Albumin: Should It Be Albumin: Should It Be Used In Clinical Used In Clinical Practice?Practice?

Presented By: Paul HebertPresented By: Paul Hebert

What is Albumin?What is Albumin?

DescriptionDescription Human plasma proteinHuman plasma protein Molecular weight of 66 KdMolecular weight of 66 Kd Most common plasma protein Most common plasma protein Synthesized in the liverSynthesized in the liver Negatively chargedNegatively chargedFunctionFunction Responsible for oncotic Responsible for oncotic pressurepressure Binds drugs and other Binds drugs and other substancessubstances Free radical scavenger Free radical scavenger

What do we use Albumin What do we use Albumin for?for?

Treatment of Treatment of HypovolemiaHypovolemia

BurnsBurns Nutritional Nutritional

replacement with TPNreplacement with TPN HypoalbuminemiaHypoalbuminemia Hyperoncotic therapyHyperoncotic therapy

IndicatedFollowing large volume paracentesisNephrotic syndrome resistant to potent diureticsVolume/Fluid replacement in plasmapheresis

Possibly indicatedAdult respiratory distress syndromeOvarian hyperstimulation syndromeCardiopulmonary bypass pump primingFluid resuscitation in shock/sepsis/burnsNeonatal kernicterusTo improve enteral feeding intolerance

Not indicatedCorrection of measured hypoalbuminemia or hypoproteinemiaNutritional deficiency, total parenteral nutritionPre-eclampsiaRed blood cell suspensionSimple volume expansion (surgery, burns)Wound healingBucur et al. Hematology:Basic Principles and Practice. 2000; 2266

What do we use Albumin for?What do we use Albumin for?

InvestigationalCadaveric renal transplantationCerebral ischemiaStroke

Common UsagesSerum albumin <2.0 g/dlNephrotic syndrome, proteinuria and hypoalbuminemiaLabile pulmonary, cardiovascular statusCardiopulmonary bypass, pump primingExtensive burnsPlasma exchangeHypotensionLiver disease, hypoalbuminemia, diuresisProtein losing enteropathy, hypoalbuminemiaResuscitationIntraoperative fluid requirement > 5-6 L in adultsPremature infant undergoing major surgery

Bucur et al. Hematology:Basic Principles and Practice. 2000; 2266

What do we use Albumin for?What do we use Albumin for?

Back to Back to BasicsBasics

Intracellular

ExtracellularCompartment

Pla

sma

40% 60%

General SchemaGeneral Schema

Inte

rsti

tial

Intracellular

EC

Pla

sma

ECP

lasm

a

What happens when you infuse 0.9% Saline in health?

Inte

rsti

tial

Inte

rsti

tial

Intracellular

EC

Pla

sma

EC

Pla

sma

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

Inte

rsti

tial

Inte

rsti

tial

Intracellular Intracellular

EC

Pla

sma

ECP

lasm

a

Effect of “Hyper”-Oncotic Colloidie 25% Albumin

Inte

rsti

tial

Inte

rsti

tial

Intracellular Intracellular

30 RCTs in systematic review30 RCTs in systematic review 1419 critically ill patients1419 critically ill patients Indications included hypovolemia, Indications included hypovolemia,

burns and hypoalbuminemiaburns and hypoalbuminemia All doses and concentrations of All doses and concentrations of

albumin (2.5, 4%, 5% and 25%)albumin (2.5, 4%, 5% and 25%) Any control group (nothing, saline, Any control group (nothing, saline,

Ringers, dextrose/Ringers)Ringers, dextrose/Ringers) No protocols of careNo protocols of care Limited assessment of qualityLimited assessment of quality

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

Copyright ©1998 BMJ Publishing Group Ltd.

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

Favors controlFavors Albumin

Copyright ©1998 BMJ Publishing Group Ltd.

