The Efficient PICU Fluid Care Evaluation (LESSER-2)

The goal of this clinical trial is to evaluate and prevent fluid overload in critically ill, mechanically ventilated children. The main questions it aims to answer are:

1. What is the effect of a restrictive fluid strategy on cumulative fluid balance on day three of invasive mechanical ventilation?
2. What is the feasibility (e.g. adherence to target intake, fluid balance and nutritional goals) of maintaining a neutral fluid balance?

Researchers will compare the effects of strict adherence to the European Society of Paediatric and Neonatal Intensive Care (ESPNIC) guidelines regarding fluid balance (i.e. restricting fluid intake and preventing a positive fluid balance) to current local practice.

From the start to the end of invasive mechanical ventilation participants will be treated according to local practice or with the strict aim to prevent a positive fluid balance. Aiming to prevent a positive fluid balance, if this is possible given the clinical context, is at descretion of the attending physician. Minimal caloric intake requirements must be met.

Participants are studied for ten days during invasive mechanical ventilation or until discharge from the intensive care

Study Overview

• Status: Not yet recruiting
• Conditions: Fluid Overload; Fluid Balance; Respiratory Insufficiency Requiring Mechanical Ventilation
• Intervention / Treatment: Other: Strict adherence to European guidelines

Detailed Description

Objectives

• Compare current practices with strict adherence to ESPNIC guidelines regarding fluid management in critically ill children.
• Assess the effectiveness of maintaining a neutral cumulative fluid balance by day 3 (CFB3).

Study Design

• Type: Multicenter prospective study with a before-after design, continuous recruitment, and single measurements.

• Groups:

  1. Current practice group.
  2. ESPNIC guideline adherence group (restrictive fluid management).

Treatment

• Current Practice Group: Standard PICU treatment per local protocols.
• ESPNIC Guideline Adherence Group: Strict restrictive fluid strategy beginning within 24 hours of intubation, focusing on preventing cumulative positive fluid balance. ESPNIC guidelines recommend restricting total fluid intake to 65-80% of the Holliday and Segar formula. The Holliday and Segar formula is tailored for children under 10 kg: 150 ml/kg/day for neonates and 100 ml/kg/day for one-year-olds. This study will aim for a 65% restriction based on these calculations.

Feeding Enteral nutrition starts within 24-48 hours unless contraindicated, with caloric intake reaching 100% of resting energy expenditure by day 7 and protein intake exceeding 1.5 g/kg/day.

Diuretics The choice and route of diuretics will be at the treating physician's discretion.

Duration of Intervention Start: Onset of mechanical ventilation. End: End of mechanical ventilation.

Study Procedures Children will have routine blood samples taken daily during invasive mechanical ventilation (IMV), which align with standard clinical diagnostics. Body weight will be measured at admission, on day 3, and before extubation. Data on fluid intake, feeding, medication, and urine output will be gathered prospectively in the electronic patient dossier (EPD).

Adverse Events All adverse events will be recorded, with serious adverse events (SAEs) reported to the sponsor promptly.

• Study Type: Interventional
• Enrollment (Estimated): 90
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Joris Lemson, MD PhD; Phone Number: 0031243617273; Email: joris.lemson@radboudumc.nl
• Study Contact Backup: Name: Michiel Schwerzel, MSc; Phone Number: 0031243617273; Email: michiel.schwerzel@radboudumc.nl

Study Locations

• Netherlands
  • Gelderland
    • Nijmegen, Gelderland, Netherlands, 6525 GA
      • Radboudumc
      • Contact: Michiel Schwerzel, MSc; Phone Number: +31 243617273; Email: michiel.schwerzel@radboudumc.nl
      • Contact: Joris Lemson, MD PhD
  • Noord-Holland
    • Amsterdam, Noord-Holland, Netherlands, 1100 DD
      • Amsterdam MC
      • Contact: Reinout Bem, MD PhD; Phone Number: +31 566 8000; Email: r.a.bem@amsterdamumc.nl
      • Contact: Reinout Bem, MD PhD
  • Zuid-Holland
    • Rotterdam, Zuid-Holland, Netherlands, 3015 CN
      • ErasmusMC
      • Contact: Hanneke Bakker, MD PhD; Phone Number: +31 10703 62 55; Email: johanna.bakker@erasmusmc.nl
      • Contact: Hanneke Bakker, MD PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age < 10 years and weight < 35 kg
• Receiving invasive mechanical ventilation (IMV) due to respiratory failure
• Inclusion possible within 24 hours of start of IMV
• Expected duration of IMV > 48 hours

