Longer Duration of Cardiopulmonary Bypass Is Associated
With Greater Numbers of Cerebral Microemboli
William R. Brown, PhD; Dixon M. Moody, MD; Venkata R. Challa, MD;
David A. Stump, PhD; John W. Hammon, MD
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Background and Purpose—Many patients who undergo cardiac surgery assisted with cardiopulmonary bypass (CPB)
experience cerebral injury, and microemboli are thought to play a role. Because an increased duration of CPB is
associated with an increased risk of subsequent cerebral dysfunction, we investigated whether cerebral microemboli
were also more numerous with a longer duration of CPB.
Methods—Brain specimens were obtained from 36 patients who died within 3 weeks after CPB. Specimens were
embedded in celloidin, sectioned 100 ␮m thick, and stained for endogenous alkaline phosphatase, which outlines
arterioles and capillaries. In such preparations, emboli can be seen as swellings in the vessels. Cerebral microemboli
were counted in equal areas and scored as small, medium, or large to estimate the embolic load (volume of emboli).
Results—With increasing survival time after CPB, the embolic load declined (P⬍0.0001). (Lipid emboli are known to
pump slowly through the brain.) Also with increasing time after CPB, the percentage of large and medium emboli
became lower (P⫽0.0034). This decline is consistent with the concept that the emboli break into smaller globules as they
pass through the capillary network. A longer duration of CPB was associated with increased embolic load (P⫽0.0026).
For each 1-hour increase in the duration of CPB, the embolic load increased by 90.5%.
Conclusions—Thousands of microemboli were found in the brains of patients soon after CPB, and an increasing duration
of CPB was associated with an increasing embolic load. (Stroke. 2000;31:707-713.)
Key Words: bypass surgery 䡲 cardiopulmonary bypass 䡲 cerebral embolism
䡲 cerebral ischemia, transient 䡲 embolism, fat
B
rain injury remains a significant sequela of cardiac
surgery despite improvements in cardiopulmonary bypass (CPB) apparatus and refinements in surgical techniques
that have greatly reduced the associated mortality rate. A
major improvement in the CPB apparatus was the replacement of the bubble oxygenator with the membrane oxygenator. Nevertheless, current estimates indicate that ⬎50% of
patients who undergo CPB have neurological or neuropsychological deficits during the first week after surgery, 10% to
30% have long-term or permanent deficits, and 1% to 5%
experience severe disability or die.1,2
Cerebral microemboli have long been a suspected cause of
this post-CPB cerebral dysfunction. Soon after the advent of
CPB, it was found that globules of silicone antifoam were
continuously released from the bubble oxygenator of the CPB
apparatus and circulated to the brain and other organs of
dogs3– 8 and humans.5,9 –11 At about the same time, numerous
fat microemboli were found after CPB in the organs of
dogs12–14 and patients.10,12,15–19
When membrane oxygenators were introduced and antifoam was nearly eliminated from the CPB apparatus, mor-
bidity rates from CPB declined greatly. Studies of brain
microemboli also declined, although the danger of fat microemboli remained. Recognition of this problem was renewed
when Moody et al,20 using alkaline phosphatase staining of
the cerebrovasculature, reported finding thousands of small
capillary and arteriolar dilatations (SCADs) in all patients
who died shortly after CPB, whereas none were found in
control subjects. The SCADs could be seen clearly in 3
dimensions. Subsequent studies with the lipid stains oil red O
and osmium demonstrated that SCADs represent microemboli that contain fat.21,22
More than 40 reports, of which we cite 7,23–29 have shown an
association between cerebral dysfunction and the duration of
CPB. It is also suspected that longer duration of CPB results in
a greater numbers of cerebral fat emboli, but this relationship has
never been clearly demonstrated. If it could be shown that the
numbers of cerebral fat microemboli increase with time on CPB,
it would provide evidence in support of the hypothesis that
post-CPB cerebral dysfunction is in large part caused by microemboli. In the present study, we counted microemboli and
determined the embolic loads in postmortem brain tissues from
Received September 13, 1999; final revision received November 17, 1999; accepted December 6, 1999.
From the Departments of Radiology (W.R.B., D.M.M.), Pathology (W.R.B., V.R.C.), Anesthesiology (D.A.S.), and Surgical Sciences-Cardiothoracic
(J.W.H.) and Program in Neuroscience (W.R.B., D.M.M., D.A.S.), Wake Forest University School of Medicine, Winston-Salem, NC.
Correspondence to Dixon M. Moody, MD, Department of Radiology, Wake Forest University School of Medicine, Medical Center Boulevard,
Winston-Salem, NC 27157-1088. E-mail [email protected]
© 2000 American Heart Association, Inc.
