Effect of Saline vs Gluconate/Acetate–Buffered Solution vs Lactate-Buffered Solution on Serum Chloride Among Children in the Pediatric Intensive Care Unit: The SPLYT-P Randomized Clinical Trial

Sainath Raman; Kristen S Gibbons; Adrian Mattke; Andreas Schibler; Peter Trnka; Melanie Kennedy; Renate Le Marsney; Luregn J Schlapbach

doi:10.1001/jamapediatrics.2022.4912

. 2022 Dec 19;177(2):122–131. doi: 10.1001/jamapediatrics.2022.4912

Effect of Saline vs Gluconate/Acetate–Buffered Solution vs Lactate-Buffered Solution on Serum Chloride Among Children in the Pediatric Intensive Care Unit

The SPLYT-P Randomized Clinical Trial

Sainath Raman ^1,^2,^✉, Kristen S Gibbons ¹, Adrian Mattke ^1,², Andreas Schibler ³, Peter Trnka ⁴, Melanie Kennedy ^1,², Renate Le Marsney ¹, Luregn J Schlapbach ^1,^2,⁵

¹Child Health Research Centre, The University of Queensland, Brisbane, Queensland, Australia

²Pediatric Intensive Care Unit, Queensland Children’s Hospital, South Brisbane, Queensland, Australia

³Wesley Medical Research, Critical Care Research Group, St Andrew’s War Memorial Hospital, Spring Hill, Queensland, Australia

⁴Department of Pediatric Nephrology, Queensland Children’s Hospital, South Brisbane, Queensland, Australia

⁵Department of Intensive Care and Neonatology, and Children’s Research Center, University Children's Hospital Zurich, Zurich, Switzerland

Accepted for Publication: September 14, 2022.

Published Online: December 19, 2022. doi:10.1001/jamapediatrics.2022.4912

Correction: This article was corrected on September 2, 2025, to fix errors in Figure 1.

^✉

Corresponding Author: Sainath Raman, PhD, Centre for Children’s Health Research, 62 Graham St, South Brisbane, QLD 4101, Australia (sainath.raman@uq.edu.au).

Author Contributions: Drs Raman and Gibbons had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Raman, Gibbons, Mattke, Schibler, Trnka, Schlapbach.

Acquisition, analysis, or interpretation of data: Raman, Gibbons, Schibler, Kennedy, Le Marsney, Schlapbach.

Drafting of the manuscript: Raman, Gibbons, Trnka, Le Marsney, Schlapbach.

Critical revision of the manuscript for important intellectual content: Raman, Gibbons, Mattke, Schibler, Trnka, Kennedy, Schlapbach.

Statistical analysis: Gibbons, Trnka, Schlapbach.

Obtained funding: Raman, Schibler, Schlapbach.

Administrative, technical, or material support: Raman, Gibbons, Schibler, Kennedy, Le Marsney, Schlapbach.

Supervision: Raman, Mattke, Schibler, Trnka, Schlapbach.

Conflict of Interest Disclosures: None reported.

Funding/Support: This trial was funded by the Study, Education and Research Trust Account funding scheme 2019, Children’s Health Queensland, Brisbane, Australia. Drs Schlapbach and Schibler have been supported by a grant from the National Health and Medical Research Council and the Children’s Hospital Foundation, Brisbane, Australia.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Data Sharing Statement: See Supplement 3.

Additional Contributions: We thank the patients and families who participated in this trial and acknowledge the support of the pediatric intensive care unit staff for the conduct of this trial.

^✉

Corresponding author.

PMCID: PMC9857166 PMID: 36534387

This randomized clinical trial assesses if balanced solutions decrease the rise of plasma chloride compared with saline, 0.9%, in critically ill children.

Key Points

Question

Do buffered solutions administered as intravenous fluid therapy limit the increase in plasma chloride in critically ill children compared with saline?

Findings

In this randomized clinical trial that included 516 critically ill children, 25.2%, 23.9%, and 40% of patients allocated to gluconate/acetate–buffered solution, lactate-buffered solution, and sodium chloride, 0.9%, respectively, developed a rise in plasma chloride of 5 mEq/L or more from baseline.

Meaning

Treatment with balanced solutions (gluconate/acetate–buffered solution or lactate-buffered solution) compared with saline was associated with significantly lower rise in plasma chloride in the first 48 hours of intravenous fluid therapy in critically ill children.

Abstract

Importance

Most children admitted to pediatric intensive care units (PICUs) receive intravenous fluids. A recent systematic review suggested mortality benefit in critically ill adults treated with balanced solutions compared with sodium chloride, 0.9% (saline). There is a lack of clinically directive data on optimal fluid choice in critically ill children.

Objective

To determine if balanced solutions decrease the rise of plasma chloride compared with saline, 0.9%, in critically ill children.

Design, Setting, and Participants

This single-center, 3-arm, open-label randomized clinical trial took place in a 36-bed PICU. Children younger than 16 years admitted to the PICU and considered to require intravenous fluid therapy by the treating clinician were eligible. Children were screened from November 2019 to April 2021.

Interventions

Enrolled children were 1:1:1 allocated to gluconate/acetate–buffered solution, lactate-buffered solution, or saline as intravenous fluids.

Main Outcomes and Measures

The primary outcome was an increase in serum chloride of 5 mEq/L or more within 48 hours from randomization. New-onset acute kidney injury, length of hospital and intensive care stay, and intensive care–free survival were secondary outcomes.

Results

A total of 516 patients with a median (IQR) age of 3.8 (1.0-10.4) years were randomized with 178, 171, and 167 allocated to gluconate/acetate–buffered solution, lactate-buffered solution, and saline, respectively. The serum chloride level increased 5 mEq/L or more in 37 patients (25.2%), 34 patients (23.9%), and 58 patients (40.0%) in the gluconate/acetate–buffered solution, lactate-buffered solution, and saline groups. The odds of a rise in plasma chloride 5 mEq/L or more was halved with the use of gluconate/acetate–buffered solution compared with saline (odds ratio, 0.50 [95% CI, 0.31-0.83]; P = .007) and with the use of lactate-buffered solution compared with saline (odds ratio, 0.47 [95% CI, 0.28-0.79]; P = .004). New-onset acute kidney injury was observed in 10 patients (6.1%), 6 patients (3.7%), and 5 patients (3.2%) in the gluconate/acetate–buffered solution, lactate-buffered solution, and saline groups, respectively.

