Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12619001244190
Ethics application status
Approved
Date submitted
27/06/2019
Date registered
9/09/2019
Date last updated
28/10/2021
Date data sharing statement initially provided
9/09/2019
Date results information initially provided
28/10/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Comparison of three intravenous fluids used in the treatment of children admitted to the paediatric intensive care unit
Scientific title
Comparison of administration of 0.9% Sodium Chloride solution versus Plasma-Lyte 148 versus Compound Sodium LacTate Solution in children admitted to PICU – a randomised controlled trial
Secondary ID [1] 298612 0
None
Universal Trial Number (UTN)
U1111-1236-0437
Trial acronym
SPLYT-P
Linked study record
None

Health condition
Health condition(s) or problem(s) studied:
Critically ill children 313469 0
Condition category
Condition code
Emergency medicine 311898 311898 0 0
Resuscitation
Emergency medicine 311900 311900 0 0
Other emergency care

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Arm 1 - Plasma-Lyte - 148
Arm 2 - Compound Sodium Lactate solution

Parent information leaflet with consent forms will be provided. The staff will be informed about the two intervention fluid arms.
The intervention will be provided individually after consent.
The research coordinator will screen and consent patients/parents. Once recruited, the junior doctor will be adviced to prescribed the appropriate intravenous fluid therapy as per randomisation. The bedside nurse will administer the intervention fluid therapy as directed by the clinician.
The amount, rate and duration of maintenance fluid and bolus therapy will be dictated by the attending clinician as per institutional protocol. The institutional protocol aligns with international practice on administering intravenous maintenance fluid therapy. Therefore, maintenance fluid requirements are calculated at 4ml/kg/hr for the first 10 kgs, 2ml/kg/hr for next 10 and 1 ml/kg/hr there after according to the weight of the child.
As our primary outcome is a biochemical end-point, we will need blood gases on admission, during PICU stay and at discharge. These will amount to 4 samples if the patient was in PICU for 2 days (usually length of stay for most PICU patients).
Blood gases will be preferentially taken from an already in-situ arterial or venous line and be collected along with routine morning bloods where appropriate. If there are no invasive lines present and the peripheral venous cannula does not bleed back, a capillary blood gas sample will be taken. This is expected to be needed in a minority of patients.

The children will be part of the trial until discharge from Paediatric Intensive Care Unit (PICU) or cessation of intravenous fluid therapy (whichever is earlier). The intervention will only occur on the PICU and be administered until discharge from PICU. The expected duration of intervention is estimated to be around 3-5 days ( around the median PICU length of stay).
All interventions will be assessed retrospectively by automated data collection on a monthly basis to ensure adherence to prescription and study protocol.
Intervention code [1] 314871 0
Treatment: Other
Comparator / control treatment
Children receiving 0.9% Sodium Chloride as the intravenous fluid solution
Control group
Active

Outcomes
Primary outcome [1] 320563 0
Proportion of patients with an increase in serum chloride level greater than or equal to 5mmol/L as a change from baseline value to the highest chloride level within 48 hours post randomization. The difference in serum chloride level from baseline to 6,12,18,24,30,36,42,48 hours after admission (at each time-point where blood gas or lab values are available) will be calculated.
Timepoint [1] 320563 0
Up to 48 hours after randomization
Secondary outcome [1] 372031 0
Proportion of patients with survival free of organ dysfunction (defined by Paediatric Logistic Organ Dysfunction 2 Score - PELOD2). Censored at 28 days post randomization. Assuming PELOD-2 is zero at discharge from PICU in survivors.
Timepoint [1] 372031 0
Censored at 28 days post randomization
Secondary outcome [2] 372032 0
Proportion of patients with survival free of Acute Kidney Injury.

Patients with acute kidney injury at discharge as per Kidney Disease: Improving Global Outcomes definition with be calculated.
Timepoint [2] 372032 0
Censored at 28 days post randomization
Secondary outcome [3] 372849 0
Proportion of patients with new-onset Acute Kidney Injury. Patients with acute kidney injury until day 7 of PICU admission or discharge (whichever is earlier) as per Kidney Disease: Improving Global Outcomes definition with be calculated.
Timepoint [3] 372849 0
Until day 7 of PICU admission or discharge (whichever is earlier)
Secondary outcome [4] 372852 0
Duration of PICU stay.

