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Positive Cumulative Fluid Balance Is Associated With Mortality in Pediatric Acute Respiratory Distress Syndrome in the Setting of Acute Kidney Injury

Zinter, Matt S., MD1; Spicer, Aaron C., MD, MAS2; Liu, Kathleen D., MD, PhD, MAS3; Orwoll, Benjamin E., MD4; Alkhouli, Mustafa F., BA1; Brakeman, Paul R., MD5; Calfee, Carolyn S., MD, MAS3; Matthay, Michael A., MD3; Sapru, Anil, MD, MAS1,6

Pediatric Critical Care Medicine: April 2019 - Volume 20 - Issue 4 - p 323–331
doi: 10.1097/PCC.0000000000001845
Renal Critical Care
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Objectives: As acute kidney injury and elevated cumulative fluid balance commonly co-occur in pediatric acute respiratory distress syndrome, we aimed to identify risk factors for their development and evaluate their independent relationships with mortality. We hypothesized that acute kidney injury and elevated cumulative fluid balance would be associated with markers of inflammation and that children with elevated cumulative fluid balance and concomitant acute kidney injury would have worse outcomes than other children.

Design: Prospective observational study using the pediatric Risk, Injury, Failure, Loss, End-Stage acute kidney injury classification.

Setting: Five academic PICUs.

Patients: Two-hundred sixty patients 1 month to 18 years old meeting the Berlin definition of acute respiratory distress syndrome between 2008 and 2014.

Interventions: None.

Measurements and Results: PICU mortality was 13% (34/260). Relative to survivors, nonsurvivors had greater cumulative fluid balance on day 3 of acute respiratory distress syndrome (+90.1 mL/kg; interquartile range 26.6–161.7 vs +44.9 mL/kg; interquartile range 10.0–111.3; p = 0.008) and also had higher prevalence of acute kidney injury on day 3 of acute respiratory distress syndrome (50% vs 23%; p = 0.001). On stratified analysis, greater cumulative fluid balance on day 3 of acute respiratory distress syndrome was associated with mortality among patients with concomitant acute kidney injury (+111.5 mL/kg for nonsurvivors; interquartile range 82.6–236.8 vs +58.5 mL/kg for survivors; interquartile range 0.9–176.2; p = 0.041) but not among patients without acute kidney injury (p = 0.308). The presence of acute kidney injury on acute respiratory distress syndrome day 3 was associated with mortality among patients with positive cumulative fluid balance (29.1% vs 10.4% mortality; p = 0.001) but not among patients with even or negative cumulative fluid balance (p = 0.430). Day 1 plasma interleukin-6 levels were associated with the development of day 3 positive cumulative fluid balance, day 3 acute kidney injury, and PICU mortality and the association between elevated day 1 interleukin-6 and PICU mortality was partially mediated by the interval development of day 3 positive cumulative fluid balance and day 3 acute kidney injury (p < 0.001).

Conclusions: In pediatric acute respiratory distress syndrome, elevated cumulative fluid balance on day 3 of acute respiratory distress syndrome is associated with mortality specifically in patients with concomitant acute kidney injury. Plasma interleukin-6 levels are associated with the development of positive cumulative fluid balance and acute kidney injury, suggesting a potential mechanism by which inflammation might predispose to mortality.

1Division of Critical Care, Department of Pediatrics, Benioff Children’s Hospital, University of California, San Francisco, San Francisco, CA.

2Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, MA.

3Departments of Anesthesia and Medicine, Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA.

4Division of Critical Care, Department of Pediatrics, Doernbecher Children’s Hospital, Oregon Health & Science University, Portland, OR.

5Department of Pediatrics, Division of Nephrology, University of California, San Francisco Benioff Children’s Hospital, San Francisco, CA.

6Department of Pediatrics, Division of Critical Care, Mattel Children’s Hospital, University of California, Los Angeles, CA.

Drs. Zinter and Spicer have shared first authorship.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/pccmjournal).

