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Feature Review Article

Balanced Versus Unbalanced Fluid in Critically Ill Children: Systematic Review and Meta-Analysis*

Lehr, Anab Rebecca MD1; Rached-d’Astous, Soha MD2; Barrowman, Nick PhD3; Tsampalieros, Anne MD3; Parker, Melissa MD4,5; McIntyre, Lauralyn MD6; Sampson, Margaret PhD7; Menon, Kusum MD1

Author Information
Pediatric Critical Care Medicine: March 2022 - Volume 23 - Issue 3 - p 181-191
doi: 10.1097/PCC.0000000000002890



IV crystalloid fluid bolus therapy is one of the most frequently administered therapies for replacement of intravascular volume and restoration of hemodynamic stability in critically ill children (1–3). However, the ideal composition of crystalloid solution remains unclear (4–9). Historically, 0.9% saline has been the most commonly used solution and is the most widely available (10). However, due to its high sodium (154 mmol/L) and chloride (154 mmol/L) concentration, 0.9% saline administration has been associated with hyperchloremic metabolic acidosis (11,12) and may therefore lead to the development or worsening of metabolic acidosis. In addition, normal 0.9% normal saline has been associated with decreased renal perfusion, acute kidney injury (AKI), increased proinflammatory state, and hemodynamic instability leading to concerns regarding its use in critically ill patients (13–17). In pediatric septic shock, hyperchloremic metabolic acidosis was associated with the amount of fluid received, and hyperchloremia (minimum serum chloride ≥ 110 mmol/L) was found to be an independent risk factor for 28-day mortality or persistence of organ failure (18,19).

As a result, balanced solutions were developed with a decreased chloride load and added buffers making their composition and pH closer to human whole blood (see Additional file 1 in the protocol: type and composition of different isotonic crystalloids solution compared to human plasma []). Ringer’s lactate (RL), the most commonly used balanced solution, contains only 109 mmol/L compared with 154 mmol/L of chloride. RL, however, has decreased availability, higher cost (C$1.80 per liter vs C$1.41 per liter of 0.9% saline), and a lack of convincing data proving its superiority to 0.9% saline (10).

Numerous randomized trials, systematic reviews, and meta-analyses in perioperative and critically ill adults have demonstrated a decreased prevalence of hyperchloremia and metabolic acidosis with balanced fluid compared with unbalanced crystalloid fluids although benefits on clinical outcomes such as AKI, renal replacement therapy (RRT), and mortality remain uncertain (20–24). In critically ill children, data are more limited with a few small and inadequately powered studies (25–34). In a recent systematic review and meta-analysis, no benefits were found from balanced fluids on in-hospital mortality or AKI in critically ill adults and children or in the pediatric subgroup mortality analysis (odds ratio [OR], 0.97; 95% CI, 0.10–9.80; p = 0.98) (35). However, this meta-analysis only included four pediatric trials with a total of 258 patients, representing 0.2% of the weight of the mortality analysis. As mortality in critically ill children is significantly lower than in critically ill adults (36), we believe metabolic acidosis is a more appropriate outcome to study.

Although more convincing pediatric data are still needed before guidelines can be firmly generated, the Canadian Pediatric Society and Pediatric Surviving Sepsis Campaign guidelines already suggest the use of balanced over unbalanced fluids (37). Therefore, the objective of this systematic review and meta-analysis was to compare the effect of balanced versus unbalanced fluid bolus therapy on serum bicarbonate or blood pH in critically ill children.


Our study was designed according to the Preferred Reporting Items for Systematic Review and Meta-analysis Protocols (PRISMA-P) guidelines and registered on PROSPERO (CRD42019134240) (see Additional file 2 in the protocol: PRISMA-P 2015 checklist) (9,38–40). A more detailed description of the methods has been previously published (9).

