Key words hepatic veins - areas - structures & systems - hepatic arteries - ultrasound-color
doppler - methods & techniques - ultrasound-spectral doppler - transplantation -
themes
Introduction
Liver transplantation (LT) is the only available treatment for end-stage liver
disease in children. Over the last decades, improvements in graft perfusion
techniques, surgical procedures, and an increasing proportion of living donor
transplantations have led to improved survival rates [1 ]
[2 ]
[3 ]
[4 ]. Donor organs are scarce, and thus graft survival is
of utmost importance. In the last decade in Europe, loss of grafts occurred in up
to
7.5% of pediatric LTs, of which the majority happened in the first month
[4 ]. Therefore, optimal surveillance by clinical
assessment, laboratory examination, and imaging is essential for early detection and
treatment of complications, thereby reducing graft loss [5 ]
[6 ]
[7 ].
Doppler ultrasound (DUS) is the primary bedside imaging technique during and after
liver transplantation (LT) in both children and adults. It provides high-resolution
dynamic imaging of the liver parenchyma and vascularization, and is inexpensive and
radiation-free. Although the diagnostic performance of DUS is operator-dependent,
assessment of pediatric LT is generally highly feasible in children due to their
lean body mass. Computed tomography (CT) and magnetic resonance imaging are mainly
reserved for preoperative assessment of anatomy and liver volume, characterization
of focal lesions, and further analysis of postoperative collections and vascular
complications in case the DUS findings are inconclusive [8 ]
[9 ].
The primary aim of DUS is to detect clinically occult vascular complications such
as
thrombosis, stenosis, and kinking [10 ]
[11 ]
[12 ]. In addition, DUS
provides information on biliary complications and fluid collections such as
hematomas [13 ]. As mentioned before, early detection
of complications followed by subsequent medical, interventional radiological, or
surgical treatment aims to improve post-transplant outcome [2 ]
[14 ]
[15 ].
Intraoperative and postoperative DUS for LT is considered the gold standard of care.
However, a large temporal heterogeneity of DUS imaging protocols has been reported
[16 ]
[17 ]
[18 ]
[19 ]
[20 ]. This heterogeneity might be caused by limited
evidence concerning the optimal timing of postoperative DUS and regarding the most
efficient postoperative DUS protocol [16 ]
[18 ]
[20 ]. For hepatic
artery thrombosis (HAT) a large review in children showed a median time to detection
of 4.8 days (range: 1.0–9.6) postoperatively [17 ]. However, for other vascular complications (e. g., portal
vein thrombosis), descriptions of incidence are limited to early or late
complications, with analysis of incidence in the first 2 weeks often grouped
together [10 ]
[20 ]
[21 ]. Therefore, it remains unclear when different types
of vascular complications may be first diagnosed by DUS.
Although various cut-off values for the diagnosis of vascular complications on DUS
are available, test performance of DUS during peri- and postoperative surveillance
in children is not clearly established [21 ]. This is
partly because DUS is already an established imaging modality. Therefore, a normal
DUS examination will not be confirmed by further imaging or surgery and true and
false negatives are not verified. A false-positive DUS result, however, has
immediate clinical significance and leads to further imaging (e. g., CT) or
surgery. Determining the positive predictive value (PPV) may add to a better
understanding of DUS test performance after pediatric LT.
Because of the limited evidence available, the primary objective of this study was
to
assess the moment of first detection of vascular complications with DUS during
standardized peri- and postoperative DUS surveillance after pediatric LT; the
secondary objective was to determine the positive predictive value of DUS.
Materials and methods
Patients
This single-center retrospective study was performed in our national pediatric
liver transplant center. The study was approved by the local research ethics
committee and the need for informed consent was waived.
All consecutive patients<18 years old who underwent LT between April 2015
and June 2019 were eligible for the study. Patients were excluded if they died
prior to the first DUS. For repeat LT, the primary and secondary LT were
included as separate entries during the 1-year follow-up.
