The effect of blood pressure on cerebral outcome in a rat model of cerebral air embolism during cardiopulmonary bypass.

Abstract

Higher mean arterial pressure during cardiopulmonary bypass may improve cerebral outcome associated with cerebral air embolism by increasing emboli clearance and collateral flow to salvage the ischemic penumbra. However, this may come at the expense of increased delivery of embolic load. This study was designed to investigate the influence of mean arterial pressures on cerebral functional and histologic outcome after cerebral air embolism during cardiopulmonary bypass in an established rat model.
Male Sprague-Dawley rats were exposed to 90 minutes of normothermic cardiopulmonary bypass with 10 cerebral air embolisms (0.3 μL/bolus) injected repetitively. Rats were randomized to 3 groups (n = 10, each) that differed in mean arterial pressure management during cardiopulmonary bypass: 50 mm Hg (low mean arterial pressure), 60 to 70 mm Hg (standard mean arterial pressure), and 80 mm Hg (high mean arterial pressure). Neurologic score was assessed on postoperative days 3 and 7 when cerebral infarct volumes were determined. Cognitive function was determined with the Morris water maze test beginning on postoperative day 3 and continuing to postoperative day 7.
Neurologic score was better in high and standard mean arterial pressure groups versus low mean arterial pressure groups. High mean arterial pressure resulted in shorter water maze latencies compared with standard and low mean arterial pressure on postoperative days 6 and 7. Total infarct volume and number of infarct areas were not different among groups.
The use of higher mean arterial pressure during cardiopulmonary bypass in a rat model of cerebral air embolism conveyed beneficial effects on functional cerebral outcome with no apparent disadvantage of increased delivery of embolic load. Maintaining higher perfusion pressures in situations of increased cerebral embolic load may be considered as a collateral therapeutic strategy.

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The effect of blood pressure on cerebral outcome in a rat model of
cerebral air embolism during cardiopulmonary bypass
Ma Qing, MD,aJae-Kwang Shim, MD, PhD,a,bHilary P. Grocott, MD, FRCPC,aHuaxin Sheng, MD,a
Joseph P. Mathew, MD,aand G. Burkhard Mackensen, MD, PhDa
Objective: Higher mean arterial pressure during cardiopulmonary bypass may improve cerebral outcome asso-
ciated with cerebral air embolism by increasing emboli clearance and collateral flow to salvage the ischemic
penumbra. However, this may come at the expense of increased delivery of embolic load. This study was de-
signed to investigate the influence of mean arterial pressures on cerebral functional and histologic outcome after
cerebral air embolism during cardiopulmonary bypass in an established rat model.
Methods: Male Sprague–Dawley rats were exposed to 90 minutes of normothermic cardiopulmonary bypass
with 10 cerebral air embolisms (0.3 mL/bolus) injected repetitively. Rats were randomized to 3 groups
(n ¼ 10, each) that differed in mean arterial pressure management during cardiopulmonary bypass: 50 mm
Hg (low mean arterial pressure), 60 to 70 mm Hg (standard mean arterial pressure), and 80 mm Hg (high
mean arterial pressure). Neurologic score was assessed on postoperative days 3 and 7 when cerebral infarct vol-
umes were determined. Cognitive function was determined with the Morris water maze test beginning on post-
operative day 3 and continuing to postoperative day 7.
Results:Neurologicscorewasbetterinhighandstandardmeanarterialpressuregroupsversuslowmeanarterial
pressure groups. High mean arterial pressure resulted in shorter water maze latencies compared with standard
and low mean arterial pressure on postoperative days 6 and 7. Total infarct volume and number of infarct areas
were not different among groups.
