Journal Logo

Feature Articles

Timing and Clinical Significance of Fluid Overload in Pediatric Acute Respiratory Distress Syndrome*

Black, Celeste G. MD1; Thomas, Neal J. MD, MSc2; Yehya, Nadir MD, MSCE3

Author Information
Pediatric Critical Care Medicine: September 2021 - Volume 22 - Issue 9 - p 795-805
doi: 10.1097/PCC.0000000000002765

Abstract

REPORT IN CONTEXT

  • While fluid overload is known to be associated with poor outcomes in pediatric ARDS, it is unknown whether this association varies with the timing after ARDS onset.
  • This is relevant, as the design of future trials of fluid management may have differential impact depending on when the intervention is initiated.
  • Our results suggest that later (after day 4 of ARDS onset) fluid overload, rather than earlier (first 3 d), has a greater association with poor outcomes.

Acute respiratory distress syndrome (ARDS) is a disease of acute hypoxemia, with 18–35% mortality in pediatrics (1–3). Increased alveolar-capillary permeability contributes to pulmonary edema (4). One proposed pathogenic mediator is angiopoietin-2, which correlates with increased mortality in pediatric ARDS (5,6). In adult ARDS, conservative fluid management resulted in improved oxygenation and more ventilator-free days (VFDs) at 28 days (7). Angiopoietin-2 predicted worse outcomes in a subset of these patients (8). In retrospective analyses of pediatric ARDS, a positive cumulative fluid balance at day 3 of illness and beyond has been associated with fewer VFDs (9), longer length of stay (10), and increased mortality (10–13).

While the correlation between fluid overload and worse outcomes is established in pediatric ARDS, it is unclear “when” in the illness time-course the relationship between fluid overload and outcomes becomes relevant, as most studies simply report cumulative balance at 72 hours. Specifically, it is unclear whether fluid overload during the initial resuscitation period in early ARDS, the period of de-resuscitation after initial stabilization, or both, carries a stronger association with outcome. A granular understanding of the temporal relationship of fluid overload with poor outcomes could clarify the timing of de-resuscitation in future studies. Furthermore, existing studies are limited by small sample sizes (9,11–13) and low mortality rates, precluding inclusion of several potential confounders. Therefore, in order to assess the relationship between the timing of fluid overload and outcomes, we leveraged an ongoing prospective cohort and abstracted detailed fluid intake, output, urine output (UOP), and cumulative fluid balance for the first 7 days after ARDS onset. Angiopoietin-2 was measured in a subset of patients to assess for utility as a predictor of fluid overload.

METHODS

Study Design and Setting

This was a retrospective analysis of a prospective cohort (July 2011 to June 2019) from the Children’s Hospital of Philadelphia’s PICU, approved by the Institutional Review Board (Number 14-011201) with requirement for informed consent waived. Ventilator escalation, fluid management, and use of diuretics or continuous renal replacement therapy (CRRT) were not protocolized. Sedation and ventilator weaning were protocolized, although the decision to extubate was also at the discretion of the attending. A subset of subjects after July 2014 were enrolled in an observational study with biomarker measurements on days 1 and 3 after ARDS onset, for which informed consent was obtained.

Participants

Intubated children meeting American-European Consensus Conference criteria for acute lung injury (two consecutive Pao2/Fio2300 separated by ≥ 1 hr with bilateral infiltrates) were included. As the study was initiated prior to the Berlin definition (14), minimum positive end-expiratory pressure (PEEP) was not specified; however, as all PEEP was greater than or equal to 5 cm H2O, all patients met Berlin criteria. Similarly, as the study was initiated prior to the Pediatric Acute Lung Injury Consensus Conference (PALICC) definition of pediatric ARDS (15), we did not screen using oxygenation index (OI); however, all but one patient met PALICC criteria by OI.

Variables and Definitions

Demographics, comorbidities, and ventilator settings for the first 72 hours from ARDS diagnosis were recorded prospectively, as the aim of the parent study was identification of determining early predictors of mortality in pediatric ARDS. Fluid variables (standardized to admission body weight) over the first 7 days were collected retrospectively. Intake and output were recorded per 24-hour period (7 am to 7 am) for the first 7 days from ARDS onset. “Day 1” was the day a subject met all ARDS criteria, irrespective of time. Total intake, output, UOP, and combination output (mixed urine and stool) from all previous 24-hour periods were summed to give cumulative daily values. Cumulative fluid balance was the primary exposure. If a patient died or was transferred out of the PICU prior to day 7, data were recorded through last 24-hour period with reliable data. If the final day had less than 8 hours of data, values were excluded; if there was greater than or equal to 8 hours of data, hourly rates were extrapolated to complete 24 hours.