Supported, in part, by grant from National Institute of Child Health and Development (NICHD) K12HD000850 (to Dr. Zinter), NICHD T32HD049303 (to Dr. Spicer), National Institute of Diabetes and Digestive and Kidney Diseases R01DK098233 and R01DK101507 (to Dr. Liu), National Heart, Lung and Blood Institute (NHLBI) R01HL110969 (to Dr. Calfee), NHLBI R37HL051856 and U01HL108713 (to Dr. Matthay), and NHLBI K23 HL085526 and R01HL114484 (to Dr. Sapru).

Dr. Zinter’s institution received funding from the National Institutes of Health (NIH) (K12 training grant). Dr. Spicer’s institution received funding from NIH (T32 training grant), and he received funding from American Academy of Pediatrics (best abstract award). Dr. Liu received funding from Potrero Medical, Quark, Theravance, National Policy Forum on Critical Care and Acute Renal Failure (funding for travel), National Kidney Foundation (Advances in Chronic Kidney Disease Associate Editor), American Society of Nephrology (funding for travel), Abbott (gift of reagents), CMIC, Inc. (gift of reagents), Amgen (stockholder), ZS Pharma (Advisory Board participant), and Durect (consultant). She received other funding from Astute (adjudicated outcomes for clinical trials), Achaogen (consultant), and the NIH/National Heart, Lung and Blood Institute (NHLBI) (Grant Awardee). Dr. Calfee’s institution received funding from GlaxoSmithKline and Bayer, and she received funding from GlaxoSmithKline, Bayer (consulting), and Boehringer Ingelheim (consulting). Dr. Matthay’s institution received funding from the NHLBI, Amgen, GlaxoSmithKline, and Bayer Pharmaceuticals (acute respiratory distress syndrome [ARDS] observational study), and he received other funding from the Department of Defense for supporting a clinical trial of ARDS and Roche-Genentec (Chair of Data Safety and Monitoring Board for asthma trials). Dr. Sapru’s institution received funding from the NIH, National Institute for Child Health and Human Development, and the NHLBI. Drs. Zinter, Spicer, Liu, Calfee, Matthay, and Sapru received support for article research from the NIH. The remaining authors have disclosed that they do not have any potential conflicts of interest.

For information regarding this article, E-mail: anilsapru@ucla.edu

Pediatric acute respiratory distress syndrome (ARDS) has been associated with mortality in 15–20% of children (1). The hallmark of ARDS is noncardiogenic pulmonary edema accompanied by inflammation and increased circulating levels of cytokines such as interleukin (IL)–6 (2 , 3). The severity of pulmonary edema, as quantified by chest radiography, chest ultrasonography, or transpulmonary thermodilution, is strongly associated with poor pulmonary compliance, oxygenation defects, duration of mechanical ventilation, and mortality (4–7). In ARDS, elevated cumulative fluid balance (CFB) has been associated with severity of ARDS, presumably by worsening pulmonary edema, and has also been associated with duration of mechanical ventilation and mortality (8–13). Efforts to minimize pulmonary edema through conservative fluid management have been associated with decreased duration of mechanical ventilation and ICU length of stay in both children and adults and have therefore gained acceptance as an important therapeutic strategy in ARDS (14 , 15).

The associations between ARDS mortality and excess CFB may be complicated by acute kidney injury (AKI). AKI frequently coexists with ARDS and is itself associated with elevated mortality, although the mechanisms of this relationship are unclear. Decreased urine output (UOP) in AKI may contribute to increasing mortality by increasing CFB and thus increasing pulmonary edema (8 , 16). However, AKI occurs in the setting of increased vascular permeability, likely caused by elevated levels of inflammatory mediators such as IL-6 (17–20). AKI may therefore be an independent marker of increased vascular permeability, which in itself is associated with both elevated CFB and mortality in ARDS (21–23).