Conclusions and Relevance

Balanced solutions (gluconate/acetate–buffered solution and lactate-buffered solution) administered as intravenous fluid therapy reduced the incidence of rise in plasma chloride compared with saline in children in PICU.

Trial Registration

anzctr.org.au Identifier: ACTRN12619001244190

Introduction

More than 500 000 children are admitted to pediatric intensive care units (PICUs) worldwide each year.^1,2,3 Intravenous fluid therapy represents one of the most common treatments applied to this patient group. Its purpose is to hydrate and to maintain normal electrolytes.^4,5 Currently, clinicians choose from several types of solutions to administer as intravenous fluid therapy.

An increasing body of evidence indicates that use of saline may be associated with harm for patients, potentially due to its higher plasma content of chloride. High plasma chloride content has been associated with higher risk of acute kidney injury (AKI)⁶ and an increased risk of death in adults.⁷

Balanced solutions, such as gluconate/acetate–buffered solution and lactate-buffered solution, have a lower chloride content, which is similar to that of plasma and have been proposed to reduce hyperchloremia and acidosis associated with intravenous fluid therapy. Several randomized clinical trials in over 34 000 critically ill adult patients have been published in the last decade exploring the effect of balanced solutions. While controversy surrounding mortality benefit associated with balanced solutions persists, a recent meta-analysis of these data reported an 89.5% likelihood of reduced mortality with the use of balanced solutions in adult intensive care unit patients.^8,9,10,11 Currently, adult international best practice guidelines on prevention of AKI and Surviving Sepsis Campaign guidelines for children and adults recommend use of balanced solutions for large volume resuscitation while monitoring plasma chloride levels.^12,13,14

In critically ill children, there is a lack of clinically directive data on the optimal choice of intravenous fluid solutions.¹⁵ In a 2021 pediatric randomized clinical trial in children presenting to the emergency department, administration of commercially available gluconate/acetate–buffered solution compared with saline, 0.45%, resulted in higher incidence of electrolyte disorders.¹⁶ In a retrospective study, a rise in plasma chloride of 5 mEq/L or more was associated with an increased mortality in children admitted to PICU and in febrile children who received saline or albumin fluid boluses.^15,17

Therefore, we designed the 0.9% Sodium Chloride, Gluconate/Acetate Buffered Solution, and Lactate Buffered Solution for Intravenous Fluid Therapy in Critically Ill Children (SPLYT-P) trial to investigate whether treatment with balanced solutions (gluconate/acetate–buffered solution or lactate-buffered solution) results in a lower rise in plasma chloride levels compared with saline in critically ill children. In addition, we explored the effect on the incidence of AKI.

Methods

Study Design and Oversight

This was a pragmatic single-center, open label, investigator-initiated 3-arm randomized clinical trial. The study was registered with the Australia New Zealand Clinical Trial Registry before commencement of recruitment. The study protocol including composition of the study fluids and the statistical analysis plan was published before completion of enrollment¹⁸ and is available in Supplement 1. Ethics approval was obtained before commencement of the trial (HREC/19/QCHQ/53177; eMethods 1 in Supplement 2). The trial was led by the Child Health Research Centre at The University of Queensland, Brisbane, Australia, and overseen by a trial steering committee who reviewed an interim analysis after data on the first 180 patients was finalized (eMethods 2 in Supplement 2). Consolidated Standards of Reporting Trials (CONSORT) reporting guideline was followed for reporting this trial.¹⁹

Patients

Children younger than 16 years admitted to the PICU at the Queensland Children’s Hospital in Brisbane, Queensland, Australia, and where the treating clinician considered that treatment with intravenous fluid therapy was indicated were eligible for randomization. Only children who had received less than 4 hours of intravenous fluid therapy after PICU admission and who were screened within 24 hours of PICU admission were eligible. Screening took place between November 12, 2019, and April 14, 2021. Children with a plasma sodium equal to or below 130 mEq/L (to convert to millimoles per liter, multiply by 1) at randomization, children with preexisting cardiac or kidney disease, burns, postorgan transplant, diabetic ketoacidosis, traumatic brain injury, and oncology patients needing hyperhydration were excluded (eMethods 3 in Supplement 2). Informed written consent was sought from all parents/carers, using both prospective consent and consent to continue. Aboriginal and Torres Strait Islander status was collected to describe the cohort of participants from the patient registration form on admission to hospital. No other data on race and ethnicity categories were collected. If these data were missing, the research coordinator reviewed the notes in the medical record to obtain this information.

Randomization and Masking

Variable block sizes of 3, 6 and 9 at 1:1:1 allocation were used to generate the randomization schedule, which was integrated into the online study database (REDCap, hosted by the University of Queensland). The trial fluid was not blinded in line with the pragmatic design of the trial and in view of considerations that clinicians may potentially identify the study group using plasma electrolyte measurements.

Interventions

Children received either gluconate/acetate–buffered solution, lactate-buffered solution, or sodium chloride, 0.9%, (saline) solutions for their intravenous fluid therapy. Intravenous fluid therapy was defined as both fluid boluses and maintenance fluid therapy. Total parenteral nutrition and drug dilutions were not considered intravenous fluid therapy. The attending clinician chose the indication, dose, and duration of intravenous fluid therapy based on individual clinical assessment. In our intensive care unit, and allowed by the protocol, potassium can be added to the intravenous fluid bags at the discretion of the clinician. The gluconate/acetate–buffered solution and lactate-buffered solution available on the intensive care unit both contain 5 mEq/L of potassium (to convert to millimoles per liter, multiply by 1).

