2091
Short Communication
Specific Changes in Human Brain Following
Reperfusion After Cardiac Arrest
Masayuki Fujioka, MD; Kazuo Okuchi, MD; Toshisuke Sakaki, MD; Ken-Ichiro Hiramatsu, MD;
Seiji Miyamoto, MD; Satoru Iwasaki, MD
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Background and Purpose Very few reports are available on
serial changes in human brain after cardiac arrest. The primary objective of this study is to investigate sequential neuroradiological changes in patients remaining in a persistent
vegetative state following resuscitation after cardiac arrest.
Methods We repeatedly studied eight vegetative patients
resuscitated from unexpected out-of-hospital cardiac arrest
using computed tomographic (CT) scanning and high-field
magnetic resonance (MR) imaging at 1.5 T.
Results In seven of the eight patients, CT scans obtained
between days 2 and 6 featured symmetrical low-density lesions
in the bilateral caudate, lenticular, and/or thalamic nuclei.
These ischemic lesions were persistently of low density on
serial CT scans. In these seven patients, MR images demonstrated what were thought to be hemoglobin degradation
products derived from minor hemorrhages localized in the
bilateral basal ganglia, thalami, and/or substantia nigra. Diffuse brain edema in the acute stage and diffuse brain atrophy
in the chronic stage were consistent neuroradiological findings.
No abnormal enhanced lesions were demonstrated by CT
scans.
Conclusions The most characteristic findings on high-field
MR images were symmetrical lesions in the bilateral basal
ganglia, thalami, and/or substantia nigra with specific changes
suggestive of minor hemorrhages that were not evident on CT
scans. We speculate that these minor hemorrhages result from
diapedesis of red blood cells in these regions during the
reperfusion period through the endothelium disrupted by
ischemia-reperfusion insult. (Stroke. 1994;25:2091-2095.)
E
the remaining 3. Four of the patients were female. The cardiac
arrest was estimated to have lasted for 10 to 25 minutes (mean,
17.1±5.0 minutes), and the time needed for cardiac output
restoration ranged from 5 to 18 minutes (mean, 8.5±3.9
minutes). All patients in this study within the first few minutes
to hours after resuscitation recovered brain stem function,
such as spontaneous respiration and cranial nerve reflexes,
and other aspects of vegetative behavior. After the patient was
transferred to the intensive care unit, various physiological
parameters were monitored continuously and maintained
within the normal ranges. All the patients remained in a
persistent vegetative state throughout the study period. Persistent vegetative state was diagnosed in accordance with the
published criteria of the American Neurological Association.4
Informed consent was obtained from each patient's nearest
relative before the study began.
CT scanning was performed using an Xpeed scanner
(Toshiba) with 10-mm cuts displayed on a 512x512 matrix
(5-second scan time). All patients underwent precontrast CT
scanning daily for the first 3 days (days 1 through 3) after
cardiovascular stability was assured, and thereafter repeatedly
every 1 to 5 days. Postcontrast CT scanning was performed in
2 patients (patient 4 on days 4 and 25, and patient 6 on day 20)
with intravenous administration of iodinated contrast medium.
MR imaging was performed twice per patient with a superconductive unit (Picker, Vista MR system) operating at a field
strength of 1.5 T. The timing of MR imaging is indicated in Fig
1. Axial, coronal, and sagittal T,- and T2-weighted sequences
were obtained using a spin-echo technique, with repetition
time (TR) of 500 or 200 milliseconds and echo time (TE) of 20
milliseconds for the short TR/TE images and TR of 2000
milliseconds and TE of 100 milliseconds for the long TR/TE
images. Other imaging parameters included 5- or 7-mm slice
thickness with an intersection gap of 0 to 5 mm, matrix size
256x256 or 192x256, and 25-cm field of view. During patient
transport and throughout CT scanning and MR imaging,
electrocardiogram and arterial blood pressure were continu-
xperimental studies have addressed various aspects of transient forebrain or global brain
ischemia.13 Very few reports are available on
serial changes in human brain following reperfusion
after complete global ischemia.
We investigated chronological changes in the brain
of patients who remained in a persistent vegetative
state after cardiac arrest using computed tomographic
(CT) scanning and high-field magnetic resonance
(MR) imaging.
