Your SlideShare is downloading. ×
The Microcirculation in Sepsis
Upcoming SlideShare
Loading in...5
×

Thanks for flagging this SlideShare!

Oops! An error has occurred.

×

Saving this for later?

Get the SlideShare app to save on your phone or tablet. Read anywhere, anytime - even offline.

Text the download link to your phone

Standard text messaging rates apply

The Microcirculation in Sepsis

1,509
views

Published on

VHIR Seminar led by Daniel De Backer, PhD., from the Dpt of Intensive Care Erasme University Hospital Brussels - Belgium. …

VHIR Seminar led by Daniel De Backer, PhD., from the Dpt of Intensive Care Erasme University Hospital Brussels - Belgium.

Abstract: Multiple studies have shown that alterations in microcirculatory perfusion are frequently observed in patients with septic shock. These alterations are characterized by heterogeneity of perfusion with capillaries with stop flow in close vicinity to well perfused capillaries. What are the consequences of these alterations? The presence of stop flow capillaries favours development of zones of tissue hypoxia, even though total perfusion to the organ is preserved. In addition, the heterogeneity in perfusion is associated with inadequate matching of flow to metabolism and is hence less well tolerated by tissues than an homogeneous decrease in perfusion. In patients with septic shock, the severity of the microvascular alterations was associated with development of organ dysfunction and an increase risk of death.
Different mechanisms have been implicated in the development of these alterations including loss of communication between vascular segments, impaired endothelial reactivity, alterations in red and white blood cells rheology, alteration in endothelial glycocalyx, platelet aggregation and microthrombosis. In view of the various mechanisms implicated in the development of these alterations, it is unlikely that therapies used in usual hemodynamic resuscitation. Novel therapies should aim at improving the matching of perfusion to metabolism rather than further increasing flow in the already perfused vessels or non selectively dilating microvessels.


0 Comments
1 Like
Statistics
Notes
  • Be the first to comment

No Downloads
Views
Total Views
1,509
On Slideshare
0
From Embeds
0
Number of Embeds
0
Actions
Shares
0
Downloads
82
Comments
0
Likes
1
Embeds 0
No embeds

Report content
Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel
No notes for slide