We therefore hypothesized that in a large cohort of children with ARDS, elevated CFB and AKI would each be associated with mortality and that patients with both elevated CFB and AKI might have particularly poor outcomes. We further hypothesized that elevations in IL-6 on day 1 of ARDS would be associated with the development of positive CFB and AKI on day 3 of ARDS, thus providing a potential mechanism by which early elevations in IL-6 might influence ARDS mortality.

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MATERIALS AND METHODS

Setting and Patients

As previously described (24), subjects were prospectively enrolled in a longitudinal study to evaluate ARDS clinical risk factors and biomarkers between September 2008 and September 2014 in five academic PICUs: University of California, San Francisco Benioff Children’s Hospitals in San Francisco and Oakland; Children’s Hospital Los Angeles; Children’s Hospital Central California; and American Family Children’s Hospital. Children were screened for eligibility if they were receiving any noninvasive or invasive positive pressure support and were eligible if they met the Berlin criteria for ARDS (25), with chest radiograph interpretation performed by site investigators (this study predated the development of Pediatric Acute Lung Injury Consensus Conference ARDS definitions). Patients were excluded from the cohort if they were less than 1 month old, less than 36 weeks corrected gestational age, greater than 18 years old, had a documented do not resuscitate or do not intubate order at the time of screening, or had been enrolled in the cohort previously. Data were recorded daily at 8:00 AM until the subject left intensive care. Cohort subjects were included in this study if height, weight, and fluid balance data were recorded. Management strategies, including ventilator management, fluid management, and other management, were not standardized across centers.

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Design and Data Collection

The primary outcome was PICU mortality, defined as death prior to discharge from the PICU. The primary predictors were CFB and AKI. “CFB”: CFB was defined as any fluid output (including but not limited to urine, chest tube, peritoneal tube, and gastrointestinal losses) subtracted from net fluid intake (including intravascular and enteral), calculated from the time ARDS criteria were met through the first, second, and third day after ARDS onset. CFB accumulated prior to the diagnosis of ARDS was not recorded. CFB was normalized to weight at ARDS onset (mL/kg), and a sensitivity analysis was performed with CFB normalized to body surface area (mL/m2) in order to account for possible preexisting fluid retention at the time of ARDS diagnosis. CFB was examined as a continuous variable and then patients with CFB of less than 0, 0 to +100, +100 to +200, and greater than +200 mL/kg were categorized as having negative fluid balance, and 0–10%, 10–20%, or greater than 20% fluid overload (FO), respectively. “AKI”: AKI was defined according to the pediatric Risk, Injury, Failure, Loss, End-Stage (pRIFLE) criteria, which incorporate estimated creatinine clearance (eCCl) derived from the Schwartz equation (26), oliguria calculated from average UOP over 24 hours, and use of renal replacement therapy (RRT), including intermittent or continuous venous or peritoneal dialysis, filtration, or diafiltration (27). Kidney injury according to pRIFLE was classified as “none” (eCCl > 75% of baseline, UOP > 0.5 mL/kg/hr, and no use of RRT), “risk” (eCCL within 50–75% of baseline, UOP > 0.5 mL/kg/hr, and no use of RRT), “injury” (eCCL within 35–50% of baseline or UOP < 0.5 mL/kg/hr but did not use RRT), or “failure” (eCCL < 35% of baseline or UOP < 0.3 mL/kg/hr or used RRT). Patient with pRIFLE classification of injury or failure were considered to have AKI. As baseline serum creatinine was not available, we assumed a baseline eCCl of 120 mL/min/1.73 m2 and performed a sensitivity analysis using an alternate baseline eCCL of 100 mL/min/1.73 m2 (28). To account for a potential underestimation of AKI due to a dilution of plasma creatinine by intravascular hypervolemia, we performed an additional sensitivity analysis using creatinine values adjusted for positive fluid balance (29 , 30).

