Hypernatremia Fluid Therapy in Childhood Diarrhoea

Diarrhoeal disease remains one of the leading causes of death among children aged under five years of age. The World Health Organization (WHO) recommends the use of appropriately prepared oral rehydration salt solution (ORS) and Zinc as the best remedy for diarrhea. At icddr,b Dhaka Hospital, every year we found 2.4-5.1% children having hypernatremia, a serum sodium ≥150 mmol/L, mostly resulting from inappropriate preparation and use of ORS. In other hospital-based studies, the reported prevalence of hypernatremia in children with diarrhoea was 11.2% in Bangladesh (non-icddr,b), 7.2% in India, 14% in Iran, and 22% in Pakistan. Hypernatremic dehydration is one of the most fatal types of dehydration, particularly in children under two years of age. Infants are at higher risk of developing hypernatremia due to immature renal function, increased insensible water loss, and limited ability to communicate thirst. Hypernatremia commonly occurs when there is excessive loss of water relative to sodium loss or disproportionate sodium intake compared to water intake. The increase in plasma tonicity causes water movement across cell membranes, leading to intra-cellular dehydration. Brain cells are particularly vulnerable, and severe hypernatremia can induce brain shrinkage, potentially causing cerebral haemorrhage, seizures, paralysis, and encephalopathy. Rapid correction of hypernatremia is associated with the potential development of oedema and high fatality rates, necessitating a controlled reduction in serum sodium levels. Incorrectly prepared oral ORS solutions, including preparation errors and improper intake frequency, have been implicated in hypernatremia severity. Mortality rates in acute hypernatremia reach up to as high as 19%, with neurological complications occurring in 15% of cases. These include intellectual deficits, seizure disorders, and spastic paralysis. Seizures may result from hypernatremia itself or from overly rapid correction.

Management Principles: Treatment of hypernatremia requires fluid administration to correct water deficits while limiting further water loss. Paediatric patients often present with concurrent hypovolemia due to gastrointestinal losses, requiring volume restoration with isotonic fluids before addressing hypernatremia. Ongoing monitoring of fluid status and frequent electrolyte assessments guide therapy adjustments.

The goal of treatment is to restore plasma tonicity gradually. Rapid correction is recommended only in acute cases to prevent cellular dehydration effects. For hypernatremia developing over days, correction of serum sodium concentration should not exceed 0.5 mmol/L/h or 12 mmol/L/day, though no randomized trials specifically support this threshold. The choice of replacement fluid depends on the type of fluid loss and concurrent electrolyte imbalances.

Paediatric textbooks such as Nelson Textbook of Pediatrics (21st edition) and Ghai Essential Pediatrics (9th edition) recommend managing hypernatremia by administering 1.25 to 1.5 times the maintenance fluid requirement over a period of 24 to 84 hours, depending on the severity of hypernatremia. The commonly recommended fluid for this purpose is 0.45% sodium chloride in 5% dextrose. This approach does not involve a direct calculation of fluid deficit using formal equations such as Edelman's. Instead, it assumes that the fluid deficit can be adequately addressed by providing a higher-than-maintenance fluid volume. The maintenance requirement can be calculated using standard Holliday Seger formula, that is 100 ml/kg/day for first 10 kg and 50ml/kg/day for next 10 kg (11-20kg) then for each kg over 20kg it will be 20ml/kg/day. formulas such as 100 mL/kg/day.

For example, in an 8 kg child (age 1 year) with a serum sodium level of 165 mmol/L, fluid would be administered at 1.5 times the maintenance rate, equivalent to 150 mL/kg/day (i.e., 150 × 8 = 1200mL/day). Dietary volume will be 70 kcal/kg/day and this volume is incorporated in the total fluid volume. So, for this child total diet volume is {70× 8(100/67)} = 835 ml milk suji (As milk suji 100 ml contain 67 kcal). And correction fluid volume is 1200-835=365 ml/day. After 24 hours if the sodium level were ≥150 mmol/L, the same volume will be delivered for next 24 hours.(21) This strategy represents a simplified, clinically practical method that indirectly addresses fluid deficit through augmented maintenance, without separate deficit and maintenance phases.

