Balanced Crystalloid vs Normal Saline in Pediatric Acute Gastroenteritis

BACKGROUND AND SCIENTIFIC RATIONALE Acute gastroenteritis causes gastrointestinal bicarbonate loss through diarrhoea, combined with reduced oral intake and, in severe cases, lactate accumulation from hypoperfusion, resulting in metabolic acidosis.

The conventional choice, 0.9% sodium chloride (NS), carries a supraphysiological chloride load (154 mEq/L versus plasma reference of 98-103 mEq/L). This reduces the strong ion difference (SID), independently precipitating hyperchloraemic metabolic acidosis and failing to correct pre-existing acidosis.

Isolyte-S has a chloride content of 98 mEq/L and contains acetate (27 mEq/L) and gluconate (23 mEq/L) as bicarbonate precursors. Acetate is rapidly metabolised in cardiac muscle, skeletal muscle, and renal cortex independently of hepatic function (half-life approximately 30 minutes) via: CH3COO- + O2 + H+ → 2CO2 + 2H2O, consuming 1 mEq of H+ per mEq of acetate. Gluconate undergoes hepatic oxidation via the pentose phosphate pathway with analogous H+ consumption. The total buffer capacity of Isolyte-S is 50 mEq/L - approximately twice that of Ringer's lactate (28 mEq/L). This active acid-neutralisation capacity is mechanistically distinct from simply avoiding chloride overload.

EVIDENCE BASE The 2023 Cochrane systematic review (Florez et al., 5 RCTs, 465 children) demonstrated improved bicarbonate and pH with balanced crystalloids but judged certainty as low to very low and explicitly called for new adequately powered studies. The meta-analysis by Lehr et al. (2022) reported a pooled delta-HCO3 of +1.60 mmol/L (95% CI 0.04-3.16) favouring balanced fluids in critically ill children. The only RCT using Plasma-Lyte A versus NS in paediatric AGE (Allen et al., 2016) reported delta-HCO3 of +1.6 versus 0.0 mEq/L at 4 hours (p=0.004) but was underpowered for clinical outcomes. No published study has investigated Isolyte-S (acetate/gluconate-buffered, 50 mEq/L total buffer capacity) specifically in children with AGE.

STUDY DESIGN Single-centre, prospective, non-interventional observational cohort study conducted in the paediatric emergency department of Aydin Adnan Menderes University Research and Training Hospital, Turkey (KAD-KLVZ-25). No randomisation, allocation, or investigator-initiated prescribing occurs. The treating physician's independent clinical decision determines group assignment before research consent and enrolment.

STATISTICAL FRAMEWORK

Sample size: 180 total enrolments (anticipated), yielding 126 evaluable participants assuming 70% T4 laboratory availability. Power calculation: minimum clinically important difference delta = 1.5 mmol/L, SD = 3.0 mmol/L, alpha = 0.05 (two-sided), power = 0.80.

Primary analysis: PS-IPTW (propensity score inverse probability of treatment weighting) combined with IPOW (inverse probability of observation weighting) to simultaneously address confounding by indication and informative T4 laboratory missingness. A pre-specified covariate list is fixed prior to data lock. Supporting analysis: multivariable linear regression with robust standard errors (HC3).

Pre-specified mechanistic mediation analysis: causal mediation framework (R package mediation) to partition the total effect on delta-HCO3 into the indirect effect mediated via delta-Cl (hyperchloraemic mechanism) and the direct effect attributable to acetate/gluconate buffering (ACME and ADE). This analysis is exploratory and will be reported as mechanism-consistent association, not causal inference. Seven pre-specified sensitivity analyses are defined in the statistical analysis plan.

Reporting standard: STROBE statement for observational studies. Software: R version 4.3 or later.

DATA COLLECTION Data are recorded on a standardised case report form at three time points: T0 (baseline, at IV fluid start), T4 (3-6 hour window, only if routine laboratory results are available), and 72 hours (electronic health record review for return visits). No study-mandated procedures, tests, or visits are added to the routine care pathway. T4 laboratory values are ascertained exclusively from blood gas or electrolyte results obtained during routine clinical management.

Inclusion criteria

• Age: 6 months to 5 years (60 months) inclusive
• Clinical diagnosis of acute gastroenteritis: acute diarrhoea (3 or more loose stools per 24 hours) with or without vomiting; symptom duration 7 days or less
• Clinician-initiated indication for intravenous rehydration
• IV fluid order placed and treatment initiated independently by the treating physician, without research team influence

Exclusion criteria

• Chronic systemic disease (congenital heart disease, chronic kidney disease, chronic lung disease, inborn errors of metabolism, primary immunodeficiency)
• Hypernatraemic dehydration (serum sodium >= 150 mEq/L at baseline)
• Diabetic ketoacidosis, primary metabolic crisis, or suspected surgical abdomen
• Bloody diarrhoea or suspected invasive enteric infection requiring alternative management algorithm
• Hypoglycaemia (blood glucose < 60 mg/dL) at presentation
• Symptom duration exceeding 7 days
• Receipt of 20 mL/kg or more of IV fluid in the 24 hours preceding enrolment