We evaluated the following a priori selected variables for a potential confounding association with PICU mortality: age, sex, race, ethnicity, route of nutrition (none vs parenteral vs enteral), lung injury etiology, preexisting medical conditions including cancer and/or hematopoietic cell transplant (HCT), the Pediatric Risk of Mortality (PRISM) III raw score (31), the worst PaO2/FIO2 ratio on day 1, and the day 1 plasma IL-6 level. As previously reported, plasma IL-6 levels were measured with a Luminex multiplex enzyme-linked immunosorbent assay immunoassay (Myriad RBM, Austin, TX) (3).

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Statistical Analysis

We evaluated the association between CFB and mortality with the nonparametric Mann-Whitney U test and logistic regression and evaluated the association between AKI and mortality with the chi-square test and logistic regression. We evaluated for significant interactions between AKI and CFB quartile with respect to their associations with mortality using a threshold p value of 0.1. We tested whether AKI and CFB mediated the association between day 1 IL-6 and mortality using a binary mediation analysis of direct and indirect effects, with 95% CI estimated using 500 bootstrapped calculations (32). IL-6 levels were log10-transformed to achieve normal distribution prior to conducting any parametric tests. All analyses were performed using STATA, Version 13.1 (StataCorp, College Station, TX).

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RESULTS

Total pediatric enrollment during the study period was 305 subjects; after exclusion of 45 subjects due to missing height, weight or daily fluid balance, the final cohort included 260 children. There were no statistically significant differences in age, sex, PaO2/FIO2 ratio, PRISM III score, and mortality between included and excluded subjects. Clinical characteristics of included patients are shown in Table 1. Thirty-four children (13.4%) died in the PICU, with deaths occurring between 3 and 109 days after ARDS onset. Nutrition practices are described in Figure E1 (Supplemental Digital Content 1, http://links.lww.com/PCC/A854) and were not associated with mortality (Table E1, Supplemental Digital Content 2, http://links.lww.com/PCC/A855).

TABLE 1

TABLE 1

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Elevated CFB Is Associated With PICU Mortality

The median CFB at the end of ARDS days 1, 2, and 3 were +26.8 mL/kg (interquartile range [IQR], 4.0–58.7 mL/kg), +47.7 mL/kg (IQR, 4.1–101.7 mL/kg), and +48.6 mL/kg (IQR, 11.3–116.3 mL/kg). Relative to survivors, nonsurvivors had similar CFB at the end of ARDS day 1, trended toward greater CFB at the end of ARDS day 2, and had significantly greater CFB at the end of ARDS day 3 (Table 2). These results were similar when calculating CFB using mL/m2 rather than mL/kg. There was a significant linear association between greater CFB on ARDS day 3 and PICU death (odds ratio [OR] 1.10 for each additional +20 mL/kg; 95% CI, 1.04–1.16; p = 0.001) (Fig. E2, Supplemental Digital Content 3, http://links.lww.com/PCC/A856). This association was robust to adjustment for day 1 PaO2/FIO2 ratio and cancer/HCT status and clustering patients according to PICU site (adjusted OR, 1.09; 95% CI, 1.02–1.16; p = 0.012). Interestingly, there was only a weak association between day 3 CFB and day 3 PaO2/FIO2 ratio (Spearman ρ = –0.168; p = 0.011). Increasing FO as determined by a priori selected categories was also associated with PICU mortality (Fig. 1). Younger age and greater day 1 plasma IL-6 level were each associated with greater day 3 CFB (Spearman ρ = –0.37; p < 0.001 and Spearman ρ = 0.23; p < 0.001, respectively).

