Hindawi Publishing Corporation

BioMed Research International

Volume 2015, Article ID 981813, 10 pages
http://dx.doi.org/10.1155/2015/981813

Review Article
How to Perfuse: Concepts of Cerebral Protection during
Arch Replacement

Andreas Habertheuer,1,2 Dominik Wiedemann,2 Alfred Kocher,2

Guenther Laufer,2 and Prashanth Vallabhajosyula1
1
Division of Cardiovascular Surgery, University of Pennsylvania Medical Center, Philadelphia, PA 19104, USA
2
Department of Cardiac Surgery, Vienna General Hospital, Medical University of Vienna, 1090 Vienna, Austria

Correspondence should be addressed to Andreas Habertheuer; andreas.habertheuer@uphs.upenn.edu

Received 25 August 2015; Accepted 19 October 2015

Academic Editor: Francesco Onorati

Copyright © 2015 Andreas Habertheuer et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
cited.

Arch surgery remains undoubtedly among the most technically and strategically challenging endeavors in cardiovascular surgery.
Surgical interventions of thoracic aneurysms involving the aortic arch require complete circulatory arrest in deep hypothermia
(DHCA) or elaborate cerebral perfusion strategies with varying degrees of hypothermia to achieve satisfactory protection of the
brain from ischemic insults, that is, unilateral/bilateral antegrade cerebral perfusion (ACP) and retrograde cerebral perfusion
(RCP). Despite sophisticated and increasingly individualized surgical approaches for complex aortic pathologies, there remains
a lack of consensus regarding the optimal method of cerebral protection and circulatory management during the time of arch
exclusion. Many recent studies argue in favor of ACP with various degrees of hypothermic arrest during arch reconstruction and
its advantages have been widely demonstrated. In fact ACP with more moderate degrees of hypothermia represents a paradigm
shift in the cardiac surgery community and is widely adopted as an emergent strategy; however, many centers continue to report
good results using other perfusion strategies. Amidst this important discussion we review currently available surgical strategies of
cerebral protection management and compare the results of recent European multicenter and single-center data.

