Effects of U74006F on Multifocal
Cerebral Blood Flow and Metabolism
After Cardiac Arrest in Dogs
Fritz Sterz, MD; Peter Safar, MD; David W. Johnson, MD;
Ken-Ichi Oku, MD; and Samuel A. Tisherman, MD
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Lipid peroxidation reactions during reperfusion after cardiac arrest may contribute to
postischemic cerebral hypoperfusion, which in turn can contribute to permanent neurological
dysfunction. We designed this study to determine whether the aminosteroid U74006F, a putative
inhibitor of lipid peroxidation, mitigates cerebral multifocal hypoperfusion after cardiac arrest.
We used our established dog model of ventricular fibrillation cardiac arrest (no blood flow) of
12.5 minutes, reperfusion by cardiopulmonary bypass of <5 minutes, and control of extracerebral variables during 4 hours postarrest. Cerebral blood flow was monitored by the stable
xenon computed tomography method. Changes in cerebral oxygen consumption were obtained
from mean blood flow values of coronal slices and the cerebral arteriovenous (sagittal sinus)
oxygen content difference. A treatment group (n=5) received U74006F starting with reperfusion
(1.5 mg/kg i.a. plus 1.5 mg/kg i.v.) and three additional (graded) doses over 4 hours (total dose
4.5, 7.5, or 14.5 mg/kg). The U74006F-treated group showed the same postarrest transient
hyperemia and protracted hypoperfusion in terms of global (computed tomography slice),
regional, and local (multifocal) cerebral blood flow values and the same global cerebral oxygen
consumption pattern as a concurrent control group (n=5). At 1-4 hours postarrest, in both
groups there was mismatching of global cerebral oxygen consumption, which reached baseline
values, in relation to global cerebral blood flow and oxygen delivery, which remained at 50% of
baseline. We conclude that treatment with U74006F after prolonged cardiac arrest causes no
deleterious side effects and does not seem to alter multifocal postarrest cerebral blood flow and
oxygen consumption. (Stroke 1991;22:889-895)
W
e hypothesize that after cardiac arrest and
reperfusion, the cerebral postresuscitation
syndrome1 consists of four components2:
1) perfusion failure, 2) reoxygenation cascades leading
to lipid peroxidation, 3) self-intoxication from postischemic extracerebral organs, and 4) blood dyscrasias
from stasis. This study concerns a drug that might
affect all four components.
U74006F {21-[4-(2,6-di-l-pyrrolidinyl-4-pyrimidinyl)-l-piperazinyl]-16a-methyl-pregna-l,4,9(ll)-
From the International Resuscitation Research Center (F.S.,
P.S., K-I.O., S.A.T.), the Departments of Anesthesiology/Critical
Care Medicine (P.S., F.S., K-I.O.), Radiology (D.W.J.), and
Surgery (S.A.T.), and Presbyterian University Hospital, University
of Pittsburgh, Pa.
Supported by National Institutes of Health grant NS24446, the
Asmund S. Laerdal Foundation, and the Upjohn Company. The
Schroedinger Foundation of Austria and the Fulbright Foundation
supported F.S.
Address for correspondence: Peter Safar, MD, International
Resuscitation Research Center, University of Pittsburgh, 3434
Fifth Avenue, Pittsburgh, PA 15260.
Received January 8, 1991; accepted March 29, 1991.
triene-3,20-dione; monomethane sulfonate},3 a new
putative inhibitor of lipid peroxidation, is a steroid
that mimics the pharmacological actions of high-dose
methylprednisolone while remaining devoid of classical glucocorticoid actions.4 U74006F inhibited irondependent lipid peroxidation in vitro,3 protected
(with pretreatment) against postischemic histological
brain damage in gerbils,5 reduced infarct size in cats
with temporary middle cerebral artery occlusion,6
attenuated cerebral hypoperfusion after global brain
ischemia in cats,7 and gave positive results in experimental central nervous system trauma,8 vasogenic
cerebral edema,9 and hemorrhagic shock.10 It seemed
to enhance survival after cardiac arrest and openchest cardiopulmonary resuscitation (CPR) in dogs.11
We evaluated the effects of U74006F on the postcardiac arrest cerebral hyperemia-hypoperfusion sequence12 as global, regional, and local (multifocal)
cerebral blood flow (CBF) measured by the stable
xenon-enhanced computed tomography (Xe-CT)
method.13"15 We also monitored postarrest changes
in global cerebral oxygen uptake (CMRO2). This
890
Stroke Vol 22, No 7 July 1991
study followed previous studies with the Xe-CT
method of postarrest CBF after external CPR,16
open-chest CPR,17 or cardiopulmonary bypass (as in
this study)17 and with postarrest hypertension and
hemodilution.18
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Materials and Methods
This project was approved by the Animal Use
Committee of the University of Pittsburgh. We used
22 healthy, custom-bred male coon hounds from the
same breeding colony, mean age 10 (range 8-12)
months and mean weight 19 (range 18-24) kg.
