Clinical Pediatrics

http://cpj.sagepub.com Hypotonic Versus Isotonic Maintenance Intravenous Fluid Therapy in Hospitalized Children: A Systematic Review
Carolyn E. Beck Clin Pediatr (Phila) 2007; 46; 764 DOI: 10.1177/0009922807303041 The online version of this article can be found at: http://cpj.sagepub.com/cgi/content/abstract/46/9/764

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Commentaries

Hypotonic Versus Isotonic Maintenance Intravenous Fluid Therapy in Hospitalized Children: A Systematic Review
Carolyn E. Beck, MD, MSc, FRCPC
A systematic review of studies comparing hypotonic versus isotonic intravenous maintenance fluids in hospitalized children was conducted to determine whether hypotonic solutions increase the risk of acute hyponatremia. Studies were identified from electronic databases and hand-searched reference lists. A total of 283 abstracts were reviewed, 55 full-text articles were retrieved, and 3 studies were included. All studies were observational and were overall inconclusive. All

Clinical Pediatrics Volume 46 Number 9 November 2007 764-770 2007 Sage Publications 10.1177/0009922807303041 http://clp.sagepub.com hosted at http://online.sagepub.com

authors cautioned against the routine use of hypotonic maintenance fluids, but hypotonic fluid administration did not always explain the development of acute hyponatremia. Further evidence is required as to the appropriate maintenance solution for hospitalized children. Keywords: intravenous infusions; hypotonic fluid; isotonic fluid; hyponatremia; pediatric

Background
etermination of maintenance fluid requirements dates back to calculations proposed by Holliday and Segar in 1957.1 Maintenance requirements for water are based on energy expenditure in healthy children and electrolyte composition reflects that of human and cows milk.1,2 These requirements translate to the use of a hypotonic saline solution for maintenance fluids, equivalent to 0.2% saline (sodium chloride) in 5% dextrose in water.3 Though practice varies between institutions, hypotonic solutions remain todays current standard of care.2,4,5 Recent concern has emerged about the routine use of intravenous hypotonic solutions in hospitalized children because cases of potentially fatal hyponatremia have been reported.3,6 Hyponatremia
From the Division of Paediatric Medicine and the Paediatric Outcomes Research Team, The Hospital for Sick Children, and the University of Toronto, Toronto, Ontario, Canada. Address correspondence to: Carolyn E. Beck, MD, Division of Paediatric Medicine, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada; e-mail: carolyn.beck@sickkids.ca.

is defined as a serum sodium concentration less than 136 mmol/L, with morbidity occurring at levels less than 125 mmol/L.7 The action of antidiuretic hormone (ADH), preventing water excretion, as well as a source of electrolyte-free water (EFW), are usually required for its development.8 Nonosmotic stimuli for ADH release in hospitalized children include malignancies, central nervous system disorders (including meningitis), pulmonary disorders (including pneumonia), and several medications.7,9 Additionally, nonspecific symptoms such as pain, nausea, and stress, as well as a postoperative state and hypovolemia, all result in an increase in ADH.7,9-11 The routine use of hypotonic maintenance fluids provides the major source of EFW for hospitalized patients. Isotonic solutions such as 0.9% saline contain 154 mmol/L of sodium, whereas solutions with less sodium are hypotonic. Though dextrose is added to maintenance fluids as a carbohydrate source, unlike sodium it is able to freely cross the cell membrane and does not contribute to the osmotic force.2 A hypotonic milieu results in cellular swelling, with symptomatic hyponatremia related to central

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nervous system dysfunction.9 This is typically characterized by headache, nausea, vomiting, muscle cramps, lethargy, restlessness, disorientation, and depressed reflexes.7 Severe outcomes include seizures, respiratory arrest, permanent neurologic dysfunction, and death, resulting from cerebral edema and brainstem herniation.6 Adverse outcomes are more strongly correlated with an acute fall in serum sodium (within 48 hours) than with the same absolute decrease occurring over a longer period of time, reflecting the brains adaptive mechanisms.2 Also important is childrens higher brain-to-skull size ratio, which leaves less room for brain expansion and places them at higher risk than adults for developing symptomatic hyponatremia.9 Reports of symptomatic hyponatremia in children have prompted some physicians to advocate for a change in practice from hypotonic to isotonic maintenance fluids, with a view to decreasing the source of EFW in hospitalized children in whom ADH levels may be increased.2-4 Others question whether severe hyponatremia is in fact a result of conventional fluid therapy and caution clinicians about potential risks of isotonic solutions, namely hypernatremia and fluid overload.12,13 The objective of this study was to conduct a systematic review of studies comparing hypotonic versus isotonic intravenous maintenance fluids in hospitalized children to determine whether the administration of hypotonic solutions increases the risk of developing acute hyponatremia.