Transcript

  • 1. The Microcirculation in sepsis Daniel De Backer Department of Intensive Care Erasme University Hospital Brussels, Belgium
  • 2. • Microcirculatory perfusion is a key determinant of tissue perfusion. • Microvascular perfusion is under control of different mechanisms than systemic hemodynamics. • O2 transport is driven at microcirculatory level by diffusion more than by convection. TISSUE PERFUSION: Key points
  • 3. Trzeciak et al Crit Care 9:S20;2005 The density of capillaries is a primary determinant of tissue oxygenation
  • 4. Saldivar-E et al AJP 285:H2064;2003 The density of capillaries is a primary determinant of tissue oxygenation Adaptation to chronic hypoxia is characterized by an increased capillary density
  • 5. MICROCIRCULATION DDB USI  r4 1 V = P 8 L  . . . . Determinants of microvascular blood flow Blood flow is adapted to local metabolic needs through local vasodilation and upstream changes in vasomotor tone
  • 6. Neural control Hungerford-JE et al FASEB 14:197;2000 Perivascular sympathetic nerves 10 µm
  • 7. Neural control Beach-JM et al AJP 275:H1489;1998 Arteriole Capillaries
  • 8. Microcirculatory alterations in experimental sepsis
  • 9. Pig Gut serosa OPS, 5x probe
  • 10. Pig Gut serosa (sepsis) OPS, 5x probe
  • 11. Pig Liver OPS, 5x probe
  • 12. Pig Liver (sepsis) OPS, 5x probe
  • 13. Sheep Brain SDF, 5x probe
  • 14. Sheep Brain (sepsis) SDF, 5x probe
  • 15. Hoffmann et al CCM 32,1011;2004 Hamster skinfold LPS DECREASED CAPILLARY DENSITY IN EXPERIMENTAL SEPSIS ENDOTOXIC SHOCK MODEL
  • 16. ANOVA: in sepsis all times p<0.0001 vs baseline Evolution of sublingual microcirculation in septic shock Verdant et al CCM 37;2875,2009 Sham Sepsis Pigs Cholangitis
  • 17. Evolution of microcirculation in unresuscitated septic shock Pranskunas A et al Crit Care 16:R83;2012 Pigs E Coli infusion
  • 18. MICROVASCULAR ALTERATIONS IN EXPERIMENTAL SEPSIS • Decreased capillary density • Heterogeneity of perfusion
  • 19. HETEROGENEITY OF CAPILLARY PERFUSION IN EXPERIMENTAL SEPSIS Ellis C et al AJP 282:H156;2002 rats SPACE
  • 20. CONTROL SINUSOIDAL BLOOD FLOW IN ENDOTOXIC SHOCK After Pannen et al. AJP 271: H1953; 1996 % 0 10 20 30 0 10 20 30 40 50 >50 Fraction of perfused capillaries ENDOTOXIN 0 10 20 30 40 0 10 20 30 40 50 >50 % Sinusoidal flow pl/s Fraction of perfused capillaries
  • 21. Increase heterogeneity of renal perfusion in sepsis Rats LPS Legrand et al ICM 2011
  • 22. EXPERIMENTAL STUDIES IN SEPSIS Microvascular blood flow alterations are frequent decreased vascular density absent or intermittent flow in capillaries heterogeneity between areas DDB USI Branemark et Urbaschek Angiology 18:667;1967 Lam et al. JCI 94: 2077; 1994 Farquhar et al. J Surg Res 61: 190; 1996 Madorin et al CCM 27:394;1999 Ellis et al AJP 282:H156;2002 Verdant et al CCM 37:2875;2009 Secor et al ICM 2010 Different models (LPS, CLP, live bacteria,…) Various species (rats, mice, hamsters, pigs, sheep…) Various organs (skin, gut, liver, lung, kidney, heart, brain…)
  • 23. Cardiomyocytes rats Bateman et al AJP 293/H448;2007 CTRL LPS Consequences…
  • 24. 0 10 20 30 40 50 60 70 80 Gut mucosa SEPSISCTRL -10 -5 0 5 10 15 p<0.01 % % Hemorrhage p<0.01 Humer et al JAP 81: 895; 1996 CRITICAL O2ER CHANGES IN CAPILLARY TRANSIT-TIME HETEROGENEITY MICROCIRCULATORY ALTERATIONS AND EO2CRIT
  • 25. Potential mechanisms ?
  • 26. PATHOPHYSIOLOGY OF MICROVASCULAR ALTERATIONS Triggered by inflammatory mediators TNF (Vicaut E JCI 87:1537;1991)
  • 27. ENDOTHELIALALTERATIONS ctrl 5 days post LPS Leclers J et al CCM 28:3672;2000 rabbits 25-35% vessels
  • 28. Loss of neural control Tyml-K et al AJP 281:H1397;2001 Change in diameter and communication rate (CR500) between 500 µm distant microvessels (retrograde communication) B: cremaster muscle (mice) C: Endothelial microlayer