First, we conducted pilot studies in two dogs
without cardiac arrest to rule out side effects of
U74006F. Therapeutic intravenous doses in the
above-mentioned studies seem to be 1-3 mg/kg. One
normal, unanesthetized, unmonitored, spontaneously breathing dog received 1 mg/kg/min i.v.
U74006F for 30 minutes (total dose 30 mg/kg). This
infusion of an overdose resulted in no abnormal
behavior, no overall functional changes, and no other
side effects. Another normal dog was anesthetized
with 50%:50% nitrous oxide:oxygen (N2O:O2) plus
0.5% halothane and paralyzed with pancuronium in a
steady state with intermittent positive-pressure ventilation and invasive monitoring without cardiac arrest. Again, 1 mg/kg/min i.v. U74O06F was administered for 30 minutes (total dose 30 mg/kg). This
infusion resulted in no change from baseline of mean
arterial blood pressure (MABP) or other monitored
cardiovascular, pulmonary, or metabolic variables
(see subsequent protocol), except that cardiac output
increased from 4.5 1 before to 7.6 1 at 2 hours after
U74006F infusion.
We then conducted the CBF study in 10 dogs,
using our established model of ventricular fibrillation
cardiac arrest (no blood flow) of 12.5 minutes with
reperfusion by cardiopulmonary bypass for s 5 minutes postarrest and intermittent positive-pressure
ventilation to 4 hours.1719'20 The five control dogs
(group I) also served other studies1718 and therefore
were not placebo controlled. The five U74006Ftreated dogs (group II) were, however, treated by the
same team concurrent with the control dogs.
Anesthesia was induced with ketamine and maintained with 50%: 50% N2O:O2 plus halothane by
endotracheal intermittent positive-pressure ventilation. We continuously monitored the electrocardiogram, heart rate, MABP, central venous pressure,
end-tidal CO2, and central venous (core) temperature (TCT). We intermittently monitored arterial
blood gases and hematocrit (Hct). We controlled
MABP at 100±10 mm Hg (mean±SD) by adjusting
the halothane concentration before and by using
norepinephrine or trimethaphan after cardiac arrest,
central venous pressure at 5-15 mm Hg, Tm at
37.5±0.5°C, PaOj at £100 mm Hg, PacOj at 30-35
mm Hg, base excess at ±7 meq/1, and blood glucose
concentration at 100-175 mg/dl before arrest. In
preparation for the insult and during paralysis with
pancuronium and intermittent positive-pressure ventilation, inhalation anesthesia was reduced with
100% O2 for 1 minute, followed by room air for 4
minutes. Ventricular fibrillation was induced by external transthoracic electric shock. At the end of
ventricular fibrillation of 12.5 minutes, resuscitation
was begun with Q.0125 mg/kg i.a. epinephrine and
cardiopulmonary bypass (resuscitation time=0 minutes). Two minutes later, external countershocks
were started and repeated until defibrillation and
restoration of a spontaneous heartbeat. All dogs
were weaned from cardiopulmonary bypass before 5
minutes. Intermittent positive-pressure ventilation
and control of physiological variables (above) were
continued to 4 hours.
In group II dogs, 1.5 mg/kg U74006F was infused
into the arterial cannula of the bypass circuit at 0-5
minutes. Three additional bolus intravenous injections of U74O06F were given—one (1.5 mg/kg) at 5
minutes, one (1.5 mg/kg) at 2.5 hours, and one at 4
hours of reperfusion. The latter was 0 mg/kg in one
dog (total dose 4.5 mg/kg), 3 mg/kg in three dogs
TABLE 1. Physiological Variables Measured at Baseline and After Cardiac Arrest in Dogs
Variable
Control group (n=5)
Tcv (°C)
MABP (mm Hg)
Arterial pH
PacOj (mm Hg)
Hct (%)
U74006F-treated group
TcCC)
MABP (mm Hg)
Arterial pH
Paccvj (mm Hg)
Hct (%)
Baseline
37.8±0.6
101 ±8
7.36±0.03
35.4±1.5
42±3
«
( =5)
37J±0.1
107±4
7.38±0.01
34.7±2.7
43 ±3
Time after arrest
2 hr
10 min
30 min
1 hr
37.0±0.2
110±8
7.34 ±0.04
34.1±2.3
30±8
36.8±0.2
110±12
7JO±0.05
34.7±5.0
32±6
37.1 ±0.2
126±4
7.35 ±0.02
34.2±1.9
32±6
36.3+0.2
128±13
7.30±0.04
34.2+3.9
34±1
36.5±0.2
120±9
7.38±0.05
30.9±3.9
34±1
37.2±0.4
125±8
737+0.02
33.5 ±3.3
36+5
3hr
4hr
37.9±0.0
121±7
7.38±0.03
34.6±3.5
34±4
37.9+0.5
119±7
7.38±0.05
37.3±3.7
36+3
38.0±0.2
113±9
7J8±0.03
35.6±3.8
39±4
37.8±0.4
123±4
7.42±0.03
31.8±2.5
39±4
38.0±0.3
124+6
7.41+0.04
32.8+1.1
41+5
37.8±0.4
118±8
7.41 ±0.03
32.9±1.0
43±5
Values are mean+SEi.