1. Introduction recent history of central neurologic events being important

It is the delicate anatomic site of the aortic arch, vascular
crossroad between body and brain, that intrigues cardiac sur-
geons as much as demanding both the finest technical skills
and thorough knowledge in neurophysiology to deal with
pathologies requiring surgical repair. Surgery for complex
aortic pathologies, that is, acute dissections and aneurysms
extending into the arch, remains one of the technically most
challenging endeavors of modern cardiac surgery [1]. Arch
reconstruction in the setting of acute type A dissection
has historically been associated with significant morbidity,
especially in terms of neurologic dysfunction, and mortality
due to ischemic end organ damage occurring during the cir-
culatory arrest period; however there is an appreciable recent
trend towards improvement. The International Registry for
Acute Aortic Dissections (IRAD) reported an in-hospital
mortality rate of 26% in 2009 [2] with urgency status and
preoperative risk factors and determinants of mortality and
neurologic outcome [3, 4]. Only recently the same registry
reported an in-hospital mortality rate of 19.7% for acute aortic
dissections cumulating the results of 4,428 patients and 28
IRAD centers [5].
Although postoperative results are important in all
aspects of cardiovascular surgery, neurologic and mortality
outcomes are especially significant in surgery of the thoracic
aorta, as these can reflect the circulation management applied
as well as the patient’s aortic pathology [6]. Reports from
several studies have shown that most permanent postop-
erative neurologic dysfunctions (defined as persistent focal
or global neurologic dysfunction with correlating structural
abnormalities upon cerebral computed tomography or mag-
netic resonance imaging) are actually caused by embolic phe-
nomena rather than the cerebral protective regimen applied.
Alternatively, transient neurologic dysfunction (defined as
2 BioMed Research International
the occurrence of postoperative, timely limited confusion,
transient motor weakness, seizure, or agitation without cor-
relation with imaging studies and with complete reversal at
the time of hospital discharge) has been more closely related
to cerebral ischemic times [6–13].
The introduction of profound hypothermia in the mid-
1970s by Griepp et al. allowing short periods of complete
circulatory arrest paved the way for modern arch surgery
requiring prolonged ischemic tolerance of the CNS for
extensive aortic repair extending into the transverse arch [14].
Over the past 2 decades various adjunctive techniques of
cerebral circulatory management have evolved to increase the
safety and duration of cerebral protection. These adjunctive
techniques all comprise distinct elaborate selective perfusion
protocols (unilateral or bilateral selective ACP and selective
RCP, resp.) in combination with various degrees of hypother-
mic circulatory arrest. The techniques of cerebral protection
during surgery of the aortic arch can be divided into those
aimed at suppressing the CNS metabolic demand and those
aimed at maintaining the metabolic supply during the time
of exclusion of the cerebral vessels. More specifically, current
protocols include DHCA alone [15, 16], selective RCP [7, 8,
12, 13, 17, 18], and selective ACP [19]. More recently, some
centers advocated for the use of more liberal circulatory
arrest temperatures and championed the merits of moderate
hypothermic circulatory arrest (MHCA) in combination with
selective ACP [11, 20–23]. A range of adverse postoperative
neurologic outcomes and early mortality is reported for each
of these techniques. Postoperative permanent neurologic
dysfunction is reported as 4.8% to 12.5% for DHCA [6, 9, 15],
2.4% to 7.1% for selective RCP/DHCA [6, 12, 17, 24, 25], 3.3%
to 9.6% for selective ACP/DHCA [6, 9, 11, 12, 19, 23, 26],
and 3.2% to 9.6% for selective ACP/modified MHCA [21,
23, 27]. Postoperative mortality is reported as 6.3% to 13.3%
for DHCA [9, 15], 2.9% to 10.1% for selective RCP/DHCA
[12, 17, 24, 25], 2.0% to 12.7% for selective ACP/DHCA [9,
11, 12, 19, 23, 26], and 9.4% to 11.5% for selective ACP/MHCA
[3, 21, 23, 27].
This paper reviews current state-of-the-art neuropro-
tective strategies and compares elaborate clinical regimens
focusing on the benefits of hypothermia and cold antegrade
cerebral perfusion. Recent trends in combining ACP with
steadily increasing mild-to-moderate hypothermic arrest are
discussed from various perspectives and under the light of
recent large-cohort trials and multicenter international meta-
analyses. The influence of the anticipated time of circulatory
arrest on the cerebral protection strategy is discussed as
widely adopted by the cardiac surgery community. Predictors
of adverse outcomes and determinants of transient neuro-
logical dysfunction and permanent neurological dysfunction,
respectively, are discussed to leave the reader with a thorough
understanding of the current literature as well as current
clinical practices.
2. Cerebral Protection: A Contemporary
Review of Available Surgical Strategies
There is no doubt that adequate cerebral protection during
aortic arch exclusion plays a key role in achieving successful
outcomes. However, it was a long road of trial and error for
cardiac surgery to develop both effective surgical techniques
to deal with pathologies of the thoracic aorta and effective
cerebral protection regimens. With the first introduction
of cardiopulmonary bypass and extracorporal circulation,
surgery of the aortic arch seemed to be an impossible under-
taking. During the 1950s, De Bakey, Crawford, and Coo-
ley in Houston introduced surgical techniques specifically
addressing pathologies of the thoracic and thoracoabdominal
aorta, including the transverse arch, and they were the first
to report on 6 cases of aortic dissection addressed surgically
[28]. However, those techniques did not gain widespread
acceptance by that time due to their high technical complexity
and limited postoperative outcomes in terms of mortality and
neurology. It took another decade for Borst and colleagues
[29] to adopt the use of profound hypothermia as an adjunct
to cardiopulmonary bypass for closure of an arteriovenous
fistula and for Griepp et al. [14] to report on their first routine
arch procedures, in profound hypothermia.
2.1. Hypothermic Circulatory Arrest. Since the discovery that
hypothermia induces neuroprotective effects, it has become a
widely adopted concept in cardiovascular surgery in general
and in surgery of the thoracic aorta specifically. Systemic
hypothermia reduces metabolic tissue rate thereby increasing
neuronal ischemic tolerance. Cerebral metabolism is progres-
sively depressed by approximately 6-7% per 1∘ C decline in
core body temperature [1]. The brain’s electrical activity starts
to decrease at mildly reduced temperatures (<33.5∘ C) and
ceases with profound hypothermia at 19.0∘ C to 20.0∘ C with no
electrical activity detectable upon assessment on electroen-
cephalogram. Accordingly, the core body temperature is a
significant determinant of cerebral metabolic demand and
oxygen consumption and, when compared to normothermia,
can be reduced anywhere in between >50% at 28∘ C (moderate
hypothermia) and >80% at 18∘ C (profound hypothermia),
respectively [4]. Thus, hypothermia alone prolongs the CNS
tolerance to ischemic insults during periods of circulatory
arrest. For some time it was tempting to assume that deep
hypothermia is sufficient to prevent any neurologic compli-
cation; however, this concept had to undergo some major
revisions [37]. Results from both experimental and clinical
studies suggest that cerebral metabolic suppression and thus
neurologic protection during profound hypothermia is less
complete than previously suspected [30, 38, 39]. Particularly
in the elderly and in patients with preexisting neurologic
dysfunctions, DHCA at intervals >25 min was associated with
TND, fine motor deficits, and prolonged hospital stays [1, 10].
More recently, Fischer et al. [40] reported that already after
30 min of HCA at 15∘ C the oxygen saturation of the frontal
cortex as measured on near infrared spectroscopy (NIRS)
drops below the relatively safe threshold of 60%, increasing
the risk of serious adverse outcomes (𝑝 = 0.038). Neurologic
complications occur more frequently following prolonged
DHCA of >40 min and may be transient or permanent [1, 10,
41].
In an attempt to calculate the safe durations of circulatory
arrest, McCullough et al. [30] used the cerebral metabolic
rate by oxygen consumption (CMRO2 ) as an estimate and
BioMed Research International 3