Data collection and reporting of analysis were performed according to the
Strengthening the Reporting of Observational Studies in Epidemiology (STROBE)
guidelines [22 ]. Clinical data, DUS images and
reports, and other types of imaging were collected during the 1-year follow-up
from our prospectively maintained institutional database.
Collected demographic data included: age, gender, and primary disease.
Disease-related data at the time of listing for LT consisted of cirrhotic or
non-cirrhotic liver disease, model for end-stage liver disease score (MELD, all
ages), pediatric end-stage liver disease score (PELD,<12 years),
international normalized ratio (INR), bilirubin level (umol/L), albumin
level (g/L), and creatinine level (umol/L). Collected surgical
variables were type of donor procedure (living or deceased donation) and type of
liver transplant (full size or partial liver).
DUS surveillance protocol and reference standard
All patients underwent DUS according to our local standardized protocol. This
protocol consists of intraoperative DUS after all vascular and surgical
anastomoses are made, immediately after wound closure, and after arrival in the
pediatric intensive care unit (day 0), daily on days 1–7, at 1 month, at
3 months, and after 1 year. To improve the readability of the paper,
intraoperative and immediate postoperative DUS examinations are sometimes
referred to as perioperative DUS. DUS examinations were performed by a team of
five dedicated radiologists and one specialized sonographer. However, for each
individual LT one person of this dedicated team was assigned 24 hours a
day for 7 consecutive days to perform all perioperative and first week DUS
examinations.
DUS criteria and registration of vascular complications
The DUS criteria used in this study for the detection of vascular complications
were any vascular thrombosis or anastomotic stenosis as described in pediatric
LT literature [6 ]
[21 ]:
Hepatic artery: The peak systolic velocity (PSV) and RI (PSV minus end
diastolic velocity, divided by PSV) were obtained. A hepatic artery
resistive index<0.5 combined with a tardus parvus spectral trace
(including a systolic acceleration time>80ms), or (if visible)
an anastomotic PSV≥200 cm/s, was considered
suggestive of a significant stenosis. The segmental hepatic artery
branches were also assessed.
Portal vein: An anastomotic PSV of>125 cm/s or a
pre- to anastomotic ratio of≥4 was considered abnormal. If the
anastomosis could not be clearly defined, the narrowest caliber of the
hilar portal vein was considered the anastomosis. In the case of an
interposition graft or patch, the narrowest caliber was sampled. The
segmental portal vein branches were also assessed.
Hepatic vein(s): The hepatic vein waveform was sampled in all veins
approximately 2 cm proximal to the anastomosis. Monophasic flow
was considered abnormal.
Vascular complications were categorized by vessel type (hepatic artery, portal
vein, hepatic vein(s)). In the case of multiple vessel-specific complications
during follow-up (e. g., HAT on day 0 and – after
revascularization – again on day 5), all complications were registered.
In the case of different types of vessel complications at one time point, all
were registered.
All ultrasound examinations were performed on a Toshiba Aplio 500 ultrasound
machine (Canon, Ōtawara, Japan). Images had been stored and were
available from our Picture Archiving and Communication System.
Abnormal DUS findings were directly compared to subsequent diagnostic or
therapeutic actions, such as surgical findings (including repeat surgery),
radiological angiography, or further imaging by CT during the first year after
LT, as the best available reference standard. Based on the confirmation or
disproof of the abnormal DUS result, the vascular complication was further
categorized (thrombosis, stenosis, kinking - including loss of signal from
compression of the abdominal wall on the graft -, extrinsic compression by a
fluid collection), and registered as a true positive or false positive. Abnormal
DUS findings without subsequent imaging or therapeutic actions (i. e.,
without a reference standard) were reported but not included in the
analyses.