Tcv, central venous (core) temperature; MABP, mean arteriaJ blood pressure; Hct, hematocrit.
No group differences with/7<0.05.
Sterz et al Aminosteroid U74006T After Cardiac Arrest
TABLE 2.
Global CBF and Local CBF Ranges Before and After Cardiac Arrest in Dogs
Before
CBF
891
lhr
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Control group (n=5)
Global
50±7
Mean±SD
% of baseline
Local
0.5 ±0-5
No flow
1.5±0.8
Trickle flow
5.8±2.9
Low flow
Normal for WM 29.6±7.1
Normal for GM 61.5±9.9
Hyperemic
1.1±1.7
U74006F-treated group («=5)
Global
47±8
Mean±SD
% of baseline
Local
0.1±0.1
No flow
0.9±0.9
Trickle flow
Low flow
5.9±2.8
Normal for WM 35.0± 14.8
Normal for GM 58.0±16.5
0.1±0.1
Hyperemic
After
30 min
10 min
30 min
1 hr
2hr
3hr
4hr
47±6
1-4 hr
106±18
48±10
28+2
26±3
24±4
26±4
26±3
100
227
104
60
56
51
55
55
0.7±0.5
1.6±1.1
7.6±3.2
30.8±6.4
59.1±10.2
0.1±0.2
0.1±0.1
0.1±0.1
0.2±0.2
1.4+0.8
63.6±20.5
34.6±19.9
3.1±4.7
3.8±2.8
11.8±4.5
34.2±12.1
42.4±7.9
4.8±6.9
2.7+1.4
7.5+2.9
24.9+3.4
46.0+2.8
18.9+4.8
0.0+0.0
5.2±2.1
9.6±2.6
23.9±3.9
43.8+3.7
17.4±7.0
0.0±0.0
7.2±2.8
13.4±5.4
263+3.4
40.6±5.4
12.5±6.2
0.0±0.0
5.3±3.0
9.7±3.1
24.6±4.0
45.2±4.9
15.1 ±4.9
0.0±0.0
5.1±2.3
10.1+3.5
24.9±3.7
43.9±4.2
16.0±5.7
0.0±0.0
49+10
83 ±29
43+13
27+9
26±6
25±4
26±6
26±6
100
171
87
55
54
51
53
53
1.6±1.6
1.3±1.0
4.9±3.9
30.9±12.0
61.0±15.6
0.3±0.5
0.1±0.0
0.4±0.5
3.2±3.4
18.3+15.4
52.4+16.1
25.7±21.8
1.0+1.6
3.2±3.8
13.0±8.4
37.9±10.8
42.8±18.4
2.1+3.1
4.3+3.7
11.8+6.1
26.0±10.3
38.0+3.4
19.9+18.1
0.0±0.0
3.4±2.3
11.1+5.8
27.2±8J
40.8±5.6
17J±11.5
0.0+0.0
3.1±2.1
9.7±2.7
31.2±5.4
42.0±2.8
14.0±6.9
0.0 ±0.0
2.8±2.2
10.1±4.5
29.5+8.0
40.6±3J
17.0±11.8
0.0±0.0
3.4±2.6
10.7±4.8
28.5±8.0
4O.3±3.8
17.1±12.1
0.0±0.0
Values are mean±SD ml/100 cmVmin for global, percentage area for local from posterior coronal slice 5 mm thick. Values from anterior
slice were similar.
CBF, cerebral blood flow. WM, white matter; GM, gray matter.
No group differences with/?<0.05.
(total dose 7.5 mg/kg), and 10 mg/kg in one dog
(total dose 14.5 mg/kg).
