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Brain death I. Angiographic correlation with the radioisotopic bolus technique for evaluation of critical deficit of cerebral blood flow

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Brain Death: I. Angiographic Correlation
with the Radioisotopic Bolus Technique for
Evaluation ofcritical Deficit 02
Cerebral Blood Flow
Julius Korein, MD, Philip Braunstein, MD, Ajax George, MD, Melvin Wichter, MD,
Irvin Kricheff, MD, Abraham Lieberman, MD, and John Pearson, M D
An innocuous intravenous portable radioisotopic test using technetium 99m pertechnetate was employed to
demonstrate the deficit of cerebral blood flow associated with brain death. The results are compared to those of
bilateral carotid and vertebral angiography in 20 patients. Absence of a bolus tracing from the head in the presence of
a control tracing of a bolus from the femoral artery in two successive studies one hour apart reliably correlated with
the clinical and electroencephalographic findings signifying cerebral death in comatose, apneic patients. Angiography indicated absence of intracranial circulation in 10 patients. Stasis filling or retrograde emptying of arterial
vessels (or both) occurred in 7 patients. There was no evidence of venous filling in any of these 17 patients; all of
them had either an absent head bolus or an “intermediate tracing.” Results indicate that either form of tracing
represents a critical decrease of cerebral blood flow. Two other patients had evidence of severely impaired abnormal
posterior fossa circulation without angiographic evidence of cerebral circulation; both of these patients had an
absent head bolus. An additional patient had an unusually small head bolus, and angiography revealed extravasation
of radiopaque material but no evidence of intracranial circulation. We conclude that the bolus technique is a helpful
adjunct in diagnosing brain death.
Korein J, Braunscein P, George A, et al: Brain death: I. Angiographic correlation with the radioisotopic bolus
technique for evaluation of critical deficit of cerebral blood flow. Ann Neurol 2:195-205, 1977
This report deals with the validation of a simple, innocuous intravenous portable radioisotope technique
for use at the bedside to test semiquantitatively for a
critical deficit of cerebral circulation [6, 71. Following
preliminary testing of this bolus technique in more
than 80 deeply comatose, unresponsive, apneic patients [ 191, a prospective study to validate its efficacy
was undertaken. Cerebral angiography was selected as
the method of comparison.
Since cerebral angiography was performed only
when justified on clinical grounds, the scope of the
study was restricted to apneic patients in coma from
causes such as intracranial trauma, hemorrhage, neoplasm, and cerebrovascular infarction. Although this
restriction excluded patients with metabolic disorders, cardiorespiratory arrest, or drug intoxication,
previous studies indicate that the findings in bolus
studies on such patients are similar t o those reported
here [2, 19, 211. This report deals with studies on 20
patients who had clinical criteria compatible with
brain death [ 2 , 31,321. Nineteen of these patients met
the electroencephalographic criteria compatible with
cerebral death; the twentieth patient had a technically
unsatisfactory EEG.
Methods
During the period of this study at Bellevue Hospital Center,
all patients above the age of 18 years who were in coma and
apneic were evaluated. Patients were considered for entry
into the study if they were in unresponsive coma and apneic
(requiring a respirator) due to causes which might require
diagnostic angiography. All patients received a complete
physical and neurological examination and a diagnostic
workup, including toxicological examinations of the blood
and urine. Appropriate treatment was instituted in all cases.
Patients were entered into the study if the level of coma
persisted despite treatment, if they remained unresponsive
to stimuli with n o spontaneous movements, and if no spontaneous respirations developed for at least 15 minutes (i.e.,
the patient required controlled ventilation and made no
effort to override the respirator for that period).
Neurologically, the patients had no cephalic reflexes,
unreactive mid or fully dilated pupils, and absent caloric
195
responses. Respirator dependency was tested by the absence of spontaneous respiration for up to six minutes of
respirator shutdown while 1009; oxygen was being diffused
through the endotracheal tube at a rate of 6 liters per minute. This test for respirator dependency indicates only the
reaction to an increase in PacOz and decrease in p H ; it does
not test the reaction to decreased Pao, 1251. At the completion of the procedure, the adequacy of the test was verified
by taking arterial blood samples for pH, PO* and PCOS.
