1. Albumin Infusions: A review of literature pertinent to IM Hospitalists
L Noronha, MD
Assistant Professor of Medicine
May 6, 2011

2. Thanks to: Shauna Rodriguez Autumn Roberts Melissa Cordero
Richard D’Angio
Jim Little
Chris McFarland
Lenka and Chris

3. Is this the face that launched 1,000,000 albumin infusions?
UNM DoIM Grand Rounds 4/21/11:
Emerging Medical Surgical Strategies in the Management of Advanced CHF
Marvin Slepian, MD
Professor of Medicine (Cardiology and Biomedical Engineering), University of Arizona
Director, Interventional Cardiology
Director, University of Arizona Tissue Engineering Lab
Chairman and Chief Scientific Officer, SynCardia Systems, Inc.

4. Objectives Describe current albumin use at UNM
Familiarize hospitalists with major trials evaluating inpatient albumin infusions
Submit guidelines for inpatient albumin administration by IM hospitalists

5. Outline
What is albumin?
Purported effects
Key trials for
Resuscitation (SAFE, SOAP, Cochrane Review)
Considerations in cirrhosis
Recommendations for Section use
There have been no studies to evaluate the role of albumin in CHF

6. Albumin Any non-glycosylated water soluble protein
Moderately soluble in salt solutions
Examples: AFP, Vit D binding protein, HSA
Albuminoids contain albumin (egg white)

7. Human Serum Albumin Negatively charged globular serum protein
585 amino acids
3 identical paired subdomains A,B
Tyrosine, methionine, lysine residues
Disulfide bonds
Tertiary structure
Binding sites!
1 free cysteine residue
Reduced sulphydryl (-SH) moiety
Inactivates reactive oxygen species

8. More on HSA… Synthesized in liver 30-40% in serum
Remainder stored in muscle and skin
Production triggered by decreased oncotic pressure

9. Albumin for the Vascular Space
60% of colloidal oncotic pressure
Attracts sodium and other osmotically active positive ions

10. Binding and Transport of Various Compounds
Endogenous
Exogenous
Unconjugated bilirubin
Free fatty acids
Calcium
Hormones
Nitric oxide
Metals
Tryptophan
Low albumin assoc c HE
Binding to albumin “keeps” drug in vascular space
Unbound drug (free) is active
High affinity drugs need to be given in higher doses
Loop diuretics, warfarin, NSAIDS, phenytoin have high affinity

11. Desired Roles of Albumin Infusion
Oncotic pressure
Anti-inflammatory
Diuretic

12. Albumin for Infusion Pooled from human donors
Pasteurized at 60⁰C for 10 hrs.
10% leaves intravasc space within 2 hours
75% after 2 days (nl capillaries)
5% (nl serum osm) for volume expansion
25% sol’n for LVP, SBP, HRS
Order sol’n as 0.5mg/kg or #g in Powerchart
$36/12.5g at UNM
UNM Allocation 600U/month

14. Should we use it?

15. Cochrane Injuries Group Albumin Reviewers - 1998
Meta analysis of 24 studies (combined 1419 pts) evaluating albumin infusion in critical illness
Absolute increase of death 6% (NNH 17) over NS
Editorial: “Albumin use should be halted”
Authors recc: “albumin should not be administered to critically ill outside the context of rigorously conducted, randomized trials.”

16. Sepsis Occurrence in Acutely ill Patients (SOAP) – Critical Care 2005
Multi-center prospective observational study
ICUs in several European countries
3047 pts adm May 1-15, 2002
354 received albumin (11.2%), 2793 did not (88.8%)
Noted that albumin given to sicker pts (cancer, cirrhosis), so matched crystalloid subgroup compared

17. SOAP Results
Albumin associated with decreased ICU and hospital survival (relative hazard 1.57)

18. Saline versus Albumin Fluid Evaluation (SAFE) - NEJM 2004
Multi-center double-blind RCT
ICUs in NZ, Australia 11/01-6/03
6997 ICU pts > 18y req fluid resus
Excluded: cardiac surgery, liver xplant, burns
Randomized to 4% albumin or NS
identical 500 mL bottles, “masking cartons, IV sets”
Add’l fluids, monitoring at provider discretion
Prim endpt: 28d mortality
Secondary: LOS (ICU, total), vent days, RRT

19. So SAFE said, “It’s Safe.”
SAFE Results
Primary and secondary 28 day endpoints equal for albumin and saline groups Subgroup analyses: - Pt baseline albumin did not impact outcomes - Trauma (brain injury) did worse
So SAFE said, “It’s Safe.”