The CBF was determined with the novel noninvasive Xe-CT method,13-15 adapted to cardiac arrest
experiments with dogs.16-18 All CBF values were
obtained from a computerized analysis of CT voxel
density changes during Xe washin over 4.5 minutes
and are expressed as milliliters per 100 cm3 (or gram)
brain tissue per minute. The Xe washin technique is
based on the Fick principle, using the CT scanner as
a densitometer. Six Xe-enhanced images were obtained, beginning 30-40 seconds after the start of Xe
inhalation. Constancy of the CT slices was ascertained from the consistent position of bony landmarks. Resolution in monkeys and humans seems to
be 2:5x5x5=125 mm3.13"15 With the dog's head
rigidly immobilized, we studied global CBF for the
tissue volumes of two 5-mm-thick coronal slices
located 10 mm apart. The anterior slice included the
hippocampus and thalamus, and the posterior slice
included the brain stem. Computer programs provided one CBF value for each voxel of 1x1x5=5
mm3. The CBF values of air voxels in each slice and in
each selected anatomic region (each ^ 5 x 5 x 5 = 125
mm3)17 were averaged to determine global and regional CBF, respectively. We calculated local CBF as
the percentage of voxels in each CT slice (percentage
area) having specific CBF ranges16-18: no flow, 0-5
ml/100 cm3/min; trickle flow, 6-10 ml/100 cm3/min;
low flow, 11-20 ml/100 cm3/min; normal flow for
white matter, 21-40 ml/100 cmVmin; normal flow for
gray matter, 41-120 ml/100 cm3/min; and hyperemic
flow, >120 ml/100 cmVmin. We arbitrarily considered gray matter with a local CBF of <20 ml/100
cm3/min as having inadequate CBF.
Because it interferes with Xe monitoring, N2O was
replaced by N2 and the analgesic effect was replaced
by fentanyl given as a continuous intravenous infusion of 10 ^g/kg/hr. Halothane (0.1-0.5%) was used
before cardiac arrest for baseline anesthesia and
MABP control. No halothane was given during CBF
measurements or after cardiac arrest. The inhaled
gas delivered contained 67% O2, the balance being
N2, which was switched to 33% Xe during CBF
measurements. Two baseline CBF studies were performed before cardiac arrest. Additional CBF studies
were performed at 10 and 30 minutes and 1,1.5, 2, 3,
and 4 hours after reperfusion. Before each CBF
measurement, MABP, Pac^, Pacc^, arterial pH, base
excess, Hct, and TCT were measured and controlled.
The CMRO2 was determined in three dogs of
group I and four dogs of group II. Via a sterile 2-cm
craniotomy, a PE50 nonocclusive catheter was inserted into the sagittal sinus with the catheter tip
placed 1 cm rostral to the confluence of the sinuses.
For each CMRO2 determination, the catheter dead
892
Stroke
Vol 22, No 7 July 1991
changes within each group over time (baseline versus
postarrest). The CMRO2 data were not statistically
analyzed because of small numbers. Results are
reported as mean±SD.
Results
WHITE MATTER
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* MIDBRAIN
-T"
THALAMUS
-30-
10mln
xmki
1h
4h
FIGURE 1. Graph of regional cerebral blood flow (ordinate)
versus time before and after ventricular fibrillation cardiac
arrest (VFCA) (abscissa) in control (group I) and U74006Ftreated (group II) dogs. From each region of about 5x5x5
mm=125 mm3 tissue, mean values were calculated from local
values in 1x1x5 mm3 voxels.
space was cleared and arterial and sagittal sinus
blood samples were drawn at a constant slow rate
into heparinized syringes, cooled, and analyzed
within 2 hours by a co-oximeter for O2 content.
Samples for arterial and sagittal sinus O2 contents
(CaO2 and CssO2, respectively) were taken just before each Xe inhalation. Global CMRO2 was calculated as the posterior CT slice global CBFx cerebral
arteriovenous O2 content gradient [i.e., global
CBFx(CaO 2 -CssO 2 )]. The cerebral O2 utilization
coefficient was calculated as global CMRCyarterial
O2 transport [i.e., global CBFx cerebral arteriovenous O2 content gradient/global CBFxCaO 2 , or
(CaO2-CssO2)/CaO2]. Although global CBF was calculated from only one CT slice and CaO 2 -CssO 2
from the entire cerebrum, relative changes of
CMRO2 were considered valid.
All data were analyzed for group differences within
times and for the time x group interaction using a
univariate repeated-measures analysis of variance.
Scheffe's post hoc procedure was used for analyzing
All 10 dogs in which CBF was measured followed
the life support protocol. There was no difference
between groups in physiological variables before or
after cardiac arrest (Table 1). Spontaneous normotension was restored within 2-3 minutes after the start of
cardiopulmonary bypass. Immediately after restoration of the heartbeat, three of five dogs in each group
developed brief episodes of hypertension (to peak
MABP values of 130-190 mm Hg), and the others had
normotensive reperfusion. Mild hemodilution caused
by cardiopulmonary bypass was transient; near-baseline Hct was restored by 2-4 hours in both groups.
Postarrest fentanyl and trimethaphan requirements
were brief, minimal, and similar in both groups. For
MABP control, dogs in group I required minimal
norepinephrine at resuscitation time 0-15 minutes,
while group II dogs required no norepinephrine.