Stroke is available at http://www.strokeaha.org
707
708
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Subject Demographics, Surgical Conditions, and Microemboli Counts
Microemboli Counts
Total
Embolic
Load
7
95
209
8
100
212
4
0
24
32
27
5
85
179
0
0
3
3
0
0
2
2
7
3
0
10
16
2
1
0
3
5
1.7
70
39
17
126
340
13.5
10
6
2
18
46
1.3
73
35
11
119
277
19.4
10
0
0
10
10
0.4
77
30
6
113
221
125
2.4
98
33
9
140
278
V
82
15.2
4
0
0
4
4
C
107
7.6
19
1
0
20
22
150
2.5
40
32
13
85
253
138
13.4
7
1
0
8
10
165
0.2
53
42
15
110
314
158
12.0
4
0
0
4
4
C
187
14.1
16
0
0
16
16
56
V
268
3.9
62
53
10
125
311
M
63
C
182
19.2
3
2
2
7
27
M
69
C
193
0.6
53
22
4
79
155
347
F
53
C
113
3.4
44
20
8
72
176
348
M
71
C, V
159
5.2
44
12
2
58
98
364
M
71
V
185
5.0
11
2
0
13
17
366
M
80
C
153
6.0
17
8
2
27
59
368
M
71
V
134
0.6
44
7
1
52
74
372
M
49
C
223
17.0
9
1
0
10
12
373
M
61
C
139
1.6
4
2
0
6
10
378
F
68
C
173
1.4
52
26
17
95
283
397
M
77
C
168
18.0
4
2
1
7
19
399
F
76
C
127
2.6
5
3
3
11
41
409
F
59
C
225
8.5
0
0
1
1
9
419
M
75
C, V
140
12.9
4
1
0
5
7
Subject
Surgery
Type
CPB Time,
min
Survival
Time, d
Small
Medium
Large
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Gender
Age, y
217
F
65
V
276
9.8
59
29
229
F
79
C
233
0.4
68
24
232
M
66
C
194
7.4
20
248
F
78
C
162
3.1
53
249
M
76
C
105
12.1
3
250
M
49
C
96
21.0
2
253
M
75
C, V
139
2.3
254
M
79
C
195
6.9
256
F
67
C, V
270
263
M
71
C
188
267
F
70
C, V
245
279
M
60
V
194
305
F
79
V
192
307
F
73
C
315
F
64
317
F
74
321
M
67
C
323
F
81
C
325
M
43
C
326
M
63
C
330
F
48
340
M
344
345
C indicates CABG; V, cardiac valve surgery.
36 subjects. Our results support the hypothesis that a longer time
on CPB results in a greater embolic load.
Subjects and Methods
Patients
We studied brain specimens obtained at autopsy from 36 subjects
who underwent CPB-assisted cardiac surgery at our institution
between 1987 and 1997 (Table). For some analyses, the patients
were divided into 2 subgroups: patients who underwent coronary
artery bypass graft surgery (CABG) only (n⫽24) and those who
underwent cardiac valve repair with or without CABG (n⫽12). All
patients included in the study were adults who died within 3 weeks
after CPB that was performed with a membrane oxygenator (not a
bubble oxygenator). Other exclusions thought to have potentially
confounding effects on the numbers of cerebral emboli included left
heart catheterization after CPB (all had left heart catheterization
before CPB), retrograde cerebral perfusion, heart transplantation,
and CPB more than once within 2 months.
Tissue Preparations
In each subject, a 1.5-cm-thick coronal brain slice was taken from the
left hemisphere at the mamillary bodies. As previously described,30
brain tissue was fixed for 24 hours in cold, buffered, weak formaldehyde (0.4%) and then dehydrated in alcohols, embedded in
celloidin, and sectioned 100 ␮m thick. Sections were dehydrated in
alcohols, and celloidin was removed in acetone. The sections were
stained for alkaline phosphatase, an endogenous enzyme in the
Brown et al
Figure 1. A lipid cerebral microembolus in an arteriole in white
matter of subject 325, who died shortly after cardiac surgery
(alkaline phosphatase–stained celloidin section, 100 ␮m thick).
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endothelium of capillaries and arterioles,30 and then cleared in
xylene and mounted on oversized glass slides. The brown-black lead
sulfide reaction product revealed the afferent vasculature in 3
dimensions within a clear background.
Microemboli Counting
Counting was performed in a standardized area of the basal ganglia.