Subjects and Methods
Subjects satisfying the following criteria were included in
this study: persons without preexisting neurological disease
suffering out-of-hospital cardiac arrest followed by successful
resuscitation at Nara Medical University Hospital during the
period September 1991 to July 1993 and the ability to undergo
multiple neuroimaging studies. During this period there were
10 such patients, but 2 (1 each with cardiac arrest due to
subarachnoid hemorrhage and lightning) were excluded from
the present study because direct effects on the brain could not
be ruled out. The Table summarizes the clinical features of
these 8 patients, who ranged in age from 30 to 86 years
(mean±SD age, 61.6±15.3 years). This study protocol was
approved by the ethics committee of our university hospital.
On admission, the electrocardiogram showed cardiac arrest
(isoelectric) in 5 of the 8 patients and ventricular fibrillation in
Received May 4, 1994; final revision received July 1, 1994;
accepted July 19, 1994.
From the Departments of Neurosurgery (M.F., K.O., T.S.,
K.-I.H.), Emergency and Critical Care Medicine (S.M.), and
Radiology (S.I.), Nara Medical University (Japan).
Correspondence to Masayuki Fujioka, MD, Department of
Neurosurgery, Osaka Police Hospital, 10-31, Kitayama-cho, Tennouji, Osaka, 543, Japan.
© 1994 American Heart Association, Inc.
Key Words • cerebral ischemia, transient • heart arrest •
hemorrhage • magnetic resonance imaging • reperfusion
2092
Stroke
Vol 25, No 10
October 1994
Clinical Features of Eight Patients With Global Brain Ischemia
Duration , min
Distribution Pattern
of Low Density on
CT (Time of First
Detection)
Outcome
B (day 6)
PVS
Age, y
Sex
Cause of CA
ECG on
Admission
CA
1
30
F
Chest trauma
Flat
20
8
2
86
M
Suffocation
Flat
18
8
B (day 3)
D on day 53
3
60
F
Anaphylactic reaction
VF
10
5
A (day 2)
D on day 32
4
69
M
Suffocation
Flat
10
5
B (day 4)
PVS
5
58
M
Asthma attack
VF
17
8
A (day 3)
D on day 36
6
74
F
Unknown (sudden
collapse at home)
Flat
22
18
C (day 6)
D on day 37
7
54
M
Acute alcoholism
Flat
15
6
N
PVS
8
62
F
AMI
VF
25
10
B (day 2)
D on day 33
(17.1 ±5.0)
(8.5+3.9)
PtNo.
(61.6± 15.3)
CPR
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Pt indicates patient; CA, cardiac arrest; ECG, electrocardiogram; CPR, cardiopuimonary resuscitation; CT, computed tomogram; AMI,
acute myocardial infarction; VF, ventricular fibrillation; A, symmetrical low-density lesions (SLDLs) in the caudate, lenticular, and thalamic
nuclei; B, SLDLs in the caudate and lenticular nuclei; C, SLDLs in the thalamic nuclei; N, no SLDLs; PVS, persistent vegetative state;
and D, death. Values in parentheses are mean±SD.
ously monitored in all patients. While the patient was in the
scanner or imager, the respiration was assisted by manual
ventilation with a Jackson-Ress circuit.
Five of the 8 patients died during the study period of
systemic complications such as respiratory, cardiac, and/or
renal failure. Unfortunately, permission for autopsy was not
obtained in any case.
Results
Both the CT scans and MR images of our patients
illustrated noteworthy changes with time in the basal
Specific Changes with time on MRI
Case
Initial MRI
Second MRI
T1WI
T2WI
1
2
3
4
5
6
7
8
I hyperintensity
isointensity
hypointensity
FIG 1. Chart shows serial changes on high-field magnetic
resonance images (MRI) in each patient. These specific changes
are considered to reflect hemoglobin degradation products.
T1WI indicates T,-weighted image; T2WI, T2-weighted image.
ganglia, thalami, and substantia nigra bilaterally (Table,
Fig 1).
Precontrast head CT scanning performed on day 1
demonstrated no abnormal findings in any patient. In 7
of the patients, CT scans obtained between days 2 and
6 revealed symmetrical low-density lesions in various
combinations of localized areas (in the bilateral caudate, lenticular nuclei, and thalami in 2, in the bilateral
caudate and lenticular nuclei in 4, and in the bilateral
thalamic nuclei in 1) (Table). The subsequent CT scans
showed these lesions as low-density areas consistently
throughout the study period. In all 8 patients, diffuse
brain edema with effacement of the cerebral sulci
appeared on CT scans in the acute stage (within 1 week
of onset) and gradually resolved with time. CT scans in
the chronic stage (from 1 week to 2 months after onset)
exhibited diffuse brain atrophy in all patients except
patient 1. Postcontrast CT scans in 2 patients (patients
4 and 6) showed no evidence of abnormal enhanced
lesions.
