Risk of Electrolyte Disorders in Acutely Ill Children Receiving Commercially Available Plasmalike Isotonic Fluids: A Randomized Clinical Trial | Acid Base, Electrolytes, Fluids | JAMA Pediatrics | JAMA Network
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Figure 1.  Study Design
Study Design

Altogether, 21 children were excluded owing to diabetes (5), pediatric cancer (1), severe hyponatremia at admission (1), severe hypokalemia at admission (1), age criterion not satisfied (7), parents did not understand the informed consent (1), and reason not specified by ED physician (5). The total number of children who both received fluid therapy and had at least 1 blood sample obtained was 283 in the isotonic group and 275 in the moderately hypotonic group. No children were lost to follow-up because the study ended at discharge from hospital. ED indicates emergency department.

Figure 2.  Potassium Concentrations at Different Time Points
Potassium Concentrations at Different Time Points

Potassium levels are presented in the intention-to-treat population of children (N = 614) randomly allocated to receive plasmalike isotonic fluid therapy or moderately hypotonic fluid therapy with 80 mmol/L of sodium and 20 mmol/L of potassium. Each dot indicates the value of 1 study subject. The short horizontal lines indicate the mean value of the group in each time frame. The long horizontal line indicates the limit of clinically significant electrolyte disorder used in the statistical analysis. Potassium values indicating hyperkalemia >5.5. mmol/L were not verified in subsequent samples but were kept in the data unless the problem with the hemolysis was specifically marked in the laboratory sheets, resulting in hyperkalemia in 1 of 308 vs 2 of 306 (95% CI of the difference, –2% to 1.2%).

Figure 3.  Sodium Concentrations at Different Time Points
Sodium Concentrations at Different Time Points

Sodium levels are presented in the intention-to-treat population of children (N = 614) randomly allocated to receive plasmalike isotonic fluid therapy or moderately hypotonic fluid therapy with 80 mmol/L of sodium and 20 mmol/L of potassium. Each dot indicates the value of 1 study subject. The short horizontal lines indicate the mean value of the group in each time frame. The long horizontal line indicates the limit of clinically significant electrolyte disorder used in the statistical analysis.