Conclusions: Theuseofhighermeanarterial pressure duringcardiopulmonarybypass inaratmodelofcerebral
air embolism conveyed beneficial effects on functional cerebral outcome with no apparent disadvantage of in-
creased delivery of embolic load. Maintaining higher perfusion pressures in situations of increased cerebral em-
bolic load may be considered as a collateral therapeutic strategy. (J Thorac Cardiovasc Surg 2011;142:424-9)
Cerebral injury, ranging from neurocognitive dysfunction to
overt stroke, remains as a significant cause of morbidity
and mortality after cardiac surgery using cardiopulmonary
bypass (CPB).1Although considered multifactorial, the
most importantly cited etiologic factors are cerebral macro-
and microembolism and hypoperfusion.2,3Among them,
the principal cause of neurocognitive impairment is
believed to be cerebral microembolization with the
majority being gaseous, which invariably occurs during
CPB.4,5Accordingly, both experimental and human studies
have demonstrated a significant correlation between the
number, as well as the volume, of cerebral air emboli
(CAE) and adverse neurologic outcome after CPB.3,5-7
With the view to provide neuroprotection during CPB,
a generally accepteddefinitionofoptimalmeanarterial pres-
sure (MAP) to ensure adequate tissue perfusion has not been
established. Although cerebral perfusion is assumed to re-
mainconstantoverawiderangeofMAPs,itisgenerallyreg-
ulatedbyMAPratherthanthepumpflowrateduringCPB.8,9
InthepresenceofpathologicCAEimpairingtissueperfusion,
maintaininghigherMAPonCPBhasthetheoreticadvantage
of enhancing collateral blood flow and facilitating emboli
clearance. Yet, this may also lead to cerebral edema or
increased delivery of embolic load to the brain.2,8In
conjunction, the results of the limited observational clinical
studies are contradictory, and no comprehensive data exist
regarding the contribution of MAP to cerebral outcome
after CPB.10-12
Therefore, the purpose of the present study was to inves-
tigate the influence of MAP during CPB on CAE-induced
functional (neurologic and cognitive) and histologic cere-
bralinjury inarandomized andcontrolledexperimentusing
an established rodent model of CPB combined with CAE.7
MATERIALS AND METHODS
The Duke University Institutional Animal Care and Use Committee ap-
proved this study, and all procedures met the National Institutes of Health
guidelines for animal care (Guide for the Care and Use of Laboratory
From the Department of Anesthesiology,aDuke University Medical Center, Durham,
NC; and Department of Anesthesiology and Pain Medicine,band Anesthesia and
Pain Research Institute, Yonsei University Health System, Seoul, Korea.
This study was funded by departmental funds.
Disclosures: Authors have nothing to disclose with regard to commercial support.
Received for publication Aug 11, 2010; revisions received Nov 9, 2010; accepted for
publication Nov 25, 2010; available ahead of print Jan 31, 2011.
Address for reprints: G. Burkhard Mackensen, MD, PhD, Department of Anesthesi-
ology, Duke University Medical Center, Box 3094, Durham, NC 27710 (E-mail:
b.mackensen@duke.edu).
0022-5223/$36.00
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Animals, available at: www.nap.edu/catalog/5140.html). Thirty male
Sprague–Dawley rats (age, 12–14 weeks; weight, 375–400 g; Charles
River Laboratories, Inc, Wilmington, Mass) were studied. Animals were
randomly assigned to 1 of 3 groups with repetitively administered CAEs
(n ¼ 10 each) that differed in the management of MAP during 90 minutes
of normothermic CPB. MAP was maintained at 80, 60–70, or 50 mm Hg in
the high, standard, and low MAP groups, respectively. MAP was adjusted
by varying the inhalational concentration of isoflurane (range, 0.5%–2.5%)
orusing phenylephrine (not exceeding 2–3 mg intravenously [IV]per bolus).
Surgical Preparation and Cardiopulmonary Bypass
Fasted rats were anesthetized with 5% isoflurane in oxygen in a plastic
induction box. After induction of anesthesia, the trachea was intubated and
the lungs were mechanically ventilated (Harvard Rodent Respirator; Bos-
ton, Mass) with a tidal volume of 10 mL/kg and respiratory rate of 50 to 55
beats/minmaintainingarterialPCO2between36and42mmHg.Duringsur-
gery,anesthesiawasmaintainedwith2.0%to2.5%isofluraneandfentanyl
(25 mg/kg, intravenous, as a bolus injection).
AnimalswerecannulatedforCPBaspreviouslyreported.7,13Briefly,the
tail artery was cannulated for aortic inflow, a multistaged venous return
cannula was placed in the heart through the right external jugular vein,
and the right superficial caudal epigastric artery was cannulated for
monitoring of MAP (model 90603A; SpaceLabs, Inc, Redmond, Wash).
