Fluid Overload and Acute Kidney Injury

Kathleen D. LiuFebruary 18, 2014

Outline

• How much fluid is enough: what do we use to guide resuscitation?

• Fluid selection in the ICU• What are potential adverse consequences of

fluid overload itself?

What do we use to guide resuscitation?

• Physical Exam• Static monitors

– BP (MAP), CVP, PAOP or “wedge pressure”, TTE • Dynamic monitors

– Systolic pressure variation– Pulse pressure variation– Stroke volume variation/arterial pulse contour– Passive leg raise– Continuous TEE

• Metabolic monitors– Lactate, SVO2

Shippy et al, CCM 1984

What do we use to guide resuscitation?

• Physical Exam• Static monitors

– BP (MAP), CVP, PAOP or “wedge pressure”, TTE • Dynamic monitors

– Systolic pressure variation– Pulse pressure variation– Stroke volume variation/arterial pulse contour– Passive leg raise– Continuous TEE

• Metabolic monitors– Lactate, SVO2

Davison and Junker, CJASN 2008

Outline

• How much fluid is enough: what do we use to guide resuscitation?

• Fluid selection in the ICU: What fluids may be harmful to the kidney?– Hydroxyethyl starch– Chloride rich solutions (normal saline)

• What are potential adverse consequences of fluid overload itself?

International Variation in Fluid Selection

Finfer et al., CC 2010

Hydroxyethyl Starch• Prior studies have suggested increased rates of AKI

with HES

• CHEST: 7000 patients (Australia/NZ) randomized to receive 130/0.4 HES or saline

• Follow up to 90 days VISEP, NEJM 2008Myburgh et al, NEJM 2012

CHEST Study

Myburgh et al, NEJM 2012

What is the impact of HES on AKI?

• How do we define AKI?

CHEST Study

Myburgh et al, NEJM 2012

CHEST Study

Myburgh et al, NEJM 2012

CHEST Study

Myburgh et al, NEJM 2012

CHEST: Conclusions

• Largest study of HES in critically ill patients• No benefit and likely harm with HES• Caveats:

– Serum Cr, urine output that are used to define AKI may be affected by type of resuscitation fluid/changes in volume of distribution

– RRT should be less affected (though subjective); blinding helps

• Additional black box warning added by FDA in June 2013

Fluid selection and AKI: Chloride rich solutions

• Rationale: Hyperchloremia can lead to renal vasoconstriction with associated reductions in RBF

NaHCO3

NaAcetate

Dextrose

NH4Acetate

NaCl

NH4Cl

-50 -40 -30 -20 -10 0 10 20 30 40

% change in RBF (dogs)

Wilcox, JCI 1983

Impact of NS on renal function• Rationale: Compared to Plasmalyte, NS

resuscitation results in greater extracellular fluid volume and decreased renal perfusion

• Design: Crossover clinical trial of 12 healthy male volunteers– 2 L of either NS or Plasmalyte administered over 1h,

with 4h of followup; participants returned 7-10 days later for the 2nd half of the study

Chowdury et al, Annals Surg 2012

NS administration is associated with greater extracellular fluid expansion

Chowdury et al, Annals Surg 2012

NS administration is associated with decreased renal perfusion

Chowdury et al, Annals Surg 2012

What is the impact of chloride-rich fluids on the incidence of AKI?

• Pre/post study:0.9% NS Hartmann

solution4% gelatin Plasmalyte-1484% albumin 20% salt-

poor albumin

Yunos et al, JAMA 2012

Chloride rich solutions and AKI

Yunos et al, JAMA 2012

Chloride rich solutions and AKI

Yunos et al, JAMA 2012

Limitations

• Multiple interventions: unclear which component of intervention was associated with change in AKI

• Other temporal changes in care?

Yunos et al, JAMA 2012

Chloride rich solutions and AKI

Shaw et al, Annals Surg 2012

Chloride rich solutions and AKI

Shaw et al, Annals Surg 2012

Chloride rich solutions and AKI

Shaw et al, Annals Surg 2012

Chloride rich solutions: Conclusions

• Results are intriguing and warrant repeating/study in other contexts

• With some exceptions, use balanced salt solutions rather than isotonic saline

Outline

• How much fluid is enough: what do we use to guide resuscitation?

• Fluid selection in the ICU• What are potential adverse consequences of

fluid overload itself?

Fluid overload has many potentially deleterious effects

Prowle et al, Nat Rev Neph 2010

Fluid overload is a risk factor for death in adult patients with AKI

Bouchard et al, KI 2009

Fluid overload is a risk factor for death in adult patients with AKI

Bouchard et al, KI 2009

Problems with observational studies of fluid balance

• Is increased mortality related to – Fluid itself?– Provider/process of care characteristics– Comorbidities associated with volume

overload (sepsis, hypotension)?– Lack of recognition of AKI?

Fluid overload is an independent risk factor for sepsis after AKI

Mehta et al, Intens Care Med, 2011

OR (95% CI)

Chronic kidney disease 0.40 (0.26-0.63)

Steroid therapy 1.93 (0.99-3.74)

Invasive procedure post-AKI 1.75 (1.15-2.66)

≥ 3 days of oliguria 3.40 (1.49-7.76)

Need for dialysis 1.58 (1.15-2.66)

SOFA score (per 1 point increase) 1.12 (1.04-1.20)

Fluid overload* 1.66 (1.05-2.64)

* 25% of AKI days with FO > 10% of body weight

What is the impact of fluid overload on antibiotic levels?

