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8/11/2019 Waschke Et Al. - 2004 - Regional Heterogeneity of Cerebral Blood Flow Response to Graded Pressure-Controlled H

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Regional Heterogeneity of Cerebral Blood Flow Response toGraded Pressure-Controlled Hemorrhage

Klaus F. Waschke, MD, Martin Riedel, MD, Christian Lenz, MD, Detlef M. Albrecht, MD,Klaus van Ackern, MD, and Wolfgang Kuschinsky, MD

Background: Little is known aboutthe regional distribution of cerebral blood

flow (CBF) in nonanesthetized animals

during periods of lowered blood pressure.

The present investigation addresses the

specific reaction patterns of local cerebral

blood flow (LCBF) in comparison with

mean CBF during graded pressure-con-

trolled hemorrhagic shock in conscious

rats.

Methods: Conscious rats were sub-jected to graded pressure-controlled hem-

orrhage (to 85, 70, 55, or 40 mm Hg) by

arterial blood withdrawal. After a period

of 30 minutes, blood pressure was stabi-

lized by withdrawal or reinfusion of

blood. LCBF was determined autoradio-

graphically by the iodo(14C)antipyrine

method in 34 brain structures, and mean

CBF was calculated and compared with

the values of nonhemorrhaged control

animals.

Results: Mean CBF remained un-changed except for the group with the

lowest blood pressure of 40 mm Hg (de-

crease in CBF of 28%). Otherwise, LCBF

was increased in some brain structures at

an unchanged mean CBF. Congruently, at

40 mm Hg, the decrease in mean CBF did

not show up in all brain structures, the

local pattern of CBF varying between an

unchanged and a profoundly decreased

CBF. The mean coefficient of variation of

CBF was increased with the severity of

hemorrhagic shock, which indicates an

enhanced heterogeneity of CBF.

Conclusion:Because of the substan-tial heterogeneity in the responses of

LCBF to pressure-controlled hemorrhage,

autoregulation of CBF during pressure-

controlled hemorrhagic shock has to be

reconsidered on a regional basis.

Key Words: Local cerebral bloodflow, Autoradiography, Hemorrhagic hy-

potension, Hemorrhagic shock.

J Trauma. 2004;56:591603.

Autoregulation is defined as a constancy of blood flow

at varying perfusion pressures. For the clinical con-

ditions of hemorrhagic shock, it is important to de-

fine the lower limit of blood pressure at which the blood

supply to the tissue is decreased. Previous studies have

addressed the responses of the cerebral circulation to hem-orrhagic hypotension with special focus on the lower limit

of cerebral autoregulation.15 Whereas such studies have

addressed the global response of cerebral blood flow

(CBF) to hypotension, other studies have focused on the

regional distribution of cerebral blood flow.613 Although

such studies raise an important issue (i.e., variable local

responses to hemorrhagic hypotension), care must be taken

in directly transferring these results to severely hemor-

rhaged patients under emergency conditions for several

reasons. One reason is that most studies have been per-

formed in anesthetized animals. The use of anesthetics

may influence the pressure-flow relationship in the brain

and may compromise cerebral autoregulation.14 A second

reason is the use of artificial ventilation, which is applied

in most studies on cerebral autoregulation to keep thearterial PCO2 constant. An increased airway pressure may

modify cerebral perfusion pressure to an undefined degree

by influencing cerebral venous and/or cerebrospinal fluid

pressure.15,16 Moreover, this approach does not reflect the

emergency situation of severe uncontrolled hemorrhage. A

third reason is that blood flow was measured in most

studies only a few minutes after perfusion pressure had

been decreased.1 4 Although this approach has the advan-

tage that secondary effects on CBF because of systemic

alterations during a prolonged hemorrhagic shock can be

avoided, the disadvantage is that the results cannot be

directly transferred to the clinical conditions of hemor-

rhagic shock. The present experiments were performed

with the intention of determining the local responses of

cerebral blood flow to a lowering of blood pressure during

graded hemorrhagic shock. To come more close to the

clinical situation of hemorrhagic shock, local cerebral

blood flow (LCBF) was measured in conscious, nonanes-

thetized, spontaneously breathing rats after a defined re-

duction of arterial blood pressure for 30 minutes. The quan-

titative autoradiographic iodo(14C)antipyrine method17 was

applied to achieve a high degree of spatial resolution for the

detection of LCBF after hemorrhage.

Submitted for publication August 4, 2002.Accepted for publication April 10, 2003.

Copyright 2004 by Lippincott Williams & Wilkins, Inc.

From the Department of Anesthesiology, Faculty of Clinical Medicine

Mannheim (K.F.W., M.R., C.L., K.V.), University of Heidelberg, Mann-

heim, Department of Anesthesiology, University of Dresden (D.M.A.),

Dresden, and Department of Physiology, University of Heidelberg (W.K.),

Heidelberg, Germany.

Supported by a grant from the Forschungsfonds der Fakultt fr Kli-

nische Medizin Mannheim der Universitt Heidelberg, Mannheim, Germany.

Address for reprints: Klaus F. Waschke, MD, Institut fr Ansthesi-

ologie und Operative Intensivmedizin, Fakultt fr Klinische Medizin Mann-

heim der Universitt Heidelberg, Theodor Kutzer Ufer 1-3, D-68167 Mann-

heim, Germany.