Severity of illness score was Pediatric Risk of Mortality (PRISM) III score at 12 hours (16). Shock was quantified using vasopressor score (17). Nonpulmonary organ failures were identified using pediatric definitions (18). “Immunocompromised” required an immunocompromising diagnosis (oncologic, immunologic, rheumatologic, or transplant) and active immunosuppressive chemotherapy, or a congenital immunodeficiency (19,20). Acute kidney injury (AKI) as Kidney Disease Improving Global Outcomes stage 2 or 3: UOP less than 0.5 mL/kg/hr, creatinine greater than or equal to 2x baseline, or use of CRRT.

The primary outcome was PICU mortality, which was assigned as either being caused primarily by hypoxemia, multisystem organ failure (MSOF), or neurologic failure. The secondary outcome was VFDs at 28 days. Noninvasive support was not counted toward ventilator days. Liberation from ventilation greater than or equal to 24 hours defined duration of ventilation. Patients requiring reinitiation of invasive ventilation had the extra days counted toward total ventilator days. VFDs were determined by subtracting total ventilator days from 28 in survivors. Patients with greater than or equal to 28 ventilator days and PICU nonsurvivors were assigned VFD equals to 0.

Plasma Collection and Angiopoietin-2 Measurements

In the subset of subjects enrolled in the biomarker study, blood was collected on days 1 and 3 of ARDS in citrated tubes (Becton, Dickinson and Co, Franklin Lakes, NJ), centrifuged within 30 minutes (2,000 g, 20 min, 20°C) to generate platelet-poor plasma, aliquoted to prevent freeze/thaw cycles, and stored at –80°C until analysis. Angiopoietin-2 was measured in duplicate using an enzyme-linked immunosorbent assay (R&D Systems, Minneapolis, MN).

Statistical Methods

Analyses were performed using Stata 16.1 SE (StataCorp, College Station, TX). Univariate comparisons were made using Wilcoxon rank-sum or Fisher exact tests. For our primary analyses, we tested the association of each cumulative fluid variables (cumulative intake, cumulative output, cumulative UOP, cumulative fluid balance for each day up to day 7) with mortality. We performed multivariable logistic regression adjusting a priori for OI, number of organ failures, immunocompromised status, and vasopressor score on day 1 of illness. These confounders were chosen as they comprise the variables in a validated mortality prediction model for pediatric ARDS (21) and are all baseline variables reflecting ARDS severity, organ failure, and shock. Results are presented as adjusted odds ratios (aORs) per change in 100 mL/kg, with analyses adjusted for multiple comparisons using Bonferroni’s method (nominal p ≤ 0.007) given separate tests for days 1 through 7. To assess association with VFDs, we tested the association of these same cumulative fluid variables with probability of extubation, treating death as a competing risk, using competing risk regression adjusting for the same confounders above (22). Censoring at day 28 makes this analysis comparable to VFDs at 28 days.

We performed multiple sensitivity analyses. First, due to bias from patients either improving rapidly or dying before 7 days, we repeated analyses restricted to cases with data for all 7 days. Second, to assess whether there was bias by analyzing UOP rather than combination output, we repeated analyses using combination output. Third, to assess the impact of temporal trends, we repeated the analysis adjusting for year. Fourth, to assess whether etiology affected our conclusions, we performed an analysis stratifying subjects according to primary diagnosis (pneumonia, nonpulmonary sepsis, or other). To assess whether the cause of death affected our conclusions, we performed an analysis stratified by cause of death (hypoxemia, MSOF, or neurologic). Finally, to test whether poor outcomes associated with fluid overload were mediated by AKI or shock, we performed mediation analysis using structural equation modeling assessing whether AKI or maximum vasopressor score by day 3 mediated the association between late (days 4 to 7) fluid overload greater than 100 mL/kg fluid balance (> 10% fluid overload) and mortality.