Study Selection

Randomized controlled trials (RCTs) and observational cohort studies evaluating the effect of administration of balanced versus unbalanced fluid bolus therapy on laboratory and/or clinical outcomes were eligible. The population of interest was critically ill children, from 28 days old to 18 years old (41), who require active fluid bolus therapy in any setting: emergency department, ICU, operating room, or inpatient step-down units. Unbalanced fluids were defined as 0.9% saline, and balanced fluids were defined as sodium-based fluids with chloride content less than 154 mmol/L and the addition of buffers (10,42). Fluid bolus therapy was defined as a minimum of 20 mL/kg or 1 L cumulative, and studies assessing only maintenance fluids were excluded (43–45). The primary outcome was the mean change in serum bicarbonate or serum pH within 24 hours of fluid bolus therapy compared with baseline levels. The primary outcome in our published protocol was intended to be the prevalence and/or time to resolution of metabolic acidosis; however, these data were unavailable for most studies. Secondary outcomes were time to resolution of metabolic acidosis, prevalence of hyperchloremia (defined as chloride > 106 mmol/L), AKI as defined by pediatric Risk, Injury, Failure, Loss End Stage Renal Disease (pRIFLE) or AKI Network or Kidney Disease Improving Global Outcomes (KDIGO) within 48 hours of the fluid bolus therapy (46–48), need and/or duration of RRT, duration of vasopressors, duration of mechanical ventilation, total volume of rehydration needed per day, need for extracorporeal membrane oxygenation (ECMO), ICU and hospital length of stay (LOS), and mortality at any time point.

Data Sources and Search Strategy

In collaboration with an experienced clinical research librarian, we developed and validated an electronic search strategy (49–51) using the following databases: MEDLINE including Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Embase, CENTRAL Trials Registry of the Cochrane Collaboration using the Ovid interface as well as (52), and the World Health Organization International Clinical Trials Registry Platform (53) (see Additional file 3 in the protocol: search strategy and Additional file 4 in the protocol: data extraction) (9). References of relevant studies, review articles, and included studies were also reviewed (54). The search included all published studies with no restriction of language or journal of publication up to November 2020.

Screening and Data Extraction

Studies were screened, selected, and data extracted by two independent authors (S.R.A., A.R.L.) using a standardized and calibrated form detailed in the published protocol (9). Disagreements were resolved by consensus and/or a third independent reviewer (K.M.). If insufficient data were provided to assess study eligibility or extract relevant data, corresponding authors were contacted.

Evidence Synthesis

Descriptive statistics were provided on all included studies. Data on study characteristics, interventions, outcomes, and important covariates were summarized using frequencies and percentages for dichotomous outcomes and means and sds or medians and interquartile ranges (IQRs), as appropriate, for continuous outcomes. For comparison purposes, when medians, ranges, or IQRs were reported, they were converted to means and sds according to the method proposed by Wan et al (55). Individual participant data were available for serum bicarbonate in one study (28), which allowed us to calculate the correlation between bicarbonate levels pre and post bolus so as to compute the se of the change. The effect measure used was mean difference for continuous outcomes and OR for dichotomous outcomes.

For the observational studies included in our systematic review, there was significant heterogeneity and a high level of bias as per the risk-of-bias tool for randomized trial (RoB 2). Therefore, we elected to conduct the meta-analysis only on the available RCT pooled data and only provide individual study results and descriptive statistics for the observational studies. We pooled results of included RCTs using a random effects model after excluding high risk of bias trials. Statistical heterogeneity among studies was examined using the I2 statistic, and observed heterogeneity was elucidated by examining various sources including patient populations, settings, and interventions. Statistical significance was determined at a level α less than or equal to 0.05 and p value used to inform on the strength of the evidence (56). Analysis was performed using the R statistical software Version 3.5.1 (57). Forest plots were created using the R package Metafor (58). Subgroup analysis was not performed due to the small numbers of studies, patients, and population heterogeneity.

Risk of Bias Assessment

Two authors independently assessed the risk of bias for each included study using Risk Of Bias in Non-randomized Studies – of Interventions (ROBINS-I) tool (59) for non-RCTs and the revised Cochrane RoB 2 (60,61).


Studies Characteristics

A total of 481 references were identified by our search. After exclusion of duplicates and abstract screening, 42 full-text articles were assessed for eligibility (Fig. 1). The Kappa score was 0.75. Characteristics of included studies are summarized in Supplemental Table 1 ( Thirteen studies with a total of 11,848 patients met eligibility criteria, including nine RCTs enrolling 557 patients and four observational studies. Three RCTs with a total of 162 patients were included in the meta-analysis of our primary outcome. Overall study populations included patients with severe gastroenteritis (27–30), severe sepsis and septic shock (31–33,62,63), dengue shock (25,26), and diabetic ketoacidosis (34,64). The majority of studies (10/13) were single center, whereas one RCT (30) and two observational studies (31,32) were multicenter. RL was the most commonly used balanced fluid (8/13), whereas 0.9% normal saline was the unbalanced fluid in all 13 studies. The bias assessment detailed in Supplemental Table 2 ( Risk of bias assessment reveals low-moderate risk of bias for seven of nine RCTs (26,27,29,30,34,62,63) and high risk of bias for two of nine RCTs (25,64).