DOI: 10.1097/01.TA.0000075335.35705.E2

The Journal ofTRAUMAInjury, Infection, and Critical Care

Volume 56 Number 3 591


2/13

MATERIALS AND METHODSAnimals

After approval by the authorsinstitutional animal inves-

tigation committee, the experiments were performed on 36

male Sprague-Dawley rats weighing 297 to 412 g (Zentralin-

stitut fr Versuchstierzucht, Hannover, Germany). The rats

were maintained under temperature-controlled environmental

conditions on a 14:10 light:dark cycle. The animals were fed

a standard diet (Altromin C 1000, Lage, Germany) and al-

lowed free access to food and potable water until starting the

experiments. The general experimental protocol is outlined in

Figure 1.

Surgical ProcedureThe rats were placed in a small box and anesthetized by

inhalation of a gas mixture of halothane (1.0 2.0%), nitrous

oxide (60 70%), and oxygen (remainder). Anesthesia was

maintained during surgery by inhalation of the gas mixture

through a nose cone. Body temperature was held at 37 to

37.5C with the use of a temperature-controlled heating pad.

Polyethylene catheters were inserted into the right and left

femoral arteries and the right femoral vein. After surgery, the

animals were placed in a rat restrainer (Braintree Scientific,

Braintree, MA). Forty-five minutes were allowed for recov-

ery from the effects of anesthesia. Blood pressure was mon-

itored continuously by a quartz pressure transducer (Hewlett-

Packard, Palo Alto, CA).

Experimental ProcedureAfter recovery from anesthesia, the rats were randomly

assigned to one of the experimental groups (Fig. 1). Hemor-rhage was induced in all rats except for the six rats of the

control group, which were subjected to no treatment apart

from the described surgical preparation. Baseline values of

physiologic variables (as shown in Table 1) were measured

after recovery from anesthesia (45 minutes after the end of

anesthesia). The rats of the hemorrhage groups were then

subjected to a pressure-controlled hemorrhage by controlled

arterial bleeding (1 mL/min) through the femoral artery cath-

eter until the intended mean arterial pressure (MAP) of either

85 mm Hg (P-85 group), 70 mm Hg (P-70 group), 55 mm Hg

(P-55 group), or 40 mm Hg (P-40 group) was achieved (Fig.

1). Blood withdrawal was followed by a state of hemorrhagic

hypotension of 30 minutesduration. If necessary, additional

blood was withdrawn or shed blood was retransfused during

this period to keep the MAP constant. Rats that died during

hemorrhagic hypotension (two in the P-55 group and four in

the P-40 group) were not replaced. Blood flow data in these

groups were derived from the surviving animals. Physiologic

variables were redetermined in the hemorrhage groups at the

Fig. 1. Flow chart of the experimental protocol.


592 March 2004


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end of the 30-minute hemorrhage state. To achieve similar

experimental durations, these measurements were performed

60 minutes after baseline measurements in the control group

because these animals had not been subjected to the 30

minutes of blood withdrawal and the following hemorrhagic

hypotension of 30 minutes duration in the hemorrhage

groups. These measurements were followed immediately bythe infusion of iodo(14C)antipyrine. Arterial pH, PO2, and

PCO2 were measured in a pH/blood gas analyzer (AVL Gas

Check 939, Graz, Austria). The hematocrit was determined

by capillary tube centrifugation. Plasma glucose and blood

hemoglobin concentrations were measured spectrophoto-

metrically by the hexokinase/glucose-6-phosphatedehydroge-

nase method (Glucoquant, Boehringer Mannheim, Mannheim,

Germany) or the hemoglobin cyanide method (Hemoglobin

Merckotest, E. Merck, Darmstadt, Germany), respectively.

Measurement of LCBF

The technique used for measurement of LCBF, the au-toradiographic 4-iodo-N-methyl-(14C)-antipyrine method

(also called the iodo(14C)-antipyrine method) in the present

investigation was developed in 1978 as a successor to previ-

ously proven methods for measurement of regional cerebral

blood flow.17 Methods for quantitative determination of

blood flow in discrete cerebral components had been reported

for the first time by Kety and others between 1951 and

1960.1821 The method was initially based on the principles

of inert gas exchange between blood and tissues,17 using an

inert radioactive gas, (131I)-labeled trifluoroiodomethane,

which appeared to satisfy the requirements as a tracer for

measurement of blood flow in various structures of thebrain.1922 Because of the short half-life of (131I)-labeled

trifluoroiodomethane and its lack of commercial availability,

another tracer was sought, and after experimentation with

iodo(131I)antipyrine and (14C)antipyrine, which did not fulfill

the requirements for unlimited diffusion capacities, this tracer

was found in iodo(14C)antipyrine. The work of Sakurada et

al.,17 demonstrating the method, showed a close correlation

between the older measurements of local cerebral blood flow

with (131I)-labeled trifluoroiodomethane and the new method

using iodo(14C)antipyrine in cats. In addition, within the

same publication, the iodoantipyrine method was established

for rats.

