SCCM Resource Library-Fluid Overload Confounds Creatinine-Based Definitions of Acute Kidney Injury in Pediatric ARDS

Video Transcription

Hello, my name is Celeste Dixon, and I'm a Pediatric Critical Care Fellow at Children's National Hospital in Washington, D.C.  I will be presenting results from our study of the effect of fluid overload on the diagnosis of acute kidney injury in pediatric acute respiratory distress syndrome.  I would also like to acknowledge the significant collaboration and contributions of my co-authors,  Dr. Samir Thadani and Dr. Issa Akan-Erakan at Baylor-Texas Children's Hospital, and Dr. Julie Fitzgerald and Dr. Nader Yahya at the Children's Hospital of Philadelphia.  This is me, and I have nothing to disclose. We know that acute kidney injury is associated with higher mortality and worse outcomes across the board in critically ill children.  Fluid overload is one of the most common consequences of AKI. Fluid overload specifically has been associated with worse outcomes in pediatric ARDS.  In our previous analysis of the ARDS cohort used in this study, we demonstrated that fluid  overload later in the ARDS time course, that is on and after day four of illness, is associated  with worse outcomes, including higher mortality and fewer ventilator-free days than early fluid overload.  Our current definitions of AKI rely on urine output and serum creatinine, which risks missing the diagnosis of AKI in some patients.  Fluid overload increases the volume of distribution of creatinine, so failing to adjust for fluid overload when measuring creatinine will underestimate creatinine levels.  There have been studies in both adult populations and in neonatal cardiac patients which demonstrate  that adjusting creatinine for fluid overload finds patients with significant elevation in creatinine that would otherwise be missed.  With that in mind, we set out with two primary aims for this study. First, to determine the relationship between the timing of AKI and outcomes in pediatric ARDS.  We know from our previous work that fluid overload after day four of ARDS is associated with worse outcomes than fluid overload before day four, so we sought to determine if the  timing of the onset of AKI in the ARDS illness course similarly impacted outcomes. Our second aim was to assess if concurrent fluid overload impacted the diagnosis of AKI  in this population through the use of fluid overload-adjusted creatinine. To briefly discuss our study design.  This cohort was initially collected for a parent study assessing risk factors and outcomes of pediatric ARDS.  Our patients came from a single large quaternary care pediatric hospital. Patients less than 18 years of age admitted to the PICU between 2011 and 2019 with a diagnosis  of ARDS were included. ARDS was defined as two consecutive PF ratios less than or equal to 300, separated by at least one hour.  This cohort was initiated prior to the adoption of the Berlin or Polisi definitions, but all but one subject met these definitions as well.  Patients with previously diagnosed chronic kidney disease were excluded. Patient demographics, severity of illness markers, including prism and vasopressor scores,  initial ventilator requirements, extra pulmonary organ failure, and outcomes including mortality and ventilator days were prospectively collected.  We retrospectively collected daily fluid metrics, daily creatinine, and use of CRRT during the first seven days of ARDS from the electronic medical record.  In order to use a consistent baseline creatinine measurement, we used a previously validated age-dependent formula to calculate expected baseline creatinine.  We adjusted measured serum creatinine for fluid overload using the formula displayed here, consistent with prior studies using adjusted creatinine.  We used KDGO stage two and three criteria to define AKI. We then classified subjects by timing of AKI onset.  Early AKI of criteria met in the first three days of ARDS illness, late AKI of criteria met on days four through seven of ARDS, and persistent AKI if they met criteria on days  during both the early and late periods. We had 720 patients in this cohort. The median age was five years. AKI was present in just over one quarter of patients.  Ten percent had early AKI, three percent had late AKI, and 13 percent had persistent AKI. We found that mortality increases in the presence of AKI.  This is consistent with other studies that demonstrate increased mortality in patients with AKI. All AKI groups, regardless of timing, had higher mortality between 36 to 38 percent  than the group without AKI, which had a mortality rate of 12 percent. Additionally, AKI groups had fewer ventilator-free days.  Those with persistent AKI in particular had fewer vent-free days than the early or late AKI groups.  We then adjusted creatinine for all subjects on each day based on their fluid balance.  With this adjustment, 33 patients who had not previously met AKI criteria were now reclassified as having AKI based on elevated creatinine.  This new AKI group had higher mortality and fewer ventilator-free days than the group that still did not meet AKI criteria.  The rate of mortality and ventilator-free days in this group were more similar to the groups that had AKI prior to adjusting for fluid overload.  For the final part of our analysis, we compared indicators of AKI between AKI groups and the group that never developed AKI.  In the first graph here on the left, unadjusted creatinine is plotted against days 1 through 7 of ARDS.  In the early AKI group, in green, creatinine is significantly elevated compared to the no AKI group from day 1, then downtrends.  In the late AKI group, in blue, creatinine is predictably elevated beginning on day 4. The persistent AKI group, in red, is elevated throughout.  The middle graph shows fluid overload-adjusted creatinine. Again, we can see the early AKI group elevated initially, then downtrending.  The persistent AKI group is elevated throughout. In the late AKI group, again in blue, fluid overload-adjusted creatinine becomes significantly  elevated compared to the no AKI group on day 3, the day before they actually start to meet AKI criteria.  A similar pattern is seen in the cumulative fluid balance, the last graph on the right. Even the no AKI group, in black, shows some positive fluid balance.  The early AKI group has elevated fluid balance in the beginning of the illness, and the persistent AKI group has elevated fluid balance throughout.  In the late AKI group, we again see that fluid balance becomes significantly elevated compared to the no AKI group beginning on day 3, the day prior to meeting AKI criteria.  So from this data, we can make the following conclusions. One, AKI is associated with higher mortality and fewer ventilator-free days in ARDS, regardless  of the timing of onset of AKI. Two, using fluid overload-adjusted creatinine in the AKI criteria detects a group of patients  that are otherwise missed, and this group has worse outcomes that are more consistent with the outcomes we see in AKI.  Three, that fluid overload and fluid overload-adjusted creatinine are significantly increased one day prior to meeting clinical AKI criteria in the late AKI group.  We do, of course, acknowledge limitations in this study. This was a single-center, retrospective cohort, with the complications inherent to that design.  Fluid management in this unit was not protocolized and at the discretion of individual providers, which may have introduced bias.  Finally, we do not have data on creatinine or fluid overload prior to the diagnosis of ARDS, which limits our ability to assess the trajectory of these variables in the early  AKI group. This study leads to some potential future directions that will be important to investigate further.  Given that we can demonstrate easily measured clinical markers that indicate worsening renal function before AKI is actually diagnosed, is it possible to predict the development  of clinical AKI sooner and therefore intervene earlier in the course of renal injury? What specific role does fluid overload play in the diagnosis and management of AKI?  And if fluid balance is managed better, can we improve the clinical outcomes of patients with AKI and ARDS?  And finally, are there unique physiologic pulmonary renal interactions that affect the outcomes observed in patients with both ARDS and AKI?  I want to touch on that last question briefly in the time remaining. A subset of the patients in our cohort were also enrolled in a biomarker trial.  They had angiopoietin 2 levels measured on days 1, 3, and 7 of ARDS. Angiopoietin 2 is a known mediator of endothelial leak.  In patients that had AKI at the start, in other words, the early and persistent AKI groups, angiopoietin was elevated from day 1.  In the late AKI group that developed AKI on day 4 or after, angiopoietin 2 levels were significantly elevated on day 3 and continued to rise on day 7 compared to the group that  did not develop AKI. This indicates that angiopoietin 2 may be a useful biomarker of endothelial dysfunction  in both the lung and the kidneys and provides a physiologic pathway to explain these pulmonary renal interactions that warrants further investigation.  Thank you very much for your time today. I appreciate the opportunity to present this exciting work at SCCM.  For additional questions or comments, please feel free to contact me at cdixon3 at childrensnational.org.

