Efficacy and safety of isotonic versus hypotonic intravenous maintenance fluids in hospitalized children: an updated systematic review and meta-analysis of randomized controlled trials
Authors: Amer Basma Ehab , Abdelwahab Omar Ahmed , Abdelaziz Ahmed , Soliman Youssef , Amin Ahmed Mostafa , Mohamed Maged Ahmed , Albakri Khaled , Zedan Esraa Mohamed , Hamouda Naema 
Published: June 2023

Abstract
Background
Iatrogenic hyponatremia is a common complication following intravenous maintenance fluid therapy (IV-MFT) in hospitalized children. Despite the American Academy of Pediatrics' 2018 recommendations, IV-MFT prescribing practices still vary considerably.

Objectives
This meta-analysis aimed to compare the safety and efficacy of isotonic versus hypotonic IV-MFT in hospitalized children.

Data sources
We searched PubMed, Scopus, Web of Science, and Cochrane Central from inception to October 1, 2022.

Study eligibility criteria
We included randomized controlled trials (RCTs) comparing isotonic versus hypotonic IV-MFT in hospitalized children, either with medical or surgical conditions. Our primary outcome was hyponatremia following IV-MFT. Secondary outcomes included hypernatremia, serum sodium, serum potassium, serum osmolarity, blood pH, blood sugar, serum creatinine, serum chloride, urinary sodium, length of hospital stay, and adverse outcomes.

Study appraisal and synthesis methods
Random-effects models were used to pool the extracted data. We performed our analysis based on the duration of fluid administration (i.e., ≤ 24 and > 24 h). The Grades of Recommendations Assessment Development and Evaluation (GRADE) scale was used to evaluate the strength and level of evidence for recommendations.

Results
A total of 33 RCTs, comprising 5049 patients were included. Isotonic IV-MFT significantly reduced the risk of mild hyponatremia at both ≤ 24 h (RR = 0.38, 95% CI [0.30, 0.48], P < 0.00001; high quality of evidence) and > 24 h (RR = 0.47, 95% CI [0.37, 0.62], P < 0.00001; high quality of evidence). This protective effect of isotonic fluid was maintained in most examined subgroups. Isotonic IV-MFT significantly increased the risk of hypernatremia in neonates (RR = 3.74, 95% CI [1.42, 9.85], P = 0.008). In addition, it significantly increased serum creatinine at ≤ 24 h (MD = 0.89, 95% CI [0.84, 0.94], P < 0.00001) and decreased blood pH (MD = –0.05, 95% CI [–0.08 to –0.02], P = 0.0006). Mean serum sodium, serum osmolarity, and serum chloride were lower in the hypotonic group at ≤ 24 h. The two fluids were comparable in terms of serum potassium, length of hospital stay, blood sugar, and the risk of adverse outcomes.

Limitations
The main limitation of our study was the heterogeneity of the included studies.

Conclusions and implications of key findings
Isotonic IV-MFT was superior to the hypotonic one in reducing the risk of iatrogenic hyponatremia in hospitalized children. However, it increases the risk of hypernatremia in neonates and may lead to renal dysfunction. Given that the risk of hypernatremia is not important even in the neonates, we propose to use balanced isotonic IV-MFT in hospitalized children as it is better tolerated by the kidneys than 0.9% saline.

Systematic review registration number
CRD42022372359.