17

For the measurement of LCBF in the present investi-

gation, 25 to 40 Ci of 4-iodo(N-methyl-14C)antipyrine

(specific activity, 54 mCi/mmol; Amersham-Buchler,

Braunschweig, Germany) dissolved in 1 mL saline was

continuously infused at a progressively increasing infusion

rate for a period of 1 minute through the femoral venous

catheter. The progressively increasing infusion rate was a

modification of the method described earlier.17 It was chosen

to minimize equilibration of rapidly perfused tissues with

arterial blood during the period of measurement. During the

1-minute infusion period, 14 to 20 timed blood samples were

collected in drops from the free-flowing arterial catheterTable

1

PhysiologicVariablesin

theControlandthePressure-ControlledHemorrhageGroups

Control

P-85

P-70

P-55

P-40

Baseline

60Minafter

Recoveryfrom

Anesthesia

Baseline

Endof30-Min

Hemorrh

age

State

Baseline

Endof30-Min

Hemorrhage

State

Baseline

Endof30-Min

Hemorrhage

State

Baseline

Endof30-Min

Hemorrhage

State

pH

7.38

0.03

7.39

0.02

7.37

0.03

7.36

0.02

7.38

0.02

7.32

0.05*

7.38

0.02

7.31

0.07*

7.39

0.02

6.9

0.24*

PO2

(mm

Hg)

93

3

91

2.6

89.2

6.3

97.3

6.3*

89

6.7

98.8

9.7*

88.0

3.7

104.0

6.0*

88.9

5.9

112.4

9.4*

PCO2

(mm

Hg)

42.0

4.0

41.6

2.9

40.9

3.6

39.7

2.4

42.1

2.9

34.2

4.0*

43.2

2.7

29.8

4.5*

42.6

4.5

20.5

5.3*

Baseexcess(mmol/L)

1.0

1.0

1.3

1.1

1.4

1.3

2.7

1.7

1.3

1.6

7.9

2.2*

0.0

1.0

9.4

4.4*

0.5

1.7

28.2

8.2*

Plasmaglucose(mg/dL)

169

20

173

18

158

17

201

46*

177

21

419

157*

177

20

471

94*

169

26

468

118*

Hemoglobin(g/dL)

14.4

0.8

14.6

0.9

15.3

0.9

12.2

1.1*

15.4

1

10.3

0.9*

14.6

1.1

9.6

0.9*

14.8

1.2

11.2

2.4*

Hematocrit(%)

44

2

45

2.6

44.9

1.7

38.4

3.0*

45.0

1.1

31.4

2.5*

45.3

1.4

30.7

4.2*

45.7

1.9

33.3

4.3*

Heartrate(1/min)

361

18

378

21

377

39

331

33

425

26

377

61

428

36

400

55

412

31

427

38

MAP1

(mm

Hg)

116

9

119

10

121

6

86

1*

127

3

70

2*

124

8

55

1*

123

9

40

2*

Shedbloodvolume(mL/

kgbodyweight)

0

16.1

2.1

26.9

1.2

30.1

3.0

37.3

2.3

n

6

6

6

6

6

Means

SD;n,no.ofanimals;*vs.

baselinevaluesineachgroup.

Heterogeneity of CBF during Pressure-Controlled Hemorrhage



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directly onto filter paper disks (1.3 cm in diameter) that

previously had been placed into small plastic beakers and

weighed. The samples were weighed and radioactivity esti-

mated with a liquid scintillation counter (Tri-Carb 4000 se-

ries, Canberra Packard, Frankfurt, Germany) after extraction

of the radioactive compound with ethanol. After the 1-minute

infusion and sampling period, the animal was decapitated,and the brain was removed as quickly as possible and frozen

in 2-methylbutane chilled to 40 to 50C with dry ice. The

frozen brains were coated with chilled embedding medium

(Lipshaw, Detroit, MI), stored at 80C in plastic bags and

sectioned into 20-m coronal sections at 20C in a cryostat,

and the first 3 sections of every 10 were autoradiographed

along with precalibrated (14C)methyl methacrylate standards.

Usually, this procedure yielded approximately 70 to 100

autoradiographed sections per brain. The cerebral regions of

interest were identified by comparison with Palkovits and

Brownsteins atlas of the rats central nervous system.23 For

the evaluation of any brain structure of interest, a series of sixconsecutive autoradiographed brain sections was chosen, rep-

resenting the optimal appearance of the concerning brain

structure. These sections were used for measurement of ce-

rebral blood flow in any structure of interest on both sides of

the brain, resulting in 12 values for LCBF in any brain

structure analyzed. The final value for LCBF in each brain

structure was derived as the mean of the values measured.

Local tissue concentrations of 14C were determined from the

autoradiographs by densitometric analysis with a densitome-

ter equipped with a 0.2-mm aperture (Parry DT1105 R; New-

bury, Berkshire, United Kingdom). LCBF was calculated

from the local concentrations of 14

C and the time course ofthe blood iodo(14C)antipyrine concentrations, including cor-

rections for the lag and washout in the arterial catheter.17 The

washout correction rate constant was 100/min. The brain-

blood partition coefficient for iodo(14C)antipyrine was found

to be 0.9 in our rats.24 LCBF was determined in 34 different

brain regions.

Statistical EvaluationValues are reported as means SD. Mean CBF was

determined as the arithmetic average of the LCBF values

obtained from the 34 brain structures analyzed. The mean

coefficient of variation of CBF (Fig. 2), which was taken asan indicator of heterogeneity of blood flow,25,26 was calcu-

lated for each experimental group from the coefficients of

variation of LCBF in each of the 34 brain structures analyzed.

Statistical differences were evaluated by analysis of variance

and Students ttest. Bonferroni correction for multiple com-

parisons was used when appropriate.

