Acta Neurochir 2003 - dott. enrico fainardi

Acta Neurochir (2003) [Suppl] 86: 361-365
© Springer-Verlag 2003
Printed in Austria
Induced acute arterial hypertension and regional cerebralflowin intracontusional
low density area
A. Chieregato^ E. Fainardi^, A. Tanfani^ G. S a b i a \. Martino^, R. Pascarella^, F . Servadei*, and L . Targa^
^ Neurorianimazione, Ospedale Bufalini-Cesena, Italy
^ Neuroradiologia, Ospedale S. Anna-Ferrara, Italy
^ Neuroradiologia, Ospedale Bufalini-Cesena, Italy
* Neurotraumatologia, Ospedale Bufalini-Cesena, Italy
Summary
Traumatic brain contusions bave been associated with regional
ischemia. We aimed to measure the eflfect of induced supra-normal
values of cerebral perfusion pressure (CFP) on regional cerebral
blood flow (rCBF) in the intracontusional low density area surrounding the contusional hemorrhagic core. I n 7 severely head i n jured patients (GCS < 8) harbouring a contusion larger than 2 cm,
the rCBF levels were measured, by means o f Xenon-enhanced CT,
in: 1) the intracontusional low density area; 2) contralaterally, i n
a normal brain symmetric area. C B F studies were performed at
a baseline CPP of 65.3 m m H g + 7 and after 20 minutes of norepinephrine-induced CPP supernormal values (88.3 m m H g ± 10.5)
(p = 0.0013). A "paradoxical" reduction of r C B F levels was observed in both the intracontusional low density area (p — 0.07) and
the contrasterai "normal" area (p = 0.08). I n particular, this decrease of r C B F in the intracontusional low density area (-25.7 ±
10 ml/lOOgr/min) (p = 0.0009) was present in only 4 cases, having a
mean rCBF at baseline of 25 ± 16 ml/lOOgr/min. I n the remaining 3
cases in which rCBF at baseline was abnormally low (12 ± 7 m i /
lOOgr/min), r C B F values improved slightly (3.6 + 2 mi/1 OOgr/min)
(p = 0.61). A n acute increase of CPP seems to marginally affect
rCBF in the intracontusional low density area having critically reduced initial values, but may greatly reduce rCBF in subjects starting
from non-critical baseline values.
Keywords: Autoregulation; cerebral blood flow; cerebral perfusion
pressure; contusion; ischemia; xenon CT.
Introductìon
Traumatic contusion has been associated with regional ischemia. Low levels of regional cerebral blood
flow (rCBF), below 18 mi/1 OOgr/min [5], have been
demonstrated in the intracontusional edematous low
density area surrounding the contusional hemorrhagic
core investigated by means of Xenon-enhanced CT
(Xe-CT) [13]. Microscopie findings of cytotoxic edema
and microvascular ischemia [13] were also detected in
this area [10]. I n the last decade, an increase of cerebral
perfusion pressure (CPP) has been suggested as a therapeutic option for the control of elevated intracranial
pressure (ICP) [12] and for the treatment of global and
focal ischemia. When elevated CPP is used to improve
ICP control, it benefìts from a presefved autoregulation ("pressure active" pattern) which, in order to
maintain CBF stability, induces a vasoconstriction
and a reduction of cerebral vascular volume and, finally, ICP [12]. I n a setting of focal and global ischemia, the pressure autoregulation is deranged and the
rCBF passively follows the changes in CPP ("pressure
passive" pattern) [11]. Experimental evidence suggests
that while normal values of CPP may be associated
with focal hypoperfusion [16] in traumatic contusions,
an increase in CPP has been associated with raised
rCBF [1, 7]. As far as we know, this concept has not yet
been verified in a clinical setting. One of the current
indications for surgery in severely head injured patients with focal parenchymal damage is the elevation
of ICP, with the aim of removing the contusional
necrotic/hemorrhagic tissue, whilst sparing any potentially viable surrounding brain matter [13]. However specific medicai therapy might contribute to this
objective and an increase of CPP, above the recommended values of 70 mmHg, could lead to an improvement of regional perfusion in intracontusional
low density tissue surrounding the hemorrhagic core.
The purpose of this study was to assess the effect of a
briefly induced increase in CPP on intracontusional
low density tissue rCBF.