Figure 1.:
Preferred Reporting Items for Systematic Review and Meta-analysis 2009 flow diagram. ICTRP = International Clinical Trials Registry Platform, WHO = World Health Organization. From Moher D, Liberati A, Tetzlaff J, et al; PRISMA Group: Preferred reporting items for systematic review and meta-analysis: The PRISMA Statement. PLos Med 21; 6:e1000097. For more information, visit

Primary Outcome

Three RCTs (27,29,30) provided adequate data to evaluate the primary outcome. In these trials, follow-up serum bicarbonate levels were measured at 4 (30), 6, (27) and 6–12 hours (29) post fluid administration. The pooled estimate of the three RCTs (27,29,30) with a total of 162 patients revealed a difference in mean change of 1.60 mmol/L in serum bicarbonate levels following fluid administration (95% CI, 0.04–3.16; I2 = 59.2%; p = 0.04) as shown in Figure 2A. Two of the three RCTs (27,29) reported follow-up measures of pH with a pooled mean difference of 0.03 (95% CI, 0.00–0.06; I2 = 14.3%; p = 0.03) in favor of balanced fluid as presented in Figure 2B.

Figure 2.:
Acidosis forest plot: forest plot comparing change in serum bicarbonate from baseline to follow-up post exposition (A) and forest plot comparing follow-up pH (B) in critically ill children exposed to balanced versus unbalanced fluids. RE = random effect.

Secondary Outcomes

Different outcome measures for resolution of metabolic acidosis were reported. In a population of diabetic ketoacidosis, Williams et al (64) and Yung et al (34) reported no significant difference in time to resolution of acidosis after fluid bolus therapy. In an observational study on patients with severe sepsis/septic shock, Samransamruajkit (33) showed a significant difference in base excess at 6 and 24 hours in the RL group compared with the 0.9% saline group (2.46 sd ± 4.07 vs –3.65 sd ± 4.14 in unbalanced; p < 0.001 at 6 hr and 3.36 sd ± 3. vs –1.18 sd ± 3.95; p = 0.002 at 24 hr), whereas Anantasit et al (63) (RCT) did not find a significant difference in the prevalence of hyperchloremic metabolic acidosis.

Three RCTs reported serum chloride levels at 4 (30), 6 (27), and 6–12 hours (29), respectively, following fluid administration. Serum chloride levels were lower in the balanced compared with unbalanced group (Fig. 3A) but did not reach statistical significance with a pooled mean difference of –1.47 mmol/L (95% CI, –4.49 to 1.56; I2 = 85.4%; p = 0.34). Two RCTs (34,63) reported a change in serum chloride levels from baseline and found a pooled estimate of the difference in mean change of –1.95 mmol/L in serum chloride levels (95% CI, –4.20 to 0.29; I2 = 0.0%; p = 0.09) measured at 6 hours (63) or unspecified time point (34) post intervention (Fig. 3B).

Figure 3.:
Chloride forest plot: forest plot comparing serum chloride level at baseline (A) and follow-up (B) in critically ill children exposed to balanced versus unbalanced fluids. RE = random effect.

AKI was defined by pRIFLE classification, KDIGO classification, or an unspecified definition in RCTs (27,34,62–64) and International Classification of Diseases, 9th Edition codes (31,32). The pooled estimate of the four RCTs (27,34) suggested no difference between both groups (OR, 0.97; 95% CI, 0.46–2.04; I2 = 0.0%; p = 0.94) as shown in Figure 4A. The two observational studies showed no significant differences in the prevalence of AKI within 24 hours (32) or during the hospital stay (31) in the balanced group. RRT was reported in three observational studies (31–33) and three RCTs (34,62–64). The pooled estimate of three of those RCTs showed no difference between balanced and unbalanced fluid groups (OR, 0.63; 95% CI, 0.08–5.31; I2 = 0.0%; p = 0.67) as shown in Figure 4B. The duration of RRT was not specified in the studies.