After the cannulation of the tail artery, animals received 150 units of
heparin. During CPB, anesthesia was maintained using 0.5% to 1.2%
isoflurane and fentanyl (150 mg/kg IV). No paralytics were administered
until just before CPB when pancuronium (0.1 mg/kg) was administered to
prevent spontaneous breathing during CPB. Fentanyl and pancuronium
were repeated (at half the dose) at 30-minute intervals, as necessary.
Pericranial temperature was monitored with CSC 32 (Omega Engineering,
Inc, Stamford, Conn) and maintained at 37.5?C ? 0.1?C using a heating
blanket and convective forced-air heating system.
The CPB circuit consisted of a venous reservoir, a peristaltic pump
(Tygon; Cole-Patmer Instrument, Vernon Hills, Ill), a membrane oxygena-
tor,andanarterialinflowcannula.Anin-lineflowprobe(2N806flowprobe
and T208 volume flowmeter; Transonics Systems, Inc, Ithaca, NY) was
used to continuously measure CPB flow. To avoid excessive hemodilution,
thebypasscircuitwasprimedwith14mLwholebloodobtainedfromahep-
arinized(150unitsIVheparinperrat)donorrat.Inaddition,6%hetastarch
(4 mL) was added to the circuit, as needed. One hundred units of heparin
were added to the prime. Arterial line inflow temperature was maintained
at 37.5?C using a circulating water bath system. Arterial blood gases
were analyzed using a GEM Premier 3000 blood gas/electrolytic analyzer
(model 5700; Instrument Laboratories, Inc, Lexington, Mass). Basic phys-
iologic data, including MAP, temperature, and blood gases, were collected
15 minutes before commencement of CPB. All animals were subjected to
90 minutes of normothermic and nonpulsatile CPB with flow rates of 160
to 180 mL/min/kg corresponding to a normal cardiac output in the rat.12
For the entire CPB period, ventilation of the lungs was discontinued. After
90 minutes of CPB, the animals were weaned from CPB without the need
for inotropic support. Heparin-induced anticoagulation was allowed to dis-
sipate spontaneously without supplemental administration of protamine.
After decannulation, rats were maintained anesthetized with 0.5% to
1.2%isoflurane,intubated,andventilatedfor 1hour.Whenadequatespon-
taneousbreathingresumed,theanimalswereextubatedandrecoveredinan
oxygen-enriched box for 24 hours with free access to water and food. Dur-
ingthefirst6hoursofrecovery,theywerecontinuouslyobservedtoidentify
signsofimmediatecerebraldeath and severe neurologicdysfunction(fixed
pupils, absence of spontaneous breathing, seizures, and inability to ambu-
late). Animals demonstrating signs of severe neurologic dysfunction were
sacrificed. All others were returned to their cages and housed individually.
Cerebral Air Embolism
The methodology of the CAE model used in the current study has been
reported.7Briefly, rats subjected to 90 minutes of normothermic CPB re-
ceived 10 equally sized CAEs (0.3 mL/single bolus). The choice of 0.3
mL per bolus was based on preliminary work showing that this size of
CAE during CPB is associated with a mortality rate of 1% (95% confi-
dence interval, 0.1–14.5) and an incidence for neurologic deficits of
85.8% (95% confidence interval, 40.7–98.2).7For the injection of
CAEs, a PE-10 catheter (Intramedic; Becton-Dickinson, Sparks, Md)
was inserted via the stump of the right external carotid artery and advanced
into the right internal carotid artery beyond the pterygopalatine branch(0.8
cm distance) that was ligated. The catheter was connected to a syringe
pump (KDS100; KD Scientific Inc, Holliston, Mass). The first embolus
was administered at 15 minutes of CPB, and the last embolus was admin-
istered at 75 minutes of CPB. By using a Hamilton syringe with a 1.2-cm
long needle (5 mL SYR, 75N; Hamilton Co, Reno, Nev), the size of the air
bubble could be exactly determined by the placement of the air between 2
mL saline aliquots. After the delivery of the last CAE, 10 mL saline were
injected to flush the last air embolus into the cerebral circulation.
