Edited by: Silviu Grisaru, University of Calgary, Canada
Reviewed by: Tauqeer Hussain Mallhi, University of Science, Malaysia, Malaysia; Emily Lauren Joyce, Children's Hospital of Pittsburgh, School of Medicine, University of Pittsburgh, United States
This article was submitted to Pediatric Nephrology, a section of the journal Frontiers in Pediatrics
†These authors have contributed equally to this work.
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There are multiple reports of observational studies demonstrating a strong, independent association between fluid accumulation and poor clinical outcomes in children (
Similar results have been seen in adult studies. The multicentre Program to Improve Care for Acute Renal Disease study showed an association between mortality and >10% fluid accumulation at RRT initiation (
There have been multiple reports that fluid overload is associated with impaired organ function (
Identifying patients who are or are not at risk for severe and long lasting AKI in the pediatric ICU (PICU) is important for every PICU. An empiric clinical model of renal angina has been recently proposed to identify which critically ill patients would be at the greatest risk of AKI using patient demographic factors and early signs of injury, where presence of renal angina may delineate patients at higher risk for subsequent severe AKI (
In this prospective study, we investigated the association of fluid overload and oxygenation, and their correlation to duration of ventilation, ICU stay and mortality. We also assessed whether RAI using injury parameters (fall in creatinine clearance from baseline or increase in fluid overload or worse) can predict mortality and AKI on day 3.
This was a prospective observational study done in a PICU in a tertiary hospital from June 2013 to 2014.
All children (<18 years) who required invasive mechanical ventilation for >24 h and an indwelling arterial catheter were included in the study. Children with congenital heart disease or those who received RRT were excluded. We excluded congenital heart disease from the study, as the oxygenation index may not be truly reflective of the severity of illness, due to underlying complex cyanotic/acyanotic congenital heart disease. There are multiple studies showing association of fluid overload and worse outcomes in patients on RRT. However, there is lack of information on fluid overload in critically ill children, who are not on any form of RRT and their outcomes. Hence we specifically looked at this subset of patients.
Parental consent was taken from all children for enrolling in the study. The Institutional Review Board approved the study.
Basic clinical data, oxygenation index, fluid overload percent (daily, cumulative), RAI, and PRISM score at admission and pediatric logistic organ dysfunction (PELOD) score were obtained in all critically ill children. Admission data for determination of RAI included the use of vasopressors; invasive mechanical ventilation; percent fluid overload and change in kidney function (estimated creatinine clearance).
Percent FO on Day 0 was determined by assessing the first 8 h of admission in the ICU on Day 0.The time frame of 8 h was felt to be beyond the generally accepted window of “early goal-directed therapy” (EGDT) of resuscitation (
Continuous variables were reported as median with interquartile range and compared using the Mann–Whitney test. Categorical variables were summarized using frequency and proportion and compared by chi-square or Fisher's exact tests.
Peak FO% and peak OI were defined as the highest FO% and OI recorded during the study period, respectively. Stepwise multiple linear regression was used to evaluate the independent association between peak FO% and peak OI, controlling for confounders (
The association between these two measures were analyzed using multivariable analyses, controlling for confounders, such as age, gender, and admission PELOD score. The relationship between each study day's FO% and OI was done using repeated measures multivariable analyses, adjusting for the same potential confounders.
All patients were classified on Day 0 as fulfilling criteria for renal angina [i.e., being ANG(+) vs. ANG(–)] using the RAI. It has been previously shown by Basu et al., that An RAI score of >8 demonstrated the highest Youden's index and the highest negative predictive value and thus ANG(+) was defined as an RAI score >8 (
The primary outcome was the presence of severe AKI 72 h after PICU admission (Day-3 AKI), denoted as “subsequent severe AKI.”
An RAI cutoff of >8 was used to analyze the predictive performance of RAI (sensitivity, specificity, NPV, and PPV). Predictive performance of admission PRISM for AKI after 72 h was also tested. Multivariable regression was performed by comparing variables carrying univariable associations with the outcome and a
One hundred and two children met the inclusion criteria. Mean age was 6.5 ± 5.9 months, and 67% were males (Table
Descriptive statistics of study parameters and outcomes.
Mean age (months) ± SD | 6.5 ± 5.9 |
Males (%) | 69 (67.6%) |
Mean PELOD score ± SD | 14.38 ± 10.86 |
Mean maximum fluid overload (FO) ± SD | 8.7 ± 8.1 |
Mean maximum oxygenation index ± SD | 9.7 ± 10.8 |
Mean ICU stay (days) ± SD | 9.1 ± 8.1 |
Mean ventilation days ± SD | 5.72 ± 4.92 |
Mean hospital stay (days) ± SD | 12.9 ± 10.0 |
Mortality (%) | 23 (22.5%) |
Number of children reaching peak fluid overload on each day of ICU admission.
For all days of ICU observation, multivariable analysis was done to determine association of FO% and OI. On every day of PICU stay, FO% was associated with OI, independent of age, gender and PELOD score (Table
Fluid overload during admission and oxygenation index.
<5% | 4.77 (3.93–5.60) |
5–9.99% | 11.47 (4.22–18.72) |
10–14.99% | 19.50 (1.6–28.4) |
Dose response relationship between fluid overload and oxygenation index.
<5% | 0.29 | 0.15 |
5–9.99% | 0.2 | 0.07 |
10–14.99% | 0.31 | <0.01 |
>15% | 0.33 | <0.02 |
Maximum fluid overload and PELOD score as predictors of peak oxygenation index.
Maximum FO | |
PELOD |
Children who died had a higher admission PELOD score, higher peak FO% and maximum OI (Table
Mortality statistics of PICU patients.
Age (years) | 6.15 ± 5.50 | 7.26 ± 6.82 | 0.38 |
Ventilation (days) | 5.42 ± 3.62 | 6.5 ± 6.87 | 0.3 |
ICU stay (days) | 8.36 ± 4.79 | 10.72 ± 12.60 | 0.17 |
PELOD Score at admission | 12.50 ± 9.75 | 18.30 ± 12.10 | 0.01 |
Maximum FO % | 7.11 ± 5.43 | 12.19 ± 11.26 | 0.002 |
Maximum oxygenation index | 6.37 ± 5.12 | 16.83 ± 15.51 | 0.0001 |
Peak FO% was independently associated with mortality, controlled for age, PELOD score, and gender, even when the FO% was divided into groups 5–9.9%, 10–14.99% and >15%. At peak FO%>15%, the adjusted OR for mortality was 3.675 (95% CI 0.28–23.18;
Independent association of peak FO with mortality.
Peak FO% | <5% (Baseline/Constant) | ||
5–9.99% | 2.520 (1.80–7.92) | 0.011 | |
10–14.99% | 2.751 (1.32–15.66) | 0.041 | |
>15% | 3.675 (1.28–23.18) | 0.039 | |
Age groups | <1 year (Baseline/Constant) | ||
1–3 years | 0.173 (0.02–1.19) | 0.075 | |
3–12 years | 0.301 (0.06–1.50) | 0.144 | |
12–18 years | 1.471 (0.41–5.22) | 0.551 |
Peak FO was significantly associated with PELOD score at admission and ventilation days on both univariable analysis (Table
Association of peak fluid overload and clinical parameters.
Age (years) | −0.234 (0.049 to 0.031) | 0.082 |
Sex | −0.732 (−4.00 to 2.54) | 0.658 |
PELOD Score at admission | 0.219 (0.075 to 0.36) | 0.003 |
Ventilation (days) | 0.342 (0.17 to 0.85) | 0.0388 |
ICU (days) | −0.029 (−0.46 to 0.40) | 0.896 |
Hospital stay (days) | 0.148 (−0.088 to 0.38) | 0.215 |
Thirty-eight children had RAI > 8 at admission (37.2%). Thirty-three children had AKI on day 3 of admission (32.3%). Discrimination of RAI by fluid overload was found to be superior than RAI calculated by change in creatinine clearance or when worse parameter was taken into consideration (Table
Value of renal angina index to predict AKI and mortality.