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

Favors Albumin Favors Control

Schierhout and Roberts. BMJ 1998;316:961-964

The controversy?...Colloids versus crystalloidsThe controversy?...Colloids versus crystalloids

Types of trials:Types of trials: 37 RCTs (n=1622) 37 RCTs (n=1622) – Excluded 11 RCTs in systematic reviewExcluded 11 RCTs in systematic review– Mortality information on 1315 patients in 19 RCTsMortality information on 1315 patients in 19 RCTs

PatientsPatients: : – All critically ill patients requiring volume replacementAll critically ill patients requiring volume replacement– Trauma, surgery, Burn, Sepsis, ARDS, Trauma, surgery, Burn, Sepsis, ARDS,

Interventions:Interventions: Any colloid (2.5% and 5% and 25% Any colloid (2.5% and 5% and 25% albumin, pentaspan, Dextran-70, 6% Dextran, albumin, pentaspan, Dextran-70, 6% Dextran, Hydroxyethyl starch, Haemacell,plasma and Hydroxyethyl starch, Haemacell,plasma and combinationcombination– Colloid in hypertonic (n=10 trials)Colloid in hypertonic (n=10 trials)– Controls included Ringers, .9% and 7.5% saline, 5% dextrose)Controls included Ringers, .9% and 7.5% saline, 5% dextrose)– No protocols of careNo protocols of care

Methods:Methods: – Fixed effect models Fixed effect models – Limited assessment of qualityLimited assessment of quality

Copyright ©1998 BMJ Publishing Group Ltd.

Schierhout and Roberts. BMJ 1998;316:961-964

The controversy?...Colloids versus crystalloidsThe controversy?...Colloids versus crystalloids

Favors colloids Favors crystalloids

Copyright ©1998 BMJ Publishing Group Ltd.

Schierhout and Roberts. BMJ 1998;316:961-964

The controversy?...Colloids versus crystalloidsThe controversy?...Colloids versus crystalloids

Inferences by AuthorsInferences by Authors

““No evidence supporting that albumin No evidence supporting that albumin administration reduces mortality”administration reduces mortality”

““Should not be used outside the context Should not be used outside the context of rigorously conducted RCTs”of rigorously conducted RCTs”

““Resuscitation with colloid solutions was Resuscitation with colloid solutions was associated with an absolute increase in associated with an absolute increase in the risk of mortality of 4%”the risk of mortality of 4%”

Inferences supported by BMJ EditorialsInferences supported by BMJ Editorials

But…Significant But…Significant Limitations with meta-Limitations with meta-analysesanalyses Primary studies were very weak…most neither Primary studies were very weak…most neither

concealed or blindedconcealed or blinded Significant statistical heterogeneitySignificant statistical heterogeneity Use of fixed effect models in analysisUse of fixed effect models in analysis Combined different interventions (2.5%, 5%, 25%)Combined different interventions (2.5%, 5%, 25%) Clinical heterogeneity a major concernClinical heterogeneity a major concern

– Populations (neonates, adults) very differentPopulations (neonates, adults) very different– Many IndicationsMany Indications– Different control groupsDifferent control groups– No protocols for administrationNo protocols for administration– Trials span 2 decadesTrials span 2 decades

Mortality primarily driven by a few unbalanced Mortality primarily driven by a few unbalanced studiesstudies

AuthorAuthor

YearYear

PopulationPopulation ComparatorComparator # Studies# Studies RR*RR* 95% CI95% CI

AldersonAlderson

20022002

Critically illCritically ill AlbuminAlbumin 3131 0.660.66 0.50 – 0.850.50 – 0.85

WilkesWilkes

20012001

No restrictionNo restriction AlbuminAlbumin 5555 0.900.90 0.78 – 1.050.78 – 1.05

RobertsRoberts

19919988

Critically illCritically ill AlbuminAlbumin 3030 0.600.60 0.45 – 0.790.45 – 0.79

AldersonAlderson

20022002

Critically illCritically ill ColloidsColloids 3838 0.660.66 0.49 – 0.930.49 – 0.93

ChoiChoi

19991999

All adult pts.All adult pts. ColloidsColloids 1717 0.860.86 0.63 – 1.170.63 – 1.17

SchierhoutSchierhout

19919988

Critically illCritically ill ColloidsColloids 1919 0.840.84 0.69 – 1.020.69 – 1.02

WadeWade

19971997

TraumaTrauma 7.5% 7.5% Saline/DextranSaline/Dextran

88 1.20**1.20** 0.94 – 1.570.94 – 1.57

*RR<1 favors crystalloids*RR<1 favors crystalloids

** Odds ratios

AuthorAuthor

YearYear

Some Sub-group Some Sub-group

Analyses: Pooled RR (95% CI’s)Analyses: Pooled RR (95% CI’s)

WilkesWilkes

20012001(A)(A)