RESULTSReaction to Hemorrhage

Because of the severity of the hemorrhage, six rats died

during hemorrhagic hypotension (two rats in the P-55 and

four rats in the P-40 group). Thirty rats survived the experi-

mental protocol. Progressive hypotension induced a transient

excitation of the animals, whereas at the end of the 30-minute

state of hemorrhagic hypotension the animals of the hemor-

rhage groups displayed some degree of lethargy, depending

on the degree of pressure-controlled hemorrhage.

Physiologic VariablesThe physiologic variables of both the control and hem-

orrhage groups are summarized in Table 1. Taking into ac-count a total blood volume of the experimental animals of 60

mL/kg,27 the total shed blood volume in the hemorrhage

groups was 27% of the circulating blood volume in the P-85

group, 45% in the P-70 group, 50% in the P-55 group, and

62% in the P-40 group. In the untreated control group, no

differences were found between the measured physiologic

variables obtained after recovery from anesthesia and 60

minutes later. Thirty minutes after pressure-controlled hem-

orrhage, profound changes were observed: the graded lower-

ing of MAP was followed by the development of a significant

metabolic acidosis with partial respiratory compensation.

Plasma glucose concentrations were significantly increased inparallel. Hemoglobin concentration and hematocrit were sig-

nificantly decreased to approximately two thirds of the base-

line values in the P-70, the P-55, and the P-40 groups.

Local Cerebral Blood FlowLCBF was determined in 34 brain structures of each

experimental group. The results are presented in Figures 3

and 4, which outline the dependency of LCBF on MAP.

Figure 3 shows the general trends, whereas Figure 4 specifies

the significant changes after grouping of the data. Figure 3

shows that, in the majority of structures, LCBF was main-

tained except for the P-40 group. In Figure 4, the blood flow

Fig. 2. Dependence of mean cerebral blood flow (CBF) and meancoefficient of variation on mean arterial blood pressure. *Signifi-

cant changes compared with the control group, p 0.05.


594 March 2004


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values of the 34 brain structures analyzed have been grouped

according to the decrease of LCBF in the P-40 group com-

pared with the control group. In the top panel, the brain

structures are shown in which blood flow was unchanged in

the P-40 group (from left to right). The structures displayed

in the bottom panel show the largest decrease in blood flow in

the P-40 group. Instead of grouping the results exclusively

according to the values of LCBF in the P-40 group, another

means of classification leads to four circumscribed groups of

brain structures:

1. In the first group, those structures would appear in

which LCBF was significantly increased in the P-85,P-70, and P-55 groups, whereas no significant LCBF

changes could be detected in the P-40 group. Such

structures were the superior olive, dentate nuclei, hip-

pocampus CA 3, mamillary body, and the substantia

nigra.

2. The second group contains structures in which signif-

icant LCBF increases could be measured in the P-85,

P-70, and P-55 groups, whereas LCBF was signifi-

cantly decreased in the P-40 group. Such structures

were the inferior colliculus, lateral lemniscus, medial

geniculate body, sensory motor cortex, and the parietal

cortex.

3. The third group encompasses structures in which

LCBF was significantly decreased in the P-40 group

exclusively, whereas no significant changes were

found in the P-85, P-70, and P-55 groups. Such struc-

tures were the pontine gray, lateral thalamus, superior

colliculus, amygdaloid complex, lateral geniculate

body, nucleus accumbens, caudate nucleus, hypothal-amus, frontal cortex, visual cortex, lateral septal nu-

clei, and the genu of corpus callosum.

4. The fourth group contains the remaining structures,

which all showed unchanged values of LCBF in the

P-85, P-70, P-55, and P-40 groups compared with the

control group. These were the vestibular nucleus, hip-

pocampus CA 2, hippocampus CA 1, hippocampus

CA 4, ventral thalamus, dentate gyrus, cerebellar cor-

tex, globus pallidus, cerebellar white matter, corpus

callosum, and the internal capsule.

Mean Cerebral Blood FlowA third means of analysis of the data in addition to those

shown in Figures 3 and 4 is to investigate the variability of

LCBF in the different experimental groups. To this end, the

LCBF values obtained from all brain structures were summed

to obtain a mean value of blood flow in each experimental

group. The mean coefficient of variation of CBF was calcu-

lated for each group. Mean CBF and the corresponding mean

coefficient of variation of CBF are plotted in Figure 2. A

significant change of mean CBF could only be found in the

P-40 group. Mean CBF was decreased by 28% compared

with the control group. The coefficient of variation was

unchanged in the P-85 and the P-70 group, whereas it in-creased significantly in the P-55 group and in the P-40 group.

This indicates an increase of heterogeneity of CBF in the

P-55 group at an unchanged mean CBF.

DISCUSSIONThe results of the present study indicate a substantial

degree of heterogeneity in the reaction of regional cerebral

blood flow to graded pressure-controlled hemorrhage that is

not reflected when only mean cerebral blood flow is

measured.2832 These data are based on autoradiographic

techniques applied to conscious, spontaneously breathing an-

imals after a period of hemorrhagic hypotension of 30 min-utes duration.

Regarding the heterogeneity of CBF, previous studies on

cerebral autoregulation under conditions of hemorrhagic hy-

potension have revealed conflicting results. In contrast to the

results of the present study, some authors did not find any

heterogeneities or indications of redistribution of CBF after

exposure of the experimental animals to acute hemorrhagic

hypotension (Table 2). Unanesthetized, spontaneously

breathing dogs11 showed that at an MAP of 50 mm Hg the

LCBF response in each brain structure measured by the

microsphere technique did not differ from the response of

mean CBF to hemorrhagic hypotension. Laughlin33 did not

Fig. 3. Mean values of local cerebral blood flow in the 34 brain

structures analyzed are related to the mean arterial blood pressure

during graded pressure-controlled hemorrhage.




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find any significant changes in LCBF and mean CBF during

graded hemorrhagic hypotension with a final MAP of 22 mm

Hg in pentobarbital-anesthetized and artificially ventilated

miniature swine as measured by the microsphere method. In

this investigation, CBF even tended to increase at the lowest

level of hypotension. Ferrari et al.7 reported that CBF was

well autoregulated down to an MAP of 40 mm Hg in anes-

thetized, mechanically ventilated dogs. In this study, mean

CBF and LCBF in all examined brain structures decreased by

50% when cerebral perfusion pressure dropped to 30 mm Hg.

Regional variations of CBF could not be detected by the

microsphere CBF measurements used by the authors of this

Fig. 4. LCBF specified for individual brain structures in the different experimental groups. The brain structures have been ranked from top

to bottom and from left to right according to the decrease of LCBF in the P-40 group compared with the control group. *Significant changes

of LCBF compared with the control group, p 0.05.


596 March 2004


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Table

2

StudiesObservingNoH

eterogeneityofLCBFduringHyp

otension

First

Author

Year

CBFCompared

withControl

Conditions

Methodof

Measure

ment

Species

Anesthesia

Ventilation

PCO2

pH

Hct

Bloo

dGlucose

Con

centration

Minimal

Blood

Pressure

(mm

Hg)

Durationof

Hypotension

Mod

elofHypotensionand

Remarks

Slater

1975

Decreased

Microsphe

res

Dogs

Conscious

Spont.

Appr.25

Appr.7.40

n.a.

n.a.

Appr.50

0and6h

Pressure-controlled

hem

orrhagichypotension

Gamache

1976

Decreased

14C-antipyrine

Rhesus

monkeys

Pentobarbital

Cont.

2636

7.357.45

n.a.

n.a.

25

30min

maximum

Hypotensioninducedby

trim

etaphan

Laughlin

1983

Nochanges

Microsphe

res

Miniature

swine

Pentobarbital

Cont.

n.a.

n.a.

n.a.

n.a.

22

1015min

Ferrari

1992

Below40mm

Hgdecreased

by50%

Microsphe

res

Dogs

Pentobarbital

Cont.

32

7.12

Hb13.0

n.a.

16

20min

Pressure-controlled

hem

orrhagichypotension

Anwar

1996

Nochanges

Microsphe

res

Newborn

pigs

Alpha-

chloralose

Cont.

35

7.23

n.a.

n.a.

31

30min

Pressure-controlled

hem

orrhagichypotension;

reductionofthenumberof

perfusedcapillaries

Komjati

1996

Nochangein

RCBFora

slight

reduction

Microsphe

res

Cats

Chloralose-

urethane

Cont.

37

7.15

n.a.

n.a.

40

10min

Pressure-controlled

hem

orrhagichypotension;

reductionofRCBFonlyin

hyp

othalamusandmedulla

oblongata

Zaharchuk

1999

Constantat

14050mm

Hg,below,fall

Hemodyna

mic

magnetic

resonance

imaging

Rats

Halothane

Cont.

28(severe

hypotension)

7.29

29

n.a.

26

1mm

Hg/min

Pressure-controlled

hem

orrhagichypotension

Nishimura

1999

Decreaseof

CBFonlyin

fewregionsof

interest

PET

Humans

Conscious

Spont.

Normocapnia

n.a.

n.a.

n.a.

Individual

Afterstable

induced

hypotension

wasobtained

Hypotensioninducedby

trim

etaphan;more

dec

reaseatpresenceof

vas

cularstenosis;

som

etimesCBFinROIs

withahighreactivityto

hyp

ercapniaincreased

duringhypotension

Hct,hematocrit;Spont.,spontaneously;Cont.,controlled;Appr.,approximately(expressionusedwhenthevalueonly

canbefoundasatargetvalueintheMethodssection);Hb,

hemoglobinconcentration;ROIs,regionsofinterest;n.a.,notavailableinthispublication;PET,positron-emissiontomogr

aphy.




8/13

study. Another study also used radioactive microspheres for

measurement of CBF during hemorrhagic hypotension inalpha-chloraloseanesthetized newborn pigs.34 At an MAP of

31 4 mm Hg, Anwar et al.34 found in this study also no

significant reduction in CBF but a reduction in the number of

perfused capillaries in all brain regions investigated. Using

spin labeling and steady-state susceptibility contrast, Zahar-

chuk et al.31 measured cerebral blood flow during hemor-

rhagic hypotension in halothane-anesthetized rats using he-

modynamic magnetic resonance imaging. In the slice of the

bregma, CBF was kept constant between an MAP of 50 and

140 mm Hg; below these values, it fell corresponding to a

falling MAP. Komjati et al.35 measured regional cerebral

blood flow (RCBF) in thalamus, hypothalamus, pituitary,

white matter, frontoparietal cortex, cerebellum, and three

locations of the spinal cord in alpha-chloralose-urethananes-thetized cats during pressure-controlled hypotension (80, 60,

and 40 mm Hg) and found no change in RCBF or a slight

reduction. From these studies, it might be concluded that

LCBF to different brain structures exhibited the same reac-

tion pattern as CBF to the brain in total. In addition, a recent

study in humans demonstrated the important role of uniform

regulatory mechanisms of the cerebral circulation in healthy

brain structures during hypotension. Nishimura et al.36 mea-

sured regional CBF in regions of interest (ROIs), mostly

covering the cortical territory of the middle cerebral artery by

positron-emission tomography in patients with occlusive dis-

ease of the carotid or middle cerebral artery during hypoten-

Table 3 Studies Observing Increased Heterogeneity of LCBF during Hypotension

First Author Year Higher CBFCompared

with ControlConditions

Lower Blood FlowCompared

with ControlConditions

Method ofMeasurement

Species

Higher CBF in deep brain regions

Sadoshima 1983 Brain stem Preserved more Cerebrum, cerebellum Preserved less Microspheres Stroke-prone

spontaneously

hypertensive

rats (SHRSP)

Wistar-Kyoto-

rats (WKY)

Tuor 1994 Deep forebrain and brain

stem structures

Maintained Cortex and subcortical

white matter

Decreased Iodoantipyrine

(laser-Doppler)

Rabbits

Tsutsui 1995 Other brain regions Maintained Neocortex and

telencephalon

Decreased Iodoantipyrine Rats

Niwa 1998 Brain stem regions Increased Supratentorial cortical

regions

Maintained Iodoantipyrine Rats

Higher CBF in hindbrainDe Witt 1992 Posterior cerebral artery

(posterior brain regions)

Maintained to

decreased

Anterior cerebral artery

(anterior brain

regions)

Maintained to

decreased

Microspheres Cats

ONeil 1997 Hindbrain Increased Forebrain Maintained Microspheres Newborn lambs

Higher CBF in cerebrum and cortex

Mueller 1977 Brain stem, cerebrum,

cerebral gray

Preserved more Cerebellum, cerebral

white

Preserved less Microspheres Dogs

Bauer 1997 Cortex Increased n.a. n.a. Colored

microspheres

Newborn swine

Komjaty 1997 Cortex Decreased Medulla Decreased H2-clearance Cats


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sion induced by trimetaphan. During hypotension, in brain

hemispheres without a vascular stenosis, they observed adecrease of CBF only in a few ROIs, but in more ROIs when

an asymptomatic vascular stenosis was present and even

more when a symptomatic vascular stenosis was present.

Sometimes, CBF in ROIs with a high reactivity to hypercap-

nia increased during hypotension.

However, other groups presented completely different

LCBF responses to hemorrhagic hypotension. In these studies

on cerebral autoregulation, LCBF changes did not parallel the

changes in mean CBF during hypotension (Table 3). In anes-

thetized and artificially ventilated dogs, Mueller et al.9 ob-

served a significant redistribution of CBF when MAP was

reduced below 65 mm Hg. Blood flow to the brain stem,

cerebrum, and cerebral gray matter was preserved more than

flow to cerebellum and cerebral white matter under hypoten-sive conditions. Using staged hemorrhagic hypotension,

Bauer et al.37 observed a slight increase of regional cerebral

blood flow in the cortex of isoflurane/nitric oxideanesthe-

tized newborn piglets at a MAP of 60 and 50 mm Hg (66

23 mL/min/100 g and 53 12 mL/min/100 g, respectively,

compared with 42 12 mL/min/100 g at control conditions).

At 40 and 35 mm Hg, RCBF in the cortex fell below the value

observed during control conditions.37 Sadoshima and

Heistad10 described larger reductions of LCBF to cerebrum

and cerebellum than to brain stem when anesthetized, me-

chanically ventilated, normal, and spontaneously hyperten-

sive rats were subjected to hemorrhagic hypotension down to

Table 3 Continues

Anesthesia Ventilation PCO2 (mm Hg) pH Hct (%)Blood GlucoseConcentration

(mg/dL)

Minimal BloodPressure(mm Hg)

Duration ofHypotension

Model of Hypotension and Remarks

Pentobarbital Cont. 35 (SHRSP)

36 (WKY)

7.34 (SHRPS)

7.36 (WKY)

n.a. n.a. 109 (SHRSP)

48 (WKY)

10 sec Pressure-controlled

hemorrhagic hypotension

Chronic sympathetic

denervation (Removal of one

superior cervical ganglion)

Urethane Spont. 45 7.28 n.a. n.a. 20 Several min Pressure-controlled


Halothane Cont. 37 7.1 36 n.a. 29 30 min Pressure-controlled


Additional groups with

hypotension by trimetaphan

and nitroprusside

Conscious Spont. 33 7.39 43 211 51 2 min Pressure-controlled


Isoflurane Cont. 31 6.93 n.a. n.a. 41 n.a. Pressure-controlled


Chloralose-

urethane

Cont. 40/41 7.30/7.36 17/28 n.a. 30/28 5 min Pressure-controlled


Infusion of autologous blood in

the 2. group to prevent

anemia

Isoflurane/

nitrous

oxide

Cont. 37 (acute)

39 (chronic)

7.33 (acute)

7.38 (chronic)

n.a. n.a. 37 (acute)

38 (chronic)

515 min Pressure-controlled


Acute and chronic sympathetic

denervation by removal of

one superior cervical

ganglion and the stellateganglion

Isoflurane/

nitrous

oxide

Cont. 44 7.24 n.a. 60 32 25 min Pressure-controlled


Reduction of blood pressure

step by step every 30 min to

60, 50, 40, and 35 mm Hg

Chloralose-

urethane

Cont. 35 (medulla)

33 (cortex)

n.a. n.a. n.a. 63 (medulla)

63 (cortex)

75 min Pressure-controlled


Hct, hematocrit; Microspheres, radioactive microspheres; Cont., controlled; Spont., spontaneously; Appr., approximately (expression used

when the value only can be found as a target value in the Methods section); Hb, hemoglobin concentration; n.a., not available in this publication.