Table 1.  Characteristics of the Patients at Baseline
Characteristics of the Patients at Baseline
Table 2.  Primary and Secondary Outcomes
Primary and Secondary Outcomes
1.
Feld  LG, Neuspiel  DR, Foster  BA,  et al; Subcommittee on Fluid and Electrolyte Therapy.  Clinical practice guideline: maintenance intravenous fluids in children.   Pediatrics. 2018;142(6):1. doi:10.1542/peds.2018-3083 PubMedGoogle ScholarCrossref
2.
Arieff  AI, Ayus  JC, Fraser  CL.  Hyponatraemia and death or permanent brain damage in healthy children.   BMJ. 1992;304(6836):1218-1222. doi:10.1136/bmj.304.6836.1218 PubMedGoogle ScholarCrossref
3.
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(7289):780-782. doi:10.1136/bmj.322.7289.780 PubMedGoogle ScholarCrossref
4.
Moritz  ML, Ayus  JC.  Preventing neurological complications from dysnatremias in children.   Pediatr Nephrol. 2005;20(12):1687-1700. doi:10.1007/s00467-005-1933-6 PubMedGoogle ScholarCrossref
5.
Koczmara  C, Hyland  S, Greenall  J.  Hospital-acquired acute hyponatremia and parenteral fluid administration in children.   Can J Hosp Pharm. 2009;62(6):512-515. doi:10.4212/cjhp.v62i6.851 PubMedGoogle Scholar
6.
Grissinger  M.  Hyponatremia and death in healthy children from plain dextrose and hypotonic saline solutions after surgery.   P T. 2013;38(7):364-388.PubMedGoogle Scholar
7.
Montañana  PA, Modesto i Alapont  V, Ocón  AP, López  PO, López Prats  JL, Toledo Parreño  JD.  The use of isotonic fluid as maintenance therapy prevents iatrogenic hyponatremia in pediatrics: a randomized, controlled open study.   Pediatr Crit Care Med. 2008;9(6):589-597. doi:10.1097/PCC.0b013e31818d3192 PubMedGoogle ScholarCrossref
8.
Yung  M, Keeley  S.  Randomised controlled trial of intravenous maintenance fluids.   J Paediatr Child Health. 2009;45(1-2):9-14. doi:10.1111/j.1440-1754.2007.01254.x PubMedGoogle ScholarCrossref
9.
Rey  C, Los-Arcos  M, Hernández  A, Sánchez  A, Díaz  JJ, López-Herce  J.  Hypotonic versus isotonic maintenance fluids in critically ill children: a multicenter prospective randomized study.   Acta Paediatr. 2011;100(8):1138-1143. doi:10.1111/j.1651-2227.2011.02209.x PubMedGoogle ScholarCrossref
10.
Brazel  PW, McPhee  IB.  Inappropriate secretion of antidiuretic hormone in postoperative scoliosis patients: the role of fluid management.   Spine (Phila Pa 1976). 1996;21(6):724-727. doi:10.1097/00007632-199603150-00013 PubMedGoogle ScholarCrossref
11.
Neville  KA, Sandeman  DJ, Rubinstein  A, Henry  GM, McGlynn  M, Walker  JL.  Prevention of hyponatremia during maintenance intravenous fluid administration: a prospective randomized study of fluid type versus fluid rate.   J Pediatr. 2010;156(2):313-319.e1, 2. doi:10.1016/j.jpeds.2009.07.059 PubMedGoogle ScholarCrossref
12.
Choong  K, Arora  S, Cheng  J,  et al.  Hypotonic versus isotonic maintenance fluids after surgery for children: a randomized controlled trial.   Pediatrics. 2011;128(5):857-866. doi:10.1542/peds.2011-0415 PubMedGoogle ScholarCrossref
13.
Coulthard  MG, Long  DA, Ullman  AJ, Ware  RS.  A randomised controlled trial of Hartmann’s solution versus half normal saline in postoperative paediatric spinal instrumentation and craniotomy patients.   Arch Dis Child. 2012;97(6):491-496. doi:10.1136/archdischild-2011-300221 PubMedGoogle ScholarCrossref
14.
McNab  S, Duke  T, South  M,  et al.  140 mmol/L of sodium versus 77 mmol/L of sodium in maintenance intravenous fluid therapy for children in hospital (PIMS): a randomised controlled double-blind trial.   Lancet. 2015;385(9974):1190-1197. doi:10.1016/S0140-6736(14)61459-8 PubMedGoogle ScholarCrossref
15.
Saba  TG, Fairbairn  J, Houghton  F, Laforte  D, Foster  BJ.  A randomized controlled trial of isotonic versus hypotonic maintenance intravenous fluids in hospitalized children.   BMC Pediatr. 2011;11:82. doi:10.1186/1471-2431-11-82 PubMedGoogle ScholarCrossref
16.
Torres  SF, Iolster  T, Schnitzler  EJ, Siaba Serrate  AJ, Sticco  NA, Rocca Rivarola  M.  Hypotonic and isotonic intravenous maintenance fluids in hospitalised paediatric patients: a randomised controlled trial.   BMJ Paediatr Open. 2019;3(1):e000385. doi:10.1136/bmjpo-2018-000385 PubMedGoogle Scholar
17.
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):445-451. doi:10.1001/jamapediatrics.2014.3809 PubMedGoogle ScholarCrossref
18.
McNab  S, Ware  RS, Neville  KA,  et al.  Isotonic versus hypotonic solutions for maintenance intravenous fluid administration in children.   Cochrane Database Syst Rev. 2014;(12):CD009457. doi:10.1002/14651858.CD009457.pub2 PubMedGoogle Scholar
19.
Van Regenmortel  N, De Weerdt  T, Van Craenenbroeck  AH,  et al.  Effect of isotonic versus hypotonic maintenance fluid therapy on urine output, fluid balance, and electrolyte homeostasis: a crossover study in fasting adult volunteers.   Br J Anaesth. 2017;118(6):892-900. doi:10.1093/bja/aex118 PubMedGoogle ScholarCrossref
20.
Marcdante  KJ, Kliegman  RM, eds. Nelson Essentials of Pediatrics. 7th ed. Elsevier Saunders; 2015.
21.
Isotonic versus hypotonic intravenous fluids in hospitalised children—a randomised controlled trial. ClinicalTrialsRegister.eu identifier: 2016-002046-23. Accessed September 19, 2020. https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2016-002046-23
22.
Intravenous fluids in hospitalized children. ClinicalTrials.gov identifier: NCT02926989. Updated August 22, 2019. Accessed September 19, 2020. https://clinicaltrials.gov/ct2/show/NCT02926989
23.
Holliday  MA, Segar  WE.  The maintenance need for water in parenteral fluid therapy.   Pediatrics. 1957;19(5):823-832.PubMedGoogle Scholar
24.
Armitage  P, Berry  G, Matthews  JNS, eds.  Statistical Methods in Research. 4th ed. Blackwell Science; 2020.
25.
Armon  K, Riordan  A, Playfor  S, Millman  G, Khader  A; Paediatric Research Society.  Hyponatraemia and hypokalaemia during intravenous fluid administration.   Arch Dis Child. 2008;93(4):285-287. doi:10.1136/adc.2006.093823 PubMedGoogle ScholarCrossref
26.
Cummings  BM, Macklin  EA, Yager  PH, Sharma  A, Noviski  N.  Potassium abnormalities in a pediatric intensive care unit: frequency and severity.   J Intensive Care Med. 2014;29(5):269-274. doi:10.1177/0885066613491708 PubMedGoogle ScholarCrossref
27.
Moritz  ML, Ayus  JC.  The changing pattern of hypernatremia in hospitalized children.   Pediatrics. 1999;104(3 Pt 1):435-439. doi:10.1542/peds.104.3.435 PubMedGoogle ScholarCrossref
28.
Valadão  MC, Piva  JP, Santana  JC, Garcia  PC.  Comparison of two maintenance electrolyte solutions in children in the postoperative appendectomy period: a randomized, controlled trial.   J Pediatr (Rio J). 2015;91(5):428-434. doi:10.1016/j.jped.2015.01.004 PubMedGoogle ScholarCrossref
29.
Shamim  A, Afzal  K, Ali  SM.  Safety and efficacy of isotonic (0.9%) vs. hypotonic (0.18%) saline as maintenance intravenous fluids in children: a randomized controlled trial.   Indian Pediatr. 2014;51(12):969-974. doi:10.1007/s13312-014-0542-5 PubMedGoogle ScholarCrossref
30.
Alobaidi  R, Morgan  C, Basu  RK,  et al.  Association between fluid balance and outcomes in critically ill children: A systematic review and meta-analysis.   JAMA Pediatr. 2018;172(3):257-268. doi:10.1001/jamapediatrics.2017.4540 PubMedGoogle ScholarCrossref
31.
Whyte  LA, Jenkins  HR.  Pathophysiology of diarrhoea.   Paediatrics & Child Health. 2012;22:443–447. doi:10.1016/j.paed.2012.05.006 Google ScholarCrossref
32.
Lehnhardt  A, Kemper  MJ.  Pathogenesis, diagnosis and management of hyperkalemia.   Pediatr Nephrol. 2011;26(3):377-384. doi:10.1007/s00467-010-1699-3 PubMedGoogle ScholarCrossref
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    3 Comments for this article
    EXPAND ALL
    Interesting Study With a Loophole
    Björn Hammarskjöld, MD & PhD | Strömstad Academy
    There was about 280 mmo/L of electrolytes in the isotonic fluid and there was about 200 mmol/L of electrolytes in the moderately hypotonic solution.

    But what about the glucose content? 50 g/L is equal to 278 mmol/L. The glucose concentration should have been added to the concentrations of electrolytes which means the "isotonic” fluid was a hypertonic solution of about 580 mmol/L and the ”moderate hypotonic” fluid is almost as hypertonic, about 480 mmol/L.
    There is no need to add any glucose to I.V. fluids as the 5 % glucose is equal to 278 mmol/L. The energy
    from 50 g glucose is just 200 kcal, negligible. Remember, the blood of a 17 kg child has 0.36 - 0.73 grams of glucose in the whole blood volume of 1.3 L. So by giving 20 mL/kg bodyweight as a bolus dose is infusing 1 g of glucose increasing the P-glucose from 5.3 mmol/L by 7.7mmol/L to about 13 mmol/L.

    I would recommend to reiterate the experiment with Plasmalyte or Ringer acetate as isotone solutions and have 80/20 NaCl/KCl as a moderate hypotonic solutions without any other additives.
    CONFLICT OF INTEREST: None Reported
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    It's not a question of tonicity
    Elliot Long, PhD | The Royal Children's Hospital Melbourne
    We read with some concern the article by Lehtiranta et al titled ‘Risk of electrolyte disorders in acutely ill children receiving commercially available plasmalike isotonic fluids’ published in JAMA Pediatrics(1).

    The primary outcome listed in the pre-trial register is the incidence of hypokalemia (<3.5mmol/L) (https://www.clinicaltrialsregister.eu/ctr-search/trial/2016-002046-23/FI). However, the primary outcome in the published article is a composite outcome of a broader range of electrolyte abnormalities. This is not listed in the trial registration even as a secondary outcome.

