Open Access Study protocol

The efficacy of hypotonic and near-isotonic saline for parenteral fluid therapy given at low maintenance rate in preventing significant change in plasma sodium in post-operative pediatric patients: protocol for a prospective randomized non-blinded study

Urban Fläring, Per-Arne Lönnqvist, Björn Frenckner, Jan F Svensson, Ingimar Ingolfsson, Lena Wallensteen, Shayarina Stigzelius, Jan Kowalski and Rafael T Krmar*

BMC Pediatrics 2011, 11:61  doi:10.1186/1471-2431-11-61

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Letter to Editor "The efficacy of different postoperative fluid therapy given at low maintenance rate in preventing hyponatremia of potential clinical significance: a stopped randomized non-blinded trial"

Rafael Tomas Krmar   (2012-08-15 14:16)  Karolinska Institutet, Department of Clinical Science, Intervention and Technology

Dear Editor, We recently started a non industry-funded randomized non-blinded clinical study [ISRCTN43896775], whose research protocol has been previously published in this Journal (1). The major objective of this single-centre based study was to evaluate whether the post-appendectomy prescription of either hypotonic or near-isotonic fluid therapy given at low maintenance rate in otherwise healthy children with normal post-operative plasma sodium (p-Na+) are equally effective in maintaining p-Na+ within the normal range throughout the 24-h period after surgery. A second objective was to determine water and electrolyte-balance following the administration of the investigational parenteral maintenance fluids as well as to investigate known regulatory hormones involved in the homeostatic control of water balance.
The trial was prematurely stopped after 12 weeks due a low recruitment rate. During the study period, a total of 63 patients underwent emergency intervention for treatment of acute appendicitis. On the basis of intra-operative findings, 32 patients had either gangrenous or perforated appendicitis, so that they were potentially candidates to be randomized into one of three treatments arms, i.e., 0.23% sodium chloride (40 mmol/L Na+ + 20 mmol/L K+ + 60 mmol/L Cl- in 5 % glucose; extempore solution), 0.40% sodium chloride (70 mmol/L Na+ + 45 mmol/L Cl- + 25 mmol/L acetate in 2.5% glucose; Braun Melsungen AG, Melsungen, Germany), or 0.81% sodium chloride (140 mmol/L Na+ + 4 mmol/L K+ + 1 mmol/L Ca2+ + 1 mmol/L Mg2+ + 118 mmol/L Cl- + 30 mmol/L acetate in 1 % glucose; Serumwerk Bernburg AG, Bernburg, Germany). Of these, parents for 16 patients were not approached before the surgical procedure to conduct the informed consent process, 8 parents declined to participate, and 8 parents gave consent to their child being initiated into the study.
Five patients were not randomized because of immediate postoperative hyponatremia (p-Na+ was 133 mmol/L in 4 patients and 129 mmol/L in 1 patient, respectively). All of them received intraoperatively 0.40% salt solution (Braun Melsungen AG, Melsungen, Germany) given at the rate of ~10 ml/kg body weight.
Of those successfully randomized, two patients dropped out of the study due to consent withdrawal (13-year-old girl, treatment arm 0.81% sodium chloride; once awake refused to continue fasting) and poor protocol compliance (6-year-old boy, treatment arm 0.40% sodium chloride; ingested oral fluids during the study period), respectively. One patient completed the study (13-year-old boy, treatment arm 0.23% sodium chloride; p-Na+ immediately after the conclusion of surgery and at 24-h following the surgical procedure were 135 mmol/L and 134 mmol/L, respectively).
The success of any clinical trial largely relies on an efficient recruitment process. Therefore, to optimize patient recruitment, we meet all staff members of the Department of Paediatric Surgery to ensure that they would receive all the information necessary to have a clear understanding of our research protocol. In addition, a study investigator called on daily basis the on-call staff pediatric surgeon in order to remind her/him on our ongoing study and that we were available 24/7 to provide logistic support. Also, concise information on the research protocol, including patient information, informed-consent forms, and a study checklist could be retrieved from our hospital��s website. Despite this integrated strategy, half of potential patients were not asked to participate in the study, therefore creating the opportunity for bias in the recruiting process, prolonging the duration of the trial, and jeopardizing the statistical power for the study and validity of the results. We believe that administrative burden required to recruit patients and busy shifts might have had a negative impact in the complex process of patient��s enrollment.
The occurrence of immediate postoperative hyponatremia, although not systematically observed in our study population, calls into question the use of intraoperative hypotonic fluid. Accordingly, our current practice has been revised and we are on the process of adopting the use of intraoperative isotonic solutions (2).
Finally, our working hypothesis was elaborated from our postoperative fluid prescribing practice that derives from a Swedish empirical study published in the early 1960s (3). The study describes the principles of the use of hypotonic parenteral fluid therapy given at low maintenance rate in the postoperative period of 3191 patients who underwent appendectomy in a single-centre. Unfortunately, p-Na+ has not been routinely measured after surgery since at that time mean corpuscular hemoglobin concentration was used as a surrogate of plasma tonicity, therefore leaving unknown the actual prevalence of hyponatremia. Nevertheless, only one death was reported and apparently none of the patients experienced neurological symptoms that could have been ascribed to unrecognized and consequently untreated hyponatremia of clinical significance.
In conclusion, the lack of solid evidence as to what constitutes the best postoperative fluid therapy to achieve optimal fluid balance demands further studies. In this context, a multi-center study would be most desirable due to the opportunity of larger sample size and greater generalizability of the findings compared to single-site studies.

Rafael T Krmar 1*
Bj��rn Frenckner 2
Jan Kowalski 1
Per-Arne L��nnqvist 3

1 Karolinska Institutet, Department for Clinical Science, Intervention and Technology, Division of Paediatrics, Karolinska University Hospital, Huddinge, S-141 86 Stockholm, Sweden
2 Department of Paediatric Surgery, Astrid Lindgren Children��s Hospital, Karolinska University Hospital, Solna, S-171 76 Stockholm, Sweden
3 Department of Paediatric Anesthesia and Intensive Care, Astrid Lindgren Children��s Hospital, Karolinska University Hospital, Solna, S-171 76 Stockholm, Sweden

*Correspondence
Rafael Tom��s Krmar, MD, PhD, Karolinska Institutet, Department for Clinical Science, Intervention and Technology, Division of Paediatrics, Karolinska University Hospital, Huddinge, S-141 86 Stockholm, Sweden. Tel: +46 8 58581480; Fax: +46 8 58581410; E-mail: rafael.krmar@ki.se

References
1 Flaring U, Lonnqvist PA, Frenckner B, et al. The efficacy of hypotonic and near-isotonic saline for parenteral fluid therapy given at low maintenance rate in preventing significant change in plasma sodium in post-operative pediatric patients: protocol for a prospective randomized non-blinded study. BMC Pediatr 2011; 11: 61.
2 Sumpelmann R, Becke K, Crean P, et al. European consensus statement for intraoperative fluid therapy in children. Eur J Anaesthesiol 2011; 28: 637-639.
3 Fock G. [Fluid Therapy in Appendicitis with Peritonitis in Children]. Nord Med 1964; 71: 237-240.

Competing interests

The authors declare that they have no competing interests.

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