Rationale for the Study:

icddr,b Dhaka Hospital is the largest diarrhoeal disease hospital in Bangladesh, managing over 200,000 diarrhoea cases annually, 60% of whom are children under five. Studies conducted at icddr,b, Dhaka Hospital during two separate periods revealed that the prevalence of hypernatremia decreased from 5.1% in 2001-2002 to 2.4% in 2009-2011, while the case fatality rate increased from 15% to 19%. During this period clinical management strategies varied based on clinician preference. These included one-portion ORS and subsequent two portion water to match ongoing stool loss. Another option was to add concentrated saline to an isotonic IV fluid to create a solution with a sodium concentration at least 20 mmol/L lower than that of plasma. More recently we are using Adrogue formula with some modification. Overall, correction using ORS was significantly associated with better survival compared to those who received IV infusion.

Despite a decline in its prevalence, recent data from icddr,b Dhaka Hospital showed that the case fatality rate remains as high as 19%, highlighting ongoing gaps in effective management. Clinical practice currently varies, with no universally accepted standard for the optimal type, rate, or route of fluid replacement. While gradual sodium correction is recommended to prevent cerebral oedema and seizures, existing protocols rely on formulas (e.g., Edelman, Adrogue-Madias) that are primarily validated in adults and require complex calculations. Moreover, the choice between oral and intravenous fluid therapy remains debated, particularly in resource-limited settings where IV therapy carries risks of iatrogenic complications and requires intensive monitoring.

This study will address a critical gap by conducting a randomized controlled trial comparing oral and intravenous fluid therapy using the same standardized volume protocol for the correction of hypernatremic dehydration in children. By evaluating key outcomes including mortality, sodium correction rates, and neurological sequelae, the trial aims to identify a safe, effective, and context-appropriate treatment strategy that can reduce preventable deaths and long-term complications in this vulnerable population.

Research Design and Methods

Methodology

Study design: Randomized, controlled, open-label, non-inferiority trial. Study settings: Dhaka Hospital, icddr,b Study Population: Children under the age of five years Study duration: 2 years Sample size: 268 (IV arm 134, Oral arm 134) Ethical Approval: Ethical approval for the trial will be taken from the institutional review board of icddr,b which is comprised of Research Review Committee and Ethical Review Committee.

Operational Definition:

Hypernatremia: Hypernatremia is defined as serum sodium level of ≥ 150 mmol/L and categorized as

* Mild hypernatremia: 150 -159.9 mmol/L
* Moderate hypernatremia: 160-169.9 mmol/L
* Severe hypernatremia: ≥ 170 mmol/L Clinical manifestation of hypernatremia: Signs and symptoms of hypernatremia may consist of excessive thirst disproportionate to dehydration, restlessness, irritability, muscular twitching or jitteriness, and a high-pitched cry. Overt signs of dehydration may not be absent, but symptoms such as tachycardia, tachypnoea, a doughy skin texture, altered mental status, vacant stare, convulsion or unconsciousness may occur. Exaggerated deep tendon reflexes are also observed.

Rapid drop of serum sodium: will be defined as when there is a reduction of serum sodium of more than 12 mEq/L in any 24-hour period.

Features of raised intracranial pressure: Following a rapid drop in serum sodium, features of raised intracranial pressure include seizure, altered mental status, obtundation, coma, abnormal breathing pattern, bradycardia, and hypotension.

AKI (Acute Kidney Injury): Elevated serum creatinine (>1.5 times the reference value) considered as AKI Normal reference value for infant 11-34 µmol/l and for children 21-65 µmol/l. So, those who have creatinine >51 µmol/l for infant and 97.5 µmol/l for children was considered as AKI. Urine output <0.5ml/kg/hour for at least 12 hours:

Poor Neurological Outcome: Poor neurological outcome will be defined as any evidence of neurological impairment either during hospitalization or after discharge. During hospitalization, this includes a Glasgow Coma Scale (GCS) score of less than 13 persisting for more than 24 hours after stabilization, new-onset focal neurological deficits (such as paralysis or hemiparesis), or two or more seizures despite appropriate treatment. At the time of discharge, poor outcome is defined as failure to return to baseline neurological status (GCS <15) or persistence of abnormal neurological signs. Post-discharge, at 1- and 6-month follow-up visits, poor neurological outcome will be identified as developmental delay in two or more domains (gross motor, fine motor, language, personal-social) assessed by the Denver Developmental Screening Test II, or the presence of persistent motor deficits or development of cerebral palsy or epilepsy.

Shock: In this study, shock is defined as the presence of clinical signs indicating inadequate tissue perfusion in children under five years of age with diarrhoea, which may result from either hypovolemia or sepsis. This includes:

* Hypotension: Systolic blood pressure below age-specific cut-offs or mean arterial pressure (MAP) less than 50 mmHg.
* Signs of poor perfusion: Prolonged capillary refill time (>3 seconds), cold extremities, weak or absent peripheral pulses, or altered mental status (lethargy or irritability).