Figure 4.:
Renal forest plot: forest plot comparing prevalence of acute kidney injury (A) and renal replacement therapy (B) in critically ill children exposed to balanced versus unbalanced fluids. RE = random effect.

Total volume of rehydration needed was reported in eight studies with means ranging from 33 to 541.33 mL/kg as shown in Supplemental Table 3 ( No meta-analysis was feasible because of significant heterogeneity in reported timing of fluid bolus therapy (25,26,28,30,33,34,62,64) and inclusion by some of maintenance fluids and/or rehydration fluids in the total IV fluid received (27,29,63). Overall, two of two observational studies and five of eight RCTs (27–30,33,34,64) who reported volume of fluid administered showed evidence toward less volume of fluid bolus needed in the balanced groups when compared with unbalanced groups (Supplemental Table 3,

Vasopressor needs were assessed in two retrospective studies (32,33) and suggested no differences between groups in inotropic score (mean 15.47 sd ± 9.04 in balanced group vs mean of 23.7 sd ± 17.36 in the unbalanced group; p = 0.1) or vasoactive infusion days within 24 hours (mean 3.4; 95% CI, 3.1–3.9 in the balanced group vs mean of 3.4; 95% CI, 3.1–3.8 in the unbalanced group; p = 0.897). The meta-analysis of two RCTs revealed no differences in the need for vasopressors (OR, 1.07; 95% CI, 0.22–5.14; I2 = 0.0%; p = 0.93) (Supplemental Fig. 1, The frequency of mechanical ventilation, reported in one observational study (33), was similar between both groups with 40% in the balanced group (6/15) versus 50% in the unbalanced group (10/20) (p = 0.4). The need for ECMO support between groups was not reported in any studies.

Hospital LOS (27,29,62,63) and PICU LOS (34,63) were reported in four and two RCTs, respectively, but a meta-analysis was not feasible as the mean and sd were not reported. No differences in overall mortality were found between groups in the three RCTs (OR, 0.95; 95% CI, 0.33–2.70; I2 = 0.0%; p = 0.92) (Fig. 5). (29,62,63)

Figure 5.:
Total mortality: forest plot comparing prevalence of mortality in critically ill children exposed to balanced versus unbalanced fluids. RE = random effect.


To our knowledge, this is the largest systematic review and meta-analysis to assess the effect of balanced versus unbalanced fluids on serum bicarbonate and blood pH and clinical outcomes in critically ill children. We identified 13 studies, including nine RCTs with a total of 11,848 patients. Although only RCTs with a low-to-moderate risk of bias were included in this meta-analysis, these studies were limited by their small sample size (range 22–77 participants per studies) and significant clinical and statistical heterogeneity; therefore, our primary outcome included 162 patients.

We found higher serum bicarbonate levels (difference of 1.60 mmol/L) and higher blood pH levels (difference of 0.03) in critically ill children treated with balanced fluid bolus therapy compared with unbalanced fluids when compared with baseline levels. These findings are comparable with the systematic review of Antequera Martín (35) who found very low-certainty evidence of higher bicarbonate level (mean difference [MD], 2.26; 95% CI, 1.25–3.27; I2 = 72%; very low-certainty evidence) and higher pH level (MD, 0.04; 95% CI, 0.02–0.06; I2 = 59%; very low-certainty evidence) in the balanced solution group of critically ill patients. However, only 99 of 344 participants for the bicarbonate outcome and zero of 200 participants for the pH outcome represented pediatric populations.

Despite a growing body of evidence suggesting unbalanced fluids are associated with increased serum chloride (24,35), we were unable to demonstrate evidence for this association. Furthermore, we reported no evidence of difference in the prevalence of AKI which is comparable with three other adult-based meta-analyses (35,65,66). We found no differences in vasopressor need, PICU LOS, hospital LOS, or mortality.

Limitations of our meta-analysis included the small sample size and high risk of bias of some of the included studies which also precluded further subgroup analysis. Furthermore, our studies included variable diagnoses, illness severities, outcome measure, and time points which limit interpretation of the findings.