The number of hours/days of stay on PICU from admission date/time to discharge date/time to the ward by extracting data from the PICU clinical information system.
Timepoint [4] 372852 0
At PICU discharge
Secondary outcome [5] 372853 0
Duration of hospital stay.

The number of hours/days of stay in hospital from admission date/time to discharge date/time to the community by extracting data from the PICU clinical information system and local ANZPIC registry data that is routinely collected.
Timepoint [5] 372853 0
At hospital discharge
Secondary outcome [6] 372854 0
PICU free survival at 28 days
Timepoint [6] 372854 0
Censored at 28 days from the post randomisation.
Secondary outcome [7] 374078 0
Number of adverse events of Hyperkalaemia, Hypokalemia, Hypercalcemia, Hypocalcemia, Hypermagnesemia, Hyponatremia, Hyperlactatemia.
These will be assessed by extracting data from PICU clinical information system with pre-set rules to capture abnormal values of each of the variables.
Timepoint [7] 374078 0
From randomisation to 48hours post randomisation.

Eligibility
Key inclusion criteria
1. All patients – birth to an age of less than 16 years - admitted to the Paediatric Intensive Care Unit (and)
2. Attending clinician decides that intravenous fluid therapy is required
3. Admission Na >130mmol/L
4. New admissions to ICU within the last 24 hours
Minimum age
0 Days
Maximum age
16 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Age greater than or equal to 16 years.
2. Patients admitted with a cardiac condition.
3. Received intravenous fluid therapy for >4 hours in PICU.
4. Patients admitted to the ICU with disease-specific protocols that necessitate specific fluid requirements such as: the treatment of burns; following liver transplantation surgery; post renal transplant surgery; diabetic ketoacidosis.
6. Patients with traumatic brain injury or those considered at risk of developing cerebral edema
7. Patients with pre-existing kidney disease (chronic kidney disease as defined by KDIGO criteria or under the ongoing care of a nephrologist)
8. Oncology patients who need hyperhydration.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation is not concealed.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Dynamic (adaptive) random allocation method using computerised randomisation. No stratification employed.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Computer-Based randomisation will be used to allocate patients in a 1:1:1 allocation between 0.9% Sodium Chloride and each of the balanced solutions (Arm 1 - Plasma-Lyte 18, Arm 2 - Compound Sodium Lactate solution).
Phase
Phase 0
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Sample size calculation:
A recently published article reported an incidence of the rise in chloride level of greater than or equal to 5mmol/L of 12.5% at the end of day 1. Based on a review of our institutional PICU retrospective data, we expect the proportion of children admitted to PICU that has a rise in chloride level of greater than or equal to 5mmol/L to be about 20% by 48 hours. To demonstrate a 10% reduction in the incidence of this primary outcome (5% alpha and 80% power), we will need 432 patients with a 1:1:1 allocation between 0.9% Sodium Chloride and each of the balanced solutions. Plasma-Lyte and Compound Sodium Lactate solution will be equally randomised. To account for a 10% attrition, we have decided to recruit 480 patients. We will complete an interim analysis after 250 patients to assess the power and estimate more accurate sample size.
After we account for the loss of recruits due to exclusions, those receiving no intravenous fluid therapy and missed randomisation, we expect to achieve our target within a 12-month study period. The QCH PICU on average admits 160 patients per month. Assuming 80% of patients will receive IVFT, and 40% drop-out because of meeting exclusion criteria, and 50% consent rates, recruitment of at least 40 patients per month is a realistic target.
Descriptive statistics will be used to report on the baseline characteristics of the total study cohort, each intervention group and the pre-defined subgroups. Associations between treatment group and outcomes will be explored using appropriate techniques, such as chi-squared (or Fisher’s Exact Test if there are low numbers of outcomes), ANOVA or Kruskal-Wallis.
Where there are repeat admissions to PICU, patients are eligible for re-randomisation if the readmission is after 28 days of the previous PICU discharge.
A priori subgroup analysis for primary outcome:
1. Age at PICU admission: less than or equal to 6 months, greater than 6 months to less than or equal to 5 years, greater than 5 years to less than 16 years
2. Elective/Non-elective
3. Patients who received IVFT >24 hours
4. Patients who received IVFT less than or equal to 24 hours
5. Patients who received IVFT >50ml/kg

