Word Count: 250
Introduction
Acute onset dissections involving the ascending arch are classified as
acute type A aortic dissection (ATAAD)1. Treatment
modalities for this condition have been improved over the years, yet
mortality and morbidity rates remain elevated2,3. In
recent years the implementation of hypothermic circulatory arrest (HCA)
along with anterograde cerebral perfusion (ACP) has decreased the
numbers of post-operative neurological deficits4.
Nevertheless, there is an ongoing debate on which ACP technique should
be implemented5. Unilateral anterograde cerebral
perfusion (UACP) implies less manipulation of the
vessels6,7, however the protection offered to the
contralateral cerebral hemisphere is debatable8.
Bilateral anterograde cerebral perfusion BACP is considered a safer
option when the duration of ACP is long and is the technique most
utilized by aortic surgeons9. Yet, the risk of
dislodging a clot and causing an embolic stroke remains one of the
biggest disadvantages of this cerebral protection
modality10.
Previous meta-analyses on the topic included non-comparative studies and
patients with heterogenous aortic pathologies which implies poor quality
of evidence11–13. Moreover, all previous
meta-analyses are outdated and inconclusive regarding the optimal
cerebral protection method11–13. Accounting our
inability to draw conclusions using current data along with the
emergence of new relevant studies, we conducted a systematic review and
meta-analysis to assess the preoperative and intraoperative
characteristics as well as the early postoperative outcomes of patients,
on whom UACP versus BACP was implemented when being surgically treated
for ATAAD.
Material and methods
Study design and inclusion/exclusion criteria
The research team complied with the PRISMA (Preferred Reporting Items
for Systematic Reviews and Meta-Analysis) guidelines for this systematic
review and meta-analysis. The research question was defined via the
PICO (Population/Participants,
Intervention, Comparison, and Outcome) criteria:
- Population/ Participants: Patients undergoing surgery for ATAAD
- Intervention: UACP
- Comparison: BACP
- Outcomes: Primary outcomes were in-hospital mortality, defined as
mortality within thirty days after surgery; post-operative permanent
neurological deficits (PND), defined as neurological deficits that
persisted after discharge, and post-operative transient neurological
deficits (TND), defined as neurological deficits that resolved during
hospitalization. Secondary outcomes were the length of hospital stay
(LOS); the length of intensive care unit (ICU) stay; renal failure,
defined as the post-operative need for hemodialysis; re-exploration
for bleeding, defined as any invasive procedure performed due to
hemodynamic instability.
All comparative studies written in English that reported on patients
with ATAAD undergoing surgery that implemented either UACP or BACP, were
deemed eligible. Studies were excluded using the following criteria: all
the studies not published in English, non-comparative studies,
meta-analyses and systematic reviews, editorials, letters to the editor,
comments, personal opinions, errata, case series and case reports,
studies that reported on patients with heterogenous aortic pathologies.
From studies with overlapping populations only one study was selected.
Search strategy
MEDLINE (via PubMed), Scopus and Cochrane library were searched (last
search August 7th, 2021) using the following
algorithm: ((Cerebral Perfusion) OR (Cerebral protection) OR (Brain
protection) OR (ACP) OR (SACP)) AND ((ATAAD) OR (Acute Type A Aortic
Dissection) OR (DeBakey type I) OR (DeBakey type II)). Title and
abstract screening and full text eligibility were performed by two
independent investigators (DNV, ENV). A third reviewer (PTT) was
consulted when there was a conflict. A thorough search of potentially
eligible articles was made via the snowball method14.
Data extraction and tabulation
Data was extracted by two independent investigators (DNV, ENV) and
disagreements reached consensus via discussion with a third investigator
(PTT). Data were inserted into a predesigned table for evidence
synthesis. The following data were extracted: study characteristics
(first author, year of publication, study design, study center, study
period, number of patients); patients baseline characteristics (age in
years, gender and various comorbidities); perioperative characteristics
(cardiopulmonary bypass [CPB] time, cross clamp [CCP] time, UACP
time, UACP time , hypothermic circulatory arrest [HCA] duration and
concomitant procedures); post-operative outcomes (mortality, PND and TND
rates, renal failure rates, LOS, length of ICU stay and re-exploration
for bleeding)
Quality of evidence assessment
Eligible studies’ quality was assessed by the implementation of the
NOS15. A study that received a grading of at least 6
or more was considered of high quality. Since all the assessed outcomes
are post-operative outcomes, all included studies were deemed adequate
regarding the follow up period.
Statistical analysis
We conducted meta-analyses to compare the outcomes of UACP versus BACP
as a cerebral protective strategy in patients undergoing surgery for
ATAAD. Continuous variables were analyzed using standardized mean
difference (SMD) and 95% confidence intervals (95% CI). A SMD greater
than zero corresponded to larger values in the UACP arm. Categorical
values were analyzed using odds ratio (OR) and 95% CI. An OR greater
than 1 indicated that the outcome was more frequently present in the
UACP arm. Inherent clinical heterogeneity between the studies was
balanced via the implementation of random effects models
(DerSimonian-Laird). Results were displayed in forest plots.