Outcomes

The primary outcome was an increase in plasma chloride of 5 mEq/L or more within 48 hours from the time of randomization. This was based on recent literature that observed a 2.3 times higher odds of death associated with an increase in plasma chloride 5 mEq/L or more.¹⁵ New-onset AKI (based on Kidney Disease Improving Global Outcome criteria and limited to patients who did not have AKI at randomization),²⁰ survival free of AKI, survival free of organ dysfunction,^21,22 length of hospital and PICU stay, and PICU-free survival were assessed as secondary outcomes. Outcomes related to AKI were censored at 7 days as secondary kidney dysfunction beyond this period was considered less likely to be due to the randomized fluid. All other outcomes were censored at 28 days. Plasma electrolyte and metabolic abnormalities (when measured as part of routine clinical care) were recorded as safety outcomes. A detailed description of the prespecified outcomes has been previously published.¹⁸

Baseline demographic data, study treatments, and outcomes were manually collected, with additional data (including intravenous fluid therapy data, components to calculate organ dysfunction scores, biochemical data) extracted from the electronic health records. A prespecified data monitoring plan was executed throughout the trial to ensure accurate data collection (eMethods 4 in Supplement 2).

Sample Size

We assumed a baseline rate of 20% increase of plasma chloride by 5 mEq/L or more based on our institutional data. To demonstrate a 10% absolute reduction in prevalence of the primary outcome with a type I error rate of 0.05 and 80% power, a total of 432 participants with a 1:1:1 allocation between saline and each of the balanced solutions (gluconate/acetate–buffered solution and lactate-buffered solution) would be required. To account for 10% attrition, the target sample size was increased to 480 participants.

Statistical Analysis

The statistical analysis plan was prespecified and reported, including the analysis code, which was uploaded to GitHub prior to completion of enrollment.¹⁸ All analyses were performed on the patient cohort who were randomized, provided written consent, did not withdraw from the study, and were analyzed according to their randomized group, consistent with an intention-to-treat principle. Rerandomizations within 28 days were excluded as the some of the secondary outcomes were censored to 28 days.

Mixed-effects logistic regression models were used to compare the odds of achieving the primary outcome between the randomized groups. Patient-level random intercepts were used to account for the correlation among repeated measures collected for patients who may have been enrolled in the study on multiple occasions. The odds ratio, 95% CI, and P values are reported.

Binary secondary and safety outcomes were analyzed using a similar approach; however, no P values are reported for these outcomes. Length of stay was analyzed using a Cox proportional hazards model with randomization group and patient treated similarly to the primary analysis, while proportionality assumption was inspected visually using Kaplan-Meier plots and log-log plot, with no clear evidence of divergence. Hazard ratios with 95% CIs are presented. Composite outcome measures (survival free of AKI, organ dysfunction, and PICU-free survival) were analyzed using quantile regression due to non-normal distribution of the outcomes, adjusting for treatment group.

Preplanned subgroup analyses were undertaken for age at PICU admission (≤6 months, >6 months to 5 years, >5 years to <16 years), and admission type (elective vs nonelective admissions). Only the primary outcome measure was assessed for subgroup analyses.

A modified per-protocol analysis was undertaken for the primary outcome. The per-protocol cohort was defined as patients who were eligible and randomized with consent and had both baseline and follow-up chloride measures, with analysis according to the intravenous fluid therapy received, independent of the treatment group they were allocated to.

Statistical significance was assessed using a P value of .05 with a 2-tailed test. No correction for multiple comparisons was applied in the evaluation of secondary or other outcomes. Thus, such results are exploratory and are reported as point estimates with 95% CIs. All analyses were performed with Stata/SE version 17.0 (StataCorp).

Results

Baseline Characteristics

Of 1747 children who were screened, 583 children underwent randomization. Six children were excluded postrandomization due to rerandomization within 28 days of a prior episode. Of the rest, 31 were not approached for consent, leaving 178, 171, and 167 children included in the primary analysis who were allocated to the gluconate/acetate–buffered solution, lactate-buffered solution, and saline groups, respectively (Figure 1 and eFigure 1 in Supplement 2). Enrollment rate was 30 per month (53.9% of eligible patients) (eTable 1 in Supplement 2).

Figure 1. — IV indicates intravenous; PICU, pediatric intensive care unit.

^aParticipants could have 1 or more reasons for ineligibility/nonenrolment.

^bCommon reasons included randomization being performed electronically but not saved in the database and previous indication by families they do not want to participate in any research.

^cParticipants could have 1 or more reasons for not being approached for consent.

^dReasons included early patient discharge, clinician direction, palliative care, and randomization error.

Baseline characteristics of the study cohort are presented in Table 1. The median (IQR) age was 3.8 (1.0-10.4) years. Sixteen (9.0%), 12 (7.1%), and 8 (4.8%) children were from the Aboriginal and Torres Straits Islander race in the gluconate/acetate–buffered solution, lactate-buffered solution, and saline groups, respectively. A total of 296 patients (57.4%) were recruited after a nonelective admission, and 143 patients (27.7%) underwent mechanically ventilation at randomization. Patients had received a median (IQR) of 26.2 (11.4-51.3) mL/kg intravenous fluid prior to randomization.

Table 1. Baseline Characteristics of the Study Cohort.