Study Selection
Studies were eligible for inclusion if patients were less than 18 years of age, hospitalized, and required the administration of intravenous maintenance fluids. Studies examining children in need of rehydration (intravenous or oral) were excluded, as the goal of fluid administration and choice of solution for these patients is different and well accepted, namely volume expansion with isotonic fluids.14 Preterm infants were also excluded on the basis of their unique sodium and water balance.15 Eligibility also required inclusion of at least 2 study arms, comparing hypotonic with isotonic maintenance fluids. With respect to outcomes, it was necessary that authors examined the outcome of acute hyponatremia developing after fluid administration. Because of an anticipated paucity of rigorous studies, study design was not a limiting criterion. The titles and abstracts from all citations were reviewed by the author, and using liberal criteria, all potentially relevant articles were retrieved in full. A selection form was applied to each full text study, to identify those meeting inclusion criteria for all 3 of population, intervention, and outcome. Study design was recorded for each paper reviewed; a critical literature review was then conducted.

Results
Description of Studies
A total of 283 titles and abstracts were reviewed. Fifty-five of these were considered potentially relevant and were retrieved in full. Twenty-two articles were original studies, to which the selection form was applied. Of the remainder, 31 were review articles or commentaries (references available upon request), and 2 were Cochrane Library meta-analyses.13,16 Of the 22 original studies, 9 were excluded on the basis of not studying the target population,6,15,17-23 and 7 were excluded as they did not study the desired outcome.3,10,11,24-27 Five studies examined the correct population and outcome but did not directly compare hypotonic versus isotonic fluid administration.8,28-31 One study met all 3 a priori selection criteria and thus was included.32 Two of the 5 studies that did not directly compare hypotonic versus isotonic fluid, did in fact address the research question by correlating the degree of EFW received with

Methods
Data Sources
The author searched 5 electronic databases to identify potentially relevant studies: Medline (1966 to March Week 2, 2007), Embase (1980 to 2007 Week 11), The Cochrane Database of Systematic Reviews (1st Quarter 2006), ACP Journal Club (1st Quarter 2006), and DARE (1st Quarter 2006). The search strategy was customized for each database but was of the general format: (fluid therapy or intravenous infusions or synonyms) AND (hypotonic and isotonic solutions) AND (hyponatremia or inappropriate ADH syndrome). The searches were carried out without language restriction. Additionally, bibliographies from included studies were reviewed.

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the development of acute hyponatremia.8,28 The a priori inclusion criteria were therefore broadened to include these 2 studies.

Critical Literature Review

Burrows FA, Shutack JG, Crone RK. Inappropriate secretion of antidiuretic hormone in a postsurgical pediatric population. Crit Care Med. 1983;11: 527-531.

Based on the knowledge that ADH secretion is increased in the perioperative period,33 the objective of the study by Burrows et al was to determine the existence and frequency of inappropriate ADH release in children undergoing elective spinal fusion surgery and to assess the effect of postoperative fluid management on ADH secretion. Burrows et al conducted an observational cohort study, selecting 24 patients from a convenience sample of consecutive patients undergoing spine surgery for idiopathic scoliosis. All patients received isotonic fluid (Ringers lactate) intraoperatively, with their postoperative fluid management based on the preference of the surgeon. The 2 groups, those who received postoperative hypotonic versus isotonic fluids, were compared. Twenty patients in the study received postoperative hypotonic fluids, whereas 4 patients were prescribed isotonic Ringers lactate. The decrease in serum sodium between the preoperative and postoperative periods was significant (P < .05) in the group receiving hypotonic fluids (mean standard deviation [SD] 138 1.7 to 131 2.8 mmol/L) but not significant in those who received Ringers lactate (138 2.7 to 135 1.9 mmol/L). Burrows et al concluded that the postoperative use of isotonic saline is advantageous in preventing a postoperative decrease in serum sodium. The study by Burrows et al has several limitations. The strategy of convenience sampling resulted in very few subjects receiving isotonic fluids compared with those receiving hypotonic fluids, a discrepancy that is likely to lead to results that are not statistically meaningful. Additionally, a surgeon aware of the study may choose to administer isotonic fluids to patients whom he or she feels are particularly susceptible to an increase in ADH, resulting in a selection bias. A second source of bias may come from confounding variables. No attempt was