  • 29. Enhanced response to vasoconstrictor substances Pannen B et al AJP 26:180;2001 CTRL HEM CTRL + ET HEM + ET Rats
  • 30. 2 µm Endothelial cell Glycocalyx 0.2 µm GLYCOCALYX ALTERATIONS van den Berg et al Circ Res 92:592;2003
  • 31. Marechal X et al Shock 29:572;2008 Role of glycocalyx in microvascular alterations Rats, ileum µm
  • 32. Gupta A et al AJP 293:F245;2007 LPS promotes rolling and adhesion in renal microcirculation Two photons videomicroscopy
  • 33. McCuskey et al Cardiovasc Res 32:752:1996 Rouleau formation Altered Red blood cell deformability
  • 34. Eichelbronner et al ICM 29:709;2003 ETX promotes adhesion of RBC to endothelium HUVEC *
  • 35. Croner et al Crit Care 10:R15;2006 Microthrombi ? Rats, CLP Vasoconstriction Platelet/WBC interaction with endothelium Microthrombi not frequent
  • 36. Secor et al ICM 36:1928; 2010 Mice, CLP
  • 37. De Backer et al Annals Intensive Care 2011 Potential mechanisms
  • 38. ALSO IN HUMANS ?
  • 39. DDB USI Vascular density (all vessels) ++ p <0.01 vs volunteers 2.5 3 3.5 4 4.5 5 5.5 6 6.5 7n/mm Volunteers (10) Septic patients (50) ++ De Backer et al AJRCCM 166:98;2002
  • 40. DDB USI Percentage of vessels perfused (large vessels) 60 65 70 75 80 85 90 95 100% Volunteers (10) Septic patients (50) MICROCIRCULATORY ALTERATIONS IN SEPTIC PATIENTS De Backer et al AJRCCM 166:98;2002
  • 41. DDB USI 0 20 40 60 80 100 Volunteers (10) Severe sepsis (50) +++ % +++ p <0.001 vs volunteers Percentage of vessels perfused (small vessels) De Backer et al AJRCCM 166:98-104;2002
  • 42. Emergency department Trzeciak et al Ann Em Med 49:1579;2007 N=26 0 0,1 0,2 0,3 0,4 0,5 0,6 0,7 Heterogeneity index CTRL SEPSIS P<0.01
  • 43. Alterations of sublingual microcirculation in patients with sepsis • De Backer et al AJRCCM 2002 • Spronk et al Lancet 2002 • Sakr et al CCM 2004 • De Backer et al CCM 2006 • De Backer et al CCM 2006 • Creteur et al ICM 2006 • Boerma et al CCM 2007 • Trzeciak et al Ann Emerg Med 2007 • Sakr et al CCM 2007 • Trzeciak et al ICM 2008 • Boerma et al ICM 2008 • Dubin et al Crit Care 2009 • Buchele et al CCM 2009 • Boerma et al CCM 2010 • Ospina et al ICM 2010 • Spanos et al Shock 2010 • Pottecher et al ICM 2010 • Morelli et al Crit Care 2010 • Ruiz et al Crit Care 2010 • Dubin et al J Crit Care 2010 • Morelli et al ICM 2011 • Edul et al CCM 2012 • Kanvundis et al ICM 2012 • Hernandez et al CCRP 2012 • Pranskunas et al ICM 2013 • ↓ total vascular density • ↓ perfusion of capillaries (no flow or intermittent flow) • Preserved venular perfusion • Heterogeneity between areas ( close by a few microns)
  • 44. baseline StO2 (%) delta StO2 (%) slope (%/sec) 0 1 2 3 4 5 6 7 8 sepsis n = 72 volunteers n = 18 icu control n = 18 Slope(%/sec) * * p < 0.001 vs volunteers and ICU control Creteur et al ICM 2007 Endothelial reacitivity is impaired in sepsis
  • 45. Alterations of NIRS vasoreactivity test in patients with sepsis • Girardis et al ICM 2003 • De Blasi et al ICM 2005 • Pareznik et al ICM 2006 • Podbregar et al Crit Care 2007 • Doerschung et al JAP 2007 • Creteur et al ICM 2007 • Skarda et al Shock 2007 • Nanas et al Aenesth Intens Care 2009 • Payen et al Crit Care 2009 • Donati et al Crit Care 2009 • Mesquida et al ICM 2009 • Mozina et al Crit Catre 2010 • Georger et al ICM 2010 • Shapiro et al Crit Care 2011 • Soga T et al Emerg Med J 2013
  • 46. Relationship with outcome ?
  • 47. Severe sepsis (n=252) Association with outcome De Backer et al CCM 41:791;2013
  • 48. Edul et al CCM 2012 Vessel density, proportion of perfused vessels and heterogeneity but not velocity differ between survivors and non survivors N=3N=15
  • 49. Severe sepsis (n=252) Association with outcome De Backer et al CCM 41:791;2013