An EEG was then performed using maximal amplification (2
pv/mm) at maximal intraelectrode distances; the EEG recording was run for at least 30 minutes according to previously described criteria [13, 29, 301. If the EEG was
isoelectric-i.e.,
demonstrated electrocerebral silence
(ECS)-or was isoelectric with artifacts, the patient was
entered into the next phase of the scudy.
At this time, an intravenous radioisotope bolus procedure was performed with technetium 93m pertechnetate
(g9mTc0,).Techniques for this procedure have been previously described [6, 7, 191. A syringe containing 2 mCi of
" T c O q diluted with saline to a volume of 2 ml was attached directly to an external connection of the intravenous
line to facilitate rapid, uniform injection. T h e volume of 2 ml
was chosen to obviate the dead space of up to 0.5 cc present
in some intravenous lines.
Two types of radioisotope detectors were used. One was a
twin-probe, modified renogram apparatus with the probes
balanced. Each probe was adapted with a linear sensitivity
settingof 100,000 counts per minute at full deflection ofthe
chart recorder pen. One probe was placed in contact with
the midline of the forehead and positioned to detect
radioisotopic activity from vessels within the supratentorial
part of the intracranial cavity (Fig l),while the other probe
was placed over a femoral artery to test for adequacy of the
injection and to confirm the presence of systemic circulation. The second instrument was a three-probe machine
(developed by Phillips Medical Systems Inc, Shelton, CT)
with two head probes, one positioned on each side of the
head (Fig 2) and the third placed over the femoral artery as a
control. The sensitivity of the sertings was adjusted so that
the single probe over the femoral artery recorded 100,000
counts per minute at full pen deflection, with linear readout.
The output from the two head probes was summated and the
tracing was recorded at a sensitivity of 300,000 counts per
minute at full pen deflection. The activity detected by the
two head probes was approximately three times greater than
that detected by the single head probe. The collimators of
both instruments were designed so as to limit the field of
detection in the adult head to structures above the posterior
fossa; if the posterior fossa is included in the field of detection with either instrument, radioisotope activity from
Fig 1. (A)Lateral uietu of thefield of detection of the single
head probe. Note that thejield excludes most of the posterior
fossa but inrorporates most of h e major components of the
i.erehralcirculation. ( B ) Topvieul ofthejieldofdetection
of the single head probe. Note that the major cerebral vessels
are umithin the fieldof detection. The anterol~teralportionof
the skull is excluded bilaterally, including componentsof
the middle menimgral and superficial temporal arteries.
I
6 5'
f
A
196 Annals of Neurology Vol 2 No 3 September 1977
t
2 0"
F i g 2. Topfiiewofplacement ofthe twin headprobesand their
fields of detection. Although the posterior fossa is excluded,
virtually the entire contents of the cranialcavity, skull,
and scalp are incorporated.
extracranial vessels in the neck will be detected and obscure
the tracings observed from the head probe.
Based on previous experience [6, 7, 191, three types of
radioisotope tracings could be expected. T h e first was that of
a radioisotopic bolus tracing from the head probe, indicating
the presence of cerebral circulation, with a concomitant
bolus tracing from the femoral control probe reflecting the
presence of systemic circulation. Confirmation of significant
CBF in 14 of 30 comatose, apneic patients in whom a head
bolus was present was made by means of cerebral angiography, brain scan with sequential gamma camera imaging,
o r quantitative measurements of CBF using the KetySchmidt inert indicator technique. These methods showed
that an unequivocal head bolus would be present even if
CBF were reduced to 24% of normal [lo]. In the remaining
16 patients evidence of cerebral circulation was indirect,
i.e., patients had manifestations of cerebral function such as
recovery, EEG activity, or transient clinical improvement.
The second type of response was absence of a bolus in the
tracing from the head probe with an adequate bolus tracing
from the femoral probe; if this response occurred and was
repeated after one hour, it was considered to indicate that
the cerebral circulation was insufficient to maintain cerebral
viability. T h e third type of response differed from these two
in that although there was clearly no prominent bolus, a
small intermediate response (Fig 3) occurred that could be
clearly differentiated from the no-bolus head tracing (Fig 4).