made to compare factors that may increase patients susceptibility to ADH secretion or hyponatremia: age, degree of nausea or postoperative stress, and medications administered during anesthesia. In terms of the exposure, postoperative management was categorized into hypotonic versus isotonic fluid administration. However, there was variability within the hypotonic fluids prescribed. Fourteen patients received 5% dextrose/0.225% sodium chloride, whereas 6 received 5% dextrose/0.45% sodium chloride. Given the differing amounts of EFW between these 2 solutions, a comparison would have been useful. Similarly, fluid volumes were not recorded despite the fact that this variable directly impacts on the EFW received. Given that the exposure is categorical and the outcome of interest (postoperative serum sodium) continuous, the analysis should have included a betweengroup comparison of the mean postoperative sodium values.34 Instead, the decrease in sodium within each group was calculated; it is possible that the betweengroup comparison was omitted as a result of very few patients having received isotonic fluids, rendering the statistical comparison meaningless. Though the authors conclude that the postoperative use of isotonic fluids is advantageous in preventing hyponatremia, the small number of patients who received an isotonic solution, combined with the lack of statistical comparisons made between the two groups, makes this conclusion difficult to justify.
Halberthal M, Halperin ML, Bohn D. Acute hyponatraemia in children admitted to hospital: retrospective analysis of factors contributing to its development and resolution. BMJ. 2001;322: 780-782.

This study is a 10-year retrospective chart review of children with a discharge diagnosis of hyponatremia. Patients were included if their serum sodium decreased to under 130 mmol/L within 48 hours, provided they were administered intravenous fluids, and had no underlying disease to compromise their renal function. Inclusion criteria was met by 30/306 patients (10%), but 7 were excluded on account of missing data. Of the remaining 23 children, 13 were hyponatremic postoperatively, whereas 10 were medical patients. Important clinical outcomes included mortality in 5 patients and severe permanent neurological damage in 1.

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All patients were administered hypotonic fluids. In 16/23 (70%), the volume of fluid received was 50% greater than the recommended maintenance. The relationship between EFW received and hyponatremia was examined in 17 patients. In 5, the EFW administered was enough to explain the decrease in serum sodium, but in 12, the acute fall could not be explained by the recorded EFW alone. Halberthal et al conclude that in the presence of ADH secretion, the routine use of hypotonic solutions presents a danger and recommend that isotonic maintenance fluids are used when a hospitalized childs initial serum sodium is less than 140 mmol/L. Several sources of bias limit this retrospective chart review. Because patients were chosen on the basis of their recorded discharge diagnoses, those with hyponatremia in the context of several other issues, or in whom the outcomes were less severe, may have been missed, leading to the selection of a group of patients on the severe end of the clinical spectrum. Additionally, the 7 patients who were excluded from the study may represent a different population from those who were ultimately included. Details were not provided for possible confounding variables such as diagnoses, age, and medications. Although the amount of EFW administered is critical to understanding why hypotonic fluids are implicated in the development of hyponatremia, its relationship to the decrease in serum sodium was only examined in 17 of the 23 patients. Furthermore, the EFW content of the recorded fluids infused only provided an explanation for the hyponatremia in 5/17 patients (29%). Finally, the authors recommendations focus on intravenous fluid content, that is, tonicity, although fluid volume was clearly also a consideration in 70% of the patients. The study by Halberthal et al is descriptive and serves to draw attention to the issue of hospitalacquired acute hyponatremia. However, the retrospective nature of the data collection and analysis makes it difficult to form any conclusions regarding the use of hypotonic or isotonic maintenance fluids.
Hoorn EJ, Geary D, Robb M, Halperin ML, Bohn D. Acute hyponatremia related to intravenous fluid administration in hospitalized children: an observational study. Pediatrics. 2004;113:1279-1284.