Characteristic	No. (%)
Characteristic	Gluconate/acetate–buffered solution (n = 178)	Lactate-buffered solution (n = 171)	Sodium chloride, 0.9% (saline) (n = 167)
Age, median (IQR), y	3.4 (0.9-10.2)	4.2 (1.1-10.8)	3.6 (0.9-10.5)
Weight, median (IQR), kg	15.3 (8.5-32.0)	16.9 (10.1-33.2)	16.0 (9.0-31.6)
Aboriginal and Torres Strait Islander	16 (9.0)	12 (7.1)	8 (4.8)
Sex
Male	94 (52.8)	94 (55.0)	79 (47.3)
Female	84 (47.2)	77 (45.0)	88 (52.7)
Presenting diagnosis
Elective admission	73 (41.0)	76 (44.4)	71 (42.5)
After general surgery	27 (15.2)	28 (16.4)	24 (14.4)
After ENT surgery	13 (7.3)	14 (8.2)	13 (7.8)
After other surgery	32 (18.0)	33 (19.3)	34 (20.4)
Other	1 (0.6)	1 (0.6)	0 (0)
Nonelective admission	105 (59.0)	95 (55.6)	96 (57.5)
Respiratory infections	37 (20.8)	34 (19.9)	42 (25.2)
Neurologic disorders	24 (13.5)	25 (14.6)	21 (12.6)
Sepsis	11 (6.2)	9 (5.3)	9 (5.4)
Trauma	8 (4.5)	4 (2.3)	11 (6.6)
Oncology disorders	0 (0)	1 (0.6)	1 (0.6)
Other	25 (14.0)	22 (12.9)	12 (7.2)
Comorbidities
Any comorbidity	61 (34.3)	59 (34.5)	66 (39.5)
Chronic neurological disorders	28 (15.7)	25 (14.6)	27 (16.2)
Syndromes	24 (13.5)	24 (14.0)	22 (13.2)
Chronic respiratory disorders	17 (9.6)	7 (4.1)	9 (5.4)
Cancer	3 (1.7)	3 (1.8)	5 (3.0)
Admission source
Operating theatre	88 (49.4)	75 (43.9)	79 (47.3)
Interhospital transfer	43 (24.2)	47 (27.5)	44 (26.4)
Emergency department	32 (18.0)	29 (17.0)	26 (15.6)
Hospital ward	14 (7.9)	19 (11.1)	17 (10.2)
Other	1 (0.6)	1 (0.6)	1 (0.6)
Biochemical values on admission, median (IQR)^a
Calcium, mg/dL	9.6 (9.2-10.4)	9.6 (9.2-10.0)	9.6 (9.2-10.0)
Chloride, mEq/L	108 (105-112)	108 (104-111)	107 (105-110)
Creatinine, mg/dL^b	0.35 (0.33-0.56)	0.35 (0.33-0.48)	0.36 (0.33-0.52)
Potassium, mEq/L	4.2 (3.6-4.5)	4.1 (3.8-4.4)	4.1 (3.7-4.5)
Sodium, mEq/L	139 (137-141)	139 (137-141)	138 (137-140)
Pediatric index of mortality 3, median (IQR)	0.32 (0.12-1.11)	0.21 (0.11-1.06)	0.30 (0.14-1.09)
Organ dysfunction (PELOD-2) on admission, median (IQR)^c	1 (0-3)	1 (0-3)	0 (0-3)
Mechanical ventilation^d	50 (28.1)	44 (25.7)	49 (29.3)
Cardiovascular support in the first hour^e	11 (6.2)	10 (5.9)	9 (5.4)
Volume of intravenous fluids received prior to randomization
Total volume, mL/kg
No.	159	153	148
Median (IQR)	23.7 (9.9-44.7)	33.9 (14.2-59.2)	23.5 (11.2-48.4)
Total maintenance, mL/kg
No.	117	113	117
Median (IQR)	10.9 (4.1-24.9)	14.6 (8.2-24.6)	14.6 (6.8-28.6)
Total boluses, mL/kg
No.	113	111	85
Median (IQR)	18.8 (9.9-30.8)	28.1 (14.5-45.0)	18.1 (10.0-33.8)
Gluconate/acetate–buffered solution, mL/kg
No.	10	3	3
Median (IQR)	1.9 (0.7-3.6)	5.0 (4.8-21.3)	9.2 (6.0-13.4)
Lactate-buffered solution, mL/kg
No.	71	76	67
Median (IQR)	12.4 (7.5-21.1)	16.7 (11.1-26.2)	16.8 (11.1-29.3)
Sodium chloride, 0.9%, mL/kg
No.	125	129	119
Median (IQR)	22.1 (9.0-36.4)	22.9 (11.2-44.3)	19.4 (8.5-35.5)

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Abbreviations: ENT, ear, nose, and throat; PELOD-2, Pediatric Logistic Organ Dysfunction–2.

SI conversion factors: To convert calcium to millimoles per liter, multiply by 0.25; chloride to millimoles per liter, multiply by 1; creatinine to micromoles per liter, multiply by 88.4; potassium to millimoles per liter, multiply by 1; sodium to millimoles per liter, multiply by 1.

^{^a}

Measured up to 12 hours before randomization.

^{^b}

Serum only.

^{^c}

PELOD-2 is a weighted score with values of 0 indicating absence of organ dysfunction, and higher values indicating increasing severity of organ dysfunction, components measured closest to pediatric intensive care unit admission time, and between 1 hour prior to 1 hour after; defined as invasive or noninvasive, excluding high-flow support.

^{^d}

Defined as use of inotropes or vasopressors.

^{^e}

Any fluids administered in the hospital admission associated with the pediatric intensive care unit admission.

Intervention

In the 48 hours postrandomization, the median (IQR) duration of intravenous fluid therapy was 18.1 (11.9-25.8), 18.9 (11.8-29.7), and 19.2 (13.2-27.4) hours in the gluconate/acetate–buffered solution, lactate-buffered solution, and saline groups, respectively (eTable 2 in Supplement 2). The total median (IQR) volume of fluid received during PICU stay was 33.7 (20.9-63.1), 39.9 (25.8-64.7), and 42.1 (23.6-66.6) mL/kg in the gluconate/acetate–buffered solution, lactate-buffered solution, and saline groups, respectively. The differences between the groups were not statistically significant (eTable 2 in Supplement 2). Of 349 patients, 71 (20.3%) in the gluconate/acetate–buffered solution and lactate-buffered solution groups received saline (eTable 2 in Supplement 2).

Primary Outcome

An increase in plasma chloride by 5 mEq/L or more during the first 48 hours was observed in 37 patients (25.2%), 34 patients (23.9%), and 58 patients (40.0%) in the gluconate/acetate–buffered solution, lactate-buffered solution, and saline groups, respectively (eFigures 2 and 3 in Supplement 2). The odds ratio of a rise in plasma chloride of 5 mEq/L or more with the use of gluconate/acetate–buffered solution compared with saline was 0.50 (95% CI, 0.31-0.83; P = .007) and 0.47 when comparing lactate-buffered solution with saline (95% CI, 0.28-0.79; P = .004) (Table 2 and Figure 2). The mean (SD) plasma chloride at 48 hours from randomization was 110.5 (5.3) in the gluconate/acetate–buffered solution arm, 110.5 (5.0) in the lactate-buffered solution arm, and 112.0 (5.5) in the saline arm. A per-protocol analysis demonstrated a similar association when comparing gluconate/acetate–buffered solution or lactate-buffered solution vs saline in relation to the primary outcome (Table 2).

