John Robert Manderville, Keigan M More, and Karthik Tennankore
Hyponatremia, the most common electrolyte disorder in hospitalized patients, is associated with both morbidity and mortality.1–6 The use of hypotonic IV fluids has been identified as an important potential cause of hospital-acquired hyponatremia, especially among children.1–6 During patient care rounds, one of the authors (J.R.M.) serendipitously discovered a bag of hypotonic IV fluid that was inappropriately labelled (at the manufacturing level). This observation prompted a more in-depth review of IV fluid labelling practices across randomly selected Canadian and US manufacturers to better understand the scope of this issue.
Risk factors for non-osmotic release of antidiuretic hormone (ADH) include pain, nausea, stress, and certain medications. Hospitalized patients regularly experience these symptoms and often have changes to their medication regime, which may impair their ability to excrete free water because of fluctuations in ADH release. In the setting of increased ADH, the free water available in hypotonic IV solutions can rapidly lead to clinically significant hyponatremia.1–6
It is important for clinicians to understand the difference between tonicity and osmolality. Tonicity is a property of a solution with reference to a particular membrane, whereas osmolality is a property of a solution that is independent of any membrane.3,5 Solutes such as dextrose (which can freely enter the cell under normal conditions) contribute to the osmolality of a solution, but they do not alter tonicity.3,5 Although the difference between tonicity and osmolality may seem inconsequential, consider how a lack of awareness of this difference might lead to potential harm when an IV solution is prescribed.
In a patient with normal serum sodium, administration of a hyperosmolar IV solution without sodium (e.g., 10% dextrose in water, D10W) could lead to hyponatremia because the solution being administered is very hypotonic. In contrast, D10NS—an IV solution with the same concentration of dextrose but, concurrently, 0.9% sodium chloride (NaCl)—would not be expected to cause hyponatremia, because the NaCl contributes to tonicity (i.e., the solution is hyperosmotic yet isotonic).
Put another way, administration of 1000 mL of D5W is analogous to administering 1000 mL of electrolyte-free water, given that dextrose, once administered under normal physiologic conditions, will be quickly metabolized, leaving only free water. Similarly, administration of 1000 mL of 0.45% NaCl can be considered equivalent to administering 500 mL of isotonic (0.9%) NaCl plus 500 mL of free water. Finally, no free water is administered when 1000 mL of isotonic (0.9%) NaCl is given.
Because of physiological differences, children are at higher risk than adults for hyponatremia-related complications.3 Cases of iatrogenic hyponatremia in children (and adults) have been outlined in recent publications by the Institute for Safe Medication Practices Canada.7,8 Partly in response to these reports, our local children’s hospital established a policy listing several hypotonic solutions, which are mostly restricted to critical care areas.9 The American Academy of Pediatrics5 and the Canadian Paediatric Society1 recommend the use of isotonic IV solutions as the standard for fluid maintenance in children, with the recognition that hypotonic IV solutions can be used in specific circumstances but only with careful monitoring.
Given that the differences between osmolality and tonicity are well established, we reviewed the labelling and product monographs of selected dextrose-containing IV solutions produced by a random selection of Canadian and US manufacturers. We conducted a Google search using the term “leading IV manufacturers Canada” and chose the first 3 manufacturers generated by the search. We reviewed labelling and monograph information from the Canadian and US subsidiaries of all 3 companies; in 1 case, the Canadian and US labelling was the same, so only the US labelling is reported here (Table 1). We found several examples of isotonic and hypotonic IV solutions that were designated as “hypertonic” both in the product monograph and on individual bags of IV fluid. Of the 5 manufacturers screened (Table 1), only 1 manufacturer’s monograph indicated that dextrose-containing fluids could become hypotonic in vivo because of rapid metabolism.
TABLE 1 Labelling of Individual IV Fluid Bags and Product Monographs from Randomly Selected North American Manufacturersa
A total of 28 IV solutions were reviewed, 27 of which had incorrect information in their respective monographs, labelling, or both. Of the 18 hypotonic fluids that we reviewed, 11 (61%) were incorrectly labelled as “hypertonic” on the IV bag.