Table 1: Calculated safe durations of HCA at different temperatures with regard to cerebral metabolic rate and by McCullough et al. [30].

Temperature (∘ C)/level of hypothermia Cerebral metabolic rate (% of baseline) Calculated safe duration of HCA (min)
37 (normothermia) 100 5
30 (moderate) 56 (52–60) 9 (8–10)
25 (deep) 37 (33–42) 14 (12–15)
20 (profound) 24 (21–29) 21 (17–24)
15 (profound) 16 (13–20) 31 (25–38)
10 (ultra profound) 11 (8–14) 45 (36–62)

achieved comparable results of 31 min at 15∘ C. According to
this equation intervals could be extended to 45 min at 10∘ C
(Table 1):
CBF × cerebral AV oxygen difference
CMRO2 = (1)
100
In terms of prolonged hypothermic arrest, immediate postop-
erative coagulation disorders have been reported in literature
[42, 43]; however, there remains a lack of scientific proof for
this claim [44] and coagulopathy is much rather thought to be
triggered by prolonged bypass and extracorporal circulation
times than pure hypothermia. In their 2-center comparative
study of moderate versus deep HCA in 776 patients, Milewski
et al. [6] found no significant difference in the incidence of
reoperation for bleeding (profound versus deep HCA: 3.8
versus 4.3%; 𝑝 = 0.783). Similarly, Harrington et al. [44] did
not find an increased risk of postoperative bleeding following
DHCA.
2.2. Selective Cerebral Perfusion, ACP. In 1956, the Houston
group successfully used normothermic ACP to resect a large
aneurysm of the ascending thoracic aorta via the common
carotid arteries [45]. One year later De Bakey et al. [46]
reported on the first successful open arch surgery in an
attempt to remove a mycotic aneurysm involving both the
ascending aorta and the transverse arch using normothermic
cerebral perfusion via direct cannulation of both carotid
arteries and distal perfusion via cannulation of the right
femoral artery. However, this approach of bicarotid perfusion
in normothermia was soon to be abandoned due to a high
incidence of thromboembolism and consecutive adverse
neurological outcome. Following the introduction of routine
surgery under profound hypothermia and circulatory arrest
in 1975 by Griepp et al. [14], it took another 10 years
for Guilmet et al. in Europe and Kazui in Japan to raise
aneurysm surgery to the next level: the principle of antegrade
cerebral perfusion in combination with hypothermic circu-
latory arrest resulted in a significantly reduced incidence of
neurological complications [47, 48]. The new neuroprotective
strategy of “cold cerebroplegia” combined profound (6–12∘ C)
selective cerebral perfusion via the carotid arteries during
circulatory arrest in deep hypothermia (26∘ C) increasing
ischemic tolerance and allowing for longer operative times
while avowing profound hypothermic body core tempera-
tures. Simultaneously, the Stanford group published their
experience with selective ACP and low-flow cerebroperfu-
sion (30 mL/kg/min) at 26–28∘ C [49]. They used 3 distinct
cannulation/perfusion strategies: unilateral via a 14-F cannula
directly into the innominate artery with occlusion of both
left carotid and left subclavian artery, unilateral via the
left carotid, and bilateral via innominate and carotid artery
simultaneously.
When considering ACP, further variables need reflection
to achieve optimal cerebral protection, that is, target cere-
bral blood flow (CBF), blood pressure, hemodilution, and
intracranial pressure (ICP). At rest, 15% of the cardiac output
is estimated to constitute normal cerebral blood flow [50].
Experimental studies highlight the association of increased
ICP and consecutive requirements for higher perfusion pres-
sures with cerebral injury and adverse neurological outcome
[51] and high cerebral pump blood flows on HCA with high
ICPs and cerebral edema alleviating any protective effect [52].
Thus the pump flows and pressures during selective ACP
must be adequately balanced. More recently, Jonsson et al.
[53] reported on their experimental results of safe mini-
mal CBF during selective ACP and identified an ischemic
threshold of at least 6 mL/kg/min. Therefore, most centers
adopting ACP into their routine surgical practice perfuse
the brain at a rate of approximately 8–12 mL/kg/min and a
perfusion pressure of 40–60 mmHg at temperatures between
23 and 28∘ C [36, 37, 44, 50]. When considering optimal
cerebral blood flow another crucial variable is that autoreg-
ulation maintains both cerebral blood flow and pressure in
a physiologic spectrum under normal circumstances but the
organisms’ ability to do so is temperature dependent and is
dramatically decreased at 25∘ C and below [1].
2.3. Selective Cerebral Perfusion: RCP. Retrograde cerebral
perfusion might be used as an adjunct to hypothermic
circulatory arrest, yet the use of RCP is source of much
wider debate in the cardiac surgery community. The use of
RCP was originally reported by Mills and Ochsner [54] for
the management of massive arterial air embolism during
cardiopulmonary bypass in 1980. In 1990 Ueda et al. [55]
first described the routine use of continuous RCP in tho-
racic aortic surgery for the purpose of cerebral protection
during periods of circulatory arrest. Retrograde perfusion
is instituted by means of both bicaval cannulation and
arterial cannulation, respectively. Arterial cannulation can
be achieved directly via the distal ascending aorta, the left
axillary artery, or femoral artery, depending on both the
patient anatomy and extent of repair. In contrast to ACP, a
shunt-line between arterial and venous cannula is employed,
which remains clamped during the cooling period. When
4 BioMed Research International