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
2/10/2019
Actual
12/11/2019
Date of last participant enrolment
Anticipated
18/11/2020
Actual
13/04/2021
Date of last data collection
Anticipated
20/01/2021
Actual
15/07/2021
Sample size
Target
480
Accrual to date
Final
524
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 14107 0
Queensland Children's Hospital - South Brisbane
Recruitment postcode(s) [1] 26900 0
4101 - South Brisbane

Funding & Sponsors
Funding source category [1] 303154 0
Other Collaborative groups
Name [1] 303154 0
Paediatric Critical Care Research Group in-kind
Country [1] 303154 0
Australia
Primary sponsor type
University
Name
University of Queensland
Address
Centre for Children's Health Research,
62 Graham Street, South Brisbane.
Queensland, Australia. 4101
Country
Australia
Secondary sponsor category [1] 303151 0
None
Name [1] 303151 0
None
Address [1] 303151 0
None
Country [1] 303151 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 303713 0
Children's Health Queensland Hospital and Health Service Human Research Ethics Committee
Ethics committee address [1] 303713 0
Children's Health Queensland Hospital and Health Service Human Research Ethics Committee,
Level 7, Centre for Children's Health Research,
62 Graham Street, South Brisbane. Queensland. Australia. 4101
Ethics committee country [1] 303713 0
Australia
Date submitted for ethics approval [1] 303713 0
19/04/2019
Approval date [1] 303713 0
06/06/2019
Ethics approval number [1] 303713 0
HREC/19/QCHQ/53177

Summary
Brief summary
Hypothesis:
Balanced fluids (Plasma-Lyte and Compound Sodium Lactate) will lower the prevalence of high chloride rise (greater than or equal to 5mmol/L) compared to 0.9 % sodium chloride solution.
Study purpose:
To demonstrate if balanced solutions are better than 0.9% sodium chloride as fluid therapy in critically ill children in PICU.
Study design:
Single centre, open label, randomised controlled trial.
Intervention:
Random assignment of individual patients (less than 16 yrs) into three groups – 0.9% Sodium Chloride solution, Plasma-Lyte 148 (PL) and Compound Sodium Lactate solution (CSL).

Outcomes
Primary Outcome
• Increase in serum chloride level greater than or equal to 5mmol/L from baseline value to the highest chloride level within 48 hours from the time of randomisation
Key Secondary Outcomes
• Survival free of Acute Kidney Injury (AKI)
• Survival free of organ dysfunction
• Survival free of new onset AKI
• Duration of ICU / Hospital stay
Trial website
None
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 94546 0
Dr Sainath Raman
Address 94546 0
Senior Lecturer,
Paediatric Critical Care Research Group,
Level 7, Centre for Children’s Health Research Queensland Children’s Hospital Precinct,
62 Graham Street, South Brisbane QLD, Australia. 4101
Country 94546 0
Australia
Phone 94546 0
+61 7 3068 5485
Fax 94546 0
Email 94546 0
[email protected]
Contact person for public queries
Name 94547 0
Dr Sainath Raman
Address 94547 0
Senior Lecturer,
Paediatric Critical Care Research Group,
Level 7, Centre for Children’s Health Research Queensland Children’s Hospital Precinct,
62 Graham Street, South Brisbane QLD 4101
Country 94547 0
Australia
Phone 94547 0
+61 7 3068 5485
Fax 94547 0
Email 94547 0
[email protected]
Contact person for scientific queries
Name 94548 0
Dr Sainath Raman
Address 94548 0
Senior Lecturer,
Paediatric Critical Care Research Group,
Level 7, Centre for Children’s Health Research Queensland Children’s Hospital Precinct,
62 Graham Street, South Brisbane QLD 4101
Country 94548 0
Australia
Phone 94548 0
+61 7 3068 5485
Fax 94548 0
Email 94548 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Anonymised data collected as in the CRF.
When will data be available (start and end dates)?
Start - 01.03.2021
End - 01.09.2021
Available to whom?
Other researchers who want to work on the research topic in question.
Available for what types of analyses?
Post-hoc exploratory analyses.
How or where can data be obtained?
By contacting the PI on [email protected]


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
Embase0.9% Sodium chloride solution versus Plasma-Lyte 148 versus compound sodium lacTate solution in children admitted to PICU-a randomized controlled trial (SPLYT-P): study protocol for an intravenous fluid therapy trial.2021https://dx.doi.org/10.1186/s13063-021-05376-5
N.B. These documents automatically identified may not have been verified by the study sponsor.