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\begin{document}

\title{Hypothermic Circulatory Arrest Time affects neurological outcomes of
Frozen Elephant Trunk for Acute Type A Aortic Dissection: a systematic
review and meta-analysis}



\author[1]{Mostafa Mousavizadeh}%
\author[1]{Mahdi Daliri}%
\author[1]{Hadi Abo Aljadayel}%
\author[2]{Mohammed Idhrees}%
\author[1]{Yousef Rezaei}%
\author[3]{Mohamad Bashir}%
\author[1]{Saeid Hosseini}%
\affil[1]{Rajaie Cardiovascular Medical and Research Center}%
\affil[2]{SRM Institutes for Medical Science Vadapalani}%
\affil[3]{Royal Blackburn Hospital}%


\vspace{-1em}



  
  \date{May 18, 2024}


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\selectlanguage{english}
\begin{abstract}
Background: The treatment of complex thoracic aorta pathologies remains
a challenge for cardiovascular surgeons. After introducing Frozen
Elephant Trunk (FET), a significant evolution of surgical techniques has
been achieved. The present meta-analysis aimed to assess the efficacy of
FET in acute type A aortic dissection (ATAAD) and the effect of
circulatory arrest time on post-operative neurologic outcomes. Methods:
A standard Preferred Reporting Items for Systematic Reviews and
Meta-Analyses search was conducted for all observational studies of
patients diagnosed with ATAAD undergoing total arch replacement with FET
reporting in-hospital mortality, bleeding, and neurological outcomes. A
random-effect meta-analysis was performed using STATA software
(StataCorp, TX, USA). Results: Thirty-five studies were eligible for the
present meta-analysis, including 3211 patients with ATAAD who underwent
total arch replacement with FET. The pooled estimate for in-hospital
mortality, postoperative stroke, and spinal cord injury were 7\% (95\%
CI 5 -- 9; I2 = 68.65\%), 5\% (95\% CI 4 -- 7; I2 = 63.93\%), and 3\%
(95\% CI 2 -- 4; I2 = 19.56\%), respectively. Univariate meta-regression
revealed that with increasing the duration of hypothermic circulatory
arrest time, the effect sizes for postoperative stroke and SCI enhances.
Conclusions: It seems that employing the FET procedure for acute type A
dissection is associated with acceptable neurologic outcomes and a
similar mortality rate comparing with other aorta pathologies. Besides,
increasing hypothermic circulation arrest time appears to be a
significant predictor of adverse neurologic outcomes after FET.%
\end{abstract}%



\sloppy


\textbf{Introduction}

Utilizing ''elephant trunk'' (ET) prosthesis first described by Borst et
al. in 1986 for aneurysmal aortic disease revolutionized treatment
strategies in managing patients with complex arch and descending aorta
pathologies (1). Antegrade open stent-grafting of the descending aorta
described in 1996 became the cornerstone of further advancement in the
arch and proximal descending aorta (2). In the early 2000s, a
custom-made hybrid prosthesis called frozen elephant trunk (FET) had
been developed (3). Subsequently, the FET technique has been extensively
engaged in various acute and chronic pathologies of the thoracic aorta.

Replacement of the ascending aorta is a well-researched conventional
treatment of acute Type A aortic dissection (ATAAD); however, residual
pathology or dissection in the arch or downstream descending aorta may
require additional treatment with high-risk redo procedures. On the
other hand, more extensive aorta replacement (e.g., employing FET)
carries the risk of complications. Therefore, there is still an ongoing
debate over the optimal indication and FET use in ATAAD. One of the main
complications associated with FET is neurologic events, particularly
spinal cord injury (SCI) and stroke. The incidence rate of permanent or
transient ischemic SCI after conventional ET has been reported between
0.4\% and 2.8\% in previous reports (4).

In contrast, the incidence of SCI after FET ranged between 8\% in
multicenter studies (5) and 20\% in single-center reports (6). Several
contributors (i.e., length of the device and distal circulatory arrest
time) have been proposed to explain SCI and stroke observed after FET
procedure, mainly derived from observational studies on patients with
diverse aortic pathologies. Previous meta-analyses performed on primary
studies included a mixture of cohorts diagnosed with acute or chronic
dissection which differ in various aspect of treatment options and also
comorbid diseases (7). Herein, we evaluated the pre-and intra-operative
characteristics of patients with ATAAD undergoing the FET procedure and
their associations with postoperative outcomes.

