting world of ante-natal approaches to make an early impact to potentially slow, if not halt, the march toward BPD is described in detail by Drs. Andre Gie, Ignacio Valenzuela, Thomas Salaets, Jan Deprest, and Jaan Toelen in Chapter 9. Work done in our research lab, as well as by other investigators, has shown the powerful impact (in experimental models of BPD) microRNAs or miRs can have as they regulate multiple downstream signaling pathways that make up the complex pathogenesis of BPD. Manipulating these molecules to provide us with their potential promise to move from the bench to the bedside has been the goal in Chapter 10 written by Drs. Charitharth Vivek Lal, Vivek Shukla, Namasivayam Ambalavanan, and Vineet Bhandari. Last, but certainly not least, the latest information about the most promising immunomodulating agents has been provided in Chapter 11 by Drs. Margaret Gilfillan and Vineet Bhandari. Of course, the speed of science is much faster than what can be included in a book chapter, and so please be on the look-out for the latest publications from this internationally respected and august group of doctors and researchers.

I am immensely thankful for the above authors for their efforts in getting the chapters to me in a timely manner, despite their additional responsibilities at work and home. It would be remiss of me not to thank Sara Pianavilla, and the entire Production Team at Elsevier for their support and dedication in seeing this through till the end. Finally, thanks to my parents, teachers, family, friends, collaborators and colleagues who have been instrumental in allowing me to continue to pursue my passion in getting rid of BPD.

Section 1

Current therapeutics: State of the art

Outline

Chapter 1. Systemic and topical glucocorticoids to prevent BPD

Chapter 2. Use of caffeine for prevention of bronchopulmonary dysplasia

Chapter 3. Next generation ventilation strategies to prevent and manage bronchopulmonary dysplasia

Chapter 1

Systemic and topical glucocorticoids to prevent BPD

Kristi L. Watterberg a , and Olivier Baud b , c       a Pediatrics, Division of Neonatology, University of New Mexico, Albuquerque, NM, United States      b Division of Neonatology, Department of Pediatrics, Gynecology and Obstetrics, School of Medicine, University of Geneva, Geneva, Switzerland      c Robert Debré Children's Hospital Inserm U1141, Paris, France

Abstract

Glucocorticoids have been a ‘tantalizing therapeutic’ for prevention and treatment of bronchopulmonary dysplasia (BPD) for over 30 years. Dexamethasone was the first drug widely adopted, based on short-term benefits, but enthusiasm waned after recognition of adverse long-term effects. The incidence of BPD increased with decreasing use of dexamethasone, and overall neurologic outcomes do not appear to have improved. Lower-dose dexamethasone may provide benefit without similar adverse effects, but more data are needed. Early low-dose hydrocortisone as prophylaxis of relative adrenal insufficiency significantly increased survival without BPD in an individual patient data meta-analysis of 982 patients (p   =   0.007). Later, higher dose hydrocortisone may have benefit; a large, randomized trial currently in process should help answer that question. Inhaled glucocorticoids have been disappointing; only one randomized trial showed benefit, and only for infants not intubated at study start. Budesonide instilled with surfactant has been promising in early studies and may be a useful future therapy if confirmed in larger trials.

Keywords

Dexamethasone; Hydrocortisone; Budesonide; Preterm infant; Bronchopulmonary dysplasia

Introduction

Pity poor King Tantalus of Phrygia. The mythic monarch offended the ancient Greek gods. As punishment, he was plunged up to his chin in water in Hades, where he had to stand beneath overhanging boughs of a tree heavily laden with ripe, juicy fruit. But though he was always hungry and thirsty, Tantalus could neither drink the water nor eat the fruit. Anytime he reached for them, they would retreat from him. Our word tantalize is taken from the name of the eternally tormented king. (https://www.merriam-webster.com/dictionary/tantalize).

Bronchopulmonary dysplasia (BPD) is the most common morbidity of extreme prematurity, and the diagnosis has increased in prevalence over time, in contrast to most other major morbidities in this population [1,2]. Glucocorticoids have been a ‘tantalizing therapeutic’ for prevention and treatment of BPD for over 30 years, in the classic sense of the word, to torment or tease (someone) with the sight or promise of something that is unobtainable. (https://en.oxforddictionaries.com/definition/tantalize). In this chapter, we will review the current evidence for benefits and hazards of both systemic and topical (inhaled and instilled) glucocorticoid therapy. Because cohort studies of therapeutic interventions are confounded by the ‘unknown unknowns’, this chapter will primarily focus on randomized clinical trials (RCTs) of dexamethasone and hydrocortisone.

