Albumin: Should It Be Used

In Clinical Practice?

Presented By: Paul Hebert

 What is Albumin?
Description
 Human plasma protein
 Molecular weight of 66 Kd
 Most common plasma protein
 Synthesized in the liver
 Negatively charged
Function
 Responsible for oncotic
pressure
 Binds drugs and other
substances
 Free radical scavenger
 What do we use Albumin for?
 Treatment of
Hypovolemia
 Burns
 Nutritional replacement
with TPN
 Hypoalbuminemia
 Hyperoncotic therapy
What do we use Albumin for?
Indicated
Following large volume paracentesis
Nephrotic syndrome resistant to potent diuretics
Volume/Fluid replacement in plasmapheresis

Possibly indicated
Adult respiratory distress syndrome
Ovarian hyperstimulation syndrome
Cardiopulmonary bypass pump priming
Fluid resuscitation in shock/sepsis/burns
Neonatal kernicterus
To improve enteral feeding intolerance

Not indicated
Correction of measured hypoalbuminemia or hypoproteinemia
Nutritional deficiency, total parenteral nutrition
Pre-eclampsia
Red blood cell suspension
Simple volume expansion (surgery, burns)
Wound healing
Bucur et al. Hematology:Basic Principles and Practice. 2000; 2266
What do we use Albumin for?
Investigational
Cadaveric renal transplantation
Cerebral ischemia
Stroke

Common Usages
Serum albumin <2.0 g/dl
Nephrotic syndrome, proteinuria and hypoalbuminemia
Labile pulmonary, cardiovascular status
Cardiopulmonary bypass, pump priming
Extensive burns
Plasma exchange
Hypotension
Liver disease, hypoalbuminemia, diuresis
Protein losing enteropathy, hypoalbuminemia
Resuscitation
Intraoperative fluid requirement > 5-6 L in adults
Premature infant undergoing major surgery
Bucur et al. Hematology:Basic Principles and Practice. 2000; 2266
Back to Basics
 General Schema

40% 60%

Interstitial Intracellular

Extracellular
Compartment
 What happens when
you infuse 0.9% Saline in health?
Interstitial

Interstitial
Intracellular Intracellular

EC
EC
 What happens when you infuse
5% Albumin (Iso-Oncotic Colloid)?

Interstitial
Interstitial

Intracellular Intracellular

EC
EC
Effect of “Hyper”-Oncotic Colloid
ie 25% Albumin
Interstitial

Interstitial
Intracellular Intracellular

EC EC
The controversy?...Albumin revisited
Cochrane Injuries Group Albumin Reviewers, BMJ 1998;317:235-240

 30 RCTs in systematic review

 1419 critically ill patients
 Indications included hypovolemia, burns and
hypoalbuminemia
 All doses and concentrations of albumin
(2.5, 4%, 5% and 25%)
 Any control group (nothing, saline, Ringers,
dextrose/Ringers)
 No protocols of care
 Limited assessment of quality
 The controversy?...Albumin revisited
Cochrane Injuries Group Albumin Reviewers, BMJ 1998;317:235-240

Favors Albumin Favors control

Copyright ©1998 BMJ Publishing Group Ltd.

 The controversy?...Albumin revisited
Cochrane Injuries Group Albumin Reviewers, BMJ 1998;317:235-240

Favors Albumin Favors Control

Copyright ©1998 BMJ Publishing Group Ltd.
The controversy?...Colloids versus crystalloids
Schierhout and Roberts. BMJ 1998;316:961-964

Types of trials: 37 RCTs (n=1622)

– Excluded 11 RCTs in systematic review
– Mortality information on 1315 patients in 19 RCTs
Patients:
– All critically ill patients requiring volume replacement
– Trauma, surgery, Burn, Sepsis, ARDS,
Interventions: Any colloid (2.5% and 5% and 25%
albumin, pentaspan, Dextran-70, 6% Dextran,
Hydroxyethyl starch, Haemacell,plasma and
combination
– Colloid in hypertonic (n=10 trials)
– Controls included Ringers, .9% and 7.5% saline, 5%
dextrose)
– No protocols of care
 Methods:
– Fixed effect models
– Limited assessment of quality
 The controversy?...Colloids versus crystalloids
Schierhout and Roberts. BMJ 1998;316:961-964

Copyright ©1998 BMJ Publishing Group Ltd.