\textbf{Methods}

\textbf{Literature Search and design}

The review team developed the literature search strategy. Studies
related to the subject were identified by searching electronic databases
and bibliographic reference lists of relevant articles. An electronic
search in PubMed/Medline, EMBASE, Scopus, and Web of Science databases
was conducted from their beginning to June 2020 to identify studies
reporting the outcomes of FET procedure in cohorts of patients diagnosed
with ATAAD. A combination of controlled vocabulary and free text terms
(utilizing Boolean operators) was used to interrogate the databases. The
search was limited to English-language articles and human studies. The
search strategy is presented in supplementary table 1. The present study
is conducted and reported following the Preferred Reporting Items for
Systematic reviews and Meta-Analyses (PRISMA) guidelines (8).

\textbf{Eligibility Criteria of Studies and Data Extraction}

Studies ascertained eligibility if those provided total aortic arch
replacement with FET through median sternotomy in the ATAAD patients.
Proximal arch or hemiarch procedures (i.e., procedures that did not
replace the entire arch) and other pathologies (i.e., aneurysm) were
excluded. Additional inclusion criteria included all observational
studies reporting more than 20 patients undergoing the FET procedure and
providing data for postoperative outcomes. Studies reported a
combination of patients with varying pathologies was excluded if pre-
and post-operative data were not reported for ATAAD individually. To
exclude duplicated or overlapped populations from the same institution,
these publications were identified. The latest report or those with the
largest sample size without overlapped time were included in the final
analysis.

After excluding case reports, conference presentations, editorials,
expert opinions, and duplicated evidence, all titles and abstracts were
reviewed by two independent reviewers (MM and YR), and irrelevant ones
were excluded. The full-text articles were retrieved in those that met
our inclusion criteria (Figure 1). The data extraction was independently
performed by two authors (MM and YR). If necessary, discrepancies were
resolved by consensus or discussion with the senior and corresponding
authors (MB and SH). The extracted data included baseline
characteristics (i.e., age, sex, cardiovascular risk factors, smoking
history, prior surgery, chronic kidney disease, and history of stroke).
Procedure-related features (i.e., concomitant procedures, procedure
duration, cardiopulmonary bypass time, circulatory arrest time,
cannulation site, and stent type) and postoperative follow-up outcomes
(i.e. mortality, acute kidney injury, post-operative bleeding, transient
or permanent stroke, and spinal cord injury) were also extracted and
recorded.

\textbf{Statistical analysis}

Study features and patients' characteristics were reported. Data are
presented as number (percentage) or mean and 95\% confidence interval
(CI), as appropriate. The pooled estimated prevalence of each outcome
was calculated utilizing a random-effect model, which is more
generalized when potential heterogeneity among studies is present. All
values were presented with 95\% confidence intervals (CI), and the
weighted prevalence of outcomes is depicted as a forest plot. We
assessed the homogeneity of incidence of events across studies using
Cochran Q for each of the outcomes. Also, to test for heterogeneity,
Higgins \emph{I\textsuperscript{2}} was
calculated.\emph{I\textsuperscript{2}} represents the percentage of
total variation across studies that can be attributed to heterogeneity
rather than chance. The \emph{I\textsuperscript{2}} value 0\% indicates
no heterogeneity, 25\% low heterogeneity, 50\% moderate heterogeneity,
and 75\% high heterogeneity (9). Funnel plots were drawn for all
extracted outcomes to assess publication bias. Visual inspection of
asymmetry was assessed to check for publication bias, and Egger's test
was also conducted to evaluate small-study effects on the pooled
estimated outcome (10). Moreover, Moment base univariate meta-regression
was performed to assess the effects of hypothermic circulatory arrest
(HCA) time on neurologic outcomes (stroke and SCI), depicted as bubble
plot. All data were analyzed using STATA software (StataCorp, TX, USA).

\textbf{Results}

\textbf{Baseline characteristics and procedural features}

After reviewing shreds of evidence, a total of 35 studies including 3211
patients were entered into the quantitative analysis (Figure 1)(11-44).
The median size of reviewed reports was 72 patients (interquartile range
38 -- 122). The majority of studies were performed in Chinese
institutions, 19 studies including 2026 patients. The patients' median
age was 52 years (interquartile range 48 -- 59). The frequency of male
and female genders were 2268 (74.6\%) and 773 (25.4\%), respectively,
reporting by 34 studies. Smoking (208 patients, 43.1\%) and hypertension
(1827 patients, 70\%) were reported by seven and 29 studies. Other
baseline characteristics are summarized in Table 1 and Supplementary
Table 2.