Because SCADs occur everywhere in the microcirculation of the
brain, selection of the basal ganglia was simply to provide an easily
recognizable anatomic feature that contains both white matter and
gray matter with numerous vessels. Microemboli were counted on a
field-by-field basis with a ⫻10 objective lens, with focusing up and
down through the sections, in 3 adjacent 1-cm2 areas. Microemboli
were recorded as small, medium, or large; size was estimated against
a grid in the visual field. For small microemboli, the diameter and
length ranged from 10⫻10 to 15⫻20 ␮m; for medium, up to
20⫻30 ␮m; and for large, up to ⬇40⫻50 ␮m. The average volumes
of small, medium, and large microemboli were estimated, respectively, as 2000 ␮m3 (12⫻12⫻14 ␮m), 6000 ␮m3 (17⫻17⫻21 ␮m),
and 18 000 ␮m3 (25⫻25⫻29 ␮m); the ratio was ⬇1:3:9. Embolic
load was calculated with this ratio and the numbers of microemboli
of each size: (1⫻small)⫹(3⫻medium)⫹(9⫻large). To determine
whether microemboli sizes decreased as time after surgery increased,
the proportion of large and medium microemboli was determined for
each subject. Counts were done by W.R.B. In a blind study of
variability in recounts, reliability was ⬇90%.31
Statistical Analysis
Statistical analysis and graphing were performed with the computer
program Prism, version 2.0 (GraphPad Software). Data were exam-
Figure 2. Decrease in ratio of large plus medium microemboli
to total microemboli with increasing time after CPB. These data
include those patients (n⫽35) who had ⱖ2 microemboli. Dotted
lines indicate 95% confidence intervals.
Cerebral Microemboli From Cardiac Surgery
709
Figure 3. Decline in embolic load with increasing time after
CPB. Dotted lines indicate 95% confidence intervals.
ined by means of linear regression and Student’s t test. Exact P
values are reported and referred to in consideration of the statistical
significance of data.
Results
Microemboli (Figure 1) were found in arterioles and capillaries
in all 36 subjects, often at bifurcations in the microvasculature.
With increasing survival time after CPB, the general tendency
was for the percentage of large and medium emboli to decline
(P⫽0.0034) (Figure 2). However, there was considerable variability, and in 4 of the 16 patients who died between 1 and 3
weeks after CPB, the trend toward a decreased size of emboli
was not apparent. With increasing time after CPB, there was a
logarithmic decline in the number of microemboli (P⬍0.0001)
and the embolic load (P⬍0.0001) (Figure 3). The decline in
embolic load was especially rapid in the first few days after
CPB. As Figure 4 shows, the rate of decline was the same for
the 2 subgroups of patients (ie, CABG only or valve repair).
The mean embolic load for valve repair patients was 46.2%
greater than that for CABG patients, but this difference may
have been due to chance (P⫽0.1576 in a 1-tailed t test).
Longer duration of CPB was associated with increased
embolic load (P⫽0.0026) (Figure 5). For each 1-hour in-
Figure 4. Decline in embolic load with increasing time after
CPB for valve and CABG subgroups. Dashed line indicates data
for subgroup who underwent CABG only (E); solid line, data for
valve subgroup (F).
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Figure 5. Increase in embolic load with longer duration of CPB
while controlling for survival time. Data point for each patient is
shown as percent deviation from predicted embolic load as
shown in regression lines for valve and CABG in Figure 4. See
Results for method of calculation. Dotted lines indicate 95%
confidence intervals.
crease in CPB duration, the embolic load increased by 90.5%.
However, when the data for the CABG and valve groups were
analyzed separately, it was found that the increase in embolic
load was much greater in the valve group (145.3% per hour)
than in the CABG group (30.5% per hour) (Figure 6). The
increase in embolic load appeared to be significant in the
valve group (P⫽0.0022) but not in the CABG group
(P⫽0.4854). It can be seen in Figure 6 that the 4 longest CPB
durations occurred in valve patients, and these patients tended
to have relatively high embolic loads. CPB duration for valve
patients averaged 17.2% longer than that for CABG patients,
but the difference did not appear to be very significant
(P⫽0.0550 in a 1-tailed t test).
The deviation from the predicted embolic load (Figures 5
and 6) was calculated as follows: from the linear regression
lines for valve and CABG in Figure 4, the Prism statistics
program was used to calculate a residual for each data point.
This residual was subtracted from the measured embolic load
to obtain the predicted embolic load for that time after
surgery. The residual and predicted values were converted
from log10 to standard numbers, and the residual value was
divided by the predicted value to obtain the percent deviation
from the regression line. Valve data were compared with the
valve regression line, and CABG data were compared with
the CABG regression line.