This was observed in 4 instances in our previous studies [ 191
and was designated an “intermediate tracing.” For reasons
that will be discussed further, the no-bolus and intermediate
tracings were considered to have the same significance.
A total of 19 patients had no bolus (including intermediate tracing) and were entered into the next phase of the
study to confirm their CBF deficit by femorocerebral angiography. An additional patient had a radioisotopic head
tracing unlike the three previously described types. This
patient (No. 14 in Table 1) had a head bolus that was
unusually small and could not be classified (Fig 5). Since the
patient met the clinical and EEG criteria of brain death, he
was included. O n the basis of clinical and EEG criteria alone,
these patients (except for 1 with a technically unsatisfactory
EEG) ultimately met modified Harvard criteria for brain
death [ 1 , 2 , 11, 321. These modified criteria consist of unresponsive coma, apnea, absence of cephalic reflexes, and an
isoelectric EEG that persists for 24 hours (less if spontaneous, irreversible cardiac arrest intervenes). T h e modified
criteria d o not include absence of spinal reflex activity; they
d o include an established etiological diagnosis and exclusion
of intoxicants and hypothermia. Informed consent for angiography was obtained from the patients’ nearest relative,
who was made aware of the purposes of the study and the
fact that brain death was considered highly probable. T h e 20
patients included 13 with intracranial hemorrhage, 5 with
craniocerebral trauma, and 2 with massive cerebral infarction presenting as an enlarging space-occupying lesion.
Angiography utilized Renografin (meglumine diatrizoate)
o r Conray (meglumine iothalamate) via a femoral artery
catheter. Catheters were introduced into each internal
carotid artery and one o r both vertebral arteries. Several
F i g 3 . Intermediate radioisotripe tracing using a single
headprobe; amplzjcation is similar to that in Figure 4.
(CPM = countsperminute.)
hu
Injection
Femoral Artery
30
20
10
0
Seconds
Korein et al: Angiographic and Bolus Correlates of Brain Death
197
Head
t
L
-71
Femoral Artery
u
1
I ,
I
1
30
20
10
1
0
30
Seconds
A
patients had more than one injection into the common
carotid as well as the internal carotid artery. Attempts were
made to overcome vascular resistance secondary to elevated
intracranial pressure by raising the injection pressure of the
radiopaque contrast material. If any components of intracranial flow were found, their time course was measured. The
term shunt was used to indicate flow of conrrast material that
made an abnormal exit from the cranial cavity via another
artery without traversing the venous sinuses, a situation
which presumably reflected absence of CBF to the brain
parenchyma. The term rejux was used to describe backflow,
when the contrast material entered and exited through the
same artery without traversing the venous circulation. The
time course and pathway of either reflux or shunt was
carefully noted. Also studied was the time course of filling of
extracranial vessels. These included the superficial temporal, middle meningeal, and occipital arteries.
Following angiography, all patients had determinations of
arterial blood p H , Pco~,and Po,. They were reexamined
neurologically, and the bolus test was repeated. Following
angiography, no patient was considered a candidate for
surgery, and all were followed until the heart stopped
B
20
10
0
bconds
F i g 4. Radioisotope$ou: tracings using the twin-probe
apparatus illitstrated in Figure 1 . ( A ) Typical radioisotope
tracing ofpatient in unresponsiwcoma uith apnea who i.r not
rerebually dead. The trar-trig (if thr radioisotope bolus
fuom the head shou8.r high blood f l o w . I n addition,
abnornial E E G artirity i n the mrtex and midtemporal leads
(T,C,, CzT3)i s present ut routine anzplificatian. (Bj Tj9ical
rudioisotope tracing of patient in unresponsiw coma
ii'ithapnea umho i.r rwebrally dead. There is no ezmidenceof
head bolus although the bolus through thefemoralartery
i.r normal. Frrrthermare, the E E G is i.roehtric at maximum
amplification. CPM refers t o counts per minzlte, and eaih
diz'ision is 10,000 counts. Amplification is thesamefor both
t b e head and femoral arterq' probes.