    It is unclear why the authors chose to compare a hypotonic maintenance fluid to an isotonic maintenance fluid. If
    the primary study question was the effect of potassium content in maintenance fluid, the base fluid should ideally have been the same between groups. Hyponatremic cerebral oedema due to the administration of hypotonic maintenance fluid is a rare but preventable cause of permanent neurological disability and death in hospitalized children(2). Blinded, randomized trials of hypotonic maintenance fluid compared to isotonic maintenance fluid have shown reduced risk of hyponatremia through the use of higher sodium containing solutions(3).

    We note that hyperkalemia was not reported for either treatment arm. This is an important safety outcome.

    Overall, this study highlights the need for ongoing electrolyte monitoring and adjustment of potassium content in hospitalized children receiving maintenance fluids.

    References
    1. Lehtiranta S, Honkila M, Kallio M, et al. Risk of Electrolyte Disorders in Acutely Ill Children Receiving Commercially Available Plasmalike Isotonic Fluids: A Randomized Clinical Trial. JAMA Pediatr. Oct 2020;doi:10.1001/jamapediatrics.2020.3383
    2. Koczmara C, Wade AW, Skippen P, et al. Hospital-acquired acute hyponatremia and reports of pediatric deaths. Dynamics. 2010;21(1):21-6.
    3. McNab S, Duke T, South M, et al. 140 mmol/L of sodium versus 77 mmol/L of sodium in maintenance intravenous fluid therapy for children in hospital (PIMS): a randomised controlled double-blind trial. Lancet. Mar 2015;385(9974):1190-7. doi:10.1016/S0140-6736(14)61459-8

    Sincerely-
    A/Prof Elliot Long
    Prof Franz E Babl
    Dr Sarah McNab
    CONFLICT OF INTEREST: None Reported
    READ MORE
    Gaps in Methodology May Limit Interpretation of Results and Conclusions
    Douglas Hansell, MD | Massachusetts General Hospital
    Dear Editor,
    We read with interest the study by Lehtiranta and colleagues.1 After careful review, we identified several gaps in methodology which may significantly limit the interpretation of the results and conclusions of the paper.
    First, the study excluded enrollment of patients with potassium levels below 3.0mmol/L, but allowed patients with levels between 3.0 and 3.5mmol/L. The primary endpoint of the study was incidence of electrolyte disorders (including hypokalemia defined as <3.5 mmol/L) any time after randomization. As Plasmalyte is not intended to treathypokalemia, by study design these patients would likely remain hypokalemic without additional potassium supplementation.
    Second,
    the study was an unblinded randomized single-center clinical where IV treatment pre-enrollment was not controlled or described. The choice of initial resuscitation fluid and the amount administered would be expected to significantly impact the patient’s electrolyte status and fluid balance, but given that pre-enrollment fluid is unknown, its impact on the trial outcome cannot be assessed. Similarly, concomitant medications that are independent risk factors for hypokalemia, like diuretics, should be analyzed.
    Third, providers changed the sodium and potassium concentrations, product and infusion rate of fluid therapy in a significant number of patients. This could impact analysis results and conclusions, as electrolyte measurements were included in the primary endpoint analysis regardless of these changes.
    Fourth, all categories of acute illnesses are grouped together. Approximately 27% of the patients in each group presented with gastroenteritis, which can impair electrolyte balance in the short term, particularly potassium loss in stool and emesis with decreased oral intake.
    Importantly, the authors refer to AAP guidelines for selecting isotonic solution (Plasmalyte) and compare it to hypotonic solution using electrolyte imbalance as outcomes. AAP Clinical Practice Guideline recommends that patients 28 days to 18 years of age requiring maintenance IVFs should receive isotonic solutions with appropriate KCl and dextrose.2 As such, this study did not follow appropriate clinical practice guidelines. In order to replace normal urinary potassium losses and provide additional electrolytes for growth, roughly 2 mEq of potassium are required for each 100 kilocalories of energy expended or 100 mLs of maintenance fluid.3 This translates into 20 mEq of potassium per liter, when Plasmalyte contains 5 mEq of potassium chloride per liter. Therefore, there is a subsequent risk of hypokalemia when using Plasmalyte for pediatric patients without potassium chloride supplementation.
    Each of these gaps, but particularly as a sum, may significantly impact the conclusions presented in this paper.
    CONFLICT OF INTEREST: Employee of Massachusetts General Hospital and Baxter Healthcare
    READ MORE
    Original Investigation
    October 26, 2020

    Risk of Electrolyte Disorders in Acutely Ill Children Receiving Commercially Available Plasmalike Isotonic Fluids: A Randomized Clinical Trial

    Author Affiliations
    • 1Department of Pediatrics and Adolescent Medicine, Oulu University Hospital, Oulu, Finland
    • 2Research Unit of Pediatrics, Dermatology, Gynecology, and Obstetrics, Medical Research Center Oulu, University of Oulu, Oulu, Finland
    • 3Department of Pediatrics, University of Eastern Finland, Kuopio University Hospital, Kuopio, Finland
    • 4Biocenter Oulu, University of Oulu, Oulu, Finland
    JAMA Pediatr. 2021;175(1):28-35. doi:10.1001/jamapediatrics.2020.3383
    Key Points

    Question  What is the risk of electrolyte disorders in acutely ill children receiving commercially available plasmalike isotonic fluids?

    Findings  In this randomized clinical trial of 614 acutely ill children, the risk of electrolyte disorders was 6.7-fold greater in children receiving plasmalike isotonic fluid therapy as compared with those receiving moderately hypotonic fluid therapy with 20 mmol/L of potassium.

    Meaning  These findings suggest that commercially available plasmalike isotonic fluids are not optimal for fluid therapy in acutely ill children.

    Abstract

    Importance  The use of isotonic fluid therapy is currently recommended in children, but there is limited evidence of optimal fluid therapy in acutely ill children.

    Objective  To evaluate the risk for electrolyte disorders, including hyponatremia, hypernatremia, and hypokalemia, and the risk of fluid retention in acutely ill children receiving commercially available plasmalike isotonic fluid therapy.

    Design, Setting, and Participants  This unblinded, randomized clinical pragmatic trial was conducted at the pediatric emergency department of Oulu University Hospital, Finland, from October 3, 2016, through April 15, 2019. Eligible study subjects (N = 614) were between 6 months and 12 years of age, required hospitalization due to an acute illness, and needed intravenous fluid therapy. Exclusion criteria included a plasma sodium concentration of less than 130 mmol/L or greater than 150 mmol/L on admission; a plasma potassium concentration of less than 3.0 mmol/L on admission; clinical need of fluid therapy with 10% glucose solution; a history of diabetes, diabetic ketoacidosis, or diabetes insipidus; a need for renal replacement therapy; severe liver disease; pediatric cancer requiring protocol-determined chemotherapy hydration; and inborn errors of metabolism. All outcomes and samples size were prespecified except those clearly marked as exploratory post hoc analyses. All analyses were intention to treat.