RESULTS

Description of the Cohort

Over the study period, 723 children had ARDS with 132 (18%) nonsurvivors (Table 1), with most deaths caused by neurologic failure or MSOF. Survivors had lower PRISM III, organ failures, and vasopressor score than nonsurvivors. Survivors had a higher diuretic use after day 2 (Supplementary Table 1, http://links.lww.com/PCC/B794), although this did not reach statistical significance after multiple testing correction (all nominal p > 0.007). Nonsurvivors had a greater CRRT use than survivors on every day. Over the study period, there was a trend toward higher use of PEEP (Supplementary Table 2, http://links.lww.com/PCC/B794), and lower daily fluid intake on days 1 and 2 (Supplementary Table 3, http://links.lww.com/PCC/B794).

TABLE 1. - Demographics of the Acute Respiratory Distress Syndrome Cohort Stratified by Survival Status
Variables All Patients (n = 723) Survivors (n = 591) Nonsurvivors (n = 132) p
Age, yr 5.1 (1.6–12.9) 4.7 (1.5–12.5) 7.2 (2.9–13.8) 0.016
Female (%) 311 (43) 255 (43) 56 (42) 0.923
Severity of illness
 Pediatric Risk of Mortality III at 12 hr 11 (5–18) 9 (5–16) 17 (12–30) < 0.001
 Nonpulmonary organ failure 2 (1–3) 1 (1–2) 3 (2–4) < 0.001
 Vasopressor score 10 (0–20) 8 (0–16) 20 (7–50) < 0.001
 Immunosuppressed (%) 154 (21) 89 (15) 65 (49) < 0.001
 Stem cell transplant (%) 65 (9) 29 (5) 36 (27) < 0.001
Comorbidities (%)
 None 275 (38) 231 (39) 44 (33) 0.235
 Prematurity 84 (12) 82 (14) 2 (2) < 0.001
 Chronic kidney disease 3 (0.4) 3 (0.5) 0 (0) 1.000
 Chronic liver disease 14 (2) 8 (1) 6 (5) 0.028
Cause of ARDS (%)
 Pneumonia 366 (51) 325 (55) 41 (31) < 0.001
 Aspiration 98 (14) 79 (13) 19 (14)
 Sepsis 160 (22) 116 (20) 44 (33)
 Trauma 42 (6) 34 (6) 8 (6)
 Other 57 (8) 37 (6) 20 (15)
At ARDS onset
 Fio 2 0.5 (0.4–0.9) 0.5 (0.4–0.8) 0.65 (0.4–1.0) 0.018
 Pao 2/Fio 2 156 (105–217) 160 (111–217) 141 (76–225) 0.067
 OI 10.4 (7.1–17.6) 10.3 (7.1–16) 12.1 (7.4–25.7) 0.003
 PEEP (cm H2O) 10 (8–12) 10 (8–12) 10 (8–12) 0.004
 ΔP (cm H2O) 21 (17–25) 20 (16–24) 21 (18–26) 0.101
24 hr after ARDS onset
 Fio 2 0.4 (0.3–0.5) 0.35 (0.3–0.45) 0.45 (0.4–0.7) < 0.001
 Pao 2/Fio 2 225 (162–284) 232 (171–292) 182 (111–248) < 0.001
 OI 6.9 (4.8–11.5) 6.6 (4.7–10.6) 9.9 (5.7–21.6) < 0.001
 PEEP (cm H2O) 10 (8–12) 10 (8–10) 10 (8–12) < 0.001
 ΔP (cm H2O) 17.5 (14–22) 17 (14–22) 20 (16–23) 0.001
Ancillary therapies in first 72 hr (%)
 Inhaled nitric oxide 261 (36) 194 (33) 67 (51) < 0.001
 Nonconventional ventilator mode 202 (28) 156 (26) 46 (35) 0.054
 Extracorporeal membrane oxygenation 32 (4) 23 (4) 9 (7) 0.158
 Corticosteroids 387 (54) 299 (51) 88 (67) 0.001
 Neuromuscular blockade 346 (48) 282 (48) 64 (48) 0.923
 Prone positioning 25 (3) 20 (3) 5 (4) 0.793
Cause of death in nonsurvivors (%)
 Multisystem organ failure 54 (41)
 Neurologic 52 (39)
 Hypoxemia 26 (20)
ARDS = acute respiratory distress syndrome, OI = oxygenation index, PEEP = positive end-expiratory pressure, ΔP = driving pressure (peak pressure minus PEEP). Data are presented as frequencies (percentages) or medians (interquartile ranges).