198 Annals of Neurology Vol 2 No 3 September 1977
1
Head
t-
lniection
spontmeously. No patient had t h e respirator turned off
before the heart stopped. Cardiac arrest occurred in most
patients within 24 hours after the first radioisotope study
had shown absence of a bolus; the longest interval to the
time of cardiac arrest was 50 hours. Autopsies were obtained i n 5 patients. Neuropathological findings are included in a companion report [24].
t
Results
30
20
T h e patients were classified into five groups depending upon their angiographic findings (Table 1).
I-
\
10
Grouj~1
T h e 10 patients i n this category had n o intracranial
flow o r filling; all had EEGs showing ECS prior to their
bolus studies and angiograms. Six patients had a n
absent bolus prior to and after angiography. In 1
patient the initial tracing was intermediate but the
postangiographic study showed n o bolus; another
initially had n o bolus, but a bolus study repeated after
angiography showed a n intermediate tracing. T w o
patients had persistent intermediate tracings. Half the
patients were studied with the single head p r o b e
apparatus, the others with the twin head probe apparatus. Although there was some variability, t h e
rapidity and extent of filling of extracerebral vessels
0
Seconds
F i g 5 . Single-probe tracing illustrating the presence o f . small
head b o b s in Patient 14. Contrast this with the usual
tracing of a headbolus in Figure 4A and the
intermediate tracing in Figure 3. Amplification i~
unchanged. (CPM = c0unt.r per minute.)
Table 1. Summary of 20 Patients with Bobs Stzrdiu Done
Group
1 (10 patients)
Angiographic
Findings
No intracranial
filling
Patient
No.
1
3
4
5
8
9
13
17
19
20
2 (3 patients)
Stasis
6
11
15
3 ( 4 patients)
4 (2 patients)
5 (1 patient)
Retrograde
emptying
Posterior
fossa flow
Extravasation
7
10
12
16
2
18
14
Sdke and aftpr Augzagraphy
Cause of
Coma
H
T
H
H
T
In
H
H
H
H
H
H
T
T
H
H
H
T
H
In
EEG
B,
lso
I
0
B,
No. of
Head
Probes
150
0
0
0
I
0
0
0
Is0
0
0
150
0
0
0
1
1
1
1
2
2
1
0
2
I
I
I
I
Is0
Is0
Is0
TU
I so
Is0a
0
0
0
0
2
2
1
2
2
Is0
0
0
Is0
Is0
0
0
Small
bolus
0
0
Small
bolus
Is0
Is0
I so
Is0
Is0
Is0
Is0 a
I
I
I
0
0
0, I
I
0
I
1
2
1
2
1
2
1
“Artifact.
B, = bolus study prior to angiography; B a = bolus study after angiography; H = hemmorhage; T = trauma; In = infarction; Is0 = isoelectric
EEG or electrocerebral silence; TU = technically unsatisfactory; I = intermediate tracing; 0 = absent bolus.
Korein et al: Angiographic and Bolus Correlates of Brain Death 199
was especially pronounced in both patients who had
persistent intermediate bolus tracings (Nos. 19 and
20, Table 1); in both, the twin head probe apparatus
was used.
Group 2
Three patients had no arteriographically demonstrated intracranial circulation but had stasis filling of
portions of the intracranial arteries at the base of the
brain. All 3 had isoelectric EEGs, and their two
radioisotope studies showed no bolus. In 1, however,
a third postangiogram radioisotope study using the
twin head probe apparatus showed an intermediate
tracing (Patient 15, Table 1).
the 2 patients (Nos. 7 and 12) with such retrograde
flow who had a persistent intermediate tracing, a
single head probe was used.
