Fluid in Sepsis: A New ParadigmPaul Marik, MD, FCCP, FCCM

Disclosures

Stocks

Advisory boards

Grants

Speakers Bureau

None

Scientific Disclosures

Three Great Myths in the management of

sepsis

Sepsis is associated with tissue hypoxia

Protocols to “optimize” CI or DO2 improve

outcome

Sepsis is “volume depleted” state

JAMA 1992;267:1503

Ronco JJ, et al. JAMA 1993;270:1724

4ml/kg/min

N Engl J Med 1994; 330:1717

From: Effect of Heart Rate Control With Esmolol on Hemodynamic and Clinical Outcomes in

Patients With Septic Shock: A Randomized Clinical Trial

JAMA. 2013;():-. doi:10.1001/jama.2013.278477

0

100

200

300

400

500

600

BL 24 hr 48 hr 72 hr

DO2

Esmolol Control

From: Effect of Heart Rate Control With Esmolol on Hemodynamic and Clinical Outcomes in

Patients With Septic Shock: A Randomized Clinical Trial

JAMA. 2013;():-. doi:10.1001/jama.2013.278477

Time Hrs

0 20 40 60 80 100 120

0

100

200

400

500

600

La

cta

te

1.0

1.5

2.0

2.5

3.0

Time vs Lactate - E

Time vs Lactate - C

DO2/VO2

DO2

From: Effect of Heart Rate Control With Esmolol on Hemodynamic and Clinical Outcomes in

Patients With Septic Shock: A Randomized Clinical Trial

JAMA. 2013;():-. doi:10.1001/jama.2013.278477

Oxygen kinetics in sepsis

Oxygen requirement are not increased in patients

with sepsis

An oxygen debt does not exist in patients with

sepsis

Lactate is produced aerobically as part of the stress

response

Attempts to increase DO2 in response to an

elevated lactate is

Illogical and devoid of scientific evidence

Likely to be harmful

Historical Perspective

Lancet, Feb 4 1882

His first patient was an elderly women who had reached

the last moments of her earthly existence. “Having no

precedent to guide me I proceeded with much caution”

His first patient was an elderly women who had reached

the last moments of her earthly existence. “Having no

precedent to guide me I proceeded with much caution”

Latta inserted a tube into the basilic vein and injected

ounce after ounce of fluid, closely observing the patient.

His first patient was an elderly women who had reached

the last moments of her earthly existence. “Having no

precedent to guide me I proceeded with much caution”

Latta inserted a tube into the basilic vein and injected

ounce after ounce of fluid, closely observing the patient.

“the sunken eyes and fallen jaw, pale and cold extremities

bearing the manifest imprint of deaths signet, began to

glow with returning animation; the pulse returned to the

wrist”

From this to …. The “Rivers” Protocol

Goals of Hemodynamic Resuscitation

Achieve an adequate perfusion pressure

MAP > 65 mmHg

Improve microcirculatory flow

Limit tissue edema

Crit Care Med 2013; 41:34

The Hemodynamic derangements of sepsis

Vasoplegic shock/vasodilatory shock

Nitric oxide

ANP

KATP

Vasopressin

Leaky capillaries

Glycocalyx

Endothelial junctions

Myocardial depression

Nitric Oxide

1. NO/ANP

2. Activation of KATP

3. Vasopressin deficiency

VGEF

Angiopoeitin 2

Starling Principle

Starling (1896) states fluid exchange is governed by

high vascular COP and low interstitial COP

Recently it is proved that intravascular COP is

almost identical to extravascular one

Jacob M. et al Cardiovascular Research 2007; 73:

575-586

EG consists of membrane-bound proteoglycans and glycoproteins network in which plasma or endothelial proteins are retained - forms the endothelial surface layer (ESL)

ESL thickness is 1μm

Jacob M. et al Cardiovascular Research 2007; 73:

575-586

Endothelial Glycocalyx

The Glycocalyx Denuded in Sepsis

Crit Care Med 2008; 36:1701

Norepi 0.8 ug/kg/min Norepi 0.4 ug/kg/min

Dobutamine 5 ug/kg/minLVFAC= left ventricular fractional area contraction

The Hemodynamic derangements of sepsis

FLUIDS INCREASE Vasoplegic shock/vasodilatory shock

Nitric oxide

BNP

KATP

Vasopressin

FLUIDS INCREASE Leaky capillaries

Glycocalyx

Endothelial junctions

FLUIDS INCREASE Myocardial depression

Nitric Oxide

Myocardial edema

Fluid may not be the most efficient method to increase

MAP in septic shock

Crit Care Med 2007;35:477

% change in cardiac Index

Eur J Pharmacology 2009;621:67

BNP damages glycocalyx

Inc atrial pressure leads to a release of natriuretic

peptides

ANP/BNP shed off the glycocalyx components

(syndecan -1) into the circulation

This is accompanied by significant rapid shifts of

intravascular fluid into interstitial space

Bruegger D. et al Am J Physiol 2005; 289: H1993

Ueda S, et al. Shock 2006;26:123

Resuscitated according to EGDRx

0

200

400

600

800

1000

1200

1400

Admission Day 1 Day 2 Day 4

Survivors Non-survivors

BNP (pg/ml)

Bark BP, et al. Crit Care Med 2013;41

CLP

Excess fluid Increases mortality in

patients with sepsis

The Evidence: Experimental Models

Crit Care 2009; 13:R186

48 pigs randomized to endotoxin infusion, fecal peritonitis

or control

Each group randomized to Moderate (10ml/kg/hr) or High

volume-EGDRx (20 ml/kg/hr) LR resuscitation for 24 hrs

High Volume-EGDRx Group

Higher CI

Higher MAP

Higher PCWP

Lower lactate

Higher SmvO2

Crit Care 2009; 13:R186

The Evidence: Clinical Studies

Alsous F et al. Chest 2000;117:1749

The Soap Study

Crit Care Med 2006; 34:344

Crit Care Med 2011;39:256-265

Crit Care Med 2011;39:256-265

Optimal survival occurred with a

positive fluid balance of approximately

3 liters at 12 hours

Patients with CVP <8

mmHg at 12 hrs had

the lowest mortality.