20. Nephrotic Syndrome
Nefrologia 2011;31(2): | Doi /Nefrologia.pre2010.Nov.10724
Avances en la fisiopatología del edema en el síndrome nefrótico
New insights into the pathophysiology of oedema in nephrotic syndrome
Enviado a Revisar: 8 Nov. 2010 | Aceptado el: 16 Nov  | En Publicación: 22 Mar. 2011
H. Rondon-Berrios
Division of Nephrology. Department of Internal Medicine. University of New Mexico School of Medicine. Albuquerque, Nuevo México (EEUU)
Correspondencia para H. Rondon-Berrios, Division of Nephrology. Department of Internal Medicine, University of New Mexico School of Medicine, ACC 5. MSC University of New Mexico, , Albuquerque, Nuevo México, EEUU
Forget albumin. It’s all about the Epithelial Sodium Channel!

21. Considerations in Cirrhosis
Diuresis/LVP
SBP
HRS

22. Diuresis in Cirrhosis
Effects of Albumin/Furosemide Mixtures on Responses to Furosemide in Hypoalbuminemic Patients, Chalasani, et al, J Am Soc Nephrol, 2001
13 Patients with cirrhosis already on spironolactone and dietary sodium restriction ALL receive different doses of furosemide with or without albumin.
No difference in diuresis (volume, urine sodium) or furosemide activity

23. Albumin for Diuresis in Cirrhosis
Mixed results in randomized studies
Heterogeneous baseline patients
Definitions of “refractory ascites”
Renal function
May decrease hospital LOS
Does not impact survival
May be cost effective

24. Large Volume Paracentesis
LVP preferable to serial 5L paracentesis + diuretics for refractory ascites in 5 RCTs - Decreased LOS - Fewer re-admissions * Refractory ascites = persists despite doses of spironolactone furosemide 160 daily or recurs rapidly after LVP Mean survival = 6mos.

25. Albumin (20% sol’n) Decreases Paracentesis Induced Circulatory Dysfunction (PICD) in RCT’s
With or without albumin – 105 pts
Albumin (18.5%) vs other volume expanders [Dextran 70 (34.4%), Polygeline(37.8%)] – 289 pts
*PICD = increase in plasma renin activity on the sixth day after paracentesis of more than 50% of the pretreatment value
- correlated with time to readmission and survival
Range of 5-10g albumin/L paracentesis used

26. SBP Multicenter RCT in Spain
EFFECT OF INTRAVENOUS ALBUMIN ON RENAL IMPAIRMENT AND MORTALITY
IN PATIENTS WITH CIRRHOSIS AND SPONTANEOUS BACTERIAL PERITONITIS, Sort, et al, NEJM, 1999
Multicenter RCT in Spain
cefotaxime (63 pts) or cefotaxime + IV albumin 20% sol’n (63)
IV albumin grp received 1.5 g/kg on diagnosis (day 1), 1 g/kg on day 3.
Primary endpt: non-reversible deterioration in renal function (Cr incr to > 1.5 or Cr incr > 50% over baseline) during hospitalization
Followed for 90 days

27. Results
Incidence of renal impairment was lower among those treated with cefotaxime + albumin (6 of 63 [10%]) compared to cefotaxime alone (21 of 63 [33%]), P= [NNT= 4 ; (33-10=23), 1/.23= 4]
In-hospital mortality was lower among those treated with cefotaxime + albumin vs. those treated with cefotaxime alone (10% vs 29%, P=0.01). [NNT= 5 (29-10=19), 1/.19= 5]
Mortality at 3 months was also lower among those treated with cefotaxime + albumin vs. those treated with cefotaxime alone (22% vs 41%, P=0.03). [NNT= 5 (41-22= 19), 1/.19= 5]
For the entire series of patients, independent predictors for developing renal impairment were: baseline serum bilirubin and Cr levels (P<0.001 and 0.01, respectively).