    Interventions  Acutely ill children were randomized to receive commercially available plasmalike isotonic fluid therapy (140 mmol/L of sodium and 5 mmol/L potassium in 5% dextrose) or moderately hypotonic fluid therapy (80 mmol/L sodium and 20 mmol/L potassium in 5% dextrose).

    Main Outcomes and Measures  The primary outcome was the proportion of children with any clinically significant electrolyte disorder, defined as hypokalemia less than 3.5 mmol/L, hypernatremia greater than 148 mmol/L, or hyponatremia less than 132 mmol/L during hospitalization due to acute illness. The main secondary outcomes were the proportion of children with severe hypokalemia and weight change.

    Results  There were 614 total study subjects (mean [SD] age, 4.0 [3.1] years; 315 children were boys [51%] and all 614 were Finnish speaking [100%]). Clinically significant electrolyte disorder was more common in children receiving plasmalike isotonic fluid therapy (61 of 308 patients [20%]) compared with those receiving moderately hypotonic fluid therapy (9 of 306 patients [2.9%]; 95% CI of the difference, 12%-22%; P < .001). The risk of developing electrolyte disorder was 6.7-fold greater in children receiving isotonic fluid therapy. Hypokalemia developed in 57 patients (19%) and hypernatremia developed in 4 patients (1.3%) receiving plasmalike isotonic fluid therapy. Weight change was greater in children receiving isotonic, plasmalike fluid therapy compared with those receiving mildly hypotonic fluids (mean weight gain, 279 vs 195 g; 95% CI, 16-154 g; P = .02).

    Conclusions and Relevance  In this randomized clinical trial, commercially available plasmalike isotonic fluid therapy markedly increased the risk for clinically significant electrolyte disorders, mostly due to hypokalemia, in acutely ill children compared with previously widely used moderately hypotonic fluid therapy containing 20 mmol/L of potassium.

    Trial Registration  ClinicalTrials.gov identifier: NCT02926989

    Introduction

    Since 2018, the American Academy of Pediatrics has been recommending isotonic solutions for intravenous maintenance fluid therapy in most children to avoid hyponatremia.1 Fatal hyponatremia or severe brain damage has been reported in children receiving hypotonic intravenous fluid therapy, in particular in postoperative patients receiving high amounts of hypotonic fluids.2-6 Decreased occurrence of mild hyponatremia in children receiving isotonic fluid therapy has been reported in randomized clinical trials in pediatric intensive care patients,7-9 in postoperative patients,10-13 and in mixed pediatric populations.14-16

    The recommendation of the American Academy of Pediatrics has markedly changed fluid therapy in children toward isotonic fluid therapy instead of moderately hypotonic fluid therapy. Yet, there is still limited evidence of isotonic fluid therapy outcomes in acutely ill children.17,18 Furthermore, isotonic fluids have been shown to result in decreased renal output in healthy adult volunteers.19 The recent American Academy of Pediatrics guideline acknowledges the limited evidence on the risk of hypernatremia and fluid retention in children receiving isotonic fluid therapy.1 Finally, clinical trials using plasmalike isotonic solutions have not reported the risk of hypokalemia in children.14,18 Thus, the appropriate amount of potassium in intravenous fluid therapy is not known.

    We conducted a large randomized trial to evaluate the risk for electrolyte disorders, including hyponatremia, hypernatremia, and hypokalemia, and the risk of fluid retention in acutely ill children receiving plasmalike, ready-to-use isotonic fluid products.14 Moderately hypotonic fluid with 80 mmol/L of sodium and 20 mmol/L of potassium was the control treatment because it was the recommended choice in pediatric textbooks when this study was started.20

    Methods
    Trial Design and Oversight

    This prespecified, unblinded, randomized, pragmatic clinical trial was conducted at the pediatric emergency department (ED) of Oulu University Hospital, Finland, from October 3, 2016, through April 15, 2019. The pediatric ED in the present study is a part of the Finnish public health care system and the only hospital in the area with pediatric wards providing intravenous fluid therapy for acutely ill children. The trial was conducted in accordance with the principles of Good Clinical Practice guidelines and the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline. This trial was registered at ClinicalTrialsRegister.eu before initiation (EUDRA-CT 2016-002046)21 and at ClinicalTrials.gov during the first days of the study (NCT02926989).22 The Finnish Medical Agency reviewed the study protocol before its initiation. The Regional Ethics Committee of the Northern Ostrobothnia Hospital District, Oulu, Finland, approved the study protocol. The study protocol with a full literature review and statistical analysis plan is available (Supplement 1 and eTable in Supplement 2). Parents or legal guardians gave their written informed consent before participation. Patients aged 6 to 12 years gave their own written consent in addition to parental consent. The authors designed the trial, collected the data, and performed the analyses. Treating physicians at the pediatric ED participated in the data collection. The first 3 authors (S.L, M.H., and M.K.) and the last author (T.T.) wrote the initial version of the manuscript, and all authors contributed to revisions. All authors approved the manuscript and vouched for the accuracy and completeness of the data.

    Patients

    Study subjects were eligible for enrollment in the trial if they were patients at the pediatric ED, were between 6 months and 12 years of age, required hospitalization due to an acute illness, and needed intravenous fluid therapy according to the clinical judgment of the treating physician. Exclusion criteria included a plasma sodium concentration of less than 130 mmol/L or greater than 150 mmol/L on admission; a plasma potassium concentration of less than 3.0 mmol/L on admission; clinical need of fluid therapy with 10% glucose solution; a history of diabetes, diabetic ketoacidosis, or diabetes insipidus; a need for renal replacement therapy; severe liver disease; pediatric cancer requiring protocol-determined chemotherapy hydration; and inborn errors of metabolism.