Biliary abnormalities and fluid collections
Biliary abnormalities were registered at the time of one of the following
interventions: biliary leakage or anastomotic stenosis requiring surgery,
endoscopic retrograde cholangiography with balloon dilatation or stenting, or
percutaneous transhepatic cholangiodrainage. In addition, the time of clinical
consensus of ischemic type biliary lesions (ITBL) was registered. For fluid
collections (hematoma, loculated ascites, abscess), interventions were either
surgery or radiological drainage. Fluid collections detected on DUS without
treatment were not included in this study. In the case of repeated biliary or
fluid collection interventions during follow-up, all were registered as separate
entities.
Statistical analysis
Data analysis was descriptive. Continuous variables were summarized using median
and interquartile range (IQR). Kaplan-Meier curves and bar charts were used to
illustrate the time points of vascular complication detection by DUS (GraphPad
Prism version 9.0, GraphPad Software, La Jolla California USA), categorized per
vessel, during the first 2 weeks, and during the 1-year follow-up. In addition,
Kaplan-Meier curves were used to illustrate the moment of DUS vascular
complication diagnosis compared to that of biliary and collection-related
interventions during the first 2 weeks and at the 1-year follow-up. Last,
Kaplan-Meier curves of DUS-detected vascular complications were stratified for
age groups (0–2 versus>2 years) and graft type (LDLT, DDLT full
size, DDLT split liver), and differences between curves were tested using the
Mantel Cox log-rank test.
Results
Patient and liver transplantation characteristics
The entire cohort of 93 consecutive LTs in 83 children was included in the study.
One patient died without undergoing DUS and was excluded. The median patient age
at the time of LT of the remaining 92 LTs was 3.9 years (IQR 0.7–10.5,
min.-max. 0.2–16.8). [Table 1 ] further
describes the patient and LT characteristics.
Table 1 Patient and liver transplantation characteristics.
Number of LTs
92 (100%)
Age at the time of LT (years), median (IQR)
3.9 (0.7–10.5)
Gender, male, N (%)
53 (57.6%)
Cirrhotic disease, N (%)
76 (82.6%)
MELD score*, median (IQR)
18 (13–23)
PELD score*, median (IQR)
9 (2–18)
Bilirubin (umol/L)*, median (IQR)
118 (36–273)
Period on waiting list, days, median (IQR)
104 (44–174)
INR*, median (IQR)
1.3 (1.1–1.6)
Albumin (g/L)*, median (IQR)
36 (30–40)
Creatinine (umol/L)*, median (IQR)
22 (16–39)
Full size
24 (26.1%)
DDLT
24 (100%)
Split liver
68 (73.9%)
LDLT
33 (48.5%)
DDLT
35 (51.5%)
*at the time of listing for LT, INR: international normalized
ratio, IQR: interquartile range, LT: liver transplantation, MELD: model
for end-stage liver disease, N: number, PELD: pediatric end-stage liver
disease, LDLT: living donor liver transplantation, DDLT: deceased donor
liver transplantation.
[Fig. 1 ] displays the study population flowchart.
Supplemental Table 1 displays all primary diseases and baseline data.
Supplemental Table 2 illustrates the distribution of the anastomotic
techniques used.
Fig. 1 Population flowchart.
Moment of detection of vascular complications on DUS after LT
44 out of 52 (84.6%) vascular complication diagnoses on DUS during the
1-year follow-up were made either perioperatively or in the first week after LT
([Tab. 2 ], [Figs.
2 ]
[3 ]). Of these, 15/52
(28.8%) were perioperative: 7/52 (13.5%) intraoperative
and 8/52 (15.4%) immediately postoperative. On postoperative
days 1–7, 29/52 (55.8%) vascular complications were
detected by DUS, while from day 8 to 1 year post-LT, this was the case in
8/52 (15.4%) LTs. Supplemental Figures
1 and 2 demonstrate Kaplan-Meier curves of vascular complication
detection categorized for age groups (0–2 versus>2 years) and
graft types (LDLT, DDLT split liver, and DDLT full size), respectively, without
significant differences.
