The Microcirculation in Sepsis
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Transcript of The Microcirculation in Sepsis
The Microcirculation in sepsis
Daniel De BackerDepartment of Intensive CareErasme University Hospital
Brussels, Belgium
• 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
Trzeciak et alCrit Care 9:S20;2005
The density of capillaries is a primary determinant of tissue oxygenation
Saldivar-E et alAJP 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
MICROCIRCULATION
DDB USI
r4 1V =
P8 L
.. . .
Determinants of microvascular blood flow
Blood flow is adapted to local metabolic needs through local vasodilation and upstream changes in vasomotor tone
Neural control
Hungerford-JE et alFASEB 14:197;2000
Perivascular sympathetic
nerves10 µm
Neural control Beach-JM et alAJP 275:H1489;1998
Arteriole
Capillaries
Microcirculatory alterations in experimental sepsis
Pig
Gut serosa
OPS, 5x probe
Pig
Gut serosa (sepsis)
OPS, 5x probe
Pig
Liver
OPS, 5x probe
Pig
Liver (sepsis)
OPS, 5x probe
Sheep
Brain
SDF, 5x probe
Sheep
Brain (sepsis)
SDF, 5x probe
Hoffmann et alCCM 32,1011;2004
Hamster skinfold LPS
DECREASED CAPILLARY DENSITY IN EXPERIMENTAL SEPSIS
ENDOTOXIC SHOCK MODEL
ANOVA: in sepsis all times p<0.0001 vs baseline
Evolution of sublingual microcirculation in septic shock
Verdant et alCCM 37;2875,2009
Sham
Sepsis
PigsCholangitis
Evolution of microcirculation in unresuscitated septic shockPranskunas A et alCrit Care 16:R83;2012
Pigs E Coli infusion
MICROVASCULAR ALTERATIONS IN EXPERIMENTAL SEPSIS
• Decreased capillary density• Heterogeneity of perfusion
HETEROGENEITY OF CAPILLARY PERFUSION IN EXPERIMENTAL SEPSIS Ellis C et al
AJP 282:H156;2002
rats
SPACE
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 ofperfusedcapillaries
ENDOTOXIN
0
10
20
30
40
0 10 20 30 40 50 >50
%
Sinusoidal flow pl/s
Fraction ofperfusedcapillaries
Increase heterogeneity of renal perfusion in sepsis
RatsLPS
Legrand et alICM 2011
EXPERIMENTAL STUDIES IN SEPSIS
Microvascular blood flow alterations are frequent
decreased vascular densityabsent or intermittent flow in capillariesheterogeneity between areas
DDB USI
Branemark et Urbaschek Angiology 18:667;1967Lam et al. JCI 94: 2077; 1994Farquhar et al. J Surg Res 61: 190; 1996Madorin et al CCM 27:394;1999Ellis et al AJP 282:H156;2002Verdant et al CCM 37:2875;2009Secor 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…)
Cardiomyocytes rats
Bateman et alAJP 293/H448;2007
CTRL LPS
Consequences…
0
10
20
30
40
50
60
70
80
Gut mucosa
SEPSIS CTRL
-10
-5
0
5
10
15
p<0.01
%
%
Hemorrhage
p<0.01
Humer et alJAP 81: 895; 1996
CRITICAL O2ER
CHANGES IN CAPILLARY TRANSIT-TIME HETEROGENEITY
MICROCIRCULATORY ALTERATIONS AND EO2CRIT
Potential mechanisms ?
