Raghavan Murugan, MD, MS, FRCPAssociate Professor of Critical Care Medicine, andClinical & Translational ScienceCore Faculty, Center for Critical Care Nephrology & CRISMA CenterUniversity of Pittsburgh School of Medicine

Fluid Balance and Long-Term

Outcomes in Critical Illness

Disclosure

• Grant from Bard Inc. – Intensity of monitoring of renal function

in critically ill patients

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 1990Vaara et. al., Crit Care 2012Bellomo et. al., Crit Care Med 2012

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)

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

Conceptual Model

Murugan R and Kellum JA. CCM 2012

Positive Fluid Balance and Outcome

Prowle, J.R. et al; Nat Rev Neprol 2010

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

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

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

Study Population

Definition of Positive, Negative, and Even FB

• Positive FB: > 5%– 4.9%

• Even FB: 0-4% – 13.3%

• Negative FB: < 0%– 81.8%

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-morbiditiesHistory of hypertension 2410(22.1) 432(24.3) 176(27) 0.0028History of vascular disease

721 (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 comorbidities 2951(27) 553(31) 268(41) <0.001Clinical CharacteristicsSurgical admission 7127 (65.2) 1047 (58.8) 410 (62.8) <0.001Vasopressors a 2622 (24) 396 (22.3) 193 (29.6) <0.001Mechanical Ventilation a 7136 (65.3) 995 (55.9) 393 (60.2) <0.001Sepsis a 1508 (13.8) 246 (13.8) 117 (17.9) 0.0128Apache 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 creatinine

0.81 (0.7 - 1.01) 0.84 (0.7 - 1.02)

0.82 (0.7 - 1.03)

0.0032

AKI within 24hrs of ICU 3110 (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

Crude Outcomes by Fluid BalanceCharacteristic Negative

(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 AKI 8741 (80) 1527 (85.7) 597 (91.4) <0.001

KDIGO Stage 1 2255 (20.6) 252 (14.2) 75 (11.5)<0.001

KDIGO Stage 2 4707 (43.1) 748 (42) 229 (35.1)

KDIGO Stage 3 1779 (16.3) 527 (29.6) 293 (44.9)

RRT requirement 362 (3.3) 229 (12.9) 128 (19.6) <0.001

Hospital mortality 1158 (10.6) 310 (17.4) 194 (29.7) <0.001

1 year mortality 2728 (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

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

Fluid Balance and Mortality

Mor

talit

y (%

)

Days from ICU admission

Positive

Even

Log Rank P <0.001

Controls (< 5%)

Days from ICU admission

Mor

talit

y (%

) Cases (> 5%)

Log Rank P <0.001

Negative

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

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

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

Fluid Balance and Renal Recovery and Mortality in

RRT SubgroupPopulation Characteristic

Adjusted Odds Ratio (95% CI) *

Renal Recovery Mortality

RRT population (n= 719)Positive vs Even FB 0.89 (0.50 – 1.59) 1.27 (0.74 – 2.17)

Negative vs Even FB 0.61 (0.39 – 0.97) 1.54 (1.02 – 2.35)

1 year survivors (n=252)

Positive vs Even FB 1.81 (0.48 – 6.86)  

Negative vs Even FB 0.95 (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.

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

Acknowledgements

Vikram Balakumar, MD Florentina Sileanu, MS John Kellum, MD

Visit us at ccm.pitt.edu/center-critical-care-nephrology-team

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