In each dog, the two baseline global CBF measurements were similar (approximately 50 ml/100 cm3/
min); there was a small standard deviation within
each group and no significant difference between
groups (Table 2, Figure 1). The first postarrest CBF
measurement showed diffuse hyperemia in both
groups, with essentially no voxels with no or trickle
flow and fewer voxels with low flow than at baseline
(i.e., there was no evidence of a protracted no-reflow
phenomenon). At 30 minutes, global CBF had returned to baseline values in both groups and the
percentage of voxels with a local CBF of <20 ml/100
cnrVmin had increased above that at baseline. During
the delayed protracted hypoperfusion phase at 1-4
hours postarrest, mean global CBF was 55% of
baseline in group I and 53% of baseline in group II
(Table 2). At 1-4 hours, the percentage of voxels
with a local CBF of <20 ml/100 cnrVmin was about
40% in both groups, significantly higher than the
baseline value of about 7% in both groups (/?<0.01).
There was no difference between groups (Table 2).
Regional CBF values (Figure 1) followed global
CBF values (Table 2). No region showed a significant
difference between groups. The initial transient hyperemia was greatest and most prolonged in the
midbrain and thalamus in both groups. During 1-4
hours postarrest, regional CBF values were about
50% of baseline values in both groups. All regional
CBF values (except for the white matter) were >20
ml/100 cnrVmin in both groups.
The CaO2 and CssO2 values (Table 3) varied
considerably between animals within times but followed a consistent pattern within dogs over time.
Pao2 remained > 100 mm Hg throughout (Pao2 not
shown in table). A transient decrease in CaO2 immediately after cardiac arrest was the result of hemodilution. CaO2 reached near-baseline values by 4 hours.
Ca0 2 -CssO 2 values (Table 3) were about 5-10 ml/dl
Sten et al Aminosteroid U74006F After Cardiac Arrest
TABLE 3.
893
Cerebral Metabolic Variables Before and After Cardiac Arrest in Dogs
Before
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Group
CaOz (ml/dl)
I Control group
n U74006F group
CssO2 (ml/dl)
I Control group
II U74006F group
CaO2-CssO2 (ml/dl)
I Control group
n U74006F group
Cerebral O2 utilization coefficient
I Control group
II U7400F group
Cerebral arterial O2 transport (ml/min)
I Control group
II U74OO6F group
CMROj (ml/100 cm3/min)
I Control group
II U74O06F group
After
1hr
30 min
10 min
30 min
lhr
2hr
4hr
20.3±2J
20.7+1.7
20.2±0.9
21.2±1.1
13.3±1.8
16.1 ±0.2
15.9±0.4
16.4±0.5
14 3+2.2
17.5±1.8
15.4+1.6
18.8+1.5
18.0+1.6
20.5 + 1.8
13.4±3.4
13.3±1.5
12.2±2.7
13.7±0.1
12.9±1.9
15.6±0.3
11.1+2.1
1U ± 2.2
7.8+2.7
6.7+1.8
6.5+3.0
7.2+2.0
5.8+1.6
7.5+2.9
6.8±3.0
7.4+1.4
8.0±2.7
7.6±1.1
0.4±0.1
0.5 ±0.4
4.8±2.4
4.9±2.2
6.5±1.6
10.9±1.2
8.9+3.1
11.5 + 1.4
12.2+23
13.0+1.7
034±0.14
0.36±0.06
0.40±0.13
0.35 ±0.03
0.03 ±0.01
0.03±0.02
0.30±0.14
0.30±0.14
0.47±0.13
0.63 ±0.08
0-58±0.18
0.62+0.09
0.67±0.10
0.64+0.11
9.8±2.0
8.5 ±0.4
8.7±1.2
8.9±0.6
12.3±4.5
9.9±4.2
8.1 ±1.3
5.9±O
3.9±0.8
3.8±0.4
4.0±0.3
4.1+0.4
4.5 ±0.5
4.5±0.2
3.1+0.9
3.1±0.5
3.3±0.8
3.2±0.2
0.4±0.2
0.4±0.3
2.2+0.8
1.7±0.5
1.8+0.3
2.4±0.4
2.4+0.9
2.5 ±0.5
3.1+0.8
2.9±0.5
Values are mean±SD, but statistical analysis not appropriate (numbers per group too small).