Group 4
Two patients had circulation through the posterior
fossa only. The transit time was markedly slowed (up to
22 seconds), and 1 of the patients also had stasis in the
middle cerebral artery. The 2 patients had no evidence of a bolus prior to or after angiography, and
their EEGs were isoelectric. An angiogram showing
circulation through the posterior fossa only is illustrated in Figure 7. There was no supratentorial filling
through either carotid artery, but delayed circulation
occurred in the posterior fossa after injection of the
Groap 3
Four patients showed a variety of reflux and shunting
phenomena by angiography. The EEG revealed ECS
in 3 of these patients, and in 1 the EEG was technically
unsatisfactory. Three had an intermediate bolus tracing prior to angiography; 2 of these retained an intermediate tracing afterward. Retrograde arteriographic
flow was occasionally associated with stasis. Figure 6
illustrates angiographic findings in the patient with the
most extensive degree of retrograde flow. Injection of
contrast material into the right carotid artery resulted
in filling of the anterior and middle cerebral arteries
bilaterally. The contrast material then rapidly escaped
in a retrograde direction through both internal carotid
arteries, simultaneously filling the extracerebral arteries. Venous opacification was absent at all times. In
F i g 6. Righr comnzon carotid angiogranzs via femoral artery
catheter (Group 3 , retrograde emptyingi. (A) Frontal
pro,jection:2 secondr. Injection ofthe right carotidartery
resulted i n oparzjii-ationo f [he right internal carotid
artey, the right middle cerebral arterji as f a r ai the
inszda, the anterior cerebral arteries proximally, and the left
middle ierebrd arterj up to the l e d of the insula. ?,he mist
distal (caat,ernou.rand suprailinoid) segments of the lefi
internal i-arotid arterj are alJ-0 opacified. (B) Frontal
projectiou: 4 secondt. Tuw tecunds later, as external carotid
brunches are ~isz~alized,
the contra.ct material has not
adranred t o smaller intracranial arteries. and the
intracranial ves.telc visualized in A are m o r e faintly
opacifed: the contrast material. hou:ewr.has now clearlji
opaciy5ed moreproximal (petrosal and cerzsicaali segnzen ts ofthe
lejt internal carotid artery, indicating retrogradefiow,
A
B
200 Annals of Neurology Vol 2
No 3
September 1977
F i g 7 . Left z'ertebral angiogram tlia .femoral arterj
catheter (Group 4 , posterior fossa circulation).
Circulation. though slowed, is demonstrated, including
a well-opacified arterial intermediate phase (thevenous
phase was wellvzsualized, though not shown here).
Note the striking depression of prmimal portions of the
saperior cerebellar arteries and cvmpression of tbe vermis as a
result of massive transtentorial herniation. The basilar
artery is displacrd anteriorly, and the tomillar loop of
the posteroinferior cerebellar arterp is unteriorlj and
inferiorly displaced, indicating tonsillar herniation.
left vertebral artery. The basilar artery was stretched
and displaced anteriorly. The contents of the posterior fossa were compressed and distorted by downward transtentorial herniation. There was also herniation through the foramen magnum. Contrast material
reached the venous system in the posterior fossa. At
the time of angiography these patients had no clinical
evidence of brainstem function; pupils were fixed and
dilated, and spontaneous respirations were absent.
Thus, both these patients met all nonangiographic
criteria of brain death. They both suffered irreversible
cardiac arrest within two days.
Group 5
One patient had an unusual pattern on angiography
suggesting supratentorial extravasation of blood and
stasis (Fig 8).This patient had an unusually small bolus
prior to and after angiography. The EEG was isoelectric with artifacts. The patient was a 46-year-old man
who had been found comatose. Angiography on admission revealed occlusion of the left internal carotid
artery. A right carotid angiogram demonstrated a shift
t o the right, with bilateral middle and anterior cerebral arteries filling from the right side. Subsequently
the patient deteriorated rapidly, fulfilling all clinical
and electroencephalographic criteria for brain death.
At that time a radioisotope study revealed an unusually small bolus (see Fig 5 ) ; repeat angiography
showed filling of the proximal portion of the right
posterior cerebral artery and extravasation. This region of extravasation persisted many minutes after the
carotid injection (see Fig S), and there was no posterior fossa filling from the vertebral arteries. Repeat
radioisotope study revealed persistence of the small
bolus from the head probe. Shortly afterward the
patient had an irreversible cardiac arrest; autopsy was
refused.
Discussion
Brain death has been defined as irreversible destruction of the neuronal contents within the intracranial
cavity [15]. Although brain death has been used
synonymously with cerebral death, there are circumstances in which the cerebral hemispheres are irreversibly destroyed but the brainstem retains viability.