Hospitalization: Any post-discharge admission of the enrolled children to a hospital, with at least an overnight stay during the 6-month follow-up period, will be considered as hospitalization.

Sepsis, Severe Sepsis and Septic Shock: Sepsis was defined as suspected or proven infection with systemic signs of inflammation (e.g., fever, tachycardia, abnormal WBC count). Severe sepsis was sepsis with poor peripheral perfusion (e.g., hypotension, prolonged capillary refill, absent peripheral pulses) not attributable to dehydration. Septic shock referred to patients with severe sepsis unresponsive to two fluid boluses (@ of 20 mL/kg; maximum 30ml/kg for severe acute malnutrition (SAM) and 60 ml/kg for non-SAM) requiring inotropic support.

Heart failure: Suspected heart failure will be identified based on clinical findings suggestive of cardiac dysfunction, including respiratory distress or tachypnoea, persistent tachycardia disproportionate to fever or dehydration, hepatomegaly, gallop rhythm, or other evidence of cardiac dysfunction. The diagnosis will be confirmed by the treating paediatrician or an appropriately experienced clinician, with relevant investigations performed when clinically indicated.

Ileus: Ileus will be suspected in children with abdominal distension and reduced or absent bowel sounds, particularly when accompanied by persistent vomiting, feeding intolerance, or failure to pass stool or flatus. The diagnosis will be based on clinical assessment by an appropriately experienced clinician, supported by investigations when indicated.

Oedematous malnutrition: Oedematous malnutrition will be identified by the presence of bilateral pitting oedema of nutritional origin, assessed by applying gentle thumb pressure to the dorsum of both feet for approximately three seconds and observing for persistent pitting. Alternative causes of bilateral oedema will be considered where clinically indicated.

Study procedure and patient management:

All children with acute watery diarrhoea who have a history of consuming an inappropriately prepared ORS and/or exhibit physical signs suggestive of hypernatremia will undergo screening and laboratory testing to confirm hypernatremia. If we find a child is eligible with a sodium level of ≥150 mmol/L, we will approach the caregiver for the consent to enrol in the study. If children present with the same history but is in shock, they will first receive standard of care treatment with a bolus of 20 mL/kg isotonic saline (Hartmann's solution) (15 ml/kg, if a child is severely malnourished). If they successful recover from shock with only fluid resuscitation then, they will be assessed for enrolment in the study.

The initial assessment will be performed by the study physician before enrolment. Suspected heart failure or ileus will be reviewed by the treating paediatrician or an appropriately experienced clinician. Relevant investigations will be obtained according to clinical need and availability; they will not be required routinely for study eligibility. The assessment findings and final eligibility decision will be documented in the screening records. Children meeting any of these exclusion criteria will not be enrolled.

After enrolment, eligible participants will be randomly assigned in a 1:1 ratio to receive either (Table 1):

* Intravenous fluid therapy or
* Oral fluid therapy Randomization will be performed by a team not involved in the study using a computer-generated permuted block randomization sequence, and allocation will be concealed using sealed, opaque envelopes to ensure unbiased assignment.

Intravenous fluid therapy: For intravenous rehydration, we will use a hypotonic solution, following the Nelson Pediatrics guidelines for hypernatremic dehydration (21st edition). The total fluid volume will be 1.5 times maintenance, administered over 24-84 hours, depending on the severity of hypernatremia. The goal is to reduce serum sodium safely, 12 mmol/L per day. Children with diarrhoea, often have metabolic acidosis, therefore, we will use ½-strength sodium acetate in 5% dextrose, instead of ½ strength normal saline. (Fig 1) This solution has osmolarity and sodium content comparable to standard 0.45% sodium chloride (½ strength normal saline) in 5% dextrose (Table 2). Acetate is metabolized to bicarbonate in the liver aiding correction of mild to moderate metabolic acidosis more effectively than chloride-based solutions.

Oral fluid therapy: For oral rehydration using ORS, we will use a standardized protocol that matches the same fluid volume calculated via the same formula, but will be administered via oral or nasogastric routes. We will use commercially available WHO recommended low osmolality ORS. The oral regimen follows the same sodium correction targets as the intravenous arm.

Both groups will undergo close monitoring of serum sodium, weight, neurological status, and fluid balance throughout the rehydration period.