Emergent/urgent surgery was implemented in 952 patients, reported by 11
studies. The cannulation site was applied in the innominate artery and
the axillary artery in 3 studies (245 patients) and 20 studies (1896
patients), respectively. Bentall and David procedures were performed in
566 of 2152 patients (22 studies) and 219 of 1550 patients (14 studies).
The ascending aorta replacement was applied in 364 patients, reporting
by six studies. The type of stent deployed in the descending aorta
included Cronus (MicroPort Medical, Shanghai, China), E-vita (JOTEC
GmbH, Hechingen, Germany), Thoraflex (Vascutek, Inchinnan, UK), and
Frozenix (Japan Lifeline, Tokyo, Japan) that those were implanted in
1413, 315, 250, and 161 patients, respectively. The stent type in other
patients is also provided in Table 2. Only 342 patients in four studies
reported the use of near-infrared spectroscopy during surgery. The
median of HCA time was 31 min (interquartile range 25 -- 35), reported
by 19 studies. Other surgery-related features are summarized in Table 2.

\textbf{Follow-up outcomes}

The pooled estimates of postoperative stroke and SCI were 5\% (95\% CI 4
-- 7; \emph{I\textsuperscript{2}} = 63.93\%) and 3\% (95\% CI 2 -- 4;
\emph{I\textsuperscript{2}} = 19.56\%), respectively (Figure 2). The
pooled estimates of acute kidney injury, bleeding, and in-hospital
mortality were found to be 12\% (95\% CI 9 --
15;\emph{I\textsuperscript{2}} = 86.65\%), 6\% (95\% CI 3 --
8;\emph{I\textsuperscript{2}} = 71.05\%), and 7\% (95\% CI 5 --
9;\emph{I\textsuperscript{2}} = 68.65\%), respectively (Figure 3).

\textbf{Publication bias and meta-regression}

The visual inspection of Funnel plots revealed asymmetries among studies
reporting major postoperative outcomes (Supplemental Figure 1). Based on
the Egger's test, there were significant for all major outcomes,
including postoperative stroke (p \textless{}0.0001), SCI (p = 0.004),
acute kidney injury (p \textless{}0.0001), bleeding (p
\textless{}0.0001), and in-hospital mortality (p \textless{}0.0001). The
univariate meta-regression showed significant relationships between the
HCA time and the development of postoperative stroke (p = 0.04) and SCI
(p = 0.05). Also, the bubble plots revealed that with increasing HCA
time, the effect sizes for postoperative stroke and SCI enhance. The
regression line provides a good fit for the data because most studies
are relatively close (Figure 4).

\textbf{Discussion}

Nowadays, the most common indication for FET is chronic or acute
dissection that involved the ascending aorta followed by degenerative
atherosclerosis aneurysm (45). The FET procedure is now potentially
indicated for varying aortic arch and descending aorta pathologies,
including chronic or acute dissection as well as aneurysmal pathologies.
It is well established that each pathology is associated with specific
risk profiles, affecting short- and long-term outcomes after aortic arch
repair (46). In addition to the type of aorta pathology, cannulation
site, concomitant surgery, neurological monitoring, the method surgeon
approached to the left subclavian artery, and intra-operative measures
would change the course of postoperative outcomes. So, we herein
conducted a systematic review focused on the outcome of FET deployment
in ATAAD patients who needs total arch replacement, taking into account
peri-operative features.

The present meta-analysis, including 35 studies with 3211 patients
diagnosed with ATAAD, revealed that the FET procedure in this subset of
patients was associated with 3\% (95\% CI 2 -- 4) and 5\% (95\% CI 4 --
7) of postoperative SCI and stroke, respectively. Additionally, the
pooled rate of in-hospital mortality was found to be 7\%. A recent
meta-analysis by Preventza et al. demonstrated a total pooled operative
mortality of 8.8\% from 34 reports on patients undergoing FET procedure
(7) comparable with rates reported by other meta-analyses (47, 48). In
the present meta-analysis, we found that the pooled estimate of
in-hospital mortality was 7\% (95\% CI 5 --
9;\emph{I\textsuperscript{2}} = 68.65\%) which is less than previous
reports. One possible explanation is that they estimated operative
mortality (variously reported operative, 30-day, and in-hospital), not
specifically in-hospital mortality estimated in our analysis. Another
drawback regarding previous reports is that they included heterogenous
populations with different pathologies or chronicity of dissection in
the final analysis. Although they tried to address this issue by
subgroup analysis (7), only 12 studies on patients with ATAAD have been
compared with other pathologies (14 studies). Besides, recent
meta-analyses (47, 48) included a mixture of patients who underwent
total arch replacement, proximal, and hemi arch replacement; meanwhile,
they reported a higher mortality rate. It is noteworthy that total arch
replacement is a more complex surgery. Hence, total arch replacement in
an urgent or emergent situation inheres with a greater peri-operative
mortality rate. The observed discrepancy and declining mortality rate
during recent years may be attributed to improved diagnostic modalities,
enhanced experience of aortic centers and aortic surgeons, and
well-established monitoring techniques (49).

