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SYSTEMATIC REVIEW
Editor’s Choice eCryopreserved Allografts for Arterial Reconstruction after
Aorto-Iliac Infection: A Systematic Review and Meta-Analysis
Constantine N. Antonopoulos
a,b,*
, Nikolaos A. Papakonstantinou
a
, David Hardy
b
, Sean P. Lyden
b
a
Cardiothoracic and Vascular Surgery Department, “Evangelismos”General Hospital, Athens, Greece
b
Department of Vascular Surgery, Cleveland Clinic, Cleveland, OH, USA
WHAT THIS STUDY ADDS
This meta-analysis on the role of cryopreserved allografts for arterial reconstruction after aorto-iliac infection is
the first to review all available data from 31 studies, including 1,377 patients. Pooled proportions for 30 out-
comes were estimated, and it was found that the use of cryopreserved allograft seems to be a safe and durable
option. This reinforces their potential as alternatives to extra-anatomic bypass or use of autologous veins for
treatment of aorto-iliac infection.
Objective: Native and aortic graft infections are rare, but they represent one of the most life threatening
complications of vascular surgery. Several materials and surgical approaches have been developed so far. Among
them, cryopreserved allografts have been proposed as a treatment option. A systematic review and meta-
analysis was conducted to investigate the role of cryopreserved allografts for arterial reconstruction after
aorto-iliac infection.
Methods: The current meta-analysis was conducted using the Preferred Reporting Items for Systematic Reviews
and Meta-Analyses (PRISMA) guidelines. Patient baseline characteristics were investigated, along with 30
outcomes after use of cryopreserved arterial allografts for reconstruction after aorto-iliac infection. Pooled
proportions with 95% CIs of outcome rates were calculated.
Results: A total of 31 studies, including 1,377 patients, finally participated in the meta-analysis. Among the early
outcomes, 30 day mortality was 14.91% (95% CI 11.78e18.31). Peri-anastomotic rupture/allograft disruption rate
was 5.90% (95% CI 2.77e9.88), while pooled aneurysmal degeneration/allograft dilatation was 4.99% (95% CI
1.60e9.68). A pooled rate of 3.11% (95% CI 1.60e4.98) was estimated for pseudoaneurysm formation after
the use of cryopreserved arterial allografts, while the allograft thrombotic/stenotic complication rate and peri-
anastomotic infection were 12.19% (95% CI 7.90e17.15) and 3.32% (95% CI 1.90e5.03), respectively.
Mortality during follow up was 19.24% (95% CI 11.97e27.58), while allograft related mortality during follow
up was 3.58% (95% CI 1.56e6.15). A pooled allograft related re-operation rate was estimated at 24.87% (95%
CI 17.89e32.51).
Conclusions: The use of cryopreserved allograft seems to be a safe and durable option with acceptable outcomes
for treatment of aorto-iliac infection.
Keywords: Allografts, Cryopreservation, Infection, Meta-analysis, Reconstructive surgical procedures, Review
Article history: Received 30 November 2018, Accepted 1 March 2019, Available online 12 June 2019
Ó2019 European Society for Vascular Surgery. Published by Elsevier B.V. All rights reserved.
INTRODUCTION
Infection of native abdominal aorta and prosthetic grafts
still remains one of the greatest challenges in vascular
surgery, with a high morbidity and mortality even after
successful intervention. The basic principle behind the
treatment of aortic graft infection is an extensive debride-
ment, with prosthetic aortic graft excision and concomitant
extra-anatomic or anatomic revascularisation, along with
repair of the bowel lesion in many cases. However, a
disadvantage of the extra-anatomic method is the risk of
aortic stump blowout, which is usually fatal.
1e3
This has led
to growing interest in in situ replacement using other ma-
terials, including antibiotic or silver coated prosthesis,
autogenous veins, and pericardial tissue. Among these al-
ternatives, in situ revascularisation with cryopreserved
* Corresponding author. Cardiothoracic and Vascular Surgery Department,
“Evangelismos”General Hospital, 45-47 Ipsilantou Street, Kolonaki, Athens,
Greece.
E-mail address: kostas.antonopoulos@gmail.com (Constantine N. Antonopoulos).
1078-5884/Ó2019 European Society for Vascular Surgery. Published by
Elsevier B.V. All rights reserved.
https://doi.org/10.1016/j.ejvs.2019.03.003
Eur J Vasc Endovasc Surg (2019) 58, 120e128
allograft has been proposed with favourable outcomes,
incorporating the advantage of a thick walled autogenous
conduit which seems to be more resistant to re-infection
and rupture.
4
However, results using this technique are
diverse and conflicting among the studies, and so far no
systematic review has been performed to pool all available
data together and there is no definite indication in the
existing guidelines.
The aim of this study was to conduct a systematic review
and meta-analysis of the published literature assessing the
outcomes of cryopreserved allografts for arterial recon-
struction after aorto-iliac infection.
MATERIALS AND METHODS
Data collection, search methodology, inclusion and
exclusion criteria
The Preferred Reporting Items for Systematic Reviews and
Meta-Analyses (PRISMA) guidelines were used to perform the
current meta-analysis. Medline, Scopus, EMBASE, Google
Scholar, Ovid, the Cochrane Library and 15 “related items”in
PubMed library were systematically searched for articles of
interest, and the reference lists of the eligible articles were
further searched for additional potentially eligible articles.
The Medical Subject Headings (MESH) terms used for the
search purpose were: “graft”[All Fields], “allograft”[All
Fields], “homograft”[All Fields], “xenograft”[All Fields],
“autograft”[All Fields], and “cryopreserved”[All Fields]. The
search covered all scientific papers, without gender or
language restriction from January 1960 to September 2018.
Two authors (CNA, NAP) independently performed the
search and selection of studies, extracted and analysed
data, and the final decision was reached by discussion and
consensus. Studies were investigated focusing on the use of
cryopreserved arterial allografts for arterial reconstruction
after abdominal aortic native or secondary graft infection.
Studies reporting any type of graft other than cry-
opreserved arterial allografts were excluded.
Baseline characteristics
Data extracted from eligible studies included the first au-
thor’s name, study year, country in which the study was
conducted, total number of patients, number of males,
mean age of study participants, prior medical history, in-
dications for treatment, type of initial surgical procedure,
indications for treatment, micro-organisms detected pre-/
intra-operatively, type of surgical reconstruction performed,
mean interval from the initial aortic graft insertion to
diagnosis of infection or allograft placement (months),
median time between diagnosis of infection and surgical
reconstruction (days), median hospital stay (days), primary
patency rate, follow up (months), and number of patients
under follow up.
Outcomes of interest
The numbers of patients with 30 outcomes of interest were
also extracted. The outcomes were categorised as:
Early mortality.(n¼2): 1) 30 day mortality and 2) intra-
operative mortality
Graft related complication. (n¼5): 1) peri-anastomotic
rupture/allograft disruption, 2) aneurysmal degeneration/
allograft dilatation, 3) pseudoaneurysm, 4) allograft
thrombotic/stenotic complications, 5) peri-anastomotic
infection
Patient related complication.(n¼19): 1) myocardial
ischaemic complications, 2) cardiac rhythm complications,
3) respiratory complications, 4) acute renal failure, 5) uri-
nary tract complications, 6) neurological complications, 7)
venous thrombosis, 8) compartment syndrome, 9) sepsis/
multi-organ failure, 10) enteric perforation, 11) prolonged
ileus, 12) cholopancreatic complications, 13) intra-
abdominal bleeding, 14) wound complications, 15) sys-
temic infections, 16) amputation, 17) haemorrhagic com-
plications, 18) aorto-enteric fistulas, 19) colonic arterial
blood supply complications
Late mortality. (n¼2): 1) mortality during follow up, 2)
graft related mortality during follow up
Reoperations. (n¼2): 1) re-operations (any), 2) graft
related reoperations
Statistical analyses
Data synthesis and treatment effects, heterogeneity, and
publication bias. The outcome rates in patients treated
with cryopreserved arterial allografts for arterial recon-
struction after native abdominal aortic or secondary graft
infection were estimated for each study and reported as
the proportion of patients with the corresponding
outcome among all patients treated with cryopreserved
arterial allografts. Values of the concomitant outcomes
were subsequently appropriately calculated, expressed as
proportions and 95% CIs and thereafter transformed into
quantities according to the Freeman-Tukey variant of the
arcsine square root transformed proportion. The pooled
effect estimates were calculated as the back trans-
formation of the weighted mean of the transformed
proportions, using DerSimonian-Laird weights of random
effects model and expressed as % proportions.
5
A formal
statistical test for heterogeneity using the I
2
test was
performed. Publication bias was assessed using the
Egger’s test for small study effects, as well as visual
inspection of funnel plots. The STATA statistical
software v14 (Stata Corp LP, USA) was used for the
analyses.
Quality assessment of eligible studies
All eligible studies were evaluated using a novel 20 item
quality appraisal checklist for case series studies. This tool
included two components: the first indicated the extent
to which a case series presented traditional features of a
statistical hypothesis testing paradigm, whereas the sec-
ond evaluated detailed descriptions of the subjects’
characteristics particularly in relation to potential source
of confounding.
6
Cryopreserved Allografts for Aorto-Iliac Reconstruction 121
RESULTS
Study characteristics
The literature search identified 789 potentially eligible
studies. After review of the titles and abstracts and appli-
cation of inclusion and exclusion criteria, 742 articles were
excluded. Two more articles were excluded for reporting
reasons.
7,8
Four articles included overlapping populations
with the eligible studies
9e12
and four articles reported
outcomes not for cryopreserved grafts
13e16
and were
excluded from the analysis. Three articles were case re-
ports
17e19
and three were reviews,
20e22
and they were also
excluded. This left 31 articles
1e4,23e49
for the meta-analysis
(Fig. S1), corresponding to a total of 1,377 patients who
received arterial allografts for aortic infection.
Baseline study characteristics of the 31 eligible studies
included in the systematic review are presented in
Table S1. The study period of all included studies ranged
from 1966
38
to 2017.
1,31,36
Interestingly, the first reported
study included a high volume of 116 patients treated
with cryopreserved allografts.
38
Males comprised 74.2%
of the entire patient cohort with a mean age >60 years.
Eighteen of the 31 studies (58%) were conducted either
in France or in the USA. Cryopreserved arterial allografts
were used for the treatment of aorto-iliac occlusive or
aneurysmal disease in the two studies published before
1970,
38,45
whereas prosthetic aortic graft infection with
or without aorto-enteric fistula was the main indication
for studies after 1996. Surprisingly, no study was pub-
lished between 1970 and 1996. Aorto-bi-iliac or aortobi-
femoral aortic reconstruction was the surgical
reconstruction performed in the vast majority of cases.
The mean interval from the initial aortic graft implanta-
tion to the diagnosis of the prosthetic graft infection and
consequent allograft placement ranged from 4 to 92
months. Among the most prevalent comorbidities were
hypertension, smoking, and coronary artery disease.
Staphylococcus species were the most common micro-
organisms detected pre- or intra-operatively, whereas
polymicrobial infection was also detected in high fre-
quency. Median hospital stay was over two weeks in
almost all studies, while median follow up ranged from
Table 1. Results of the meta-analysis
Outcome
category
Outcome No. of studies
n
Effect estimate
Pooled outcome
rate % (95% CI)
Heterogeneity
I
2
(pvalue)
Publication bias
t(pvalue)
Early mortality 30 day mortality 27 14.91 (11.78e18.31) 54.5 (<.01) 1.68 (.11)
Intra-operative mortality 13 0.30 (0.00e1.34) 0.0 (.68) 0.52 (.62)
Graft related Peri-anastomotic rupture/allograft
disruption
15 5.90 (2.77e9.88) 71.2 (<.01) 1.04 (.32)
Aneurysmal degeneration/allograft
dilatation
15 4.99 (1.60e9.68) 76.8 (<.01) 0.09 (.93)
Pseudoaneurysm 10 3.11 (1.60e4.98) 8.6 (.36) 0.56 (.59)
Allograft thrombotic/stenotic
complications
24 12.19 (7.90e17.15) 78.6 (<.01) 0.13 (.90)
Peri-anastomotic infection 14 3.32 (1.90e5.03) 31.9 (.13) 0.43 (.67)
Patient related Myocardial ischaemic complications 8 5.58 (3.08e8.62) 0.0 (.80) 1.69 (.14)
Cardiac rhythm complications 2 2.31 (0.00e7.12) ee
Respiratory complications 9 12.86 (9.42e16.68) 4.8 (.10) 0.80 (.45)
Acute renal failure 10 6.07 (3.76e8.78) 0.0 (.58) 2.76 (.03)
Urinary tract complications 3 1.35 (0.00e5.57) 0.0 (.66) 0.08 (.95)
Neurological complications 7 4.25 (1.71e7.58) 0.0 (.96) 1.00 (.36)
Venous thrombosis 5 9.24 (5.03e14.37) 0.0 (.63) 1.23 (.31)
Compartment syndrome 4 0.60 (0.00e2.04) 5.3 (.37) 6.70 (.02)
Sepsis/multi-organ failure 9 6.99 (4.81e9.49) 0.0 (.56) 0.30 (.77)
Enteric perforation 5 0.56 (0.00e2.15) 33.6 (.20) 13.98 (.001)
Prolonged ileus 5 4.00 (1.31e7.69) 0.0 (.98) 1.58 (.21)
Cholopancreatic complications 2 3.92 (0.00e11.97) ee
Intra-abdominal bleeding 4 3.43 (1.11e6.67) 28.9 (.24) 2.16 (.16)
Wound complications 9 8.76 (3.59e15.54) 68.2 (<.01) 0.41 (.70)
Infectious complications 5 2.68 (0.60e5.71) 11.02 (.34) 0.55 (.62)
Amputation 13 3.78 (1.93e6.04) 13.4 (.31) 0.54 (.60)
Haemorrhagic complications 5 4.29 (0.76e9.75) 54.8 (.06) 0.89 (.44)
Aorto-enteric fistula 7 3.46 (1.19e6.53) 0.0 (.79) 1.51 (.19)
Colonic arterial blood supply
complications
5 5.03 (1.20e10.67) 54.1 (.07) 0.66 (.56)
Late mortality Mortality during follow up 27 19.24 (11.97e27.58) 88.8 (<.01) 1.34 (.19)
Graft related mortality during follow
up
22 3.58 (1.56e6.15) 52.64 (<.01) 1.98 (.06)
Reoperations Any reoperations 22 24.87 (17.89e32.51) 82.7 (<.01) 1.01 (.32)
Graft related reoperations 17 23.52 (15.94e31.97) 81.5 (<.01) 1.49 (.16)
CI ¼confidence interval; I
2
¼percentage of variation.
122 Constantine N. Antonopoulos et al.
6.2 to 53 months. Freedom from re-operation rate was
rather high; in all but seven studies, it was >75%, while
in 10 studies, it was >85%. Cryopreserved allografts were
patent in >56% of cases among the studies that reported
patency rates, while in the majority of studies reporting
late outcomes, patency rates ranged from 81% at three
years to 97% at five years follow up. Quality assessment
of the eligible studies showed that, although they were
retrospective in nature and case series, they were mostly
of sufficient study design and execution (Table S2).
Meta-analysis
Pooled outcome rates with 95% CIs and estimations of
heterogeneity and publication bias are presented in Table 1.
A total of 27 studies reported data on 30 day mortality,
which was estimated at 14.91% (95% CI 11.78e18.31;
Fig. 1). The peri-anastomotic rupture/allograft disruption
rate was 5.90% (95% CI 2.77e9.88; Fig. 2), while pooled
aneurysmal degeneration/allograft dilatation was 4.99%
(95% CI 1.60e9.68; Fig. 3). A pooled rate of 3.11% (95% CI
1.60e4.98) was estimated for pseudoaneurysm formation
after use of cryopreserved arterial allografts, while allograft
thrombotic/stenotic complications rate and peri-
anastomotic infection was 12.19% (95% CI 7.90e17.15)
and 3.32% (95% CI 1.90e5.03), respectively. Mortality
during follow up was 19.24% (95% CI 11.97e27.58), while
allograft related mortality during follow up was 3.58% (95%
CI 1.56e6.15; Fig. 4). Furthermore, a pooled re-operation
rate was estimated at 24.87% (95% CI 17.89e32.51). All
outcomes are shown in Table 1.