Fig. 2 Kaplan-Meier (inverted) curves of vascular complications
diagnosed by DUS during 1-year follow-up, detailed for day 0–130
(Left (a )) and day 0–14 (right (b )), categorized
for the hepatic artery, portal vein, and hepatic veins.
Fig. 3 Histogram of vascular complications diagnosed by DUS,
perioperatively and during the first postoperative week.
Table 2 Vascular complication diagnosis by DUS categorized per
period. For each vessel the reference standard diagnosis and the
true- and false-positive cases are specified.
Perioperative
Days 1–7
Days 8–365
Total
Hepatic artery
Thrombotic
TP
2
2
1
5
FP
1
1
Kinked
TP
4
4
8
Extrinsic compression
TP
2
2
Significant stenosis
TP
1
2
3
Total
7
11
1
19
Portal vein
Thrombotic
TP
5
5
1
11
Kinked
TP
2
2
Significant stenosis
TP
4
6
10
FP
2
1
3
Total
7
12
7
26
Hepatic vein
Thrombotic
TP
1
1
Extrinsic compression
TP
2
2
Significant stenosis
TP
4
4
Total
1
6
7
Total
15
29
8
52
DUS: Doppler ultrasound; TP: true positive; FP: false positive.
19 hepatic artery complications were diagnosed by DUS during the 1-year
follow-up. Eighteen of them (94.7%) were diagnosed either
perioperatively or in the first postoperative week ([Tab. 2 ], [Fig. 2, 3 ]). True-positive
HAT was diagnosed in 5 out of 92 LTs (5.4%), with the median day of
diagnosis being 6 days after LT (IQR 0–12 days).
26 portal vein complications were diagnosed during the 1-year follow-up. 19 of
them (73.1%) were diagnosed either perioperatively or in the first
postoperative week ([Tab. 2 ], [Fig. 2, 3 ]).
7 hepatic vein complications were diagnosed with DUS. All diagnoses were made
either perioperatively or in the first postoperative week ([Tab. 2 ], [Figs. 2,
3 ]).
There were 6 instances of an abnormal DUS without subsequent actions
(i. e., without a reference standard), which were not included in the
analysis. Five out of six patients did not suffer graft loss at the 1-year
follow-up. These are further detailed in Supplemental Table 3 .
PPV of DUS for vascular complication detection
48 out of 52 vascular complication diagnoses on DUS were true positive, resulting
in a PPV of 92.3%.
The PPV for the hepatic artery was 94.7% (18 true positive/19
total). The only false-positive hepatic artery diagnosis was a HAT registered on
day 5, which immediately underwent surgery after DUS.
Three false-positive portal vein stenoses were suggested with DUS, 2
postoperatively after wound closure, and 1 at 4 months after LT. CT during
follow-up ruled out stenoses in these cases. This resulted in a PPV for the
portal vein of 88.5% (23/26).
No false-positive hepatic vein complications were diagnosed on DUS, resulting in
a PPV of 100% (7/7).
Biliary abnormalities and fluid collections
18 biliary complications were registered, including 2 cases of ITBL. 24 fluid
collection-related interventions were performed. [Fig.
4 ] illustrates the time points of biliary and fluid collection
interventions in comparison to vascular complications diagnosed via DUS.
Fig. 4 Kaplan-Meier (inverted) curves of vascular complications
diagnosed on DUS confirmed by the reference standard, and interventions
for biliary abnormalities, and fluid collection interventions during
1-year follow-up. The complications are given for day 0–250
(left) and day 0–14 (right), and categorized for vascular,
biliary, and collection-related complications. The vertical dotted line
in figure A marks postoperative day 7.
Discussion
This study determined at what time points after pediatric LT radiologists can first
detect vascular complications with DUS during standardized DUS surveillance. We also
determined the PPV of DUS in this setting. We found that the vast majority of
vascular complications were diagnosed with DUS perioperatively or during the first
postoperative week, with only a small percentage of vascular complications diagnosed
in the subsequent one-year follow-up (84.6% versus 15.4%,
respectively). The PPV for vascular complication detection by DUS was high
(92.3%). As with vascular complications, fluid collections requiring
interventions occurred mostly in the first postoperative week, whereas biliary
abnormalities were diagnosed mostly at a later time.
