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Three Part Question

In [hospitalised children needing intravenous maintenance fluids] do [hypotonic infusion solutions compared to isotonic solutions] lead to [hyponatremia]?

Clinical Scenario

A 6-year-old boy weighing 23 kg is repatriated to your unit from a Dutch hospital after appendectomy complicating a short holiday trip abroad. He is still on parenteral hydration. You notice that the prescribed intravenous solution of 1600 ml a day is hypotonic: dextrose 5%, NaCl 0.45% with 2 mmol potassium/kg/day added. His serum electrolytes and glucose are within the normal range. You wonder why your colleagues abroad did not prescribe isotonic maintenance solution so you decide to contact them. You are informed by the referral hospital that it is common practice to prescribe hypotonic fluids as maintenance solution, and you wonder whether your routine of prescribing isotonic fluids as maintenance is be preferred.

Search Strategy

Embase and Medline via PubMed were the primary sources of articles.
Search terms were: (hypotonic solution OR isotonic solution OR sodium chloride OR normal saline OR hypotonic saline OR isotonic saline OR hypotonic fluid OR isotonic fluid) AND (intravenous) NOT (oral OR enteral) AND hyponatremia. Limits were 0–18 years.

Dates included 1950 to July 2010. A secondary search of the Cochrane database was conducted.

