Perioperative fluid management in children undergoing neurosurgery presents special challenges. These patients are at increased risk of intracranial hypertension, and use of hypotonic solutions should be avoided to prevent hyponatremia and cerebral edema.1 Maladaptation of the brain to hyponatremia further increases the risk of cerebral damage and death in children.2 In addition, neurosurgical patients are prone to sodium homeostasis disruptions,3 and inappropriate fluid administration may worsen this situation.
Balanced crystalloid solutions have been increasingly adopted as the fluid of choice because they mimic plasma composition and cause less acidosis and electrolyte abnormalities than chloride-rich solutions.4 However, 0.9% saline is often used during neurosurgery because it is slight hypertonic and may protect against cerebral edema. Notably, potential side effects related to saline use have been identified, including hyperchloremic acidosis, nephrotoxicity, and increased mortality.5–7
Pediatric fluid management guidelines have been changing over the past few years and recommend the use of saline as well as balanced crystalloids (isotonic) instead of hypotonic solutions8 to decrease the risk of hyponatremic encephalopathy in hospitalized children.9 However, there is a lack of evidence to recommend one isotonic crystalloid over another in children.
We hypothesized that perioperative use of balanced crystalloid infusion induces less metabolic derangements than 0.9% saline solution in children undergoing neurosurgery for brain tumor resection. The primary outcome was a hypothetical reduction in preoperative to postoperative chloride variation (post-preopΔCl). The secondary outcomes were variations (post-preopΔ) in other electrolytes and base excess (BE); hyperchloremic acidosis incidence; and the level of brain swelling (edema).
This randomized controlled trial was conducted at the Instituto de Oncologia Pediátrica of the Federal University of São Paulo, Brazil. The hospital’s Human Research and Ethics Committee approved the trial protocol (# 1.135.418), which was conducted in accordance with the Declaration of Helsinki; after approval, the trial was registered with Clinical Trials (NCT02707549). Written informed consent was obtained from the parents or guardians of all participants, and informed consent was obtained from the children when appropriate (the physician in charge evaluated whether the child was able to provide the consent by himself).
Children aged between 6 months and 12 years, with American Society of Anesthesiologists (ASA) physical status 1 to 3, undergoing craniotomy for brain tumor resection were enrolled between August 2015 and November 2016. Patients were excluded if they had severe intracranial hypertension; significant cardiorespiratory impairment; electrolyte abnormalities (Na+ <130 or Na+ >150 mmol/L; serum Cl− <90 or Cl−>110 mmol/L); or brain tumor reoperation during the study period. Before the surgery, patients were randomized in a 1:1 ratio (random permuted blocks) to the normal saline 0.9% (saline) or balanced crystalloid solution (balanced) groups after written informed consent had been obtained. The randomization list was created by an independent web-based randomization service (Sealed Envelope, UK). Crystalloid solutions were covered with an opaque plastic bag during the surgery. However, nurses and attending physicians were not blinded to treatment group allocation. Surgeons and the independent outcome assessor were blinded to group allocation.
According to current recommendations, children were fasted of clear liquids for 2 hours; breast milk for 4 hours; infant formula for 6 hours and solids for 8 hours before surgery. Induction of general anesthesia was accomplished with fentanyl, propofol, and cisatracurium. Intravenous midazolam 0.1 mg/kg premedication was provided before the patient was moved to the operating room. Anesthesia was maintained with intravenous administration of propofol 100 to 200 μg/kg/min and remifentanil up to 0.2 μg/kg/min. Inhaled anesthetics were not administered before brain relaxation score (BRS) evaluation. Pulse oximetry, cardioscopy, invasive blood pressure, capnography, temperature, and diuresis were used for patient monitoring. Ventilation was regulated to achieve an end-tidal carbon dioxide partial pressure between 30 and 35 mm Hg. At the end of the surgeries, the patients were extubated at the discretion of the attending anesthesiologist and all patients were taken to the Pediatric Intensive Care Unit (PICU).
Patients were randomized to receive saline 0.9% (saline group) or balanced crystalloids (balanced group; Plasma-Lyte A, Baxter Healthcare, Deerfield, IL) exclusively from anesthesia induction until 24 hours postoperatively (Table 1, online supplement, Supplemental Digital Content 1, http://links.lww.com/JNA/A62). Anesthesiologists and intensivists followed the 4-2-1 rule for perioperative fluid administration: 4 mL/kg/h for the first 10 kg of body weight, 2 mL/kg/h from 11 to 20 kg, and 1 mL/kg/h per kg over 20 kg. In cases of hypotension or clinical signs of hypovolemia, an additional bolus of 10 mL/kg was given as many times as required. When needed, 5% human albumin, packed red blood cells, or fresh frozen plasma were also administered. When significant brain edema (bulging) was present, 20% mannitol was given. Dilution of drugs and medication with 0.9% saline was permitted throughout the study, and it was not considered a priori as a protocol violation.