DUS surveillance during and after LT is focused on vascular complications, with the
aim of detecting these often clinically occult complications as early as possible.
The most urgent vascular complication is thrombosis. Early HAT in children carries
a
hazard ratio for graft loss of up to 14 [23 ], and
appropriate treatment will improve long-term graft and patient survival [14 ]
[15 ]
[17 ]
[23 ]. Similarly,
pediatric portal vein thrombosis is associated with higher mortality, and prompt
detection and treatment are instrumental in reducing mortality and graft loss [24 ]. In our study, the majority of cases of vascular
thrombosis in the first year occurred perioperatively (N=8 out of 17) or in
the first week (N=7 out of 17). Daily DUS in the first postoperative week in
our center allows for a timely diagnosis and treatment of thrombosis, and based on
the aforementioned studies, we believe this will likely improve outcomes.
In addition to daily postoperative DUS in the first week, we also perform
intraoperative and immediate postoperative DUS as part of our standardized DUS
surveillance protocol. This has also been suggested in previous pediatric studies
[25 ]
[26 ], but to our
knowledge, its implementation varies between LT centers. Perioperative DUS detected
several thromboses and kinked vessels (including loss of signal from compression of
the abdominal wall at the graft), which required immediate intervention. The
detection rate was similar for intraoperative and immediate postoperative DUS
(N=12 and N=13, respectively), and this underlines the importance of
performing DUS at both time points.
Peri- and postoperative hemodynamic changes, soft tissue swelling, a hypercoagulable
state, and hematomas may also affect the LT [15 ]
[27 ], and these factors may cause early vascular
complications. However, these factors may also lead to a false-positive stenosis
diagnosis on DUS, which may be the explanation for the 3 cases of false-positive
portal vein stenosis in our study. In the case of perioperative or first
postoperative week portal vein stenoses diagnosed by DUS, we suggest DUS follow-up
instead of immediate surgical correction.
The main limitation of our study is the suboptimal reference standard caused by the
retrospective study design. Although surgery or radiological imaging and
interventions are the best option for comparing DUS findings, they are not fully
DUS-independent because DUS already has an established role in vascular complication
detection. In addition, we could not assess false-negative or true-negative rates
for DUS because LTs with normal DUS findings did not undergo further imaging. Last,
we found 6 abnormal DUS cases in our cohort without a reference standard. The
optimal design for a prospective study would be to verify each DUS finding with CT
or surgery. However, this would not be ethically justifiable. To further investigate
the usefulness of DUS surveillance after pediatric LT, a prospective observational
study with predefined criteria could be of value.
Although our data suggests that perioperative DUS and daily first week postoperative
DUS would benefit all pediatric LTs, our methodology was not suitable to investigate
whether this surveillance protocol reduced co-morbidity and improved graft survival.
Nevertheless, despite this limitation, we believe that our data justifies the use
of
this protocol at our center. In the absence of studies with superior methodology,
our data could provide guidance for other LT centers.
In conclusion, the vast majority of vascular complications during the first year
after pediatric LT are diagnosed by DUS during the operation, immediately after the
operation, or during the first postoperative week during daily DUS surveillance,
with a high PPV. Fluid collection-related complications requiring intervention occur
mostly in the first postoperative week, while most biliary abnormalities are
diagnosed later. Our findings provide important information for pediatric LT centers
regarding when to expect different types of vascular complications on DUS during and
after pediatric LT, which might further improve the DUS post-LT surveillance
protocol.
Notice
This article was changed according to the following Erratum
on April 12th 2023.
Erratum
In the above-mentioned article a specification in Table 2 was
not correct. The corrected Table 2 is shown below. This was
corrected in the online version on April 12th, 2023.