Discussion
Our finding of cerebral fat microemboli in all subjects who
died shortly after CPB confirmed the results of previous
studies.16,20 The rapid decline in microemboli found in this
study is consistent with observations in dogs showing that
after CPB, most microvascular occlusions had disappeared
within 7 days,32,33 and with the observations of Blauth et al34
that vascular occlusions in the retinas of CPB patients were
more numerous during CPB than after CPB.
Our finding that the percentage of large and medium
microemboli declined with time after CPB is consistent with
the hypothesis that fat emboli break into smaller globules as
they pass through the capillary network.35 CPB-induced
Figure 6. Increase in embolic load with longer duration of CPB
for valve and CABG subgroups while controlling for survival
time. Data point for each patient is shown as percent deviation
from predicted embolic load as shown in regression lines for
valve and CABG in Figure 4. See Results for method of calculation. Dashed line indicates data for subgroup who underwent
CABG only (E); solid line, data for valve subgroup (F).
cerebral microemboli in dogs also have been reported to
become smaller with time,10 and fat emboli in the lungs of
dogs became smaller within 2 hours; some passed through to
the brain within 1 hour.36 It has also been shown that fat
injected into the carotid arteries of rabbits37 passes through
the brain to the lungs.
After CPB, good blood flow through the brain might hasten
the clearance of microemboli, and increased perfusion pressure during CPB has been proposed as a means of forcing air
bubbles through the cerebral microcirculation.38 In contrast,
diminished blood flow during CPB might be expected to
reduce the number of emboli carried to the brain. Consistent
with this concept, microemboli counts were very low in the 2
subjects (subjects 253 and 373) in our study who had brain
edema, which tends to reduce brain blood flow. The brain
edema may have begun in these patients as a result of severe
myocardial infarction the day before surgery. Their embolic
loads were 26.6% and 6.6%, respectively, of that which
would be predicted on the basis of CPB duration and survival
time after surgery.
Of potential clinical significance is our finding that the
embolic load tended to be higher in patients who underwent
prolonged CPB. This increase was most apparent in the valve
repair patients, perhaps because CPB tended to be longer for
valve patients than for CABG patients. There was no indication that the rate of clearance of microemboli from the brain
was different for valve and CABG patients. On the contrary,
the clearance curves (Figure 4) were nearly parallel, indicating similar rates of clearance. The essential difference between CABG and valve patients, in regard to microemboli,
appeared to be that valve patients tended to have longer CPB
and greater numbers of microemboli. One factor that was not
analyzed but may be relevant is the potential effect of reduced
cardiac output on cerebral blood flow and clearance of
microemboli.
That longer CPB might cause more emboli has long been
suspected, but until now the number and volume of cerebral
microemboli have not been systematically quantified. Blauth
Brown et al
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et al34 counted microvascular occlusions in retinas, but they
found no correlation between CPB time and the number of
vascular occlusions. However, they did find a tendency
toward a correlation between CPB time and psychometric
deficits (P⬍0.075). Others have observed an increase in
microemboli with longer CPB time, but no counts were made.
These reports involved fat emboli in human brain,15 kidney,15
and lung39 and silicone antifoam emboli in human brain40 and
kidney5,9 and in dog kidney.5 Contrary to those observations,
in 1962 Miller et al16 noted no apparent relationship between
CPB duration and the degree of fat embolization in various
tissues. It is important to note that none of those studies
considered that survival time after CPB could affect the
counts. We have shown that the counts rapidly decline with
increasing survival time.
Caguin and Carter18 found cerebral fat emboli in CPB
patients after noticing that the pattern of cerebral dysfunction
in an orthopedic patient with cerebral fat embolism was the
same as that in some CPB patients. Hodge et al41 reported a
case of fatal cerebral fat embolism resulting from CPB and
suggested that the fat embolism syndrome is present subclinically in the majority of CPB patients. Such subclinical
effects may correspond to the transient or permanent neuropsychological or neurological deficits that can now be detected in many CPB patients after detailed preoperative and
postoperative evaluations.
Numerous reports over the years have shown that CPB
duration is associated with neurological dysfunction.23–29
Both brain emboli and brain injury were found to increase
with prolonged CPB.5,9 However, because current membrane
oxygenators release far fewer antifoam emboli into the blood
than did bubble oxygenators, the association between CPB
duration and cerebral dysfunction is likely to be weaker now.
We examined archival material from a patient who died at 0.2
day after CPB with a bubble oxygenator (data not shown),
and she had far more microemboli than did any other patient:
571 microemboli with an embolic load of 1323 compared
with a predicted embolic load of 324 for her length of survival
after surgery and duration of CPB (199 minutes).
