Classification of
microcirculatory abnormalities
in distributive shock
Can Ince
Clinical Physiology
Academic Medical Center
University of Amsterdam
Declared interest: I am CSO of MicroVision Medical an AMC based company
Proposed reclassification of shock states
with special reference to distributive defects.
Weil MH, Shubin H (1971) Adv Exp Med Biol 23:13-23.
• Hypovolemic, cardiogenic, and obstructive
shock occurs as a result of decrease in cardiac
output leading to anaerobic tissue metabolism.
• Septic shock results from distributive alterations
in tissue perfusion caused by abnormal control of
microvasculature with abnormal distribution of a
normal or increased cardiac output.
• Hence end-points have been difficult to define.
Vincent JL Hemodynamic support in septic shock
Intensive Care Medicine (2001) 27:S80-S92
“…Our understanding of hemodynamic mechanisms
(in distributive shock) depends not so much on the
total volume of blood that flows past the aortic valve or the
cardiac output as on the amount of blood delivered to the
exchange sites. Even though cardiac output may be
substantial, if that blood flow does not arrive at
the exchange sites, the ultimate metabolic detriment is
no different from low cardiac output without shunt flow.”
Weil MH, Shubin H (1971) Adv Exp Med Biol 23:13-23.
Shunting model of sepsis
Implication : that active recruitment of the microcirculation
is an important component of resuscitation.
O2
a
v
lactate
CO2
Ince C & Sinaasappel M (1999) Crit Care Med 27:1369-1377
Why the microcirculation is important in shock.
– It is where oxygen exchange takes place.
– Every parameter in the
microcirculation is different
than in the systemic circulation.
– It plays a central role in the
immune system.
– During sepsis and shock it the first to go
and last to recover.
– Rescue of the microcirculation = resuscitation end-point.
Sepsis is a disease of the microcirculation
Spronk P, Zandstra D, Ince C (2004) Critical Care 8:462-468
Sepsis is a disease of the microcirculation
(vessels < 250 m)
•Inflammatory activation
•Coagulatory/RBC dysfunction
•Endothelial barrier dysfunction
Capillary fall out
Weak microcirculatory units are shunted
Hypoxia, apoptosis, organ dysfunction
Not detected by systemic variables
Not responsive to therapy per se Spronk P, Zandstra D, Ince C
Microcirculatory and Mitochondrial Distress Syndrome
(MMDS)
MMDS = sepsis +genes+ therapy + time
HIT
infection
trauma
burns
etc.
Host
genetic background
co-morbidity
time
therapy
MMDS
Figure 2
Ince C (2005) Critical Care 9:S13-S19
Microcirculatory Mitochondrial Distress Syndrome
.
Critical Care (2005) 9:S13-S19
Initial Hit
Co-morbidity
Genes
Time
Therapy
Circulatory Shock + Inflammation
Resuscitation based on
correction of systemic hemodynamics+ inflammation
Time
Therapy
Microcirculatory Dysfunction
Endothelial Dysfunction
RBC
Barrier, Communication
Coagulation, Regulation
Deformability,Aggregation
O2 transport
Coagulation
Leukocytes
Natural Anticoagulants
Microvascular Thrombosis Adhesion, Cytokines, ROS
Dysfunction Autoregulation
Cellular Distress
Microcirculatory shunting
supply-demand mismatch
Hypoxia
Mitochondria
Hibernation
Apoptosis
Organ
Failure
Microcirculation is shunted when
µpO2 becomes less than venous pO2
values remain unchanged.
Sinaasappel & Ince (1996) J. Appl. Physiol. 81:2297-2303.
Sinaasappel, Donkersloot, vanBommel & Ince(1999) Am.J.Physiol 276: G1515-G1520.
Functional shunting is more severe in septic shock than in
blood pressure matched hemorrhagic shock in pig intestines
Ince C & Sinaasappel M (1999) Crit Care Medicine 27:1369-1377
Gut microcirculatory shunt (pO2 gap) and tissue CO2
pO2 gap
µPo2/Mes Ven. Hem .
1.00.1
0.730.1
µPo2/Mes Ven. Sep.
1.10.1
0.570.1
494
1.220.1
483
1.440.1
Pco2 gut (mmHg) Hem
tissue CO2
Pco2 gut. (mmHg) Sep.
p=0.02
p=0.002
Gut Regional flow and oxygen delivery
SMA blood flow. (ml/min)
Hem
SMA blood flow (ml/min) Sep
51069
0.440.1
50738
0.460.1
Do2 gut (mM/min) Hem
3.5 0.4
0.380.1
Do2 gut (mM/min) Sep
3.20.2
0.480.1
NS
P=0.04
Hb based oxygen carriers (DCLHb)
resuscitates gut serosa and mucosa equally
following hemhorrhage.
heart
mucosa
Van Iterson M, Siegemund M, Burhop K, Ince C
(2003) J. of Trauma 55:1111-1124
serosa
Dopexamin resuscitates the microcirculation of the
mucosa but not of the serosa and gut tissue CO2.