The clinical relevance of our findings on the statistical differences in serum bicarbonate levels and blood pH is unclear. However, these biochemical markers may serve as intermediate outcomes in the causal pathway to more relevant clinical benefits such as AKI, RRT, and LOS. Therefore, rigorous well-powered trials comparing the effect of balanced versus unbalanced fluids on clinical outcomes in critically ill children are needed to provide high-quality evidence and allow generation of clinical recommendations and guide clinical practice. If future studies can establish clinical benefits of balanced fluids, it would legitimize their use as first-line agents, whereas if no clinical benefits are found, their use would no longer be justified as they are more expensive and less accessible. Therefore, no matter the outcome, future studies would standardize practice and optimize resource utilization in the healthcare system.


Fluid bolus therapy is a widespread treatment in the resuscitation of critically ill children. However, there is no clear evidence to support the choice of balanced versus unbalanced fluid. The present systematic review suggests improved serum bicarbonate and blood pH values in critically ill children after fluid bolus therapy with balanced fluid compared with the unbalanced fluid although no clear benefits on clinical outcomes were demonstrated. Although no recommendation can be generated at this point, our systematic review provides background information for further robust methodical studies on the choice of fluid bolus therapy in critically ill children.


We would like to acknowledge Jemila Hamid, PhD, and Katie O’Hearn, MSc, for their support in this project.