Table 2. Primary Outcome in the Whole Cohort and Subgroups.

Characteristic	No./total No. (%)			Odds ratio (95% CI)^a		P value for interaction^a
Characteristic	Gluconate/acetate–buffered solution (n = 178)	Lactate-buffered solution (n = 171)	Sodium chloride, 0.9% (saline) (n = 167)	Gluconate/acetate–buffered solution vs saline	Lactate-buffered solution vs saline	P value for interaction^a
Total trial cohort: intention-to-treat
Increase in serum chloride by ≥5 mEq/L during the first 48 h	37/147 (25.2)	34/142 (23.9)	58/145 (40.0)	0.50 (0.31-0.83)^b	0.47 (0.28-0.79)^c	NA
Total trial cohort: per-protocol^d
Increase in serum chloride by ≥5 mEq/L during the first 48 h	34/128 (26.6)	32/115 (27.8)	58/128 (45.3)	0.44 (0.26-0.74)	0.47 (0.27-0.80)	NA
Subgroup: age group
≤6 mo	6/26 (23)	11/19 (58)	15/22 (68)	0.14 (0.039-0.50)	0.64 (0.18-2.30)	.004
>6 mo-5 y	16/61 (26)	9/53 (17)	19/56 (34)	0.66 (0.26-1.72)	0.36 (0.098-1.33)
>5 y	15/60 (25)	14/70 (20)	24/67 (36)	0.60 (0.28-1.29)	0.45 (0.21-0.97)
Subgroup: admission type
Elective	12/56 (21)	7/62 (11)	12/58 (21)	1.05 (0.42-2.57)	0.49 (0.18-1.34)	<.001
Nonelective	25/91 (27)	27/80 (34)	46/87 (53)	0.34 (0.18-0.63)	0.45 (0.24-0.85)	<.001

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Abbreviation: NA, not applicable.

SI conversion factor: To convert chloride to millimoles per liter, multiply by 1.

^{^a}

Adjusted for patient to account for readmissions.

^{^b}

P = .007.

^{^c}

P = .004.

^{^d}

A total of 145 individuals had no outcome due to missing baseline chloride or chloride value in first 48 hours.

Figure 2. — Findings are shown for the overall cohort and subgroups. GBS indicates gluconate/acetate–buffered solution; LBS, lactate-buffered solution.

Secondary Outcomes

New-onset AKI was observed in 10 patients (6.1%), 6 patients (3.7%), and 5 patients (3.2%) in the gluconate/acetate–buffered solution, lactate-buffered solution, and saline groups, respectively (Table 3).^23,24 The median (IQR) survival free of organ dysfunction was 27 (26-27) days in all 3 groups. The median (IQR) length of PICU stay was 1.1 (0.8-2.4), 1.1 (0.8-2.4), and 1.2 (0.8-3.1) days in the gluconate/acetate–buffered solution, lactate-buffered solution, and saline group, respectively (eFigure 4 in Supplement 2). None of the other secondary outcomes were different between the groups.

Table 3. Secondary Outcomes in the Whole Cohort and Subgroups.

Characteristic	Median (IQR)			Estimate of difference (95% CI)^a
Characteristic	Gluconate/acetate–buffered solution (n = 178)	Lactate-buffered solution (n = 171)	Sodium chloride, 0.9% (saline) (n = 167)	Gluconate/acetate–buffered solutions vs saline	Lactate-buffered solutions vs saline
Clinical outcomes
New-onset AKI using predicted baseline values^b	NA	NA	NA	2.52 (0.36 to 17.77)	1.24 (0.24 to 6.32)
No.	165	161	157
No. (%)	10 (6.1)	6 (3.7)	5 (3.2)
Survival free of AKI, d	7 (7 to 7)	7 (7 to 7)	7 (7 to 7)	NA^d	NA^d
Survival free of organ dysfunction, d^c	27 (26 to 27)	27 (26 to 27)	27 (26 to 27)	NA^d	NA^d
Length of PICU stay, d	1.1 (0.8 to 2.4)	1.1 (0.8 to 2.4)	1.2 (0.8 to 3.1)	1.76 (1.15 to 2.70)	2.19 (1.38 to 3.47)
Length of hospital stay, d	5.6 (3.0 to 10.1)	5.7 (2.7 to 9.9)	5.6 (3.1 to 15.0)	1.48 (0.96 to 2.29)	2.05 (1.30 to 3.22)
PICU-free survival, d	26.9 (25.6 to 27.2)	26.9 (25.6 to 27.2)	26.8 (24.9 to 27.2)	0.13 (−0.19 to 0.44)	0.081 (−0.24 to 0.40)
Safety outcomes, No. (%)
At least 1 adverse event	7 (3.9)	9 (5.3)	6 (3.6)	1.14 (0.27 to 4.77)	1.68 (0.38 to 7.34)
Hyponatremia^e	0 (0)	0 (0)	0 (0)	NA	NA
Hyperkalemia^f	1 (0.6)	2 (1.2)	1 (0.6)	NA	NA
Hypokalemia^g	0 (0)	0 (0)	0 (0)	NA	NA
Hyperlactemia^h	5 (2.8)	7 (4.1)	4 (2.4)	NA	NA

Open in a new tab

Abbreviations: AKI acute kidney injury; NA, not applicable; PICU pediatric intensive care unit.

^{^a}

Adjusted for patient to account for readmissions.