  • 50. De Backer et al CCM 41:791;2013 Severe sepsis (n=252)
  • 51. Doerschug et al AJP 293:1065;2007 Severe sepsis 24 / volunteers 15
  • 52. Shapiro et al Crit Care 15 R223; 2011 50 5860 168 pts at emergency dpt
  • 53. 33 pts with septic shock Trzeciak et al ICM 34:2210; 2008 • 1st SDF evaluation within 3 hours after EGDT initiation • 2nd SDF evaluation 3 to 6 hours after EGDT initiation • SOFA changes between 0 and 24 h
  • 54. DDB USI EVOLUTION OF MICROCIRCULATORY ALTERATIONS IN SEPTIC PATIENTS Death after shock ANOVA p<0.01* * * Sakr et al CCM 32:1825;2004
  • 55. Top et al CCM 39:8; 2011 Persistent microcirculatory alterations in pediatric sepsis N=3N=15
  • 56. 0 1 2 3 4 5 6 7 8 Baseline 24hrs 48 hrs Nonsurvivors (24/52) Survivors (28/52) * *analysis of variance: p < 0.01 Slope(%/sec) n = 52 septic patients Creteur et al ICM 2007 Alterations of NIRS vasoreactivity test in patients with sepsis
  • 57. Vallee F et al Chest 138:1062;2012 Septic shock (n=46) Ear Lobe PCO2
  • 58. But isn’t it just the consequence of the altered global hemodynamics ? Subtitle: could you detect it using hemodynamic measurements, clinical assessment or biomarkers?
  • 59. Cardiac indexMean arterial pressure LactateSvO2 mmHg L/min.M² % mEq/L 40 50 60 70 80 90 100 1 2 3 4 5 6 7 20 30 40 50 60 70 80 90 Septic shockSevere sepsis p<0.01 0 2 4 6 8 10 12 Septic shockSevere sepsis DDB USI MICROCIRCULATORY ALTERATIONS IN SEPTIC PATIENTS De Backer et al AJRCCM 166:98-104;2002
  • 60. De Backer et al CCM 41:791;2013 Severe sepsis (n=252) Association with systemic variables ?
  • 61. De Backer et al CCM 41:791;2013 Early severe sepsis (n=204) Association with systemic variables ?
  • 62. Primary event or adaptive phenomenon ?
  • 63. Ellis C et al AJP 282:H156;2002 In perfused capillaries, O2 extraction is INCREASED in sepsis Single perfused capillary
  • 64. Cardiomyocytes rats Bateman et al AJP 293/H448;2007 During LPS, ICAM-1 expression and HIF gene induction are heterogeneous, and inversely related to flow.
  • 65. Microcirculatory alterations are associated with renal impairment Wu L et al AJP 292:F261; 2007
  • 66. Alteration in redox potential are proportional to microcirculatory alterations Wu L et al AJP 292:F261; 2007 Mice / LPS Peritubular capillaries
  • 67. Microcirculatory alterations are associated with renal hypoxia (co-localized with NADH) Wu L et al AJP 292:F261; 2007 CTRL LPS Peritubular capillaries Mice NADHHypoxia
  • 68. Fink T et al Shock 2013 Liver microvascular perfusion and redox state are inversely related Rats / Fecal peritonitis / pretreatment / absence of shock
  • 69. Brain microcirculation alteration precedes the loss of function Rosengarten B et al Crit Care 13:R139;2009 Rats / LPS
  • 70. R 2 = 0,80 0 20 40 60 80 100 20 40 60 80 Baseline % well perfused capillaries PslCO2gap => Microcirculatory alterations are primary events rather than secondary to altered cellular metabolism. Creteur et al ICM 32:516;2006 Expected (flow adapted to metabolism) Stagnation of waste products
  • 71. b-adrenoceptor stimulation improved liver microvascular perfusion and redox state Rats / Fecal peritonitis Fink T et al Shock 2013 Sham Sepsis DobuSham Sepsis Dobu
  • 72. Change in Lactate % Change in capillary perfusion mEq/L DOBU 5 mcg/kg.min -1 -0,8 -0,6 -0,4 -0,2 0 0,2 0,4 0 10 20 30 40 50 De Backer et al CCM 34:403;2006
  • 73. Effects of fluids
  • 74. Influence of timing of fluid resuscitation Rats LPS Legrand et al ICM 37:1534; 2011
  • 75. 20 30 40 50 60 70 80 90 100 Baseline Fluids Late stage (>48h) N=23 Early stage (<24h) N=37 Proportion of perfused small vessels % $ p<0.01 fluids vs baseline and + p<0.01 late vs early + $ Microvascular effects of fluid challenge in patients with septic shock Ospina et al ICM 35:949;2010