The NO donor SIN-1 resuscitates gut serosal and mucosal
microcirculation as 60well as gastric CO2
Serosa (μpO2)
PserO2 [mmHg]
SIN 1
Fluid
50
*
*
40
30
20
bl
lps
shock
t-30
t-60
Gastric CO2
PiCO2-gap [mmHg]
35
30
t-90
t-120
SIN 1
Fluid
*
t-90
t-120
25
20
15
10
5
bl
lps
shock
t-30
*
Mucosa (μpO2)
PmucO2 [mmHg]
30
25
t-60
*
*
*
20
15
10
SIN 1
Fluid
5
bl
lps
shock
t-30
t-60
t-90
t-120
Siegemund M, van Bommel J,
Vollebrecht K, Dries J,
Ince C (2000)
Intensive Care Med 26:S 362
Microcirculation Recruitment Manoeuvres
Correct pathological flow heterogeneity,
microcirculatory shunting and restore autoregulatory
dysfunction by control of inflammation, vascular
function and coagulation.
Open the microcirculation and keep it open by
support of the pump, fluids, vasodilators and
restricted use of vasopressor agents.
Ince C (2005) Critical Care 9:S13-S19
OPS imaging validated against capillary microscopy
Analyzer
Polarizer
3 cm
Mathura et al. (2001) J. Applied
Physiology 91:74-78.
First direct visualizations of the microcirculation in human
internal organs using OPS imaging.
Brain tumours
SAH
during hyperventilation
Before HV
Groner et al. (1999) Nature Med 5:1209
Mathura et al. (2001) The Lancet 58:1698
Mathura et al. (2001) J. Appl Physiol 91:74
Spronk et al. (2001) The Lancet 360:1395
Pennings et al. (2004) Stroke 35:1284
After HV
SDF imaging
Sidestream Dark Field imaging for improved technique for observation
of the microcirculation
Ince C (2005)
Calcu
late
veloci
ty
(30.4
9
Critical
Care 9:S13-S19
Flow score:
0 = no flow
1 = intermittent
2 = sluggish
3 = continuous
Small: 10-25 μm
Medium: 26-50 μm
Large: 51-100 μm
Boerma et al (2005) Crit Care 9:R601-R606
De Backer, Creteur, Preiser,
Dubois, Vincent
Am J Respir Crit Care Med
(2002) 166:98-104.
There was no difference in sytemic hemodynamic and oxygenation
variables or the amount or type of drugs used between survivors and
non-survivors.
Microcirculatory dysfunction was the single most sensitive and
specific predictor of outcome.
Sakr et al. Crit Care Med (2004) 32:1825-1831
Resuscitatation is affective in recruitment of
capillaries and correction of sub-lingual CO2
Creteur, J., De Backer, D. Sakr, Y.Koch, M., Vincent, J.L. (2004)
Crit Care Med Suppl Vol. 31 (12):419
Nitroglycerin promotes microvascular
recruitment in septic and cardiogenic
shock patients
Sublingual OPS imaging in a patient
with septic shock after pressure
guided volume resuscitation.
the same patient after subsequent
nitroglycerin 0.5 mg ivbolus
Spronk, Ince, Gardien, Mathura, Oudemans-van Straaten, Zandstra DF. (2002) The Lancet 360:1395-1396.
.Nitroglycerin promotes microvascular recruitment in pressure
resuscitated septic shock patients sub-lingual OPS imaging
Spronk, Ince, Gardien, Mathura, Oudemans-van Straaten, Zandstra DF.
The Lancet 2002; 360(9343):1395-1396.
3,5
3
2,5
2
1,5
1
0,5
0
10 - 25  m
-0,5
3,5
3
2,5
2
1,5
1
0,5
0
25 - 50  m
-0,5
before
after TNT
P=0.012
P=0.012
microvascular flow index
P=0.018
microvascular flow index
microvascular flow index
3,5
3
2,5
2
1,5
1
0,5
0
50 - 100  m
-0,5
before
before
after TNT
after TNT
• Capillary flow but to a much lesser degree venular flow, is impaired
during pressure guided resuscitation from septic shock.
• NO donor can recruit the microcirculation by promoting flow.
