mira mandelbaum-livnat, efrat barbiro-michaely and avraham mayevsky
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EFFECT OF PARTIAL BRAIN ISCHAEMIA ON THE METABOLIC AND EFFECT OF PARTIAL BRAIN ISCHAEMIA ON THE METABOLIC AND
HAEMODYNAMIC RESPONSES TO HAEMORRHAGE HAEMODYNAMIC RESPONSES TO HAEMORRHAGE
HYPOTENSION MEASURED IN THE BRAIN AND SMALL INTESTINEHYPOTENSION MEASURED IN THE BRAIN AND SMALL INTESTINE
Mira Mandelbaum-Livnat, Efrat Barbiro-Michaely
and Avraham Mayevsky
The Mina & Everard Goodman Faculty of Life-Sciences and
The Gonda Multidisciplinary Brain Research Center
Bar-Ilan University, Ramat-Gan, Israel
ESCTAIC 23rd Congress 2012
Timisoara, Romania
October 4th 2012
Systemic
level
Tissue
level
cellular
level
Mitochondrial function preservation
Anaerobicmetabolism
Cell injury
Metabolicacidosis
Lactic acidosis
Mitochondrial dysfunction
Cell death
Circulatory blood volume
O2
deliveryBlood flow
redistribution
Blood flow Blood flow
Sympathetic Nervous System activation
Vasoconstriction
Cardiac output Mean Arterial Pressure
Vessels resistance
Autoregulation
Vessels resistance
less vital organs vital organs
Hemorrhage
Ionic homeostasis disruption
ATP
During hemorrhage blood is
redistributed in favor of the vital organs and on the expense of the
less vital organs.
LDF-Laser Doppler Flowmetry
3
Simultaneous Real Time Monitoring of a Vital Organ - the Simultaneous Real Time Monitoring of a Vital Organ - the Brain, and a Less Vital Organ - Brain, and a Less Vital Organ - the Small Intestinethe Small Intestine, under, under
Body Emergency Metabolic StatesBody Emergency Metabolic States (BEMS)BEMS)–– a New Approach a New Approach of Diagnosticsof Diagnostics
BrainVital Organ
Small IntestineLess Vital Organ
Blood FlowBlood FlowRedistributionRedistribution under BEMSunder BEMS
4
Work hypothesis
During hemorrhage the body suffers from a decrease in oxygen delivery affecting primarily mitochondrial function.
During hemorrhage there is a redistribution of blood from the "less vital organs" (i.e. intestine and skin) to the life preserving circulation of the "vital organs" (i.e. brain and heart).
Monitoring of a “less vital organ” may early detect body emergency metabolic state occurring during hemorrhage.
5
Importance of research
50% of the patients with hemorrhagic shock die of substantial blood loss within an hour from the insult.
Another 30% of deaths result from severe internal organ injury during the following 60-120 minutes.
Those who survive their initial injury are at a high risk of developing infection and multi organ failure, which can further lead to death.
Early diagnosis of hemodynamic catastrophe and early resuscitation is most important in hemorrhagic shock
in order to improve the final outcome.
6
Comparison of “vital organ” and a “less vital organ” may enable a better understanding of the process occurring on a daily basis in the clinic.
The monitoring of less vital organ during hemorrhage has two important roles:
1. The early detection of the hemorrhage insult itself.
2. The early detection of resuscitation end point.
7
METHODS
The Multi-Site Multi-Parametric system for monitoring cerebral and The Multi-Site Multi-Parametric system for monitoring cerebral and intestinal blood flow and mitochondrial NADHintestinal blood flow and mitochondrial NADH
A1
A2
ABC
B1
B2
C
BrainLiver & kidney
Testis
D
10
The development of the monitoring model
In accordance to recent studies reporting about homodynamic differences between two intestinal layers, namely the serosa and mucosa, following hemorrhage we carried out two protocols of short anoxia and epinephrine injection, in order to assure monitoring from both layers and to find out which intestinal location is better for intestinal monitoring.