A. Chieregato et al.
362
Material and methods
Seven severely head injured patients (GCS < 8) harbouring seven
traumatic mixed density contusions larger than 2 cm. were included
in the study. Patients with cardiovascular dysfunctions and those
with unstable ICP were excluded. In agreement with guidehnes [8],
ali patients were managed using a staircase protocol to maintain ICP
below 20 mmHg and cerebral perfusion pressure (CPP) above
70 mmHg. The outcome at six months post-injury was measured by
means of the Glasgow Outcome Scale (GOS) [4].
Stable xenon-enhanced CT CBF measurement
CBF studies were conducted by a wash-in protocol based on the
inhalation of a mixture of 28% Xenon, 40% Oxygen and 32% room
air using a CT scanner (Picker 5000) equipped for Xe-CT CBF
imaging (Xe/TC system-2™, Diversified Diagnostic Products, Inc.,
Houston, TX). Ali patients were artificially ventilated, sedated, and
paralysed.
Results
The demographic, clinical and radiologica! data of
our case material are reported in Table 1. Three cases
had initial values of GCS above 8, but rapidly deteriorated during the acute phase.
Main results ( Table 2)
A significant difference was found between M A P
and CPP measured at baseline and after the induced
increase with norepinephrine. N o significant changes
were observed for ICP, nor between PaC02 measured
at baseline and during hypertension. After induced
hypertension, the r C B F mean levels decreased, to level
nearly statistically significant, both in the intracontusional low density area (—13.1 + 17.2 ml/lOOgr/min)
CBF analysis
(p = 0.07) and the contralateral area (—11.3 + 6.4 m i /
The rCBF was measured by means of Xenon-enhanced computerized tomography (Xe-CT) in two different ROIs drawn freehand
on the CT scan: 1) the intracontusional low density area surrounding
the contusional hemorrhagic core; 2) contralaterally, in a normalappearing area corresponding to total contusional brain tissue
(hemorrhagic core plus intracontusional low density area) located
symmetrically to the contusion. According to previous authors
[3, 9, 13], a value of CBF below 18 ml/lOOgr/min, traditionally considered to be the threshold indicating ischemia [5], was used to dichotomize the rCBF measurements.
lOOgr/min) (p = 0.08).
Exploratory
A
analysis ( Table 2)
reduction of r C B F mean levels in the
con-
tralateral area was observed after the induction of arterial hypertension in ali "pressure hyper-active" and
"pressure passive" subjects (Fig. 1). I n the "pressure
hyper-active group", a significant reduction of in-
Increase in CPP
tracontusional low density area r C B F mean levels
Baseline rCBF values were obtained during an initial Xe-CT
study. Following this, a progressive increase of mean arterial pressure (MAP) was induced and maintained for a total time of 20
minutes, by means of a continuous norepinephrine infusion. A stable
increase of CPP, averaging 20 mmHg, was then obtained and a second Xe-CT measurement was carried out. Arterial blood gas analysis was performed before xenon administration, both at baseline and
during hypertension phase. AH efforts were made to maintain paC02
stable throughout both studies.
(-25.7 + 10 ml/lOOgr/min),
18 ml/lOOgr/min,
was
below the threshold of
seen in ali four patients. I n
this subset of patients, the baseline r C B F mean levels
were above 18 ml/lOOgr/min. I n the "pressure hyper
active" group the reduction of r C B F was more relevant in the edematous area than contralaterally. I n
the "pressure passive group", r C B F mean values improved slightly (3.6 + 2 ml/lOOgr/min) but without
Statistical analysis
The baseline and post-hypertension values of physiological variables and rCBF were compared by means of the paired t-test. Frequencies of rCBF values below 18 ml/lOOgr/min were compared
using the Fisher exact test. A value of p below 0.05 was considered
significant.
Exploratory analysis
A relevant dispersion was noted in the mean value of rCBF
changes in the intracontusional low density area during data analysis. Graphical analysis of data revealed that following the improvement of CPP, the intracontusional low density area rCBF increased
(the rCBF follows passively the CPP, "pressure passive group") in
three patients, whereas this did not occur in the remaining four patients ("pressure hyper-active group"). An exploratory analysis was
applied with regard to the subgroups.
any
statistical significance (Fig. 2). Two of the
patients had
3
r C B F mean values at baseline below
18 ml/lOOgr/min
and
the
remaining third
patient
showed an individuai baseline CBF value of 20 m i /
lOOgr/min.