28. HRS
Terlipressin therapy with and without albumin for patients with hepatorenal syndrome: Results of a prospective, nonrandomized study, Ortega, Hepatology 2002
Single center. Sept 1999-May 2001
21 patients. HRS per IAC Criteria
All given 60-80g IV albumin over 2 days
8 have LVP with more albumin
All start terlipressin
First 13 receive more albumin 20% sol’n: 1g/kg Day 1, then 20-40g/d
Final 8 do not receive add’l albumin.
More “responders” in albumin group, alive in 1 month, transplanted.
No randomization!

29. Albumin for HRS No randomization!
Treatment of Hepatorenal Syndrome as Defined by the International Ascites Club by Albumin and Furosemide Infusion According to the Central Venous Pressure: A Prospective Pilot Study, Peron, Gastroenterology 2005
20 patients with HRS
Albumin to keep CVP > 3 (no limit) + Furosemide (to maintain UO > 50mL/h) given 250mg over 4h, increased for up to 1.5g/d
Range 40 to 600g albumin/day
11 patients “responded” (Cr clearance rose to > 40).
No randomization!

30. This created pressure… As seen in “Deathly Hallows: Part 2”
Use albumin in HRS!
Nephrologist
Hospitalist

31. HRS
Terlipressin and albumin vs albumin in patients with cirrhosis and hepatorenal syndrome: a randomized study. Martin, Gastroenterology 2008
46pts with HRS randomized to:
terlipressin + albumin or albumin alone
Improved renal function without survival benefit
Several subsequent studies built on adding vasoactive medications to albumin.

32. Section Recommendations
LVP (> 5L) 25% albumin: 5-10g/L removed (as bolus) SBP 25% albumin: 1.5g/kg on dx, 1g/kg on Day 3

34. 100g, 75g
50g
Consider giving 75g for 10L or more paracentesis

35. Section Recommendations
HRS 20 or 25% albumin sol’n in consultation with nephrology Stay tuned for emerging data on vasopressin analogues, prostaglandins,

36. Additional References
Cochrane Injuries Group Albumin Reviewers. Human albumin administration in critically ill patients: systematic review of randomized controlled trials. BMJ. 1998;317:235–40. Bunn F, Lefebvre C, Li Wan Po A, et al. Human albumin solution for resuscitation and volume expansion in critically ill patients: The albumin reviewers. Cochrane Database Syst Rev :CD Finfer S, Bellomo R, Boyce N, et al. A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med. 2004;350:2247–56. Vincent JL, Navickis RJ, Wilkes MM. Morbidity in hospitalized patients receiving human albumin: a meta-analysis of randomized, controlled trials. Crit Care Med. 2004;32:2029–38. SAFE Study Investigators. Finfer S, Bellomo R, McEvoy S, et al. Effect of baseline serum albumin concentration on outcome of resuscitation with albumin or saline in patients in intensive care units: analysis of data from the saline versus albumin fluid evaluation (SAFE) study. BMJ. 2006;333:1044–9. Quinlan GJ, Martin GS, Evans TW. Albumin: biochemical properties and therapeutic potential. Hepatology. 2005;41:1211–9. Gentilini P, Casini-Raggi V, Di Fiore G, et al. Albumin improves the response to diuretics in patients with cirrhosis and ascites: results of a randomized, controlled trial. J Hepatol. 1999;30:639–45. Chalasani N, Gorski JC, Horlander JC, et al. Effects of albumin/furosemide mixtures on responses to furosemide in hypoalbuminemic patients. J Am Soc Nephrol. 2001;12:1010–6. Gines P, Guevara M, Arroyo V, Rodes J. Hepatorenal syndrome. Lancet. 2003;362:1819–27. Sort P, Navasa M, Arroyo V, et al. Effect of intravenous albumin on renal impairment and mortality in patients with cirrhosis and spontaneous bacterial peritonitis. N Engl J Med. 1999;341:403–9. Akcicek F, Yalniz T, Basci A, et al. Diuretic effect of furosemide in patients with nephrotic syndrome: is it potentiated by intravenous albumin? BMJ. 1995;310:162–3. Peron JM, Bureau C, Gonzalez L, et al. Treatment of hepatorenal syndrome as defined by the international ascites club by albumin and furosemide infusion according to the central venous pressure: a prospective pilot study. Am J Gastroenterol 2005;100(12): Martin-Llahi, M, Pepin, MN, Guevara, M, et al. Terlipressin and albumin versus albumin in patients with cirrhosis and hepatorenal syndrome: a randomized study. Gastroenterology 2008;134: