Colloids versus Crystalloids:
Do we have an answer yet??
Lauralyn McIntyre MD, FRCP(C), MHSc
Scientist, Ottawa Hospital Research Institute
Assistant Professor, University of Ottawa
Department of Epidemiology and Community Medicine
Center for Transfusion and Critical Care Research
Conflicts of Interest
• Unrestricted funds CSL Behring
The Colloid Crystalloid Question……
• Is one of the oldest
• Basic yet fundamental question
• The first intervention given
• To every patient
• Often several litres
• Since fluids critical for achievement of
hemodynamic stability, there is a potential for
impact on clinically important outcomes
Main categories of usual care
resuscitation fluids
Crystalloid Fluid
Normal Saline
Ringers Lactate
Colloid Fluid
Albumin
Hydroxyethyl starch
Main categories of usual care
resuscitation fluids
Crystalloid Fluid
Normal Saline
Ringers Lactate
Other Colloids:
Gelatins
Dextrans
Colloid Fluid
Albumin
Hydroxyethyl starch
Components of Normal Saline and
Ringers Lactate
Normal
Na+
Cl-
K+
Ca++
Lactate
mmol/L
mmol/L
mmol/L
mmol/L
mmol/L
Osmolarity
154
154
0
0
0
308
130
109
4
2.7
28
272
Saline
Ringers
Lactate
Albumin
•
•
•
•
Most common human plasma protein (60%)
Synthesized in the liver
Molecular weight of 66 Kd
Responsible for 80% osmotic pressure
•
Available:
• Iso – oncotic (4 – 5%)
• Hyper – oncotic (20 – 25%)
Quinlan et al, Hepatology, 2005
What are hydroxyethyl starch (HES) fluids?
•
Amylopectin starch (branched chain
glucose molecules)
Hydroxyethylation at C2 and C6
carbon units (substitution)
Vary in size (130 – 200 kD)
Vary in the amount of substitution
and ratio of substitution
Rationale for Resuscitating with
Colloids compared to Crystalloids
Plasma
3L
ISS
10 L
Blood Cells
2L
IC
30 L
Rationale for Resuscitating with
Colloids compared to Crystalloids
Plasma
3L
ISS
10 L
Blood Cells
2L
Iso-oncotic colloid
IC
30 L
Rationale for Resuscitating with
Colloids compared to Crystalloids
Plasma
3L
ISS
10 L
IC
30 L
Blood Cells
2L
Iso-oncotic colloid
Hyper-oncotic colloid
Rationale for Resuscitating with
Colloids compared to Crystalloids
Plasma
3L
ISS
10 L
IC
30 L
Blood Cells
2L
Iso-oncotic colloid
Hyper-oncotic colloid
Rationale for Resuscitating with
Colloids compared to Crystalloids
Plasma
Optimization
3L
of the microcirculation
?Impact on microcirculatory dysfunction
ISS
?Modulation 10
of Linflammatory
IC
30 L
response
Blood Cells
2L
Iso-oncotic colloid
Hyper-oncotic colloid
The Colloid Crystalloid Question…
• Research on this question for several decades
• And yes, there have been many studies and
many systematic reviews
Cochrane Systematic Reviews
Author/Year
Perel, 2011
Fluids compared
Colloids vs Crystalloids
# Studies
56
Bunn, 2011
Colloid vs Colloid
72
Alderson 2009
Albumin vs no albumin
37
Dart 2010
HES vs other fluid
34
Cochrane Systematic Reviews
Author/Year
Perel, 2011
Fluids compared
Colloids vs Crystalloids
# Studies
56
Bunn, 2011
Colloid vs Colloid
72
Alderson 2009
Albumin vs no albumin
37
Dart 2010
HES vs other fluid
34
So why are we still studying this question?
• Cochrane
Small sample
size
Systematic
Reviews
• Single centre
• Dated resuscitation protocols
# Studies
•Author/Year
Insufficient doseFluids compared
2011
Colloids vs Crystalloids
56
•Perel,
Surrogate
outcomes
Colloid
vs Colloid
72
•Bunn,
Few2011
studies in the
critically
ill
Alderson 2009
Albumin vs no albumin
37
• Low methodological rigor (risk of bias high)
Dart 2010
HES vs other fluid
34
So why are we still studying this question?
