Fluid Treatments in Sepsis: Recent Trials andRecent Trials and

Meta-AnalysesLauralyn McIntyre MD, FRCP(C), MSc

Scientist, Ottawa Hospital Research InstituteAssistant Professor, University of Ottawa

Department of Epidemiology and Community Medicinep p gy yCentre for Transfusion Research

Chinese Society of Critical Care Medicine Conference Beijing September 14 – 16 2012Beijing, September 14 16, 2012

Conflicts of InterestConflicts of Interest

• CSL Behring g• Baxter Inc• Plasma Protein Therapeutics Association

Why may we use colloid clinically?

PlasmaPlasma

ISS10 L

IC30 L

as a3 L3 L

ISS10 L

IC30 L

For Replacement 10 L 30 L

Blood CellsBlood Cells

10 L 30 L

2 L2 L

Iso-oncotic colloid Hyper-oncotic colloid

Cochrane Systematic Reviews of Fluid Resuscitation

Author/yr Fluids compared # StudiesPerel, 2011 Colloids vs Crystalloids 56

Few Critical Care TrialsOutdated protocols

Bunn, 2011 Colloid vs Colloid 72Alderson 2009 Albumin vs no albumin 37

Heterogenous fluidsDifferent fluid comparators

Different dosesNEJM, 2007

Cochrane 2010 HES vs other fluid 34Different dosesTiming of fluidsHigh risk of bias

So why are we still talking about and studying this question???????

Safe Study Investigators, 2010

International Cross Sectional Study of Resuscitation Fluid Episodes in 391 ICUsResuscitation Fluid Episodes in 391 ICUs

Finfer, S et al Critical Care 2010; 14: 1-24

International Cross Sectional Study of Resuscitation Fluid Episodes in 391 ICUsResuscitation Fluid Episodes in 391 ICUs

Finfer, S et al Critical Care 2010; 14: 1-24

The “type of fluid” question: heightened controversy and new evidencecontroversy and new evidence

Perner et al, NEJM 2012; 367: 124-134

Snap Shot: Use of Colloids Internationally Over Time

AlbuminSynthetic ColloidsSynthetic Colloids

71 6

11.7

71.6

Jones, D et al, Anesthesia and Intensive Care 2010: 38; 266 - 273

What are hydroxyethyl starch (HES) fluids?

• Amylopectin starch (branched chain glucose molecules)• Corn• Corn• Potato

• Rapid hydrolysis via amylase (t1/2 = 10 minutes)• Hydroxyethylation at C2 and C6 carbon units (substitution)

What is the current evidence for hydroxyethyl starch fluids for severehydroxyethyl starch fluids for severe

sepsis and septic shock?

HES and requirement for renal replacement therapy in the critically ill: A meta - analysis

FavoursOdds ratioNo. of events

No. of participantsSt di FavoursOdds ratio

No. of events

No. of participantsSt di

y y y

FavoursHydroxyethyl Starch Favours Control

Odds ratio(95% CI)HES Control

events participantsStudy

Brunkhorst, 2008 26 1.95 (1.30-2.91)81/261 51/272All studies

Studiesn

FavoursHydroxyethyl Starch Favours Control

Odds ratio(95% CI)HES Control

events participantsStudy

Brunkhorst, 2008 26 1.95 (1.30-2.91)81/261 51/272All studies

Studiesn

McIntyre, 2008 28 3.00 (0.28-31.63)Schortgen, 200116 1.20 (0.49-2.93)Cittanova, 1996 27 9.50 (1.09-82.72)

1.90 (1.22- 2.96)

3/21 1/1913/65 11/649/27 1/20

Overall 106/374 64/3754

McIntyre, 2008 28 3.00 (0.28-31.63)Schortgen, 200116 1.20 (0.49-2.93)Cittanova, 1996 27 9.50 (1.09-82.72)

1.90 (1.22- 2.96)

3/21 1/1913/65 11/649/27 1/20

Overall 106/374 64/3754

Patient populationSubgroup analyses

Severe sepsis/septic shock 1.82 (1.27-2.62)Organ transplantation 9 50 (1.09-82.72)

97/347 53/3559/27 1/20

31

Patient populationSubgroup analyses

Severe sepsis/septic shock 1.82 (1.27-2.62)Organ transplantation 9 50 (1.09-82.72)

97/347 53/3559/27 1/20

31

Type of comparator

Organ transplantation 9.50 (1.09 82.72)9/27 1/20

Gelatin 2.64 (0.37-18.96)Crystalloid 1.98 (1.33-2.94)

22/92 12/8484/282 52/291

1

22

Type of comparator

Organ transplantation 9.50 (1.09 82.72)9/27 1/20

Gelatin 2.64 (0.37-18.96)Crystalloid 1.98 (1.33-2.94)

22/92 12/8484/282 52/291

1

22

Odds ratio and 95% CI

0.01 0.1 1 10 100

Odds ratio and 95% CI

0.01 0.1 1 10 100

Zarychanski et al, Open Medicine, 2009: 3; 196 - 209

Perner et al, NEJM 2012; 367: 124-134

• Multi-center randomized double blind controlled trial 798 patients in ICU with severe sepsis who met eligibility criteria within the prior 24 hours

• Tetraspan (6% HES 130/0.42) versus Ringers Acetate• Maximum daily dose 33 mls/kg• Primary Outcome: Mortality or dependence on dialysis at 90 days

Baseline Characteristics HES (n = 398)

Ringers Acetate (n = 400)

Age Median (IQR) 66 (56 – 75) 67 (56 – 76)Age Median (IQR) 66 (56 75) 67 (56 76)Male No (%) 239 (60) 244 (61)SAPS II Median (IQR) 50 (40 – 60) 51 (39 – 62)Shock No (%) 366 (84) 337 (84)Shock No (%) 366 (84) 337 (84)Acute Kidney Injury No (%) 142 (36) 140 (35)Mechanical Ventilation No (%) 240 (60) 245 (61)

Perner et al, NEJM 2012; 367: 124-134

HES Ringers AcetateHES (n = 398)

Ringers Acetate (n = 400)

Fluid 24 hours prior to randomization Median (IQR)

3500 (2000 – 4938) 3000 (2000 – 4868)

HES (n = 398)

Ringers Acetate (n = 400)

Relative Risk95% Confidence

Intervals( Q )

Study Fluid Median (IQR) 3000 (1507 – 5100) 3000 (2000 – 5750)

Open label synthetic colloid No(%) 39 (10) 38 (9.5)

Dead or dialysis dependent 90 days No(%)

202 (51) 173 (43) 1.17 (1.07 – 1.36)

Dead 90 days No(%) 201 (51) 172 (43) 1.17 (1.01 – 1.36)

Doses > protocol maximum No(%) 28 (7)* 41 (10)Dependent on dialysis 90 days No(%)

1 (0.25) 1 (0.25) ---

Renal replacement 87 (22) 65 (16) 1 35 (1 01 – 1 80)

* 2 patients in the HES group received doses higher than maximum recommended from manufacturer (> 50 mls/kg/day

Renal replacement therapy No(%)

87 (22) 65 (16) 1.35 (1.01 1.80)

Insert our updated forrest plot of all HES RCTs t d t CHEST T i l lt tto date, CHEST Trial results to come

Human plasma protein

ALBUMINHuman plasma protein• Derived from pooled plasma• Molecular weight of 66 Kd

S th i d i th li• Synthesized in the liver• Negatively charged• Most common plasma protein (60%)

C t ti i l 40 /L• Concentration in plasma 40 g/L

Available:I i (4 %)– Iso – oncotic (4 – 5%)

– Hyper – oncotic (20 – 25%)

• Responsible for 75 80% oncotic pressure• Responsible for 75-80% oncotic pressure

• Oncotic effect of albumin due to:

Direct effect of albumin: 60%

Gibbs-Donnan effect: 40%

Quinlan, GJ et al, Hepatology, 2005: 41; 1211 - 1219

What are albumin’s functions?

• Maintenance of colloidMaintenance of colloid oncotic pressure

• Transport protein

• Binds inflammatory mediatorsed ato s

• Anti-oxidant effectsAnti oxidant effects

Vincent, JL Best Practise and Research Clinical Anesthesiology 2009; 23: 183 - 191

What is the evidence for albumin as aWhat is the evidence for albumin as a volume resuscitation fluid?

Are colloid fluids better maintained in theAre colloid fluids better maintained in the intravascular space as compared to crystalloids in

critical illness?

RCT/Yr Population Fluid Comparators

Ratio Colloid/CrystalloidComparators Colloid/Crystalloid

SAFE/04 Critically illN = 6997

4% albumin vs normal saline

1:1.4

VISEP/08 Severe Sepsis/Septic

Shock

10% HES vs ringers lactate

1:1.4

ShockN = 537

McIntyre/08 Septic ShockN = 40

10% HES vs0 9% saline

1:1.1N = 40 0.9% saline

McIntyre/12 Septic ShockN = 50

5% albumin vs0.9% saline

1:1.4

Perner/12 Severe Sepsis and shockN 800

tetraspan vs ringers acetate

1:1.1

N = 800

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

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

N = 460

GCS 3 – 12 and an abnormal CTGCS 3 12 and an abnormal CT scan

Myburgh J et al, NEJM 2008; 357: 874 - 884

SAFE TBI: Baseline Characteristics

Albumin (n=231)

Normal Saline (n=229)

Age Median (IQR) 37 (23-55) 35 (23-50)

Male (%) 77.5 73.8

*APACHE II 20.4±6.1 19.7±6.4

*AISS 28.6±9.9 28.2±10.5

*MAP mm Hg 82.5±13.7 84.0±13.7

*CVP H 3 3 3 8*CVP mm Hg 7.3±3.5 7.5±3.8

*GCS 7 (4-9) 7 (5-9)

*ICP 15 0±12 9 12 4±7 2ICP 15.0±12.9 12.4±7.2

Hypotension (%) 30.4 33

* mean±SDMyburgh J et al, NEJM 2008; 357: 874 - 884

Survival in SAFE TBI sub-groupSurvival in SAFE TBI sub group

Survival 28 Days Survival 24 Months

20.4%

Mortality Severe TBI (N = 290)

33.2%RR and 95% CI: 1.88 (1.31 to 1.70)

Predefined sub-group with severe sepsis n = 1218

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

Baseline Characteristics

CVP missing 707 (58%)n=707 (58%)

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

Fluids and Co-Interventions

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

MAP HRMAP HR

CVP ALB

SAFE Severe Sepsis: 28 day mortality

No differences in renal injury

between the fluid groups

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

What is the evidence for use of albumin for patients who

are hypoalbuminemic?are hypoalbuminemic?

Albumin levels are decreased in the critically ill…..the critically ill…..

• Altered production• Increased degredation• Increased losses• Leak from capillaries

Vincent, JL Best Practise and Research Clinical Anesthesiology 2009; 23: 183 - 191

• Single center, non-blinded RCT pilot study in Brussels, Belgium.

100 patients ith se m alb min < 30 g/L• 100 patients with serum albumin < 30 g/L

• 300 mls of 20% albumin on day 1 followed by 200 mls/day if serum albumin ≤ 30 g/L versus ringers lactate as standard therapy

• Primary Outcome: change SOFA score baseline to day 7

Albumin Control P Value

Delta SOFA 3.1 (1.0) 1.4 (1.1) 0.03

Fluid Gain mls(Mean (SD))

658(1101)

1679(1156)

0.04

Caloric intake Kcal 1122 760 0 05Caloric intake Kcal(Median, IQR)

1122 (935, 1158)

760 (571, 1077)