    Trial Treatment

    Patients were randomly assigned in a 1:1 ratio to receive isotonic or moderately hypotonic fluid therapy. The isotonic fluid (commercially available as Plasmalyte Glucos 50 mg/mL [Baxter UK]) contained 140 mmol/L of sodium in 5% dextrose, 5 mmol/L of potassium, 1.5 mmol/L of magnesium, 98 mmol/L of chloride, 23 mmol/L of acetate, and 23 mmol/L of gluconate. The moderately hypotonic solution contained 80 mmol/L of sodium chloride and 20 mmol/L of potassium chloride in 5% dextrose based on the existing recommendations in pediatric textbooks at the beginning of the study. Patients were allowed to receive fluid replacement of 20 mL/kg lactated Ringer solution or other isotonic crystalloids if clinically indicated before the initiation of the study fluid. A statistician created a computerized randomization list using permuted blocks of 4. Sealed, numbered, opaque envelopes contained the name of the study fluid according to the randomization list. Treating physicians enrolled patients, opened the randomization envelopes after receiving written informed consent, and assigned patients to intervention groups. The study investigators, treating physicians, nurses, patients, and patients’ legal guardians were aware of the intravenous fluid administered. Laboratory personnel performing laboratory analysis for electrolyte concentrations were unaware of the treatment group.

    After randomization, the treating physician determined the infusion rate based on the daily fluid requirements estimated according to the Holliday-Segar formula23 and fluids needed for rehydration (weight decrease, g = mL, or clinical judgment, 5%-10% of weight). Fluids were administered using electronic delivery pumps programmed for an hourly infusion rate and continued until the treating physician decided to stop the administration. For safety reasons, the study design was open. The treating physicians were allowed to change the sodium or potassium concentrations, the fluid therapy product, or the infusion rate when clinically indicated.

    Blood electrolytes were determined every morning, or more frequently when clinically indicated, during the acute illness until discharge from the hospital. All laboratory values were immediately available to the treating physicians. A venous blood sampling technique was recommended, but when unsuccessful, capillary blood sampling by skin puncture was performed. The study patients were weighed before the onset of fluid therapy, daily while in the hospital, and after the fluid therapy had stopped. The duration of the intravenous fluid therapy and the weight change were collected from the hospital medical records. Other laboratory tests were performed as clinically indicated.

    Outcomes

    The primary outcome was the proportion of children with any clinically significant electrolyte disorder, defined as hypokalemia less than 3.5 mmol/L, hypernatremia greater than 148 mmol/L, or hyponatremia less than 132 mmol/L during hospitalization due to acute illness. The secondary outcomes were the proportion of children with severe hypokalemia, defined as potassium less than 3.0 mmol/L; the proportion of children with mild hyponatremia, defined as plasma sodium 132 to 135 mmol/L; the fluid retention measured by weight change (in grams) during hospitalization: weight (in grams) at discharge – weight (in grams) on admission; the proportion of children requiring any change of fluid therapy; the proportion of children admitted to intensive care after admission; the duration of intravenous fluid therapy (hours); the duration of hospitalization; and the number of deaths. All secondary outcomes were reported during hospitalization due to acute illness except the number of deaths within 30 days of randomization. Exploratory post hoc analyses, added to the analyses after starting the study, included the time to electrolyte disorder (hours), analyses regarding metabolic acidosis in those with available blood gas samples, and copeptin values as a precursor for antidiuretic hormone in a random sample of patients at 6 to 24 hours.

    Statistical Analysis

    The occurrence of any clinically significant electrolyte disorder in children receiving isotonic fluid therapy was estimated to be 13% based on a previous study reporting the need of adding potassium in plasmalike fluid in children.14 We considered the difference between groups to be clinically significant if the occurrence of an electrolyte disorder was 7% lower in children receiving moderately hypotonic fluid. We set the α error at 5% and the β error at 20%, ie, a power of 80%, which resulted in 275 children per group. To ensure that the final analysis included the required number of children with a measured primary outcome, we decided to recruit 305 children per group. All analyses were performed in strict intention-to-treat population. Primary and secondary outcomes were specified in the protocol before starting the study. Post hoc analyses after the original statistical analysis are presented separately (Supplement 1).

    In hospitalized participants, missing data were rare. Risk ratios and the number needed to treat to avoid 1 patient developing an electrolyte disorder in the hypotonic fluid therapy group were calculated. The number needed to harm was used if isotonic fluid increased the risk. For primary and secondary outcomes, we calculated 95% CIs of the differences using a standard normal deviate test for the proportions and a t test for continuous variables with a statistical significance level of <.05.24 P values were 2-sided. The widths of CIs were not adjusted for multiplicity and should not be interpreted as definite treatment effects. All analyses were performed using IBM Statistics for Windows, version 26 (IBM Corp) and StatsDirect statistical software, version 3 (StatsDirect Ltd). Statistical analyses were performed from May 20, 2019, to January 8, 2020.

    Results
    Characteristics of the Patients

    From October 3, 2016, to April 15, 2019, a total of 713 acutely ill children potentially in need of maintenance fluid therapy were evaluated for suitability for the study (Figure 1). Altogether, 84 patients were excluded, either because they declined to participate, did not meet the inclusion criteria, or the randomization envelope or patient identification were missing. Only the first visit was included in the analysis for 20 patients (6 isotonic and 14 hypotonic) enrolled more than once during different visits at the ED. Thus, 614 patients were included in the intention-to-treat population (mean [SD] age, 4.0 [3.1] years; 315 children were boys [51%] and all 614 were Finnish speaking [100%]; Table 1). The mean (SD) duration of hospitalization was 2.3 (3.8) days, and the mean (SD) duration of intravenous fluid therapy was 29 (41) hours. The most common reasons for hospitalization were respiratory infections, gastroenteritis, and other viral infections. Nine patients (1.5%) were admitted to the pediatric intensive care unit from the ED. A total of 73 patients (12%) needed anesthesia during hospitalization. Mean (SD) time from stopping intravenous fluid therapy to discharge from the hospital was 19.3 (31.1) hours in children receiving isotonic fluid therapy and 19.1 (31.3) hours in patients receiving moderately hypotonic therapy.

    Primary Outcome

    Clinically significant electrolyte disorders were more common in children receiving isotonic fluid therapy (61 of 308 patients, 20%) compared with those receiving moderately hypotonic fluid therapy (9 of 306 patients, 2.9%) (95% CI of the difference, 12%-22%; P < .001) (Table 2, Figures 2 and 3). The risk ratio for clinically significant electrolyte disorder was 6.7 (95% CI, 3.5-13), and the number needed to harm was 6 (95% CI, 5-9) in children receiving isotonic fluid therapy compared with those receiving moderately hypotonic fluid therapy. Hypokalemia developed in 57 patients (19%) receiving isotonic fluid therapy and in 9 patients (2.9%) receiving moderately hypotonic fluid therapy (95% CI, 11%-21%) (P < .001). Hypernatremia developed in 4 patients (1.3%) receiving isotonic fluid therapy and in none of those receiving moderately hypotonic fluid therapy (95% CI of the difference, 0.05%-3.3%; P = .04) (Table 2). None of the patients developed severe hyponatremia (sodium <132 mmol/L) (Table 2).