CaO2, arterial oxygen content; CssO2, sagittal sinus oxygen content; CMRC4, global cerebral oxygen uptake; group I, control dogs (n=3);
group II, U74006F-treated dogs (n=4).
before arrest, decreased (as expected) to very low
values immediately after arrest during transient hyperemia, and increased to above baseline values at
1-4 hours in all dogs, with no difference between
groups. The cerebral O2 utilization coefficient (Table
3), 0.18-0.57 at baseline, was very low during hyperemia and about doubled (worsened) in all dogs
between 1 and 4 hours postarrest. Cerebral arterial
O2 transport (Table 3) varied before cardiac arrest,
increased less than expected during hyperemia (because of hemodilution), and decreased to about 50%
of baseline values at 1-4 hours postarrest because
CBF was about 50% of baseline at that time (Table
2). Global (slice) CMRO2 (Table 3) ranged between
2.7 and 4.5 ml/100 cm3/min at baseline, was 0.1-0.9
ml during hyperemia (electroencephalographic and
metabolic silence), and recovered gradually toward
baseline values at approximately 2-4 hours in all
dogs (mismatched with low CBF). There was no
difference between groups.
Discussion
U74006F exerts favorable cardiovascular effects.
The two dogs without cardiac arrest showed that
even a massive overdose (10 times the therapeutic
dose) is well tolerated. In the monitored dog without
cardiac arrest, 30 mg/kg i.v. U74006F almost doubled
cardiac output without causing hypertension. After
cardiac arrest, MABP was controlled and cardiac
output was not monitored, but the U74006F-treated
group required no norepinephrine while the control
group did. Postarrest arrhythmias were transient and
similar in the two groups. The model to 4 hours
postarrest was appropriate. The same model, when
life support was prolonged to 96 hours, resulted
consistently in the same outcome — survival with severe brain damage21-22—and mild hypothermia before19 or after22 arrest improved cerebral outcome.
Postarrest patterns of global, regional, and local
CBF and CMRO2 were the same in both groups. CBF
followed the known hyperemia-hypoperfusion sequence.12 We used the stable Xe-CT method for CBF
measurements because it is noninvasive and provides
data for small regions, even regions deep within brain
tissue. Verification of the Xe-CT method with autoradiography and micTosphere methods in baboons
has shown that regional CBF values of foci ^ 5 x 5 x 5
mm3 are real.13-15 The local CBF values of 1x1x5mm3 voxels could partly be by chance due to system
noise and possible computational and physical limitations of the method with low blood flows.17'23'24
The negative CBF results with use of U74006F
immediately after ventricular fibrillation suggest that
factors other than lipid peroxidation cascades are
responsible, at least in part, for the multifocal postarrest hypoperfusion. CBF values did not change
when we gave 3 mg/kg i.v. U74006F in an additional
dog at 4 hours postarrest. However, acidification with
acetazolamide increased CBF.18 Thus, the hypoperfusion is not due to fixed obstruction. We have shown
that deferoxamine and superoxide dismutase following asphyxiation cardiac arrest in dogs can mitigate
the transient hyperemia and delayed hypoperfusion.25 Hemodilution to a Hct of 20% improved
CBF18 but did not improve outcome unless accompanied by hypertension.21 Mild postarrest hypother-
894
Stroke Vol 22, No 7 July 1991
mia (34°C) did not improve CBF26 but improved
outcome.22
The CMRO2 data are preliminary because of the
few dogs investigated. Although for global CMRO2
determinations we used CBF for one CT slice and
arteriovenous O2 content gradients for the entire
cerebrum, the relative changes of these values are
valid and baseline values were similar to those reported for the entire cerebrum. Postarrest reduction of CBF to 50% of baseline might worsen outcome only if arterial O2 delivery is reduced below a
critical level in relation to O2 need (i.e., CMRO2) and
in multiple foci. In both groups, at 2 and 4 hours
postarrest, approximately 50% CBF (Table 2) and
100% CMRO2 (Table 3) suggest mismatching, as we
reported b e f o r e . - - This mismatching was missed
in a recent study by Michenfelder and Milde, since
they reported no mismatching in dogs only up to 1
hour after cerebrospinal fluid compression ischemia.
Downloaded from http://stroke.ahajournals.org/ by guest on June 16, 2017
The only published outcome study of U74006F
after cardiac arrest in dogs11 does not meet our
model requirements.22 Those investigators measured
U74006F plasma levels to be 20 fig/ml immediately
after a 1.5 mg/kg i.v. bolus and 0.1 yu-g/ml during a
continued infusion of 0.25 mg/kg/hr. We did not
measure plasma U74006F levels but infused more of
the drug for longer periods. The optimal dosing and
timing of U74006F are not known. After temporary,
complete global brain ischemia induced by cerebrospinal fluid compression, protective pretreatment
with U74006F showed benefit.29 We conducted four
pilot experiments with larger doses of U74006F,
given before and/or after ventricular fibrillation of
12.5 minutes' duration in our canine outcome model22; by 24-96 hours postarrest, all four dogs had a
best overall performance category of 3 or 4 (severe
deficit or coma), as in historic controls.22 Outcome
studies should be reexamined for life support factors
that have been found to influence cerebral outcome,
such as slight differences in brain temperature before1920 or after22 the insult or differences in perfusion
pressure.21 We conclude that U74006F, even in massive overdose, is well tolerated by the healthy organism. The established delayed postcardiac arrest cerebral hypoperfusion, mismatched by CMR0 2 returning
to baseline values, does not seem to be influenced by
the immediate postarrest administration of U74006F.