Neurologic and Neurocognitive Testing
Onthethirdandseventhpostoperative days(PODs),animalsunderwent
standardized functional neurologic testing using an established neurologic
scoring system that evaluates 4 different functions, including general sta-
tus, simple motor deficit, complex motor deficit, and sensory deficit.14
The score given to each animal at the completion of the testing (by an ob-
server blinded to group assignment) was the sum of all 4 individual scores:
0 was the minimum (best) score and 48 was the maximum (worst) score.
In addition to the neurologic evaluation, neurocognitive outcome was
evaluated daily (starting on POD 3) in the Morris water maze using a com-
puterized video tracking system (EthoVision; Noldus, Wageningen, The
Netherlands).15The Morris water maze consisted of a 1.5-m diameter,
30-cm deep pool of water (27?C) with a hidden submerged (3 cm below
surface) platform in 1 quadrant. Rats were placed in the water in a dimly
lit room with various visual clues around the maze. The time to locate
the submerged platform (defined as the latency) was measured to test for
impairment invisuospatial learning and memory components of neurocog-
nition. Rats underwent daily testing in thewater mazewith 4 trials per test-
ing period, each limited to a 90-second water exposure. Each of the trials
was begun from a separate quadrant. Testing was performed for 5 consec-
utive days until POD 7.
Histologic Examination
After completion of the testing on the final day, the animals were anes-
thetized with 5% isoflurane and decapitated. The brains were removed,
snap-frozen at ?40?C in 2-methyl-butane, and stored at ?80?C for later
analysis.
Infarct volumewas measured by using previously published methods.14
Serial quadruplicate 20-mm–thick coronal sections were taken by using
a cryotome at 660-mm intervals over the rostrocaudal extent of the infarct.
The sections were dried and stained with hematoxylin–eosin. A represen-
tative sectionfromeach660-mmintervalwasdigitizedwithavideocamera
controlled by an image analyzer (M2 Turnkey System; Imaging Research,
Abbreviations and Acronyms
CAE ¼ cerebral air emboli
CPB ¼ cardiopulmonary bypass
IV
¼ intravenously
MAP ¼ mean arterial pressure
POD ¼ postoperative day
ROI ¼ regions of interest
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St Catharines, Ontario, Canada). The following regions of interest (ROI)
were cursor-outlined: noninfarcted ipsilateral cerebral cortex, noninfarcted
ipsilateral subcortex, contralateral cerebral cortex, and contralateral sub-
cortex. The area within each ROI (square millimeters) was determined
by automated counting of the calibrated pixels contained within the ROI.
Ipsilateral noninfarcted cortex and subcortex areas were subtracted from
the corresponding contralateral ROI values. Infarct volumes (cubic milli-
meters) were computed as running sums of subtracted infarct area multi-
plied by the known interval (eg, 660 mm) between sections over the
rostrocaudal extent of the infarct calculated as an orthogonal projection.
The number of infarct areas was also counted.
Statistical Analysis
Statistical analyses were performed using SPSS 12.0 (SPSS Inc,
Chicago, Ill). All data are expressed as mean ? standard deviation. Data
among the groups were compared using chi-square test, Fisher’s exact
test, or 1-way analysis of variance followed by post hoc Bonferroni test
as appropriate. Data within the group were compared using paired t test
or repeated-measures analysis of variance followed by post hoc Dunnett’s
test as appropriate.
RESULTS
Physiologic Parameters
Table 1 displays the physiologic variables of rats treated
with high, standard, and low MAP during CPB combined
with CAE. In intergroup comparisons, hemoglobin and glu-
cose concentrations,pH,PaCO2,andpericranial temperature
were statistically different at various time points of mea-
surements; however, all within normal limits.
Neurologic Outcome
In intergroup comparisons, neurologic scores were better
in the high and standard MAP group compared with the low
MAP group at both POD 3 (7.1 ? 5.6, P ¼ .0183; 5.4 ? 2.6,
P ¼ .0025; and 12.2 ? 4.8 in the high, standard, and low
MAP groups, respectively) and POD 7 (4.8 ? 4.1,
P ¼ .0287; 4.6 ? 2.0, P ¼ .0217; and 9.2 ? 5.8 in the
high, standard, and low MAP groups, respectively;
Figure 1). In intragroup comparisons, neurologic scores in
all of the 3 groups were significantly improved on POD 7
compared with POD 3 (P ¼ .041, P<.001, and P ¼ .021
in the high, standard, and low MAP groups, respectively).