Unadjusted Analysis

In unadjusted analysis (Supplementary Fig. 1, http://links.lww.com/PCC/B794), there was no difference in daily intake between survivors and nonsurvivors until day 7 (median 83 vs 101 mL/kg on day 7). Daily output was not different on any day; UOP was always higher in survivors. When assessing cumulative fluid metrics (Fig. 1), there was no difference between survivors and nonsurvivors in cumulative intake until day 7 (median 690 vs 774 mL/kg on day 7). Survivors had a slower rate of fluid accumulation (median 81 mL/kg/d) relative to nonsurvivors (92 mL/kg/d; p = 0.002). Beginning on day 3, nonsurvivors had a greater cumulative balance than survivors (median 79 vs 109 mL/kg on day 3), which was maintained through day 7.

Figure 1.
Figure 1.:
Comparison between survivors (white) and nonsurvivors (gray) without adjustment for severity of illness, of cumulative fluid intake, cumulative fluid output, cumulative urine output (UOP), and cumulative fluid balance in mL/kg for days 1 through 7 (each day’s metrics adding upon the previous). Box plots represent median (line), lower and upper quartiles (boxes), and range (error bars). Comparisons with statistical significance p value of less than 0.05 after Bonferroni correction (nominal p ≤ 0.007) are depicted with an asterisk. The number of subjects in each group available for comparison over all 7 d is provided. ARDS = acute respiratory distress syndrome.

Adjusted for Severity of Illness

In multivariable analysis (Fig. 2), cumulative intake on day 7 was associated with increased mortality, while cumulative output and UOP were not. Higher cumulative balances on days 5 to 7 were associated with increased mortality (aOR, 1.34 per 100 mL/kg on day 5; 95% CI, 1.11–1.61). Higher cumulative intake and cumulative balance on days 4 to 7 were also associated with a lower likelihood of successful extubation (Fig. 3). Findings were consistent when analyzing complete cases (Supplementary Figs. 2 and 3, http://links.lww.com/PCC/B794), when analyzing combination output (Supplementary Fig. 4, http://links.lww.com/PCC/B794), and when adjusting for study year (Supplementary Fig. 5, http://links.lww.com/PCC/B794).

Figure 2.
Figure 2.:
Adjusted association (adjusted for oxygenation index, number of nonpulmonary organ failures, immunocompromised status, and vasopressor score) of the association between cumulative fluid intake, cumulative fluid output, cumulative urine output (UOP), and cumulative fluid balance with mortality over the first 7 d of ARDS (each day’s metrics adding upon the previous). Adjusted odds ratios are plotted per day and are scaled per increase in 100 mL/kg. Comparisons with statistical significance p value of less than 0.05 after Bonferroni correction (nominal p ≤ 0.007) are depicted with an asterisk. ARDS = acute respiratory distress syndrome.
Figure 3.
Figure 3.:
Adjusted association (adjusted for oxygenation index, number of nonpulmonary organ failures, immunocompromised status, and vasopressor score) of cumulative fluid intake, cumulative fluid output, cumulative urine output (UOP), and cumulative fluid balance with probability of extubation, given the competing risk of death, over the first 7 d of ARDS (each day’s metrics adding upon the previous). Adjusted subdistribution hazard ratios (SHRs) are plotted per day and are scaled per increase in 100 mL/kg. Adjusted SHR less than 1 implies slower extubation/fewer ventilator-free days. Comparisons with statistical significance p value of less than 0.05 after Bonferroni correction (nominal p ≤ 0.007) are depicted with an asterisk. ARDS = acute respiratory distress syndrome.

Analysis Stratified by ARDS Etiology

We assessed the daily association of cumulative balance with outcomes according to ARDS etiology (Supplementary Fig. 6, http://links.lww.com/PCC/B794). The association between cumulative fluid balance and mortality was driven by pneumonia, with increased mortality risk starting on day 5. By contrast, the association between cumulative balance and decreased probability of extubation was driven by nonpulmonary sepsis, with lower probability of extubation starting on day 4.