Renal Angina Index ≤8, |
38 (37.2%) |
AKI by Day 3, |
33 (32.3%) |
Sensitivity to predict Day 3 AKI, % (95% CI) | 81.8 (67–91.9) |
Specificity to predict Day 3 AKI, % (95% CI) | 69.6 (62.5–74.4) |
PPV to predict Day 3 AKI, % (95% CI) | 56.3 (46.1–63.2) |
NPV to predict Day 3 AKI, % (95% CI) | 88.9 (79.8–95.0) |
AUC for any RAI, % (95% CI) | 0.73 (0.61–0.82) |
AUC, RAI as change CrCl, % (95% CI) | 0.62 (0.57–72) |
AUC, RAI as Fluid overload, % (95% CI) | 0.78 (0.59–0.88) |
AUC, PRISM, % (95% CI) | 0.66 (0.61–0.73) |
In this prospective study, we looked at fluid overload and oxygenation status in children, and also correlations of RAI. Previous studies done by Ayse et al. (retrospective chart review of 80 patients) (
Our study showed that fluid overload occurs early during the ICU stay and is detrimental to oxygenation, ventilation and overall outcome of critically ill children. Peak fluid overload and daily cumulative fluid overload positively correlated with oxygenation index, and the strength of association increased with increasing fluid overload.
A similar pattern of early occurrence of fluid overload was shown by Ayse et al. in a retrospective chart review of 80 patients(
In our study, fluid overload and PELOD scores determined oxygenation indices of the patients. ICU survivors had a low PELOD score at admission, were less fluid overloaded, and had a low oxygenation index, which was statistically significant. However, Ayse et al. could only show less fluid overload in the survivors in their retrospective review.
Fluid overloaded children were sick as per the daily PELOD scores and required more ventilation. Fluid overload was an independent predictor of mortality, and with increasing fluid overload, the adjusted odds ratio increased. Children who were more than 15% overloaded had higher odds of mortality. Thus the goal of >15% in critically sick children in ICU to start contemplating about decongestive therapy could be taken by the treating physician. The current guidelines for management of septic shock in children call for intervention for fluid removal beyond 10% fluid overload with diuretics or intra- or extracorporeal RRTs (
One of the strengths of the present study is the increased prevalence of nervous system (27.5%), hepatic (23.5%), and septic (15.7%) dysfunction in the prospective cohort. This is unlike Ayse et al. study where primary respiratory diagnosis was seen in 62.5% (
Our study shows that the RAI is better than conventional PRISM scoring for predicting AKI on day 3 of admission. The prediction when RAI was calculated as per fluid overload was better than when calculated as per change in creatinine. Basu et al. have showed this in a previous cohort study (
The negative predictive value of 89% in our study population indicates that Day 0 ANG(–) patients have a very low likelihood of having a AKI or prolonged oliguria on Day 3 of ICU stay. This data may suggest that AKI biomarkers should not be obtained to predict AKI in Day 0 ANG(–) children, given the chances of Day-3 AKI, and will be worthwhile for clinicians taking care of critically sick children.
The RAI is easy to perform and can be done at bedside in the PICU. Identification of patients at a higher AKI risk using RAI stratification could theoretically guide the enrollment for a novel AKI biomarker or therapy trial, which could ultimately guide treatment strategy (
A limitation of our study is that serum creatinine was not corrected as per the fluid overload status of the child, and hence maybe more children have AKI, and missed due to the fluid imbalance. Future studies may help delineate whether FO truly is a causative factor in oxygenation failure and outcome. A daily bedside assessment of fluid balance should now be taken as a vital parameter.
This study emphasizes that positive fluid balance adversely affects the ICU course in critically ill children. The RAI prediction model may further help optimize treatment and predict AKI.
This study was carried out in accordance with the recommendations of IRB committee, at Medanta with written informed consent from all subjects. All subjects gave written informed consent in accordance with the Declaration of Helsinki. The protocol was approved by the IRB Committee, Medanta, The Medicity.
All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
This study was presented as an Oral paper at the 12th Asian Congress of Pediatric Nephrology, New Delhi, December 2014, and won the best prize.