Cognitive Outcome
In intergroup comparisons of the water maze latencies,
denoting the cumulative time taken by animals to find the
platform based on the 4 trials of each day, animals in the
TABLE 1. Physiologic parameters
ParametersBaseline
CPB
After CPB
60 min 30 min60 min90 min
MAP (mm Hg)
High MAP
Standard MAP
Low MAP
Hemoglobin (mg/dL)
High MAP
Standard MAP
Low MAP
Glucose (mg/dL)
High MAP
Standard MAP
Low MAP
pHa
High MAP
Standard MAP
Low MAP
PaO2(mm Hg)
High MAP
Standard MAP
Low MAP
PaCO2(mm Hg)
High MAP
Standard MAP
Low MAP
Pericranial temperature (?C)
High MAP
Standard MAP
Low MAP
62 ? 6
56 ? 5*,y
65 ? 8
82 ? 12y
56 ? 4*
50 ? 2
84 ? 7
59 ? 5*,y
49 ? 5*
87 ? 7
63 ? 5*,y
50 ? 4*
82 ? 6
79 ? 11
76 ? 10
12.3 ? 0.8
11.5 ? 1.2
12.1 ? 0.6
10.2 ? 0.7
9.7 ? 0.5
9.7 ? 0.6
10.7 ? 0.6
9.7 ? 0.6
9.9 ? 0.6
11.0 ? 0.6
10.0 ? 0.6*
10.0 ? 0.7*
10.6 ? 0.5
10.9 ? 1.3
10.3 ? 0.9
123 ? 31
114 ? 18
126 ? 24
120 ? 21
111 ? 9y
129 ? 22
111 ? 24
88 ? 15y
112 ? 34
7.47 ? 0.05
7.46 ? 0.07
7.47 ? 0.05
7.42 ? 0.12
7.43 ? 0.04
7.40 ? 0.02
7.39 ? 0.03
7.43 ? 0.04*
7.41 ? 0.03
7.38 ? 0.04
7.43 ? 0.05*,y
7.38 ? 0.04
7.37 ? 0.10
7.40 ? 0.04
7.37 ? 0.10
181 ? 35
173 ? 49
155 ? 52
454 ? 57
450 ? 40
454 ? 57
473 ? 67
463 ? 108
469 ? 41
474 ? 48
467 ? 102
459 ? 125
309 ? 104
252 ? 113
253 ? 97
34 ? 4
36 ? 8
35 ? 3
41 ? 4
38 ? 3y
41 ? 2
41 ? 4
39 ? 3
40 ? 2
40 ? 4
39 ? 4
39 ? 4
40 ? 9
39 ? 6
38 ? 4
37.0 ? 0.8
36.8 ? 0.6
36.9 ? 0.5
37.1 ? 0.6
36.5 ? 0.5*
36.6 ? 0.7
37.4 ? 0.3
37.0 ? 0.5*,y
37.4 ? 0.3
37.5 ? 0.2
37.3 ? 0.2
37.3 ? 0.4
37.5 ? 0.5
37.7 ? 0.4
37.7 ? 0.5
CPB, Cardiopulmonary bypass; MAP, mean arterial pressure; PaO2,, arterial oxygen tension; PaCO2,, arterial carbon dioxide tension. Values are mean ? standard deviation. Each
group consists of 10 rats. *P<.05 compared with high MAP group. yP<.05 compared with low MAP group.
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standard MAP group had shorter latencies compared with
the high MAP group at POD 3 (P ¼ .019; Table 2). Laten-
cies were significantly shorter in the high MAP group com-
pared with the standard MAP group on POD 6 (P ¼ .0327)
and POD 7 (P ¼ .0271). Latency in the high MAP group
also demonstrated a trend toward being shorter compared
with the low MAP group on POD 6 (P ¼ .0852). In intra-
group comparisons, latencies were improved in the high
MAP group on PODs 4 to 7 compared with the baseline
value on POD 3 (all P<.001). Latency was also improved
in the low MAP group on PODs 5 (P ¼ .049), 6 (P ¼ .044),
and 7 (P ¼ .014) compared with the baseline value on POD
3, whereas it remained similar in the standard MAP group
throughout. There were no intergroup or intragroup differ-
ences in swimming speeds at all time points of measure-
ments (Table 2).