Despite the improved results of extensive aortic surgery since the
introduction of HCA and brain protection techniques, these procedures
are still associated with neurologic impairments. Neurologic
complications such as stroke and SCI are the most disastrous
complication of aortic surgery, especially after thoracic and arch
procedures, with a high burden of morbidity and health-related costs
(50). In a single-center series of 25 patients who underwent thoracic
aorta aneurysm repair with FET, 24\% of patients developed SCI after
surgery which is a significant rate of this dreaded complication (6). On
the other hand, data from multicenter studies revealed a considerably
lower rate of stroke and SCI. A report from the International E-vita
Open Registry (IEOR) indicated a 6\% and 8\% incidence rate of stroke
and SCI, respectively (5). We found that the pooled estimate for overall
stroke reported in 24 studies was 5\%, and 3\% for SCI reported in 16
studies. A different definition of SCI and diagnostic criteria and
distinct baseline characteristics could explain the inconsistency
observed amongst previous reports. However, the impact of the indication
of total arch replacement (ATAAD versus chronic dissection and aneurysm)
is arguable. This was the main rationale behind including only studies
of patients diagnosed with ATAAD in the present meta-analysis. Several
hypotheses proposed to explain SCI after FET, including the level of
distal landing zone of the stent, hemodynamic instability after
cardiopulmonary bypass, age, compromising segmental spinal cord blood
supply, and HCA time (6, 51, 52). The effect of the distal stent landing
zone on the incidence of SCI has been explored previously; however,
different results indicated the possibility of other contributing
factors (6, 53). We examined the effect of HCA time on the development
of neurologic adverse events. Nowadays, isolated HCA as a protective
strategy is not recommended (36). Recent publications indicate that
milder hypothermic circulatory arrest in combinations of routine
selective antegrade cerebral perfusion improves brain and end-organ
protection (54). Unfortunately, we could not evaluate the relationship
between core temperature during arch replacement and neurologic events
due to lack of data and inconsistency between reports regarding
measurements. A total of 19 studies reported circulatory arrest time,
and we observed that with a longer duration of circulatory arrest time,
a higher rate of neurologic adverse events would be expected. A similar
concern regarding the role of HCA time has been raised by Tian et al.
while they found a significant strong positive linear relationship
between mortality and circulatory arrest time (r = 0.715) (48). Hence,
companies and surgeons endeavor to simplify the anastomosis of the
prosthesis to the distal aortic stump allowing less HCA time and
starting rewarming swiftly (55). In addition to the HCA time, the degree
of hypothermia and cerebral perfusion method to achieve the best
neurologic outcome is of paramount (56). In the present series of
studies included in the meta-analysis, only four authors did not
mentioned the cerebral perfusion method, while in all other reports
antegrade cerebral perfusion has been utilized.

\textbf{Limitations}

The present findings are limited by several key constraints which should
be considered when interpreting the results. Firstly, all the studies
were retrospective, and the main results are based on non-randomized
observational studies, which impose a considerable selection bias.
Secondly, due to the lack of a standard reporting schema for total arch
replacement using FET, some important data are missing, which
incapacitates us to perform subgroup analysis.

\textbf{Conclusions}

In summary, the FET procedure provides an optimal option with an
acceptable rate of mortality and adverse neurologic events. As FET is
gaining more popularity for aortic arch and proximal descending aorta
procedures, the magnitude of operative adjuncts on the outcomes became
more apparent. A lot of effort must be put into reducing HCA time and
improving device profile to achieve the minimum time for graft
anastomosis.

\textbf{Conflict of interests}

The authors have none to declare.

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\textbf{Figure legends}

\textbf{Figure 1-} PRISMA flow diagram

\textbf{Figure 2-} Pooled estimates of (A) postoperative stroke and (B)
SCI

\textbf{Figure 3-} Pooled estimates of (A) acute kidney injury, (B)
bleeding, and (C) in-hospital mortality

\textbf{Figure 4-} The graph shows the effect sizes for (A)
postoperative stroke and (B) SCI plotted against the HCA time. The
regression line and corresponding confidence intervals are plotted

\textbf{Supplementary Figure 1-} Funnel plots showing the publication
bias for (A) postoperative stroke, (B) SCI, (C) acute kidney injury, (D)
bleeding, and (E) in-hospital mortality\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-1/Figure-1}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-2-A/Figure-2-A}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-2-B/Figure-2-B}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-3-A/Figure-3-A}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-3-B/Figure-3-B}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-3-C/Figure-3-C}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-4-A/Figure-4-A}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-4-B/Figure-4-B}

\end{center}
\end{figure}

\selectlanguage{english}
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