1. Raghavan Murugan, MD, MS, FRCP Associate Professor of Critical Care Medicine, and Clinical & Translational Science Core Faculty, Center for Critical Care Nephrology & CRISMA Center University of Pittsburgh School of Medicine Fluid Balance and Long-Term Outcomes in Critical Illness

2. Disclosure Grant from Bard Inc. – Intensity of monitoring of renal function in critically ill patients

3. Background Fluid balance (FB) is frequently disrupted in critically ill patients with acute kidney injury (AKI) Positive FB prevalent in up to 40% of ICU patients Negative FB prevalent in up to 50% of patients However, association between exposure to FB and long term outcomes is unclear Lowell et. al., Crit Care Med 1990 Vaara et. al., Crit Care 2012 Bellomo et. al., Crit Care Med 2012

4. Positive Fluid Balance Previous studies that have examined association between positive FB and outcomes – Conflicting results – Indication bias – Compared patients with only negative FB – Examined only short term outcomes – Included patients for propensity to fluid overload (e.g., Heart failure)

5. Negative Fluid Balance Negative FB is thought to be associated with improved survival – Compared patients to positive FB – Biologic plausibility – Short term outcomes Bellomo et. al., Crit Care Med 2012

6. Conceptual Model Murugan R and Kellum JA. CCM 2012

7. Positive Fluid Balance and Outcome Prowle, J.R. et al; Nat Rev Neprol 2010

8. Hypothesis Among critically ill patients, positive FB, compared with even FB, is associated with increased 1-year mortality Negative FB, compared with even FB, is associated with lower 1-year mortality Among patients receiving RRT, positive and negative FB would be associated with impaired renal recovery

9. Methods HIDenIC Dataset – Adults admitted to 8 different UPMC ICUs between July, 2000 and October, 2008 Mortality data from SSDMF and dialysis data from USRDS * FB = Cumulative daily fluid input – output X 100 Hospital admission weight Propensity score was created to account for indication bias for fluid use AKI was defined using the KDIGO criteria * Slewiski et. al., Intensive Care Medicine 2011

10. Methods Propensity matched case-control study to examine positive FB and mortality Grays model to estimate risk-adjusted hazard ratios of positive and negative FB Logistic regression model to estimate risk-adjusted OR for renal recovery

11. Study Population

12. Definition of Positive, Negative, and Even FB Positive FB: > 5% – 4.9% Even FB: 0-4% – 13.3% Negative FB: < 0% – 81.8%

13. Age, yrs, median (IQR)60 (47-73)65 (51-77)65 (51-78)<0.001 BMI, kg/m2 median (IQR) 26.8 (23.4 - 31.2) 27.1 (23.6 - 31.6) 24.6 (21.3 - 28.7) <0.001 Co-morbidities History of hypertension2410(22.1)432(24.3)176(27)0.0028 History of vascular disease721 (6.6)140(7.9)56(8.6)0.0305 History of malignant neoplasms 361(3.3)84(4.7)42(6.4)<0.001 Multiple comorbidities2951(27)553(31)268(41)<0.001 Clinical Characteristics Surgical admission7127 (65.2)1047 (58.8)410 (62.8)<0.001 Vasopressors a 2622 (24)396 (22.3)193 (29.6)<0.001 Mechanical Ventilation a 7136 (65.3)995 (55.9)393 (60.2)<0.001 Sepsis a 1508 (13.8)246 (13.8)117 (17.9)0.0128 Apache III score mean (SD) 62.8 (26.2)65.6 (29.2)72.3 (29.9)<0.001 Fluids in 1st 24hrs, L/day, median (IQR) 3.4 (2.4 - 5)3.54 (2.5 - 5.3)4.4 (3 - 7)<0.001 Average daily fluid balance, L/day median -0.9 (-1.4 to -0.5)0.3 (0.1 - 0.6)1 (0.5 - 1.7)<0.001 Baseline serum creatinine0.81 (0.7 - 1.01)0.84 (0.7 - 1.02)0.82 (0.7 - 1.03)0.0032 AKI within 24hrs of ICU3110 (28.4 )686 (38.5)260 (40)<0.001 Characteristic Negative (N=10,925) Even (N=1,780) Positive (N=653) P Value Key Baseline Characteristics