^{^b}

AKI was assessed using serum creatinine levels according to Kidney Disease: Improving Global Outcomes (KDIGO) criteria.²⁰Where baseline creatinine values were not available, we applied the age-specific thresholds used in Boer et al²³ for children younger than 1 year and used the formula: mean creatinine (μmol/L) = −2.37330 − 12.91367 × log_e (age) + 23.93581 × (age)^½; thresholds in Ceriotti et al²⁴ for children 1 year or older were used to define the predicted baseline creatinine values. KDIGO stage 1 was defined as an increase in creatinine to 1.5 to 1.9 times the baseline and/or an increase of 26.5 μmol/L or more in 48 hours; stage 2 as an increase 2.0 to 2.9 times; and KDIGO 3 as an increase 3.0 or more baseline and/or and increase to 353.6 μmol/L or more and/or the use of kidney replacement therapy.

^{^c}

Organ dysfunction defined as Pediatric Logistic Organ Dysfunction–2 more than 0.

^{^d}

Due to lack of variation in outcome between groups, no estimate of differences generated.

^{^e}

Hyponatremia defined as plasma sodium less than 125 mEq/L.

^{^f}

Hyperkalemia defined as plasma potassium more than 6.2 mEq/L.

^{^g}

Hypokalemia defined as plasma potassium less than 2.5 mEq/L.

^{^h}

Hyperlactemia defined as arterial or free-flowing venous gas lactate more than 36.0 mg/dL.

Subgroup Analyses

In subgroup analyses on age and admission type, the primary outcome occurred consistently less frequently in the gluconate/acetate–buffered solution and lactate-buffered solution groups compared with the saline group. The most evident association of a lower incidence of the primary outcome was in the subgroups of infants younger than 6 months and nonelective admissions treated with gluconate/acetate–buffered solution and lactate-buffered solution compared with saline (Table 2 and Figure 2).

Protocol Deviations and Adverse Events

Overall, there was at least 1 protocol deviation in 157 enrolled patients (30.4%), with 59 patients having 2 or more protocol deviations of a total of 343 protocol deviations reported (eTable 3 in Supplement 2). Of 343 protocol violations, 285 (83.1%) affected administration of a nonrandomized fluid to the patient.

Potassium was added in 174 of 178 patients (97.8%), 165 of 171 patients (96.5%), and 48 of 167 patients (28.7%) in the gluconate/acetate–buffered solution, lactate-buffered solution, and saline groups, respectively, reflecting a median (IQR) potassium addition of 0.17 (0.11-0.32), 0.20 (0.13-0.38), and 0.81 (0.28-1.81) mmol/kg. Adverse events were observed in 22 patients (4.3%) (Table 3). One episode (0.6%) of hyperkalemia was noted in the gluconate/acetate–buffered solution group, 2 (1.2%) in the lactate-buffered solution group, and 1 (0.6%) in the saline group. Hyperlactemia was noted in 5 patients (2.8%), 7 patients (4.1%), and 4 patients (2.4%) in the gluconate/acetate–buffered solution, lactate-buffered solution, and saline groups. There were no documented episodes of hyponatremia, hypercalcemia, hypocalcemia, hypokalemia, or hypermagnesemia.

Discussion

Main Findings

In this randomized clinical trial, children admitted to the PICU who received either gluconate/acetate–buffered solution or lactate-buffered solution as intravenous fluid therapy less frequently developed a rise in plasma chloride of 5 mEq/L or more when compared with saline. Our findings indicate that balanced solutions reduce hyperchloremia, with the per-protocol analysis and several subgroup analyses confirming the main results. While the trial was not powered for secondary clinical outcomes, we did not observe substantial differences in patient-centered outcomes such as new-onset AKI, PICU and hospital length of stay, or mortality.

Comparison With Other Studies

We chose a metabolic end point in our trial as previous pediatric and adult retrospective studies have demonstrated associations between increases in plasma chloride level and mortality.^15,17,25,26 In addition, hyperchloremia has been associated with AKI,^27,28 possibly caused by decreased kidney blood flow.²⁹ In our study, the mean plasma chloride levels were similar to a recent adult trial where the mean difference was −1.99 (95% CI, −2.21 to −1.76) mmol/L with the strongest difference observed on day 2.³⁰ The results of our trial are supported by the findings from 2 recently published large trials that investigated the effect of balanced solution compared with saline on mortality in adult intensive care patients, both of which did not show a mortality benefit with a balanced solution.^30,31 Our secondary outcomes, especially new-onset AKI, were not different between the groups. While 0 adult study reported similar results,⁹ another observed a lower major adverse kidney event rate within 30 days but no difference in mortality in patients treated with balanced solutions.¹⁰ A systematic review of 6 low-bias adult trials including 34 450 participants estimated a mean mortality reduction of 0.96 (95% CI, 0.91-1.01) associated with balanced solutions in critically ill adult patients.⁸ With millions of patients being exposed to intravenous fluid therapy worldwide, even such a marginal benefit becomes relevant at a population level.

While lactate-buffered solutions have been the most widely used buffered fluid solution internationally,^10,11 more recently, gluconate/acetate–buffered solution has been increasingly used in many settings.³⁰ Theoretical advantages of gluconate/acetate–buffered solution include a closer composition to plasma with a lower chloride content. For this reason, the study was designed as a 3-arm study, comparing gluconate/acetate–buffered solution, lactate-buffered solution, and saline.

In our study, we consistently observed approximately half the incidence of chloride rise in patients treated with buffered solutions compared with saline across intention-to-treat, per-protocol, and subgroup analyses. This association was strongest in those who were aged 6 months or younger. A possible cause could be a lower excretion of chloride by the immature kidney in this age group. We did not observe any episodes of severe hypokalemia (defined as <2.5 mmol/L), whereas Lahtiranta et al¹⁶ reported an incidence of hypokalemia (defined as <3.0 mmol/L) of 2.6% in patients receiving commercially available plasma-like isotonic fluid. Of note, the study protocol of the present study allowed clinicians to supplement potassium at their discretion.

While the study design was highly pragmatic, protocol deviations occurred in 30.6% of patients, primarily related to the administration of nonallocated fluids dictated by the clinical needs.