Search Outcome

Two hundred and six papers were found, nine of which were relevant to the question. The references of these papers were checked and one further article was found.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Hoorn et al, 2004	148 patients (1–13 years old) in an emergency department receiving more or less EFW	Retrospective case–control study	Amount of EFW (ml/kg/h) in hospital-acquired hyponatremia (<136 mmol/l) vs the normonatremic control group	EFW was 2±2 ml/kg/h in hyponatremic patients vs 1±1 in the normonatremic patients (p<0.001) The most important factor for hospital-acquired hyponatremia is the administration of hypotonic fluid	EFW was given as oral fluid as well as intravenous fluid 2 hyponatremic patients had major neurological sequelae, 1 of whom died
Neville et al, 2010	124 patients (6 months to 15 years of age), admitted for surgery, randomised into 4 groups (N=31) to receive either 0.9% NaCl or 0.45% NaCl, at maintenance or 50% maintenance rates	Prospective, randomised (non-blinded) trial	Primary outcome: change in P Na from induction of anaesthesia to 8 and 24 h after extubation	P Na at t=8 h fell by ≥2 mmol/l in 35/62 patients on 0.45% NaCl, compared to 12/62 in the 0.9% NaCl group (p<0.001) No difference in the incidence of hyponatremia at t=24 h	Non-blinded trial, patients not stratified for severity of (underlying) disease Observation period limited to 24 h The risk of hyponatremia was decreased by isotonic saline solution but not fluid restriction
			Secondary outcome: frequency of hyponatremia (P Na <135 mmol/l) 8 and 24 h after end of extubation (t=8 h, t=24 h)	P Na <135 mmol/l at t=8 h: 19/62 children in the 0.45% NaCl group compared to 6/62 patients in the 0.45% NaCl group (p=0.02) P Na <135 mmol/l at t=24 h: 5/31 patients in the 0.45% NaCl group compared to 9/36 patients in the 0.45% NaCl group (NS)
Yung et al, 2009	50 patients admitted to a paediatric intensive care unit, randomised to receive 0.9% NaCl or 4% dextrose and 0.18% NaCl at either 100% maintenance or 2/3 of that rate Age not mentioned	Prospective, randomised double-blind trial, factorial design	Change in P Na from time of admission to 12–24 h later	P Na was 0.2 mmol/l lower in the isotonic group, restricted rate P Na was 1.5 mmol/l lower in the isotonic group, normal rate P Na was 3 mmol/l lower in the hypotonic group, restricted rate P Na was 4.9 mmol/l lower in the hypotonic group, normal rate No patient developed hyper- or hyponatremia	Surgical patients demonstrated a larger fall in P Na than medical patients. In surgical patients, the decrease in P Na was greater with 0.18% NaCl, in medical patients no differences were found Not clear at what time P Na was measured The risk of hyponatremia was decreased by isotonic saline solution but not fluid restriction
Brazel et al, 1996	12 female patients (12.3–18.1 years old), undergoing idiopathic scoliosis correction receiving either isotonic saline (0.76% NaCl) or hypotonic saline (0.18–0.3% NaCl)	RCT unmasked	Decrease in P Na at t=0, 6, 24 and 72 h	Greater and more sustained decrease in P Na in the hypotonic group; 1/5 patients in isotonic group <135 mmol/l vs 7/7 in the hypotonic group (p=0.01)	Small trial Numbers and time (t=0, 6, etc) not mentioned
Burrows et al, 1983	24 (6–16 years old) idiopathic scoliosis patients undergoing surgical correction receiving isotonic (0.78% NaCl) or hypotonic solution 0.225–0.45% NaCl)	Cohort Study	Decrease in P Na	Preoperative P Na in both the hypotonic (n=20) and isotonic (n=4) groups was 138 mmol/l. Postoperative P Na was 131 mmol/l in the hypotonic group (p 0.05) and 135 mmol/l in the isotonic group (NS)	Small trial with only 4 patients in the isotonic group, no randomisation, fluid correction in case of oliguria (<1 ml/kg/h) Packed cells were given in cases of Hct 30% Not clear at what time P Na was measured
Neville et al, 2006	104 patients (6 months–14 years old) with gastroenteritis and dehydration, receiving either 0.9% NaCl or 0.45% NaCl as rehydration fluid	Prospective, randomised trial. Unmasked.	Change in P Na after 4 h of rehydration compared to the initial P Na: hyponatremic patients (P Na <135 mmol/l) or normonatremic (P Na 135–145 mmol/l) patients	In patients given 0.45% NaCl: in hyponatremic patients (n=16) P Na 132 mmol/l changed to 133 mmol/l (NS); n normonatremic patients (n=35) P Na 137 mmol/l changed to 135 mmol/l (p<0.001) In patients given 0.9% NaCl: n hyponatremic patients (n=21) P Na 132 mmol/l changed to 134 mmol/l (p<0.001); in normonatremic patients (n=30) P Na 137 mmol/l changed to 138 mmol/l (NS) Normal saline protected against hyponatremia without causing hypernatremia	36% of patients were hyponatremic at t=0 (P Na <135 mmol/l) Maximum increase in P Na was 12 mmol/l in 24 h to 136 mmol/l Rehydration study, not maintenance fluids
Au et al, 2008	Charts of 145 postoperative paediatric patients receiving either isotonic fluids (0.76–0.9% NaCl) or hypotonic fluids (<0.76% NaCl) Age not mentioned	Retrospective descriptive study	Presence of moderate hyponatremia (P Na <130 mmol/l) and severe hyponatremia (P Na <125 mmol/l) or any neurological symptoms attributable to hyponatremia with less than normal sodium concentration	The incidence of moderate hyponatremia was 12/116 in the hypotonic group vs 1/29 in the isotonic group (p=0.423) Severe hyponatremia was observed in 3/116 patients in the hypotonic group vs 0/29 in the isotonic group (p=0.881) No neurological symptoms attributable to severe hyponatremia were observed	Retrospective study, asymmetrical distribution of the fluid regimen, lack of statistical power A trend towards an increased incidence of hyponatremia in patients receiving hypotonic fluid, no statistical significance
Montañana et al, 2008	122 PICU patients (1 month–8 years old), 63 in hypotonic (<0.59% NaCl) group, 59 in isotonic group (>0.59% NaCl)	Prospective, randomised, controlled, blind and open phases study conducted at admission, t=6 and t=24	Presence of hyponatremia (Na <130 mmol/l)	At 24 h, hyponatremia in the hypotonic group was present in 13/63 patients compared to 3/59 in the isotonic group (p=0.02) The use of hypotonic fluids increases the risk of hyponatremia compared to isotonic fluids at 24 h following infusion	Not blinded, a significant number withdrew from the study No explanation for the high incidence of hyponatremia (except hypotonic fluid)
Wilkinson et al, 1992	56 patients (2 months–14 years old) undergoing craniopharyngeal procedures, receiving either isotonic (0.76–0.9% NS) or hypotonic (0.16–0.5% NaCl) fluids	Retrospective Chart Review	P Na levels on postoperative day and days 1, 2 and 3	Median P Na 130.5 (range 121–136) mmol/l in hypotonic group Median P Na 139 mmol/l in isotonic group Hyponatremia (<136 mmol/l) in 20/26 in hypotonic group and in 2/30 in isotonic group Fluids used to replace loss from tissues that have been manipulated surgically, or to replace blood loss, should have an electrolyte composition similar to plasma	Seizures in 2/26 in the hypotonic group Not clear at what time P Na was measured As craniopharyngeal procedures are often long and associated with significant blood loss, blood and blood products have been given peri-operatively