Exclusion Criteria:

• Preterm (<37weeks gestational age)
• Preexistent (clinical) diagnosis of kidney disease
• Congenital cardiac defect with hemodynamic consequences or reduced cardiac function
• (Ongoing) shock with need for fluid resuscitation and/or vasoactive drugs
• Cardiovascular (including diuretics) drug use on admission (home medication)
• Pre-existent (clinical) diagnosis of liver failure
• Right of left heart failure
• Pulmonary hypertension
• ECMO treatment
• Receiving total parenteral nutrition on admission which won't be stopped
• Failure to include within 12 hours after start of IMV
• Expected duration of IMV < 48 hours
• Parents or caretakers unable to understand/speak Dutch language
• Surgery < 48 hours

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Observation of current local practices; Current local practices regarding fluid management will be observed. Population: Critically ill children receiving mechanical ventilation due to respiratory insufficiency. Patients will be treated according to local protocols at the discretion of the attending physicians.
Active Comparator: Strict adherence to european guidelines; In this intervention attending physicians will be encouraged to strictly adhere the European (ESPNIC) guidelines regarding fluid management.	Other: Strict adherence to European guidelines; The goal is to maintain a neutral fluid balance throughout the course of intubation if clinical practice allows. Therefore: From the start of mechanical ventilation, the maximum maintenance fluids is 65% of the maintenance fluids proposed by the Holliday & Segar formula. Fluid resuscitation in the first hours after intubation is at the discretion of the attending physician.; Any other interventions to maintain a neutral fluid balance (e.g., starting diuretics, reducing fluid boluses, decreasing creep fluids, or using more concentrated enteral feeding) are at the discretion of the attending physician.; Throughout the intervention, the attending physician decides if clinical practice allows for a decrease in fluid balance, and international feeding goals must always be met.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cumulative fluid balance on day 3 in ml/kg	Cumulative fluid balance (CFB) over the course of three days after the start of mechanical ventilation is noted in ml/kg. CFB is calculated as a sum of daily (fluid intake [liters] - total output [liters])/ body weight (kilograms).	From start mechanical ventilation to 72 hours after start of mechanical ventilation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Daily cumulative fluid balance on in ml/kg	Daily cumulative fluid balance (CFB) over the course of mechanical ventilation is noted in ml/kg. CFB is calculated as a sum of daily (fluid intake [liters] - total output [liters])/ body weight (kilograms).	For 10 days, CFB is noted every day at 00:00
Protein intake in gr/kg/day	Protein intake in gr/kg/day will be daily noted	For ten days after start of mechanical ventilation
Bodyweight in grams	Bodyweight in grams	Bodyweight in grams will be measured at start of mechanical ventilation and at 72 hours after start of mechanical ventilation
Daily cumulative diuretics dose in mg/kg	Cumulative diuretics dose will be daily noted in mg/kg.	From start of mechnical ventilation for ten days, cumulative diuretic dose will be noted at 00:00
Blood urea nitrogen (BUN) in mmol/L	During the course of mechanical ventilation blood urea nitrogen (BUN) is measured in mmol/L	BUN will be measured at 24 hours, 72 hours and at 120 hours after start of mechanical ventilation
Daily creatinine level in µmol/L	Daily creatinine level in µmol/L	Creatinine levels will be noted at: 24, 72 hours and 120 after start of mechanical ventilation
Daily KDIGO stages (1,2 or 3) will be noted every 24 hours	Daily KDIGO stages will be noted every 24 hours depending on their urine production. KDIGO 1= <0.5ml/kg/h for 6-12 hours, KDIGO 2 = <0.5ml/kg/h for >12 hours, KDIGO 3 = <0.3ml/kg/h for 24 hours or anuria for >12 hours	From start of mechanical ventilation to 120 hours after start of mechanical ventilation.
Daily potassium levels in mmol/L every 24 hours	During mechanical ventilation daily potassium levels in mmol/L every 24 hours	From start of mechanical ventilation for ten days, at 08:00 in the morning