Crit Care Med 2011;39:256-265

Days

Association of cumulative fluid balance on outcome

in ALI: A review of the ARDSnet cohort

J Intens Care Med 2009;24:35

2009; 136:102-109

Non-survivors

Survivors

Resp Med 2008;102:956

Mortality 48 hrs Mortality 4 weeks

Maitland K, et al. NEJM 2011; 364:2483

Fluid resuscitation in sepsis

“Give them as much as they need and

not a drop more”….

Where's the Blood Volume?

Crit Care Med 2012;40:3146

Before After

Dose norepinephrine

(ug/kg/min)0.3 0.19

CI (l/min/M2) 3.47 3.28

CI change by PLR (%) 1 8

Mean systemic pressure

(mmHg)33 26

GEDVI (ml/m2) 819 774

The lowest mortality was seen in patients with lower SOFA scores

and early norepinephrine administration after admission.

Conclusion: Both the time of starting norepinephrine after

admission to the

ICU and the degree of organ dysfunction have an important bearing

on subsequent

Outcome

Crit Care Med 2000;28:947

Geleon A, et al. Crit Care Med 2014 (ePub

Normal adrenal function

Impaired adrenal function

Before HC After HC

Annane, British Journal of Clinical Pharmacology, 1998

Effect of Hydrocortisone on Sepsis-Induced

Hypotension

SV

EVLW

Preload

Large increase in EVLW

Small increase in CO

The Frank-Starling & Marik-Phillips Curves

Large increase in CO

Small increase in EVLW

Sepsis

Techniques to Assess Fluid Responsiveness

Excellent

Fair-Good

Worthless

ROC Curves & Diagnostic Accuracy

Assessment of fluid

responsivenessTechnique

CVP/PAOP

IVC/SVC diameter

FTc (LVETc)

RVEDV/LVEDA/GEDI

IVC/SVC - respiratory variation

PPV/SVV/PVI

Aortic blood flow - respiratory

variation

Passive Leg Raising

(PLR)

Technology

CVP/PAC

Non calibrated pulse contour

Bioimpedance

Ultrasound (IVC/SVC)

Ultrasound (IVC/SVC resp. variability)

Pleth waveform (PVI)

ECHO- Aortic Doppler (resp. variability)

Calibrated pulse contour (PPV/SVV)

Esophageal Doppler (PLR &

volume)

Calibrated pulse contour (PLR &

volume)

Assessment of fluid responsiveness

Technique

PLR

Volume

Challenge

Technology

Esophageal Doppler

Calibrated pulse

contour

NICOM -

Bioreactance

Study name sample size AUC

Monnet CCM 2006 71 0.96

Lafanéchère CC 2006 22 0.95

Lamia ICM 2007 24 0.96

Maizel ICM 2007 34 0.89

Monnet CCM 2009 34 0.94

Thiel CC 2009 102 0.89

Biais CC 2009 30 0.96

Preau CCM 2010 34 0.94

351 0.95

Study name sample size AUC

Monnet CCM 2006 71 0.75

Monnet CCM 2009 34 0.68

Preau CCM 2010 34 0.86

139 0.76

PLR-induced changes in PP

Which Fluid?

Crystalloids

Balanced Salt Solutions (BSS)

Ringers

Plasmalyte

Un-physiologic Salt Solutions

(USS)

NaCl

Colloids

Albumin (USS)

Starches (USS)

Chloride liberal vs. Chloride Restrictive

Strategy

Anesth Analg 2013:117:412

“Ab-Normal” Saline vs. Balanced Salt

Solution Metabolic and dilutional acidosis

Decreased renal blood flow

Coagulopathy- more bleeding

Increased inflammation

Increased risk of renal failure

Increased risk of death

NEJM 2008;358:125

5% Albumin

Maintains endothelial glycocalyx and “endothelial

function”

Anti-oxidant properties

Anti-inflammatory properties

May limit “third” space loss

Albumin has a number of features that may be theoretically advantageous

in patients with sepsis and SIRS including:

Kozar R, et al. Anesth Analg

2011;112:1289

Pts. with severe sepsis or septic shock (6-24 hr)

Albumin Crystalloid

s

crystalloids

Albumin:

[300 ml at 20% in 3* hrs]

+

crystalloids

Study design

Randomization

Volume replacement

Study design

from day 1 to day 28

Plasma albumin

level

< 30 g/L

≥ 25 g/L≥ 30 g/L

No infusion

of Albumin

Infusion of

Albumin:

200 ml at 20%

in 3* hrs

< 25 g/L

Infusion of

Albumin:

300 ml at 20%

in 3* hrs

Albumin

Marik PE. Chest 2014 (in press)