Discussion
The pathophysiological background of the present
study indicates that an improvement of r C B F levels in
the intracontusional low density area, surrounding the
hemorrhagic core of a brain contusion, may be obtained by means of an acute increase in CPP.
This
could be the consequence of a focal derangement of the
Induced acute arterial hypertension and regional cerebral flow in intracontusional low density area
363
Table 1. Characteristics of 7 severely head injured patients undergoing Xe- CT studies
Patients (n)
Age (years)
Sex (n)
Best initial GCS
Best initial motor GCS
Worst initial GCS
Worst initial motor GCS
Worst initial pupillary reactivity
Worst initial hypotension (n and % )
Worst initial hypoxia (n and % )
Worst CT and main lesions (n)
Outcome at discharge (n)
Outcome at 6 months (n)
Contusions
Intracontusional low density area (mm^)
Xenon studies
Time post injury of Xenon studies (hrs)
Contusions studied per time intervals (hours post injury)
Hemoglobin
Hematocrit
mean ± SD
male/female
median ( I Q R )
median ( I Q R )
median ( I Q R )
median ( I Q R )
normal (n)
one pupil dilated unreactive (n)
bilaterally dilated unreactive pupils (n)
no hypotension
hypotension
no hypoxia
hypoxia
DI II
EML
• SDH
• contusion
NEML
• contusion
obeying
not obeying
dead
good recovery or moderate disability
severe disability
persistent vegetative state or death
n
mean + SD
n
mean + SD
24
24-96
post 96
gr/dl
%
pressure autoregulation due to ischemie damage [11].
However the results did not support the hypothesis
of the study, showing, on the contrary, that a supranormal CPP was associated with a reduction, instead
of an improvement, of rCBF mean levels in the intracontusional low density area. Similar results were
obtained for mean values of rCBF in the contralateral
area. A possible explanation for the rejection of the
study hypothesis may be that our case selection could
not confirm the background of the study. I n fact
the intracontusional low density area rCBF was ischemie at baseline, below 18 ml/lOOgr/min [5], in only 2
patients. As a consequence the possible association
between focal edema, ischemia and impaired autoregulation was not a common finding within the subjects studied. Moreover, contusion associated ischemia
was found to be highly variable also in previous reports [3, 9, 13]. While the previous consideration excludes a diffuse derangement of pressure autoregula-
7
48.4 + 20.4
6/1
10(5)
5(1)
7(5)
4(2)
6 (86%)
1 (14%)
0 (0%)
6 (86%)
1 (14%)
5 (71%)
2 (29%)
2
4
• 2
• 2
1
• 1
1
6
0
5
1
1
7
1257 ± 378
14
133 ± 50
0
2
5
10.4 ± 1.6
30.6 ± 4 . 5
tion in the lesions studied, it remains however to be
explained why we observed, on average, an overregulation of rCBF foUowing an increase of CPP. This
"paradox" response had already bave been reported in
a similar experimental setting involving patients with
subarachnoid hemorrhage and vasospasm [2], but the
physiological reasons are unclear, even i f a direct effect
on brain microvessels of norepinephrine may be advocated [15].
Exploratory
analysis
The exploratory analysis suggests that the induced
increase in CPP could determine an improvement of
rCBF in the low density tissue surrounding the hemorrhagic core only in a subset of patients. These
"pressure passive" subjects, bave pathological baseline
values of rCBF, below or approximating the ischemia
threshold [5]. I n these areas the suggested association
A . Chieregato et al.
364
Table 2. Physiological
variables (mean ± SD) in the three
CBFphases
Baseline
n
intracontusional low density C B F (ml/lOOgr/min)
individuai subjects with intracontusional low density
CBF below 18 ml/lOOgr/min (n)
contralateral C B F (ml/lOOgr/min)
individuai subjects with contralateral C B F below
18 ml/lOOgr/min (n)
M A P (mmHg)
CPP(mmHg)
ICP (mmHg)
PaC02 (mmHg)
Sa02(%)
n
intracontusional low density C B F (mi/lOOgr/min)
individuai subjects with intracontusional low density
C B F below 18 ml/lOOgr/min (n)
contralateral C B F (ml/lOOgr/min)
individuai subjects with contralateral C B F below
18 ml/100gr/min(n)
M A P (mmHg)
CPP(mmHg)
ICP (mmHg)
PaC02 (mmHg)
Sa02 (%)
n
intracontusional low density C B F (ml/lOOgr/min)
individuai subjects with intracontusional low density
C B F below 18 ml/lOOgr/min (n)
contralateral C B F (ml/lOOgr/min)
individuai subjects with contralateral C B F below
18 ml/lOOgr/min (n)
M A P (mmHg)
CPP(mmHg)
ICP (mmHg)
PaC02 (mmHg)
Sa02 (%)
A l i patients
Pressure passive patients
Pressure hyper-active patients
p
7
25 + 16
2
7
12 + 7
6
0.07
0.10
27.6 + 12.6
2
16.3 + 9.4
5
0.08
0.28
94
66
26
35.8
97.3
3
12
2
121
90
27
35.6
97.3
3
15.3
2
0.0025
0.0003
0.88
0.94
0.93
+
+
+
±
+
9
7
9
3.9
1.8
+ 7
18 + 2
2
90
62
28
35
95.7
4
36
0
+
+
+
+
+
94
71
25
36.3
97.3
8
4
11
5
3
116
84
32
33
95.8
4
10
4
± 13
±
+
+
±
±
+
+
±
±
±
14
10
12
4.2
2
0.61
1
+ 9
0.0563
1
13 + 3
3
35 ± 1 3
0
60
60
During hypertension
+
+
+
+
±
0.12
0.03
0.77
0.7
0.7
21
11
16
5
3
0.0009
0.03
+ 4
0.12
0.42
19 ± 12
2
11
7
7
3
1
117
93
23.5
37.4
97.4
±
+
±
±
±
0.02
0.005
0.83
0.66
0.86
10
9
8
2.8
1
-I
50
40
intracontusional
low density area
rCBF
(ml/IOOgr/min)
contralateral area
rCBF
30
{ml/100gr/min)
20
10
0
0
pre
post
Fig. 1. Reduction of r C B F in the normal appearing contralateral
brain (each line, a subject). Squares (pressure hyper-active subjects),
triangles (pressure passive subjects)
-I
,
pre
post
Fig. 2. Different patterns of r C B F in the intracontusional low density tissue (each line, a subject). Squares (pressure active subjects),
triangles (pressure passive subjects)
Induced acute arterial liypertension and regional cerebral flow in intracontusional low density area
between ischemia and deranged pressure autoregulation may be confirmed. However the change in rCBF
seems to be, beside not statistically significant, also
hardly biological relevant. Probably by the time we
appHed the elevated CPP, cytotoxic edema and microvascular ischemia were already well estabhshed and
the microvessels in the intracontusional low density
area may have been no more sensitive to reperfusion.
In the experimental setting, the efficacy showed in
restoring contusional CBF with cahecolamines may
be in fact related to the early intervention post-injury
[1,7].
The exploratory analysis more clearly showed the
extent of the paradoxical reduction of rCBF in the intracontusional low density area in the pressure "hyperactive" subjects. I n these patients supra-normal CPP
inevitability converted normal (for comatose patients)
rCBF into ischemie values. A less pronounced reduction of rCBF was found in contrasterai areas in the
same subjects, suggesting that the damaged area may
be relatively more sensitive to norepinephrine-induced
arterial hypertension. The intracontusional low density area especially foUowing some days [6] may be affected by vasogenic edema which does not invoive a
reduction of rCBF [14]. That may be the reason why
we found, in the "pressure hyper-active" subjects, an
association between preserved baseline rCBF and
edema. I n the case of the intracontusional edema in
the damaged area, the edema was predominantly of
the vasogenic type, and it may be associated with a
blood brain barrier defect and the dififusion of neorepinephrine into the perivascular space. The present
results suggest that intracontusional areas seem to behave, even in cases not associated with severe CBF
disturbance, as in a penumbral area, more sensitive,
than apparently normal brain, to para-physiological
changes.