Cerebral fat embolism produces less brain injury than
might be expected, perhaps because the emboli are small and
transient.22 However, the evidence that microemboli can
cause severe brain injury is most impressively shown in the
fatal case reported by Hodge et al.41 Furthermore, the use of
filters in the CPB apparatus has reduced the number of
microemboli and the incidence of neurological injury.8,23,25,42
Cerebral microemboli may also cause neuronal dysfunction
without killing the cells,8 as has been observed in cases of
intermittent monocular blindness.43,44 Vision returned when
the retinal microvascular emboli moved and circulation was
restored. Mild emboli-induced ischemia may cause transient
dysfunction in the vital centers of the brain stem and
contribute to the immediate mortality rates associated with
CPB.8
Sternal bone marrow is an important source of lipid
microemboli. Sternotomy reportedly results in more fat in the
blood24 and fat emboli in the tissues16 than does thoracotomy.
During sternal division, numerous fat emboli have been found
in the right atrium.45 Perhaps more important is fat that
Cerebral Microemboli From Cardiac Surgery
711
washes into the pool of pericardial blood from the sternum
and the incised thoracic tissues, particularly the large amount
of fat that is found in the sternum of older patients. Shed
blood around the heart is often scavenged with a suction line
and returned to the patient via the CPB apparatus. It has been
reported that the majority of microemboli come from the
cardiotomy suction line.46 – 48 In dogs undergoing CPB,
Brooker et al49 found a 10-fold increase in microemboli when
pericardial blood was scavenged and returned to the circuit.
Evidently, embolic fat is a major problem with the pericardial
blood.17–19,50 –52 A strong association has been reported between the reuse of scavenged blood and a negative outcome
after CPB,53 and superior results have been shown when
cardiotomy suction blood is discarded.18,54 Increased blood
scavenging during prolonged CPB may be one cause of the
association found between CPB duration and embolic load in
this report and between CPB duration and cerebral dysfunction in reports of ⬎40 other studies.
Atheromatous debris may contribute to brain emboli during CPB.55 Proximal aortic atherosclerosis, the strongest
predictor of stoke, stupor, or coma after CPB, increases the
risk by ⬎4-fold.55 However, aortic atheroma does not appear
to be associated with the more subtle cognitive deficits,55
which we suspect may be caused by lipid microemboli. In 7
subjects who had left heart catheterization after CPB (data not
shown), we found more microemboli than would be expected
from CPB alone. This finding is consistent with the fact that
left heart catheterization is known to cause cerebral emboli,20,56 apparently due to the disruption of aortic and coronary
artery atheroma. The disruption of aortic or carotid atheroma
may release lipid microemboli as well as larger emboli of
atheromatous debris and cholesterol crystals. After carotid
angiography, atheromatous debris was found in the arteries,
whereas the small lipid emboli lodged in arterioles and
capillaries.57
Retrograde cerebral perfusion, which was first used to treat
air embolism during CPB,58 may be useful to wash out
particulate emboli.59 We have data from a single case that
supports that concept. We studied a subject who had retrograde cerebral perfusion (data not shown), and we found far
fewer microemboli than would be predicted. This patient died
4.1 days after surgery and had a very long CPB duration (279
minutes). On the basis of the data for the 36 patients in the
present study, the predicted embolic load for this patient
would be 200; however, her embolic load was only 21.
Positioning the patient head down during CPB might help
to steer fat emboli away from the origins of the arteries that
supply the brain. Evidence that fat emboli float in the blood
and that a change in a patient’s position can alter the route of
circulating fat emboli has been shown in 12 cases of traumatic fat embolism.60
In conclusion, we have shown that microemboli were numerous in all CPB patients examined within a few days after CPB
and that most microemboli had cleared from the vessels within
1 week. Microemboli tended to be more numerous in patients
who underwent CPB of longer duration. From this study, it is not
clear why this should be so. However, previous studies have
suggested that the scavenging of pericardial blood is a potential
major source of lipid emboli. If prolonged CPB is associated
712
Stroke
March 2000
with increased scavenging of pericardial blood, then elimination
of the use of scavenged blood or removal of lipid emboli from
scavenged blood may be important to reduce post-CPB cerebral
dysfunction.
Acknowledgments
This work was supported by NIH grants NS-27500 and NS-20618.
We thank Donna S. Garrison, PhD, for editorial assistance; Patricia
Wood and Shirley Blakemore for technical assistance; and acknowledge our late associate, Mary A. Bell, DPhil, who developed the
alkaline phosphatase enzyme histochemistry method that we use.
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Stroke. 2000;31:707-713
doi: 10.1161/01.STR.31.3.707
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