Histology
No differences were found between groups with respect
to total infarction volume (Figure 2). The number of infarct
areas was also similar among the groups (1.3 ? 0.7, 0.8 ?
0.6, 1.2 ? 0.9 in the high, standard, and low MAP groups,
respectively, P ¼ .106)
DISCUSSION
The current study provides primary evidence that using
a higher MAP during CPB improved postoperative func-
tional neurologic and neurocognitive outcome induced by
CAE and CPB. These functional benefits, however, could
not be extended to a reduced cerebral infarct volume.
Inadditiontothelessfrequentovertmanifestationofcere-
bral injury stroke, neurocognitive decline is a well-
recognized complication after cardiac surgery with high
prevalence and persistence leading to long-term conse-
quences mandating the need for strategies aimed at reducing
its occurrence.16Among the complex and multifactorial
causes, the principal cause of neurocognitive dysfunction is
considered to be cerebral microembolic load during
CPB.2,3Cerebral microemboli occur in virtually all patients
undergoing CPB with the majority being gaseous.4,5
Clinically, cerebral emboli during CPB were associated
with impaired memory and demonstrated to be a significant
predictor of neuropsychologic dysfunction.3,5,6Moreover,
a recent study in a similar rat model of CPB demonstrated
the relationship between CAE and postoperative cerebral
injury.7Inthatstudy,totalcerebralinfarctionvolumeinduced
by air emboli correlated with postoperative neurologic func-
tion, confirming the role of CAE during normothermic CPB
onpostoperativeneurologicandneurocognitivedysfunction.
In view of neuroprotective strategies in the setting of
acute ischemic stroke as caused by CAE during CPB,
none of the pharmacologic agents developed to interrupt
biochemical mechanisms leading to neuronal death demon-
strated clinical success.17Thus, the importance of collateral
FIGURE 1. Neurologic function was evaluated on PODs 3 and 7 using a protocol that included assays of general status, vertical screen climbing, balance
beam, and sensory performance (total possible deficit points ¼ 48, 0 ¼ no deficit). Animals exposed to MAP of 80 mm Hg (HM) or 60 to 70 mm Hg (ST)
during normothermic CPB combined with CAE demonstrated significantly lower neurologic score on both PODs 3 and 7 compared with those exposed to
MAP of 50 mm Hg (LM). HM, High MAP; ST, standard MAP; LM, low MAP.
TABLE 2. Morris water maze test
Day 3Day 4Day 5 Day 6Day 7
Latencies (s)
High MAP
Standard MAP
Low MAP
Swimming speed (cm/min)
High MAP
Standard MAP
Low MAP
260 ? 59
178 ? 81*
243 ? 77
108 ? 37y
155 ? 109
150 ? 108
70 ? 55y
131 ? 102
111 ? 116y
39 ? 24y
126 ? 107*
110 ? 108*,y
36 ? 29y
126 ? 123*
91 ? 82y
22.6 ? 2.2
20.6 ? 3.0
21.6 ? 4.1
24.4 ? 3.8
24.6 ? 6.6
24.4 ? 5.6
26.7 ? 5.3
23.1 ? 4.6
23.9 ? 4.1
26.2 ? 4.6
22.1 ? 5.8
26.4 ? 6.6
23.6 ? 5.6
26.4 ? 4.8
25.4 ? 5.3
MAP, Mean arterial pressure. Values are mean ? standard deviation. *P<.05 compared with high MAP group. yP<.05 compared with baseline value in each group.