Favors colloids Favors crystalloids
 The controversy?...Colloids versus crystalloids
Schierhout and Roberts. BMJ 1998;316:961-964

Copyright ©1998 BMJ Publishing Group Ltd.

Inferences by Authors

 “No evidence supporting that albumin

administration reduces mortality”
 “Should not be used outside the
context of rigorously conducted RCTs”
 “Resuscitation with colloid solutions
was associated with an absolute
increase in the risk of mortality of 4%”
 Inferences supported by BMJ Editorials
But…Significant Limitations
with meta-analyses
 Primary studies were very weak…most neither
concealed or blinded
 Significant statistical heterogeneity
 Use of fixed effect models in analysis
 Combined different interventions (2.5%, 5%, 25%)
 Clinical heterogeneity a major concern
– Populations (neonates, adults) very different
– Many Indications
– Different control groups
– No protocols for administration
– Trials span 2 decades
 Mortality primarily driven by a few unbalanced
studies
 Author Population Comparator # Studies RR* 95% CI
Year

Alderson Critically ill Albumin 31 0.66 0.50 – 0.85

2002
Wilkes No restriction Albumin 55 0.90 0.78 – 1.05
2001
Roberts Critically ill Albumin 30 0.60 0.45 – 0.79
1998
Alderson Critically ill Colloids 38 0.66 0.49 – 0.93
2002
Choi All adult pts. Colloids 17 0.86 0.63 – 1.17
1999
Schierhout Critically ill Colloids 19 0.84 0.69 – 1.02
1998
Wade Trauma 7.5% 8 1.20** 0.94 – 1.57
1997 Saline/Dextran

*RR<1 favors crystalloids

** Odds ratios
 Author Some Sub-group
Year Analyses: Pooled RR (95% CI’s)

Wilkes Surgery/trauma 0.89 (0.69 - 1.18)

2001(A) Ascites 1.08 (0.78 – 1.49)
Alderson Hypovolemia 0.68 (0.90 - 1.03)
2002 (A) Burns 0.42 (0.19 - 0.90)
Hypoalbuminemia 0.73 (0.49 – 1.06)
Schierhout Trauma 0.77 (.057 – 1.05)
1998 (C) Surgery 1.82 (0.61 – 5.56)
Burns 0.83 (0.60 – 1.14)
Choi Trauma 0.39 (0.17 - 0.89)
1999 (C) Non-Trauma 0.98 (0.70 - 1.36)
Alderson HES 0.86 (0.51 - 1.47)
2002 (C) Gelatin 2.0 (0.33 – 12.5)
Dextran 0.81 (0.61 – 1.06)

*RR < 1 favors crystalloids

Why do meta-analyses report discordant results?

Clinical Question Study selection and inclusion

Populations of patients Selection criteria

Interventions Application of the selection criteria
Outcome measures Strategies to search the literature
Settings

Data Extraction Assessment of study quality

Methods to measure outcomes Methods to assess quality
End points Interpretations of quality assessments
Human error (random or systematic) Methods to incorporate quality
assessments in review

Assessment of the ability to combine Statistical methods for data synthesis

Studies Fixed versus random effects
Statistical methods
Clinical criteria to judge
the ability to combine studies

Jadad, Cook, Browman CMAJ 1997:156(10); 1411-1416

Types of discordance

Type Example
___________________________________________________________________

Results

Direction of Effect One review favors the experimental treatment

and another favors the control treatment.

Magnitude of Effect One review suggests that the intervention results

in a 30% reduction in mortality and another
suggests that it results in a 5% reduction in
mortality.

Statistical Significance One review shows a statistically significant

difference between the experimental and the
control treatments and another review shows a
non-significant difference between them.

Interpretation Authors interpret same results differently

Jadad, Cook, Browman CMAJ 1997:156(10); 1411-1416

 Has use of Albumin decreased?
Roberts, I. et al. BMJ 1999;318:1214b

Copyright ©1999 BMJ Publishing Group Ltd.

What type of fluid would you administer in
the first 6 hours of resuscitation? (N=210)

rarely/never
sometimes
88% often/always
56% 53%

4% 1%
Normal saline Ringers lactate Pentastarch 5% Albumin 25% Albumin
Does albumin supplementation
improve oxygenation?