  • 76. Sensitivity Specificity Pos pred val Neg pred val Correct classifica tion MAP 0.55 0.50 0.42 0.64 0.52 CI 0.42 0.68 0.42 0.68 0.58 DPP 0.50 0.56 0.42 0.64 0.53 The microvascular response to fluids cannot be predicted by global hemodynamic changes (including indices of fluid responsiveness) ! Ospina et al ICM 35:949;2010
  • 77. 20 30 40 50 60 70 80 90 100 Late, RL Late, alb Early, RL Early, alb Baseline After fluids Proportion of perfused vessels $ p<0.01 fluids vs baseline Coll vs cryst p = NS % $ $ The time of administration but not the type of fluid influenced the microvascular response Ospina et al ICM 35:949;2010
  • 78. Pottecher et al ICM 2010
  • 79. Futier E et al Crit Care 15:R214;2011 High risk surgery (n=42) Fluids improve microvascular reactivity (NIRS ascending slope)
  • 80. Futier E et al Crit Care 15:R214;2011 High risk surgery (n=42) Relationship with systemic response
  • 81. Vallée et al Chest 138:1062;2010 Ear lobe PCO2 Relationship with systemic response
  • 82. Effects of RBC transfusions
  • 83. EFFECTS OF RED BLOOD CELL TRANSFUSIONS N=35 RBCBaseline Capillary density 7 6 5 4 3 2 Sakr et al CCM 35:1639;2007
  • 84. Baseline capillary perfusion, % Deltacapillaryperfusion,% EFFECTS OF RED BLOOD CELL TRANSFUSIONS N=35 Sakr et al CCM 35:1639;2007
  • 85. Vasoactive agents ?
  • 86. Secchi et al Journ Crit Care 12:137;1997 Rats, gut villi Sham LPS LPS + Dobu 2.5 Dobutamine in experimental sepsis
  • 87. Secchi et al CCM 29:597;2001 Rats, liver sinusoids Dobutamine in experimental sepsis
  • 88. b-adrenoceptor stimulation improved liver microvascular perfusion Rats / Fecal peritonitis / pretreatment / absence of shock Fink T et al Shock 2013
  • 89. Capillary Perfusion Dobutamine 5 mcg/kg.min De Backer et al CCM 34:403;2006 21 patients in septic shock
  • 90. Change in Lactate % Change in capillary perfusion mEq/L DOBU 5 mcg/kg.min -1 -0,8 -0,6 -0,4 -0,2 0 0,2 0,4 0 10 20 30 40 50 De Backer et al CCM 34:403;2006
  • 91. Beta-adrenergic stimulation blunt PAF mediated leucocyte adhesion and rolling HUVEC
  • 92. Red blood cell White blood cell/platelet Arterioles Capillaries BETA (vasodilatation) BETA (WBC / PLT) Decrease rolling et adhesion Effects of adrenergic agents on the microcirculation
  • 93. Vasopressor agents ?
  • 94. Influence of blood pressure on microvascular perfusion ?
  • 95. Cerebral microcirculation Sheep, peritonitis Taccone FS et al Crit Care 14 R140; 2010
  • 96. Cerebral microcirculation and metabolism Sheep, peritonitis Taccone FS et al CCM (in press)
  • 97. De Backer et al CCM 41:791;2013 Severe sepsis (n=252) No clear cut-off….
  • 98. Blood pressure targets Impact of vasopressor agents
  • 99. 0 20 40 60 80 100 120 MAP (mmHg) Vasodilation Ctrl Vasoconstiction
  • 100. Impact of vasopressors on the microcirculation (Norepinephrine vs Vasopressine) Hamster, control condition Friesenecker et al Crit Care 10:R75;2006
  • 101. Maier-S et al BJA 2009 Phenylephrine impairs microvascular perfusion in CPB
  • 102. Impact of vasopressors on the microcirculation Rats, LPS, gut muscularis Nacul F et al Anesth Analg 110:447;2010 No fluids Doses: NE 5 mcg/kg.min EPI 5 mcg/kg.min PHE 10 mcg/kg.min DOPA 20 mcg/kg.min Dobu 12 mcg.kg.min Normotensive sepsis
  • 103. Red blood cell White blood cell/platelet Arterioles Capillaries BETA (vasodilatation) BETA (WBC / PLT) Decrease rolling et adhesion Effects of adrenergic agents on the microcirculation ALPHA (vasoconstriction)
  • 104. Flow Mean arterial pressure Kidney Muscle Liver Brain / heart Different vascular beds have different vascular resistances Gut
  • 105. DDB USI Does correction of hypotension result in an improved tissue perfusion ?