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therapeuticsaimedattreatingthesalvageableischemicpen-
umbra is being increasingly emphasized, which can be
achieved by deliberate elevation of blood pressure to pro-
mote collateral circulation.17,18Higher MAP during CPB
may also facilitate emboli clearance. On the other hand,
higher MAP during CPB may paradoxically increase the
delivery of embolic load to the brain and promote
hyperemiaandcerebral
conjunction, clinical studies addressing the relationship
between MAP during CPB and neurologic outcome
demonstrated conflicting results.10-12Most of the studies
areretrospective reviews
between lower MAP and adverse cerebral outcome. The
only existing randomized clinical trial revealed better
combined cardiac and neurologic outcome in the higher
MAP group, although there was not a statistically
significant difference in these outcomes when examined
individually.12Moreover,theaverageMAPinthehighpres-
sure group was actually significantly lower than their tar-
geted pressure. As the results of the current study indicate,
using higher MAP during CPB in the presence of CAE
was consistently associated with improved overall neuro-
logic score and shorter latencies in water maze compared
with lower MAP. Although standard MAP resulted in better
neurologic score than lower MAP, it was associated with
longer latencies in water maze compared with the high
MAP group. The neurologic scoring system was derived
to evaluate 4 different functions (general status, simple mo-
tor deficit, complex motor deficit, and sensory deficit) by
combiningelementsfromseveralpreviouslydescribedscor-
ing systems. Lesions in distinct brain regions, such as the
hippocampus, striatum,basalforebrain,cerebellum,andce-
rebral cortex, have been demonstrated to impair perfor-
mance in the Morris water maze. The test measures the
edemaformation.2,8,19
In
depictingtherelationship
latencytofindasubmergedplatformwithinthemaze,which
serves as a surrogate of impairment in visuospatial learning
and memory components of neurocognition.15Therefore,
thecurrentstudyclearlydepictsimprovedfunctionalneuro-
logic and neurocognitive outcome after CAE and CPB by
using higher MAP during CPB. These functional benefits,
however, were not accompanied by reduced cerebral infarct
volume.ThemainpotentialadvantageofusinghigherMAP
in regional ischemia would be to increase collateral flow to
the viable penumbral regions adjacent to areas embolized
during cardiac surgery, which would lead to decreased in-
farct volume. In our study, however, although the high
MAP group had the lowest infarct volume, this was not sta-
tistically significant. The discordance between function and
histology in this present study is, however, in agreement
with the findings of previous regional ischemia models in
which infarct size often poorly correlates with functional
outcome.20,21This discrepancy may be attributable to the
ability of air bubbles to not only occlude small arterioles
and cause distal ischemia
inflammatory cascade exacerbating the ischemic insult,
which was not assessed in this study, because higher MAP
may facilitate the clearance of emboli as well.22,23
Although cerebral perfusion is assumed to be constant
over a wide range of MAPs, substantial variability exists
at the lower limit of cerebral autoregulation, with some
studies reporting the lower limit at the range of 73 to 88
mm Hg.2,8Moreover, embolism itself caused regional
impairment of cerebral autoregulation in a dog model of
CPB supporting the dominant role of perfusion pressure
on cerebral blood flow potentially affecting the fate of the
deliveredairemboli.24Thehistologicfindingsofthecurrent
studydemonstrate thattheinfarctvolumeandespeciallythe
number of infarcted areas were similar among groups. Be-
cause the flow rate during CPB was maintained constant,
this implies that using higher MAP at least does not result
in an increased embolic load to the brain and standard or
even lower MAP during CPB is not advantageous in terms
of reduced embolic load delivery.
To delineate the effects of various MAP on neurologic
outcome after CPB with minimal confounders, we used
a well-established animal model of cerebral injury induced
by CAE during CPB, which enables long-term follow-up
and assessment.7However, even the most sophisticated an-
imal models will likely fail to simulate the clinical situation
completely, and several limitations should be acknowl-
edged. These include the health characteristics of animals
becausetheratsthatwere studiedwere healthy,whereashu-
mans who undergo CPB often have other comorbidities af-
fecting the cerebral vasculature. Also, species difference
regarding the susceptibility to ischemia–reperfusion-
induced neurologic injury should be taken into consider-
ation. Limitations inherent to the current rat model of
CPB combined with CAE are as follows. Because of
butalso toactivate
FIGURE2. Histologic outcome7 dayafter normothermicCPB combined
withCAEwasevaluatedbycerebralinfarctionvolume.Nostatisticallysig-
nificant differences were noted in respect to the different MAP manage-
ment (80 mm Hg, 60–70 mm Hg, and 50 mm Hg in the HM, ST, and
LM groups, respectively) during CPB. HM, High MAP; ST, standard
MAP; LM, low MAP.
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