Clinical aspects of perioperative fluid, sodium and glucose balance in children

Background
Perioperative fluid therapy aims at compensating for deficits related to preop- erative fasting or disease as well as covering basal needs and ongoing losses to keep the homeostasis of metabolism, electrolyte- and glucose balance. In gen- eral, the former widespread use of hypotonic solutions in paediatric anaesthesia has been replaced by isotonic solutions mainly due to the risk of dilutional hypo- natraemia caused by Arginine Vasopressin (AVP) induced water retention. In par- allel, low plasma sodium concentration (p-Na) has been found to be associated with disease severity. Therefore, p-Na may be used as a predictor to differenti- ate between different disease states such as perforated versus non-perforated acute appendicitis, which may bring substantial clinical benefits. Furthermore, in modern paediatric perioperative care, maintenance fluids with high glucose content have been abandoned in order to avoid intraoperative hyperglycaemia. New formulas with an isotonic profile, ensuring adequate sodium supply, and low glucose content are now predominant. However, the safe use in the smallest chil- dren, with their higher metabolic rate and smaller energy reserves, with regards to the risk of hypoglycaemia has not been proven.

Aims
1. To investigate possible differences in p-Na between children with non-perfo- rated and perforated acute appendicitis and if p-Na can be used as a predictor of perforation (Studies I and IV).

2. To describe the physiological changes of p-Na and fluid balance in children with acute appendicitis (Study II).
3. To investigate the safety of a balanced electrolyte solution with 1% glucose as intravenous maintenance fluid for infants undergoing surgery focusing on glu- cose, electrolyte and acid-base balance (Study III).

Methods
Study I, a prospective observational study, included 80 children with appendi- citis at Karolinska University Hospital. Blood sampling for p-Na and inflamma- tory markers was performed before any drug or fluid administration. The primary outcome was perforation status as decided by postoperative histopathological analysis. Study II investigated the same cohort as in study I. The children were followed prospectively from admission to hospital until end of surgery. Blood and urine sampling including blood-gas analysis, osmolality and regulatory hormones was done at admission, after induction of anaesthesia and postoperatively. Study III, a prospective observational multicentre study, included 365 infants (1-12 months of age) undergoing surgery. The participants were given a balanced elec- trolyte solution with 1% glucose as maintenance infusion during surgery. Blood- gas and ketone bodies were analysed after induction of anaesthesia and at the end of surgery. Study IV, a prospective observational multicentre study, included 451 children undergoing appendectomy. Blood sampling for blood-gas analysis and inflammatory markers as well as clinical examination was performed at ad- mission. Main outcome was perforation status decided by postoperative histo- pathological analysis or surgeon's assessment.

Results
In study I, p-Na was lower in patients with perforated appendicitis as compared to those with non-perforated appendicitis, 134 (interquartile range (IQR) 132-136) mmol/L and 139 (IQR 137-140) mmol/L, respectively. A ROC-curve analysis re- sulted in an area under the curve (AUC) of 0.93 (95 % Confidence Interval (CI) 0.87-0.99) with a cut-off value of < 136 mmol/L showing the best sensitivity and specificity, 0.82 (95% CI, 0.70-0.90) and 0.87 (95% CI, 0.60-0.98) respectively. P-Na of ≤ 136 mmol/l resulted in an odds ratio of 31.9 (95% CI 6.3-161) for perfo- ration. In study II, all patients received isotonic rehydration. 2/3 of the patients received hypotonic maintenance fluid until surgery, whereas the remaining pa- tients were operated soon after rehydration and were given no maintenance fluid. During surgery, 2/3 of patients received half-isotonic maintenance fluid and the remaining patients were given Ringer's Acetate. P-Na decreased from ad- mission to end of surgery and, in parallel, plasma AVP increased. There was no difference in change of p-Na between those who had received hypotonic fluids before surgery as compared to those who had not. However, p-Na decreased more in those who received hypotonic intraoperative maintenance fluid. No cor- relation between AVP and serum- or urine osmolality was found. In study III, no event of intraoperative hypoglycaemia was found. Plasma glucose concentra- tion increased during surgery from 5.3 (standard deviation (SD) 0.8) to 6.1 (SD 1.1) mmol/L whereas p-Na remained stable. Ketone bodies, chloride concentra- tion and Base Excess remained within normal limits. In study IV, p-Na was lower in perforated as compared to non-perforated acute appendicitis, 133.6 (SD 4.0) vs 138.2 (SD 2.7). P-Na dichotomised at ≤ 136 mmol/L resulted in an odds ratio of 8.96 (95% CI 5.85-13.72) for perforation. In a multivariate logistic regression analysis p-Na and C-reactive protein (CRP) were the strongest predictors of per- foration with a combined AUC of 0.86 (95% CI 0.82-0.89).

Conclusions

• Children with perforated acute appendicitis have lower p-Na at hospital admission as compared with children with non-perforated acute appendicitis.
• P-Na at hospital admission has a strong predictive value regarding perforation status in children with acute appendicitis.
• AVP secretion is increased in children with acute appendicitis as compared to normal levels, likely due to non-osmotic stimuli. The highest AVP secretion was seen if the appendix was perforated.
• Hypotonic maintenance infusion in the pre- and intraoperative phases may increase the risk of postoperative hyponatraemia in children with acute appendicitis.
• Intravenous near-isotonic maintenance solution with 1% Glucose, infused at rates corresponding to basal needs, is a safe alternative for infants (age 1-12 months) undergoing surgery.

Keywords: Acid-base physiology, acute appendicitis, Arginine Vasopressin, diagnos- tic accuracy, electrolyte, glucose, infants, ketone bodies, paediatric, perioperative fluid management, plasma sodium concentration.

List of scientific papers

I. Low Plasma Sodium Concentration Predicts Perforated Acute Appendicitis in Children: A Prospective Diagnostic Accuracy Study Ulf Lindestam, Markus Almström, Johannes Jacks, Pia Malmquist, Per-Arne Lönnqvist, Boye L Jensen, Mattias Carlström, Rafael T Krmar, Jan F Svensson, Åke Norberg, Urban Fläring. European Journal of Pediatric Surgery, 30(4):350-356 (2020) https://doi.org/10.1055/s-0039-1687870

II. Sodium and water homeostasis in children admitted with acute appendicitis: a prospective study Ulf Lindestam, Urban Fläring, Markus Almström, Andreas Andersson, Jan F Svensson, Pia Malmquist, Johannes Jacks, Per-Arne Lönnqvist, Boye L Jensen, Mattias Carlström, Rafael T Krmar. Pediatric Research, 86(1):5-8 (2019) https://doi.org/10.1038/s41390-019-0353-4

III. Balanced electrolyte solution with 1% glucose as intraoperative maintenance fluid in infants. A prospective study of glucose, electrolyte, and acid-base homeostasis Ulf Lindestam, Åke Norberg, Peter Frykholm, Olav Rooyackers, Andreas Andersson, Urban Fläring. British Journal of Anaesthesia. [Accepted]

IV. Plasma Sodium as a predictor of perforation in acute appendicitis, a prospective multi-centre study Ulf Lindestam, Åke Norberg, Jan F Svensson, Markus Almström, Andreas Andersson, Per-Arne Lönnqvist, Mark Bremholm Ellebæk, Inger Marie Drage, Kjetil Juul Stensrud, Marc Reismann, Heidi M Meyer, Urban Fläring. [Manuscript]