  • 106. Impact of vasopressors on the microcirculation (Norepinephrine vs Vasopressin) Rats, LPS Baseline value Shock value Nakajima et al CCM 34:1847;2006 MAP 46 71 70 mmHg
  • 107. Fries et al CCM 36:1886; 2008 Norepinephrine improved slightly microvascular perfusion but not µPO2 Rats / CLP Buccal mucosa
  • 108. Correction of hypotension improves microvascular reactivity (NIRS) MAP 54 => 77 mmHg Georger et al ICM 36:1882;2010
  • 109. DDB USI What is the optimal blood pressure target for the microcirculation ?
  • 110. Jhanji et al CCM 37:1961;2009 p<0.05 p=0.45 N=16 Impact of MAP/NE on microvascular perfusion
  • 111. Dubin et al Crit Care 2009 N=20 Impact of MAP/NE on microvascular perfusion
  • 112. Thooft et al Crit Care 2011 Impact of MAP/NE on microvascular perfusion Density of perfused small vessels 65 (baseline) 75 85 65 6 8 10 12 level of mean arterial pressure, mmHg FCDsmallvessels,n/mm * *
  • 113. Thooft et al Crit Care 2011 Impact of MAP/NE on microvascular perfusion 65 (baseline) 75 85 65 0 100 200 300 400 500 * * level of mean arterial pressure, mmHg AscendingSlope%/min * *
  • 114. • Vasopressor agents have a dual effect on the microcirculation: on the one hand vasopressors decrease microvascular perfusion by constriction of precapillary sphincters. • On the other hand, achievement of a minimal perfusion pressure is needed to preserve organ blood flow and microcirculatory perfusion. • Optimal pressure targets are variable and should be individualized. Vasopressors and the microcirculation
  • 115. Vasodilatory agents ?
  • 116. 65 70 75 80 85 90 95 100 BASE Proportion of perfused vessels (all vessels) ++ p <0.01 vs base TOPICAL ACETYLCHOLINE (10-2 M) Patients with septic shock (n = 11) % DDB USI MICROCIRCULATORY ALTERATIONS IN SEPTIC PATIENTS De Backer et al AJRCCM 166:98;2002
  • 117. Spronk et al Lancet 360:1395;2002 Effects of nitroglycerin 8 pts with septic shock
  • 118. Boerma E et al CCM 38:93-100;2010 Effects of nitroglycerin 70 pts with severe sepsis
  • 119. Effects of nitroglycerin 70 pts with severe sepsis But can normal be more normal than normal ? Boerma E et al CCM 38:93-100;2010
  • 120. Proportion of Perfused Small Vessels BA SELIN E BEFO R E D R U G SH O C K N E 1H N E 2H 0 20 40 60 80 100 ENALAPRILAT PLACEBO Enalaprilat Placebo n=8 n=8 n=8 n=8 n=6 n=7 n=7 n=7 n=6 n=7 * p<0.05 vs baseline and before drug p=0.83 for trend in enalaprilat group p=0.006 for trend in placebo group p=0.48 for group/time interaction * * PPVsmallvessels,% ACE inhibitors? Salgado D et al Shock 2011 Sheep CLP But no impact on • outcome • organ function
  • 121. Magnesium sulfate? Pranskunas A et al BMC Anesth 11:12; 2011 14 pts severe sepsis
  • 122. Modulation of endothelial function ?
  • 123. Vitamin C Tyml K et al CCM 33,1823;2005 Rat / muscle CLP Ascorbate 7.6g/100g BW 1h or 24h post CLP
  • 124. Vitamin C The effect is related to endothelial NOS Tyml K et al CCM 2008 Mice / muscle Feces in peritoneum Ascorbate 10-200 mg/kg 6h post peritonitis
  • 125. BH4 (tetrahydrobiopterin) Effect on NO metabolism at endothelial level Schmidt S and Alp N Clinical Science 113: 47; 1997
  • 126. He X et al CCM 20:2833; 2012 Sheep CLP BH4 (tetrahydrobiopterin)
  • 127. He X et al CCM 20:2833; 2012 Sheep CLP BH4 (tetrahydrobiopterin) Improved • outcome • organ function
  • 128. • Multiple experimental and clinical studies suggest that microvascular alterations play a key role in the pathophysiology of sepsis and in the development of sepsis-induced organ failure. CONCLUSIONS • These alterations are due to several factors (endothelial dysfunction, interaction with circulating cells) that make unlikely that classical hemodynamic resuscitation can be effective in restoring an adequate microcirculation. • Modulation of endothelial NO synthase seems promizing.