PATHOPHYSIOLOGY OF MICROVASCULAR ALTERATIONS
Triggered by inflammatory mediatorsTNF (Vicaut E JCI 87:1537;1991)
ENDOTHELIAL ALTERATIONS
ctrl
5 dayspost LPS
Leclers J et alCCM 28:3672;2000
rabbits
25-35% vessels
Loss of neural control Tyml-K et alAJP 281:H1397;2001
Change in diameter and
communication rate (CR500)
between 500 µm distant
microvessels(retrograde
communication)
B: cremaster muscle (mice)C: Endothelial microlayer
Enhanced response to vasoconstrictor substances Pannen B et alAJP 26:180;2001
CTRL
HEM
CTRL + ET
HEM + ET
Rats
2 µm
Endothelialcell
Glycocalyx
0.2 µm
GLYCOCALYX ALTERATIONS van den Berg et alCirc Res 92:592;2003
Marechal X et alShock 29:572;2008
Role of glycocalyx in microvascular alterations
Rats, ileum
µm
Gupta A et alAJP 293:F245;2007
LPS promotes rolling and adhesion in renal microcirculation
Two photons videomicroscopy
McCuskey et alCardiovasc Res32:752:1996
Rouleau formation
Altered Red blood cell deformability
Eichelbronner et alICM 29:709;2003
ETX promotes adhesion of RBC to endothelium
HUVEC
*
Croner et alCrit Care 10:R15;2006
Microthrombi ?
Rats, CLP
VasoconstrictionPlatelet/WBC interaction with endotheliumMicrothrombi not frequent
Secor et alICM 36:1928; 2010
Mice, CLP
De Backer et alAnnals Intensive Care 2011
Potential mechanisms
ALSO IN HUMANS ?
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 alAJRCCM 166:98;2002
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 alAJRCCM 166:98;2002
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
Emergency department
Trzeciak et alAnn 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
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)
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
Slo
pe
(%
/sec
)
*
* p < 0.001 vs volunteers and ICU control
Creteur et alICM 2007
Endothelial reacitivity is impaired in sepsis
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
Relationship with outcome ?
Severe sepsis (n=252)
Association with outcome De Backer et alCCM 41:791;2013
Edul et alCCM 2012
Vessel density, proportion of perfused vessels and heterogeneity but not velocity differ between survivors and non survivors
N=3N=15
Severe sepsis (n=252)
Association with outcome De Backer et alCCM 41:791;2013
De Backer et alCCM 41:791;2013
Severe sepsis (n=252)
Doerschug et alAJP 293:1065;2007
Severe sepsis 24 / volunteers 15
Shapiro et alCrit Care 15 R223; 2011
50 5860168 pts at emergency dpt
33 pts with septic shockTrzeciak et alICM 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
DDB USI
EVOLUTION OF MICROCIRCULATORY ALTERATIONS IN SEPTIC PATIENTS
Death after shock
ANOVAp<0.01* * *
Sakr et alCCM 32:1825;2004
Top et alCCM 39:8; 2011
Persistent microcirculatory alterations in pediatric sepsis
N=3N=15
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
Slo
pe
(%/s
ec)
n = 52 septic patients Creteur et alICM 2007
Alterations of NIRS vasoreactivity test in patients with sepsis
Vallee F et alChest 138:1062;2012
Septic shock (n=46)
Ear Lobe PCO2
But isn’t it just the consequence of the altered global hemodynamics ?
Subtitle: could you detect it using hemodynamic measurements, clinical assessment or biomarkers?
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 sepsisDDB USI
MICROCIRCULATORY ALTERATIONS IN SEPTIC PATIENTS
De Backer et al AJRCCM 166:98-104;2002
De Backer et alCCM 41:791;2013
Severe sepsis (n=252)
Association with systemic variables ?
De Backer et alCCM 41:791;2013
Early severe sepsis (n=204)
Association with systemic variables ?
Primary event or adaptive phenomenon ?
Ellis C et alAJP 282:H156;2002
In perfused capillaries, O2 extraction is INCREASED in sepsis
Single perfused capillary
Cardiomyocytesrats
Bateman et alAJP 293/H448;2007
During LPS, ICAM-1 expression and HIF gene
induction are heterogeneous, and inversely related to flow.