All enrolled patients will receive care in the Intensive Care Unit (ICU) and will be monitored closely by the study team. Each child's clinical status will be assessed hourly, including evaluation of hydration status, consciousness level (using AVPU and Glasgow Coma Scale), vital signs, fluid balance (intake/output). Weight will be recorded every 6 hours. Detailed neurological assessments including motor and sensory evaluation, jerks and reflexes, pupillary response, and fundoscopy will be performed once daily to detect signs of cerebral oedema, haemorrhage, or other complications.

Fluid administration will be strictly guided by baseline serum sodium levels (Table 3). It will be reassessed and adjusted every 24-hour as necessary based on serial electrolyte measurements and clinical parameters such as weight changes, presence of cerebral oedema or not. If the rate of serum sodium reduction exceeds the recommended safety threshold (>12 mmol/L within 24 hours) the fluid volume will be reduced by up to 25%.

More precisely if serum sodium reduces 0.5 to 0.7 mmol/L/hour the volume of the fluid will not be modified. If serum sodium decreasing rate is > 0.7 to 1 mmol/L/hour the volume of fluid will be reduced by 10-12%. If serum sodium decreasing rate is > 1mmol/L/hour then the volume of the fluid will be reduced by 20-25%. Similarly, in the event of significant weight gain (>5% within 12 hours) or clinical evidence of volume overload (weight gain, oedema) or anuria/ oliguria the fluid volume will also be reduced by up to 25%. Electrolytes will be rechecked at 6 hours, 24 hours, and then every 24 hours until normalization, or more frequently if clinically indicated. Ongoing stool output will be assessed every four hours and replaced accordingly.

Standard of care:

Electrolyte supplementation: Serum electrolytes, including potassium and calcium, will be monitored and corrected as needed.

Micronutrients: Children with severe malnutrition will receive micronutrients, including multivitamins, zinc, and folic acid, as per standard guidelines.

Seizure control: If a child develops seizure during fluid therapy, they will be managed promptly with sequential standard anticonvulsant therapy (e.g., lorazepam, phenobarbitone or phenytoin) following established guidelines. If seizures are suspected to result from cerebral oedema, due to rapid sodium decline, 3% NaCl will be administered as per protocol (3 ml/kg over 1 hr).

Nutritional support: Age and weight-adjusted appropriate therapeutic food, without additional salt, will be provided to all children. We will provide milk suji (67 kcal /100 ml) for children aged 6 months and above. For children below 6 month we will provide modified infant formula (68 kcal /100 ml). For a breast-fed child we will continue breast feeding as expressed. Total 70 kcal/kg/day will be provided. Dietary volume will be incorporated in total fluid calculation. We will keep the record of diet volume administered meticulously. Free water intake will be restricted during the correction phase.

Antibiotics: Antibiotics will be prescribed for confirmed or suspected sepsis, pneumonia, urinary tract infection, invasive diarrhoea, or other bacterial infections, following existing icddr,b's clinical guidelines. Standard empiric antibiotics will be initiated and later adjusted based on culture results. Children with severe acute malnutrition will receive antibiotics as per standard protocols.

Regular follow-up: Dehydration status, mentation of the patient (AVPU, GCS scale), vital signs, weight change, input-output chart, calorie intake, associated condition status, neurological examination (pupil, reflex and jerk), fundoscopic examination (any haemorrhage, blurred optic disc) will be done periodically.

The study team responsible for the management of enrolled children will be dedicated solely to this project, rather than the regular ICU staff. This will ensure consistent and standardized care for all participants, minimizing variability in clinical management. The dedicated team will strictly follow the study protocol for fluid therapy, monitoring, and other interventions, which will maintain uniformity in treatment across both study arms and enhance the reliability of study outcomes.

Referral outside: Patients will be referred to a tertiary hospital for dialysis if hypernatremia is complicated by persistent renal impairment, evidenced by elevated creatinine (>5 times the age-specific upper limit) or low urine output (<0.5 ml/kg/hour for > 12 hours).

Neurodevelopmental Evaluation and Follow-Up After Hospital Discharge: Following hospital discharge, patients will be followed up in a structured schedule. Initial follow-up will be conducted via telephone at 3 days and 2 weeks post-discharge to assess the child's general condition, provide support to caregivers, and identify any early concerns. Any events of hospitalization during the follow-up period will be recorded.