A sample with 4 mL of arterial blood was collected at 3 timepoints: (1) shortly after induction of anesthesia, defined as before surgery or baseline; (2) immediately after admission to the PICU, defined as after surgery; and (3) 24 hours after admission to the PICU, defined as day 1. All samples were sent to the central laboratory for electrolyte, albumin, urea, creatinine, glucose, and hemoglobin determination. Blood gases were analyzed at all 3 timepoints as well. Other perioperative examinations were performed at the discretion of the attending physician. The central laboratory processes daily internal quality controls for all parameters analyzed and processes proficiency tests using the Controllab proficiency-testing program. It is also accredited by the laboratory quality control program in Brazil (Programa de acreditação de laboratórios—PALC) of the Brazilian Society of Clinical Pathology/Laboratory Medicine.
An ABL-700 blood gas analyzer (Radiometer, Denmark) was used to measure arterial blood pH (pHa), partial pressure of oxygen (PaO2), and partial pressure of carbon dioxide (PaCO2) with standard electrodes. A Roche/Hitachi Cobas c 6000 analyzer (Roche Diagnostics International, Switzerland) was used to measure (Na+), (K+), (Cl−), and (Ca++) via ion-selective electrode; and (Mg++), inorganic phosphate (Pi−), and albumin, via the colorimetric method (xylidyl-blue, molybdate-ammonium, and bromocresol-green, respectively). Ionized calcium (iCa++) was calculated using total (Ca++) corrected for albumin.10 Bicarbonate (HCO3 −) and whole blood (BE) were calculated using the Henderson-Hasselbalch and Van Slyke equations, respectively.
The primary outcome of this trial was the absolute difference between “after surgery” and baseline Cl− plasma concentrations (post-preopΔCl−). Secondary outcomes were variations (post-preopΔ) of other electrolytes and BE, incidence of hyperchloremic acidosis, and BRS. Excess of (Cl−) and decreases in (BE) were calculated as the difference between normal laboratory reference and observed values. (Cl−)corrected was calculated using the formula: (Cl−)corrected=(Cl−)corrected ([Na+]normal/[Na+]observed).11 Hyperchloremic acidosis was defined as (Cl−)corrected >110 mEq/L plus excess of (Cl− corrected) >50% of the decrease in (BE).12 The intraoperative BRS reflects brain swelling13,14 and is recorded on a 4-point scale (1, slack brain; 2, mild brain herniation; 3, moderate brain herniation; 4, severe brain herniation). The threshold for intervention is generally considered to be a BRS≥3. BRS was evaluated by the neurosurgeon after the dura mater was opened.
We also calculated the individuals changes in chloride and sodium values considering Clinical Laboratory Improvement Amendments (CLIA) criteria for acceptable analytical performance (baseline [Cl−]±5% and baseline [Na+]±4%, respectively). We reported the proportions of participants in each group that had a significant change in baseline (Cl−) and (Na+). Serum osmolarity was calculated using the formula: calculated osmolarity=2 Na+glucose+urea (all in mmol/L).
Sample Size Calculation
We calculated the sample size based on the primary outcome (post-preopΔCl−) using the results of previously published studies.15–17 We calculated that 46 participants (23 per group) would be required to detect a difference of 2.5 mmol/L (SD 3.0) between groups from baseline to after surgery, assuming a type I error of 0.05 and a power of 0.8. To account for possible losses during follow-up and missing data, we added 10% to the calculation, resulting in an estimate of 52 patients.
The Shapiro-Wilk test was used to test the assumption of a normal distribution. Normally distributed data are presented as the mean and SD, and were analyzed using independent t tests. Non-normally distributed interval and ordinal data are reported as the median (interquartile range), and were compared using the Mann-Whitney U test. Categorical variables were presented as counts and evaluated using the χ2 test, or the Fisher exact test when the expected count was <5. Patients who had a diagnosis of diabetes insipidus, salt-wasting syndrome, or syndrome of inappropriate antidiuretic hormone secretion during the study intervention were excluded from analysis. Study data were collected and managed using the web-based application REDCap (Research Electronic Data Capture), and were then evaluated statistically using IBM SPSS version 21 (IBM, Armonk, NY). Significance was set at P<0.05.