DISCUSSION
The present meta-analysis has estimated a pooled early
mortality of <15%, with almost zero intra-operative
Overall (I^2 = 54.5%, p = 0.000)
Minga Lowampa (2016)
Noel (2002)
Bisdas (2010) & Bisdas (2011)
Lesèche (2001)
Lejay (2017)
Lavigne (2003)
Chiesa (1998)
Desgranges (1998)
Zhou (2006)
Koskas (1996)
Vardanian (2009)
Chaufour (2016)
Vogt (2002)
Study
Gabriel (2004)
Saito (2012)
Ben Ahmed (2017)
Meade (1966)
Touma (2014)
Verhelst (2000)
McCready (2011)
Brown (2009)
Kieer (2001)
Harlander- Locke (2014)
Nevelsteen (1998)
Batt (2011)
Heo (2017)
Mestres (1996)
14.91 (11.78, 18.31)
11.46 (5.86, 19.58)
17.86 (8.91, 30.40)
8.77 (2.91, 19.30)
17.86 (6.06, 36.89)
8.00 (0.98, 26.03)
13.64 (2.91, 34.91)
12.90 (3.63, 29.83)
22.22 (6.41, 47.64)
16.67 (6.97, 31.36)
18.07 (10.48, 28.05)
0.00 (0.00, 16.11)
39.39 (22.91, 57.86)
6.12 (1.28, 16.87)
ES (95% CI)
13.33 (5.05, 26.79)
27.27 (6.02, 60.97)
14.08 (6.97, 24.38)
11.21 (6.10, 18.40)
33.33 (21.09, 47.47)
17.78 (10.52, 27.26)
25.58 (13.52, 41.17)
11.11 (1.38, 34.71)
27.27 (6.02, 60.97)
9.09 (5.64, 13.69)
26.67 (12.28, 45.89)
25.00 (3.19, 65.09)
8.00 (0.98, 26.03)
12.50 (1.55, 38.35)
100.00
5.45
4.52
4.55
3.21
3.00
2.78
3.40
2.44
3.97
5.21
2.70
3.52
4.27
Weight
4.11
1.72
4.95
5.74
4.45
%
5.35
4.02
2.44
1.72
6.53
3.34
1.35
3.00
2.25
ES (95% CI) Weight
%
000 65.1
Figure 1. Forest plot presenting the meta-analysis of 30 day mortality based on event rates for use of cryopreserved allografts for aorto-iliac
infection. Event rates in the individual studies are presented as squares with 95% Confidence Intervals (CIs) presented as extending lines. The
pooled 30 day mortality rate of 14.91% (dashed line) with its 95% CIs of 11.78e18.31) is shown as a diamond. ES ¼Effect size; I
2
¼
percentage of variation.
Cryopreserved Allografts for Aorto-Iliac Reconstruction 123
mortality. Late mortality was 20%; however, <4% was
attributed to the complications of the technique, again
highlighting its safety. Complications after surgery concerning
the use of the cryopreserved allograft, such as anastomotic
rupture, allograft degeneration, and pseudoaneurysm for-
mation were between 3% and 6%. Importantly, 14 studies
reported on re-infection rates and the pooled rate was
estimated at a low of 3%. Complications after surgery were
mainly respiratory. These figures taken together, point to the
durability of the technique, adding a good alternative for
treating aorto-iliac native and synthetic graft infection.
The risk of native aortic or prosthetic graft infection,
although rare at 0.2e5% of all open aortic repairs,
30
has
remained stable over the past two decades, indicating a
continuing life threatening condition and at the same time
posing the greatest challenge in vascular surgery. Ideally,
the treatment involves removal of the infected graft ma-
terial, along with all surrounding necrotic tissues and inline
arterial reconstruction, which can be performed with extra-
anatomic bypass. However, because of the high potential
risk of aortic stump blowout with this technique, in situ
reconstruction followed by omental wrapping has been
used as an alternative. Many different types of synthetic
graft have been tested for that reason, mainly irrigated with
rifampicin or triclosan. Moreover, new prostheses, such as
silver coated, covalent bonded silver coated prostheses, or
the novel glutaraldehyde fixed bovine collagen with an in-
tegrated polyester graft have shown good patency rates.
However, the re-infection rates with these grafts may vary
from 4% to 17%, which led to another treatment option,
arterial reconstruction using femoral veins (neo-aorto-iliac
system), with good results. However, even this operation is
not ideal; it is lengthy, with significant venous morbidity,
including post-operative fasciotomy and higher late rupture
rate and secondary interventions.
1,36
To anticipate the disadvantages of synthetic and venous
grafts, allografts have been used for in situ arterial recon-
struction. Fresh allografts have been mainly abandoned
because of high dilatation rates over the time.
30
Conversely,
cryopreserved allografts taken from dead donors have gained
popularity, because they have better collagen preservation
and mechanical stability and they do not affect the visco-
elasticity of muscular arteries and the wall structure of
elastic arteries.
1
Their main cryopreservation action appears
to diminish the immune response induced by fresh arterial
allografts, thus improving their behaviour after grafting.
1
Among their main advantages is that they are less prone to
infection, require only a short surgical duration, and are
Overall (I^2 = 71.1%, p = 0.000)
Study
Saito (2012)
Chiesa (1998)
Lejay (2017)
Kieer (2001)
Zhou (2006)
Noel (2002)
Lavigne (2003)
McCready (2011)
Koskas (1996)
Brown (2009)
Chaufour (2016)
Ben Ahmed (2017)
Nevelsteen (1998)
Pirrelli (2005)
Desgranges (1998)
5.90 (2.77, 9.88)
ES (95% CI)
0.00 (0.00, 10.89)
10.59 (4.96, 19.15)
5.00 (0.13, 24.87)
0.00 (0.00, 20.59)
0.00 (0.00, 10.00)
7.14 (0.18, 33.87)
4.41 (0.92, 12.36)
15.38 (5.86, 30.53)
9.09 (1.12, 29.16)
4.76 (0.99, 13.29)
4.00 (1.74, 7.73)
4.35 (0.53, 14.84)
50.00 (29.12, 70.88)
3.03 (0.63, 8.60)
8.47 (2.81, 18.68)
100.00
Weight
6.21
8.24
5.04
%
4.49
6.43
4.16
7.85
6.68
5.28
7.70
9.30
7.06
5.50
8.48
7.58
ES (95% CI) Weight
%
000 70.9
Figure 2. Forest plot presenting the meta-analysis of peri-anastomotic rupture/allograft disruption based on event rates for use of cry-
opreserved allografts for aorto-iliac infection. Event rates in the individual studies are presented as squares with 95% Confidence Intervals
(CIs) presented as extending lines. The pooled peri-anastomotic rupture/allograft disruption rate of 5.90% (dashed line) with its 95% CIs of
2.77e9.88 is shown as a diamond. ES ¼Effect size; I
2
¼percentage of variation.
124 Constantine N. Antonopoulos et al.
associated with low morbidity and mortality.
36
Furthermore,
cryopreserved allografts are processed so that they do not
require blood group matching, they can be pre-selected to
match the size of the recipient’s aorta and branches and they
generally include visceral, renal, and hypogastric side
branches, which can be used for bypass to renal and visceral
vessels.