TABLE 2

TABLE 2

Figure 1

Figure 1

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AKI Is Associated With PICU Mortality

Rates of AKI on ARDS days 1, 2, and 3 were 25.1%, 27.8%, and 26.2%. On ARDS day 3, the majority of patients qualified for a diagnosis of AKI based on decreased eCCl alone (39/68), whereas an additional 29 of 68 patients had oliguria or used of RRT (Fig. 2). Relative to survivors, nonsurvivors had similar rates of AKI on ARDS day 1 but significantly greater rates on ARDS days 2 and 3 (Table 2). Increasing pRIFLE severity was associated with increasing mortality with the notable exception that on ARDS day 1, patients with pRIFLE risk demonstrated higher mortality than those with already existing injury or failure (Fig. 3). The prevalence of AKI was slightly less if a baseline eCCl of 100 mL/min/1.73 m2 rather than 120 mL/min/1.73 m2 was assumed, and the prevalence of AKI was slightly greater if the creatinine values were adjusted based on the assumption of plasma dilution in patients with FO (Table E2, Supplemental Digital Content 4, http://links.lww.com/PCC/A857). However, the associations between AKI and mortality remained significant, suggesting validity of the original classification approach. AKI on day 3 was strongly associated with PICU mortality (OR, 3.4; 95% CI, 1.6–7.2; p = 0.001) and this finding was independent of the day 1 PaO2/FIO2 ratio, cancer/HCT status, and clustering by site (adjusted OR, 3.8; 95% CI, 1.6–9.2; p = 0.003). History of cancer/HCT and IL-6 level on day 1 were both associated with the development of AKI on ARDS day 3 (OR, 3.4; 95% CI, 1.7–6.8; p < 0.001 if cancer/HCT present and OR, 2.1; 95% CI, 1.4–3.1; p < 0.001 per log10 IL-6, respectively).

Figure 2

Figure 2

Figure 3

Figure 3

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Stratified Analyses

A logistic regression model demonstrated that both day 3 AKI and day 3 CFB were independently associated with PICU mortality with adjustment for cancer/HCT, day 1 PaO2/FIO2 ratio, and clustering by site (AKI OR, 2.1; 95% CI, 1.3–3.3; p = 0.002 and CFB OR 1.06 per each +20 mL/kg; 95% CI, 1.02–1.09; p = 0.001). To test for an association between day 3 CFB and day 3 AKI, we noted that day 3 CFB was significantly higher in the presence of AKI (+82.3 mL/kg; IQR 11.2–182.5 vs +44.9 mL/kg; IQR 11.6–100.3; p = 0.013). Relative to patients without AKI on day 3, patients with AKI on day 3 had greater net fluid intake (+109.9 mL/kg; IQR 770.3–16.2 vs +93.7 mL/kg; IQR 61.0–118.7; p = 0.010) but similar net fluid output (–80.7 mL/kg; IQR 39.9–134.5 vs –80.9 mL/kg; IQR 55.9–117.4; p = 0.972). Given the strong associations between CFB and mortality as well as between AKI and mortality, we tested for an interaction between CFB and AKI with respect to their associations with mortality. There was a strong statistical interaction between day 3 CFB and day 3 AKI with respect to mortality in a logistic model (p = 0.001), and therefore, we stratified further analyses based on presence or absence of AKI. Among patients with day 3 AKI (n = 68), day 3 CFB was significantly greater for nonsurvivors than survivors (+111.5 mL/kg; IQR 82.6–236.8 vs +58.5 mL/kg; IQR 0.9–176.2; p = 0.041) (Fig. 4). The presence of any positive day 3 CFB was associated with mortality (29.1% mortality if positive CFB vs 10.4% if even or negative CFB; p = 0.001), and each additional +20 mL/kg of CFB was associated with an 8% increase in the odds of mortality (OR, 1.08; 95% CI, 1.01–1.17; p = 0.032). In contrast, among patients without day 3 AKI (n = 192), day 3 CFB was similar among nonsurvivors and survivors (+60.1 mL/kg; IQR 18.4–134.4 vs +43.0 mL/kg; IQR 11.6–96.1; p = 0.308). The presence of positive day 3 CFB was not associated with mortality (7.7% mortality if positive CFB vs 2.7% if even or negative CFB; p = 0.430), and there was no linear relationship between mortality and each additional +20 mL/kg of CFB (p = 0.252).