Table 2: Best evidence papers.

Circulatory arrest
Number of Perfusion strategy Temperature (∘ C) In-hospital mortality PND 𝑛 (%) TND 𝑛 (%) Ref.
time (min), mean ±
patients 𝑛 (%)
SD or median (range)
1002 30.0 ± 2.0 36.0 ± 19.0 52.0 (5.0) 28.0 (3.0) 42.0 (4.0) [31]
412 25.7 ± 2.8 30 ± 15 29 (7.0) 15 (3.6) 21 (5.1) [32]
252 ACP/MHCA 26.3 ± 0.9 23.5 ± 15.8 20.0 (7.9) 13.0 (5.1) 32.0 (12.6) [33]
206 27.4 ± 1.6 39.0 ± 20.0 19.0 (9.2) 17.0 (8.3) [23]
47 25.9 ± 1.6 28.0 ± 6.0 7.0 (14.9) 1.0 (2.1) 10.0 (21.3) [34]
7038 24.2 ± 3.2 5.9% 7.0% 3.8% [35]
125 23.2 ± 1.2 34.1 ± 24.4 14.0 (11.2) 10.0 (8.0) 28.0 (22.4) [33]
91 ACP/DHCA 30.0 (14.0–92.0) 12 (13.0) 11 (12.0) 2 (2.0) [20]
88 21.6 ± 2.1 37.0 ± 20.0 12.0 (14.6) 7.0 (8.5) [23]
51 20.0 ± 2.2 31.5 ± 5.7 10.0 (19.2) 2.0 (3.8) 21.0 (40.4) [34]
242 bACP/DHCA 25.0 ± 4.0 23.0 ± 21.0 34 (14.0) 20 (8.3) 36 (14.9) [36]
123 uACP/DHCA 24.0 ± 3.0 22.0 ± 17.0 9 (7.3) 13 (10.6) 22 (17.9) [36]
1141 21.2 ± 3.7 7.2% 8.5% 4.4% [35]
122 RCP/DHCA 30.0 (14.0–88.0) 20 (16.0) 15 (12.0) 0 (—) [20]
51 23.0 ± 3.0 18.0 ± 12.0 4 (7.8) 8 (15.7) 9 (17.6) [36]
220 22.0 ± 2.0 15.0 ± 13.0 25 (11.4) 31 (14.1) 28 (12.7) [36]
DHCA
116 36.0 (12.0–88.0) 30 (26.0) 27 (23.0) 1 (1.0) [20]

