Risk of acute hyponatremia in hospitalized children and youth receiving maintenance intravenous fluids

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The problem

Hyponatremia, defined as a serum sodium (Na) <135 mmol/L, has become increasingly recognized as a cause of morbidity and mortality in hospitalized children.^[1]-[9] In recent years there have been many reports of serious morbidity, including severe neurological injury, as well as many deaths among children who developed hospital-acquired hyponatremia while receiving IV fluids.^[1]-[9] A case-control study reported that 40 of 432 (9%) of hospitalized children on IV fluids who had a normal baseline serum Na had a subsequent serum Na <136 mmol/L.^[3] Other studies have shown an incidence of hyponatremia in hospitalized children as high as 24%.^[10]

Hyponatremia has been attributed primarily to the use of hypotonic maintenance IV fluids. The administration of such fluids provides a source of electrolyte-free water (EFW) to a population of children who are at risk for increased antidiuretic hormone (ADH) secretion.^[3][11][12] Clinical sequelae of acute hyponatremia (a decrease in Na over ≤48 h) result from acute cerebral edema, and may include headache, lethargy and seizures, and potentially even respiratory and cardiac arrest secondary to brain stem herniation. These outcomes are more likely to be seen with severe acute hyponatremia (Na <130 mmol/L). Because of their higher brain/intracranial volume ratio, children are at increased risk for these sequelae compared with adults.

The routine practice of providing hypotonic maintenance IV solutions, usually containing 20 mmol/L to 30 mmol/L of Na, is based on Holliday and Segar’s seminal paper published in 1957 ^[13] and translates to the use of 0.2% NaCl/dextrose 5%. These recommendations were based on caloric expenditure in healthy children, and electrolyte composition was derived from that of human and cow’s milk.

It has been recognized that the great majority of hospitalized children are at risk of nonphysiological antidiuretic hormone (ADH) secretion — due to nausea, stress, pain, pulmonary and central nervous system disorders, surgical interventions, and commonly used medications such as morphine sulfate — which implies that Holliday and Segar’s traditional recommendations for administering hypotonic IV fluids are probably inappropriate. The high percentage of EFW in hypotonic IV fluids (78% EFW) compared with normal saline (0% EFW), in combination with an impaired ability to excrete water as a result of ADH secretion, places hospitalized children at increased risk of developing acute hyponatremia.

IV fluid prescription practices for children vary widely among physicians both within and between hospitals. A cross-sectional survey carried out in multiple hospitals in the United Kingdom revealed that 77 of 99 children receiving IV fluids during one day of a specified week were receiving hypotonic solutions. Twenty-one of the 86 children (24%) who had serum electrolytes measured were found to be hyponatremic, and the vast majority of these were receiving hypotonic IV fluids.^[10]

To avoid the development of acute hyponatremia, it has been recommended that isotonic 0.9% NaCl/dextrose 5% (normal saline with dextrose) should be the standard maintenance IV solution.^{[2][11][12][14]} Normal saline contains 154 mmol/L of Na, which is isotonic with respect to the cell membrane. This suggestion has raised concerns regarding the potential for hypernatremia and salt and water overload.^[15] However, unless the child has an impaired ability to excrete Na, a renal concentrating defect, significant water loss or prolonged fluid restriction, these risks appear to be largely theoretical. The risk of developing hyperchloremic metabolic acidosis has been recognized in the context of rapid isotonic saline infusion delivered perioperatively ^[16] but has not been reported in the trials of IV saline used for maintenance requirements in children to date.

New information

Initial prospective trials comparing the tonicity of IV fluids were primarily focused on surgical and intensive care populations, with some smaller studies including children admitted to medical units.^[17]-[25] Five systematic reviews and meta-analyses published in 2014/2015 all concluded that maintenance isotonic fluids posed a lower risk of hyponatremia when compared with hypotonic fluids.^[26]-[30] Two specifically commented, however, that the evidence focused on surgical and intensive care populations, with insufficient data to allow generalization of the recommendations to children on medical wards.^[26][27]

More recently, three randomized controlled trials have addressed the issue of tonicity of IV maintenance fluid and hyponatremia in both medical and surgical paediatric populations.^[31]-[33] The first study, from Australia, is the largest to date, having randomized 690 children with medical and surgical diagnoses to isotonic (140 mmol/L sodium) or hypotonic (77 mmol/L sodium) fluids. ^[31] The study fluids were continued until patients were receiving less than 50% of their maintenance requirement by IV, to a maximum of 72 h. The primary outcome was the occurrence of hyponatremia, defined as a serum sodium <135 mmol/L with a minimum decrease of 3 mmol/L from baseline to make it clinically significant. The investigators concluded that isotonic fluids led to a lower risk for hyponatremia compared with hypotonic fluids (4% versus 11%; p=0.001), with no increase in adverse effects.^[31]

The second study was Canadian, with a similar design to the Australian trial. ^[32] One hundred and ten children, all on a general paediatric medical unit, were randomized to isotonic (0.9% NaCl, or 154 mmol/L sodium) or hypotonic (0.45% NaCl, or 77 mmol/L sodium) IV maintenance solutions. There was no difference between the two groups in the primary outcome, mean serum sodium at 48 h (p=0.60). However, there were two cases of hyponatremia in the hypotonic group compared with none in the group receiving isotonic fluids.