Fig 1 shows the serial changes on high-field MR
images in each patient. The most common pattern was
isointensity/hyperintensity on the ihitial T,/T2-weighted
images, respectively, in the caudate nuclei, lenticular
nuclei, and/or thalamic nuclei followed by hyperintensity/hyperintensity or hyperintensity with central hypointensity in the same sites on the later Ti/T2-weighted
images, respectively. In addition, in 1 patient (patient 4)
isointensity/hyperintensity followed by hyperintensity/
hyperintensity was found in the substantia nigra on the
initial and later T,/T2-weighted images, respectively
(Figs 2 and 3). In 1 patient each (patients 6 and 1),
hyperintensity/hyperintensity was found in the substantia nigra on the initial and later T,/T2-weighted images,
respectively.
This pattern of specific changes was found in all but 1
of the patients (patient 7), in whom neither CT nor MR
imaging detected any symmetrical ischemic lesions.
Discussion
In humans, brief cardiac arrest typically leads to
transient complete global brain ischemia. Previous CT
Fujioka et al Specific Changes in Human Brain After Cardiac Arrest
2093
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FIG 2. A, Computed tomographic scan obtained on day 4
reveals symmetrical low-density
lesions in the bilateral caudate
and lenticular nuclei. D, Computed tomographic scan on day
37 consistently shows the symmetrical lesions as of low density.
B, C, E, F, Magnetic resonance
images on day 5 show the bilateral basal ganglia, thalami, and
substantia nigra (arrows) as isointense on T,-weighted images (B,
C) and hyperintense on T2weighted images (E, F).
and pathological studies revealed that hypoxic-ischemic
insult predominantly affects the cerebral cortex, basal
ganglia, thalamus, hippocampus, and brain stem. 512
Cohan et al13 suggested that cerebral hyperemia in the
resuscitated patient induced increased blood-brain barrier permeability and might contribute to the development of cerebral edema or increased intracranial pressure, leading to a poor outcome. Martin et al14
considered that the heterogeneous cerebral metabolic
response to the global ischema might result from inhomogeneous cerebral blood flow due to a "no-reflow"
phenomenon. Recently, Roine et al15 reported that
cardiac arrest was significantly associated with deep
cerebral infarcts in the first controlled MR imaging
study that used a 0.02-T ultra-low-field scanner.
The results of the present study can be summarized as
follows. First, specific and symmetrical ischemic brain
damage was demonstrated neuroradiologically in the
brains of humans in a persistent vegetative state after
cardiac arrest. Second, these ischemic lesions were
distributed bilaterally in the basal ganglia, thalami,
and/or substantia nigra. Third, high-field MR images
showed what were thought to be minor hemorrhages in
the ischemic lesions. Fourth, diffuse brain edema in the
acute stage and diffuse brain atrophy in the chronic
stage were consistent neuroradiological findings.
MR signal characteristics of hemorrhagic cerebral
infarcts can be explained on the same basis as those of
intracranial hematomas.16 MR imaging is most sensitive
for detecting hemorrhage into cerebral infarcts. In this
study, in which hemorrhagic transformation on MR
images was diagnosed according to the criteria of Gomori et al17 and Hecht-Leavitt et al,18 the most consis-
tent MR imaging patterns were isointensity/hyperintensity in the basal ganglia, thalami, and/or substantia
nigra on the initial T,/T2-weighted images, respectively,
followed by hyperintensity/hyperintensity or hyperintensity with central hypointensity in the same sites on
the later T^Tj-weighted images, respectively. These
patterns of changes on MR images were interpreted to
suggest the presence of methemoglobin inside or outside red blood cells during the process of hemoglobin
degradation.16"18 This type of hemorrhage with its characteristic distribution seems to differ from the usual
hematomas caused by vascular destruction because CT
scans consistently showed the hemorrhagic lesions as
low-density areas. In our patients, we speculate that
transient global brain ischemia associated with cardiac
arrest induced diapedesis of red blood cells in the basal
ganglia, thalami, and/or substantia nigra during the
reperfusion period through the endothelium disrupted
by the ischemia-reperfusion insult. Bryan et al19 reported that increased signal intensity on T,-weighted
MR images in patients with cerebral infarction without
high density on CT scans resulted from ischemic lesions
with damaged capillary endothelium through which red
blood cells had leaked. The mechanism of this type of
hemorrhage is undoubtedly a remarkably complex and
dynamic process, involving a combination of vascular
disruption with altered permeability and reperfusion of
the damaged vascular bed.