Analysis Stratified by Cause of Death

We assessed whether the etiology of death affected the temporal association of cumulative fluid balance with mortality (Supplementary Fig. 7, http://links.lww.com/PCC/B794). Subjects assigned MSOF as the primary cause of death demonstrated higher adjusted mortality risk for all 7 days, although statistical significance was only achieved after day 4. Subjects dying of hypoxemia or neurologic failure demonstrated a pattern of increased mortality more similar to the primary analysis, with increased cumulative fluid balance being associated with mortality after day 5; however, with the fewer number of deaths, results were not significant after Bonferroni correction.

Mediation Analysis

Given that cumulative fluid balance was associated with worse outcomes after day 4 of ARDS, we dichotomized early versus late fluid overload at day 4. We then tested whether early AKI or maximum vasopressor score by day 3 mediated the association between late (day 4 to 7) fluid overload greater than 10% and mortality (Supplementary Fig. 8, http://links.lww.com/PCC/B794). There was minimal evidence for mediation by either AKI (7% mediated) or vasopressor score (13% mediated), with most of the association between fluid overload and mortality representing a direct effect.

AT THE BEDSIDE

  • Later (after day 4 of ARDS onset) fluid overload, rather than earlier (first 3 d), has a greater association with increased PICU mortality and fewer VFDs.
  • Our longitudinal analysis provides a more complete picture of fluid overload in pediatric ARDS by providing granular daily analysis over the first 7 days in a large cohort, adjusting for confounders.
  • Our results provide guidance for the design of future trials of fluid management in pediatric ARDS and suggest that de-resuscitation strategies should be tested starting after day 4 of ARDS.

Angiopoietin-2 Predicts Fluid Overload

In the subset of patients in the biomarker study, we tested the association between angiopoietin-2 with subsequent greater than 10% fluid overload. Angiopoietin-2 on day 1 (n = 333) predicted early (first 3 d) fluid overload (Fig. 4), with an area under the receiver operating characteristic curve (AUROC) of 0.61 (95% CI, 0.55–0.67). Similarly, day 3 angiopoietin-2 levels (n = 266) predicted fluid overload on days 4 to 7, with an AUROC 0.62 (95% CI, 0.56–0.69).

Figure 4.
Figure 4.:
Comparison of plasma angiopoietin-2 (Ang-2) levels in subjects with and without fluid overload (FO) measured on day 1 and day 3 of illness. Early FO defined as greater than 100 mL/kg positive cumulative fluid balance on days 1–3 of illness, late FO defined as greater than 100 mL/kg positive cumulative fluid balance on days 4–7 of illness.

DISCUSSION

Increasing cumulative fluid balance after day 5 of ARDS was associated with mortality in pediatric ARDS, and increasing fluid intake and balance after day 4 was associated with decreased probability of extubation. There was no association between fluids and outcomes in the first 72 hours. Angiopoietin-2 predicted subsequent fluid overload on both day 1 and day 3 after ARDS onset. Our data suggest that positive fluid balance later in the illness time-course, rather than earlier, had greater association with outcomes. This association was not primarily mediated by AKI or shock. This suggests that future interventions aimed at managing fluid overload may have differential efficacy depending on when in the time-course of ARDS they are initiated.

It is neither surprising nor novel that fluid balance is associated with worse outcomes. In the Fluid and Catheter Treatment Trial (FACTT) of adult ARDS, patients given less fluid had more VFDs (7). Our results were consistent with this; however, as FACTT was a trial, it was better able to assign causality than our study. In prior pediatric cohorts, day 3 fluid balance was associated with fewer VFDs (9) and increased mortality (11). A reanalysis of 109 subjects from a calfactant trial confirmed this, with nonsurvivors having a higher fluid balance than survivors over the first 7 days (12). A more recent study found that an association between day 3 fluid balance and mortality in children with AKI (13). Lima et al (10) also observed increased mortality in critically ill children in whom fluid overload peaked between days 3 and 7 of PICU admission, confirming greater prognostic importance to later fluid overload.

The timing of this association between fluid overload and outcomes has not previously been as clearly delineated as in our study. Using the resuscitation, optimization, stabilization, and evacuation framework of fluid management (23), our study suggests ongoing fluid overload later in the illness (stabilization and evacuation phases) as having an important role in the association of fluid balance with outcomes. Angiopoietin-2, which increases endothelial permeability and fluid extravasation, suggests a mechanism for fluid accumulation (24). Thus, angiopoietin-2 is a useful marker to identify patients at risk for fluid overload and is potentially a therapeutic target.