1. American Heart Association: Part 10: Pediatric advanced life support. Circulation. 2000; 102(Suppl_1):I-291–I-342
2. Carcillo JA. Intravenous fluid choices in critically ill children. Curr Opin Crit Care. 2014; 20:396–401
3. El-Bayoumi MA, Abdelkader AM, El-Assmy MM, et al. Normal saline is a safe initial rehydration fluid in children with diarrhea-related hypernatremia. Eur J Pediatr. 2012; 171:383–388
4. Matsuno WC, Yamamoto LG. Terminology used to describe volume expanding resuscitation fluid. Resuscitation. 2006; 68:371–377
5. Medeiros DN, Ferranti JF, Delgado AF, et al. Colloids for the initial management of severe sepsis and septic shock in pediatric patients: A systematic review. Pediatr Emerg Care. 2015; 31:e11–e16
6. Santi M, Lava SA, Camozzi P, et al. The great fluid debate: Saline or so-called “balanced” salt solutions? Ital J Pediatr. 2015; 41:47
7. Weinberg L, Collins N, Van Mourik K, et al. Plasma-lyte 148: A clinical review. World J Crit Care Med. 2016; 5:235–250
8. Allen SJ. Fluid therapy and outcome: Balance is best. J Extra Corpor Technol. 2014; 46:28–32
9. Lehr AR, Rached-d’Astous S, Parker M, et al. Impact of balanced versus unbalanced fluid resuscitation on clinical outcomes in critically ill children: Protocol for a systematic review and meta-analysis. Syst Rev. 2019; 8:195
10. Awad S, Allison SP, Lobo DN. The history of 0.9% saline. Clin Nutr. 2008; 27:179–188
11. Kellum JA, Bellomo R, Kramer DJ, et al. Etiology of metabolic acidosis during saline resuscitation in endotoxemia. Shock. 1998; 9:364–368
12. Li H, Sun SR, Yap JQ, et al. 0.9% saline is neither normal nor physiological. J Zhejiang Univ Sci B. 2016; 17:181–187
13. Wilcox CS. Regulation of renal blood flow by plasma chloride. J Clin Invest. 1983; 71:726–735
14. 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
15. Kellum JA, Song M, Almasri E. Hyperchloremic acidosis increases circulating inflammatory molecules in experimental sepsis. Chest. 2006; 130:962–967
16. Kellum JA, Song M, Venkataraman R. Effects of hyperchloremic acidosis on arterial pressure and circulating inflammatory molecules in experimental sepsis. Chest. 2004; 125:243–248
17. Weinberg L, Li M, Churilov L, et al. Associations of fluid amount, type, and balance and acute kidney injury in patients undergoing major surgery. Anaesth Intensive Care. 2018; 46:79–87
18. 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
19. O’Dell E, Tibby SM, Durward A, et al. Hyperchloremia is the dominant cause of metabolic acidosis in the postresuscitation phase of pediatric meningococcal sepsis. Crit Care Med. 2007; 35:2390–2394
20. Semler MW, Self WH, Wanderer JP, et al.; SMART Investigators and the Pragmatic Critical Care Research Group. Balanced crystalloids versus saline in critically ill adults. N Engl J Med. 2018; 378:829–839
21. Self WH, Semler MW, Wanderer JP, et al.; SALT-ED Investigators. Balanced crystalloids versus saline in noncritically ill adults. N Engl J Med. 2018; 378:819–828
22. Burdett E, Dushianthan A, Bennett-Guerrero E, et al. Perioperative buffered versus non-buffered fluid administration for surgery in adults. Cochrane Database Syst Rev. 2012; 12:CD004089
23. 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
24. Serpa Neto A, Martin Loeches I, Klanderman RB, et al.; PROVE Network Investigators. 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
25. Ngo NT, Cao XT, Kneen R, et al. Acute management of dengue shock syndrome: A randomized double-blind comparison of 4 intravenous fluid regimens in the first hour. Clin Infect Dis. 2001; 32:204–213
26. Dung NM, Day NP, Tam DT, et al. Fluid replacement in dengue shock syndrome: A randomized, double-blind comparison of four intravenous-fluid regimens. Clin Infect Dis. 1999; 29:787–794
27. Kartha GB, Rameshkumar R, Mahadevan S. Randomized double-blind trial of Ringer Lactate versus normal saline in pediatric acute severe diarrheal dehydration. J Pediatr Gastroenterol Nutr. 2017; 65:621–626
28. Gutierrez-Camacho C, Posadas Tello NML, Mota-Hernandez F. Hidratacion mixta en lactantes con choque hipovolemico por diarrea. Bol Med Hosp Infant Mex. 1994; 51:379–383
29. Mahajan V, Sajan SS, Sharma A, et al. Ringers lactate vs normal saline for children with acute diarrhea and severe dehydration- A double blind randomized controlled trial. Indian Pediatr. 2012; 49:963–968
30. 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
31. Weiss SL, Keele L, Balamuth F, et al. Crystalloid fluid choice and clinical outcomes in pediatric sepsis: A matched retrospective cohort study. J Pediatr. 2017; 182:304–310.e10
32. Emrath ET, Fortenberry JD, Travers C, et al. Resuscitation with balanced fluids is associated with improved survival in pediatric severe sepsis. Crit Care Med. 2017; 45:1177–1183
33. Samransamruajkit R, Saelim K, Hantragool S, et al. A comparison of NSS vs balanced salt solution as a fluid resuscitation and impact of fluid balance on clinical outcomes in pediatric septic shock. Crit Care Shock. 2017; 20:68–75
34. Yung M, Letton G, Keeley S. Controlled trial of Hartmann’s solution versus 0.9% saline for diabetic ketoacidosis. J Paediatr Child Health. 2017; 53:12–17
35. Antequera Martín AM, Barea Mendoza JA, Muriel A, et al. Buffered solutions versus 0.9% saline for resuscitation in critically ill adults and children. Cochrane Database Syst Rev. 2019; 7:CD012247
