Colloids versus Crystalloids: Do we have an answer … versus Crystalloids: Do we have an answer...

Colloids versus Crystalloids: Do we have an answer yet??

Lauralyn McIntyre MD, FRCP(C), MHScScientist, Ottawa Hospital Research Institute

Assistant Professor, University of OttawaDepartment 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 FluidNormal SalineRingers Lactate

Colloid FluidAlbuminHydroxyethyl starch

Main categories of usual care resuscitation fluids

Crystalloid FluidNormal SalineRingers Lactate

Colloid FluidAlbuminHydroxyethyl starch

Other Colloids:GelatinsDextrans

Components of Normal Saline and Ringers Lactate

28

0

Lactatemmol/L

272

308

Osmo-larity

2.7

0

Ca++mmol/L

4

0

K+mmol/L

109130Ringers Lactate

154154Normal Saline

Cl-mmol/L

Na+mmol/L

• 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

Albumin

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

ISS10 L

IC30 L

Plasma3 L

Blood Cells2 L

Rationale for Resuscitating with Colloids compared to Crystalloids

ISS10 L

IC30 L

Plasma3 L

Blood Cells2 L

Rationale for Resuscitating with Colloids compared to Crystalloids

Plasma3 L

Blood Cells2 L

Iso-oncotic colloid

ISS10 L

IC30 L

Plasma3 L

Blood Cells2 L

Rationale for Resuscitating with Colloids compared to Crystalloids

Plasma3 L

Blood Cells2 L

Iso-oncotic colloidHyper-oncotic colloid

ISS10 L

IC30 L

Plasma3 L

Blood Cells2 L

Rationale for Resuscitating with Colloids compared to Crystalloids

Plasma3 L

Blood Cells2 L

Iso-oncotic colloidHyper-oncotic colloid

ISS10 L

IC30 L

ISS10 L

IC30 L

Plasma3 L

Blood Cells2 L

Rationale for Resuscitating with Colloids compared to Crystalloids

Plasma3 L

Blood Cells2 L

Iso-oncotic colloidHyper-oncotic colloid

ISS10 L

IC30 L

Optimization of the microcirculation?Impact on microcirculatory dysfunction?Modulation of inflammatory response

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 Fluids compared # StudiesPerel, 2011 Colloids vs Crystalloids 56Bunn, 2011 Colloid vs Colloid 72Alderson 2009 Albumin vs no albumin 37Dart 2010 HES vs other fluid 34

Cochrane Systematic Reviews

Author/Year Fluids compared # StudiesPerel, 2011 Colloids vs Crystalloids 56Bunn, 2011 Colloid vs Colloid 72Alderson 2009 Albumin vs no albumin 37Dart 2010 HES vs other fluid 34

So why are we still studying this question?

Cochrane Systematic Reviews

Author/Year Fluids compared # StudiesPerel, 2011 Colloids vs Crystalloids 56Bunn, 2011 Colloid vs Colloid 72Alderson 2009 Albumin vs no albumin 37Dart 2010 HES vs other fluid 34

So why are we still studying this question?

• Small sample size• Single centre• Dated resuscitation protocols• Insufficient dose• Surrogate outcomes• Few studies in the critically ill• Low methodological rigor (risk of bias high)