Implications

The results indicate that the use of balanced solutions leads to a lower incidence of plasma chloride rise. Given that many critically ill children receive a high amount of intravenous fluid therapy and in our single-center trial we were able to recruit 30 patients per month, a larger pediatric fluid trial powered for patient centered–outcomes is warranted and potentially feasible.^32,33 Major Adverse Kidney Events at 30 days (MAKE30) has been proposed as a patient-centered relevant outcome for this population.³⁴ MAKE30 is a composite metric of death, new kidney replacement therapy, and persistent kidney dysfunction, censored at 30 days postrandomization. We cannot estimate the prevalence of MAKE30 from the current study as we did not collect persistent kidney dysfunction data in our study; however, in our previous retrospective review we noted that 30% of children did not regain normal kidney function by discharge or at day 7 of PICU admission.³⁵

With no clear demonstrable benefit from the 2 buffered solutions used in this present study, a pragmatic future trial could be limited to include 2 arms, buffered vs normal saline, to investigate superiority. To demonstrate a relative reduction in MAKE30 from 4% to 2% with power of 90% and type I error of 0.05 in a randomized clinical trial with 2 treatment groups, 1524 patients per group will be required. Such a trial would be feasible as a multicenter collaboration.

Limitations

Several limitations of this trial need to be considered. First, 72.3% of patients received saline before randomization. In addition, there were 285 instances (140 maintenance and 145 bolus) of fluid contamination during the study. Second, the single-center design may limit generalizability. Third, the open-label design may have introduced clinician bias in terms of choice of fluid volumes. This design was chosen to enable a highly pragmatic trial.^36,37 Fourth, we excluded several diagnostic groups of children, which, per our institutional practice, receive disease-specific fluid therapies, such as diabetic ketoacidosis or traumatic brain injury, limiting the generalizability of our findings. Fifth, the acuity of this PICU cohort was relatively low as measured by the Pediatric Logistic Organ Dysfunction–2 score. Accordingly, exposure to intravenous fluid therapy was limited with a mean of 34.5 mL/kg delivered in the first 24 hours after randomization. Sixth, the study was not powered for patient-centered end points. Finally, we were unable to estimate the exact prevalence of MAKE30 from the collected data in our study.

Conclusions

Among critically ill children requiring intravenous fluid therapy, balanced solutions (gluconate/acetate–buffered solution and lactate-buffered solution) reduced the incidence of rise in plasma chloride compared with saline. These results assessed alongside the recent adult systematic review results justify performing a larger pediatric trial powered for patient-oriented primary outcomes.

Supplement 1.

Trial protocol

jamapediatr-e224912-s001.pdf^{(394.3KB, pdf)}

Supplement 2.

eMethods 1. List of ethics approval numbers and approved protocol modifications

eMethods 2. Results of interim analyses

eMethods 3. Inclusion and exclusion criteria

eMethods 4. Data monitoring plan

eFigure 1. Recruitment graph

eFigure 2. Change in plasma chloride from randomization up to day 7 of enrolment

eFigure 3. Comparison of baseline serum chloride to highest chloride in first 48 hours

eFigure 4. Kaplan-Meier curves for length of stay in a) intensive care unit and b) hospital

eTable 1. Feasibility metrics

eTable 2. Description of intravenous fluid therapy administered to the enrolled cohort in the first 24 hours post-randomization, first 48 hours post-randomization, and until PICU discharge

eTable 3. Description of protocol deviations

jamapediatr-e224912-s002.pdf^{(575.9KB, pdf)}

Supplement 3.

Data sharing statement

jamapediatr-e224912-s003.pdf^{(16.7KB, pdf)}

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplement 1.

Trial protocol

jamapediatr-e224912-s001.pdf^{(394.3KB, pdf)}

Supplement 2.

eMethods 1. List of ethics approval numbers and approved protocol modifications

eMethods 2. Results of interim analyses

eMethods 3. Inclusion and exclusion criteria

eMethods 4. Data monitoring plan

eFigure 1. Recruitment graph

eFigure 2. Change in plasma chloride from randomization up to day 7 of enrolment

eFigure 3. Comparison of baseline serum chloride to highest chloride in first 48 hours

eFigure 4. Kaplan-Meier curves for length of stay in a) intensive care unit and b) hospital

eTable 1. Feasibility metrics

eTable 2. Description of intravenous fluid therapy administered to the enrolled cohort in the first 24 hours post-randomization, first 48 hours post-randomization, and until PICU discharge

eTable 3. Description of protocol deviations

jamapediatr-e224912-s002.pdf^{(575.9KB, pdf)}

Supplement 3.

Data sharing statement

jamapediatr-e224912-s003.pdf^{(16.7KB, pdf)}

[poi220078r1] 1.Australian and New Zealand Paediatric Intensive Care Registry Annual Activity Report 2018. Australian and New Zealand Intensive Care Society. Accessed November 10, 2022. https://www.anzics.com.au/wp-content/uploads/2020/02/Australian-and-New-Zealand-Paediatric-Intensive-Care-Registry-Activity-Report-2018.pdf

[poi220078r2] 2.Typpo K, Watson RS, Bennett TD, Farris RWD, Spaeder MC, Petersen NJ; Pediatric Existing Data Analysis (PEDAL) Investigators and Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network . Outcomes of day 1 multiple organ dysfunction syndrome in the PICU. Pediatr Crit Care Med. 2019;20(10):914-922. doi: 10.1097/PCC.0000000000002044 [DOI] [PMC free article] [PubMed] [Google Scholar]

[poi220078r3] 3.Paediatric Intensive Care Audit Network Annual Report 2021. Healthcare Quality Improvement Partnership. Accessed November 10, 2022. https://www.picanet.org.uk/wp-content/uploads/sites/25/2022/04/PICANet-2021-Annual-Report_v1.1-22Apr2022.pdf

[poi220078r4] 4.Feld LG, Neuspiel DR, Foster BA, et al. ; Subcommittee on Fluid and Electrolyte Therapy . Clinical practice guideline: maintenance intravenous fluids in children. Pediatrics. 2018;142(6):e20183083. doi: 10.1542/peds.2018-3083 [DOI] [PubMed] [Google Scholar]