Comment(s)

Intravenous maintenance fluid therapy is one of the most common medical interventions administered to children in developed countries. For the last 50 years this therapy has been based on a single publication,(Holliday). which is still the basis for recommendations in current paediatric medical textbooks to use hypotonic maintenance solutions (Nelson). Most paediatricians outside the UK use hypotonic maintenance solutions. Within the UK, where the National Patient Safety Agency (NPSA) issued a guideline in 2008 stating the risks of using too hypotonic solutions such as sodium 0.18%, a significant number of doctors still prescribe hypotonic solutions (Davies). The guideline however, does state that the majority of children may be safely administered sodium chloride 0.45% with glucose.

.Serious consequence of hyponatremia, occurring within 48 h, include brain cell swelling and herniation (Halberthal, Ray, Moritz). Signs and symptoms may be non-specific or subtle (eg, nausea and vomiting) before progressing to seizures and more overt signs of cerebral oedema and intracranial hypertension.

In an unselected population of hospitalised adults, mortality due to hospital-acquired hyponatremia (P Na <138 mmol/l) was 2.9%. In some patients, serious symptoms become evident at higher plasma sodium concentrations (Hoorn, Wald). We did not found comparable data for children (Ray).

It is not uncommon for hyponatremia to develop in the first 48 h of hospital admission, related in large part to intravenous fluid administration (Hoorn). The incidence of hyponatremia (<135 mmol/l) in hospitalised children is between 17% and 45% (Moritz). wo factors are required for hyponatremia to develop: a source of electrolyte free water and the presence of vasopressin to prevent the excretion of that water. Hospitalised patients have multiple non-osmotic stimuli for vasopressin that put them at risk of developing hyponatremia. Patients with increased risk of developing hyponatremia include those with meningitis, encephalitis, head injury, bronchiolitis, gastroenteritis or chronic lung disease, and postoperative patients (Hoorn, Neville 2010, Yung, Brazel, Burrows).Children are more vulnerable to the development of hyponatremic encephalopathy than adults as their brain cell volume is larger in proportion to extracellular volume (Halberthal, Ray, Moritz).

The potential risks of hypernatremia and hyperchloremic acidosis have led to a reluctance to recommend the use of isotonic saline solution as maintenance fluid in children. However, the examined literature suggests that inadequate volume, rather than sodium load, is critical to the development of hypernatremia (Hoorn, Neville 2010). With an adequate fluid volume, the risk of hypernatremia from isotonic solutions is small, unlike the risks of developing hyponatremia with 0.45% saline or more hypotonic solutions. Furthermore, isotonic solutions, to some degree, protect against hyponatremia (Neville 2010, Brazel, Neville 2006).

The current level of evidence suggests that hypotonic maintenance solutions, including 0.45% saline, are potentially dangerous in children from 6 months to 18 years of age.

Regular measurement of serum glucose and urine ketones should be performed in order to maintain glucose homeostasis(Halberthal, Neville 2010).

Although no information, protocols or guidelines could be retrieved from the literature regarding evaluation of plasma sodium, we recommend that plasma sodium concentration should be measured when the patient receives more than 5% of total body water (30 ml/kg) by parenteral infusion (Halberthal).

Furthermore, since patients, especially after procedures, may develop inappropriate antidiuretic hormone secretion, total maintenance volumes should be critically reviewed.