satisfactory hypothermia is achieved (depending on the
institution’s guidelines), the arterial line is clamped to engage
into circulatory arrest, the superior vena cava (SVC) is snared,
and the shunt-line is opened to achieve venous cerebral
perfusion, in a retrograde fashion. RCP is usually adjusted
to 100–500 mL/min to maintain a central venous pressure of
15–25 mmHg [56]. Desaturated blood from the arch vessels is
returned to the heart lung bypass via a cardiotomy sucker.
There is evidence that RCP may accomplish neuropro-
tection by providing cerebral metabolic support, retrogradely
expelling atheromatous and gaseous emboli from the cere-
bral vasculature and maintaining cerebral hypothermia [57].
However, there remains the concern that very little of the
perfusate actually reaches the cerebral microvasculature to
provide adequate neuroprotection. In experimental studies
led by Ehrlich et al. [58] from the Mount Sinai Medical
Center in New York, retrograde cerebral perfusion provided
negligible flow through brain capillaries in pigs. Calculations
based on the number of fluorescent microspheres trapped in
the brain showed flows as low as 0.02 ± 0.02 mL/min/100 g
brain parenchyma. Less than 13% of retrograde superior vena
caval inflow blood returned to the aortic arch.
3. Cerebral Protection: A Strategic
Comparison of Current Clinical Practice
Best evidence papers are shown in Table 2. Based on the
above reasoning, cerebral protection during arch exclusion
may potentially be achieved using various surgical techniques
and neuroprotective principles. The therapeutic armamen-
tarium ranges from DHCA, via ACP with moderate to deep
hypothermic circulatory arrest, which might be extended
from unilateral to bilateral cerebral perfusion (Figure 1) to
RCP with deep hypothermic arrest. Recent data from Euro-
pean surveys suggest that moderate hypothermia in combi-
nation with selective ACP as opposed to deep hypothermic
arrest is an emergent strategy and in fact is the strategy more
often used [31, 59].
3.1. Antegrade versus Retrograde with DHCA: Does It Matter?
Based on conflicting anatomical, clinical [20], and experi-
mental animal data [58] the effectiveness of RCP to perfuse
the brain to an extent as to support aerobic metabolism is still
questioned.
Misfeld et al. [36] from the Leipzig Heart Center recently
reported on their 6-year, 636-patient experience. They found
statistically significant differences in their circulatory arrest
times dependent on the perfusion strategy applied: 22 ± 17
minutes for unilateral ACP, 23 ± 21 minutes bilateral ACP,
18 ± 12 minutes for RCP, and 15 ± 13 minutes DHCA (𝑝 <
0.001). The use of any form of ACP (versus DHCP alone or
RCP) was identified as protective against the development of
PND by multivariate analysis (odds ratio: 0.4; 95% CI: 0.2 to
0.7; 𝑝 = 0.005) despite longer circulatory arrest times. Early
mortality for the entire cohort was 11% (𝑛 = 72) and was
not statistically different between patients receiving different
modes of cerebral protection (𝑝 = 0.2). Multivariate analysis
identified acute type A aortic dissection (OR: 2.4; 95% CI:
1.4 to 4.2; 𝑝 = 0.001), history of preoperative myocardial
infarction (OR: 2.4; 95% CI: 1.07 to 5.4; 𝑝 = 0.03), total aortic
arch replacement with elephant trunk (OR: 1.9; 95% CI: 1.07
to 3.5; 𝑝 = 0.03), and duration of CPB (OR: 1.011 per minute
of CPB; 95% CI: 1.007 to 1.01; 𝑝 = 0.01) as independent
predictors of early mortality.
BioMed Research International
(a) (b)
(c) (d)
Figure 1: Various techniques for unilateral and bilateral ante-
grade cerebral perfusion. (a) Schematic presentation of an isolated
ascending aortic aneurysm. (b) Unilateral ACP using direct arterial
cannulation of the axillary artery. (c) Bilateral ACP with perfusion
of the axillary artery and the left common carotid artery with a
balloon cannula. (d) Antegrade bicarotid perfusion with two balloon
occlusion cannulas.
Milewski et al. [6] from the Hospital of the University
of Pennsylvania, Philadelphia, found slightly contradicting
results in terms of PND when comparing their 2-center,
776-patient experience. They found no significant differ-
ence in permanent neurologic deficit, temporary neuro-
logic dysfunction, or renal failure, between RCP/DHCA
and ACP/MHCA. Mean cerebral ischemic time and vis-
ceral ischemic time differed between RCP/DHCA and
ACP/MHCA (𝑝 < 0.001). Increasing arch reconstruction
times were associated with a worse neurologic outcome
irrespective of the technique applied. For arch reconstructive
times less than 45 minutes, univariate analysis revealed