Microcirculatory alterations are
associated with renal impairment
Wu L et alAJP 292:F261; 2007
Alteration in redox potential are proportional to microcirculatory alterations
Wu L et alAJP 292:F261; 2007
Mice / LPSPeritubular capillaries
Microcirculatory alterations are associated with renal hypoxia (co-localized with NADH)
Wu L et alAJP 292:F261; 2007
CTRL
LPS
Peritubular capillaries
Mice
NADH Hypoxia
Fink T et alShock 2013
Liver microvascular perfusion and redox state are inversely related
Rats / Fecal peritonitis / pretreatment / absence of shock
Brain microcirculation alteration precedes the loss of function
Rosengarten B et alCrit Care 13:R139;2009
Rats / LPS
R2 = 0,80
0
20
40
60
80
100
20 40 60 80
Baseline
% well perfused capillaries
Psl
CO
2gap
=> Microcirculatory alterations are primary events rather than secondary to altered cellular metabolism.
Creteur et alICM 32:516;2006
Expected(flow adapted to metabolism)
Stagnation of waste products
b-adrenoceptor stimulation improved liver microvascular perfusion and redox state
Rats / Fecal peritonitis
Fink T et alShock 2013
Sham Sepsis DobuSham Sepsis Dobu
Change in Lactate
%
Change in capillary perfusion
mEq/LDOBU 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 alCCM 34:403;2006
Effects of fluids
Influence of timing of fluid resuscitation
RatsLPS
Legrand et alICM 37:1534; 2011
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 alICM 35:949;2010
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 alICM 35:949;2010
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 alICM 35:949;2010
Pottecher et alICM 2010
Futier E et alCrit Care 15:R214;2011
High risk surgery (n=42)
Fluids improve microvascular reactivity (NIRS ascending slope)
Futier E et alCrit Care 15:R214;2011
High risk surgery (n=42)
Relationship with systemic response
Vallée et alChest 138:1062;2010
Ear lobe PCO2
Relationship with systemic response
Effects of RBC transfusions
EFFECTS OF RED BLOOD CELL TRANSFUSIONS
N=35 RBC Baseline
Capillary density
Ca
pill
ary
de
nsi
ty (
/mm
)
7
6
5
4
3
2
Sakr et alCCM 35:1639;2007
Baseline capillary perfusion, %
De
lta
ca
pill
ary
pe
rfu
sio
n,
%
EFFECTS OF RED BLOOD CELL TRANSFUSIONS
N=35
Sakr et alCCM 35:1639;2007
Vasoactive agents ?
Secchi et alJourn Crit Care 12:137;1997
Rats, gut villi
ShamLPS
LPS + Dobu 2.5
Dobutamine in experimental sepsis
Secchi et alCCM 29:597;2001
Rats, liver sinusoids
Dobutamine in experimental sepsis
b-adrenoceptor stimulation improved liver microvascular perfusion
Rats / Fecal peritonitis / pretreatment / absence of shock
Fink T et alShock 2013
Capillary Perfusion
Dobutamine 5 mcg/kg.min De Backer et alCCM 34:403;2006
21 patients in septic shock
Change in Lactate
%
Change in capillary perfusion
mEq/LDOBU 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 alCCM 34:403;2006
Beta-adrenergic stimulation blunt PAF mediated leucocyte adhesion and rolling
HUVEC
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
Vasopressor agents ?
Influence of blood pressure on microvascular perfusion ?
Cerebral microcirculation
Sheep, peritonitis
Taccone FS et alCrit Care 14 R140; 2010
Cerebral microcirculation and metabolism
Sheep, peritonitis
Taccone FS et alCCM (in press)
De Backer et alCCM 41:791;2013
Severe sepsis (n=252)
No clear cut-off….