11
Short anoxia Epinephrine I.V. injection
50
100
150
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150
200
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0
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100
150
0
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150
200
-2 0 2 4 6 8
Ref
(%
)T
BF
(%
)N
AD
H (
%)00
00
MA
P (
mm
Hg
)%)
50
100
150 Mucosa Serosa
50
100
150
0
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150
0
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100
150
-2 0 2 4 6
N2
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0
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0
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-2 0 2 4 6 8
Ref
(%
)T
BF
(%
)N
AD
H (
%)00
00
MA
P (
mm
Hg
)%
)
50
100
150 Mucosa Serosa
50
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200
0
50
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150
0
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150
200
-2 0 2 4 6 8
Epinephrine
0 15 45 105 Time (min)
N2 N2N2 - deathStart
0 15 45 105 Time (min)
N2 Epinephrine N2 - deathStart
No significant differences between the serosa and mucosa were observed in any of the protocols. Therefore, we have decided to place the intestinal probe on the serosa, since it is less invasive and easier to manipulate.
12
Brain versus
Intestine
13
Normotensive control
0 1 2 3 Time (hour)
N2 N2 - deathStart Start
control
0
100
200
0 30 60 90 120 150 180
0
100
200
0
100
200Brain Intestine
0
100
200
50
150
Ref
(%
)T
BF
(%)
NA
DH
(%
)SP
O2
(%)
0
100
200
0 30 60 90 120 150 180
MA
P (m
mH
g)
N=4
14
Intestinal and Brain responses to Anoxia
50
100
150N
AD
H (
%)
* *
10
100
190
280
370
TB
F (
%) * *
0
50
100
0 30 60 90 120 150 180 210
MA
P (
mm
Hg
)
* *
(
Start StopAnoxia
Time (sec)
Small Intestinal Serosa
Brain
15
Response of Intestine and Brain to Hypoxia
Start Stop
Hypoxia
60
100
140
180
NA
DH
(%
)
* *
40
70
100
130
160
TB
F (
%) * *
0
50
100
150
0 20 40 60 80 100
MA
P (
mm
Hg
)
* *
((
Time (min)
Small Intestinal Serosa
Brain
16
Response of Intestine (gray) and Brain (black) to Hypercapnia
50
100
150
RE
F (
%) * *
50
100
150
NA
DH
(%
)
0
100
200
TB
F (
%)
-50
0
50
-10 0 10 20 30 40 50 60 70 80
MA
P (
m
mH
g)
TIME (min)
AIR10% CO2
Intestinal Serosa Brain
17
Responses of Intestine (gray) and Brain (black) to Hyperoxia
80
100
120
RE
F (
%)
80
100
120
NA
DH
(%
)
0
100
200
TB
F (
%)
AIR
-50
0
50
-10 0 10 20 30 40 50 60 70 80
MA
P (
m
mH
g)
100% O2
Intestinal Serosa Brain
TIME (min)
18
0
100
200
* *
0
100
200 * *
0
100
200
300
400
* *
0
100
200
-2 -1 0 1 2 3 4
Time (min)
* *
EPINEPHRINE 10µ
M
AP
)m
mH
g
(T
BF
(%
)
N
AD
H
(%
)R
EF
(
%)
Intestinal and Brain responses to Epinephrine 10 µg/kg
Small Intestinal Serosa
Brain
19
50
100
150
200
**
**
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200
* *
0
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200
300
400
* *
*
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2 μg 4 μg 6 μg 8 μg 10 μg
***
M
AP
)m
mH
g
(
TB
F
(%)
NA
DH
(
%)
RE
F
(%
)
**
Intestinal and Brain responses to Epinephrine 2-10 µg/kg
Small Intestinal Serosa
Brain
20
Anoxia
R2 = 0.8898R2 = 0.9978
50
100
150
50 100 150
TBF (%)
NA
DH
(%)Brain Tissue Intestine Tissue
(%)
******
21
Hypoxia
R2 = 0.6677
R2 = 0.8942
50
100
150
50 100 150TBF (%)
NA
DH
(%)
Brain Tissue Intestinal Tissue
(%) ***
***
22
Hypercapnia(%
)
***
R2 = 0.1448
R2 = 0.9043
50
100
150
50 100 150
TBF (%)
NA
DH
(%)Intestine Tissue Brain Tissue
23
Correlations between NADH & TBF under Epinephrine 2-10g/kg
(I.V)
90
100
110
0 100 200 300
CBF (%)
NA
DH
(%
)
2 Mg
4 Mg
6 Mg
8 Mg
10 Mg
0
100
200
0 100 200
IBF (%)
NA
DH
(%
)
2 Mg
4 Mg
6 Mg
8 Mg
10 Mg
24
Hemorrhage
Decreased circulatory blood volume
Decreased tissue perfusion and O2 delivery
Oxygen demand exceeds oxygen supply
Hemorrhagic shock
25
Bleeding down to
40 mmHg and
maintenance
1 2 3 4 Time (hour)
N2 N2 - deathStart
0
Operation Resuscitation
15 min
Sample protocol
26
Protocols
ProtocolProtocolNumber of animalsNumber of animals
Development of the monitoring model
Short anoxia7
Epinephrine I.V. injection7
The hemorrhage models
Normotensive group4
Uncontrolled hypotension for 30 min9
Controlled hypotension for 15 min9
Controlled hypotension for 30 min12
Controlled hypotension for 60 min13
Partial cerebral ischemic control group4
Partial cerebral ischemia combined with hypotension9
27
Uncontrolled hypotension
50
100
150
200
50
100
150 Brain Intestine
50
100
150
0
50
100
150
Time (min)
Bleeding Resuscitation
0 30 60 90 120-5 150
Ref
(%
)N
AD
H (
%)
MA
P (m
mH
g)T
BF
(%)
Bleeding
0 1 2 3
N2 Resuscitation N2 - deathStart
0 1 2 3 Time (hour)30 min
Averaged amount of shed blood was calculated to be 12±3% of rat’s total blood volume.
N=9
28
Controlled hypotension for 15 minAveraged amount of shed blood was calculated to be 31±2% of rat’s total blood volume.
N=9
50
75
100
50
100
150
0
50
100
150
50
100
150Brain Intestine
8
50
100
150
0
50
100
150
Ref
(%
)T
BF
(%
)N
AD
H (
%)
MA
P (
mm
Hg)
Sp
O2(
%)
-5
Bleeding Resuscitation
0 30 90 1206015 45 105 13575
Flu
(%
)
Time (min)
29
0
50
100
150
50
100
150
200
0
50
100
150
50
100
150
200 Brain Intestine
Ref
(%
)T
BF
(%)
NA
DH
(%
)M
AP
(mm
Hg)
Time (min)
Bleeding Resuscitation
0 30 60 90 120-5 150
Bleedingand maintenance
0 1 2 3
N2 Resuscitation N2 - deathStart
0 1 2 3 Time (hour)30 min
Controlled hypotension for 30 minAveraged amount of shed blood was calculated to be 40±1.5% of rat’s total blood volume.