no significant difference in permanent neurologic deficit
between RCP/DHCA (2.8%) and ACP/MHCA (3.2%). Simi-
lar results could be shown for TND.
Ganapathi et al. [60] from the Duke University Medical
Center retrospectively compared their 440-patient cohort
5
experience. An unadjusted comparison of the primary end-
points did not reveal any differences in neurologic compli-
cations (10.8% ACP versus 7.5% RCP; 𝑝 = 0.36), 30-day in-
hospital mortality (3.6% ACP versus 2.5% RCP; 𝑝 = 0.61),
or composite 30-day in-hospital major morbidity (17.5% ACP
versus 15.0% RCP; 𝑝 = 0.59).
In total, those studies [6, 36, 60] comprised 1852 patients
with unequivocal results regarding primary neurological
endpoints.
3.2. Unilateral versus Bilateral Cerebral Perfusion. Antegrade
cerebral perfusion became the method of choice for cerebral
protection during aortic arch surgery in many centers in the
past decade [9, 26, 61, 62]. Controversies exist with regard
to unilateral versus bilateral ACP. This question becomes
increasingly imminent when considering pathologies like
carotid artery stenosis, previous stroke, or anatomical vari-
ants like incomplete circle of Willis with missing anterior of
posterior communicating arteries.
In a recent meta-analysis comprising 5100 patients con-
ducted by Angeloni et al. [63, 64] twenty-eight studies were
analyzed with a total of 1894 patients receiving unilateral
ACP versus 3206 receiving bilateral ACP. Pooled analysis
showed similar rates of 30-day mortality (8.6% versus 9.2%
for unilateral ACP and bilateral ACP, resp.; 𝑝 = 0.78), PND
(6.1% versus 6.5%; 𝑝 = 0.80), and TND (7.1% versus 8.8%;
𝑝 = 0.46).
Previous studies comparing unilateral with bilateral ante-
grade perfusion [65–67] are discordant and ineffectual to
reach a final conclusion [64]. The first study published in 2006
[66] involved only 65 patients. The stunning differences in
mortality rates between bilateral ACP (12%) and unilateral
ACP (1%) that could only be reached without propensity
score matching were soon put into perspective if correct
statistical measure was applied. The second study [67] (𝑛 =
280) found only an improved quality of life in patients with
bilateral ACP but not significantly lower rates of mortality
and/or neurologic complications.
The last report of the German Registry for Acute Aortic
Dissection Type A [65] published in Circulation and includ-
ing 1081 patients showed equivalent outcomes for bilateral
ACP versus unilateral ACP. In accordance with this latest and
largest comparative study, there is no difference in perform-
ing cerebral protection with bilateral ACP or unilateral ACP.
Those results could be supported by Vienna group of
Wiedemann et al. [20]. They found no difference in the 30-
day mortality (𝑝 = 0.59) and PND incidence (𝑝 = 0.699).
The circulatory arrest time was slightly longer for the bilateral
ACP group (29 minutes, range: 11–74 versus 33 minutes,
range: 15–113; 𝑝 = 0.023). Kaplan-Meier analysis revealed
no significant differences in long-term survival between the
bilateral ACP and unilateral ACP groups (1-, 3-, and 5-year
survival rate: 90%, 81%, and 73% versus 79%, 77%, and 77%,
resp.; 𝑝 = 0.885).
3.3. Moderate versus Deep Hypothermia. DHCA has been
widely used with or without adjunctive cerebral perfusion
and is considered by many experts to be the standard of care
for surgical repair of acute aortic dissection [14, 15, 55, 68].
6 BioMed Research International
However, because of the potential side effects of profound
hypothermia on bypass, there has been increasing interest in
performing aortic arch surgery using warmer temperatures
with selective antegrade cerebral perfusion [69–72]. Avoid-
ing profound hypothermia is associated with a reduction
in bypass times, postoperative bleeding, requirement for
blood transfusions in the clinical setting, and a reduction in
endothelial cell dysfunction and neuronal apoptosis in the
experimental setting [33, 73–75]. Consequently, a growing
tendency to increase the body temperature during circulatory
arrest with ACP has recently been reported from various
institutions [31]. Studies in animal models have convincingly
shown that cerebral oxygen consumption decreases by 50%
of baseline at 28∘ C core body temperature. Further cooling
does not effectively decrease brain oxygen consumption and
neuronal metabolism [76]. Moreover, profound hypother-
mia impairs cerebral autoregulation and vasoconstriction
decreases regional cerebral blood flow in selective ACP [77].
When comparing profound versus moderate hypother-