Conclusions
The present study failed to demonstrate that arterial
hypertension induced a systematic improvement in
rCBF in the intracontusional low density area and, on
the contrary, showed an average reduction in rCBF.
Although in an exploratory approach, a marginally
relevant improvement in intracontusional rCBF was
found in patients with criticai rCBF values at baseline
that needs more extensive research. More immediately
relevant seems to be the detection of a specific vasoconstrictive response when the low density area was
365
not associated with baseline ischemia. That suggests a
further re-evaluation of the medicai protocols based on
standardized CPP elevation.
References
1. Cherian L, Chacko G, Goodman JC, Robertson CS (1999) Cerebral hemodynamic effects of phenylephrine and L-arginine
after cortical impact injury. Crit Care Med 27: 2512-2517
2. Darby JM, Yonas H, Marks EC, Durham S, Snyder RW,
Nemoto EM (1994) Acute cerebral blood flow response to
dopamine-induced hypertension after subarachnoid hemorrhage. J Neurosurg 80: 857-864
3. Hoelper BM, Reinert M M , Zauner A, Doppenberg E, Bullock
R (2000) rCBF in hemorrhagic, non-hemorrhagic and mixed
contusions after severe head injury and its effect on perilesional
cerebral blood flow. Acta Neurochir (Wien) [Suppl] 76: 21-25
4. Jennett B, Bond M (1975) Assessment of outcome after severe
brain damage. A practical scale. Lancet 1: 480-484
5. Jones TH, Morawetz RB, Crowell R M , Marcoux FW, Fitz
Gibbon SJ, DeGirolami U, Ojemann RG (1981) Thresholds of
focal cerebral ischemia in awake monkeys. J Neurosurg 54: 773782
6. Kushi H, Katayama Y, Shibuya T, Tsubokawa T, Kuroha T
(1994) Gadolinium DTPA-enhanced magnetic resonance imaging of cerebral contusions. Acta Neurochir (Wien) [Suppl] 60:
472-474
7. Kroppenstedt SN, Sakowitz OW, Thomale UW, Unterberg
AW, Stover JF (2002) Norepinephrine is superior to dopamine
in increasing cortical perfusion following controlied cortical impact injury in rats. Acta Neurochir (Wien) [Suppl] 81: 225-227
8. Maas AIR, Dearden M , Teasdale GM, Braakman R, Cohadon
F, lannotti F, Karimi A, Lapierre F, Murray G, Ohman J,
Persson L, Servadei F, Stocchetti N , Unterberg A (1997) EBICguideline for management of severe head injury in adults. Acta
Neurochir (Wien) 139: 286-294
9. McLaughlin MR, Marion DW (1996) Cerebral blood flow and
vasoresponsivity within and around cerebral contusions. J Neurosurg 85: 871-876
10. Muizelaar JP, Fatouros PP, Schroder M L (1997) A new method
for quantitative regional cerebral blood volume measurements
using computed tomography. Stroke 28: 1998-2005
11. Paulson OB, Strandgaard S, Edvinsson L (1990) Cerebral autoregulation. Cerebrovasc Brain Metab Rev 2: 161-192
12. Rosner MJ, Rosner SD, Johnson A H (1995) Cerebral perfusion
pressure: management protocol and clinical results. J Neurosurg
83: 949-962
13. Schroder ML, Muizelaar JP, Bullock MR, Salvant JB, Povlishock JT (1995) Focal ischemia due to traumatic contusions
documented by stable xenon-CT and ultrastructural studies. J
Neurosurg 82: 966-971
14. Sutton LN, Greenberg J, Welsh F (1990) Blood flow and metaboHsm in vasogenic oedema. Acta Neurochir (Wien) [Suppl]
51: 397-400
15. Toda N (1976) Influence of dopamine and noradrenaline on
isolated arteries of the dog. Br J Pharmacol 58: 121-126
16. Zhuang J, Schmoker D, Shackford SR, Pietropaoh JA (1992)
Focal brain injury results in severe cerebral ischemia despite
maintenance of cerebral perfusion pressure. J Trauma 33: 83-88
Correspondence: Arturo Chieregato, Unità Operativa di Neurorianimazione, Ospedale M . Bufalini, viale Ghirotti 286, 47023, Cesena, Italy. e-mail: acliiere@ausl-cesena.emr.it