 Objective: to determine if 25% albumin

added to furosemide improve urine output
and pulmonary physiology
 Design:Double blind RCT
 Patients: 37 mechanically ventilated patients
with low total protein and ALI
 Interventions:5 day infusion of 100 mls of
Albumin TID plus furosedmide infusion
versus furosemide alone

Martin et al, CCM,2002; pp2175-2182

What did they find?

 5.3 kg more weight loss in albumin group

(p=0.04)
 Improved PaO2/FIO2 ratio (171 vs 236,
p=0.02)
 Improved hemodynamics with decreased
heart rate and increased blood pressure
 No change in other measures of lung
mechanics

Martin et al, CCM,2002; pp2175-2182

Does albumin supplementation improve
outcomes in spontaneous bacterial
peritonitis?
 Objective: to determine whether plasma expansion
with 20% albumin prevents renal impairment and
reduces mortality
 Design: randomized trial involving 7 tertiary centres
 Patients: 126 patients with cirrhosis and
spontaneous bacterial peritonitis
 Interventions: cefotaxime versus cefotaxime and
albumin infusion of 1.5 g/kg with cefotaxime.
 No active controls and not blinded

Sort et al, NEJM 1999 pp 403-9

 What did they find?
Outcomes Albumin Control p value
(n=63) (n=63)

Resolution of infection 98% 94% 0.36

Renal impairment n(%) 21(33%) 6(10%) 0.002
Hospital mortality n(%) 18(29%) 6(10%) 0.01
3 month mortality 26(41%) 14(22%) 0.03

Sort et al, NEJM 1999 pp 403-9

 Do protocols of
care
and timing matter?
? Harmful

Evolving Knowledge and

Treat in early stage of
Lessons Learned:
disease
High risk patients with
? Helpful global tissue hypoxia
Oxygen Debt: To Pay or Not to
Pay
Optimization Trials
“Every hemodynamic study is not Shoemaker”

Late

Early

Mortality

(Boyd, New Horiz, 1996) (Kern, Crit Care Med, 2002)

 Goal Directed Therapy in
the Critically Ill
Goal: to determine if early Goal-directed therapy targeting
treatment of venous hypoxia improved clinical outcomes
Setting: Single centre study
Study Population:263 patients with EARLY sepsis and septic
shock
Study Design: Open labeled RCT
Intervention:Goal-directed vs standard therapy initiated in ER
for 6 hours
Outcome: In-hospital mortality

Rivers et al NEJM 2001;345:1368

 Goal Directed Therapy in
the Critically Ill

 0 – 6 hours, Goal vs Standard Therapy

 Fluids: 4981 ml vs 3499 ml, p < .001
 RBC: 64.1% vs 18.5%, p < .001
 Vasopressor: 27.4% vs 30.3%, p = 0.62
 Inotropes: 13.7% vs 0.8%, p < .001

Rivers et al NEJM 2001;345:1368

Early Goal directed therapy(1)

Dead Alive %Dead

Goal-directed A=38/130=30.5%
38 92
Control B=59/133=46.5%
59 74
Absolute Risk Reduction(ARR)= 16%
Relative Risk (RR)= 30.5 /46.5=0.66 (95% CI of 0.38 – 0.87)
Relative Risk Reduction(RRR)= (1- 0.66) x 100= 34%
Odds Ratio (OR)= a*d /b*c = 0.52

Number needed to treat (NNT)= 1/0.16= 6

(1)Rivers et al, NEJM, 2001,1368-77
What can we infer?
 The type, timing and quantity of fluid resuscitation
may impact on mortality
 Complex area of care with few high quality trials
 Meta-analyses primarily highlight deficiencies in
literature
 Can’t and should not infer treatment choices based
upon meta-analyses
 Albumin may be beneficial in improving oxygenation
in ALI and supporting patients with cirrhosis who
have bacterial peritonitis
 Early aggressive fluid resuscitation may save lives
 Less evidence in support of other colloids
What do I recommend?

 Further clinical trials addressing

following questions:
– Different % albumin versus crystalloid in
various settings
– Different colloids versus crystalloids in
various settings
– All crystalloids not created equal either???
– Treatment protocols versus usual care
And then we were SAFE’ed
Thank You