mic arrest with selective ACP during acute aortic dissection
repair, Algarni et al. [59] from the Toronto General Hos-
pital found that moderate hypothermia was independently
associated with a lower risk of a composite outcome of
mortality and major adverse cardiac and cerebrovascular
events. The composite outcome of mortality, low cardiac
output syndrome, or stroke was higher in the profound
hypothermia group (52.8% versus 24%, 𝑝 < 0.001) and
cardiopulmonary bypass times and blood transfusions were
significantly higher (𝑝 = 0.04). The authors even concluded
that profound hypothermia was an independent predictor of
composite outcome by multivariable analysis (odds ratio: 7.6;
95% confidence interval: 3.0–21.1).
Kamiya et al. [33] in their propensity score analysis
on 377 patients found no significant differences in mortal-
ity or morbidity between deep and moderate lower body
circulatory arrest, in either the entire study cohort or the
propensity-matched cohort. Results suggest that moderate
lower body circulatory arrest can be safely performed for
aortic arch repair and postoperative inflammatory responses
tended to be lower in patients with moderate lower body
circulatory arrest than those with deep lower body circulatory
arrest. Zierer et al. [31] reported their impressive 1002-patient
single-center experience in 2012 using selective ACP with
mild (28–30∘ C) hypothermic arrest for arch replacement and
stated that the use of selective ACP makes deep hypothermia
nonessential for aortic arch replacement. Their results suggest
that ACP/MHCA can be safely applied to complex aortic arch
surgery even in a subgroup of patients with up to 90 minutes
of ACP. Very recently Leshnower et al. [23] from Emory
University in Atlanta found in their cohort of 288 patients
who underwent axillary artery cannulation and selective uni-
lateral antegrade perfusion in moderate hypothermic versus
deep hypothermic arrest (DHCA 21.6 ± 3.1∘ C versus MHCA
27.4 ± 1.6∘ C, 𝑝 < 0.01) no differences in cardiopulmonary
bypass, cross-clamp, or HCA times. Mortality was 14.6%
for DHCA patients and 9.2% for MHCA patients (𝑝 =
0.17). There was no significant difference in stroke, tem-
porary neurologic dysfunction, or dialysis-dependent renal
failure.
4. Discussion
The optimal cerebral protection strategy to prevent brain
injury during complex aortic arch surgery is an area of
active interest. It is generally accepted that neurologic com-
plications are one of the most devastating complications
in cardiovascular surgery [36]. The incidence of PND in
patients undergoing aortic surgery is reported to be 5% [78]
but is approximately twice as high in patients undergoing
aortic arch surgery [11, 79, 80]. It is well known that PND
is associated with longer ventilation times and prolonged
intensive care unit and hospital lengths of stay [81]. Therefore,
the optimal strategy to provide best possible neuroprotection
even in complicated aortic pathologies and long ischemia
times becomes increasingly important. One of the most
challenging aspects of comparing patient cohorts with acute
dissections requiring circulatory arrest is the uncertainty
of the extent of aortic replacement and other concomitant
procedures that are required to ensure patient survival. Often
these decisions are made intraoperatively after the aortic
intima has been examined from the level of the valve to the
left subclavian artery. Therefore, the operations performed
to repair acute dissections can be highly variable, making
it difficult to create homogenous groups of patients for the
purpose of comparing various perfusion strategies.
Probably the most essential question to address is which
cerebral protective strategy to offer for which patient pop-
ulation and under which circumstances. Important vari-
ables are the extent of aortic disease (hemiarch versus total
arch), the urgency of surgical intervention (dissection with
malperfusion versus chronically expanding aneurysm), and
the expected duration of circulatory arrest.
The Emory group recently analyzed their experience of
708 patients who had undergone aortic arch surgery since
2004 [71]. Five hundred patients had hemiarch replacement
at temperatures of 22∘ C with unilateral ACP. Leshnower et
al. [71] propensity matched 277 patients who had undergone
hemiarch replacement at more moderate temperatures of
28.6∘ C with 233 patients who had undergone hemiarch
replacement at an average temperature of 24.3∘ C. They found
similar operative mortalities for elective and urgent cases, no
difference in the incidence of temporary neurological deficits,