14. Crude Outcomes by Fluid Balance CharacteristicNegative (N=10,925) Even (N=1,780) Positive (N=653) P Value Length of hospital stay (days, median, interquartile range) 15 (9-25)11 (7-19)17 (10-28)<0.001 All AKI8741 (80)1527 (85.7)597 (91.4)<0.001 KDIGO Stage 12255 (20.6)252 (14.2)75 (11.5) <0.001 KDIGO Stage 24707 (43.1)748 (42)229 (35.1) KDIGO Stage 31779 (16.3)527 (29.6)293 (44.9) RRT requirement362 (3.3)229 (12.9)128 (19.6)<0.001 Hospital mortality1158 (10.6)310 (17.4)194 (29.7)<0.001 1 year mortality2728 (25)569 (32)302 (46.3)<0.001 1 year renal recovery*96 (26.5)72 (31.4)42 (32.8)0.2695 * Defined as alive and independent of RRT in the RRT subgroup

15. Outcomes in the Propensity Matched Cohort Characteristic N (%) Controls (<5% FB) (n = 1366) Cases (>=5% FB) (n = 480) P value Length of hospital stay (days, median, interquartile range) 17 (10-30)17 (10-28)0.7111 AKI during hospitalization (KDIGO criteria) Stage 1 179 (13.1)58 (12.1)0.0983 Stage 2 508 (37.2)161 (33.5) Stage 3 544 (39.8)222 (46.3) RRT requirement 171 (12.5)104 (21.7)<0.001 Hospital Mortality 265 (19.4)146 (30.4)<0.001 1 year Mortality 503 (36.8)229 (47.7)<0.001 1 year Renal Recovery 41 (3)32 (6.67)0.216

16. Fluid Balance and Mortality Mortality (%) Days from ICU admission Positive Even Log Rank P <0.001 Controls (< 5%) Days from ICU admission Mortality (%) Cases (> 5%) Log Rank P <0.001 Negative

17. Negative vs Even FB on Mortality Adjusted for age, sex, race, surgical admission, comorbidity, malignancy, baseline creatinine, BMI, mechanical ventilation, vasopressor use, sepsis, hypotensive index, APACHE III, AKI severity, oliguria Adjusted Hazard Ratio Range = 0.60 – 1.32, P <0.001

18. Positive vs. Even FB on Mortality Adjusted Hazard Ratio Range= 1.24 – 1.41, P =0.003 Adjusted for age, sex, race, surgical admission, comorbidity, malignancy, baseline creatinine, BMI, mechanical ventilation, vasopressor use, sepsis, hypotensive index, APACHE III, AKI severity, oliguria

19. Positive vs. Negative FB on Mortality Adjusted for age, sex, race, surgical admission, comorbidity, malignancy, baseline creatinine, BMI, mechanical ventilation, vasopressor use, sepsis, hypotensive index, APACHE III, AKI severity, oliguria Adjusted Hazard Ratio Range= 1.16 – 1.80, P <0.001

20. Fluid Balance and Renal Recovery and Mortality in RRT Subgroup PopulationCharacteristic Adjusted Odds Ratio (95% CI) * Renal RecoveryMortality RRT population (n= 719) Positive vs Even FB0.89 (0.50 – 1.59)1.27 (0.74 – 2.17) Negative vs Even FB0.61 (0.39 – 0.97)1.54 (1.02 – 2.35) 1 year survivors (n=252) Positive vs Even FB1.81 (0.48 – 6.86) Negative vs Even FB0.95 (0.36 – 2.49) * Models adjusted for age, sex, race, reference estimated glomerular filtration rate, surgery, comorbidities, oliguria, modality and timing of RRT, Apache III score, vasopressors, mechanical ventilation, suspected sepsis, and hypotensive index.

21. Conclusions Positive, compared with even and negative FB, is associated with increased 1 year mortality Negative, compared with even FB, has variable association with 1 year mortality Among patients receiving RRT, negative and positive FB were not associated with renal recovery

22. Acknowledgements Vikram Balakumar, MDFlorentina Sileanu, MS John Kellum, MD Visit us at ccm.pitt.edu/center-critical-care-nephrology-team Follow