30
Limitations of the technique include that a pre-
defined, dedicated, and very detailed protocol of tissue
harvesting is mandatory. Furthermore, careful use of cryo-
protectants, freezing temperatures, controlled freezing
rate,
31
temperature storing, thawing, and washing before
implantation are crucial. Moreover, allografts usually require
several parts to be connected, anastomoses should be ten-
sion free, side branches should be ligated securely when not
needed, and sufficient tissue debridement in the area before
implantation should be performed meticulously to avoid
reinfection.
36
Lastly, although allografts are soaked in anti-
biotics during their preparation, patients should receive long-
term antibiotic therapy after implantation.
1
However, it
should be highlighted that antibiotic soaking of allografts is a
prophylactic measure, which is not part of the long-term
antibiotic treatment of the initial infection, which duration
depends on many other factors, such as the type of the initial
infection and the results of the per-operative microbiological
samples.
Among the patient related adverse event predictors after
the implantation of cryopreserved allografts, studies have
highlighted the important role of type 1 diabetes mellitus,
American Society of Anesthesiology class 4, advanced age,
chronic renal insufficiency, emergency surgery, and coro-
nary heart disease.
1
Furthermore, the bacteriological viru-
lence and clinical severity of the native or secondary graft
infection presentation are directly related to mortality.
1
Moreover, differences in the underlying cause of aortic
infection (primary aortic infection vs. prosthetic graft
infection vs. aorto-enteric fistula) and surgery urgency (ur-
gent vs. elective, ruptured vs. intact) have also been iden-
tified as potential factors contributing to the heterogeneity
of published results.
31
These differences are mainly
responsible for the diversity of the reported mortality rates
among the eligible studies. The present meta-analysis has
estimated a pooled 30 day mortality rate of 15%, ranging
from a minimum of zero mortality as reported by Vardanian
et al.
4
up to 39% as reported by Chaufour et al.,
26
in which
abdominal aortic endograft explantation for infection was
high risk and associated with graft-enteric fistula in one
Overall (I^2 = 76.8%, p = 0.000)
Pirrelli (2005)
Bisdas (2010) & Bisdas (2011)
Minga Lowampa (2016)
Harlander- Locke (2014)
Noel (2002)
Vogt (2002)
Lavigne (2003)
Touma (2014)
Brown (2009)
Study
Chiesa (1998)
Kieer (2001)
Ben Ahmed (2017)
Saito (2012)
Heo (2017)
Zhou (2006)
4.99 (1.60, 9.68)
3.03 (0.63, 8.60)
35.85 (23.14, 50.20)
0.00 (0.00, 20.59)
13.64 (2.91, 34.91)
14.29 (1.78, 42.81)
13.16 (4.41, 28.09)
5.88 (1.63, 14.38)
5.00 (0.13, 24.87)
11.11 (4.59, 21.56)
ES (95% CI)
1.18 (0.03, 6.38)
0.00 (0.00, 20.59)
2.17 (0.06, 11.53)
0.00 (0.00, 10.89)
2.13 (0.05, 11.29)
0.00 (0.00, 10.00)
100.00
8.13
7.40
5.14
5.82
4.84
6.87
7.73
5.62
%
7.63
Weight
7.98
5.14
7.18
6.57
7.22
6.73
4.99 (1.60, 9.68)
3.03 (0.63, 8.60)
35.85 (23.14, 50.20)
0.00 (0.00, 20.59)
13.64 (2.91, 34.91)
14.29 (1.78, 42.81)
13.16 (4.41, 28.09)
5.88 (1.63, 14.38)
5.00 (0.13, 24.87)
11.11 (4.59, 21.56)
ES (95% CI)
1.18 (0.03, 6.38)
0.00 (0.00, 20.59)
2.17 (0.06, 11.53)
0.00 (0.00, 10.89)
2.13 (0.05, 11.29)
0.00 (0.00, 10.00)
100.00
8.13
7.40
5.14
5.82
4.84
6.87
7.73
5.62
%
7.63
Weight
7.98
5.14
7.18
6.57
7.22
6.73
000 50.2
Figure 3. Forest plot presenting the meta-analysis of aneurysmal degeneration/allograft dilatation based on event rates for use of cry-
opreserved allografts for aorto-iliac infection. Event rates in the individual studies are presented as squares with 95% Confidence Intervals
(CIs) presented as extending lines. The pooled aneurysmal degeneration/allograft dilatation rate of 4.99% with its 95% CIs of 1.60e9.68 is
shown as a diamond. ES ¼Effect size; I
2
¼percentage of variation.
Cryopreserved Allografts for Aorto-Iliac Reconstruction 125
third of the cases. Interestingly, there was no late mortality
resulting from allograft related complications in a study by
Brown et al.
2
Proposed adjunctive techniques to improve
outcomes after cryopreserved allograft implantation include
the support of large anastomoses with allograft strips, use
of additional sealing with antibiotic impregnated fibrin glue,
through and through suturing of the allograft side branch
with polypropylene suture, and omental wrapping.
31
An important issue with the use of allografts is degen-
eration of the allograft material. Mechanisms of cry-
opreserved allograft degeneration include aortic wall injury
and immune related tissue damage during cryopreserva-
tion. Interestingly, fractures seem to be more frequent
below 150 C,
1
although other studies support that cry-
opreserved protocols at 80 C and 150 C did not have a
significant influence on early mortality or the post-operative
complication rate.
46
Furthermore, mechanical injury of the
crystallised allograft prior to thawing, during intra-operative
manipulations or during clamping of the thawed allograft is
also implicated in allograft degeneration.
31
This
degeneration might be responsible for the late adverse
events, including rupture, disruption, and pseudoaneurysm.
The present meta-analysis has estimated a pooled pseu-
doaneurysm formation in approximately 3%, peri-
anastomotic rupture and allograft disruption in less than
6%, while allografts dilated in 5% of cases. These rates might
vary significantly from study to study and might be related
to the technique of the cryopreservation on diminishing the
antigenicity of allografts.