Our study had limitations. It was a retrospective single center cohort, which limits generalizability, albeit similar to other single (25) and multicenter (2,3) cohorts. Fluid data were retrospectively collected; however, all other data were collected prospectively. Fluid management was not protocolized, and data on individual providers making fluid management decisions were not available, and management subject to practice variability. We did not collect longitudinal ventilator settings or metrics of oxygenation, which could inform the mechanism between fluid overload and probability of extubation. Confounders were chosen a priori based on plausibility and the analysis performed in a causal framework. Our primary exposures were continuous, precluding the use of other causal inference methods like propensity matching. However, logistic regression outperforms propensity scores when there are sufficient events and few confounders (26), as in this study. However, we acknowledge that alternative analyses of causal inference, including propensity scores, may give different answers than in our study. We are reassured that sensitivity analyses did not change our conclusions.

Finally, we only incompletely assessed the role of AKI in our study with mediation analysis; however, AKI remains a potential source of residual confounding. Both UOP and fluid balance were likely impacted by AKI, reflecting both illness severity and a mechanism contributing to fluid overload. Analysis of renal function as it relates to fluid overload and outcomes in pediatric ARDS is an important topic for future study, requiring dissection of the complex interplay between AKI, UOP, and fluid overload. We did not collect dosing of diuretics or CRRT, or disentangle the relationship between diuretic use, CRRT, UOP, fluid balance, and outcomes. Our focus was on the timing of the relationship between fluid metrics and outcome, rather than how these metrics were achieved, or the role of AKI in how this occurred. The contribution of mode of fluid removal on outcome deserves further study, since “how” fluid is removed may be as important as “when” fluid is removed.

CONCLUSIONS

We found no association between early fluid balance and outcomes in pediatric ARDS until after day 4 of illness, providing a nuanced perspective on how timing impacts the relationship between fluid overload and outcomes. Future studies should explicitly disentangle the differential roles of initial fluid resuscitation and subsequent fluid removal on outcome in pediatric ARDS, as well as clarify the optimal methods of de-resuscitation.