Pre-specified random effects meta-regression analyses were conducted to
examine the impact of moderator variables on outcomes. Specifically,
using this technique we attempted to assess the effect of total arch
repair (TAR), implementation of Bentall procedure and performing
concomitant coronary artery bypass graft (CABG) during the surgical
repair of ATAAD on PND and TND.
Between-study statistical heterogeneity was assessed with the Cochran Q
statistic and by estimating I2 . High
heterogeneity was confirmed with a significance level of
p<0.10 and I2 of at least 50% or
more. Publication bias was assessed via funnel plots and Eggers’ test
for each outcome of interest and p<0.10 was considered
statistically significant. All analyses were performed using STATA
IC16.0 (StataCorp LLC, College Station, Texas).
-
-
- Results
- Study selection and baseline characteristics
Through the systematic search we conducted, a total of 1183 articles
were retrieved. Detailed study selection process is presented inSupplemental Figure 1 . Ultimately, 8 studies reporting on
cumulatively 2416 patients, 843 patients undergoing UACP and 1573
patients undergoing BACP were included in this
meta-analysis6,7,16–21. Study characteristics are
reported in Table 1 . Patient baseline and clinical
characteristics are cumulatively reported intraoperative characteristics
in Table 2. All outcomes are cumulatively presented inSupplemental table 1 .
Intraoperative characteristics
CCP time was reported in 7 studies6,16–21 and no
difference was noted between UACP and BACP groups (SMD: -0.04, 95%CI:
[-0.38] – [0.29], p =0.79, I2=91.29%).
CPB duration was reported in 7
studies6,7,16,17,19–21. CPB time did not differ
significantly between the groups (SMD: 0.11, 95%CI: [-0.22] –
[0.44], p =0.52, I2=89.65%). Regarding HCA
duration, meta-analysis of all included studies demonstrated that there
was no difference between the two groups (SMD: -0.12, 95%CI:
[-0.55] – [0.30], p =0.57, I2=95.10%).
All included studies implemented deep (<24°C) or moderate
hypothermia (>24°C) during aortic repair, however further
details were not available.
Primary outcomes
In-hospital mortality
In- hospital mortality was reported in all included studies. Overall,
there were 96 (11.4%, n=96/1275) in-hospital mortalities in the UACP
group and 289 (18,4%, n=289/1486) in the BACP group during the hospital
stay. No statistically significant difference was observed between the
UACP group and BACP group in terms of in-hospital mortality (OR:1.05,
95%CI [0.70] – [1.57], p =0.80,
I2=39.58%). (Figure 1)
PND
PND events were reported in all studies. A total of 87 patients were
reported with PND in the UACP group (10.3%, n=87/843) and 196 patients
in the BACP group (12.5%, n=196/1573). The two groups were comparable
in terms of PND (OR: 0.94, 95%CI: [0.52] – [1.70],p =0.84, I2=69.34%). (Figure 2.A)
TND
TND events were reported in seven included
studies6,7,16,17,19–21. Overall, 85 patients
presented TND in the UACP group (11.7%, n=85/726) and 76 patients in
the BACP group (9.3%, n=76/813). The two groups were comparable
regarding TND (OR: 1.37, 95%CI: [0.98] – [1.92],p =0.07, I2=0.0%). (Figure 2.B)
Secondary outcomes
LOS
LOS was reported in four studies6,7,19,20. UACP was
associated with decreased LOS compared to BACP (SMD: -0.25, 95% CI:
[-0.45] – [-0.06], p =0.01,
I2=54.39%).
ICU stay
ICU stay duration was reported in five
studies7,16,17,19,20. UACP demonstrated increased ICU
stay length compared to BACP (SMD: 0.16, 95%CI: [0.01] –
[0.31], p =0.04, I2=28.56%).
Renal failure
Renal failure events were available in all included studies. There was
no statistically significant difference between the UACP group and the
BACP group in terms of renal failure (OR: 0.96, 95%CI: [0.70] –
[1.32], p =0.80, I2=20.39%).
Re-exploration for bleeding
Re-exploration for bleeding was available in 6
studies6,7,17–20. No statistically significant
difference was observed between the UACP group and the BACP group in
terms of re-exploration for bleeding (OR: 0.77, 95%CI: [0.48] –
[1.22]. p =0.27, I2=18.53%).
Meta-regression analysis
Random-effects meta-regression analysis was performed to examine
potential relationships between PND or TND and TAR. Data separating
patients with ATAAD undergoing TAR or hemiarch repair were reported in
seven sudies. Implementation of TAR was expressed as difference of rate
of occurrence in the UACP versus BACP groups. Meta-regression analysis
revealed that TAR had no statistically significant influence on PND
(p =0.49) (Supplemental Figure 2) nor on TND
(p =0.91).
Additional meta-regression analyses were conducted to explore a
potential influence of Bentall procedure or CABG on both PND and TND.
Utilization of Bentall procedure or CABG was expressed as a difference
of rate of occurrence in the UACP versus BACP groups. Meta-regression
analysis revealed that Bentall procedure and CABG had no statistically
significant influence on PND and TND (Supplemental Table 2) .