This discussion equates cerebraldeath with irreversible
destruction of the cerebral hemispheres 1171. Although brain and cerebral death are forms of irreverJible coma [ l l , 201, the latter term may be used to
include many other clinical entities such as persistent
vegetative states (e.g., coma vigil, akinetic mutism,
and apallic syndrome) as well as comas resulting from
brainstem lesions [14, 16, 251, including those that
separate the cerebrum from the brainstem due to
hemorrhage at the intercollicular level [ 181. Thesc
brainstem lesions are irreversible and may lead to
Korein ec al: Angiographic and Bolus Correlates of Brain Death 201
brain death as defined here, but they should be clearly
differentiated despite the fact some investigators consider “brain death” to occur if brainstem death alone is
present, regardless of the state of the cerebral hemispheres [22].
The study was directed only toward brain and cerebral death and did not address problems relating to
other forms of irreversible comas, persistent vegetative states, or discontinuation of resuscitative measures in such patients. Irreversible comatose states
must be unequivocally distinguished from reversible
comatose states such as those due to drug intoxication
o r hypothermia, metabolic disease, and encephalitis;
in addition, patients with ”locked-in syndrome” must
also be identified [3, 25, 261. Specific laboratory tests
often are essential to confirm o r establish the diagnosis and clinical impression of brain death. Drug
toxicity is the most common cause of a reversible
clinical and EEG picture suggesting brain death, but
toxicological assay can be difficult and has inherent
restrictions [2, 261. Great limitations beset the use of
electroencephalography to determine ECS despite
strict adherence to the apropriate techniques required
for performance of this procedure [3, 131. The first
major limitation involves the ability to obtain a technically acceptable, artifact-free record despite the use
of muscle paralytants or monitoring sources of artifact
(e.g., electrocardiogram, electromyogram, or respiration). The second limitation is the possibility of ECS
occurring in reversible situations, including not only
intoxication but conceivably certain other brain insults as well [ 3 , 4 , 8 ] .The physician’s clinical judgment
should always be considered primary, and we do not
believe itulwuys needs confirmation by a specific labo-
202
Annals of Neurology
Vol 2
No 3
F i g a.Left com7non carotid uxgiogram. lateral projection, of
the .single patient in Group 5. 1‘hi.r injection was obtained
several minutes after a right carotid angiogram that
had demonstrated only the proximal portion of the right
posterior cerebral artery. A large amount of contrast
material u’as extravasated in the vicinity of the right
posterior cerebralarterj and thefree tentorial edge. The
extravasated material persists, rcnchanged in
appearance. The lejt internal carotid artery and left
ophthalmic artery are partially opacified. E.xrellent
visualization of external carotid artery branches,
including the middle meningeal artery. is demonstrated.
There c i m n o evidence of tenoiis filling.
ratory test. There are situations, however, in which
laboratory confirmation is desirable, and such procedures should be performed to establish or refute the
diagnosis of brain death without undue delay. Although a variety of techniques such as recording the
absence of cortical and brainstem evoked potentials,
echoencephalography, and others have been proposed [2], a direct test of the critical deficit of cerebral
circulation is the ancillary procedure of choice. It is
especially useful for patients in whom a rapid diagnosis of brain death is desirable (e.g., for organ transplantation) o r for patients in whom the exclusion of
brain death will alter management (e.g., unproved
drug intoxication requiring dialysis). Although many
authorities consider four-vessel angiography the
diagnostic procedure of choice, it is complex and
difficult and is not without risk [9, 151. As demonstrated by our experience with 100 comatose apneic
patients (Table 2), the bolus technique reliably indicates critical and persistent deficits of cerebral circulation that are incompatible with cerebral viability. The
September 1977
Table 2. Comparison of E E G FindiEgs and Results of Radioisotopic Bo1u.i Studies in 100 Comatose Apneir Patients
~
EEG Findings
Result of
Radioisotope
Study
Head bolus present
Head bolus absent
Intermediate tracing
Small bolus
Unsatisfactory study
EEG
No. of
Patients
ECS
30
47 a
0
41
8
2
7b
9“
2a
12
Technically
Unsatisfactory
3
6
1
0
3
Not ECS
27
0
0
0
2
‘Includes patients with coma from causes other than intracranial hemorrhage or head trauma, such as cardiorespiratory arrest and endogenous
and exogenous intoxications. N o n e of these patients survived.