A total of 95 patients were screened for inclusion in this trial. After exclusions, 53 patients were enrolled and 49 were followed to the final analysis; of these, 26 were randomized to the saline group and 27 to the balanced group (Fig. 1). The 2 groups were similar in terms of patient demographics and perioperative characteristics (Table 1). The total volume of fluid administered was similar between the groups. Baseline electrolyte concentrations and BE were within the normal range in both groups.
We found that saline infusion increased significantly post-preopΔCl− compared with balanced crystalloid. post-preopΔBE also differed significantly between the groups and post-preopΔMg++ had a slight but statistically significant difference between the groups. Variations in the other electrolytes were not significantly different across groups (Table 2).
After surgery, 17/25 (68%) versus 2/24 (8%) patients had a significant increase in baseline (Cl−) in the saline group compared with balanced group (P<0.01). At postoperative day 1, 6/25 (24%) patients in the saline group (versus 0 in the balanced group, P=0.022) still had a significant increase in baseline (Cl−). In the balanced group, 3 patients (1 after surgery and 2 at day 1) had a significant decrease in (Na+) versus 0 in the saline group. Hyperchloremic acidosis incidence was higher in the saline compared with the balanced group after surgery (6/25 [24%] vs. 0; P=0.022) but not at day 1 (when only 1 patient in the saline group had hyperchloremic acidosis).
Packed red cell transfusion, electrolyte replacement, mannitol use, and vasopressor support were comparable between groups. There was a trend toward greater median intraoperative diuresis in the balanced group than in the saline group, but postoperative diuresis and creatinine values measured both after surgery and at day 1 were similar in both groups. Only 1 patient, from the saline group, developed acute kidney injury stage ≥2 according to KDIGO (The Kidney Disease: Improving Global Outcomes) criteria.18 The BRS was 1 or 2 in 76% of the saline and 83% of the balanced group patients, and the difference was not statistically significant (Table 3).
In the present randomized controlled trial in children undergoing neurosurgery, we found that perioperative serum chloride variation is better controlled with balanced crystalloid solution than with normal saline. After surgery, hyperchloremic acidosis incidence was significantly higher in the saline compared with the balanced group. Further, in the saline compared with the balanced group, the perioperative variation in the BE was higher, resulting in a worse electrolyte profile and metabolic acidosis control. There was no other evidence of relevant differences in electrolyte variation, including sodium, between the groups.
There are few clinical studies comparing distinct types of isotonic crystalloids in children, and this is the first randomized controlled trial in children undergoing neurosurgery. We performed a complete analysis of the metabolic profile from the beginning of surgery until the first postoperative day, allowing a better understanding of the metabolic variations throughout this period. We also assessed the BRS, as brain edema control is a priority during neurosurgery.
The effects of saline on serum chloride in children are in line with, but greater than those previously reported15 (6 [3.5; 8.5] vs. 4 [2; 6] mmol/L). We speculate that this is due to fact that in the present study, patients received a higher intraoperative volume of crystalloids (76 [65; 112] vs. 36 [28; 47] mL/kg). Regarding the BRS, 15/49 (30.6%) patients had a grade 2 or 3, reflecting mild or moderate brain swelling. This incidence was not affected the by treatment group and was close to that reported by Rasmussen et al.19
We found that the saline group had a higher before to after surgery chloride variation and a higher incidence of hyperchloremic acidosis. Experimental20 and human studies21 have shown that hyperchloremia produces renal vasoconstriction and results in reduced renal cortical tissue perfusion. Both a high chloride variation22 and hyperchloremia23 have been linked to poor outcomes. Observational studies found an association between hyperchloremia and a higher incidence of acute kidney injury.24 Hyperchloremia has also been linked to increased mortality with adverse outcomes on survival out to 1 year.25
In adults, several studies have reported a higher incidence of metabolic acidosis and hyperchloremia in patients who received saline compared with balanced solutions.26,27 However, other studies failed to show differences in clinically relevant endpoints.28,29 Recent data from large randomized clinical trials showed a higher incidence of major adverse kidney events in both critically and noncritically ill adults who received saline versus balanced crystalloids.7,30
In children, although there are many studies comparing hypotonic and isotonic crystalloids—showing the latter protects against hyponatremia,31 data are scarce regarding the comparison between balanced solutions versus saline use in this population. Observational and interventional studies reported that balanced crystalloids are safe and cause less metabolic derangements15,16,32 than saline. A study in septic children showed that hyperchloremia is independently associated with increased odds of complicated course and mortality.33
Despite emerging safety concerns regarding hyperchloremia, use of 0.9% saline is still the standard of care in brain-injured and neurosurgical patients34 as its supraphysiological sodium content may protect against cerebral edema—in contrast to slightly hypotonic lactated Ringer’s solution, which may increase cerebral water. However, data from brain-injured patients showed a higher incidence of hyperchloremic acidosis with saline compared with newer balanced solutions, without a difference in intracranial pressure.35
Our study provided a qualitative evaluation of cerebral edema by the surgeon, which was found to be comparable between the groups, and an overall high percentage of good operative conditions (BRS≤2). These findings can be justified by a comparable serum osmolarity between the groups since osmolarity is a major determinant of fluid movement across blood-brain barrier.