Quality of evidence and publication bias assessment
All included studies were retrospective cohorts and thus for quality
assessment we utilized the NOS. Detailed NOS quality assessment for each
of the eligible studies is shown in Supplemental table 3.In addition, statistically
significant heterogeneity was found in PND rate, CPB time, CCP time and
HCA time (Supplemental Table 1) .
Egger’s test revealed no publication bias in the funnel plots of most
studied outcomes, except for CPB time (p <0.01), CCP
time (p <0.01), and HCA time (p =0.02)(Supplemental Figure 3) .
Conclusions
The outcomes of the present systematic review and meta-analysis indicate
that UACP and BACP are comparable in terms of in-hospital mortality,
PND, TND, renal failure, and re-exploration for bleeding. Particularly
for PND and TND, our meta-regression analysis showed that the proportion
of patients who underwent TAR, Bentall procedure and concomitant CABG
during ATAAD repair in each arm of our study, did not significantly
influence the rate of PND and TND events. The two cerebral protection
techniques were also similar regarding CPB time, CCP time and HCA time.
However, ICU stay was found to be borderline increased in the UACP
group, while the LOS was found to be increased in the BACP group.
In contrast to previous meta-analyses which included both comparative
and single arm studies as well as studies reporting on patients with
heterogenous aortic pathologies11–13, we incorporated
only comparative studies reporting solely on patients with ATTAD to
limit potential confounding biases. It should also be noted that, except
for one study7, all our individual studies were
published after 2017 and consequently were not included in the previous
meta-analyses. Yet, our findings are in accordance with the findings of
these previous reports11–13. Moreover, our cumulative
results were consistent with the corresponding results in the included
individual studies.
Aiming to reveal potential factors influencing our results, we examined
through meta-regression analysis the effect of TAR, Bentall procedure
and concomitant CABG on the PND and TND incidence. Additionally, longer
circulatory arrest time was associated with increased risk for mortality
and PND in patients operated with UACP compared to
BACP12,13. Therefore, to further limit potential
confounders, we compared the intra-operative characteristics of the
incorporated studies. Cumulatively, no differences were noted in terms
CPB, CCP and HCA times and thus further analysis on the impact of these
factors on our findings was deferred.
For post-operative patient care, our analysis revealed that UACP offers
marginally increased length of ICU. On the other hand, LOS was found to
be longer in BACP arm. Accounting that BACP is a more demanding
procedure where more vessels are manipulated and
anastomosed19,21, it is logical to assume that
patients would require longer periods for recovery and thus longer LOS.
These findings, however, should be interpreted cautiously since ICU and
LOS were reported only in few studies and displayed considerable
heterogeneity.
Nevertheless, while UACP is supported by available evidence to provide
equivalent results compared to BACP, most aortic surgeons insist on
opting for BACP9. UACP’s efficacy was considered to be
inextricably connected to the patency of the circle of Willis, in order
to maintain adequate blood supply to the contralateral hemisphere. It is
true that anatomic variations on the circle of Willis are very common in
the population, however, studies assessing UACP in patients with
incomplete circle of Willis reported that the incidence of neurological
adverse events was not affected by the anatomy of the circle of
Willis22,23. This finding could be explained by the
fact that in UACP contralateral cerebral perfusion can be facilitated by
extracranial vessels, and that watershed cerebral infarcts have various
clinical presentations and are not easily diagnosed and documented. On
the other hand, BACP increases the risk for clot dislodging and air
embolism in the cerebral circulation, due to excess manipulation and
cannulation of the supra-aortic vessels6,19.
Additionally, in patients with aortic dissections, manipulation of the
fragile pathologic vessel wall imposes the risk of vessel rapture and
could lead to catastrophic complications11.
Transcranial doppler of the middle cerebral artery, CT angiography of
the circle of Willis, near-infrared spectroscopy (NIRS) and blood
backflow from left common carotid or subclavian artery are some of the
pre-operative and intra-operative techniques used to facilitate the
selection of the optimal cerebral perfusion
modality7,24. NIRS is used to provide information
regarding brain’s perfusion intra-operatively, and some surgeons
recommend switching UACP to BACP intraoperatively when NIRS suggests
decreased cerebral perfusion7. However, in cases of
ATAAD there is limited time for pre-operative assessment. Additionally,
NIRS provides information about the perfusion of few brain areas while
the brainstem along with other parts of the brain are not
assessed11. These barriers render the selection of the
proper cerebral perfusion modality in patients with ATAAD very
challenging.
Accounting that both UACP and BACP are comparable regarding the
post-operative outcomes in patients with ATAAD, we conclude that the
utilization of BACP over UACP should be tailored according to the
surgeon’s and the center’s experience and requires individualized
patient selection considering the anticipated duration of the operation
as well as the anatomy and the integrity of the patient’s supra-aortic
vessels. Implementation of the available pre-operative and
intra-operative means could also decisively influence the appropriate
cerebral perfusion technique for each individual case.