Restricted Versus Liberal Fluid Intake for Prevention of Bronchopulmonary Dysplasia (RELIEF)

Restricted Versus Liberal Fluid Intake for Prevention of Bronchopulmonary Dysplasia - RELIEF Trial. A Cluster-randomised Multiple Period Cross-over Trial.

The aim of this study is to determine whether restricted fluid intake (135 ±5 mL/kg/day) compared to liberal fluid intake (165 ±5 mL/kg/day) from day 8 of life reduces the incidence of bronchopulmonary dysplasia (BPD) at 36 weeks postmenstrual age or prior death in preterm infants born <30 weeks gestational age.

Study Overview

• Status: Recruiting
• Conditions: Bronchopulmonary Dysplasia
• Intervention / Treatment: Other: Fluid restriction; Other: Liberal fluid intake

Detailed Description

Complications of preterm birth remain the leading cause of death in children under five years of age worldwide, accounting for approximately one million deaths annually. Among the survivors, bronchopulmonary dysplasia (BPD) is the most common severe complication. BPD is a chronic lung disease characterized by prolonged need for respiratory support and oxygen therapy, poor postnatal growth, and long-term impairments in lung function and neurodevelopment.

Despite advancements in neonatal care, BPD is the most common chronic lung disease in infancy and associated with increased mortality, repeated hospitalisation throughout childhood, impaired lung function up into adulthood, and long-term neurodevelopmental impairment. The incidence of BPD has remained stable over the past 15 years. This is likely due to the improved survival of extremely preterm infants, who are at the highest risk for BPD.

A key feature of evolving BPD is the accumulation of interstitial pulmonary edema, which reduces lung compliance and increases the need for respiratory support, thereby perpetuating a cycle of lung damage.

Currently, diuretics are sometimes used to manage pulmonary edema in preterm infants. While they can improve lung function in the short term, they come with potential risks including bone demineralization, nephrotoxicity, electrolyte imbalances, and impaired growth.

As a potentially safer alternative, fluid restriction is sometimes used to prevent or manage pulmonary edema. It is hypothesized to improve lung mechanics and reduce the need for respiratory support, without the adverse effects associated with medications. However, there is no robust evidence on optimal fluid targets in these patients.

SwissNeoNet, consisting of all nine Swiss NICUs, is a mandatory national registry, where data on all infants born before 32 weeks of gestation and/or with a birth weight < 1501 g are collected. Fluid management practices vary among Swiss neonatal intensive care units (NICUs) following international guidelines recommending 135 to 180 mL/kg/day of fluids. This variation may contribute to the differing rates of BPD and mortality observed across centers, but fluid intake is not routinely captured in SwissNeoNet data, making it difficult to assess its impact.

In summary, although fluid restriction shows potential as a simple and low-risk intervention to reduce the incidence of BPD, current evidence is insufficient to support its routine use. There is a clear need for a robust, contemporary, and pragmatic trial to evaluate whether fluid restriction, started after the first week of life, can safely and effectively reduce the incidence of BPD or death in very preterm infants.

• Study Type: Interventional
• Enrollment (Estimated): 750
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Anne Carrer; Phone Number: +4161 704 2853; Email: anne.carrer@ukbb.ch
• Study Contact Backup: Name: Michel Schrutt; Email: relief@ukbb.ch

Study Locations

• Switzerland
  • Aarau, Switzerland, 5001
    • Recruiting
    • Kantonsspital Aarau AG, Klinik für Kinder u. Jugendliche
    • Contact: Philipp Meyer, KD Dr. med.; Phone Number: +41 62 838 49 48; Email: philipp.meyer@ksa.ch
    • Principal Investigator: Philipp Meyer, KD Dr. med.
  • Basel, Switzerland, 4056
    • Recruiting
    • University Children's Hospital Basel (UKBB)
    • Contact: Sven Schulzke, Prof. MD; Phone Number: +41 61 5565486; Email: sven.schulzke@ukbb.ch
    • Contact: Benjamin Stöcklin, PD MD; Email: benjamin.stoecklin@ukbb.ch
    • Principal Investigator: Sven Schulzke, Prof. MD
  • Bern, Switzerland, 3010
    • Recruiting
    • Inselspital Bern, Kinderklinik
    • Contact: André Kidszun, Prof. MD; Phone Number: +41 31 632 21 11; Email: andre.kidszun@insel.ch
    • Contact: Marta Busso, MD; Phone Number: +41 76 2324427; Email: marta.busso@insel.ch
    • Principal Investigator: André Kidszun, Prof. MD
  • Chur, Switzerland, 7000
    • Recruiting
    • Kantonsspital Graubünden, Departement Kinder- und Jugendmedizin
    • Contact: Bjarte Rogdo, Dr. med.; Phone Number: +41 81 256 6400; Email: bjarte.rogdo@ksgr.ch
    • Principal Investigator: Bjarte Rogdo, MD
  • Geneva, Switzerland, 1205
    • Recruiting
    • Hôpitaux universitaires de Genève (HUG), Unité de Néonatologie
    • Contact: Francisca Barcos Munoz, MD; Phone Number: +41 22 372 68 16; Email: francisca.barcos@hug.ch
    • Contact: Riccardo Pfister, Prof. MD; Email: riccardo.pfister@hug.ch
    • Principal Investigator: Riccardo Pfister, Prof. MD
  • Lausanne, Switzerland, 1011
    • Recruiting
    • Centre hospitalier universitaire vaudois (CHUV) - Service de néonatologie
    • Contact: Eric Giannoni, Assoc. Prof.; Phone Number: +41 21 314 34 60; Email: Eric.Giannoni@chuv.ch
    • Contact: Sébastien Joye, MD; Phone Number: +41 21 314 3464; Email: Sebastien.Joye@chuv.ch
    • Principal Investigator: Eric Giannoni, Assoc. Prof.
  • Lucerne, Switzerland, 6000
    • Recruiting
    • Luzerner Kantonsspital, Kinderspital
    • Contact: Martin Stocker, Prof. MD; Phone Number: +41 (0)41 205 32 31; Email: martin.stocker@luks.ch
    • Principal Investigator: Martin Stocker, Prof. MD
  • Sankt Gallen, Switzerland, 9006
    • Recruiting
    • Ostschweizer Kinderspital & Neonatologie und Frauenklinik KSSG, Perinatalzentrum St. Gallen
    • Contact: André Birkenmaier, Dr.med.; Phone Number: +41 (0)71 243 71 11; Email: Andre.Birkenmaier@kispisg.ch
    • Principal Investigator: André Birkenmaier, MD
  • Zurich, Switzerland, 8091
    • Recruiting
    • UniversitätsSpital Zürich, Klinik für Neonatologie
    • Contact: David Glauser, MD; Phone Number: +41 43 253 87 59; Email: david.glauser@usz.ch
    • Contact: Dirk Bassler, Prof. MD; Phone Number: +41 44 255 11 11; Email: dirk.bassler@usz.ch
    • Principal Investigator: Dirk Bassler, Prof. MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Hospitalised preterm infants born before 30 weeks 0 days gestation
• Signed informed consent for further research use of health-related data