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 RatioCrystalloid/Colloid

SAFE/04 Critically illN = 6997

4% albumin vs normal saline

1.4

VISEP/08 Severe Sepsis/Septic Shock

N = 537

10% HES vs ringers lactate

1.4

McIntyre/08 Septic ShockN = 40

10% HES vsnormal saline

1.1

Hartog et al, Anesth and Anal 2011, 112:635-645

RCT/Yr Population Fluid Comparators RatioCrystalloid/Colloid

SAFE/04 Critically illN = 6997

4% albumin vs normal saline

1.4

VISEP/08 Severe Sepsis/Septic Shock

N = 537

10% HES vs ringers lactate

1.4

McIntyre/08 Septic ShockN = 40

10% HES vsnormal saline

1.1

Hartog et al, Anesth and Anal 2011, 112:635-645

RCT/Yr Population Fluid Comparators RatioCrystalloid/Colloid

SAFE/04 Critically illN = 6997

4% albumin vs normal saline

1.4

VISEP/08 Severe Sepsis/Septic Shock

N = 537

10% HES vs ringers lactate

1.4

McIntyre/08 Septic ShockN = 40

10% HES vsnormal saline

1.1

Hartog et al, Anesth and Anal 2011, 112:635-645

RCT/Yr Population Fluid Comparators RatioCrystalloid/Colloid

SAFE/04 Critically illN = 6997

4% albumin vs normal saline

1.4

VISEP/08 Severe Sepsis/Septic Shock

N = 537

10% HES vs ringers lactate

1.4

McIntyre/08 Septic ShockN = 40

10% HES vsnormal saline

1.1

Hartog et al, Anesth and Anal 2011, 112:635-645

? Endothelial Cell Leak

Are there potential harms associated with the use of colloid fluid in the

Hydroxyethyl starches Albumin

Coagulopathy yes yes

Transmission viral infection no yes

Anaphylaxis yes(<0.006%)

yes(<0.1%)

Pruritis yes no

Renal Failure yes ?

Grocott, M, Anesthesia and Analgesia, 2005

Hydroxyethyl starches Albumin

Coagulopathy yes yes

Transmission viral infection no yes

Anaphylaxis yes(<0.006%)

yes(<0.1%)

Pruritis yes no

Renal Failure yes ?

Grocott, M, Anesthesia and Analgesia, 2005

Brunkhorst et al, NEJM, 2008

Baseline CharacteristicsMean (SD)

Ringers LactateN=275

HESN=262

P value

Age 64.9 ±4.1 64.4 ± 13.3

Sex (male) (%) 59.6 60.3

APACHE II Score 20.3 ± 6.7 20.1 ± 6.7

Results (%) *RRT 18.8% 31% 0.001

Acute renal failure 22.8 34.9 0.001

28 day Mortality 24.1% 26.7% 0.484

90 day Mortality 33.9% 41% 0.092

Brunkhorst et al, NEJM, 2008*RRT = renal replacement therapy

VISEP trial: HES dose and RRT

Brunkhorst et al, NEJM, 2008

VISEP trial: HES dose and RRT

Brunkhorst et al, NEJM, 2008

Limitations of the VISEP Trial

• Fluid protocol violations • No criteria for dialysis

• Un-blinded study

What evidence related to HES is forthcoming?

Trial Population Fluids compared Primary Outcome

6S Severe SepsisN = 800

Voluven vsRingers lactate

90 Day Mortality or Dialysis

CHEST Critically illN = 7000

Voluven vsNormal Saline

90 Day Mortality

Finfer et al, NEJM 2004; 350: 2247 - 2256

Survival 28 Days Survival 24 Months

Survival in SAFE TBI sub-group (n = 460)

20.4%

33.2%

Survival 28 Days Survival 24 Months

Survival in SAFE TBI sub-group (n = 460)

20.4%

33.2%

Severe TBI (N = 290)

RR and 95% CI: 1.88 (1.31 to 1.70)

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 SalineAge 60.5 ±17.2 61.0±17.1

Gender (male) 59.6% 57.1%

APACHE II 21.6±7.8 21.8±7.7

Septic Shock 34.8% 37.3%ARDS 6.5% 6.8%Ventilation 56.8% 59.4%

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

Finfer et al, Intensive Care Medicine, published on line, October 6, 2010

No differences in renal injury between fluid groups

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

Maitland et al, NEJM, 2011

Bolus5% 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%

More evidence for albumin in sepsis is coming……

EARRS Trial ALBIOS Trial PRECISE Trial

Population

Septic shock within first 6 hours ICU

admission

Severe Sepsis/Septic Shock within 24 hours in

ICU

Early Septic shock from the ED

Sample Size

800 1800 1808

Intervention

Open label100 mls 20% albumin Q8H versus normal

saline for first 3 days in ICU

Open labelUp to 300 mls infused

20% albumin vs crystalloid fluid according to albumin levels in ICU

Double blindHead to Head 500 ml

boluses 5% albumin versus normal saline starting in ED

Primary Outcome

28 Day Mortality

28 Day Mortality 90 Day Mortality

Colloids versus Crystalloids for Fluid Resuscitation: Do we have the ANSWERS yet?

Populations Albumin Hydroxyethyl starch

Heterogeneous critically ill Yes Evidence coming

Septic shock Evidence coming Evidence coming

Trauma SG evidence SG evidence

ARDS SG evidence SG evidence

Traumatic Brain Injury SG evidence SG evidence

Sub Arachnoid Hemorrhage ? ?

SG = evidence from sub group