Transcript The Treatment Effect - Hastaneciyiz's Blog

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?
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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
Interstitial
40%
Extracellular
Compartment
60%
Intracellular
EC
Intracellular
Interstitial
Interstitial
What happens when
you infuse 0.9% Saline in health?
EC
Intracellular
EC
Interstitial
Interstitial
What happens when you infuse
5% Albumin (Iso-Oncotic Colloid)?
Intracellular
EC
Intracellular
Effect of “Hyper”-Oncotic Colloid
EC
Intracellular
Interstitial
Interstitial
ie 25% Albumin
EC
Intracellular
The controversy?...Albumin revisited
Cochrane Injuries Group Albumin Reviewers, BMJ 1998;317:235-240
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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
Copyright ©1998 BMJ Publishing Group Ltd.
Favors control
The controversy?...Albumin revisited
Cochrane Injuries Group Albumin Reviewers, BMJ 1998;317:235-240
Favors Albumin
Copyright ©1998 BMJ Publishing Group Ltd.
Favors Control
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
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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
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“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
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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
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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
Year
Population
Comparator
# Studies
RR*
95% CI
Alderson
2002
Critically ill
Albumin
31
0.66
0.50 – 0.85
Wilkes
2001
No restriction
Albumin
55
0.90
0.78 – 1.05
Roberts
1998
Critically ill
Albumin
30
0.60
0.45 – 0.79
Alderson
2002
Critically ill
Colloids
38
0.66
0.49 – 0.93
Choi
1999
All adult pts.
Colloids
17
0.86
0.63 – 1.17
Schierhout
1998
Critically ill
Colloids
19
0.84
0.69 – 1.02
Wade
1997
Trauma
7.5%
Saline/Dextran
8
1.20**
0.94 – 1.57
*RR<1 favors crystalloids
** Odds ratios
Author
Year
Some Sub-group
Analyses:
Wilkes
2001(A)
Surgery/trauma
Ascites
0.89
1.08
(0.69 - 1.18)
(0.78 – 1.49)
Alderson
2002 (A)
Hypovolemia
Burns
Hypoalbuminemia
0.68
0.42
0.73
(0.90 - 1.03)
(0.19 - 0.90)
(0.49 – 1.06)
Schierhout
1998 (C)
Trauma
Surgery
Burns
0.77
1.82
0.83
(.057 – 1.05)
(0.61 – 5.56)
(0.60 – 1.14)
Choi
1999 (C)
Trauma
Non-Trauma
0.39
0.98
(0.17 - 0.89)
(0.70 - 1.36)
Alderson
2002 (C)
HES
Gelatin
Dextran
0.86
2.0
0.81
(0.51 - 1.47)
(0.33 – 12.5)
(0.61 – 1.06)
*RR < 1 favors crystalloids
Pooled RR (95% CI’s)
Why do meta-analyses report discordant results?
Clinical Question
Study selection and inclusion
Populations of patients
Interventions
Outcome measures
Settings
Selection criteria
Application of the selection criteria
Strategies to search the literature
Data Extraction
Methods to measure outcomes
End points
Human error (random or systematic)
Assessment of study quality
Methods to assess quality
Interpretations of quality assessments
Methods to incorporate quality
assessments in review
Assessment of the ability to combine
Studies
Statistical methods
Clinical criteria to judge
the ability to combine studies
Statistical methods for data synthesis
Fixed versus random effects
Jadad, Cook, Browman CMAJ 1997:156(10); 1411-1416
Types of discordance
Type
Example
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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
often/always
88%
56%
Normal saline
Ringers lactate
53%
Pentastarch
4%
1%
5% Albumin
25% Albumin
Does albumin supplementation
improve oxygenation?
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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?
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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?
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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
(n=63)
Control
(n=63)
p value
Resolution of infection
Renal impairment n(%)
Hospital mortality n(%)
3 month mortality
98%
21(33%)
18(29%)
26(41%)
94%
6(10%)
6(10%)
14(22%)
0.36
0.002
0.01
0.03
Sort et al, NEJM 1999 pp 403-9
Do protocols of
care
and timing matter?
? Harmful
Evolving Knowledge and
Lessons Learned:
? Helpful
High risk patients with
global tissue hypoxia
Treat in early stage of
disease
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
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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
Goal-directed
%Dead
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?
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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?
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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