Surgery/trauma 0.89 (0.69 - 1.18)Surgery/trauma 0.89 (0.69 - 1.18)

Ascites 1.08 (0.78 – 1.49)Ascites 1.08 (0.78 – 1.49)

AldersonAlderson

2002 2002 (A)(A)

Hypovolemia 0.68 (0.90 - 1.03)Hypovolemia 0.68 (0.90 - 1.03)

Burns 0.42 (0.19 - 0.90)Burns 0.42 (0.19 - 0.90)

Hypoalbuminemia 0.73 (0.49 – 1.06)Hypoalbuminemia 0.73 (0.49 – 1.06)

SchierhoutSchierhout

1998 1998 (C)(C)

Trauma 0.77 (.057 – 1.05)Trauma 0.77 (.057 – 1.05)

Surgery 1.82 (0.61 – 5.56)Surgery 1.82 (0.61 – 5.56)

Burns 0.83 (0.60 – 1.14)Burns 0.83 (0.60 – 1.14)

ChoiChoi

1999 1999 (C)(C)

Trauma 0.39 (0.17 - 0.89) Trauma 0.39 (0.17 - 0.89)

Non-Trauma 0.98 (0.70 - 1.36)Non-Trauma 0.98 (0.70 - 1.36)

AldersonAlderson

2002 2002 (C)(C)

HES 0.86 (0.51 - 1.47)HES 0.86 (0.51 - 1.47)

Gelatin 2.0 (0.33 – 12.5) Gelatin 2.0 (0.33 – 12.5)

Dextran 0.81 (0.61 – 1.06)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 criteriaInterventions Application of the selection criteriaOutcome measures Strategies to search the literatureSettings

Data Extraction Assessment of study qualityMethods to measure outcomes Methods to assess qualityEnd points Interpretations of quality assessmentsHuman error (random or systematic) Methods to incorporate quality

assessments in review

Assessment of the ability to combine Statistical methods for data synthesisStudies Fixed versus random effectsStatistical methodsClinical criteria to judge the ability to combine studies

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

Types of discordance

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

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

Copyright ©1999 BMJ Publishing Group Ltd.

Roberts, I. et al. BMJ 1999;318:1214b

Has use of Albumin decreased?

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

53%

4%

88%

56%

1%

Normal saline Ringers lactate Pentastarch 5% Albumin 25% Albumin

rarely/never

sometimes

often/always

Does albumin Does albumin supplementation improve supplementation improve oxygenation? oxygenation?

Objective:Objective: to determine if 25% albumin to determine if 25% albumin added to furosemide improve urine added to furosemide improve urine output and pulmonary physiologyoutput and pulmonary physiology

Design:Design:Double blind RCTDouble blind RCT Patients:Patients: 37 mechanically ventilated 37 mechanically ventilated

patients with low total protein and ALIpatients with low total protein and ALI Interventions:Interventions:5 day infusion of 100 mls 5 day infusion of 100 mls

of Albumin TID plus furosedmide of Albumin TID plus furosedmide infusion versus furosemide alone infusion versus furosemide alone

Martin et al, CCM,2002; pp2175-2182

What did they find?What did they find?

5.3 kg more weight loss in albumin 5.3 kg more weight loss in albumin group (p=0.04)group (p=0.04)

Improved PaO2/FIO2 ratio (171 vs 236, Improved PaO2/FIO2 ratio (171 vs 236, p=0.02)p=0.02)

Improved hemodynamics with Improved hemodynamics with decreased heart rate and increased decreased heart rate and increased blood pressureblood pressure

No change in other measures of lung No change in other measures of lung mechanicsmechanics

Martin et al, CCM,2002; pp2175-2182

Does albumin supplementation Does albumin supplementation improve outcomes in spontaneous improve outcomes in spontaneous bacterial peritonitis?bacterial peritonitis?

Objective:Objective: to determine whether plasma to determine whether plasma expansion with 20% albumin prevents renal expansion with 20% albumin prevents renal impairment and reduces mortalityimpairment and reduces mortality

Design: randomized trial involving 7 tertiary randomized trial involving 7 tertiary centrescentres

Patients:Patients: 126 patients with cirrhosis and 126 patients with cirrhosis and spontaneous bacterial peritonitisspontaneous bacterial peritonitis

Interventions:Interventions: cefotaxime versus cefotaxime cefotaxime versus cefotaxime and albumin infusion of 1.5 g/kg with and albumin infusion of 1.5 g/kg with cefotaxime.cefotaxime.