Figure 4

Figure 4

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Day 1 IL-6 Levels Are Associated With CFB, AKI, and Mortality

IL-6 levels were measured on day 1 in 186 patients (n = 74 patients had insufficient study plasma for IL-6 measurement). There were no statistically significant differences in age, gender, day 1 PaO2/FIO2 ratio, PRISM III score, and mortality between subjects with and without measured IL-6; however, Caucasian race was overrepresented in the group with IL-6 levels. Day 1 IL-6 was strongly associated with PICU mortality (OR 2.2 per log10 increase in IL-6; 95% CI, 1.3–3.5; p = 0.002). On univariate regression, elevated plasma IL-6 on ARDS day 1 was associated with the development of AKI on ARDS day 3 (OR 2.1 per log10 increase in IL-6; 95% CI, 1.4–4.1; p < 0.001) and was also associated with greater positive CFB on ARDS day 3 (+37 mL/kg per log10 increase in IL-6; 95% CI, 20–54; p < 0.001). On mediation analysis, 33.1% of the association between day 1 IL-6 and ICU mortality was mediated by the combination of day 3 AKI and day 3 positive CFB (95% CI, 14.8–51.5%; p< 0.001) (Fig. 5).

Figure 5

Figure 5

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DISCUSSION

In this study, we found that both CFB and AKI are associated with mortality in children with ARDS. There is a statistically significant interaction between elevated CFB and AKI with respect to their association with mortality, such that positive CFB is “most harmful” amongst children with AKI and appears less harmful in the absence of AKI. Further, day 1 plasma IL-6 levels are associated with the development of day 3 AKI, day 3 positive CFB, and PICU mortality and the association between day 1 plasma IL-6 and PICU mortality appears to be partially mediated by the development of day 3 AKI and positive CFB.

Our finding that elevated CFB is associated with PICU mortality adds to the growing body of work associating FO with poor clinical outcomes in pediatric acute lung injury, sepsis, and renal failure (9–11 , 13 , 33 , 34). We confirmed work associating severe FO (>20%) with mortality and also demonstrated a near-linear relationship between incremental increases in positive CFB and mortality even among patients with less than 10% FO. Although the direct mechanisms by which excess CFB might increase mortality risk are unknown, we speculate that due to increase pulmonary capillary permeability, ARDS patients are likely to be sensitive to CFB-induced changes in hydrostatic pressure, resulting in worsened pulmonary edema, escalating mechanical ventilation needs, and subsequent atelectotrauma, barotrauma, and volutrauma (23 , 35). Others have proposed that FO may increase atrial natriuretic peptide secretion, impair the endothelial glycocalyx, and worsen microvascular perfusion (36–40).

Our finding that excess CFB is associated with PICU mortality specifically among patients with AKI is novel as it suggests that appropriate renal clearance might mitigate the deleterious state of FO even prior to reestablishing a euvolemic state. We speculate this may be due to improved solute clearance and improved homeostasis of renal hormone signaling, although we were not able to test these hypotheses in this study (41). As 50% of nonsurvivors had AKI by ARDS day 3, this study adds to a growing list of investigations demonstrating an association between AKI and PICU mortality (27 , 42–44). In 2008, Zappitelli et al (28) demonstrated that the prevalence of and mortality rates associated with AKI vary according to underlying assumptions about baseline renal function. In our study, AKI was less prevalent when assuming a baseline eCCL of 100 mL/min/1.73 m2 rather than 120 mL/min/1.73 m2 and was more prevalent when adjusting serum creatinine levels for hemodilution due to FO; however, associations between AKI and mortality remained significant despite varying definitions.