These authors used a casecontrol design to examine risk factors for the development of acute hospitalacquired hyponatremia in children. By examining all

visits to a tertiary care center via the emergency department over a 3-month period, 40 cases of children with 1 normal sodium and a subsequent sodium value less than 136 mmol/L were identified. Controls had at least 2 sodium measurements, both greater than 136 mmol/L and were matched for age, gender, and weight in a 1:3 ratio. The mean SD sodium in the cases decreased from 139 3 to 133 2 mmol/L, over a mean of 19 hours. The input of EFW adequately explained the decrease in sodium in 22 of the 40 cases (55%), none of whom received fluid boluses for a contracted extracellular space. In 16 cases, 11 of whom received normal saline boluses for volume expansion, exogenous EFW administration was not enough to explain the hyponatremia. The discrepancy of 2 patients was not addressed. Significantly, more cases than controls experienced nausea and vomiting (P = .008) and underwent surgery (P = .04). Cases also received 3 times more EFW (P < .001), received a greater total amount of intravenous fluid (P < .001), and were more likely than controls to receive intravenous fluid in greater volumes than the recommended maintenance (P < .001). Hoorn et al conclude that in children whose sodium is less than 138 mmol/L, hypotonic fluids should not routinely be used. Additionally, isotonic fluid boluses should be reserved for patients in whom there are clear indications of volume contraction. In this casecontrol study, finding patients via emergency department visits led to a sampling of cases that are likely to be representative of the spectrum of those at risk for developing hyponatremia. The tertiary care setting, however, may select for more children with chronic or complex illnesses than seen in other hospitals, which must be kept in mind when generalizing the results. The controls are matched to the cases by age, gender, and weight, which eliminates the possibility that comparisons on other factors between the 2 groups are biased by these variables. Diagnosis is another variable important to this study, in that it may influence ADH secretion as well as indications for fluid administration. The authors were arguably correct in not matching for this factor, given that they would subsequently be unable to assess the effect of diagnosis on the risk of developing acute hyponatremia.35 However, only main disease categories were compared between cases and controls in

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the analysis. Though they were determined not to be risk factors, the authors did not account for more specific diagnoses or for comorbidity. There was no discussion of sample size in this study. Rather, a convenience sample was recruited over a 3-month period. Adopting sample size calculations for casecontrol studies with multiple controls per case, it can be shown that more than 40 cases are required in order to achieve statistical power.35 Hoorn et al compare the mean values of EFW administered between the cases and controls. Ultimately, the reader is not interested in the average amount of EFW required to contribute to acute hyponatremia but rather what volume of EFW is safest when providing fluids to hospitalized children. In order to establish a better estimate of the effect of specific quantities of EFW on the development of hyponatremia in hospitalized children, the authors could have dichotomized the quantity of EFW or categorized it to establish a dose-response relationship. This strategy would have allowed for the association to be expressed as an odds ratio, providing more practical information to the reader. The observational study by Hoorn et al detects cases of acute hyponatremia from a relatively generalizable population of hospitalized children and correlates the amount of free water they received with the outcome. The authors succeed in correlating the two, but the methods by which the information is presented leave the association difficult for the clinician to interpret, in that the amount of EFW deemed to place a child at risk cannot be inferred. Additionally, the study concludes that the major source for water input was the administration of hypotonic fluid. However, this is in fact only true in 66% of those in whom exogenous EFW explains the development of hyponatremia, which represents only 37% of all of the studys cases. Thus, Hoorn et al draw attention to the potential risks associated with hypotonic fluid administration, in what is the most rigorous study on the subject to date. However, it is difficult to justify the conclusion that hypotonic fluids be avoided in children whose sodium is less than 138 mmol/L based on the data presented.

Discussion
Studies examining the relationship between the administration of hypotonic fluids and the development of

