This document discusses fluid management in sepsis. It begins by outlining three common myths in sepsis management: that sepsis causes tissue hypoxia, that protocols to optimize cardiac index or oxygen delivery improve outcomes, and that sepsis causes volume depletion. The document then reviews the historical perspective on fluid resuscitation in sepsis. It discusses the hemodynamic derangements in sepsis, including vasodilation and effects on the endothelial glycocalyx. Clinical studies are presented showing that excess fluid administration is associated with increased mortality in sepsis patients. The document evaluates different fluid types and techniques for assessing fluid responsiveness. It concludes by discussing optimal fluid strategies and the benefits of albumin versus crystalloid solutions.

1. Fluid in Sepsis: A New Paradigm
Paul Marik, MD, FCCP, FCCM

2. Disclosures
 Stocks
 Advisory boards
 Grants
 Speakers Bureau
None

3. 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

4. JAMA 1992;267:1503

5. Ronco JJ, et al. JAMA 1993;270:1724
4ml/kg/min

7. N Engl J Med 1994; 330:1717

8. 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

9. 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
Lactate
1.0
1.5
2.0
2.5
3.0
Time vs Lactate - E
Time vs Lactate - C
DO2/VO2
DO2

10. 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

13. 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

14. Historical Perspective

15. Lancet, Feb 4 1882

18. 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”

19. 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.

20. 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”

21. From this to …. The “Rivers” Protocol

22. Goals of Hemodynamic Resuscitation
 Achieve an adequate perfusion pressure
 MAP > 65 mmHg
 Improve microcirculatory flow
 Limit tissue edema

24. Crit Care Med 2013; 41:34

25. The Hemodynamic derangements of sepsis
 Vasoplegic shock/vasodilatory shock
 Nitric oxide
 ANP
 KATP
 Vasopressin
 Leaky capillaries
 Glycocalyx
 Endothelial junctions
 Myocardial depression
 Nitric Oxide

27. 1. NO/ANP

28. 2. Activation of KATP

29. 3. Vasopressin deficiency

30. VGEF
Angiopoeitin 2

31. 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:

32.  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:
Endothelial Glycocalyx

34. The Glycocalyx Denuded in Sepsis

36. Crit Care Med 2008; 36:1701
Norepi 0.8 ug/kg/min Norepi 0.4 ug/kg/min
Dobutamine 5 ug/kg/min
LVFAC= left ventricular fractional area contraction

37. 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

38. Fluid may not be the most efficient method to increase
MAP in septic shock

39. Crit Care Med 2007;35:477
% change in cardiac Index

40. Eur J Pharmacology 2009;621:67

41. 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

42. 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)

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

46. Excess fluid Increases mortality in
patients with sepsis

47. The Evidence: Experimental Models

48. 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

49. Crit Care 2009; 13:R186

52. The Evidence: Clinical Studies

53. Alsous F et al. Chest 2000;117:1749

54. The Soap Study
Crit Care Med 2006; 34:34

55. Crit Care Med 2011;39:256-2

56. Crit Care Med 2011;39:256-2
Optimal survival occurred with a
positive fluid balance of approximately
3 liters at 12 hours

57. Patients with CVP <8
mmHg at 12 hrs had
the lowest mortality.
Crit Care Med 2011;39:256-2

59. Days

60. Association of cumulative fluid balance on outcome
in ALI: A review of the ARDSnet cohort
J Intens Care Med 2009;24:35

61. 2009; 136:102-109
Non-survivors
Survivors

62. Resp Med 2008;102:956

63. Mortality 48 hrs Mortality 4 weeks
Maitland K, et al. NEJM 2011; 364:2483

67. Fluid resuscitation in sepsis
“Give them as much as they need and
not a drop more”….

68. Where's the Blood Volume?

70. 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

71. 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

72. Geleon A, et al. Crit Care Med 2014 (ePu

73. Normal adrenal function
Impaired adrenal function
Before HC After HC
Annane, British Journal of Clinical Pharmacology, 19
Effect of Hydrocortisone on Sepsis-Induced
Hypotension

74. 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

75. Techniques to Assess Fluid Responsiveness

76. Excellent
Fair-Good
Worthless
ROC Curves & Diagnostic Accuracy

77. 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 &

78. Assessment of fluid responsiveness
Technique
PLR
Volume
Challenge
Technology
Esophageal Doppler
Calibrated pulse
contour
NICOM -
Bioreactance

79. 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

80. Which Fluid?
 Crystalloids
 Balanced Salt Solutions (BSS)
 Ringers
 Plasmalyte
 Un-physiologic Salt Solutions
(USS)
 NaCl
 Colloids
 Albumin (USS)
 Starches (USS)

82. Chloride liberal vs. Chloride Restrictive
Strategy

83. Anesth Analg 2013:117:412

84. “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

85. NEJM 2008;358:125

87. 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 adv
in patients with sepsis and SIRS including:

88. Kozar R, et al. Anesth Analg

89. 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

90. 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

93. Marik PE. Chest 2014 (in press)