29
As the risk of wall rupture and
degeneration is very high following incorrect manipulation,
one of the most recent studies
1
suggested that the cryo-
preservation technique should include viral and bacterio-
logical screening of the harvested allografts, immersion in
antibiotic solution, freezing to 140 C, and storing in
vapour phase nitrogen until defrosting in the operating
room. Of note, it has been proposed that cellular compo-
nents of the vessel wall are able to trigger the immuno-
logical reaction and as a result, allografts should not be
considered weakly antigenic. This might have clinical
implication because the cryopreservation technique does
Overall (I^2 = 52.6%, p = 0.002)
Study
Brown (2009)
Verhelst (2000)
Lavigne (2003)
Kieer (2001)
Szilagyi (1970)
Nevelsteen (1998)
Touma (2014)
Koskas (1996)
Pirrelli (2005)
Lesèche (2001)
Desgranges (1998)
Zhou (2006)
Harlander- Locke (2014)
Vardanian (2009)
Heo (2017)
Gabriel (2004)
Chaufour (2016)
Bisdas (2010) & Bisdas (2011)
Minga Lowampa (2016)
Ben Ahmed (2017)
McCready (2011)
Vogt (2002)
3.58 (1.56, 6.15)
ES (95% CI)
6.35 (1.76, 15.47)
33.33 (4.33, 77.72)
5.88 (1.63, 14.38)
6.25 (0.16, 30.23)
0.00 (0.00, 23.16)
25.00 (9.77, 46.71)
0.00 (0.00, 16.84)
0.00 (0.00, 15.44)
2.02 (0.25, 7.11)
11.11 (2.35, 29.16)
8.47 (2.81, 18.68)
2.86 (0.07, 14.92)
0.00 (0.00, 15.44)
0.00 (0.00, 36.94)
2.13 (0.05, 11.29)
11.11 (0.28, 48.25)
0.50 (0.01, 2.75)
9.43 (3.13, 20.66)
6.25 (0.16, 30.23)
6.52 (1.37, 17.90)
2.56 (0.06, 13.48)
2.63 (0.07, 13.81)
100.00
Weight
6.27
1.49
6.44
3.06
2.80
3.96
3.54
3.76
7.23
4.23
6.12
4.86
3.76
1.86
5.58
2.03
%
8.37
5.87
3.06
5.53
5.13
5.06
ES (95% CI) Weight
%
000 77.7
Figure 4. Forest plot presenting the meta-analysis of allograft related mortality based on event rates for use of cryopreserved allografts for
aorto-iliac infection. Event rates in the individual studies are presented as squares with 95% Confidence Intervals (CIs) presented as extending
lines. The pooled allograft related mortality rate of 3.58% with its 95% CIs of 1.56–6.51 is shown as a diamond. ES ¼Effect size;
I
2
¼percentage of variation.
126 Constantine N. Antonopoulos et al.
not guarantee complete antigenicity clearance and blood
group matching alone might not be entirely appropriate.
50
The opportunity to offer in situ revascularisation after
aortic infection is highly attractive, but it may be
hampered by the potential for re-infection. In a study by
Nevelsteen et al.,
41
the authors reported three cases of
re-infection in 25 patients. Interestingly, Lehalle et al.
35
reported four fatal cases of rupture within the third
month after implantation of a cryopreserved allograft and
afifth allograft related death a long time later. All of
their allograft rupture deceased patients had aorto-
enteric fistula (AEF) as first presentation. They hypoth-
esised that a large tissue involvement and complete
debridement is not always possible in these “high grade
infections”and this is responsible for a continuous
degeneration of the native aortic wall, which is in prox-
imity to the allograft suture line.
Although this meta-analysis is the first to analyse data,
from a pool of 31 articles and more than 1 300 patients, on
cryopreserved allografts for aortic arterial reconstruction,
some limitations should be reported. Firstly, the level of ev-
idence of the included studies is low. However, this is inevi-
table because of the rarity of the condition and because only
small series have been published so far. Furthermore, most
of the studies were retrospective in nature and information
on whether consecutive patients were finally included is
lacking. As a result, the possibility for selection bias may exist.
What is more, although publication bias was only statistically
evident in a minority of the evaluated secondary outcomes,
the potential publication of only favourable outcomes by
some of the studies might have existed. Additionally, no
separate results were provided for each one of the aortic
pathologies among the eligible studies, because of a lack of
reporting. Some clinical entities, such as AEF were more se-
vere than others, such as low grade infections, leading to
different results among the studies. However, the eligible
studies did not report data separately for patients with vs.
without AEF or native aorta vs. prosthetic graft infection and
as a result, it is impossible to estimate pooled outcomes with
AEF or type of infection as confounders. As distinction was
not made between persistent or recurrent infection, no
conclusion could be drawn about the effect of the type of
infection on outcomes. Furthermore, differences among the
eligible studies in the cryopreservation protocol, surgical
technique, initial indication, severity of aorto-iliac infection,
study sample characteristics, and definition of graft patency
might explain part of the heterogeneity of the results. What
is more, differences concerning medical treatment, including
length of antibiotic therapy, as well as the systematic use of
antifungal therapy are also of importance to explain the
heterogeneity. As a result, more and better studies on the
topic are needed to draw conclusions on the benefit of the
technique.
CONCLUSION
In conclusion, use of cryopreserved allograft for arterial
reconstruction after aorto-iliac infection appears to be safe
and durable. As no guidelines are clearly established con-
cerning treatment of aorto-iliac infection, further studies,
with a randomised control design comparing these methods
might help in identifying the best method for treating this
severe aortic pathology.
CONFLICT OF INTEREST
None.
FUNDING
None.
APPENDIX A. SUPPLEMENTARY DATA
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.ejvs.2019.03.003.
REFERENCES
1Ben Ahmed S, Louvancourt A, Daniel G, Combe P, Duprey A,
Albertini JN, et al. Cryopreserved arterial allografts for in situ
reconstruction of abdominal aortic native or secondary graft
infection. J Vasc Surg 2018;67:468e77.