0.05

Dubois et al. Crit Care Med. 2006; 34: 2536 - 2540

• 6045 patients from SAFE trial

• Baseline serum albumin• Baseline serum albumin levels < 25 versus ≥ 25 g/L

• Resuscitated with normal saline or 4% albumin

Finfer, S et al, BMJ 2006; 333: 1 - 6

What is the evidence for albumin d bili ti f i t titi land mobilization of interstitial

fluid? ARDS Network, NEJM, 2006: 354; 2564 - 2575

Boyd, JH, Critical Care Medicine, 2011: 39; 1 - 7

Hyperoncotic albumin and lasix bi i i icombination: systematic review

• Martin et al: 2 randomized controlled trials• Patient populations: mechanical ventilation with

acute lung injuryacute lung injury• N = 77 patients studied

• Results:• Achievement negative fluid balance

Greater eight loss• Greater weight loss• Improved oxygenation

Thiboutot et al, Am J Respir Crit Care Med 2009: 179, A3089

• 126 patients with cirrhosis and SBP

CefotaximeN = 63

Cefotaxime + albumin

N = 63

P value

• Cefotaxime vs cefotaxime + 20%

lb i

N 63Renalimpairment

21(33) 6(10) 0.002

Death:albumin

P i O t

Death:Hospital3 months

18(29)26(41)

6(10)14(22)

0.010.03

• Primary Outcome:• Renal impairment

Pao, S, NEJM, 1999

5% albumin versus normal saline for resuscitation in early septicfor resuscitation in early septic

shock (PRECISE)

• Design: Multi - center double blind randomized controlled trialSetting 6 Canadian tertiar care centers• Setting: 6 Canadian tertiary care centers

• Population: 50 patients with early suspected septic shock recruited from: emergency department (ED) and g y p ( )intensive care unit (ICU)

• Intervention: Blinded 500 ml boluses of 5% albumin or l li f fl id it ti fi t 7 d i ICUnormal saline for fluid resuscitation first 7 days in ICU

• Primary outcome: Feasibility

McIntyre, L et al, Journal of Critical Care, 2012; 27: 317

Additional albumin in sepsis evidence is l ialso coming…….

ALBIOS Trial EARRS Trial RASP TrialALBIOS Trial EARRS Trial RASP Trial

Population Severe Sepsis/Septic Shock within 24 hours in

ICU

Septic shock within first 6 hours ICU admission

Severe sepsis/septic shock within 6 hours of evolution

Sample Size 1800 800 360

Intervention Open labelUp to 300 mls infused

20% albumin vs crystalloid fluid

according to albumin

Open label100 mls 20% albumin Q8H

versus normal saline for first 3 days in ICU

Blinded 500 ml boluses of 4% albumin versus ringers lactate until CVP is ≥ 8 mm

Hg or recovery from hypotensionaccording to albumin

levels in ICUhypotension

Primary Outcome

28 and 90 Day Mortality

28 Day Mortality 28 Day Mortality

Feast Trial

Maitland et al, NEJM, 2011

Although FEAST was conducted in a pediatric• 3141 African children with febrile illness and impaired perfusion

• Randomized boluses:5% albumin 0 9% saline or no bolus

Although FEAST was conducted in a pediatric patient population, in Africa, with the majority of

children having malaria…..• Randomized boluses:5% albumin, 0.9% saline, or no bolus

Bolus 5% albumin

Bolus normal saline

Control

children having malaria…..

5% albumin normal saline48 hour death 10.6% 10.5% 7.3%

4 week death 12.2% 12.0% 8.7%

Results of FEAST should at least cause us to question some of the very basics of our fluid

it ti tiee deat % 0% 8 %

Neurological sequlae

2.2% 1.9% 2.0%resuscitation practises…….

Increased ICP/ pulmonary edema

2.6% 2.2% 1.7%

A summary of the evidence for lb i i i 2012albumin in sepsis year 2012

• With the present level of evidence 2012:• Consider use for septic shock

A id i t ti b i i j• Avoid use in traumatic brain injury• Mobilization fluid from interstitial space

• Acute lung Injury/Acute respiratory distress syndromeAcute lung Injury/Acute respiratory distress syndrome• Paracentesis for cirrhosis

• More evidence is coming to understand the place of albumin in the critically ill

Thank you for your attention!Thank you for your attention!