(Stroke. 2000;31:707.)
© 2000 American Heart Association, Inc.
Original Contributions |
Longer Duration of Cardiopulmonary Bypass Is Associated With Greater Numbers of Cerebral Microemboli
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 moodyd{at}rad.wfubmc.edu
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Abstract |
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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 µm 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.
Key Words: bypass surgery • cardiopulmonary bypass • cerebral embolism • cerebral ischemia, transient • embolism, fat
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Introduction |
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Brain 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 4 5 6 7 8 and humans.5 9 10 11 At about the same time, numerous fat microemboli were found after CPB in the organs of dogs12 13 14 and patients.10 12 15 16 17 18 19
When membrane oxygenators were introduced and antifoam was nearly eliminated from the CPB apparatus, morbidity 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 24 25 26 27 28 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 36 subjects. Our results support the hypothesis that a longer time on CPB results in a greater embolic load.
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Subjects and Methods |
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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.
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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 µm thick. Sections were
dehydrated in alcohols, and celloidin was removed in acetone. The
sections were stained for alkaline phosphatase, an
endogenous enzyme in the 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 x10 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 10x10 to 15x20
µm; for medium, up to 20x30 µm; and for large, up to
40x50 µm. The average volumes of small, medium, and large
microemboli were estimated, respectively, as 2000
µm3 (12x12x14 µm), 6000
µm3 (17x17x21 µm), and 18 000
µm3 (25x25x29 µm); the ratio was
1:3:9. Embolic load was calculated with this ratio and the numbers
of microemboli of each size: (1xsmall)+(3xmedium)+(9xlarge).
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
examined 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.
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Results |
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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).
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2 microemboli. Dotted lines indicate
95% confidence intervals.
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); solid line, data for valve
subgroup (•).
Longer duration of CPB was associated with increased embolic load
(P=0.0026) (Figure 5). For
each 1-hour increase 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).
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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.
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Discussion |
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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 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 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 24 25 26 27 28 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 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 47 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 18 19 50 51 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 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.
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Acknowledgments |
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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.
Received September 13, 1999; revision received November 17, 1999; accepted December 6, 1999.
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