    Secondary Outcomes

    Severe hypokalemia (<3.0 mmol/L) was significantly more common in patients receiving plasmalike isotonic fluid therapy (8 of 308 patients, 2.6%) compared with patients receiving moderately hypotonic fluid therapy (1 of 306 patients, 0.3%) (95% CI of the difference, 0.5%-4.8%; P = .02) with a risk ratio of 7.9 (95% CI, 1.3-49) and number needed to harm of 45 (95% CI, 22-211). The patients with severe hypokalemia in the isotonic fluid therapy group (8 total) were hospitalized due to gastroenteritis (3 adenoviruses [37.5%], 1 rotavirus [12.5%]), severe pneumonia requiring intensive care (2 [25%]), pneumonia (1; 12.5%), and severe viral wheezing requiring intensive care (1 [12.5%]). The patient who developed severe hypokalemia in the moderately hypotonic fluid therapy group was hospitalized due to pneumonia. The occurrence of mild hyponatremia (sodium, 132-135 mmol/L) did not differ between children receiving isotonic fluid therapy (7 of 308 patients, 2.3%) and children receiving moderately hypotonic fluid therapy (11 of 306 patients, 3.6%) (difference, –1.3%; 95% CI, –4.3 to 1.5; P = .33).

    Children receiving isotonic fluid therapy had a greater weight gain during the hospitalization (279 g) as compared with those receiving moderately hypotonic fluid therapy (195 g) (95% CI of the difference, 16-154 g; P = .02) (Table 2). There was no difference in the total proportion of children whose fluid therapy was modified by clinicians either by adding electrolytes or by changing fluid therapy otherwise between the 2 study groups. The need for pediatric intensive care unit treatment, duration of intravenous fluid therapy, and time to discharge from hospital did not differ between the groups. There were no deaths in the study population.

    Exploratory Post Hoc Analyses

    Mean (SD) time to the development of hypernatremia was 12 (4.9) hours in children receiving isotonic fluid therapy. Mean (SD) time to the development of hypokalemia was 14 (8.4) hours in children receiving isotonic fluid and 31 (26) hours in children receiving moderately hypotonic fluid (95% CI, –37 to –2.2; P = .07). Metabolic acidosis, measured by base excess and bicarbonate levels in blood gas analysis, resolved faster in children receiving isotonic fluid therapy compared with children receiving moderately hypotonic fluid therapy. Low bicarbonate levels on the day after admission were detected in 7 of 132 patients (5.3%) with a measurement in the isotonic group and in 39 of 152 patients (26%) with a measurement in the moderately hypotonic group (difference, –21%; 95% CI, –29% to –12%; Table 2). In retrospect, in a random sample of participants (10%), copeptin levels were examined in frozen plasma samples, obtained at 6 to 24 hours after starting fluid therapy, to evaluate whether copeptin levels were higher in children exposed to isotonic fluid therapy and higher concentrations of sodium. Copeptin values were higher in children receiving isotonic fluid therapy vs those receiving moderately hypotonic fluid therapy (mean [SD], 8.1 [5.4] vs 7.3 [4.6] pmol/L), but the difference was not statistically significant (Table 2).

    Severe Adverse Events

    There were no reported neurologic complications in the study population. One patient who received isotonic fluid therapy was transferred to the pediatric intensive care unit due to severe hypokalemia (potassium, 2.2 mmol/L) on the third day of fluid therapy. This patient had the Finnish type of congenital nephrosis without severe renal dysfunction or need for dialysis and was hospitalized due to adenovirus gastroenteritis. Another patient, with rotavirus infection and mild hypokalemia (potassium, 3.1 mmol/L) in the isotonic fluid group, had myoclonus and seizures during hospitalization and was later diagnosed with epilepsy.

    Discussion

    In this randomized, pragmatic single-center trial of 614 acutely ill children at a pediatric ED of a university hospital, commercially available plasmalike isotonic fluid increased the risk of clinically significant electrolyte disorder compared with moderately hypotonic fluid containing 80 mmol/L of sodium and 20 mmol/L of potassium. The risk of developing electrolyte disorder was 6.7-fold greater in children receiving isotonic fluid therapy, mostly due to the increased risk of hypokalemia. Electrolyte disorders were not prevented by the open study design, which allowed physicians to change fluid therapy during hospitalization. The length of stay did not differ between the treatment groups.

    Most electrolyte disorders observed in children receiving plasmalike isotonic fluid therapy in the present study were due to hypokalemia. Hypokalemia is a common electrolyte disorder among children receiving intravenous fluid therapy or treated at an intensive care unit.25,26 The recent guideline by the American Academy of Pediatrics recommends adding an appropriate amount of potassium in fluids.1 Yet, commercially available plasmalike isotonic fluids have been used in earlier randomized controlled trials without reporting the risk of hypokalemia.14,18 Our study shows that the use of isotonic fluid therapy with a plasmalike potassium concentration is potentially dangerous in acutely ill children because it increased the risk of hypokalemia. Thus, adding potassium routinely to commercially available plasmalike fluids appears to be essential in acutely ill children, even in the absence of hypokalemia at admission.

    In the present study, children receiving plasmalike isotonic fluid therapy had an increased risk for hypernatremia. Before the present study, the risk of hypernatremia was poorly documented in acutely ill children receiving isotonic fluid therapy.1,18 The earlier meta-analysis showed wide and inconclusive 95% CIs for the risk of hypernatremia (RR, 0.6-2.4) in children receiving isotonic fluids.18 Untreated hypernatremia has previously been associated with an increased risk of mortality in hospitalized children.27 Even though all children with hypernatremia in the present study were asymptomatic, our results raise concerns about the risks of using isotonic fluid in acutely ill children.

    Weight gain was greater in children receiving isotonic fluid therapy than in those receiving moderately hypotonic fluids. The mean difference was minimal and most likely clinically insignificant. Yet, water retention due to excess amounts of sodium might be associated with increased weight in a few patients. In the largest17 of 3 earlier studies reporting weight gain, with 110 acutely ill children, greater weight gain among children receiving isotonic fluid therapy was observed, but the difference was not statistically significant.17,28,29 The greater weight gain suggested by the present study may be clinically insignificant for most pediatric patients, but it might cause a risk for vulnerable patient populations.30

    The risk of hyponatremia was not increased in patients receiving moderately hypotonic fluid therapy, which is contrary to the risk reported earlier.1,18 This discrepancy is likely explained by the different patient populations, as previous studies mainly included pediatric patients receiving intensive care7-9 and postoperative patients10-13 but only a few acutely ill children. Furthermore, one-third of our patients suffered from dehydration due to viral gastroenteritis, suggesting hypotonic fluid losses before the fluid therapy.31 One of the few earlier studies with a similar study population of acutely ill children did not show an increased risk of hyponatremia in those receiving moderately hypotonic fluids either.17 Finally, our study allowed changes in fluid therapy, which may have prevented the development of hyponatremia in a few patients.

