1. Fluid Overload and Acute Kidney Injury Kathleen D. Liu February 18, 2014

2. 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?

3. 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

4. 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

5. 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?

6. International Variation in Fluid Selection Finfer et al., CC 2010

7. 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 2008 Myburgh et al, NEJM 2012

8. CHEST Study Myburgh et al, NEJM 2012

9. What is the impact of HES on AKI? How do we define AKI?

10. CHEST Study Myburgh et al, NEJM 2012

11. CHEST Study Myburgh et al, NEJM 2012

12. CHEST Study Myburgh et al, NEJM 2012

13. 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

14. Fluid selection and AKI: Chloride rich solutions Rationale: Hyperchloremia can lead to renal vasoconstriction with associated reductions in RBF Wilcox, JCI 1983

15. 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 2 nd half of the study Chowdury et al, Annals Surg 2012

16. NS administration is associated with greater extracellular fluid expansion Chowdury et al, Annals Surg 2012

17. NS administration is associated with decreased renal perfusion Chowdury et al, Annals Surg 2012

18. What is the impact of chloride-rich fluids on the incidence of AKI? Pre/post study: 0.9% NSHartmann solution 4% gelatinPlasmalyte-148 4% albumin20% salt-poor albumin Yunos et al, JAMA 2012

19. Chloride rich solutions and AKI Yunos et al, JAMA 2012

20. Chloride rich solutions and AKI Yunos et al, JAMA 2012

21. Limitations Multiple interventions: unclear which component of intervention was associated with change in AKI Other temporal changes in care? Yunos et al, JAMA 2012

22. Chloride rich solutions and AKI Shaw et al, Annals Surg 2012

23. Chloride rich solutions and AKI Shaw et al, Annals Surg 2012

24. Chloride rich solutions and AKI Shaw et al, Annals Surg 2012

25. 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

26. 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?

27. Fluid overload has many potentially deleterious effects Prowle et al, Nat Rev Neph 2010

28. Fluid overload is a risk factor for death in adult patients with AKI Bouchard et al, KI 2009

29. Fluid overload is a risk factor for death in adult patients with AKI Bouchard et al, KI 2009

30. 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?

31. Fluid overload is an independent risk factor for sepsis after AKI Mehta et al, Intens Care Med, 2011 OR (95% CI) Chronic kidney disease0.40 (0.26-0.63) Steroid therapy1.93 (0.99-3.74) Invasive procedure post-AKI1.75 (1.15-2.66) ≥ 3 days of oliguria3.40 (1.49-7.76) Need for dialysis1.58 (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

32. What is the impact of fluid overload on antibiotic levels? MIC AUC/MIC Peak/MIC Time above MIC Time Concentration Concentration Dependency Time Dependency

33. 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

34. Fluid overload is associated with antibiotic volume of distribution Bauer et al, CJASN 2012

35. What is the impact of fluid management (diuretics) on AKI outcomes? How does fluid balance impact AKI outcomes and ascertainment?

36. Impact of fluid balance on other organs: ALI and the FACTT trial KIDNEY Favors Dry LUNG CVP < 4 PAOP < 8 MAP < 60 Low 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

37. Impact of fluid balance on other organs: ALI and the FACTT trial ARDS Network, N Engl J Med 2006

38. Fluid conservative approach has no impact on mortality P = 0.30 ARDS Network, N Engl J Med 2006

39. Fluid conservative approach increases the number of VFDs P=0.0002 ARDS Network, N Engl J Med 2006

40. Dialysis to Day 60 Conservative Liberal P value Patients (%) 10140.06 Days11.0 + 1.710.9 + 1.40.96 What is the impact of the fluid conservative approach on AKI? ARDS Network, N Engl J Med 2006

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

42. 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 And may mask AKI…

43. Failure to account for fluid overload delays recognition of AKI Macedo et al, Critical Care 2010

45. AKI incidence is higher with FC approach only before adjusting for fluid balance Liu et al, CCM 2011 Renal Outcomes LiberalConservative Not Adjusted AKIN Stage 1253*288* AKIN Stage 25469 AKIN Stage 375

46. AKI incidence is higher with FC approach only before adjusting for fluid balance Liu et al, CCM 2011 Renal Outcomes LiberalConservative Not AdjustedAdjustedNot AdjustedAdjusted AKIN Stage 1253*328**288*290** AKIN Stage 2541066987 AKIN Stage 375897583

47. Patient Groupings GROUP AKIN Stage 1 AKI Patients Before Adjustment for Fluid Balance & After Adjustment for Fluid Balance A NO& 328 B NO&YES131 C YES&NO54 D YES& 487 Liu et al, CCM 2011

48. AKIN Stage 1: Groups and Outcomes: Mortality Liu et al, CCM 2011

49. AKIN Stage 1: Groups and Outcomes: Mortality and VFDs Liu et al, CCM 2011

50. Short timed creatinine clearance – a useful measurement in critically ill patients? Pickering et al, Crit Care, 2012

51. 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

52. “ 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

53. What is the impact of diuretic use and fluid balance on AKI? FACTT N=1000 AKI N=306 No AKI N=794 Impact of post- AKI diuretic use and fluid balance Grams et al, CJASN 2011

54. Positive fluid balance is associated with increased mortality Grams et al, CJASN 2011

55. Furosemide administration is associated with decreased mortality Grams et al, CJASN 2011