Exclusion Criteria:

• congenital malformations
• diseases likely to affect life expectancy, lung function, fluid strategy, or neurodevelopment
• renal disease requiring fluid management outside the clinical standard of care
• congenital heart disease not including patent ductus arteriosus (PDA)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Liberal fluid intake; Liberal fluid intake strategy (fluid target 165 ± 5 mL/kg/d) in line with international best practice recommendations on nutrition.	Other: Liberal fluid intake; Liberal fluid intake strategy (fluid target 165 ± 5 mL/kg/d)
Experimental: Fluid restriction; Fluid restriction strategy (fluid target 135 ±5 mL/kg/d). This is standard of care.	Other: Fluid restriction; Fluid restriction strategy (fluid target 135 ±5 mL/kg/d)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Bronchopulmonary dysplasia (BPD)	Proportion of infants with BPD measured at 36 weeks postmenstrual age or prior death.	From enrolment to 36 weeks postmenstrual age

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complications of prematurity	Major complications of prematurity including necrotising enterocolitis ≥ Bell's stage 2, retinopathy of prematurity requiring treatment, patent ductus arteriosus requiring treatment, abnormal brain ultrasound, late onset sepsis	From enrolment to 36 weeks postmenstrual age
Need of diuretics	Treatment with diuretics (days on diuretics)	From enrolment to 36 weeks postmenstrual age
Need of corticosteroids	Systemic postnatal corticosteroids for prevention or treatment of bronchopulmonary dysplasia	From enrolment to 36 weeks postmenstrual age
Need of respiratory support	Duration of mechanical ventilation, non-invasive respiratory support, total positive pressure support, supplemental oxygen support, supplemental home oxygen, home ventilation	At first discharge home, on average 37 weeks postmenstrual age
Growth	difference in weight, length, and head circumference z-score at 36 weeks postmenstrual age and at birth, respectively	at birth and 36 weeks postmenstrual age
Daily caloric intake	Daily caloric intake from day 8 of life to 36 weeks postmenstrual age	From enrolment to 36 weeks postmenstrual age
Dehydration	Dehydration (sodium level ≥ 150 mmol/L plus clinical signs of dehydration)	From enrolment to 36 weeks postmenstrual age
Fluid overload	Fluid overload (sodium level ≤ 130 mmol/L plus clinical signs of fluid overload)	From enrolment to 36 weeks postmenstrual age
Age at discharge	Postmenstrual age at discharge home	At first discharge home, on average 37 weeks postmenstrual age
Days to reach full feeds	Days to reach full feeds defined as 150 ml/kg/d or being off parenteral nutrition	From enrolment to 36 weeks postmenstrual age
Tube feeding	Tube feeding at discharge home	At first discharge home, on average 37 weeks postmenstrual age

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Visits to the emergency	Visits to the emergency department from discharge to 6-12 months for any reason	From discharge to 6-12 and 18-24 months
Growth	Growth (weight, length, and head circumference z-score)	from 36 weeks postmenstrual age, 6-12 and 18-24 months post-term
Respiratory outcome	Respiratory outcome as per Basel-Bern-Infant-Lung-Development cohort study questionnaire	from 36 weeks postmenstrual age, 6-12 and 18-24 months post-term
Neurodevelopmental outcome	Neurodevelopmental outcome as per PARCA-R questionnaire	from enrolment to 18-24 months post-term

Collaborators and Investigators

• Sponsor: University Children's Hospital Basel
• Collaborators: Swiss Neonatal Network; SwissPedNet
• Investigators: Principal Investigator: Sven Schulzke, Prof.MD, University Children's Hospital Basel

Study record dates

Study Major Dates

• Study Start (Actual): July 12, 2025
• Primary Completion (Estimated): December 1, 2029
• Study Completion (Estimated): December 1, 2029

Study Registration Dates

• First Submitted: April 15, 2025
• First Submitted That Met QC Criteria: April 23, 2025
• First Posted (Actual): May 1, 2025

Study Record Updates

• Last Update Posted (Actual): May 8, 2026
• Last Update Submitted That Met QC Criteria: May 4, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Fluid Restriction; Preterm Infants
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Lung Diseases; Infant, Premature, Diseases; Infant, Newborn, Diseases; Lung Injury; Ventilator-Induced Lung Injury; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Bronchopulmonary Dysplasia
• Other Study ID Numbers: 2025-00321; ks22Schulzke

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No