’Includes 3 patients from the initial group in whom no control was available.
ECS
=
electrocerebral silence or isoelectric EEG.
test is performed rapidly, simply, and safely at the
bedside.
The results of this angiographic study provide validation of the efficacy of the bolus technique as an
indicator of critical deficit in cerebral circulation;
simultaneously, the limitations of the technique are
also demonstrated. Circulation in the posterior fossa
is not measured, as illustrated i n Patients 2 and 18,
Group 4 (see Table 1). Both patients had ECS and
absent bolus, with no cerebral circulation demonstrable on angiography. Circulation in the posterior fossa
in these subjects was severely abnormal, and they had
no evidence of brainstem function. If the physician
wishes to include brainstem death in his diagnosis, he
must use additional criteria.
Pertinent factors in interpreting an intermediate
tracing are the number and location of the head
probes used, the extracerebral circulation, and abnormal
retrograde flow in the cerebral arteries. Use of a single
head probe placed anteriorly results in far fewer intermediate tracings than occur with the use of dual
head probes placed laterally. Angiographic studies in
the patients with intermediate tracings indicate that
the disproportionate increase in sensitivity achieved
in radioisotope detection using dual head probes is
further accentuated by sensors placed in close proximity to the extracerebral vessels on both sides of the
head (see Fig 2 ) . This undoubtedly explains the higher
frequency of intermediate tracings. O n the other
hand, rapid retrograde arterial emptying with angiographic demonstration of contrast material entering
and exiting through the intracranial arterial system
above the posterior fossa results in a persistent intermediate tracing even with a single head probe (Group
3). This does not invalidate the technique, since such
retrograde arterial emptying is incompatible with
cerebral viability [ 10, 2 11. Transient intermediate
tracings were rarely recorded from patients in Group
1 when a single head probe was used, and stasis filling
did not cause an intermediate tracing (Group 2). Thus,
recording an intermediate tracing does not reduce the
value of the bolus test. Both “no bolus” and “intermediate tracing” are indicative of a critical deficit in
CBF, and we recommend the use of a single, frontally
placed head probe in routine application of the bolus
technique. In practice, there is no difficulty distinguishing a head tracing with an absent bolus from one
in which a bolus is present. Likewise, as seen in Figures
3 and 4 , the intermediate response can be clearly
distinguished. The magnitude and characteristics of
the head tracing and their relationship to the femoral
tracing are distinctive. The presence of a small bolus
that was apparently related to repeated extravasation
of radioisotope during each test, as seen in the single
patient in Group 5 , may cause some difficulty in interpretation. Despite the observation that there was
no clear evidence of CBF in this patient, the results of
the bolus study might be considered a false indication
of cerebral circulation. We have not encountered situations suggesting a graded diminution of CBF. If the
occurrence of a small bolus is interpreted as suggesting cerebral viability, this would result in the error of
diagnosing a patient with a dead brain as being alive.
Provided that it occurs infrequently, such aresult is, of
course, acceptable. A bolus would be anticipated in a
patient who has cerebral circulation but in whom all
neuronal elements are dead secondary to a toxic or
anoxic insult, and we have encountered such a problem [19, 241.
We assume that a head bolus would be present in
patients with reversible coma [31. The lowest value of
CBF we have calculated (by means of the KetySchmidt technique) in a comatose, apneic patient in
conjunction with a head bolus is 24% of normal.
Patients who are in deep coma due to vascular disease
o r barbiturate intoxication have their CBF reduced t o
40% of normal [51. This indicates that patients with
clinical and EEG findings compatible with brain death,
Korein et al: Angiographic and Bolus Correlates of Brain Death 203
but who are in a potentially reversible state, would
have a head bolus. In contrast, the marked reduction
of CBF reported in patients who are brain dead is
almost always below 20% of normal CBF, and most
often below 10% [ 5 , 9 , 25,281. Thus, given the clinical features of brain death, 20% of normal CBF appears to be beneath the lower limit compatible with
cerebral viability. This critical deficit of CBF is below
the level at which a bolus would be present, supporting the conclusion that the ancillary finding of an
absent bolus confirms cerebral death.