acute hyponatremia in hospitalized children are inconclusive. All are observational studies in which considerable biases are inherent and in which it is difficult to adequately account for confounding variables. Although authors of all 3 studies advocate for the use of isotonic fluids, the study by Burrows et al is the only one that compares hypotonic with isotonic solutions.32 Very few patients in this study, however, received isotonic fluids, rendering the comparison meaningless. Additionally, the patient population of interest was very specific, limiting the studys generalizability beyond postoperative patients. Despite the implication that EFW from hypotonic fluids, in the presence of increased ADH secretion, is responsible for acute hyponatremia in these patients, the 2 studies in which the correlation was directly examined failed to explain the decrease in sodium in all of the children.8,28 In the study by Halberthal et al, the development of hyponatremia in 12/17 patients (70%) was not explained by exogenous EFW, and Hoorn et al could not account for the outcome in 16/40 (40%). Additionally, in those in whom Hoorn et al could explain the decrease in sodium, intravenous fluid was not always the major source accountable.28 One possible explanation is an unrecorded fluid source, a limitation of retrospective data collection. Excretion of hypertonic urine with secondary generation of EFW by the kidney is a second rationale, particularly plausible in that it may follow acute volume expansion with isotonic fluid boluses.28 This mechanism was also postulated in a prospective cohort study of adults who postoperatively all received isotonic solutions, yet still encountered a decrease in serum sodium.18 Despite EFW being a function of both tonicity and volume,28 the recommendations from all 3 studies reviewed focus mainly on tonicity.8,28,32 Clearly, fluid volume is also an important consideration. In the retrospective review, 70% of the hyponatremic patients received greater than 50% of their recommended maintenance volume,8 whereas in the casecontrol study, the cases received a significantly greater fluid volume compared with controls (mean SD: 98 77 mL/h vs 47 46 mL/h, P < .001).28 Additionally, isotonic fluid boluses were administered in 28% of hyponatremic patients in the study by Hoorn et al.28 Care must be taken, however, not to interpret these observations as an argument for fluid restriction, given that hypovolemia is an important stimulus for ADH secretion.11

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A further challenge to this area of study relates to the heterogeneous group of patients at risk for developing acute hyponatremia. This is reflected in the 3 studies reviewed, with a broad range of medical and surgical patients represented.8,28,32 Though the recommendations emerging from these studies are general ones, it is known that some hospitalized children are at higher risk than others, in terms of their degree of ADH secretion. In particular, postoperative patients are at high risk for hyponatremia,11,29,32 as are children with pulmonary or central nervous system infections.7,30 One prospective study showed that 46% of children diagnosed with bacterial meningitis or pneumonia already had a serum sodium of less than 134 mmol/L upon hospital admission.26 Perhaps, then, recommendations concerning maintenance fluid administration should be tailored to children at higher risk for adverse events. Recommendations for the adoption of isotonic maintenance fluids must be regarded with caution. Given that no trials have adequately compared them with hypotonic solutions, and that clinical experience using maintenance isotonic solutions is limited, neither their effectiveness with respect to preventing acute hyponatremia nor their safety has been established. Their effectiveness is particularly questionable given that the hyponatremia seen in study patients was not always explained by hypotonic fluid administration8,28 and that a decrease in serum sodium has been demonstrated postoperatively, despite the administration of isotonic fluids.18 In fact, the administration of isotonic fluids with subsequent natriuresis and EFW generation by the kidney has been proposed as a mechanism for hyponatremias development.18,28 With respect to safety, there are theoretical concerns that hypernatremia and fluid overload are risks of using isotonic saline as routine maintenance.12,13 Despite observational studies suggesting adverse outcomes secondary to the use of hypotonic solutions in hospitalized children, isotonic saline has not been evaluated with respect to either its effectiveness in preventing acute hyponatremia or its risk profile. Strengths of this study include addressing a focused and current clinical question, carrying out a thorough literature search of 5 electronic databases and hand-searched reference lists, full text review of all potentially relevant articles, the use of a selection form for study inclusion, and conducting critical reviews of each included study. Limitations relate to

a paucity of relevant articles and a single reviewer screening citations and determining final eligibility. Had more applicable studies been available for review, the a priori inclusion criteria would have applied, resulting in a more rigorous systematic review. Further research on appropriate maintenance fluids for hospitalized children should prospectively directly compare hypotonic with isotonic fluids. Additionally, the contribution of fluid volume and the role that isotonic fluid boluses play in the development of hyponatremia require further exploration.

Acknowledgments
Dr Beck was supported through a studentship, fully or in part, by the Ontario Student Opportunity Trust FundHospital for Sick Children Foundation Student Scholarship Program and by a Canadian Institute for Health Research Fellowship. The author would like to thank Ms Elizabeth Uleryk for assistance with the literature search, and Drs Patricia Parkin, Catherine Birken, and Jeremy Friedman for helpful comments on this manuscript.

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