and a similar reoperation rate for bleeding complications.
However, patients with moderate versus deep temperature
management had a significantly lower rate of PND (2.5 versus
7.2%; 𝑝 = 0.01), which was confirmed by propensity score
analysis (odds ratio of 0.28; 𝑝 = 0.02). In fact, many are
progressively moving towards the new perfusion strategy
of ACP and more moderate perfusion temperatures. This
paradigm shift is driven by the promising results advocating
the routine use of moderate-to-mild (28–35∘ C) hypothermia
during aortic arch operations. Consequently, a growing ten-
dency to increase the body temperature during circulatory
arrest with ACP has recently been reported from various
institutions [31]; however, care has to be taken regarding safe
ischemic limits. The temperature relationship for the safe
interruption of blood flow has been considered similar for
the brain and the spinal cord; however, the absolute times for
safe ischemia for the brain and spinal cord differ because of
BioMed Research International
a 4-fold difference in baseline metabolism at normothermia
of 37∘ C (5 min for the brain versus 20 min for the spinal cord)
[76]. This has to be considered given the fact that not only
the brain has to be protected during circulatory arrest and
as shown by Etz et al. [82] moderate hypothermia (28∘ C)
clearly has safety limits with regard to spinal cord integrity.
Furthermore high body core temperatures are difficult to
correct during the procedure—in the case of unpredicted
technical problems—and only a minority of experienced
centers so far use additional distal perfusion.
In terms of prolonged circulatory arrest (>40 min) a study
conducted by the Bern University Hospital in Switzerland
[67] including 129 patients with unilateral and 162 patients
with bilateral perfusion suggests an advantage for bilateral.
Malvindi et al. [83] also concluded that bilateral ACP may be
favorable in cases of prolonged circulatory arrest durations
(>40–50 min) after comparing several studies on aortic arch
surgery, including more than 3500 patients treated with either
unilateral (𝑛 = 599) or bilateral (𝑛 = 2949) ACP.
There is evidence that bilateral ACP with hypothermic
arrest is currently the best method for cerebral protection,
particularly in more complex cases of total arch replace-
ment (>30–40 min), but unilateral ACP may be adequate
if circulatory arrest is limited [36]. Given the importance
of neuroprotection, recent published data have called for a
consensus regarding cerebral protection during aortic arch
surgery, specifically pertaining to the optimal adjunctive cere-
bral perfusion strategy and patient temperature. A uniform
terminology of the different stages of hypothermia to allow
for better comparison as well as a clear definition of the extent
of the procedure to be undertaken (e.g., hemiarch/total arch;
moderate hypothermia/deep hypothermia) appears essential
to facilitate discussion among experts in the field and helps
guide future path of modern arch surgery.
When DHCA gained widespread acceptance as the stan-
dard approach for arch surgery, antegrade cerebral perfusion
(ACP) as an adjunct to deep hypothermic arrest began its
triumphal march offering both improved neuroprotection
and operative outcomes. This encouraged the use of ACP
in combination with steadily increasing core body tem-
peratures, cumulating in the advocation of moderate-to-
mild temperatures up to 35∘ C. The impetus for progressive
temperature elevation was the limitation of adverse effects of
profound hypothermia and the most welcome side effect of
significantly shorter cooling and rewarming periods, poten-
tially alleviating systemic inflammatory responses, that is,
impaired coagulation. However, the safe limits of prolonged
circulatory arrest have not yet been clearly defined. In light of
those recent developments, trading effective neuroprotection
and excellent outcomes for the risk of prolonged “warm”
ischemia might constitute a “new” risk factor, jeopardizing
central nervous system integrity, especially of those under-
going extensive arch repair or with previous neurologic
deficits.
Despite sophisticated and increasingly individualized
surgical approaches for complex aortic pathologies, there
remains a lack of consensus regarding the optimal method of
cerebral protection and circulatory management during the
time of arch exclusion.
7
Conflict of Interests
The authors declare that there is no conflict of interests
regarding the publication of this paper.
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