10/13

70% and 50% of the baseline MAP values. DeWitt et al.6

observed no significant changes of mean CBF until MAP was

reduced to 40 mm Hg in isoflurane-anesthetized and venti-

lated cats, although LCBF in brain structures supplied by the

anterior cerebral artery only decreased at a MAP of 60 and 40

mm Hg. LCBF in most regions supplied by the posterior

cerebral artery and the basilar artery was preserved even at aMAP of 40 mm Hg.

In contrast to the above-cited investigations that used the

microsphere method to measure LCBF, studies that use au-

toradiographic methods for the measurement of LCBF are

able to provide a higher spatial resolution, but also demon-

strate conflicting results. By use of the (14C)-antipyrine

method, Gamache et al.8 showed that in anesthetized and

ventilated rhesus monkeys the pattern of LCBF responses to

a hemorrhagic hypotension at 25 mm Hg did not differ from

the distribution pattern of LCBF during normotension.

In contrast to these findings, Niwa et al.12 induced hy-

potension in conscious rats by hemorrhagic hypotension andmeasured LCBF in 18 brain regions by the iodo(14C)-anti-

pyrine method 2 minutes after the desired MAP level had

been achieved. During exsanguination down to a MAP of 50

mm Hg, they observed that LCBF was maintained in most of

the supratentorial cortical regions, whereas LCBF in most of

the brain stem regions showed a tendency to increase. These

authors characterized this predysautoregulatory overshoot

of CBF as a defense mechanism against hemorrhagic

hypotension.12,38

The present investigation was designed to study the ef-

fects of graded pressure-controlled hemorrhage on local vari-

ations of CBF. Therefore, on the one hand, a direct compar-ison of the present results with those of previous reports on

autoregulation of the cerebral circulation with changing per-

fusion pressure always has to consider the specific character-

istics of the present experimental protocol (no anesthesia, no

maintained arterial PCO2 by artificial ventilation, profound

systemic effects of hemorrhage such as severe metabolic

acidosis, autoradiographic measurements of LCBF). On the

other hand, the presented results have provided additional

knowledge of the reaction patterns of LCBF during pressure-

controlled hemorrhage, especially under conditions of severe

hemorrhagic shock. Although our data and the majority of

previous investigations on cerebral autoregulation show thatthe response of the cerebral circulation to hemorrhagic hy-

potension is not uniform, there are substantial differences of

our results in comparison with those autoregulation studies

that also reported some degree of heterogeneity and regional

variations of CBF during hemorrhagic hypotension. The pref-

erential preservation of CBF to brain stem structures during

hemorrhagic hypotension as described previously9 could not

be confirmed in the present investigation. As outlined in

Figures 3 and 4, there were brain structures in which LCBF

is preserved even at an MAP of 40 mm Hg, but these struc-

tures cannot be assigned exclusively to the brain stem. In

addition, significant decreases in LCBF could be detected in

some brain stem structures at this level of hemorrhage. The

phenomenon of predysautoregulatory overshoot of CBF12,38

could also be observed in our study. However, an exclusive

limitation of this effect to brain stem structures as described

by Niwa et al.12 was not obvious in our data (Figs. 3 and 4).

In general, the described pattern of LCBF found in the

present study during graded pressure-controlled hemorrhagedoes not conform to any previously described specific reac-

tion patterns of the cerebral circulation during hemorrhage. In

addition, there is no obvious concept to explain the observed

pattern of CBF.

The present experiments have been conducted in con-

scious animals. The use of anesthetics in most other stud-

ies might have contributed to differences in the results.

Seyde et al.39 reported a decrease in CBF and a redistri-

bution of LCBF during pentobarbital and chloralose-ure-

thane anesthesia in rats. Furthermore, Enlund et al.40 mea-

sured RCBF in frontal, temporal, parietal, occipital and

cerebellar cortex, striatum, thalamus, cerebellar vermis,and white matter by the use of positron-emission tomog-

raphy in rhesus monkeys with hypotension at an MAP of

50 to 60 mm Hg induced by isoflurane or propofol anes-

thesia. Compared with baseline anesthesia with a low dose

of either anesthetic, they found an increase of RCBF in the

majority of brain structures observed during hypotension

induced by isoflurane anesthesia, but a decrease of RCBF

in all brain structures investigated during hypotension in-

duced by propofol anesthesia. Because hypotension in this

study was induced by anesthetic agents, the increases and

decreases observed may be because of the combined phar-

macodynamic effects of the agents on cerebral rate ofoxygen metabolism and on vasodilation of cerebral blood

vessels and not because of the induced hypotension per se.