Daily sodium levels in mmol/L every 24 hours	During mechanical ventilation daily sodium levels in mmol/L every 24 hours	From start of mechanical ventilation for ten days, at 08:00 in the morning
Daily lactate measurement in mmol/L every 24 hours	During mechanical ventilation daily lactate measurement in mmol/L every 24 hours	From start of mechanical ventilation for ten days, at 08:00 in the morning
Daily pH measurement every 24 hours	During mechanical ventilation daily pH measurement every 24 hours	From start of mechanical ventilation for ten days, at 08:00 in the morning
Daily ketone levels in blood every 24 hours in mmol/L	During mechanical ventilation daily ketone levels in blood every 24 hours in mmol/L	From start of mechanical ventilation for ten days, at 08:00 in the morning
Daily vasoactive-inotropic score every 24 hours	Vasoactive-inotropic score is calculated by: [dopamine dose (μg/kg/min) + dobutamine dose (μg/kg/min) + 100 × epinephrine dose (μg/kg/min) + 10 × milrinone dose (μg/kg/min) + 10 000 × vasopressin dose (unit/kg/min) + 100 × norepinephrine dose (μg/kg/min)]	From start of mechanical ventilation for ten days
Daily highest heart rate in beats per minute from every previous 24 hours	Daily highest heart rate in beats per minute from every previous 24 hours	From start of mechanical ventilation for ten days
Daily lowest heart rate in beats per minute from every previous 24 hours	Daily lowest heart rate in beats per minute from every previous 24 hours	From start of mechanical ventilation for ten days
Daily mean mean arterial pressure (so mean MAP) over every previous 24 hours	Daily mean mean arterial pressure (so mean MAP) over every previous 24 hours. Mean MAP is calculated by calculating the mean from blood pressure from hourly collected data	From start of mechanical ventilation for ten days
Daily mean heart rate in beats per minute over every previous 24 hours	Daily mean heart rate in beats per minute over every previous 24 hours. Mean Mean heart rate is calculated by calculating the mean heartrate from hourly collected data	From start of mechanical ventilation for ten days
Duration of IMV in days	Duration of invasive mechanical ventilation is noted in days	From start of mechanical ventilation for ten days
Duration of high flow nasal canula therapy after end of mechanical ventilation in hours	Duration of high flow nasal canula therapy after end of mechanical ventilation in hours	From the end of mechanical ventilation up to ten days after start of mechanical ventilation
Need for extracorporeal organ support (ECMO) is noted (yes/no)	Need for extracorporeal organ support (ECMO) is noted (yes/no)	From start of mechanical ventilation to day ten after start of emchanical ventilation
Daily mean oxygenation saturation index is noted every 24 hours only when SpO2 was below 97%	During IMV daily mean oxygenation saturation index is noted every 24 hours only when SpO2 was below 97%. This is calculated by: ([Paw x FiO2]/SpO2) × 100	From start of mechanical ventilation for ten days
Mean daily P/F ration is noted from every previous 24 hours	During IMV mean daily P/F ration is noted from every previous 24 hours	From start of mechanical ventilation for ten days
Lenght of pediatric intensive care (PICU) stay in days	Lenght of pediatric intensive care (PICU) stay in days	From start of mechanical ventilation to 10 days after start mechanical ventilation
Newly acquired pulmonary infections (yes/no)	Newly acquired pulmonary infections (yes/no)	From start of mechanical ventilation for ten days
Total daily fluid balance is noted in ml/kg every 24 hours	Total daily fluid balance is noted in ml/kg every 24 hours	From start of mechnical ventilation for ten dys
Daily fluid intake in ml/kg every 24 hours	Daily fluid intake will be noted in ml/kg ervery 24 hours	From start of mechanical ventilation for ten days
Caloric intake in kcal/kg every 24 hours	Daily caloric intake in kcal/kg will be noted every 24 hours	From start of mechanical ventilation for ten days
Daily urine production in ml//kg from every 24 hours	Daily urine production in ml//kg from every 24 hours	From start of mechnical ventilation for ten days

Collaborators and Investigators

• Sponsor: Radboud University Medical Center
• Investigators: Principal Investigator: Joris Lemson, MD PhD, Radboud University Medical Center