The ability of U74006F administration after cardiac
arrest to improve outcome remains to be documented
with dose-response studies. If it does, it might be due
to mechanisms other than improved O2 need/O2 delivery relations.
Acknowledgments
l
Edward Hal , PhD, and Eugene Means, MD, of the
Upjohn Laboratories, Kalamazoo, Mich., provided
supplies of U74006F and valuable advice. Stephen
Hecht, MD, Robert Tarr, MD, and Ann Radovsky,
DVM, PhD, helped with CBF imaging. David Gur,
PhD, Walter Good, PhD, Walter Obrist, PhD, Sidney
Wolfson, MD, and Howard Yonas, MD, gave advice
on CBF calculations. Janine E. Janosky, PhD, helped
with statistical analysis. Yuval Leonov, MD, helped
Dr. Sterz with team leadership. Mr. William Stezoski
and Mr. Henry Alexander coordinated life support.
Alan Abraham, Scott Nagel, Annette Pastula, and
Mark Ritchey helped with the experiments. Teresa
Adams, Pat Colorito, Franca Defelice, Vikie
Mavrakis, William Wigginton, and Donna Wojciechowski were radiotechnologists. Lisa Cohn provided editorial assistance, and Gale Foster helped
with preparation of the manuscript.
References
1. Negovslcy VS, Gurvitch AM, Zolotokryiina ES: Postresuscitotion Disease. Amsterdam, Elsevier Science Publishing Co, Inc,
1983
2. Safar P: Cerebral resuscitation after cardiac arrest: A review.
Circulation 1986;74(suppl IV):IV-138-IV-153
3. Braughler JM, Pregenzer JF, Chase RL, Duncan LA, Jacobsen EJ, McCall JM: Novel 21-aminosteroids as potent inhibitors of iron-dependent lipid peroxidation. / Biol Chan 1987;
262:10438-10440
4. Braughler JM, Chase RL, Neff GL, Yonkers PA, Day JS, Hall
ED, Sethy VH, Lahti RA: A new 21-amino steroid antioxidant
lacking glucocorticoid activity stimulates ACTH secretion and
blocks arachidonic acid release from mouse pituitary tumor
(AtT-20) cells. / Pharmacol Exp Ther 1988;244:423-427
5. Hall ED, Pazara KE, Braughler JM: 21-Aminosteroid lipid
peroxidation inhibitor U74006F protects against cerebral ischemia in gerbils. Stroke 1988;19:997-1002
6. Sylvia RC, Picrcey MF, Hoffmann WE, Chase RL, Braughler
JM, Tang AH: U74006F, an inhibitor of lipid peroxidation,
protects against lesion development following experimental
stroke in the cat: Histological and metabolic analysis
(abstract). Soc Neurosd Abst 1987;13:1495
7. Hall ED, Yonkers PA: Attenuation of postischemic cerebral
hypoperfusion by the 21-aminosteroid U74006F. Stroke 1988;
19:340-344
8. Hall ED, Yonkers PA, McCall JM, Braughler JM: Effects of
the 21-aminosteroid U74006F on experimental head injury in
mice. / Neurosurg 1988;68:456-461
9. Hall ED, Travis MA: Inhibition of arachidonic acid-induced
vasogenic brain edema by the non-glucocorticoid 21-aminosteroid U74006F. Brain Res 1988;451:350-352
10. Hall ED, Yonkers PA, McCall JM: Attenuation of hemorrhagic shock by the non-glucocorticoid 21-aminosteroid
U74006F. Eur J Pharmacol 1988;147:299-303
11. Natale JE, Schott RJ, Hall ED, Braughler JM, D'Alecy LG:
Effect of the aminosteroid U74006F after cardiopulmonary
arrest in dogs. Stroke 1988;19:1371-1378
12. Snyder JV, Nemoto EM, Carroll RG, Safar P: Global ischemia
in dogs: Intracranial pressures, brain blood flow and metabolism. Stroke 1975;6:21-27
13. Gur D, Good WF, Wolfson SK Jr, Yonas H, Shabason L: In
vivo mapping of local cerebral blood flow by xenon-enhanced
computer tomography. Science 1982;215:1267-1268
14. Yonas H, Good WF, Gur D, Wolfson SK Jr, Latchaw RE,
Good BC, Leanza R, Miller SL: Mapping cerebral blood flow
by xenon-enhanced computed tomography: Clinical experience. Radiology 1984;152:435-442
15. Wolfson SK Jr, Clark J, Greenberg JH, Gur D, Yonas H,