Dexamethasone

Although one very small RCT in the early 1970s examined the effects of high-dose hydrocortisone (15   mg/kg×2) on acute respiratory distress syndrome (RDS) [3], the glucocorticoid predominantly studied for prevention or treatment of BPD has historically been dexamethasone. Why dexamethasone? Authors of the first published RCT chose it because of its nearly complete glucocorticoid activity and its long half-life, and because there is reasonable experience with its use in neonates and children [4]. And why an initial dose of 0.5   mg/kg/day? The answer to that question is less clear, but subsequent studies were perhaps influenced by an improved response of two babies to 0.5   mg/kg/day compared to a dose of 0.1   mg/kg/day in the first published RCT [4,5]. Although dexamethasone is described in various textbooks as 25–40 times more potent than hydrocortisone (HC), studies have shown that it is actually closer to 80 times more potent in suppressing the adrenal axis [6]. Thus, a dose of 0.5   mg/kg/day represents a very high glucocorticoid exposure, especially over the prolonged courses used in many studies [7,8]. Many studies of lower dexamethasone doses, alternative therapeutic agents, and topical administration of glucocorticoids by aerosol or instillation were prompted by the recognition of adverse effects resulting from the higher dose initially studied.

Randomized clinical trials (RCTs) of dexamethasone for established BPD were first reported in the 1980's. Initially, the drug looked like a major step forward in neonatal care, improving oxygenation, facilitating extubation, reducing the need for invasive ventilation at 28 days of postnatal age, and decreasing the incidence of BPD at 36 weeks post menstrual age (PMA) [4,5,7]. Short-term benefits led to widespread clinical use and to studies of earlier treatment, eventually starting on the first postnatal day [8–10]. These subsequent RCTs produced evidence documenting numerous short- and long-term adverse effects, such as hyperglycemia, hypertension, gastrointestinal perforation, growth delay, cardiac hypertrophy, and late-onset sepsis, among others; but most worrisome was a dawning awareness of its impairment of long-term growth and neurodevelopment [8,11,12]. In a meta-analysis in 2001, Barrington concluded that Postnatal steroid therapy is associated with an increase in cerebral palsy and neurodevelopmental impairment. As there is no clear evidence in the literature of long term benefit, their use for this indication should be abandoned. [11]. Subsequently, in some of the most compelling evidence of the hazards of high-dose dexamethasone, Yeh et al. reported school age outcomes of children treated with a 28-day course of dexamethasone beginning with a dose of 0.5   mg/kg/day on the first postnatal day [12,13]. They found that dexamethasone-treated children were significantly shorter than the controls and had a significantly smaller head circumference. In addition, they had poorer motor skills, lower IQ scores, and a higher incidence of significant disabilities [12]. Finally, a small study reported that dexamethasone was associated with acutely reduced motility and changes in the speed and amplitude of general movements, markers of brain lesions, and subsequent cerebral palsy [14].

As negative reports accumulated and the American Academy of Pediatrics cautioned against the use of glucocorticoids in 2002 [13], its use decreased markedly, while BPD increased significantly [15–17]. Unfortunately, this reduction in dexamethasone use did not result in the hoped-for improvement in neurodevelopmental outcomes [17], likely at least in part because BPD is also a risk factor for adverse neurodevelopmental outcomes [18,19]. In an unfortunate side effect, clinical trials of lower-dose dexamethasone for prevention or treatment of BPD came to a halt, as clinicians became reluctant to enroll patients [20,21]. The last patients included in a published RCT of dexamethasone to prevent or decrease BPD were enrolled by 2002. Consequently, guidance from meta-analysis of these studies has not changed since then: analyzing 32 RCTs of glucocorticoids begun in in the first postnatal week (21 using dexamethasone), the 2017 Cochrane review concluded that: Benefits of early postnatal corticosteroid treatment (≤7 days), particularly dexamethasone, may not outweigh adverse effects associated with this treatment. Further, subgroup analyses by type of corticosteroid revealed that most of the beneficial and harmful effects of treatment were attributable to dexamethasone [22]. And after reviewing 21 RCTs of treatment started after the first postnatal week, evidence showing both benefits and harms of treatment and limitations of available evidence suggests that it may be prudent to reserve the use of late corticosteroids for infants who cannot be weaned from mechanical ventilation, and to minimize both dose and duration for any course of treatment [23].