The third trial studied a combined medical and surgical paediatric population, and was conducted in Mexico. ^[33] One hundred and fifty-one children were randomized to one of two hypotonic solutions (0.3% saline or 0.45% saline) or to isotonic maintenance fluids (0.9% saline). The mean serum sodium at 8 h, the primary outcome, was lower in both hypotonic fluid groups compared with the group receiving isotonic fluids (p<0.0001).

These recent RCTs have broadened the scope of available literature on IV maintenance fluid tonicity in paediatrics, and have continued to consistently find that, compared with hypotonic fluids, isotonic maintenance solutions decrease the risk of iatrogenic acute hyponatremia, without an increase in significant side effects.

TABLE 1 Definitions
Definition	Serum (Na+) mmol/L
Normonatremia	135–145
Hyponatremia	<135
Severe acute hyponatremia	<130 within 48 h in child with normal baseline Na
Hypernatremia	>145

Recommendations ^[34]-[36]

The following recommendations ^[34]-[36] apply to the prescription of IV maintenance fluids in children one month corrected age to 18 years of age, excluding patients with renal or cardiac disease, diabetic ketoacidosis, severe burns or other underlying conditions that significantly affect electrolyte regulation.

General principles

1. Any child in hospital who requires IV fluids should be considered at risk for developing hyponatremia due to increased risk of ADH secretion. At particular risk are:
   • children undergoing surgery
   • children with acute neurological or respiratory infections (eg, meningitis, encephalitis, pneumonia and bronchiolitis).
2. Oral fluids are generally very low in Na content (hypotonic). Where the total fluid intake (TFI) is a combination of oral and IV fluids, both need to be accounted for.
3. Because infants and young children have limited glycogen stores, dextrose should be part of the IV maintenance fluid prescription (eg, D5W.0.9%NaCl or D5W.0.45%NaCl) if no other source of glucose is provided.
4. The approach to prescribing IV fluids should be as cautious as that for medications, with close attention paid to indications, monitoring, the type of fluid and the volume/rate of administration.

Monitoring

1. Baseline serum electrolytes (Na, K, glucose, urea, creatinine) should be measured when starting IV fluid therapy in hospitalized children.
2. Children receiving maintenance IV fluids should have their serum electrolytes checked regularly, with patients who may be at high risk of impaired renal water excretion checked daily if not more frequently.
3. All children receiving IV maintenance fluids should have their intake/output carefully monitored, as well as a daily weight measurement.
4. Clinicians should be aware of the symptoms of hyponatremia, which may include headache, nausea and vomiting, irritability, decrease in level of consciousness, seizures and apnea.

Prescription of IV fluids for maintenance requirements

1. In children whose serum sodium is normal at baseline but who are considered to be at particularly high risk of ADH secretion (eg, peri- or postoperative; with respiratory or neurological infections) the use of isotonic saline (D5W.0.9% NaCl) is recommended.
2. For other hospitalized children whose serum sodium is normal, the options are D5W.0.9% NaCl or D5W.0.45% NaCl. The first option is preferred, especially when serum Na is in the low normal range (135 mmol/L to 137 mmol/L inclusive).
3. Hypotonic IV fluids containing <0.45% NaCl should not be used to provide routine fluid maintenance and should not be generally available on paediatric wards.
4. When serum electrolyte results are not yet available, it is recommended that D5W.0.9% NaCl be initiated as the maintenance IV fluid.
5. If the serum sodium is 145 mmol/L to 154 mmol/L, then D5W.0.45% NaCl should be initiated and frequent monitoring of the serum sodium performed.
6. Ringer’s Lactate is commonly used in the operating room but the absence of dextrose and presence of lactate make it generally inappropriate for maintenance IV therapy, especially in young children.

Note that these recommendations are not intended for use in infants and youth outside the one month to 18 year age group.

TABLE 2 Available intravenous fluids
Fluid	Na mmol/L	K mmol/L	CI mmol/L	Lactate mmol/L	Dextrose gram/L	Tonicity versus plasma
D5W.0.9% NaCl	154	0	154	0	50	Isotonic
D5W.0.45% NaCl	77	0	77	0	50	Half-isotonic (hypotonic)
D5W.0.2% NaCl	33	0	33	0	50	Very hypotonic
2/3–1/3	45	0	45	0	33	Very hypotonic
Ringer’s Lactate	130	4	110	28	0	Isotonic

TABLE 3 Intravenous (IV) fluid maintenance recommendations based on plasma Na+ level
Children one month –18 years of age	Recommended IV fluid
Na <138 mmol/L	Isotonic IV solutions
Na 138 mmol/L –144 mmol/L	Isotonic IV solutions preferred; half-isotonic solutions may be used
Perioperative period	Isotonic IV solutions

Acknowledgements

This practice point has been reviewed by the Canadian Paediatric Society’s Community Paediatrics Committee.

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CPS ACUTE CARE COMMITTEE

Members: Laurel Chauvin-Kimoff MD (Chair); Isabelle M Chevalier MD (Board Representative); Catherine A Farrell MD; Jeremy N Friedman MD; Angelo Mikrogianakis MD (past Chair); Oliva Ortiz-Alvarez MD
Liaisons: Dominic Allain MD, CPS Paediatric Emergency Medicine Section; Marilyn Monk, Canadian Association of Paediatric Health Centres; Jennifer Walton MD, CPS Hospital Paediatrics Section
Principal author: Jeremy N Friedman MD
Updated by: Carolyn Beck MD

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References

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Disclaimer: The recommendations in this position statement do not indicate an exclusive course of treatment or procedure to be followed. Variations, taking into account individual circumstances, may be appropriate. Internet addresses are current at time of publication.