No active controls and not blindedNo active controls and not blinded

Sort et al, NEJM 1999 pp 403-9

What did they find?What did they find?

OutcomesOutcomes AlbuminAlbumin ControlControlp valuep value

(n=63)(n=63) (n=63)(n=63)

Resolution of infection Resolution of infection 98%98% 94%94% 0.360.36

Renal impairment n(%)Renal impairment n(%) 21(33%)21(33%) 6(10%)6(10%)0.0020.002

Hospital mortality n(%)Hospital mortality n(%) 18(29%)18(29%) 6(10%)6(10%)0.010.01

3 month mortality3 month mortality 26(41%)26(41%) 14(22%)14(22%) 0.030.03Sort et al, NEJM 1999 pp 403-9

Do protocols of Do protocols of care care

and timing and timing matter?matter?

Evolving Knowledge and Lessons Learned:

High risk patients with global tissue hypoxia? Helpful

? Harmful

Treat in early stage of disease

Oxygen Debt: To Pay or Not to Pay

Optimization TrialsOptimization Trials“Every hemodynamic study is not “Every hemodynamic study is not Shoemaker”Shoemaker”

Mortality

(Boyd, New Horiz, 1996)

Early

Late

(Kern, Crit Care Med, 2002)

Goal Directed Therapy in Goal Directed Therapy in the Critically Illthe Critically Ill

Goal: Goal: to determine if early Goal-directed therapy to determine if early Goal-directed therapy targetingtargeting

treatment of venous hypoxia improved clinical treatment of venous hypoxia improved clinical outcomes outcomes

Setting: Setting: Single centre studySingle centre study

Study Population:Study Population:263 patients with EARLY sepsis and 263 patients with EARLY sepsis and septicseptic

shockshockStudy Design: Open labeled RCT Intervention:Goal-directed vs standard therapy

initiated in ER for 6 hoursOutcome: In-hospital mortality

Rivers et al NEJM 2001;345:1368

Goal Directed Therapy in Goal Directed Therapy in the Critically Illthe Critically Ill

0 – 6 hours, Goal vs Standard TherapyFluids: 4981 ml vs 3499 ml, p < .001Fluids: 4981 ml vs 3499 ml, p < .001 RBC: 64.1% vs 18.5%, p < .001RBC: 64.1% vs 18.5%, p < .001 Vasopressor: 27.4% vs 30.3%, p = 0.62Vasopressor: 27.4% vs 30.3%, p = 0.62 Inotropes: 13.7% vs 0.8%, p < .001Inotropes: 13.7% vs 0.8%, p < .001

Rivers et al NEJM 2001;345:1368

Early Goal directed therapyEarly Goal directed therapy(1)(1)

DeadDead AliveAlive %Dead%Dead

Goal-Goal-directed directed 3838 9292

A=38/130=30.5%A=38/130=30.5%

ControlControl

5959 7474B=59/133=46.5%B=59/133=46.5%

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?What can we infer?

The type, timing and quantity of fluid The type, timing and quantity of fluid resuscitation may impact on mortalityresuscitation may impact on mortality

Complex area of care with few high quality trialsComplex area of care with few high quality trials Meta-analyses primarily highlight deficiencies in Meta-analyses primarily highlight deficiencies in

literature literature Can’t and should not infer treatment choices Can’t and should not infer treatment choices

based upon meta-analysesbased upon meta-analyses Albumin may be beneficial in improving Albumin may be beneficial in improving

oxygenation in ALI and supporting patients with oxygenation in ALI and supporting patients with cirrhosis who have bacterial peritonitiscirrhosis who have bacterial peritonitis

Early aggressive fluid resuscitation may save Early aggressive fluid resuscitation may save lives lives

Less evidence in support of other colloidsLess evidence in support of other colloids

What do I recommend?What do I recommend?

Further clinical trials addressing Further clinical trials addressing following questions:following questions:– Different % albumin versus crystalloid Different % albumin versus crystalloid

in various settingsin various settings– Different colloids versus crystalloids in Different colloids versus crystalloids in

various settingsvarious settings– All crystalloids not created equal All crystalloids not created equal

either???either???– Treatment protocols versus usual care Treatment protocols versus usual care

And then we were And then we were SAFE’edSAFE’ed

Thank You