No single fluid rate or composition is ideal for all children between the ages of 6 months and 18 years. Isotonic solutions should be avoided in patients with extracellular fluid overload, for example, in heart failure, liver and renal failure, or with large water losses. Premature infants and neonates up to the age of 6 months are beyond the scope of this study and so our conclusions are limited to patients above this age.

Editor Comment

EFW, electrolyte free water; Hct, haematocrit; Na, sodium;. NS, normal saline; P, plasma; RCT, randomised controlled trial; t, time.

Clinical Bottom Line

Hospital-acquired hyponatremia in paediatric patients aged 6 months to 18 years can result from the administration of hypotonic intravenous fluids. (Grade B)

Use of isotonic maintenance fluids reduces the risk of hyponatremia. (Grade B)

Isotonic solutions, when prescribed below the maintenance rate, may lead to hypernatremia; the mechanism is dehydration rather than sodium overload. (Grade B)

References

1. Holliday MA, Segar WE. The maintenance need for water in parenteral fluid therapy. Pediatrics 1957;19:823–32.
2. Kliegman RM, Behrman RE, Jenson HB et al. Nelson Textbook of Pediatrics, 19th Edition. 2010 Elsevier. ISBN: 978-1-4377-0755-7.
3. National patient safety. Reducing the risk of hyponatraemia when administering intravenous infusions to children. [Online] http://www.nrls.npsa.nhs.uk/resources/?entryid45=59809 2010
4. Davies P, Hall T, Ali T, et al . Intravenous postoperative fluid prescriptions for children: a survey of practice. BMC Surg 2008;8:10.
5. Halberthal M, Halperin ML, Bohn D . Lesson of the week: Acute hyponatraemia in children admitted to hospital: retrospective analysis of factors contributing to its development and resolution. BMJ 2001;322:780–2.
6. Ray PE . Neurological complications from dysnatremias in children: a different point of view. Pediatr Nephrol 2006;21:1048–9
7. Moritz ML, Ayus JC . New aspects in the pathogenesis, prevention, and treatment of hyponatremic encephalopathy in children. Pediatr Nephrol 2010;25:1225–38.
8. Hoorn EJ, Geary D, Robb M, et al . Acute hyponatremia related to intravenous fluid administration in hospitalized children: an observational study. Pediatrics 2004;113:1279–84.
9. Wald R, Jaber BL, Price LL, et al . Impact of hospital-associated hyponatremia on selected outcomes. Arch Intern Med 2010;170:294–302.
10. Neville KA, Sandeman DJ, Rubinstein A, et al . Prevention of hyponatremia during maintenance intravenous fluid administration: a prospective randomized study of fluid type versus fluid rate. J Pediatr 2010;156:313–19.
11. Yung M, Keeley S . Randomised controlled trial of intravenous maintenance fluids. J Paediatr Child Health 2009;45:9–14.
12. Brazel PW, McPhee IB . nappropriate secretion of antidiuretic hormone in postoperative scoliosis patients: the role of fluid management. Spine 1996;21:724–7.
13. Burrows FA, Shutack JG, Crone RK . Inappropriate secretion of antidiuretic hormone in a postsurgical pediatric population. Crit Care Med 1983;11:527–31.
14. Neville KA, Verge CF, Rosenberg AR, et al . Isotonic is better than hypotonic saline for intravenous rehydration of children with gastroenteritis: a prospective randomised study. Arch Dis Child 2006;91:226–32.
15. Au AK, Ray PE, McBryde KD, et al . Incidence of postoperative hyponatremia and complications in critically-ill children treated with hypotonic and normotonic solutions. J Pediatr 2008;152:33–8.
16. Montañana PA, Modesto i Alapont V, cón AP, et al . The use of isotonic fluid as maintenance therapy prevents iatrogenic hyponatremia in pediatrics: a randomized, controlled open study. Pediatr Crit Care Med 2008;9:589–97.
17. Wilkinson E, Rieff J, Rekate HL, et al . Fluid, blood, and blood product management in the craniofacial patient. Pediatr Neurosurg 1992;18:48–52.