The current study has limitations. First, our study is underpowered regarding evaluation of acute kidney injury, mortality, and other clinically relevant outcomes. Second, the attending physicians were not blinded to the crystalloid assignment, although it has been shown that attending clinicians can correctly guess the type of fluid most of the time despite blinding.28 Third, hypoalbuminemia may result in inaccurate chloride measurements using indirect assay.36 However, we reported a slight and close to normal range variation in median albumin values over time. Regarding interpretation of BE (derived from pHa, PaCO2, and hemoglobin), we detected no significant differences between “after surgery” and baseline PaCO2 levels as well as between hemoglobin levels. Therefore, we can attribute the variation in BE values to the metabolic component. Finally, this study was carried out in a tertiary university-affiliated hospital in concert with procedures of high complexity and long duration.
In conclusion, in children undergoing craniotomy for brain tumor resection, saline infusion resulted in increased serum chloride variation from before to after surgery. Balanced crystalloid was associated with a safer electrolyte and acid-base profile compared with the use of saline. Our findings support the use of balanced crystalloid solutions rather than normal saline in children undergoing brain tumor resection.
The authors thank Dr. Carlos Ferreira for his critical revision of the manuscript.
1. Tommasino C, Moore S, Todd MM. Cerebral effects of isovolemic hemodilution with crystalloid or colloid solutions. Crit Care Med. 1988;16:862–868.
2. Ayus JC, Achinger SG, Arieff A. Brain cell volume regulation in hyponatremia: role of sex, age, vasopressin, and hypoxia. Am J Physiol Renal Physiol. 2008;295:F619–F624.
3. Madden JR, Dobyns E, Handler M, et al. Experience with electrolyte levels after craniotomy for pediatric brain tumors. J Pediatr Oncol Nurs. 2010;27:21–23.
4. Cecconi M, Hofer C, Teboul JL, et al. Fluid challenges in intensive care: the FENICE study: a global inception cohort study. Intensive Care Med. 2015;41:1529–1537.
5. Serpa Neto A, Martin Loeches I, Klanderman RB, et al. Balanced versus isotonic saline resuscitation—a systematic review and meta-analysis of randomized controlled trials in operation rooms and intensive care units. Ann Transl Med. 2017;5:323–333.
6. Bampoe S, Odor PM, Dushianthan A, et al. Perioperative administration of buffered versus non-buffered crystalloid intravenous fluid to improve outcomes following adult surgical procedures. Cochrane Database Syst Rev. 2017;9:CD004089.
7. Semler MW, Self WH, Wanderer JP, et al. Balanced crystalloids versus saline in critically ill adults. N Engl J Med. 2018;378:829–839.
8. Sumpelmann R, Becke K, Brenner S, et al. Perioperative intravenous fluid therapy in children: guidelines from the Association of the Scientific Medical Societies in Germany. Paediatr Anaesth. 2017;27:10–18.
9. 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;385:1190–1197.
10. Burtis CA, Ashwood ER, Bruns DE, et al. Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. St Louis, MO: Saunders; 2013.
11. Dubin A, Menises MM, Masevicius FD, et al. Comparison of three different methods of evaluation of metabolic acid-base disorders. Crit Care Med. 2007;35:1264–1270.
12. Masevicius FD, Rubatto Birri PN, Risso Vazquez A, et al. Relationship of at admission lactate, unmeasured anions, and chloride to the outcome of critically ill patients. Crit Care Med. 2017;45:e1233–e1239.
13. Chui J, Mariappan R, Mehta J, et al. Comparison of propofol and volatile agents for maintenance of anesthesia during elective craniotomy procedures: systematic review and meta-analysis. Can J Anaesth. 2014;61:347–356.
14. Gelb AW, Craen RA, Rao GS, et al. Does hyperventilation improve operating condition during supratentorial craniotomy? A multicenter randomized crossover trial. Anesth Analg. 2008;106:585–594.
15. Disma N, Mameli L, Pistorio A, et al. A novel balanced isotonic sodium solution vs normal saline during major surgery in children up to 36 months: a multicenter RCT. Paediatr Anaesth. 2014;24:980–986.
16. Sumpelmann R, Mader T, Eich C, et al. A novel isotonic-balanced electrolyte solution with 1% glucose for intraoperative fluid therapy in children: results of a prospective multicentre observational post-authorization safety study (PASS). Paediatr Anaesth. 2010;20:977–981.
17. Mann C, Held U, Herzog S, et al. Impact of normal saline infusion on postoperative metabolic acidosis. Paediatr Anaesth. 2009;19:1070–1077.
18. Selewski DT, Cornell TT, Heung M, et al. Validation of the KDIGO acute kidney injury criteria in a pediatric critical care population. Intensive Care Med. 2014;40:1481–1488.
19. Rasmussen M, Bundgaard H, Cold GE. Craniotomy for supratentorial brain tumors: risk factors for brain swelling after opening the dura mater. J Neurosurg. 2004;101:621–626.
20. Wilcox CS. Regulation of renal blood flow by plasma chloride. J Clin Invest. 1983;71:726–735.
21. Chowdhury AH, Cox EF, Francis ST, et al. A randomized, controlled, double-blind crossover study on the effects of 2-L infusions of 0.9% saline and Plasma-Lyte 148 on renal blood flow velocity and renal cortical tissue perfusion in healthy volunteers. Ann Surg. 2012;256:18–24.
22. Thongprayoon C, Cheungpasitporn W, Cheng Z, et al. Chloride alterations in hospitalized patients: prevalence and outcome significance. PLoS One. 2017;12:e0174430.
23. McCluskey SA, Karkouti K, Wijeysundera D, et al. Hyperchloremia after noncardiac surgery is independently associated with increased morbidity and mortality: a propensity-matched cohort study. Anesth Analg. 2013;117:412–421.
24. Shaw AD, Bagshaw SM, Goldstein SL, et al. Major complications, mortality, and resource utilization after open abdominal surgery: 0.9% saline compared to Plasma-Lyte. Ann Surg. 2012;255:821–829.
25. Sen A, Keener CM, Sileanu FE, et al. Chloride content of fluids used for large-volume resuscitation is associated with reduced survival. Crit Care Med. 2017;45:e146–e153.
26. Young JB, Utter GH, Schermer CR, et al. Saline versus Plasma-Lyte A in initial resuscitation of trauma patients: a randomized trial. Ann Surg. 2014;259:255–262.
27. Mahler SA, Conrad SA, Wang H, et al. Resuscitation with balanced electrolyte solution prevents hyperchloremic metabolic acidosis in patients with diabetic ketoacidosis. Am J Emerg Med. 2011;29:670–674.
28. Young P, Bailey M, Beasley R, et al. Effect of a buffered crystalloid solution vs saline on acute kidney injury among patients in the intensive care unit: the SPLIT Randomized Clinical Trial. JAMA. 2015;314:1701–1710.
29. Semler MW, Wanderer JP, Ehrenfeld JM, et al. Balanced crystalloids versus saline in the intensive care unit. The SALT Randomized Trial. Am J Respir Crit Care Med. 2017;195:1362–1372.
30. Self WH, Semler MW, Wanderer JP, et al. Balanced crystalloids versus saline in noncritically ill adults. N Engl J Med. 2018;378:819–828.
31. McNab S, Ware RS, Neville KA, et al. Isotonic versus hypotonic solutions for maintenance intravenous fluid administration in children. Cochrane Database Syst Rev. 2014:CD009457.
32. Allen CH, Goldman RD, Bhatt S, et al. A randomized trial of Plasma-Lyte A and 0.9% sodium chloride
in acute pediatric gastroenteritis. BMC Pediatr. 2016;16:117–125.
33. Stenson EK, Cvijanovich NZ, Anas N, et al. Hyperchloremia is associated with complicated course and mortality in pediatric patients with septic shock. Pediatr Crit Care Med. 2018;19:155–160.
34. van der Jagt M. Fluid management of the neurological patient: a concise review. Crit Care. 2016;20:126–136.
35. Roquilly A, Loutrel O, Cinotti R, et al. Balanced versus chloride-rich solutions for fluid resuscitation in brain-injured patients: a randomised double-blind pilot study. Crit Care. 2013;17:77–89.
36. Story DA, Morimatsu H, Egi M, et al. The effect of albumin concentration on plasma sodium and chloride measurements in critically ill patients. Anesth Analg. 2007;104:893–897.
brain tumor; crystalloid solutions; sodium chloride; hyperchloremic acidosis
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