Publications and helpful links

General Publications

• Arrahmani I, Ingelse SA, van Woensel JBM, Bem RA, Lemson J. Current Practice of Fluid Maintenance and Replacement Therapy in Mechanically Ventilated Critically Ill Children: A European Survey. Front Pediatr. 2022 Feb 23;10:828637. doi: 10.3389/fped.2022.828637. eCollection 2022.
• Valentine SL, Sapru A, Higgerson RA, Spinella PC, Flori HR, Graham DA, Brett M, Convery M, Christie LM, Karamessinis L, Randolph AG; Pediatric Acute Lung Injury and Sepsis Investigator's (PALISI) Network; Acute Respiratory Distress Syndrome Clinical Research Network (ARDSNet). Fluid balance in critically ill children with acute lung injury. Crit Care Med. 2012 Oct;40(10):2883-9. doi: 10.1097/CCM.0b013e31825bc54d.
• Ingelse SA, Geukers VG, Dijsselhof ME, Lemson J, Bem RA, van Woensel JB. Less Is More?-A Feasibility Study of Fluid Strategy in Critically Ill Children With Acute Respiratory Tract Infection. Front Pediatr. 2019 Dec 10;7:496. doi: 10.3389/fped.2019.00496. eCollection 2019.
• Diaz F, Nunez MJ, Pino P, Erranz B, Cruces P. Implementation of preemptive fluid strategy as a bundle to prevent fluid overload in children with acute respiratory distress syndrome and sepsis. BMC Pediatr. 2018 Jun 26;18(1):207. doi: 10.1186/s12887-018-1188-6.
• Charaya S, Angurana SK, Nallasamy K, Jayashree M. Restricted versus Usual/Liberal Maintenance Fluid Strategy in Mechanically Ventilated Children: An Open-Label Randomized Trial (ReLiSCh Trial). Indian J Pediatr. 2023 Oct 18. doi: 10.1007/s12098-023-04867-4. Online ahead of print.
• Brossier DW, Tume LN, Briant AR, Jotterand Chaparro C, Moullet C, Rooze S, Verbruggen SCAT, Marino LV, Alsohime F, Beldjilali S, Chiusolo F, Costa L, Didier C, Ilia S, Joram NL, Kneyber MCJ, Kuhlwein E, Lopez J, Lopez-Herce J, Mayberry HF, Mehmeti F, Mierzewska-Schmidt M, Minambres Rodriguez M, Morice C, Pappachan JV, Porcheret F, Reis Boto L, Schlapbach LJ, Tekguc H, Tziouvas K, Parienti JJ, Goyer I, Valla FV; Metabolism Endocrinology and Nutrition section of the European Society of Pediatric and Neonatal Intensive Care (ESPNIC). ESPNIC clinical practice guidelines: intravenous maintenance fluid therapy in acute and critically ill children- a systematic review and meta-analysis. Intensive Care Med. 2022 Dec;48(12):1691-1708. doi: 10.1007/s00134-022-06882-z. Epub 2022 Oct 26. Erratum In: Intensive Care Med. 2023 Jan;49(1):128-129. doi: 10.1007/s00134-022-06933-5. Intensive Care Med. 2023 Sep;49(9):1151-1153. doi: 10.1007/s00134-023-07119-3.

Study record dates

Study Major Dates

• Study Start (Estimated): October 1, 2024
• Primary Completion (Estimated): May 1, 2025
• Study Completion (Estimated): May 1, 2025

Study Registration Dates

• First Submitted: October 10, 2024
• First Submitted That Met QC Criteria: October 14, 2024
• First Posted (Actual): October 16, 2024

Study Record Updates

• Last Update Posted (Actual): October 16, 2024
• Last Update Submitted That Met QC Criteria: October 14, 2024
• Last Verified: September 1, 2024

More Information

Terms related to this study

• Keywords: Edema; Fluids; Respiratory Insufficiency; Mechanical ventilation; Fluid Balance; Fluid Overload; Childeren; Lenght of mechanical ventilation; Maintenance fluids
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Respiration Disorders; Respiratory Insufficiency
• Other Study ID Numbers: 2023-16717

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Demograpghics data; Outcome data
• IPD Sharing Time Frame: From publication until 15 years after publication
• IPD Sharing Access Criteria: Data will be made available upon reasonable request to the corresponding author
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No