Brenner RP, Cook EE, Lordeon PA; Xenon-enhanced computed tomography compared with [14C]iodoantipyrine for normal and low cerebral blood flow states in baboons. Stroke
1990;21:751-757
16. Wolfson SK, Safar P, Reich H, Clark J, Gur D: Multifocal,
dynamic cerebral hypoperfusion after prolonged cardiac arrest
in dogs, measured by the stable xenon-CT technique
(abstract). Crit Care Med 1988;16:390
Sterz et al Aminosteroid U74006F After Cardiac Arrest
Downloaded from http://stroke.ahajournals.org/ by guest on June 16, 2017
17. Safar P, Sterz F, Leonov Y, Johnson D, Oku K, Tisherman SA,
Latchaw R, Obrist W, Stezoski SW, Janosky JE: Multifocal
cerebral blood flow by stable xenon-computed tomography
and global cerebral metabolism, after cardiac arrest in dogs
(abstract). / Cereb Blood Flow Metab (in press)
18. Sterz F, Safar P, Leonov Y, Johnson D, Latchaw R, Hecht S,
Oku K: Cerebral multifocal hypoperfusion after cardiac arrest
in dogs, mitigated by hypertension and hemodilution
(abstract). Ann Emerg Med 1989;18:468
19. Safar P, Abramson NS, Angelos M, Cantadore R, Leonov Y,
Levine R, Pretto E, Reich H, Sterz F, Stezoski SW, Tisherman
S: Emergency cardiopulmonary bypass for resuscitation from
prolonged cardiac arrest. Am J Emerg Med 1990;8:55-67
20. Safar P, Sterz F, Leonov Y, Radovsky A, Tisherman S, Oku K:
Systematic development of cerebral resuscitation after cardiac
arrest. Three promising treatments: Cardiopulmonary bypass,
hypertensive hemodilution, and mild hypothermia, in Baethmann A (ed): Causes and Mechanisms of Secondary Brain
Damage. Heidelberg, Springer Verlag (in press)
21. Sterz F, Leonov Y, Safar P, Radovsky A, Tisherman SA, Oku
K: Hypertension with or without hemodilution after cardiac
arrest in dogs. Stroke 1990;21:1178-1184
22. Leonov Y, Sterz F, Safar P, Radovsky A, Oku K, Tisherman S,
Stezoski SW: Mild cerebral hypothermia during and after
cardiac arrest improves neurologic outcome in dogs. J Cereb
Blood Flow Metab 1990;10:57-70
23. Good WF, Gur D: The effect of computed tomography noise
and tissue heterogeneity on cerebral blood flow determination
24.
25.
26.
27.
28.
29.
895
by xenon-enhanced computed tomography. Med Phys 1987;14:
557-561
Gur D, Yonas H, Good WF: Local cerebral blood flow by
xenon-enhanced CT: Current status, potential improvements,
and future directions. Cerebrovasc Brain Metab Rev 1989;1:
68-86
Cerchiari EL, Hoel TM, Safar P, Sclabassi RJ: Protective
effects of combined superoxide dismutase and deferoxamine
on recovery of cerebral blood flow and function after cardiac
arrest in dogs. Stroke 1987;18:869-878
Oku K, Kuboyama K, Safar P, Johnson D, Sterz F, Obrist W,
Leonov Y, Tisherman S: Multifocal cerebral blood flow (CBF)
and global metabolism (CMR) after prolonged cardiac arrest
in dogs: Effect of mild hypothermia (34°C) (abstract). Anesthesiology 1990;73:A302
Lind B, Snyder J, Safar P: Total brain ischemia in dogs:
Cerebral physiological and metabolic changes after 15 minutes
of circulatory arrest. Resuscitation 1975;4:97-113
Michenfelder JD, Milde JH: Postischemic canine cerebral
blood flow appears to be determined by cerebral metabolic
needs. J Cereb Blood Flow Metab 1990;10:71-76
Perkins WJ, Milde LN, Milde JH, Michenfelder JD: Effect of
a 21-aminosteroid oxygen-free radical scavenger on neurological outcome following complete cerebral ischemia in dogs
(abstract). / Cereb Blood Flow Metab 1989;9:S562
KEY WORDS
resuscitation
• cerebral blood flow
dogs
lipid peroxidation
Effects of U74006F on multifocal cerebral blood flow and metabolism after cardiac arrest in
dogs.
F Sterz, P Safar, D W Johnson, K Oku and S A Tisherman
Stroke. 1991;22:889-895
doi: 10.1161/01.STR.22.7.889
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