[poi220078r5] 5.Finfer S, Myburgh J, Bellomo R. Intravenous fluid therapy in critically ill adults. Nat Rev Nephrol. 2018;14(9):541-557. doi: 10.1038/s41581-018-0044-0 [DOI] [PubMed] [Google Scholar]

[poi220078r6] 6.Krajewski ML, Raghunathan K, Paluszkiewicz SM, Schermer CR, Shaw AD. Meta-analysis of high- versus low-chloride content in perioperative and critical care fluid resuscitation. Br J Surg. 2015;102(1):24-36. doi: 10.1002/bjs.9651 [DOI] [PMC free article] [PubMed] [Google Scholar]

[poi220078r7] 7.Sen A, Keener CM, Sileanu FE, et al. Chloride content of fluids used for large-volume resuscitation is associated with reduced survival. Crit Care Med. 2017;45(2):e146-e153. doi: 10.1097/CCM.0000000000002063 [DOI] [PMC free article] [PubMed] [Google Scholar]

[poi220078r8] 8.Hammond NE, Zampieri FG, Di Tanna GL, et al. Balanced crystalloids versus saline in critically ill adults—a systematic review with meta-analysis. NEJM Evidence. 2022;1(2). doi: 10.1056/EVIDoa2100010 [DOI] [PubMed] [Google Scholar]

[poi220078r9] 9.Young P, Bailey M, Beasley R, et al. ; SPLIT Investigators; ANZICS CTG . Effect of a buffered crystalloid solution vs saline on acute kidney injury among patients in the intensive care unit: the SPLIT randomized clinical trial. JAMA. 2015;314(16):1701-1710. doi: 10.1001/jama.2015.12334 [DOI] [PubMed] [Google Scholar]

[poi220078r10] 10.Semler MW, Self WH, Wanderer JP, et al. ; SMART Investigators and the Pragmatic Critical Care Research Group . Balanced crystalloids versus saline in critically ill adults. N Engl J Med. 2018;378(9):829-839. doi: 10.1056/NEJMoa1711584 [DOI] [PMC free article] [PubMed] [Google Scholar]

[poi220078r11] 11.Self WH, Semler MW, Wanderer JP, et al. ; SALT-ED Investigators . Balanced crystalloids versus saline in noncritically ill adults. N Engl J Med. 2018;378(9):819-828. doi: 10.1056/NEJMoa1711586 [DOI] [PMC free article] [PubMed] [Google Scholar]

[poi220078r12] 12.Joannidis M, Druml W, Forni LG, et al. Prevention of acute kidney injury and protection of renal function in the intensive care unit: update 2017: expert opinion of the Working Group on Prevention, AKI section, European Society of Intensive Care Medicine. Intensive Care Med. 2017;43(6):730-749. doi: 10.1007/s00134-017-4832-y [DOI] [PMC free article] [PubMed] [Google Scholar]

[poi220078r13] 13.Evans L, Rhodes A, Alhazzani W, et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021. Crit Care Med. 2021;49(11):e1063-e1143. doi: 10.1097/CCM.0000000000005337 [DOI] [PubMed] [Google Scholar]

[poi220078r14] 14.Weiss SL, Peters MJ, Alhazzani W, et al. Surviving sepsis campaign international guidelines for the management of septic shock and sepsis-associated organ dysfunction in children. Intensive Care Med. 2020;46(suppl 1):10-67. doi: 10.1007/s00134-019-05878-6 [DOI] [PMC free article] [PubMed] [Google Scholar]

[poi220078r15] 15.Barhight MF, Brinton J, Stidham T, et al. Increase in chloride from baseline is independently associated with mortality in critically ill children. Intensive Care Med. 2018;44(12):2183-2191. doi: 10.1007/s00134-018-5424-1 [DOI] [PubMed] [Google Scholar]

[poi220078r16] 16.Lehtiranta S, Honkila M, Kallio M, et al. Risk of electrolyte disorders in acutely ill children receiving commercially available plasmalike isotonic fluids: a randomized clinical trial. JAMA Pediatr. 2021;175(1):28-35. doi: 10.1001/jamapediatrics.2020.3383 [DOI] [PMC free article] [PubMed] [Google Scholar]

[poi220078r17] 17.Levin M, Cunnington AJ, Wilson C, et al. Effects of saline or albumin fluid bolus in resuscitation: evidence from re-analysis of the FEAST trial. Lancet Respir Med. 2019;7(7):581-593. doi: 10.1016/S2213-2600(19)30114-6 [DOI] [PMC free article] [PubMed] [Google Scholar]

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PERMALINK

Effect of Saline vs Gluconate/Acetate–Buffered Solution vs Lactate-Buffered Solution on Serum Chloride Among Children in the Pediatric Intensive Care Unit

Sainath Raman, PhD

Kristen S Gibbons, PhD

Adrian Mattke, MD

Andreas Schibler, MD

Peter Trnka, MD

Melanie Kennedy, BNurs

Renate Le Marsney, MPH

Luregn J Schlapbach, PhD

Key Points

Question

Findings

Meaning

Abstract

Importance

Objective

Design, Setting, and Participants

Interventions

Main Outcomes and Measures

Results

Conclusions and Relevance

Trial Registration

Introduction

Methods

Study Design and Oversight

Patients

Randomization and Masking

Interventions

Outcomes

Sample Size

Statistical Analysis

Results

Baseline Characteristics

Figure 1. Participant Flow Through the Trial.

Table 1. Baseline Characteristics of the Study Cohort.

Intervention

Primary Outcome

Table 2. Primary Outcome in the Whole Cohort and Subgroups.

Figure 2. Adjusted Estimate of Difference and 95% CI for the Primary Outcome Measure for the Intention-to-Treat Cohort and Subgroups.

Secondary Outcomes

Table 3. Secondary Outcomes in the Whole Cohort and Subgroups.

Subgroup Analyses

Protocol Deviations and Adverse Events

Discussion

Main Findings

Comparison With Other Studies

Implications

Limitations

Conclusions

References

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

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