Fact

1. Fact The evidence base for most of what we do in intensive care is rather poor

4. Albumin - properties • Volume expansion 4% x 0.8, 5%, 20% x 3 • Maintenance of colloid osmotic pressure (COP) • Need a lot….no effect on other serum proteins.. • Binding and transport - drugs (frusemide, antibiotics) toxins….. • Free radical scavenging • Immunological : stimulatory and inhibitory • Anticoagulatory effects and Procoagulatory effects : • inhibit plat aggregation, inhibition of factor Xa by ATIII, TEG shows early hypocoagulable effects Tobias et al, Jorgensen et al • Vascular permeability and over albuminisation Qiao et al • What are we prescribing 5%, 20%, 25% +/- crystalloid • Aluminum toxicity, hypotension (vasoactive peptides) • Myocardial depression (animal work ; Ca binding)

10. Post transcriptional Proteins Advanced glycylation end product Wild mice Rage -/- mice

11. HAS and HES increased No rolling and decreased adherence and aggregation Albumin decreased activation of No and platelets Albumin and HES decrease E Selectin release Alb and HES decrease to varying degrees decrease No : endothelial interactions

12. Albumin : Sepsis and thiol repletionQuinlan et al, Clinical Science 1998 95, 459 200 ml 20% albumin or placebo

13. Which fluid ……SOAP-study Role of balanced solutions - acidosis, consider Cl levels

19. Albumin and frusemide in hypoalbuminaemia in ALI Martin G Crit Care Med 2002 ; 30:2175 • 37 ventilated acute lung injury • Total protein < 5 g/dl • 5 day protocol of 25 g of 25% HAS 8 hrly + frusemide or placebo • Frusemide titrated to weight loss > 1kg/day • Total protein 1.9 vs 0.7 g/dl Albumin 1.5 vs 0.3 g/dl • Increased COP 8.3 vs 2.9 mmHg at study end • Weight loss 10 vs 4.7 Kg • Increased Na, HCO3 and decreased K • No change in creatinine

20. Improved oxygenation : improved Pa02/Fi02 ratio by 40% No difference in PEEP No changes in SOFA scores, shock free days or rates of re-intubation No difference in % requiring mechanical ventilation

21. Acute kidney injury

22. mortality

28. Albumin and diuretics and ascites • 126 cirrhotics ascites • Diuretics vs Diuretics + Alb 12.5 g/day • Diuretics vs Diuretics + Alb 25g/week as outpatient. Follow up over 3 yrs • Hospital stay shorter in Alb grp 20±1 vs 24±2 days p<0.05 • Risk of developing ascites lower in Alb grp • 19%, 56%, 69% vs 30%, 74%, 79% (p<0.02) • Survival similar in both groups • Gentilini et al J Hepatol 30(4):639 1999

29. Terlipressin and albumin vs albuminMartin-Llahi M Gastroenterology 2008:134 • 1-2 mg 4hrly • Albumin daily 1g/kg • N=23 each grp • Improved renal function 43 vs 8% • No difference in 2 mnth survival • CVS complications • 4 Alb vs 10 T + Alb

30. RCT Terlipressin in Type I HRSSanyal A Gatroenterology 2008 :134:1360 1 mg 6 hrly vs placebo Albumin in both groups If no response (30% decrease in creat) at day 4 : to 2mg 6 hrly 14 days Rx : 56 in each grp Success defined as creatinine < 1.5 mg/dl for 48 hrs by Day 14 Rx success : 25 vs 12.5 % Baseline to day 14 decrease in creatinine 0.7 vs 0 mg/dl Similar survival between grps HRS reversal improved 180 day outcome

31. Terlipressin + Albumin vs Albumin

32. 10 trials only type I and II Drug ± alb vs no intervention Vasoconstrictors + Alb : Effect on mortality at 15 days but not at 30, 90 or 180 days RR 0.6 (0.37-0.97) Terlipressin + Albumin vs Albumin : decreased mortality in type I RR 0.83 (0.65-1.05)

33. Multivariate – baseline creatinine

34. Albumin and renal impairment in patients with cirrhosis and SBPSort P et al N Engl J Med 1999 5; 341 (6):403 • SBP frequently associated with renal failure • Associated with decreased effective blood volume and high mortality • 126 patients iv cefotaxime or iv cefotaxime plus albumin (1.5g/kg) at day 0 and day 3 (1.0 g/kg) • 94% and 98 % had resolution of infection • Renal failure in 21 (33%) cefgrpvs 6 (10%) in alb/cefgrp p=0.002 • Mortality 18 (29%) vs 6 (10%) • At 3 months the mortality was 41% vs 22% p=0.03

35. HAS (4.5%) vs HES (6%,0.5) in paracetamol hepatotoxicity: prospective cohort studyBernal W Lancet 2001 • Albumin HES • Number 51 51 • Age 35 (20) 35 (22) • Apache II 14 (17) 15 (16) • INR 3.3 (2) 3.3 (2.6) • Creatinine 124 (132) 142 (167) • ARF o/a 14 (27%) 17 (33%)

36. Albumin HES • Crystalloid (72 hrs) • ml 6237 (6086) 6670 (6078) • ml/kg 29 (42) 38 (52) • Colloid (72 hrs) • ml 2000 (2875) 3000 (2812) • ml/kg 96 (104) 112 (92) • No differences in creatinine at any time point • RRT (n) 24 (47%) 25 (49%) • Death / LT 19 (37%) 22 (44%) • ICU stay 3 (6) 2 (11) • No relationship between colloid used and ARF on multivariate analysis • No difference if established ARF patients are excluded from study

38. Today’s evidence .. tomorrow’s chip paper?

39. 20 patients with SBP : randomized within 12 hrs 1.5 g/kg at day 1 and 1.0 g/kg at day 3 20% albumin given over 6 hours 18 hrs HES 6% given over 18 hours Well matched Studied at resolution of SBP ( ascitic taps)

42. terlipressin Hepatology 2011 placebo 3 mmHg MAP, Bilirubin

46. plasmapheresis standard Rx 67% NNT 5 46%

47. Recognize Fluids and CVS status Ventilatory issues Drain ascites Ileus : stop feeding Ng drainage , flatus tubes Open abdomen Incidence 8 - 50%

49. Albumin : Sepsis and thiol repletionQuinlan et al, Clinical Science 1998 95, 459 • Ligand binder, extracellular metal ion-binding and radical-scavenging antioxidant. • Baseline bloods • 200 ml 20% albumin or placebo • Alb 12.6 , 22.3 , 19 mg/ml at 0, 5min and 4 hrs • Thiol levels rose 138, 192 , 192 uM at 0, 5min and 4 hrs • Thiol levels remain elevated for 8 hrs - (33% of rise lost at 4 hrs)