    Strengths and Limitations

    The strengths of the study include a large cohort of acutely ill children with a thorough clinical follow-up in a pragmatic randomized trial. The study design with access to unmasked laboratory values reflects a real-life situation. There were several limitations. This was a single-center study. Despite a rather large sample size, the statistical power of the study is insufficient to assess mortality and neurologic sequelae. In addition, we included only children with normal kidney function.32 Thus, the results of the present study are not generalizable to children with kidney failure or other conditions used as exclusion criteria. The unblinded study design might interfere with the outcomes based on the clinical evaluation, such as the length of stay. The commercial product used may not be available in all institutions.

    Conclusions

    In this randomized clinical trial, commercially available plasmalike isotonic fluid increased the risk for clinically significant electrolyte disorders in acutely ill children compared with previously widely used moderately hypotonic fluid therapy containing 80 mmol/L of sodium and 20 mmol/L potassium. These findings suggest that plasmalike isotonic fluid may be unsuitable for fluid therapy in acutely ill children unless extra potassium is added. The clinical significance of hypernatremia and weight gain in children receiving isotonic fluid therapy should be investigated in the future.

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    Article Information

    Accepted for Publication: June 17, 2020.

    Published Online: October 26, 2020. doi:10.1001/jamapediatrics.2020.3383

    Correction: This article was corrected on December 7, 2020, to fix some incorrect values in Figure 1.

    Corresponding Author: Terhi Tapiainen, MD, PhD, Department of Pediatrics and Adolescent Medicine, Oulu University Hospital, PO Box 23, FIN-90029, Oulu, Finland (terhi.tapiainen@oulu.fi).

    Author Contributions: Drs Tapiainen and Pokka had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

    Concept and design: Lehtiranta, Honkila, Peltoniemi, Renko, Tapiainen.

    Acquisition, analysis, or interpretation of data: Lehtiranta, Honkila, Kallio, Paalanne, Peltoniemi, Pokka, Tapiainen.

    Drafting of the manuscript: Lehtiranta, Honkila, Kallio, Pletoniemi, Pokka, Tapiainen.

    Critical revision of the manuscript for important intellectual content: All authors.

    Statistical analysis: Lehtiranta, Honkila, Pokka, Tapiainen.

    Obtained funding: Lehtiranta, Tapiainen.

    Administrative, technical, or material support: Kallio, Paalanne.

    Supervision: Honkila, Kallio, Paalanne, Peltoniemi, Tapiainen.

    Conflict of Interest Disclosures: Dr Lehtiranta reported receiving grants from the Finnish Pediatric Research Foundation, the Stiftelsen Alma and K.A. Snellman Foundation, and the Uskela Student Grant Foundation during the conduct of the study. Dr Kallio reported receiving grants from the Finnish Foundation for Pediatric Research during the conduct of the study. Dr Tapiainen reported receiving a grant from the Academy of Finland for part-time clinical research and from the Pediatric Research Foundation of Finland, used for the part-time salary of a study nurse in the pediatric clinical research projects. All products used in the study were paid for by the hospital as a part of routine patient care. No other disclosures were reported.

    Funding/Support: The study was supported by a grant from the Academy of Finland (Dr Tapiainen) and from the Pediatric Research Foundation of Finland (Dr Tapiainen).

    Role of the Funder/Sponsor: The Academy of Finland or Pediatric Research Foundation of Finland had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

    Data Sharing Statement: See Supplement 3.

    Additional Contributions: We thank Kimmo Halt, MD, Jarmo Salo, MD, PhD, and Marika Sipola, MD, PhD, Department of Pediatrics and Adolescent Medicine, Oulu University Hospital, Finland, for their thoughtful comments on the last version of the manuscript before submission. There was no financial compensation for these contributions.

    Additional Information: This was an independent, investigator–driven clinical trial. All fluid products were used as a part of normal clinical care.