The effects of dobutamine on microcirculatory alterations in
patients with septic shock are independent of its systemic
effects.
De Backer D et al. (2006) Crit Care Med 2006; 34:403–408)
Thrombolysis in fulminant purpura:
observations on changes in microcirculatory perfusion
during successful treatment.
Spronk PE Rommes JH, Schaar C, Ince C
(2006) Thromb Haemost. 95(3):576-8
Microvascular flow index (MFI) of small vessels in
the sublingual region versus the MFI in the stoma region
3,5
MFI sublingual, small vessels
3,0
2,5
2,0
1,5
1,0
,5
Christian Boerma
0,0
,5
1,0
1,5
2,0
2,5
MFI stoma
3,0
3,5
Inflammatory Response to Cardiopulmonary Bypass
Mechanisms Involved and Possible Therapeutic Strategies
S Wan, JL LeClerc, JL Vincent. Chest 1997;112
Median FCD
ECMO reduces FCD in premature infants
8,5
8,0
8,1
7,5
7,4
7,3
7,0
6,7
6,5
0-7 days (n=3)
1-6 months (n=21)
8-28 days (n=10)
7-12 months (n=1)
Age category
J.E. van Velzen, C Ince, D Tibbeau
Proc. Symp.Micro. Mit. Dysfuntion in ICM (2003)
Healthy sub lingual microcirculation observed by SDF imaging
Cardiogenic Shock
Capillary hemodynamics underlying distributive defect
Classifying microcirculatory flow abnormalities in
distributive shock
Capillary hemodynamics
Observed in diseased states
I
Stagnant
Pressure guided resuscitation from sepsis
II
Continuous/capillary fall-out
On-pump CABG surgery, ECMO
III
Continuous/stagnant
Resuscitated Sepsis, reperfusion injury,
sickle cell crises, malaria
IV
Hyperdynamic/stagnant
Resuscitated sepsis
V
Hyperdynamic
Resuscitated sepsis, exercise
Clas
s
Functionally all classes cause a distributive defect and
functional shunting of the microcirculation.
Conclusions
1) Distributive shock has a bad
prognosis with difficult to define
hemodynamics end-points.
2) It causes a distributive defect at the
capillary level of the microcirculation causing functional
shunting of weak microcirculatory units.
3) It is the reason why distributive shock cannot be adeqautely
monitored by systemic hemodynamic parameters.
4) OPS/SDF en tissue capnography provide an integrative
evaluation of the functional state of the microcirculation.
5) Microcirculatory Recruitment Maneuvres are affective in
correcting distributive shock
200
A
B
Vessel length (μm)
150
ν2
100
ν3
ν1
50
0
1
2
3
4
0
1
Time (sec)
2
3
4
A typical space-time diagram of microvascular bloodflow before pump (A) and during pump (B). showing a
pulsatile flow and respectively a continuous flow. Ligth bands represent either plasma gaps or white blood cells
and dark bands represent red blood cells. The slope (v) of a band in a space-time diagram is the velocity. The
horizontal light and dark bands are indicative of variations in the background light intensity. Panel A shows waivy
bands indicating pulsatile flowpattern with a rapid (v1) and a slow (v2) phase. Panel B shows straight linear bands
indicating non-pulsatile continuous flowpattern. The velocities are v1=428 μm/s v2=86 μm/s v3=327 μm/s.
5
Microcirculation Recruitment Manoeuvres
Ince C (2005) Critical Care 9:S13-S19
Correct pathological flow heterogeneity,
microcirculatory shunting and restore autoregulatory
dysfunction by control of inflammation, vascular
function and coagulation.
Avontuur (1997) Cardiovas Res 35:368-376.
Siegmund M (2005) Inten Care Med 31:985-992.
Open the microcirculation and keep it open by
support of the pump, fluids, vasodilators and
restricted use of vasopressor agents. :
Boerma (2005) Acta Anaesthesiol Scand. 49(9):1387-90.
Spronk (2001) The Lancet 360:1395-1396
Siegemund (2006) Intensive Care Med
Heart and gut serosa
Gut serosa and mucosa
Brain cortex
Signs of regional dysoxia in the presence of
apparent adequate oxygen delivery.
• Cytopathic hypoxia:
mitochondrial dysfunction
in the presence of adequate
tissue oxygenation.
Fink MP (1997) Acta
Anaesth. Scan.110:87-95.
• Shunting theory of sepsis:
microcirculatory shut down
of weak microcirculatory
units creating hypoxic
pockets.
Ince C & Sinaasappel M
(1999) Crit Care Med.
27:1369-1377.