REFERENCES

1. Schouten LR, Veltkamp F, Bos AP, et al. Incidence and mortality of acute respiratory distress syndrome in children: A systematic review and meta-analysis. Crit Care Med. 2016; 44:819–829
2. López-Fernández Y, Azagra AM, de la Oliva P, et al.; Pediatric Acute Lung Injury Epidemiology and Natural History (PED-ALIEN) Network. Pediatric Acute Lung Injury Epidemiology and Natural History study: Incidence and outcome of the acute respiratory distress syndrome in children. Crit Care Med. 2012; 40:3238–3245
3. Khemani RG, Smith L, Lopez-Fernandez YM, et al.; Pediatric Acute Respiratory Distress syndrome Incidence and Epidemiology (PARDIE) Investigators; Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network. Paediatric acute respiratory distress syndrome incidence and epidemiology (PARDIE): An international, observational study. Lancet Respir Med. 2019; 7:115–128
4. Ingelse SA, Wösten-van Asperen RM, Lemson J, et al. Pediatric acute respiratory distress syndrome: Fluid management in the PICU. Front Pediatr. 2016; 4:21
5. Zinter MS, Spicer A, Orwoll BO, et al. Plasma angiopoietin-2 outperforms other markers of endothelial injury in prognosticating pediatric ARDS mortality. Am J Physiol Lung Cell Mol Physiol. 2016; 310:L224–L231
6. Yehya N, Thomas NJ, Meyer NJ, et al. Circulating markers of endothelial and alveolar epithelial dysfunction are associated with mortality in pediatric acute respiratory distress syndrome. Intensive Care Med. 2016; 42:1137–1145
7. The National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network. Comparison of two fluid-management strategies in acute lung injury. N Engl J Med. 2006; 354:2564–2575
8. Calfee CS, Gallagher D, Abbott J, et al.; NHLBI ARDS Network. Plasma angiopoietin-2 in clinical acute lung injury: Prognostic and pathogenetic significance. Crit Care Med. 2012; 40:1731–1737
9. Valentine SL, Sapru A, Higgerson RA, et al.; Pediatric Acute Lung Injury and Sepsis Investigator’s (PALISI) Network; Acute Respiratory Distress Syndrome Clinical Research Network (ARDSNet). Fluid balance in critically ill children with acute lung injury. Crit Care Med. 2012; 40:2883–2889
10. Lima L, Menon S, Goldstein S, et al. Timing of fluid overload and association with patient outcome. Pediatr Crit Care Med. 2021; 22:114–124
11. Flori HR, Church G, Liu KD, et al. Positive fluid balance is associated with higher mortality and prolonged mechanical ventilation in pediatric patients with acute lung injury. Crit Care Res Pract. 2011; 2011:854142
12. Willson DF, Thomas NJ, Tamburro R, et al.; Pediatric Acute Lung and Sepsis Investigators Network. The relationship of fluid administration to outcome in the pediatric calfactant in acute respiratory distress syndrome trial. Pediatr Crit Care Med. 2013; 14:666–672
13. Zinter MS, Spicer AC, Liu KD, et al. Positive cumulative fluid balance is associated with mortality in pediatric acute respiratory distress syndrome in the setting of acute kidney injury. Pediatr Crit Care Med. 2019; 20:323–331
14. Ranieri VM, Rubenfeld GD, Thompson BT, et al.; ARDS Definition Task Force. Acute respiratory distress syndrome: The Berlin definition. JAMA. 2012; 307:2526–2533
15. The Pediatric Acute Lung Injury Consensus Conference Group. Pediatric acute respiratory distress syndrome: Consensus recommendations from the Pediatric Acute Lung Injury Consensus Conference. Pediatr Crit Care Med. 2015; 16:428–439
16. Pollack MM, Patel KM, Ruttimann UE. PRISM III: An updated Pediatric Risk of Mortality score. Crit Care Med. 1996; 24:743–752
17. Gaies MG, Gurney JG, Yen AH, et al. Vasoactive-inotropic score as a predictor of morbidity and mortality in infants after cardiopulmonary bypass. Pediatr Crit Care Med. 2010; 11:234–238
18. Goldstein B, Giroir B, Randolph A; International Consensus Conference on Pediatric Sepsis. International pediatric sepsis consensus conference: Definitions for sepsis and organ dysfunction in pediatrics. Pediatr Crit Care Med. 2005; 6:2–8
19. Yehya N, Topjian AA, Thomas NJ, et al. Improved oxygenation 24 hours after transition to airway pressure release ventilation or high-frequency oscillatory ventilation accurately discriminates survival in immunocompromised pediatric patients with acute respiratory distress syndrome*. Pediatr Crit Care Med. 2014; 15:e147–e156
20. Yehya N, Keim G, Thomas NJ. Subtypes of pediatric acute respiratory distress syndrome have different predictors of mortality. Intensive Care Med. 2018; 44:1230–1239
21. Yehya N, Harhay MO, Klein MJ, et al.; Pediatric Acute Respiratory Distress Syndrome Incidence and Epidemiology (PARDIE) V1 Investigators and the Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network. Predicting mortality in children with pediatric acute respiratory distress syndrome: A pediatric acute respiratory distress syndrome incidence and epidemiology study. Crit Care Med. 2020; 48:e514–e522
22. Fine JP, Gray RJ. A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc. 1999; 94:496–509
23. Malbrain MLNG, Van Regenmortel N, Saugel B, et al. Principles of fluid management and stewardship in septic shock: It is time to consider the four D’s and the four phases of fluid therapy. Ann Intensive Care. 2018; 8:66
24. Augustin HG, Koh GY, Thurston G, et al. Control of vascular morphogenesis and homeostasis through the angiopoietin-Tie system. Nat Rev Mol Cell Biol. 2009; 10:165–177
25. Khemani RG, Rubin S, Belani S, et al. Pulse oximetry vs. PaO2 metrics in mechanically ventilated children: Berlin definition of ARDS and mortality risk. Intensive Care Med. 2015; 41:94–102
26. Cepeda MS, Boston R, Farrar JT, et al. Comparison of logistic regression versus propensity score when the number of events is low and there are multiple confounders. Am J Epidemiol. 2003; 158:280–287
Keywords:

acute respiratory distress syndrome; angiopoietin 2; fluid balance; fluid overload; pediatric acute respiratory distress syndrome; ventilator-free days

Supplemental Digital Content

Copyright © 2021 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies