Clinical Trial

. 2024 Dec 10;332(22):1889-1899.

doi: 10.1001/jama.2024.17380.

Intratracheal Budesonide Mixed With Surfactant for Extremely Preterm Infants: The PLUSS Randomized Clinical Trial

Brett J Manley^{1

2

3}, C Omar F Kamlin^{1

2}, Susan M Donath^{3

4}, Kate L Francis^{3

4}, Jeanie L Y Cheong^{1

2

3}, Peter A Dargaville^{5

6}, Jennifer A Dawson^{1

3}, Susan E Jacobs^{1

2}, Pita Birch⁷, Steven M Resnick^{8

9}, Georg M Schmölzer¹⁰, Brenda Law¹⁰, Risha Bhatia^{11

12}, Katinka P Bach¹³, Koert de Waal¹⁴, Javeed N Travadi^{14

15}, Pieter J Koorts¹⁶, Mary J Berry^{17

18}, Kei Lui^{19

20}, Victor S Rajadurai²¹, Suresh Chandran²¹, Martin Kluckow²², Elza Cloete²³, Margaret M Broom²⁴, Michael J Stark^{25

26}, Adrienne Gordon^{27

28}, Vinayak Kodur²⁹, Lex W Doyle^{1

2

3}, Peter G Davis^{1

2

3}, Christopher J D McKinlay^{30

31}; PLUSS Trial Investigators

Collaborators, Affiliations

Collaborators

PLUSS Trial Investigators:
Bernice Mills, Li Huang, Kim Dalziel, Rodney Wilson, Scott Morris, Ajit Aiyappan, Tim Cochrane, Arun Nair, Renae Allen, Tim Schindler, Tara Crawford, Callum Gately Gately, Yip Wai Yan, Krishna Revanna, Chua Mei Chien, Polglase Polglase, Stuart Hooper, Huda Ismail, Christine Gilmartin, Wirawan Jeong

Affiliations

¹ Newborn Research, The Royal Women's Hospital, Melbourne, Victoria, Australia.
² Department of Obstetrics, Gynaecology and Newborn Health, The University of Melbourne, Melbourne, Victoria, Australia.
³ Murdoch Children's Research Institute, Melbourne, Victoria, Australia.
⁴ Department of Paediatrics, The University of Melbourne, Melbourne, Victoria, Australia.
⁵ Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia.
⁶ Neonatal and Paediatric Intensive Care Unit, Department of Paediatrics, Royal Hobart Hospital, Hobart, Tasmania, Australia.
⁷ Department of Neonatology, Mater Mother's Hospitals, Brisbane, Queensland, Australia.
⁸ King Edward Memorial Hospital, Perth, Western Australia, Australia.
⁹ University of Western Australia, Perth, Western Australia, Australia.
¹⁰ Centre for the Studies of Asphyxia and Resuscitation, Department of Pediatrics, University of Alberta, Edmonton, Canada.
¹¹ Monash Newborn, Monash Children's Hospital, Melbourne, Victoria, Australia.
¹² Department of Paediatrics, Monash University, Melbourne, Victoria, Australia.
¹³ Newborn Services, Starship Child Health, Te Toku Toma, Auckland, New Zealand.
¹⁴ John Hunter Children's Hospital and University of Newcastle, Newcastle, New South Wales, Australia.
¹⁵ School of Medical Sciences, Paediatrics, Child and Youth Health-Waikato, University of Auckland, Waikato, New Zealand.
¹⁶ Grantley Stable Neonatal Unit, Royal Brisbane and Women's Hospital, University of Queensland, Brisbane, Australia.
¹⁷ Health New Zealand, Capital and Coast DHB, Wellington, New Zealand.
¹⁸ Department of Paediatrics and Child Health, University of Otago, Wellington, New Zealand.
¹⁹ Royal Hospital for Women, Randwick, New South Wales, Australia.
²⁰ Discipline of Paediatrics and Child Health, School of Clinical Medicine, University of New South Wales, Sydney, Australia.
²¹ Department of Neonatology, KK Women's and Children's Hospital, Singapore.
²² Royal North Shore Hospital and University of Sydney, Sydney, New South Wales, Australia.
²³ Neonatal Unit, Christchurch Women's Hospital, Christchurch, New Zealand.
²⁴ Department of Neonatology, Canberra Hospital, Canberra, Australian Capital Territory, Australia.
²⁵ Department of Neonatal Medicine, The Women's and Children's Hospital, Adelaide, South Australia, Australia.
²⁶ Robinson Research Institute, University of Adelaide, Adelaide, South Australia, Australia.
²⁷ Newborn Care, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia.
²⁸ Discipline of Obstetrics, Gynaecology, and Neonatology, University of Sydney, Sydney, New South Wales, Australia.
²⁹ Neonatal and Perinatal Medicine, Te Whatu Ora Waikato, Hamilton, New Zealand.
³⁰ Kidz First Neonatal Care, Te Whatu Ora Counties Manukau, Auckland, New Zealand.
³¹ Department of Paediatrics: Child and Youth Health, University of Auckland, Auckland, New Zealand.

PMID: 39527075
PMCID: PMC11555571
DOI: 10.1001/jama.2024.17380

Clinical Trial

Intratracheal Budesonide Mixed With Surfactant for Extremely Preterm Infants: The PLUSS Randomized Clinical Trial

Brett J Manley et al. JAMA. 2024.

. 2024 Dec 10;332(22):1889-1899.

doi: 10.1001/jama.2024.17380.

Authors

Collaborators

PLUSS Trial Investigators:
Bernice Mills, Li Huang, Kim Dalziel, Rodney Wilson, Scott Morris, Ajit Aiyappan, Tim Cochrane, Arun Nair, Renae Allen, Tim Schindler, Tara Crawford, Callum Gately Gately, Yip Wai Yan, Krishna Revanna, Chua Mei Chien, Polglase Polglase, Stuart Hooper, Huda Ismail, Christine Gilmartin, Wirawan Jeong

Affiliations

¹ Newborn Research, The Royal Women's Hospital, Melbourne, Victoria, Australia.
² Department of Obstetrics, Gynaecology and Newborn Health, The University of Melbourne, Melbourne, Victoria, Australia.
³ Murdoch Children's Research Institute, Melbourne, Victoria, Australia.
⁴ Department of Paediatrics, The University of Melbourne, Melbourne, Victoria, Australia.
⁵ Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia.
⁶ Neonatal and Paediatric Intensive Care Unit, Department of Paediatrics, Royal Hobart Hospital, Hobart, Tasmania, Australia.
⁷ Department of Neonatology, Mater Mother's Hospitals, Brisbane, Queensland, Australia.
⁸ King Edward Memorial Hospital, Perth, Western Australia, Australia.
⁹ University of Western Australia, Perth, Western Australia, Australia.
¹⁰ Centre for the Studies of Asphyxia and Resuscitation, Department of Pediatrics, University of Alberta, Edmonton, Canada.
¹¹ Monash Newborn, Monash Children's Hospital, Melbourne, Victoria, Australia.
¹² Department of Paediatrics, Monash University, Melbourne, Victoria, Australia.
¹³ Newborn Services, Starship Child Health, Te Toku Toma, Auckland, New Zealand.
¹⁴ John Hunter Children's Hospital and University of Newcastle, Newcastle, New South Wales, Australia.
¹⁵ School of Medical Sciences, Paediatrics, Child and Youth Health-Waikato, University of Auckland, Waikato, New Zealand.
¹⁶ Grantley Stable Neonatal Unit, Royal Brisbane and Women's Hospital, University of Queensland, Brisbane, Australia.
¹⁷ Health New Zealand, Capital and Coast DHB, Wellington, New Zealand.
¹⁸ Department of Paediatrics and Child Health, University of Otago, Wellington, New Zealand.
¹⁹ Royal Hospital for Women, Randwick, New South Wales, Australia.
²⁰ Discipline of Paediatrics and Child Health, School of Clinical Medicine, University of New South Wales, Sydney, Australia.
²¹ Department of Neonatology, KK Women's and Children's Hospital, Singapore.
²² Royal North Shore Hospital and University of Sydney, Sydney, New South Wales, Australia.
²³ Neonatal Unit, Christchurch Women's Hospital, Christchurch, New Zealand.
²⁴ Department of Neonatology, Canberra Hospital, Canberra, Australian Capital Territory, Australia.
²⁵ Department of Neonatal Medicine, The Women's and Children's Hospital, Adelaide, South Australia, Australia.
²⁶ Robinson Research Institute, University of Adelaide, Adelaide, South Australia, Australia.
²⁷ Newborn Care, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia.
²⁸ Discipline of Obstetrics, Gynaecology, and Neonatology, University of Sydney, Sydney, New South Wales, Australia.
²⁹ Neonatal and Perinatal Medicine, Te Whatu Ora Waikato, Hamilton, New Zealand.
³⁰ Kidz First Neonatal Care, Te Whatu Ora Counties Manukau, Auckland, New Zealand.
³¹ Department of Paediatrics: Child and Youth Health, University of Auckland, Auckland, New Zealand.

PMID: 39527075
PMCID: PMC11555571
DOI: 10.1001/jama.2024.17380

Abstract

Importance: Bronchopulmonary dysplasia (BPD) is a common adverse outcome in extremely preterm infants born at less than 28 weeks' gestation. Systemic corticosteroids are effective against BPD but may be associated with adverse outcomes. Corticosteroids given directly into the lungs may be effective and safer.

Objective: To investigate the effectiveness of early intratracheal corticosteroid administration on survival free of BPD in extremely preterm infants.

Design, setting, and participants: Double-blind randomized clinical trial conducted in 21 neonatal units in 4 countries (Australia, New Zealand, Canada, and Singapore), enrolling infants born at less than 28 weeks' gestation and less than 48 hours old who were mechanically ventilated (regardless of ventilator settings or oxygen requirements) or who were receiving noninvasive respiratory support and had a clinical decision to treat with surfactant. Recruitment occurred from January 2018 to March 2023. The last participant was discharged from the hospital in August 2023.

Interventions: Infants were randomly allocated (1:1) to receive budesonide, 0.25 mg/kg, mixed with surfactant (poractant alfa), administered via an endotracheal tube or thin catheter, or surfactant only.

Main outcomes and measures: The primary outcome was survival free of BPD at 36 weeks' postmenstrual age. There were 15 secondary outcomes, including the 2 components of the primary outcome (survival at 36 weeks and BPD among survivors), and 9 predefined safety outcomes (adverse events).

Results: The primary analysis included 1059 infants, 524 in the budesonide and surfactant group and 535 in the surfactant-only group. Overall, infants had a mean gestational age of 25.6 weeks (SD, 1.3 weeks) and a mean birth weight of 775 g (SD, 197 g); 586 (55.3%) were male. Survival free of BPD occurred in 134 infants (25.6%) in the budesonide and surfactant group and 121 infants (22.6%) in the surfactant-only group (adjusted risk difference, 2.7% [95% CI, -2.1% to 7.4%]). At 36 weeks' postmenstrual age, 83.2% of infants were alive in the budesonide and surfactant group and 80.6% in the surfactant-only group. Of these, 69.3% and 71.9% were diagnosed with BPD, respectively.

Conclusions and relevance: In extremely preterm infants receiving surfactant for respiratory distress syndrome, early intratracheal budesonide may have little to no effect on survival free of BPD.

Trial registration: anzctr.org.au Identifier: ACTRN12617000322336.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest Disclosures: Dr Manley reported a fellowship from the National Health and Medical Research Council of Australia outside the submitted work. Dr Kamlin reported being an employee of Orphalan SA. Dr Dargaville reported personal fees from Chiesi Farmaceutici (advisory board consultancy in 2021; surfactant symposium in 2023); in addition, Dr Dargaville had a patent for a surfactant instillation catheter (USD752215S) issued and held by Chiesi Farmaceutici (no royalty claims). Dr Doyle reported National Health and Medical Research Council of Australia Center of Research Excellence Grant 1153176 outside the submitted work. No other disclosures were reported.

Figures

**Figure 1.. Participant Flow Through the PLUSS Trial**

**Figure 2.. Percentage of Infants Alive and Free of Bronchopulmonary Dysplasia at 36 Weeks’ Postmenstrual Age by Subgroup**
Subgroup analyses are adjusted for the 3 strata variables except for subgroups that are the strata variables, which are adjusted only for the remaining strata variables. The small-for-gestational-age subgroup risk difference is unadjusted due to small numbers. ^aPost hoc subgroup analysis.

See this image and copyright information in PMC

Comment in

doi: 10.1001/jama.2024.19641

References

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1. Chow SSW, Creighton P, Holberton JR, Chambers GM, Lui K. Report of the Australian and New Zealand Neonatal Network 2021. ANZNN; 2023.
1. Jensen EA, Edwards EM, Greenberg LT, Soll RF, Ehret DEY, Horbar JD. Severity of bronchopulmonary dysplasia among very preterm infants in the United States. Pediatrics. 2021;148(1):148. doi:10.1542/peds.2020-030007 - DOI - PMC - PubMed
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Intratracheal Budesonide Mixed With Surfactant for Extremely Preterm Infants: The PLUSS Randomized Clinical Trial

Collaborators

Affiliations

Intratracheal Budesonide Mixed With Surfactant for Extremely Preterm Infants: The PLUSS Randomized Clinical Trial

Authors

Collaborators

Affiliations

Abstract

Conflict of interest statement

Figures

Comment in

References

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