The precise mechanism of selective damage to the
basal ganglia, thalami, and substantia nigra could not be
elucidated by our study. However, the present findings
are consistent with several animal experiments that have
noted a heterogeneous increase in blood-brain barrier
2094
Stroke
Vol 25, No 10
October 1994
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FIG 3. Patient 4. Magnetic resonance images on day 27 reveal
symmetrical hyperintense lesions
on both T,- (A, B, C) and T2- (D, E,
F) weighted images in the bilateral caudate nuclei, thalami, and
substantia nigra (C, F; arrows).
The lenticular nuclei appear hyperintense on the T, -weighted images (A, B, C) and hyperintense
with a central hypointense zone
on the T2-weighted images (D, E,
F). These magnetic resonance
imaging findings (bright signal on
T,-weighted images and high signal or high signal with hypointense center on T2-weighted images) suggest the presence of
methemoglobin inside or outside
red blood cells.
permeability in particular areas, including the striatum
and thalamus, after transient global cerebral ischemia. 2022 Some combination of the following factors
may play a role in the selective damage to the basal
ganglia, thalami, and substantia nigra: uncoupling23-24 of
heterogeneous regional cerebral blood flow25-26 and
regional cerebral metabolic rate,1427-28 iron-catalyzed
reaction-associated reperfusion injury29-30 due to the
fact that iron is unevenly distributed in brain tissues,
and selective neuronal vulnerability.
A hyperintensity on T,-weighted MR images could
just as well represent ectopic calcifications as hemorrhagic transformations. According to the early literature, 3133 calcined lesions of the brain occasionally appear bright on T,-weighted MR images at 1.5 T.
However, they report that such calcined lesions appear
hypointense on T2-weighted images and of high density
on CT scans. Based on these reports, the specific
changes in the present study, which exhibit hyperintensity/hyperintensity or hyperintensity with central hypointensity on T,/T2-weighted MR images, respectively,
and appear of low density on CT scans, are thought
unlikely to represent ectopic calcifications.
Diffuse brain edema8-15-34 due to cytotoxic and vasogenic causes in the early stage has been shown to occur
in ischemic-anoxic encephalopathy, consistent with the
neuroradiological findings in the present study. Brain
edema as observed in our patients has been proposed to
predict a poor neurological outcome after cardiac arrest.815-34 Diffuse brain atrophy was a common finding
in our patients and could be interpreted as diffuse loss
of neurons and glial cells.
Conclusions
To our knowledge, this is the first study on serial
changes in the brain of humans remaining in a persistent vegetative state following resuscitation after cardiac arrest using high-field MR imaging. MR images,
but not CT scans, revealed what were thought to be
hemoglobin degradation products derived from minor
hemorrhages localized in the bilateral basal ganglia,
thalami, and substantia nigra. We speculate that these
minor hemorrhages on MR images result from diapedesis of red blood cells through the damaged vascular
wall exposed to ischemia-reperfusion insult. Further
studies on larger series of patients will be needed to
determine the clinical and prognostic significance of
these findings. It is not clear from this study whether the
presence of such minor hemorrhages on MR images
indicates a need for a change in therapy, but it is hoped
that a better understanding of the mechanisms involved
will help to identify areas of the human brain at
particular risk of ischemic injury and rationalize the
treatment of postischemic-anoxic encephalopathy.
Acknowledgments
We greatly appreciate the thoughtful comments and expert
assistance of H. Nakagawa, MD, Y. Tatematsu, MD, Y.
Kamada, MD, I. Hayashi, MD, A. Fujikawa, MD, A. Nishimura, MD, J. Sogami, MD, N. Doi, MD, Y. Inada, MD, and K.
Nishio, MD. We also thank K. Fujioka and M. Onoue for their
secretarial help.
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Specific changes in human brain following reperfusion after cardiac arrest.
M Fujioka, K Okuchi, T Sakaki, K Hiramatsu, S Miyamoto and S Iwasaki
Stroke. 1994;25:2091-2095
doi: 10.1161/01.STR.25.10.2091
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