In our review, most of the solutions labelled as hypertonic are in fact hyperosmolar but not hypertonic. While it may be worthwhile to know the osmolarity of IV solutions (for example, hyperosmolar solutions may be associated with an increased risk of venous irritation10), the tonicity needs to be correctly described on both the label and product monograph to help ensure appropriate fluid selection in the clinical environment.
Hospital policies may help to provide guidance around the principles of IV fluid therapy. As previously noted, our local children’s hospital has established a policy regarding IV fluid administration. This policy lists several hypotonic solutions (for example, D5W, D10W, D5W + 0.2% NaCl, and dextrose 3.3% + 0.3% NaCl) which should not be routinely stocked outside of critical care areas,9 in part to avoid inadvertent administration when not clinically indicated. Moreover, the policy requires some hypotonic solutions (some of which are labelled as hypertonic by the manufacturer) to be labelled with a sticker reading “high-risk hypotonic solution”. Clearly, labelling a bag of IV solution with separate, yet conflicting, information is less than ideal. Correcting the labelling of these products at the time of manufacture would be a better approach to avoid potential errors.
We acknowledge that clinicians do not make decisions about IV fluid administration on the basis of product labelling, but rather according to education and teaching that would be gained through medical training. Therefore, the realized clinical impact of this labelling error has likely been negligible. However, the potential for severe harm, especially in pediatric patients, cannot be overstated. The inadvertent administration of hypotonic fluid that is labelled as hypertonic could be catastrophic and could result in morbidity and mortality.6 Therefore, we should not wait for a negative outcome but rather should recommend that companies change their product labelling so that negative outcomes can be avoided altogether.
We intend to submit our observations regarding inappropriate IV solution labelling to Canadian and US regulatory bodies in the hope that our analysis spurs changes toward more accurate labelling in the future.
1 Friedman JN. Risk of acute hyponatremia in hospitalized children and youth receiving maintenance intravenous fluids. Canadian Paediatric Society; 2018 [cited 2022 Oct 25]. Available from: https://www.cps.ca/en/documents/position/acute-hyponatremia-in-hospitalized-children-and-youth
2 Friedman JN, Beck CE, DeGroot J, Geary DF, Sklansky DJ, Freedman SB. Comparison of isotonic and hypotonic intravenous maintenance fluids. a randomized clinical trial. JAMA Pediatr. 2015;169(5):445–51.
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4 Patient safety alert 22: Reducing the risk of hyponatraemia when administering intravenous infusions to children. National Safety Patient Agency (UK); 2007 Mar 28 [cited 2022 Oct 25]. Available from: https://media.gosh.nhs.uk/documents/NPSA_Reducing_the_risk_ofs_fluids_to_children.pdf
5 Feld LG, Neuspiel DR, Foster BA, Leu MG, Garber MD, Austin K, et al.; Subcommittee on Fluid and Electrolyte Therapy. Clinical practice guideline: maintenance intravenous fluids in children. Pediatrics. 2018;142(6):e20183083
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7 Knowledge and monitoring deficits contribute to hospital-acquired hyponatremia. ISMP Can Saf Bull. 2015;15(11):1–5.
8 Hospital-acquired acute hyponatremia: two reports of pediatric deaths. ISMP Can Saf Bull. 2009;9(7):1–4.
9 Clinical practice guideline no. 80.30: IV fluids – infants, children and adolescents (prescribing, administration, safe storage/labeling). IWK Health Centre; 2014.
10 Uslusoy E, Mete S. Predisposing factors to phlebitis in patients with peripheral intravenous catheters: a descriptive study. J Am Acad Nurse Pract. 2008;20(4):172–80.
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Competing interests: For activities unrelated to the work reported here, Karthik Tennankore received an investigator-initiated grant from Otsuka; consulting fees from Baxter, Bayer, Otsuka, Astra Zeneca, GSK, and Vifor; and speaker’s fees from Bayer, Otsuka, Vifor, and Bayer; Dr Tennankore has also participated on an advisory board for Quanta. No other competing interests were declared.
Funding: None received.
Canadian Journal of Hospital Pharmacy, VOLUME 76, NUMBER 4, Fall 2023