Although this study strongly implicates excess CFB and AKI with mortality, it does not provide evidence that minimizing excess CFB through either conservative fluid administration, increased diuresis, or diafiltration can improve clinical outcomes. However, a recent report by Díaz et al (15) demonstrated that a bundle to reduce exogenous fluid administration was associated with decreased length of mechanical ventilation and a shorter PICU length of stay. Similarly, in adults, the Fluid and Catheter Treatment Trial and other studies have demonstrated that a conservative fluid administration strategy is associated with decreased length of mechanical ventilation (14 , 45). Although no interventional studies of conservative versus liberal fluid administration or removal in pediatric patients have been performed, data do support that greater FO at the onset of RRT therapy is associated with mortality (8 , 46–48). Interestingly, we found that on day 3 of ARDS, patients with AKI had significantly greater net fluid intake but similar net fluid output. Ultimately, a prospective randomized controlled trial is required to assess whether modulation of CFB in ARDS patients with AKI might be associated with improved survival.

Given our previous work associating elevated day 1 IL-6 with PICU mortality in ARDS (3), and the established literature associating elevated IL-6 with the development of AKI (17–20), a primary aim of this study was to establish whether elevated day 1 IL-6 could be associated with AKI and positive CFB in ARDS. In this cohort, elevated day 1 IL-6 was associated both with the development of day 3 AKI and with the development of day 3 positive CFB, and the development of these interim complications appeared to mediate a portion of the association between day 1 IL-6 and PICU mortality. Recently, Famous et al (49) demonstrated that adult ARDS patients with a hyper-inflamed endotype characterized by elevated IL-6 displayed significant markers of renal injury and showed more favorable response to fluid conservative therapy (50). Together, these data suggest that children with ARDS and early elevations in IL-6 are at increased risk for renal injury and might be an ideal subpopulation for a future interventional trial aimed at reducing FO in ARDS.

Our study has several strengths. Specifically, this is a novel analysis with biological plausibility undertaken in a large, multicenter, prospectively enrolled cohort with broad inclusion criteria. Second, the inclusion of children with a history of cancer/HCT in our cohort enabled study of the population at highest risk of ARDS mortality (51 , 52). Prior work in this population has demonstrated the increased mortality risk with FO in the setting of AKI, and although these prior analyses did not specifically evaluate ARDS patients, they indirectly support our hypothesis that early fluid conservative management may be most effective in children with AKI (53). Third, we addressed the classification of CFB and AKI using several sensitivity analyses to confirm internal validity of our results.

Our study does have limitations. First, as we did not have access to baseline renal function data, we may have misclassified some patients with nondialysis-dependent chronic kidney disease as having AKI. However, chronic kidney disease is rare in children, with a prevalence of 75 or fewer cases per million age-related population (54), and whether acute versus chronic renal injury differentially affect pediatric ARDS pathobiology and outcomes is currently unknown. Second, actual AKI likely predates the date of assignment in our study, as rises in serum creatinine are known to lag behind actual injury. Third, CFB was not assessed prior to the onset of ARDS, and therefore this study could not assess whether elevated CFB can prognosticate the development of ARDS in high-risk cohorts, or whether elevated CFB prior to ARDS onset might be associated with downstream clinical outcomes such as mortality and ventilator-free days. As our study remains observational in nature, a prospective trial of a conservative versus liberal fluid management in pediatric ARDS patients with or at high risk for AKI, perhaps including measurement of IL-6, could determine the safety and potential therapeutic value of reducing CFB.

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CONCLUSIONS

In summary, the combination of elevated CFB and AKI on the third day after ARDS onset was associated with higher mortality in a cohort of 260 children with ARDS. Elevated CFB and AKI were each associated with mortality, and patients with both elevated CFB and AKI were most at risk. Day 1 IL-6 levels are associated with the development of elevated CFB and AKI on day 3. These findings suggest that patients with both ARDS and AKI are most at risk from deleterious effects of FO and may benefit more than other ARDS patients from careful fluid management.

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ACKNOWLEDGMENTS

We would like to thank our patients and their families for participating in this research. We also would like to thank Heidi Flori, MD; Robinder Khemani, MD; Ana Graciano, MD; and Juan Boriosi, MD for their assistance recruiting patients for this study.

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Keywords:

acute kidney injury; acute lung injury; acute respiratory distress syndrome; interleukin-6; pediatric intensive care unit

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