36. Seferian EG, Carson SS, Pohlman A, et al. Comparison of resource utilization and outcome between pediatric and adult intensive care unit patients. Pediatr Crit Care Med. 2001; 2:2–8
37. Weiss SL, Peters MJ, Alhazzani W, et al. Surviving sepsis campaign international guidelines for the management of septic shock and sepsis-associated organ dysfunction in children. Pediatr Crit Care Med. 2020; 21:e52–e106
38. Shamseer L, Moher D, Clarke M, et al.; PRISMA-P Group. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: Elaboration and explanation. BMJ. 2015; 350:g7647
39. Chien PF, Khan KS, Siassakos D. Registration of systematic reviews: PROSPERO. BJOG. 2012; 119:903–905
40. Booth A, Clarke M, Dooley G, et al. PROSPERO at one year: An evaluation of its utility. Syst Rev. 2013; 2:4
41. World Health Organization: Guideline: Updates on Paediatric Emergency Triage, Assessment and Treatment: Care of Critically-Ill Children. Geneva, Switzerland, World Health Organization, 2016
42. Baskett TF. The resuscitation greats: Sydney Ringer and lactated Ringer’s solution. Resuscitation. 2003; 58:5–7
43. de Caen AR, Berg MD, Chameides L, et al. Part 12: Pediatric advanced life support: 2015 American Heart Association Guidelines update for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation. 2015; 132:S526–S542
44. Davis AL, Carcillo JA, Aneja RK, et al. American College of Critical Care Medicine clinical practice parameters for hemodynamic support of pediatric and neonatal septic shock. Crit Care Med. 2017; 45:1061–1093
45. Long E, Babl F, Dalziel S, et al.; Paediatric Research in Emergency Departments International Collaborative (PREDICT). Fluid resuscitation for paediatric sepsis: A survey of senior emergency physicians in Australia and New Zealand. Emerg Med Australas. 2015; 27:245–250
46. 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
47. Sutherland SM, Byrnes JJ, Kothari M, et al. AKI in hospitalized children: Comparing the pRIFLE, AKIN, and KDIGO definitions. Clin J Am Soc Nephrol. 2015; 10:554–561
48. Soler YA, Nieves-Plaza M, Prieto M, et al. Pediatric risk, injury, failure, loss, end-stage renal disease score identifies acute kidney injury and predicts mortality in critically ill children: A prospective study. Pediatr Crit Care Med. 2013; 14:e189–e195
49. Bramer WM. Improving efficiency and confidence in systematic literature searching. In: EAHIL+ICAHIS + ICLC. June 10–12, 2015, Edinburgh
50. Sampson M, McGowan J. Inquisitio validus Index Medicus: A simple method of validating MEDLINE systematic review searches. Res Synth Methods. 2011; 2:103–109
51. Booth A. How much searching is enough? Comprehensive versus optimal retrieval for technology assessments. Int J Technol Assess Health Care. 2010; 26:431–435
52. U.S. National Library of Medicine: February 29, 2000. Available at:
53. International Clinical Trials Registry Platform (ICTRP): 2004. Available at:
54. Horsley T, Dingwall O, Sampson M. Checking reference lists to find additional studies for systematic reviews. Cochrane Database Syst Rev. 2011; (8):MR000026
55. Wan X, Wang W, Liu J, et al. Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. BMC Med Res Methodol. 2014; 14:135
56. Sterne JA, Smith GD. Sifting the evidence-what’s wrong with significance tests? Phys Ther. 2001; 81:1464–1469
57. R Core Team: R: A Language and Environment for Statistical Computing, Vienna, Austria, 2018
58. Viechtbauer W. Conducting meta-analyses in R with the metafor package. J Stat Softw. 2010; 36:1–48
59. Sterne JA, Hernán MA, Reeves BC, et al. ROBINS-I: A tool for assessing risk of bias in non-randomised studies of interventions. BMJ. 2016; 355:i4919
60. Sterne JAC, Savović J, Page MJ, et al. RoB 2: A revised tool for assessing risk of bias in randomised trials. BMJ. 2019; 366:l4898
61. Higgins JP, Altman DG, Gøtzsche PC, et al.; Cochrane Bias Methods Group; Cochrane Statistical Methods Group. The Cochrane collaboration’s tool for assessing risk of bias in randomised trials. BMJ. 2011; 343:d5928
62. Balamuth F, Kittick M, McBride P, et al. Pragmatic pediatric trial of balanced versus normal saline fluid in sepsis: The PRoMPT BOLUS randomized controlled trial pilot feasibility study. Acad Emerg Med. 2019; 26:1346–1356
63. Anantasit N, Thasanthiah S, Lertbunrian R. Balanced salt solution versus normal saline solution as initial fluid resuscitation in pediatric septic shock: A randomized, double-blind controlled trial. Crit Care Shock. 2020; 23:158–168
64. Williams V, Jayashree M, Nallasamy K, et al. 0.9% saline versus plasma-lyte as initial fluid in children with diabetic ketoacidosis (SPinK trial): A double-blind randomized controlled trial. Crit Care. 2020; 24:1
65. Zwager CL, Tuinman PR, de Grooth HJ, et al. Why physiology will continue to guide the choice between balanced crystalloids and normal saline: A systematic review and meta-analysis. Crit Care. 2019; 23:366
66. Liu C, Lu G, Wang D, et al. Balanced crystalloids versus normal saline for fluid resuscitation in critically ill patients: A systematic review and meta-analysis with trial sequential analysis. Am J Emerg Med. 2019; 37:2072–2078

balanced fluid; critically ill children; crystalloid fluid; normal saline; Ringer’s lactate; resuscitation

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Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.