30
0
50
100
150
50
100
150
-5 20 45 70 95 120 145 170 195 220
0
50
100
150
50
100
150
200
50
100
150 Brain Intestine
70
80
90
100
110
Ref
(%)
TBF
(%)
NA
DH
(%)
MA
P (m
mH
g)
5 10 15 20 25 30 35 Resuscitation
Bleeding percentages
Graded Hemorrhage
31
Controlled hypotension under Normal cerebral perfusionNormal cerebral perfusion
versus
Partial cerebral ischemiaPartial cerebral ischemia
Comparison between various models of hypotension
32
0
50
100
150
-5 15 35 55 75 95 115 135
50
100
150 BrainIntestine
8
50
100
150
50
100
150
Ref
(%
)T
BF
(%
)N
AD
H (
%)
MA
P (
mm
Hg)
80
100
120
SPO
2(%
)
Control Unilateral carotid Occlusion
N=4
33
0
50
100
150
50
100
150BrainIntestine
8
50
100
150
200
0
50
100
150R
ef (
%)
TB
F (
%)
NA
DH
(%
)M
AP
(m
mH
g)
-5
Bleeding
( Time)min
Resuscitation
0 30 90 1206015 45 105 13575
60
80
100
120
SPO
2(%
)
Bleeding after Unilateral carotid
Occlusion
N=9
25 26 27 28 Time (hour)
N2 N2 - deathStart
0
Bilateral carotid
occlusion
24
Operation Startcontrol
Partial cerebral ischemia - control group (no hemorrhage)Partial cerebral ischemia - control group (no hemorrhage)
0
100
200
0 30 60 90 120 150 180
50
100
150
50
100
150 Brain Intestine
50
100
150
50
100
150
0 35 70 105 140T im e (m in )
Ref
(%
)T
BF
(%
)N
AD
H (
%)
MA
P (
mm
Hg
)
Bilateral carotid occlusion (BCO) is an animal model of arteriosclerosis, which is considered to be the leading cause of mortality in industrialized countries.
50
100
150
200 Brain Intestine
50
100
150
200
0
50
100
150
200
0
50
100
150
-5Time (min)
Bleeding Resuscitation
0 30 90 1206015 45 105 13575
Ref
(%
)T
BF
(%)
NA
DH
(%
)M
AP
(mm
Hg)
Controlled hypotension for 15 min under partial cerebral ischemiaControlled hypotension for 15 min under partial cerebral ischemia
Bleeding and
maintenance
25 26 27 28 Time (hour)
N2 N2 - deathStart
0
Bilateral carotid
occlusion
24
Operation Resuscitation
15 min
0
50
100
150 Isch Nor
Ref
(%
)T
BF
(%)…
...N
AD
H (
%)…
..M
AP
(mm
Hg)
50
100
150
200 Isch Nor
0
50
100
150
200
50
100
150
200
Bleeding
Time (min)
Resuscitation
35 950 15 75 115 135-5 55
Ref
(%
)T
BF
(%)0
000
NA
DH
(%
)M
AP
(mm
Hg)
50
100
150
200
0
50
100
150 Isch Nor
50
100
150
200 Isch Nor
0
50
100
150
200
35 950 15 75 115 135-5 55
Bleeding
Time (min)
Resuscitation
Brain Brain IntestineIntestine
The differences between the two models are manifested mainly by the cerebral responses .
Comparison between the two organs in both experimental groupsComparison between the two organs in both experimental groups
TBFNADHControlled 15 min
Partial cerebral Ischemia
The brain and intestinal responses to hemorrhageThe brain and intestinal responses to hemorrhage
ConclusionsConclusions
Under normal conditionsUnder normal conditions
The early signs of the hemorrhage insult were detected in the intestine.
The initial deterioration of the intestine, following resuscitation, was not accompanied by a deterioration of MAP.
In all of the models the intestine suffered from irreversible damage, whereas the brain remained protected.
NADH responses to hemorrhage were higher in the intestine compared to the brain.
Under partial cerebral ischemiaUnder partial cerebral ischemia
The response of the ischemic brain, to hemorrhage, was very similar to the intestinal response. The cerebral tissue was suffering from extensive
reduction of blood flow. The combination of partial cerebral ischemia and hemorrhagic hypotension
blurs the differences between the brain and the small intestine.
39
Conclusions
The intestine may serve as a surrogate organ for monitoring under hemorrhagic insults, due to its capability for early detection of whole body deterioration.
The monitoring of mitochondrial NADH redox state can be used as an indicator of different hemorrhage stress severities.
The application of the Multi-site Multi-parametric monitoring system is clearly advantageous under
hemorrhagic hypotension.
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