SAFE TRIPS II: International cross sectional
study 391 ICUs and 25 countries
Finfer et al, Critical Care, 2010; 14:R185
SAFE TRIPS II: International cross sectional
study 391 ICUs and 25 countries
Finfer et al, Critical Care, 2010; 14:R185
SAFE TRIPS II: International cross sectional
study 391 ICUs and 25 countries
Finfer et al, Critical Care, 2010; 14:R185
SAFE TRIPS II: International cross sectional
study 391 ICUs and 25 countries
Finfer et al, Critical Care, 2010; 14:R185
SAFE TRIPS II: International cross sectional
study 391 ICUs and 25 countries
Finfer et al, Critical Care, 2010; 14:R185
Are colloid fluids better maintained in the
intravascular space as compared to
RCT/Yr
Population
Fluid Comparators
Ratio
Crystalloid/Colloid
SAFE/04
Critically ill
N = 6997
4% albumin vs
normal saline
1.4
VISEP/08
Severe Sepsis/
Septic Shock
N = 537
10% HES vs
ringers lactate
1.4
Septic Shock
N = 40
10% HES vs
normal saline
1.1
McIntyre/08
Hartog et al, Anesth and Anal 2011, 112:635-645
RCT/Yr
Population
Fluid Comparators
Ratio
Crystalloid/Colloid
SAFE/04
Critically ill
N = 6997
4% albumin vs
normal saline
1.4
VISEP/08
Severe Sepsis/
Septic Shock
N = 537
10% HES vs
ringers lactate
1.4
Septic Shock
N = 40
10% HES vs
normal saline
1.1
McIntyre/08
Hartog et al, Anesth and Anal 2011, 112:635-645
RCT/Yr
Population
Fluid Comparators
Ratio
Crystalloid/Colloid
SAFE/04
Critically ill
N = 6997
4% albumin vs
normal saline
1.4
VISEP/08
Severe Sepsis/
Septic Shock
N = 537
10% HES vs
ringers lactate
1.4
Septic Shock
N = 40
10% HES vs
normal saline
1.1
McIntyre/08
Hartog et al, Anesth and Anal 2011, 112:635-645
RCT/Yr
Population
Fluid Comparators
Ratio
Crystalloid/Colloid
SAFE/04
Critically ill
N = 6997
4% albumin vs
normal saline
1.4
VISEP/08
Severe Sepsis/
Septic Shock
N = 537
10% HES vs
ringers lactate
1.4
Septic Shock
N = 40
10% HES vs
normal saline
1.1
McIntyre/08
? Endothelial Cell Leak
Hartog et al, Anesth and Anal 2011, 112:635-645
Are there potential harms associated
with the use of colloid fluid in the
Hydroxyethyl starches
Albumin
Coagulopathy
yes
yes
Transmission viral infection
no
yes
yes
(<0.006%)
yes
(<0.1%)
Pruritis
yes
no
Renal Failure
yes
?
Anaphylaxis
Grocott, M, Anesthesia and Analgesia, 2005
Hydroxyethyl starches
Albumin
Coagulopathy
yes
yes
Transmission viral infection
no
yes
yes
(<0.006%)
yes
(<0.1%)
Pruritis
yes
no
Renal Failure
yes
?
Anaphylaxis
Grocott, M, Anesthesia and Analgesia, 2005
Brunkhorst et al, NEJM, 2008
Baseline Characteristics
Mean (SD)
Ringers Lactate
N=275
HES
N=262
64.9 ±4.1
64.4 ± 13.3
59.6
60.3
20.3 ± 6.7
20.1 ± 6.7
18.8%
31%
0.001
22.8
34.9
0.001
28 day Mortality
24.1%
26.7%
0.484
90 day Mortality
33.9%
41%
0.092
Age
Sex (male) (%)
APACHE II Score
P value
Results (%)
*RRT
Acute renal failure
*RRT = renal replacement therapy
Brunkhorst et al, NEJM, 2008
VISEP trial: HES dose and RRT
Brunkhorst et al, NEJM, 2008
VISEP trial: HES dose and RRT
Limitations of the VISEP Trial
•
Fluid protocol violations
•
No criteria for dialysis
•
Un-blinded study
Brunkhorst et al, NEJM, 2008
What evidence related to HES is
forthcoming?