MIC

AUC/MIC

Peak/MIC

Time above MIC

Time

Con

cent

ratio

n

Concentration Dependency

Time Dependency

Antibiotic levels in patients on CRRT

• Prospective study of 52 patients receiving piperacillin/tazobactam on CRRT

• Patients received a mean of 8.6±1.5 g pip/tazo/24 hours (our standard dosing is 13.5 g/24 hours)

• Depending on what antibiotic breakpoint is used, up to 23% of cohort failed to achieve “adequate” antibiotic levels

Bauer et al, CJASN 2012

Fluid overload is associated with antibiotic volume of distribution

Bauer et al, CJASN 2012

What is the impact of fluid management (diuretics) on AKI outcomes?

How does fluid balance impact AKI outcomes and ascertainment?

Impact of fluid balance on other organs: ALI and the FACTT trial

KIDNEY

FavorsDry

LUNG

CVP < 4PAOP < 8

MAP < 60Low flow by exam or CI <2.5

UOP < 0.5 ml/kg/h &

CVP or PAOP low

Furosemide

ARDS Network, N Engl J Med 2006

Impact of fluid balance on other organs: ALI and the FACTT trial

ARDS Network, N Engl J Med 2006

0 1 2 3 4 5 6 7

-2000

0

2000

4000

6000

8000

LiberalConservativeARMA 6 ml (1996-1999)

Study Day

ml o

f fl

uid

Fluid conservative approach has no impact on mortality

Liberal Conservative15

20

25

30

28.4 25.5

Mor

talit

y(%

)

P = 0.30

ARDS Network, N Engl J Med 2006

Fluid conservative approach increases the number of VFDs

Liberal

Conservative

0 2 4 6 8 10 12 14 16

12.09

14.55

P=0.0002

ARDS Network, N Engl J Med 2006

Dialysis to Day 60

Conservative Liberal P value

Patients (%) 10 14 0.06

Days 11.0 + 1.7 10.9 + 1.4 0.96

What is the impact of the fluid conservative approach on AKI?

ARDS Network, N Engl J Med 2006

What is the impact of fluid conservative management on smaller changes in serum Cr?

Volume overload impacts AKI ascertainment: an underappreciated

problem in critically ill patients• The volume of distribution of Cr is total body

water• Volume overload therefore dilutes serum Cr

Cr

Cr

Cr

CrCr

Cr

CrCr

CrCr

CrCr

Cr

Cr

CrCr

And may mask AKI…

Failure to account for fluid overload delays recognition of AKI

Macedo et al, Critical Care 2010

AKI incidence is higher with FC approach only before adjusting for fluid balance

Liu et al, CCM 2011

Renal Outcomes

Liberal Conservative

Not Adjusted Not Adjusted

AKIN Stage 1 253* 288*

AKIN Stage 2 54 69

AKIN Stage 3 75 75

AKI incidence is higher with FC approach only before adjusting for fluid balance

Liu et al, CCM 2011

Renal Outcomes

Liberal Conservative

Not Adjusted Adjusted Not Adjusted Adjusted

AKIN Stage 1 253* 328** 288* 290**

AKIN Stage 2 54 106 69 87

AKIN Stage 3 75 89 75 83

Patient Groupings

GROUP

AKIN Stage 1 AKI

PatientsBefore

Adjustment for Fluid Balance

&After

Adjustment for Fluid Balance

A NO & NO 328B NO & YES 131C YES & NO 54D YES & YES 487

Liu et al, CCM 2011

AKIN Stage 1: Groups and Outcomes: Mortality

A (-/-) B (-/+) C (+/-) D (+/+)0

5

10

15

20

25

30

35

40

Liu et al, CCM 2011

AKIN Stage 1: Groups and Outcomes: Mortality and VFDs

A (-/-) B (-/+) C (+/-) D (+/+)0

5

10

15

20

25

30

35

40

Liu et al, CCM 2011

Short timed creatinine clearance – a useful measurement in critically ill patients?

Pickering et al, Crit Care, 2012

Summary

• Fluid selection matters: avoid HES, await additional evidence with regards to use of NS versus balanced salt solutions

• Fluid overload is associated with adverse outcomes

• Fluid overload may affect:– Antibiotic levels– AKI ascertainment

“ The treatment of anuria should be conservative. If circulatory failure is present, appropriate steps should be taken to correct it. Otherwise, therapy is limited to the balanced maintenance of the patient until the kidneys have a chance to affect recovery…It is easy to expand the body fluids to such an extent as to produce dangerous pulmonary edema and perhaps to promote the formation of renal edema.”

-- Homer Smith, 1951

What is the impact of diuretic use and fluid balance on AKI?

FACTTN=1000

AKIN=306

No AKIN=794

Impact of post-AKI diuretic use and fluid balance

Grams et al, CJASN 2011

Positive fluid balance is associated with increased mortality

Grams et al, CJASN 2011

Furosemide administration is associated with decreased mortality

Grams et al, CJASN 2011