Thus, general anesthetic agents may change the hemody-

namic response to acute hemorrhage, varying from agent

to agent and species to species.39,4143 Therefore, to

achieve identical values of reduced MAP in conscious

animals, a substantially larger amount of withdrawn blood

is required in hemorrhage models of conscious than in

anesthetized animals. Because of this, a degree of meta-

bolic acidosis has been found in the present study (Table 1)

that has not been described previously in the literature in

connection with CBF measurements during hemorrhagichypotension. It remains unknown whether this severe systemic

acidosis, secondary to low tissue perfusion, has contributed to

the increase in cerebral blood flow found in some of the brain

structures analyzed in the present study. The observed fall in

arterial PCO2 should decrease cerebral blood flow. However,

previous studies have shown an impaired carbon dioxide respon-

siveness of CBF during hypotensive conditions.44

In addition, variations in blood glucose concentration also

may contribute to heterogeneities of LCBF, resulting in even

reductions of LCBF during acute hyperglycemia but different

reductions of LCBF during chronic hyperglycemia.45,46 This

finding may further complicate the comparison between the


600 March 2004


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various studies investigating pressure-controlled hemorrhagic

hypotension.

To make all these comparisons easier, two tables have

been included in this presentation (Tables 2 and 3). These

tables present many of the characteristics of the cited studies

at a glance, especially potential causes for the differing re-

sults mentioned above. However, this presentation is limited,because in a great number of these studies, the values for

some parameters of interest were not available in the corre-

sponding study, especially values for blood glucose concen-

tration or hematocrit. These tables demonstrate the varying

results of investigations during hemorrhage with respect to

absolute levels of CBF. Undoubtedly, the cause for the het-

erogeneity of the results observed are the myriad variations in

experimental paradigms including but not limited to species,

anesthesia, duration and depth of hypotension, stress or pain

in the animals, blood glucose concentration, and other

factors.

A cause for the observed differences of the presentfindings compared with the study of Niwa et al.12 may

consist of the measurement of LCBF after a defined re-

duction of arterial blood pressure for 30 minutes, whereas

Niwa et al.12 measured LCBF only 2 minutes after the

desired level of arterial blood pressure had been achieved.

Therefore, secondary effects on CBF caused by systemic

alterations during a prolonged hemorrhagic shock may

have been missed by the latter approach. In contrast, the

present study was intended to come close to the clinical

situation of prolonged hemorrhagic shock and therefore

used a more realistic model of hemorrhagic hypotension in

the trauma situation. Thus, the findings of the presentinvestigation may be more directly transferred to the clin-

ical conditions of hemorrhagic shock than the findings

from previous autoregulation studies.

In the period between anesthesia and the onset of

hemorrhage, the rats obviously were undergoing some

stress, with consequent cerebral effects. However, this fact

also may better reflect the clinical situation, when patients

are conscious and exposed to stresses, even before hem-

orrhage. Because no values of cerebral blood flow could be

obtained in the animals that diedtheir ultimate CBF

would be zerothe higher mortality in the severely hem-

orrhaged rats may implicate that considerably lower CBFsmight have prevailed in this group as a whole than could be

obtained by measurement of CBF in surviving animals.

One could further speculate, therefore, that the heteroge-

neity of blood flow might have been even greater, as the

measurements in the surviving animals in the P-55 and

P-40 groups indicate.

Strikingly high values for local cerebral blood flow could

be observed in the auditory cortex. This finding may impli-

cate sensorial stimulation of this brain region during the

experiments. Measurements were obtained during the normal

acoustic atmosphere of a closed room in a physiologic labo-

ratory. Most noise came from verbal communication between

the members of the experimental team. Immediately during

the 1-minute infusion period of iodoantipyrine, the number of

each droplet from the arterial catheter was announced to a

technician, who noticed the time of each droplets fall. The

other type of noise was a quiet humming from the motor

injection syringe for iodoantipyrine. During the experiment,

there was no noise from other laboratory machines such ascentrifuges or shaking baths.

At a whole, during all states of even potentially lethal

hypotension, LCBF did not decrease to ischemic values for

brain tissue, known from previous investigations.47 This ob-

servation may reflect the stability of the cerebral perfusion

during hemorrhagic shock. However, conclusions drawn

from the values of LCBF observed in this setting are limited,

because the reduction of cerebral blood flow that causes

ischemic depolarization and ischemic sensitivity itself varies

not only among species but also dramatically among specific

populations of brain neurons.48

Although in contrast to other species, blood vessel anat-omy and blood flow distribution in rat brain is very similar

to blood vessel anatomy and blood flow distribution in

humans,49 the limitations of this study include further that the

observations made are preferentially applicable to the ob-

served animal species, rats. It can only be a matter of further

speculation and research whether the observed results can be

applied to larger animals and humans. However, the experi-

ments in the present study are faithful replications of the

clinical situation in the animals investigated with the excep-

tion perhaps of the absence of pain, which is typically asso-

ciated with traumatic hemorrhage.

In conclusion, the results of the present investigationindicate distinct patterns of local cerebral blood flow during

pressure-controlled hemorrhage in conscious rats. The lower

limit of autoregulation is highly dependent on the cerebral

region analyzed. The regional variations of LCBF are not

reflected in the mean CBF which, without values of LCBF,

would indicate perfect autoregulation.

ACKNOWLEDGMENTSWe thank T. Lorenz, T. Fuchs, P. Strau, and M. Harlacher for

excellent technical assistance.

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