2Brown KE, Heyer K, Rodriguez H, Eskandari MK, Pearce WH,
Morasch MD. Arterial reconstruction with cryopreserved human
allografts in the setting of infection: a single-center experience
with midterm follow-up. J Vasc Surg 2009;49:660e6.
3Leseche G, Castier Y, Petit MD, Bertrand P, Kitzis M, Mussot S,
et al. Long-term results of cryopreserved arterial allograft recon-
struction in infected prosthetic grafts and mycotic aneurysms of
the abdominal aorta. J Vasc Surg 2001;34:616e22.
4Vardanian AJ, Chau A, Quinones-Baldrich W, Lawrence PE.
Arterial allograft allows in-line reconstruction of prosthetic graft
infection with low recurrence rate and mortality. Am Surg
2009;75:1000e3.
5Stuart A, Ord J. Kendall’s Advanced Theory of Statistics. 6th ed.
London: Edward Arnold; 1994.
6Guo B, Moga C, Harstall C, Schopflocher D. A principal component
analysis is conducted for a case series quality appraisal checklist.
J Clin Epidemiol 2016;69:199e207 e2.
7Teebken OE, Pichlmaier MA, Brand S, Haverich A. Cryopreserved
arterial allografts for in situ reconstruction of infected arterial
vessels. Eur J Vasc Endovasc Surg 2004;27:597e602.
8Smeds MR, Duncan AA, Harlander-Locke MP, Lawrence PF,
Lyden S, Fatima J, et al. Treatment and outcomes of aortic
endograft infection. J Vasc Surg 2016;63:332e40.
9Kieffer E, Bahnini A, Koskas F, Ruotolo C, Le Blevec D,
Plissonnier D. In situ allograft replacement of infected infrarenal
aortic prosthetic grafts: results in forty-three patients. J Vasc Surg
1993;17:349e55. discussion 55e6.
10 Vogt PR, von Segesser LK, Goffin Y, Niederhauser U, Genoni M,
Kunzli A, et al. Eradication of aortic infections with the use of
cryopreserved arterial homografts. Ann Thorac Surg 1996;62:
640e5.
11 Vogt PR, Brunner-La Rocca HP, Carrel T, von Segesser LK, Ruef C,
Debatin J, et al. Cryopreserved arterial allografts in the treatment
of major vascular infection: a comparison with conventional sur-
gical techniques. J Thorac Cardiovasc Surg 1998;116:965e72.
12 Vogt PR, Turina MI. Management of infected aortic grafts:
development of less invasive surgery using cryopreserved homo-
grafts. Ann Thorac Surg 1999;67:1986e9.
13 Capoccia L, Speziale F, Menna D, Esposito A, Sirignano P,
Rizzo AR, et al. Preliminary results from a national enquiry of
infection in abdominal aortic endovascular repair (registry of
infection in EVAR–R.I.EVAR). Ann Vasc Surg 2016;30:198e204.
Cryopreserved Allografts for Aorto-Iliac Reconstruction 127
14 Kieffer E, Gomes D, Chiche L, Fleron MH, Koskas F, Bahnini A.
Allograft replacement for infrarenal aortic graft infection:
early and late results in 179 patients. J Vasc Surg 2004;39:
1009e17.
15 Mirelli M, Buzzi M, Pasquinelli G, Tazzari PL, Testi G, Ricchi E,
et al. Fresh and cryopreserved arterial homografts: immunological
and clinical results. Transpl Proc 2005;37:2688e91.
16 Pupka A, Skora J, Janczak D, Plonek T, Marczak J, Szydelko T. In
situ revascularisation with silver-coated polyester prostheses and
arterial homografts in patients with aortic graft infection–a pro-
spective, comparative, single-centre study. Eur J Vasc Endovasc
Surg 2011;41:61e7.
17 Balaz P, Rokosny S. Infected aortic stentgraft treated with fresh
cold stored arterial allograft. Eur J Vasc Endovasc Surg 2016;52:
123.
18 Nevelsteen A, Goffin Y, Lacroix H, Vandeginste N, Suy R. Recur-
rent aortic infection: treatment by arterial homograft replace-
ment. Cardiovasc Surg 1995;3:441e4.
19 Weymann A, Ruhparwar A, Karck M. Management of abdominal
stent graft infection with cryopreserved aortic allograft. Asian
Cardiovasc Thorac Ann 2016;24:904.
20 Laohapensang K, Arworn S, Orrapin S, Reanpang T, Orrapin S.
Management of the infected aortic endograft. Semin Vasc Surg
2017;30:91e4.
21 O’Connor S, Andrew P, Batt M, Becquemin JP. A systematic re-
view and meta-analysis of treatments for aortic graft infection.
J Vasc Surg 2006;44:38e45.
22 Vogt PR. Arterial allografts in treating aortic graft infections:
something old, something new. Semin Vasc Surg 2011;24:227e33.
23 Batt M, Jean-Baptiste E, O’Connor S, Saint-Lebes B, Feugier P,
Patra P, et al. Early and late results of contemporary management
of 37 secondary aortoenteric fistulae. Eur J Vasc Endovasc Surg
2011;41:748e57.
24 Bisdas T, Bredt M, Pichlmaier M, Aper T, Wilhelmi M, Bisdas S,
et al. Eight-year experience with cryopreserved arterial homo-
grafts for the in situ reconstruction of abdominal aortic infections.
J Vasc Surg 2010;52:323e30.
25 Bisdas T, Wilhelmi M, Haverich A, Teebken OE. Cryopreserved
arterial homografts vs silver-coated Dacron grafts for abdominal
aortic infections with intraoperative evidence of microorgan-
isms. J Vasc Surg 2011;53:1274e12781 e4.
26 Chaufour X, Gaudric J, Goueffic Y, Khodja RH, Feugier P,
Malikov S, et al. A multicenter experience with infected
abdominal aortic endograft explantation. J Vasc Surg 2017;65:
372e80.