Trial
6S
CHEST
Population
Fluids compared
Primary Outcome
Severe Sepsis
N = 800
Voluven vs
Ringers lactate
90 Day Mortality or
Dialysis
Critically ill
N = 7000
Voluven vs
Normal Saline
90 Day Mortality
Finfer et al, NEJM 2004; 350: 2247 - 2256
Survival in SAFE TBI sub-group (n = 460)
Survival 28 Days
Survival 24 Months
20.4%
33.2%
Survival in SAFE TBI sub-group (n = 460)
Survival 28 Days
Survival 24 Months
20.4%
Severe TBI (N = 290)
RR and 95% CI: 1.88 (1.31 to 1.70)
33.2%
SAFE TBI comments
• Post - hoc sub group analysis
• Co-interventions for TBI not described
• Biological mechanisms not clear
• Intracranial hypertension
• 30% vs 34% albumin vs normal saline
Predefined sub-group with severe sepsis n = 1218
Finfer et al, Intensive Care Medicine, published on line, October 6, 2010
SAFE Severe Sepsis:
Baseline Characteristics
Albumin
Saline
60.5 ±17.2
61.0±17.1
59.6%
57.1%
21.6±7.8
21.8±7.7
Septic Shock
34.8%
37.3%
ARDS
6.5%
6.8%
Ventilation
56.8%
59.4%
Age
Gender (male)
APACHE II
SAFE Severe Sepsis: 28 day mortality
Finfer et al, Intensive Care Medicine, published on line, October 6, 2010
SAFE Severe Sepsis: 28 day mortality
Finfer et al, Intensive Care Medicine, published on line, October 6, 2010
SAFE Severe Sepsis: 28 day mortality
No differences in renal
injury between fluid groups
Finfer et al, Intensive Care Medicine, published on line, October 6, 2010
FEAST Trial
• 3141 African children with febrile illness and impaired
perfusion
• Randomized to boluses of 5% albumin, normal saline, or
no bolus
Maitland et al, NEJM, 2011
FEAST Trial
• 3141 African children with febrile illness and impaired
perfusion
• Randomized to boluses of 5% albumin, normal saline, or
no bolus
Bolus
5% albumin
Bolus
normal saline
Control
48 hour death
10.6%
10.5%
7.3%
4 week death
12.2%
12.0%
8.7%
Neurologic
sequlae
2.2%
1.9%
2.0%
Increased ICP or
pulmonary edema
2.6%
2.2%
1.7%
Maitland et al, NEJM, 2011
More evidence for albumin in sepsis is coming……
EARRS Trial
ALBIOS Trial
PRECISE Trial
Septic shock within
first 6 hours ICU
admission
Severe Sepsis/Septic
Shock within 24 hours in
ICU
Early Septic shock from the
ED
800
1800
1808
Interventi
on
Open label
100 mls 20% albumin
Q8H versus normal
saline for first 3 days
in ICU
Open label
Up to 300 mls infused
20% albumin vs
crystalloid fluid according
to albumin levels in ICU
Double blind
Head to Head 500 ml
boluses 5% albumin versus
normal saline starting in ED
Primary
Outcome
28 Day
Mortality
28 Day Mortality
90 Day Mortality
Populatio
n
Sample
Size
Colloids versus Crystalloids for Fluid
Resuscitation: Do we have the ANSWERS yet?
Albumin
Hydroxyethyl
starch
Yes
Evidence
coming
Evidence coming
Evidence
coming
Trauma
SG evidence
SG evidence
ARDS
SG evidence
SG evidence
Traumatic Brain Injury
SG evidence
SG evidence
?
?
Populations
Heterogeneous critically ill
Septic shock
Sub Arachnoid Hemorrhage
SG = evidence from sub group