Video Summary

In this video transcript, Celeste Dixon, a Pediatric Critical Care Fellow, presents the results of a study on the effect of fluid overload on the diagnosis of acute kidney injury (AKI) in pediatric acute respiratory distress syndrome (ARDS). The study aimed to determine the relationship between the timing of AKI and outcomes in pediatric ARDS, as well as assess if concurrent fluid overload impacted the diagnosis of AKI. The study found that AKI was associated with higher mortality and fewer ventilator-free days, regardless of the timing of onset. Adjusting creatinine for fluid overload identified additional patients with AKI and worse outcomes. The study also discussed the potential role of angiopoietin 2 as a biomarker of endothelial dysfunction in both the lung and kidneys.

Asset Subtitle

Renal, Pulmonary, Pediatrics, 2022

Asset Caption

INTRODUCTION/HYPOTHESIS: Fluid overload (FO) is a risk factor for higher mortality and fewer ventilator free days (VFDs) in pediatric acute respiratory distress syndrome (ARDS). The interplay between acute kidney injury (AKI), fluid balance, and outcomes remains understudied. We utilized a large pediatric ARDS cohort to assess the association between AKI and outcomes. We hypothesized that timing of AKI onset is associated with differences in mortality and VFDs in pediatric ARDS, and explored whether AKI diagnosis is affected by concurrent FO. METHODS: We performed a secondary analysis of a prospective ARDS cohort of intubated children meeting Berlin criteria, excluding subjects with chronic kidney disease. Daily fluid intake, urine output, fluid balance, measured creatinine, FO-adjusted creatinine (creatinine x [1+ fluid balance/total body water]), and use of continuous renal replacement therapy on days 1-7 from ARDS onset were retrospectively abstracted. Baseline creatinine was determined using an age-dependent formula. Subjects were classified by timing of AKI onset (KDIGO 2/3) into 4 groups: no AKI (never met criteria), early AKI (onset days 1-3), late AKI (onset days 4-7), and persistent AKI (onset early, continued past day 4). Primary outcomes (mortality and VFDs) and daily FO and FO-adjusted creatinine were compared between AKI groups using Fisher exact or Kruskal-Wallis tests. RESULTS: The cohort comprised 720 children, of whom 26% had AKI (early 10%; late 3%; persistent 13%). AKI groups had higher mortality (36-38%) than the no AKI group (12%; all p < 0.001), and fewer VFDs (all p < 0.001). Thirty-three (6%) subjects were reclassified from no AKI to AKI when FO-adjusted creatinine replaced measured creatinine; this subset had higher mortality (24%) than the rest of the no AKI group (11%; p = 0.043) and fewer VFDs (p < 0.001). In the late AKI group, FO and FO-adjusted creatinine increased one day prior to meeting AKI criteria. CONCLUSIONS: AKI is associated with higher mortality and fewer VFDs in pediatric ARDS regardless of time of onset. FO-adjusted creatinine identifies patients who do not otherwise meet AKI criteria yet have worse outcomes, suggesting cryptic but potentially significant AKI. FO and FO-adjusted creatinine may predict development of AKI before creatinine and urine output.

Meta Tag

Content Type Presentation

Knowledge Area Renal

Knowledge Area Pulmonary

Knowledge Area Pediatrics

Knowledge Level Advanced

Membership Level Select

Tag Renal

Tag Acute Respiratory Distress Syndrome ARDS

Tag Pediatrics

Year 2022

Keywords

fluid overload

acute kidney injury

pediatric acute respiratory distress syndrome

mortality

creatinine

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