27 Chiesa R, Astore D, Piccolo G, Melissano G, Jannello A, Frigerio D,
et al. Fresh and cryopreserved arterial homografts in the treat-
ment of prosthetic graft infections: experience of the Italian
Collaborative Vascular Homograft Group. Ann Vasc Surg 1998;12:
457e62.
28 Desgranges P, Beaujan F, Brunet S, Cavillon A, Qvarfordt P,
Melliere D, et al. Cryopreserved arterial allografts used for the
treatment of infected vascular grafts. Ann Vasc Surg 1998;12:583e8.
29 Gabriel M, Pukacki F, Dzieciuchowicz L, Oszkinis G, Checinski P.
Cryopreserved arterial allografts in the treatment of prosthetic
graft infections. Eur J Vasc Endovasc Surg 2004;27:590e6.
30 Harlander-Locke MP, Harmon LK, Lawrence PF, Oderich GS,
McCready RA, Morasch MD, et al. The use of cryopreserved
aortoiliac allograft for aortic reconstruction in the United
States. J Vasc Surg 2014;59:669e74.
31 Heo SH, Kim YW, Woo SY, Park YJ, Kim DK, Chung DR. Recent
results of in situ abdominal aortic reconstruction with cry-
opreserved arterial allograft. Eur J Vasc Endovasc Surg 2017;53:
158e67.
32 Kieffer E, Sabatier J, Plissonnier D, Knosalla C. Prosthetic graft
infection after descending thoracic/thoracoabdominal aortic
aneurysmectomy: management with in situ arterial allografts.
J Vasc Surg 2001;33:671e8.
33 Koskas F, Plissonnier D, Bahnini A, Ruotolo C, Kieffer E. In situ
arterial allografting for aortoiliac graft infection: a 6-year expe-
rience. Cardiovasc Surg 1996;4:495e9.
34 Lavigne JP, Postal A, Kolh P, Limet R. Prosthetic vascular infec-
tion complicated or not by aortoenteric fistula: comparison of
treatment with and without cryopreserved allograft (homograft).
Eur J Vasc Endovasc Surg 2003;25:416e23.
35 Lehalle B, Geschier C, Fieve G, Stoltz JF. Early rupture and
degeneration of cryopreserved arterial allografts. J Vasc Surg
1997;25:751e2.
36 Lejay A, Delay C, Girsowicz E, Chenesseau B, Bonnin E,
Ghariani MZ, et al. Cryopreserved cadaveric arterial allograft for
arterial reconstruction in patients with prosthetic infection. Eur J
Vasc Endovasc Surg 2017;54:636e44.
37 McCready RA, Bryant MA, Fehrenbacher JW, Beckman DJ,
Coffey AC, Corvera JS, et al. Long-term results with cryopreserved
arterial allografts (CPAs) in the treatment of graft or primary
arterial infections. J Surg Res 2011;168:e149e53.
38 Meade JW, Linton RR, Darling RC, Menendez CV. Arterial homo-
grafts. A long-term clinical follow-up. Arch Surg 1966;93:392e9.
39 Mestres CA, Mulet J, Pomar JL. Large-caliber cryopreserved
arterial allografts in vascular reconstructive operations: early
experience. Ann Thorac Surg 1995;60:S105e7.
40 Minga Lowampa E, Holemans C, Stiennon L, Van Damme H,
Defraigne JO. Late fate of cryopreserved arterial allografts. Eur J
Vasc Endovasc Surg 2016;52:696e702.
41 Nevelsteen A, Feryn T, Lacroix H, Suy R, Goffin Y. Experience
with cryopreserved arterial allografts in the treatment of pros-
thetic graft infections. Cardiovasc Surg 1998;6:378e83.
42 Noel AA, Gloviczki P, Cherry Jr KJ, SafiH, Goldstone J,
Morasch MD, et al. Abdominal aortic reconstruction in infected
fields: early results of the United States cryopreserved aortic
allograft registry. J Vasc Surg 2002;35:847e52.
43 Pirrelli S, Arici V, Bozzani A, Odero A. Aortic graft infections:
treatment with arterial allograft. Transpl Proc 2005;37:2694e6.
44 Saito A, Motomura N, Hattori O, Kinoshita O, Shimada S, Saiki Y,
et al. Outcome of surgical repair of aorto-eosophageal fistulas
with cryopreserved aortic allografts. Interact Cardiovasc Thorac
Surg 2012;14:532e7.
45 Szilagyi DE, Rodriguez FJ, Smith RF, Elliott JP. Late fate of arte-
rial allografts. Observations 6 to 15 years after implantation. Arch
Surg 1970;101:721e33.
46 Touma J, Cochennec F, Parisot J, Fialaire Legendre A,
Becquemin JP, Desgranges P. In situ reconstruction in native and
prosthetic aortic infections using cryopreserved arterial allografts.
Eur J Vasc Endovasc Surg 2014;48:292e9.
47 Verhelst R, Lacroix V, Vraux H, Lavigne JP, Vandamme H,
Limet R, et al. Use of cryopreserved arterial homografts for
management of infected prosthetic grafts: a multicentric study.
Ann Vasc Surg 2000;14:602e7.
48 Vogt PR, Brunner-LaRocca HP, Lachat M, Ruef C, Turina MI.
Technical details with the use of cryopreserved arterial allografts
for aortic infection: influence on early and midterm mortality.
J Vasc Surg 2002;35:80e6.
49 Zhou W, Lin PH, Bush RL, Terramani TT, Matsuura JH, Cox M, et al. In
situ reconstruction with cryopreserved arterial allografts for man-
agement of mycotic aneurysms or aortic prosthetic graft infections:
a multi-institutional experience. Tex Heart Inst J 2006;33:14e8.
50 Faggioli G, Ricotta JJ. Cryopreserved vein homografts for arterial
reconstruction. Eur J Vasc Surg 1994;8:661e9.
128 Constantine N. Antonopoulos et al.