    References
    1.
    Feld  LG, Neuspiel  DR, Foster  BA,  et al; Subcommittee on Fluid and Electrolyte Therapy.  Clinical practice guideline: maintenance intravenous fluids in children.   Pediatrics. 2018;142(6):1. doi:10.1542/peds.2018-3083 PubMedGoogle ScholarCrossref
    2.
    Arieff  AI, Ayus  JC, Fraser  CL.  Hyponatraemia and death or permanent brain damage in healthy children.   BMJ. 1992;304(6836):1218-1222. doi:10.1136/bmj.304.6836.1218 PubMedGoogle ScholarCrossref
    3.
    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(7289):780-782. doi:10.1136/bmj.322.7289.780 PubMedGoogle ScholarCrossref
    4.
    Moritz  ML, Ayus  JC.  Preventing neurological complications from dysnatremias in children.   Pediatr Nephrol. 2005;20(12):1687-1700. doi:10.1007/s00467-005-1933-6 PubMedGoogle ScholarCrossref
    5.
    Koczmara  C, Hyland  S, Greenall  J.  Hospital-acquired acute hyponatremia and parenteral fluid administration in children.   Can J Hosp Pharm. 2009;62(6):512-515. doi:10.4212/cjhp.v62i6.851 PubMedGoogle Scholar
    6.
    Grissinger  M.  Hyponatremia and death in healthy children from plain dextrose and hypotonic saline solutions after surgery.   P T. 2013;38(7):364-388.PubMedGoogle Scholar
    7.
    Montañana  PA, Modesto i Alapont  V, Ocón  AP, López  PO, López Prats  JL, Toledo Parreño  JD.  The use of isotonic fluid as maintenance therapy prevents iatrogenic hyponatremia in pediatrics: a randomized, controlled open study.   Pediatr Crit Care Med. 2008;9(6):589-597. doi:10.1097/PCC.0b013e31818d3192 PubMedGoogle ScholarCrossref
    8.
    Yung  M, Keeley  S.  Randomised controlled trial of intravenous maintenance fluids.   J Paediatr Child Health. 2009;45(1-2):9-14. doi:10.1111/j.1440-1754.2007.01254.x PubMedGoogle ScholarCrossref
    9.
    Rey  C, Los-Arcos  M, Hernández  A, Sánchez  A, Díaz  JJ, López-Herce  J.  Hypotonic versus isotonic maintenance fluids in critically ill children: a multicenter prospective randomized study.   Acta Paediatr. 2011;100(8):1138-1143. doi:10.1111/j.1651-2227.2011.02209.x PubMedGoogle ScholarCrossref
    10.
    Brazel  PW, McPhee  IB.  Inappropriate secretion of antidiuretic hormone in postoperative scoliosis patients: the role of fluid management.   Spine (Phila Pa 1976). 1996;21(6):724-727. doi:10.1097/00007632-199603150-00013 PubMedGoogle ScholarCrossref
    11.
    Neville  KA, Sandeman  DJ, Rubinstein  A, Henry  GM, McGlynn  M, Walker  JL.  Prevention of hyponatremia during maintenance intravenous fluid administration: a prospective randomized study of fluid type versus fluid rate.   J Pediatr. 2010;156(2):313-319.e1, 2. doi:10.1016/j.jpeds.2009.07.059 PubMedGoogle ScholarCrossref
    12.
    Choong  K, Arora  S, Cheng  J,  et al.  Hypotonic versus isotonic maintenance fluids after surgery for children: a randomized controlled trial.   Pediatrics. 2011;128(5):857-866. doi:10.1542/peds.2011-0415 PubMedGoogle ScholarCrossref
    13.
    Coulthard  MG, Long  DA, Ullman  AJ, Ware  RS.  A randomised controlled trial of Hartmann’s solution versus half normal saline in postoperative paediatric spinal instrumentation and craniotomy patients.   Arch Dis Child. 2012;97(6):491-496. doi:10.1136/archdischild-2011-300221 PubMedGoogle ScholarCrossref
    14.
    McNab  S, Duke  T, South  M,  et al.  140 mmol/L of sodium versus 77 mmol/L of sodium in maintenance intravenous fluid therapy for children in hospital (PIMS): a randomised controlled double-blind trial.   Lancet. 2015;385(9974):1190-1197. doi:10.1016/S0140-6736(14)61459-8 PubMedGoogle ScholarCrossref
    15.
    Saba  TG, Fairbairn  J, Houghton  F, Laforte  D, Foster  BJ.  A randomized controlled trial of isotonic versus hypotonic maintenance intravenous fluids in hospitalized children.   BMC Pediatr. 2011;11:82. doi:10.1186/1471-2431-11-82 PubMedGoogle ScholarCrossref
    16.
    Torres  SF, Iolster  T, Schnitzler  EJ, Siaba Serrate  AJ, Sticco  NA, Rocca Rivarola  M.  Hypotonic and isotonic intravenous maintenance fluids in hospitalised paediatric patients: a randomised controlled trial.   BMJ Paediatr Open. 2019;3(1):e000385. doi:10.1136/bmjpo-2018-000385 PubMedGoogle Scholar
    17.
    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):445-451. doi:10.1001/jamapediatrics.2014.3809 PubMedGoogle ScholarCrossref
    18.
    McNab  S, Ware  RS, Neville  KA,  et al.  Isotonic versus hypotonic solutions for maintenance intravenous fluid administration in children.   Cochrane Database Syst Rev. 2014;(12):CD009457. doi:10.1002/14651858.CD009457.pub2 PubMedGoogle Scholar
    19.
    Van Regenmortel  N, De Weerdt  T, Van Craenenbroeck  AH,  et al.  Effect of isotonic versus hypotonic maintenance fluid therapy on urine output, fluid balance, and electrolyte homeostasis: a crossover study in fasting adult volunteers.   Br J Anaesth. 2017;118(6):892-900. doi:10.1093/bja/aex118 PubMedGoogle ScholarCrossref
    20.
    Marcdante  KJ, Kliegman  RM, eds. Nelson Essentials of Pediatrics. 7th ed. Elsevier Saunders; 2015.
    21.
    Isotonic versus hypotonic intravenous fluids in hospitalised children—a randomised controlled trial. ClinicalTrialsRegister.eu identifier: 2016-002046-23. Accessed September 19, 2020. https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2016-002046-23
    22.
    Intravenous fluids in hospitalized children. ClinicalTrials.gov identifier: NCT02926989. Updated August 22, 2019. Accessed September 19, 2020. https://clinicaltrials.gov/ct2/show/NCT02926989
    23.
    Holliday  MA, Segar  WE.  The maintenance need for water in parenteral fluid therapy.   Pediatrics. 1957;19(5):823-832.PubMedGoogle Scholar
    24.
    Armitage  P, Berry  G, Matthews  JNS, eds.  Statistical Methods in Research. 4th ed. Blackwell Science; 2020.
    25.
    Armon  K, Riordan  A, Playfor  S, Millman  G, Khader  A; Paediatric Research Society.  Hyponatraemia and hypokalaemia during intravenous fluid administration.   Arch Dis Child. 2008;93(4):285-287. doi:10.1136/adc.2006.093823 PubMedGoogle ScholarCrossref
    26.
    Cummings  BM, Macklin  EA, Yager  PH, Sharma  A, Noviski  N.  Potassium abnormalities in a pediatric intensive care unit: frequency and severity.   J Intensive Care Med. 2014;29(5):269-274. doi:10.1177/0885066613491708 PubMedGoogle ScholarCrossref
    27.
    Moritz  ML, Ayus  JC.  The changing pattern of hypernatremia in hospitalized children.   Pediatrics. 1999;104(3 Pt 1):435-439. doi:10.1542/peds.104.3.435 PubMedGoogle ScholarCrossref
    28.
    Valadão  MC, Piva  JP, Santana  JC, Garcia  PC.  Comparison of two maintenance electrolyte solutions in children in the postoperative appendectomy period: a randomized, controlled trial.   J Pediatr (Rio J). 2015;91(5):428-434. doi:10.1016/j.jped.2015.01.004 PubMedGoogle ScholarCrossref
    29.
    Shamim  A, Afzal  K, Ali  SM.  Safety and efficacy of isotonic (0.9%) vs. hypotonic (0.18%) saline as maintenance intravenous fluids in children: a randomized controlled trial.   Indian Pediatr. 2014;51(12):969-974. doi:10.1007/s13312-014-0542-5 PubMedGoogle ScholarCrossref
    30.
    Alobaidi  R, Morgan  C, Basu  RK,  et al.  Association between fluid balance and outcomes in critically ill children: A systematic review and meta-analysis.   JAMA Pediatr. 2018;172(3):257-268. doi:10.1001/jamapediatrics.2017.4540 PubMedGoogle ScholarCrossref
    31.
    Whyte  LA, Jenkins  HR.  Pathophysiology of diarrhoea.   Paediatrics & Child Health. 2012;22:443–447. doi:10.1016/j.paed.2012.05.006 Google ScholarCrossref
    32.
    Lehnhardt  A, Kemper  MJ.  Pathogenesis, diagnosis and management of hyperkalemia.   Pediatr Nephrol. 2011;26(3):377-384. doi:10.1007/s00467-010-1699-3 PubMedGoogle ScholarCrossref
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