Blood pressure targets
Impact of vasopressor agents
0
20
40
60
80
100
120
Arter
ioles
Aorta
Capill
aries
Arter
ies
Venul
es
Veins
MAP (mmHg)
Vasodilation
Ctrl
Vasoconstiction
Impact of vasopressors on the microcirculation(Norepinephrine vs Vasopressine)
Hamster, control condition
Friesenecker et alCrit Care 10:R75;2006
Maier-S et alBJA 2009
Phenylephrine impairs microvascular perfusion in CPB
Impact of vasopressors on the microcirculation
Rats, LPS, gut muscularis
Nacul F et alAnesth Analg 110:447;2010
No fluidsDoses:NE 5 mcg/kg.minEPI 5 mcg/kg.minPHE 10 mcg/kg.minDOPA 20 mcg/kg.minDobu 12 mcg.kg.min
Normotensive sepsis
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)
Flow
Mean arterial pressure
Kidney
Muscle
Liver
Brain / heart
Different vascular beds have different vascular resistances
Gut
DDB USI
Does correction of hypotension result in an improved tissue perfusion ?
Impact of vasopressors on the microcirculation(Norepinephrine vs Vasopressin)
Rats, LPS
Baseline value
Shock value
Nakajima et alCCM 34:1847;2006
MAP 46 71 70 mmHg
Fries et alCCM 36:1886; 2008
Norepinephrine improved slightly
microvascular perfusion but not
µPO2
Rats / CLPBuccal mucosa
Correction of hypotension improves microvascular reactivity (NIRS)
MAP 54 => 77 mmHg
Georger et alICM 36:1882;2010
DDB USI
What is the optimal blood pressure target for the microcirculation ?
Jhanji et alCCM 37:1961;2009
p<0.05
p=0.45
N=16
Impact of MAP/NE on microvascular perfusion
Dubin et alCrit Care 2009
N=20
Impact of MAP/NE on microvascular perfusion
Thooft et alCrit Care 2011
Impact of MAP/NE on microvascular perfusion
Density of perfused small vessels
65 (baseline) 75 85 656
8
10
12
level of mean arterial pressure, mmHg
FC
D s
mal
l ve
ssel
s, n
/mm
*
*
Thooft et alCrit Care 2011
Impact of MAP/NE on microvascular perfusion
65 (baseline) 75 85 650
100
200
300
400
500 * *
level of mean arterial pressure, mmHg
Asc
endi
ng S
lope
%/m
in
* *
• 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
Vasodilatory agents ?
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 alAJRCCM 166:98;2002
Spronk et alLancet 360:1395;2002
Effects of nitroglycerin
8 pts with septic shock
Boerma E et alCCM 38:93-100;2010
Effects of nitroglycerin
70 pts with severe sepsis
Effects of nitroglycerin
70 pts with severe sepsis
But can normal be more normal than normal ?
Boerma E et alCCM 38:93-100;2010
Proportion of Perfused Small Vessels
0
20
40
60
80
100
ENALAPRILATPLACEBO
Enalaprilat
Placebo
n=8n=8
n=8n=8
n=6n=7
n=7n=7
n=6n=7
* p<0.05 vs baseline and before drugp=0.83 for trend in enalaprilat groupp=0.006 for trend in placebo groupp=0.48 for group/time interaction
* *
PP
V s
mal
l ves
sels
, %
ACE inhibitors?Salgado D et alShock 2011
SheepCLP
But no impact on • outcome• organ function
Magnesium sulfate?Pranskunas A et alBMC Anesth 11:12; 2011
14 pts severe sepsis
Modulation of endothelial function ?
Vitamin CTyml K et alCCM 33,1823;2005
Rat / muscleCLP
Ascorbate 7.6g/100g BW 1h or 24h post CLP
Vitamin CThe effect is related to endothelial NOS
Tyml K et alCCM 2008
Mice / muscleFeces in peritoneum
Ascorbate 10-200 mg/kg 6h post peritonitis
BH4 (tetrahydrobiopterin)
Effect on NO metabolism at endothelial level
Schmidt S and Alp NClinical Science113: 47; 1997
He X et alCCM 20:2833; 2012
SheepCLP
BH4 (tetrahydrobiopterin)
He X et alCCM 20:2833; 2012
SheepCLP
BH4 (tetrahydrobiopterin)
Improved• outcome• organ function
• 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.