The basis for the concept of an “all-or-none”
semiquantitative phenomenon (i.e., bolus versus no
bolus or intermediate tracing) has been criticized because one cannot distinguish differences between
cerebral and extracerebral circulation by means of
external detection of an intravenously injected
radioisotope [33]. However, one may consider that
the head flow tracings represent the summation of the
radioisotope’s passage through two fundamentally different kinds of circulation. The cerebral circulation
involves rapid transit of a large amount of blood
through a relatively small vascular reservoir. It. has
been calculated that the CBF normally is at least 7 5 0
ml per minute and passes through a blood pool reservoir of about 130 ml[9,12,34]. This very rapid transit
through the relatively small cerebral blood reservoir
causes distinct registering of the arrival and departure
of an intravenously injected bolus which remains reasonably coherent after emergence from the left ventricle. The appearance of such a tracing is comparable
to that which might be obtained over any large artery.
In contrast, the extracerebral circulation involves a
relatively small amount of blood with slower and less
coherent transit through a larger vascular reservoir in
the scalp and skull. In this situation there is no clearcut bolus tracing. Apparently, no distinct transit effect
occurs in such a dispersed, peripheral type of circulation. Research on blood flow through various cerebral
and extracerebral compartments has confirmed such
major differences [ 2 7 ] .Flow tracings in the situation
of cerebral death with arrested cerebral circulation
represent only the extracerebral compartment. This
can be simulated by a bolus study performed with one
probe over t h e femoral artery and another over the
foot (Fig 9).The results confirm the similarity of rapid
transit of blood through a large artery (the femoral)
with the transit of CBF that is not critically diminished. In contrast, the tracing representing
peripheral blood flow through the foot is similar to
that of extracerebral structures when blood flow
through the cerebrum is absent or critically impaired
[191.
A final limitation of the bolus technique is that its
use is limited to adults. For children and infants, sen-
204
Annals of Neurology
Vol 2
No 3
F
tt
Foot
-11
b t m fr
Femoral Artery
36
io
secad,
la
6
E
0
F i g 9. Comparison offoot tracing (top) with collimator
over thefemoralartery (bottom) reveals t w o types of
circulation after intravenous injection of isotope (9”iTcO$.
The bottom tracing shows a holm indicative of rapid
circulation of a large quantity of blood through a small blood
pool(thefemaral6rtery) which i.r similar t o thecerebral
circulation. I n thefoot tracing theslou. dispersed,peripheral
type of circulation shous a pattern similar t o that of the
head tracings uith no bolus. This suggests that in the
absence ofhigh cerebralcircr~lation.bloodjou dtvectedby this
technique i.r AUKt o circulation through the skuLland scalp.
Amplification is sinzilur t o that in Figure 4.
(CPM = countsper n2inute.i
I
sors collimated to detect smaller fields of radioisotope
activity must be used to avoid contamination derived
from vessels in the neck. An alternative technique
might be the use of portable gamma cameras that can
image the passage of a bolus. These are now commercially available [23]. It remains to be demonstrated
that such crude images are as reliable in detecting a
critical deficit in CBF as we have found the curve
display to be, although portable gamma cameras with
data processing capabilities may produce curves as
well as images.
Supported in part by NINCDS Contracts 71-23 19 and 1-NS-2307,
National Institutes of Health, and Neurology Research Fund No.
8-0168-708, New York University Medical Center.
We wish to acknowledge the aid, cooperation, and participation
of numerous individuals in the Departments of Neurology,
Neurosurgery, and Radiology and the Division of Nuclear Medicine during this study, especially Drs C. T. Randt, J. Ransohoff,
and N. Chase. The technical assistance ofMr C. Pierno in performing the bolus studies and of Ms M. Kalmijn, Ms E. Falek, Ms V.
Chao, and Ms L. Levidow for performance of the EEGs is especially
appreciated. The manuscript was prepared by Ms P. Kronhaus.
September 1977
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205
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