A small study comparing 0.5   mg/kg/day of dexamethasone with a lower dose (0.2   mg/kg/day for 3 days followed by 0.1   mg/kg/day for 4 days) appeared to show that the lower dose was as effective as the higher one [24,25]. Subsequently, an influential trial of lower-dose dexamethasone, the DART trial, planned to enroll 814 patients in an RCT of 0.15   mg/kg/day begun after the first postnatal week and tapered over 10 days, with a primary endpoint of survival without major neurosensory impairment at age 2 [26]. Unfortunately, this trial started at the time of increasing reports of adverse effects from higher dose dexamethasone therapy and was stopped for slow enrollment after only 70 patients. The DART trial did not show a significant decrease in BPD at 36 weeks PMA (dexamethasone group: 85%; control group: 91%; OR: 0.58 (95% CI: 0.13–2.66)), but did show other short-term benefits compared to placebo, including increased extubation during the treatment period, improved ventilator and oxygen requirements, and decreased duration of intubation. However, severe BPD, defined as receiving >0.30 fraction of inspired oxygen (FiO2) occurred in 30% versus 41% of survivors. While not significantly different (p   =   0.38), such a difference would be both clinically and statistically significant if confirmed in a larger sample size. No short-term adverse effects were noted, and at two-year follow-up, the authors cautiously concluded, Although this trial was not able to provide definitive evidence on the long-term effects of low-dose dexamethasone after the first week of life in chronically ventilator-dependent infants, our data indicate no strong association with long-term morbidity [26].

The persistent prevalence of BPD has led to continuing clinical use of the DART protocol after the first or second postnatal week. Unfortunately, because higher doses were studied first, follow-up data at 18 months–2 years from RCTs are only available for 76 infants treated with this dose of dexamethasone in the first postnatal week and 29 treated after the first postnatal week [26,27]. Both of these studies found that outcomes were apparently similar between dexamethasone-treated and control groups. Interestingly, a recent small randomized trial (59 infants) compared a 42-day and a 9-day tapering course of dexamethasone with a starting dose of 0.5   mg/kg, with results suggesting fewer morbidities and increased survival without handicap in the 42-day group [28].

These numbers are far from sufficient to conclude that this dose of dexamethasone does not cause long-term harm. After so many years and so many trials, it appears that further studies with longer-term follow up are still required in order to better understand the benefits and risks of dexamethasone therapy for patients with evolving BPD. The one question that appears to have been answered is that dexamethasone therapy has no place in the first postnatal week.

Dexamethasone and hydrocortisone in the brain: different actions, different outcomes?

Cohort studies of dexamethasone therapy in extremely preterm infants have shown adverse outcomes on brain structure and function at term-equivalent age through school age [29,30]. While it is not unexpected that sicker babies would be more likely both to receive dexamethasone and to have more adverse outcomes, it is consequently notable that hydrocortisone has not been found to have the same effects. In a cohort of 73 infants treated with a 3-week tapering course of HC starting at a dose of 5   mg/kg and 73 matched controls, no reduction in brain tissue or cerebellar volumes could be found on MRI at term-equivalent age [31]. At age 8, comparing 62 infants treated with a similar course of HC and 164 untreated infants, there were no significant differences in intellectual or motor function, cerebral palsy, or brain lesions on MRI, after adjusting for perinatal factors [32]. Similar results were reported in an RCT of 64 extremely preterm infants, where hydrocortisone therapy after 10 days of age (3   mg/kg/day tapered over 10 days) had no statistically significant effect on brain volumes at term-equivalent PMA or on the incidence of death or neurodevelopmental impairment (NDI) at 18–22 months [33,34].

Dexamethasone and hydrocortisone have many differences that may contribute to their apparently different effects, including differences in half-life, potency, and relative balance between mineralocorticoid and glucocorticoid actions [6,35].