Subsequent physical follow-up visits will be scheduled at 1 month (±7 days) and 6 months (±7 days) post-discharge. At each of these visits, a comprehensive neurodevelopmental assessment will be performed using the Denver Developmental Screening Test II (DDST-II).

These assessments will be conducted by a trained pediatrician experienced in administering and interpreting the DDST-II, a standardized tool used to assess developmental progress in children from birth to 6 years of age across the following four domains:

1. Gross motor skills (e.g., sitting, walking)
2. Fine motor-adaptive skills (e.g., grasping, object manipulation)
3. Language (e.g., responding to sound, speaking)
4. Personal-social behavior (e.g., smiling, interacting) This structured follow-up approach is designed to identify early signs of developmental delay and ensure timely intervention and support.

Laboratory Investigations: Laboratory investigations will include serum electrolytes and creatinine at baseline, 6 hours after initiation of fluid therapy, and then daily until the serum sodium level normalizes. Serum osmolarity will be measured at baseline and upon recovery. Urine electrolytes, urine osmolarity, specific gravity, blood urea nitrogen (BUN) will be assessed at base line and upon recovery and complete blood count (CBC) will be assessed at baseline Adverse events monitoring: Participants enrolled in the hypernatremia fluid therapy study will be closely monitored for both general and serious adverse events throughout hospitalization and follow-up. General adverse events include phlebitis, abdominal distension, hyperkalemia, volume overload, rapid decline in serum sodium concentration, seizure, cerebral oedema, acute kidney injury (AKI), pneumonia, sepsis, septic shock, re-hospitalization and healthcare-associated infections (HAI). Serious adverse events (SAEs) are defined as life-threatening or fatal outcomes, including respiratory failure requiring mechanical ventilator support and death. All adverse events will be documented, assessed for severity and potential relationship to the study intervention and managed according to standard clinical protocols. Any SAE identified during the study will be reported to the Data and Safety Monitoring Board (DSMB) within 24 hours of notification and reviewed promptly to ensure participant safety.

• Oral rehydration solution (ORS) (Drug): For participants of oral arm, the study will use a standardized protocol that matches the same fluid volume calculated via the same formula but will be administered via oral or nasogastric routes. The study will use commercially available WHO recommended low osmolality ORS. The oral regimen follows the same sodium correction targets as the intravenous arm.

Primary outcomes

• All-cause mortality from initiation of the intervention until hospital discharge among children under five years of age with hypernatremic dehydration associated with diarrhoea. [From enrollment to discharge (approximately 7 days)]: Events of death any time during hospitalization after initiation of intervention until discharge.

Secondary outcomes

• Incidence of rapid serum-sodium (>12 mmol/L in 24 hours) [From enrollment to the normalization of sodium level (Approximately 3 days from enrollment)]: Serum sodium will be measured at 0 hours, 6 hours and then 24 hourly and there after until normalization of sodium.
• Need for ancillary interventions (e.g., 3% NaCl, anticonvulsants) [From enrollment to discharge (approximately 7 days)]: Incidence of convulsions and use of anti-convulsant and 3% NaCl during the rehydration period
• Acute kidney injury (AKI) events [From enrollment to the normalization of both sodium and creatinine level (Approximately 3 days from enrollment)]: Serum creatinine level at 0 hours, 6 hours, every 24 hour then there after until normalization of creatinine
• Poor neurological outcome at month 1 and month 6 [After treatment complete to end of follow up at month 6]: Neurodevelopmental outcomes (cerebral oedema, developmental delay) at discharge (Approximately at Day7) from hospital and during follow-up visits at month 1, month 6
• The case fatality at 6-month follow-up [After discharge o end of follow up at month 6]: Events of death any time after discharge from hospitalization to complete of 6 month follow up period

Sex: All, ages: 1 Day to 59 Months

Inclusion Criteria:

* Children of either sex with diarrhoea
* Children with serum sodium concentration ≥150 mmol/L with or without symptoms
* Parent(s) provide informed written consent for the child's participation in the study

Exclusion Criteria:

* Children with any congenital anomaly or features suggestive of any syndrome
* Critically ill children (e.g., septic shock, multi-organ failure) requiring inotrope or mechanical ventilation
* Children with features of heart failure, ileus, or oedematous malnutrition
* Any children with baseline creatinine >5 times normal

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• Study Protocol, Statistical Analysis Plan, and Informed Consent Form (PDF, 2026-01-12)

• Haimanti Saha, Principal investigator, International Centre for Diarrhoeal Disease Research, Bangladesh