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Received: 2 November 2022    Revised: 28 February 2023    Accepted: 27 March 2023

DOI: 10.1111/petr.14524

ORIGINAL ARTICLE

Perioperative risk factors for neurological impairment in infants

with acute liver failure following liver transplantation

Kentaro Ide1,2  | Hajime Uchida3  | Seisuke Sakamoto3  | Itaru Hayakawa4  |

Satoshi Nakagawa1 | Tohru Kobayashi2,5  | Shuichi Ito2 | Mureo Kasahara3

1
Critical Care Medicine, National Center
for Child Health and Development, Tokyo, Abstract
Japan
Background: Neurological impairment is not rare in infants with acute liver failure
2
Department of Pediatrics, Yokohama City
University Graduate School of Medicine,
(ALF). This study aimed to investigate the perioperative risk factors for neurological
Yokohama, Japan impairment following liver transplantation (LT) in infantile ALF.
3
Organ Transplantation Center, National Methods: Retrospective analysis was performed in infants who were younger than
Center for Child Health and Development,
Tokyo, Japan 1 year with ALF who subsequently underwent LT at our hospital between January
4
Division of Neurology, National Center 2005 and December 2016. Patients were considered to have neurological impairment
for Child Health and Development, Tokyo,
if the Pediatric Cerebral Performance Category score was between 2 and 5 at the age
Japan
5
Department of Data Science, Clinical of 6 years. A comparison between the groups of infants with and without neurological
Research Center, National Center for Child impairment was performed, and factors with p < .10 in the comparison were analyzed
Health and Development, Tokyo, Japan
using univariate logistic regression analysis for neurological impairment.
Correspondence Results: Twenty-­six infants survived until 6 years of age, and 31% (8/26) of them had
Kentaro Ide, National Center for Child
Health and Development, 2–­10-­1 Okura, neurological impairment. Patients with neurological impairment were significantly
Setagaya-­ku, Tokyo 157–­8535, Japan. younger in age at ALF onset, had significantly higher pre-­LT bilirubin and prothrombin
Email: ide-k@ncchd.go.jp
time/international normalized ratio, and stayed significantly longer in the intensive
Funding information care unit than those without neurological impairment. Total bilirubin (odds ratio
National Center for Child Health and
Development (OR) = 1.12, 95% confidence interval (CI) 1.02–­1.22, p = .012), indirect bilirubin
(OR = 1.10, 95% CI 1.01–­1.20, p = .025), direct bilirubin (OR = 1.22, 95% CI 1.01–­1.47,
p = .040), and age in month at ALF (OR = 0.76, 95% CI 0.58–­0.999, p = .049) showed
significant association with neurological impairment.
Conclusions: High pre-­LT peak bilirubin value and younger age at ALF onset can be
perioperative risk factors for neurological impairment after LT in infantile ALF.

KEYWORDS
acute liver failure, child, hyperbilirubinemia, liver transplantation, neurological impairment,
neurological outcome

Abbreviations: ALF, acute liver failure; CVVHDF, continuous venovenous hemodiafiltration; HE, hepatic encephalopathy; LT, liver transplantation; NI, neurological impairment; PCPC,
Pediatric Cerebral Performance Category; PICU, pediatric intensive care unit; PT-­INR, prothrombin time/international normalized ratio.

Pediatric Transplantation. 2023;27:e14524. wileyonlinelibrary.com/journal/petr |

© 2023 Wiley Periodicals LLC.     1 of 8
https://doi.org/10.1111/petr.14524
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1  |  I NTRO D U C TI O N
Acute liver failure (ALF) is a rare, life-­threatening condition that fre-
quently affects formerly healthy patients and is characterized by
coagulopathy and neurological dysfunction.1,2 The overall survival
of patients with ALF has improved with advances in intensive care
and timely liver transplantation (LT).3–­5 However, neurological im-
pairment (NI) after recovery from ALF, such as neurocognitive im-
pairment or neuropsychiatric disturbances, has been reported.1,6,7
Neurological dysfunction due to hepatic encephalopathy (HE)
leading to NI occurs by multifactorial events, such as astrocyte
swelling due to hyperammonemia or mitochondrial dysfunction,
1,2
altered blood–­brain barrier, or loss of cerebral autoregulation.
Furthermore, perioperative hyperammonemia has been reported to
8
be a risk factor for mortality in pediatric ALF. However, to the best
of our knowledge, no study has reported the perioperative risk fac-
tors for long-­term outcomes, such as NI in pediatric ALF.
NI, defined as an increased Pediatric Cerebral Performance
Category (PCPC) score,9 was observed in 23% (12/52) of the pedi-
atric ALF survivors.10 They were classified into three types accord-
ing to the possible cause: patients with underlying systemic disease,
patients with perioperative brain lesions, and patients with unclas-
10
sified NI. Patients with unclassified NI were all infants less than
12 months old. Thus, we presumed that ALF, its perioperative care,
and the vulnerable infant brain were the possible causes of unclassi-
fied NI. Identifying perioperative risk factors for NI in infantile ALF
that seemed to be at high risk for NI may help decrease the number
of infants with NI.
This study aimed to investigate the perioperative risk factors for
NI following LT in infantile ALF.
2  |  PATI E NT S A N D M E TH O DS
2.1  |  Study design and patients
All infants younger than 1 year with ALF, who subsequently under-
went LT at the National Center for Child Health and Development,
Tokyo, Japan, between January 2005 and December 2016, were
retrospectively reviewed. Patients were diagnosed with ALF if the
prothrombin time/international normalized ratio (PT-­INR) was 1.5
or more due to severe liver damage within 8 weeks of the onset of
disease symptoms.11 Patients who died before 6 years of age were
excluded since the neurological assessment was performed in ac-
cordance with the conditions at 6 years of age. Furthermore, patients
who were with underlying systemic diseases, such as chromosomal
abnormalities, metabolic diseases, or mitochondrial respiratory
chain disorder, or those with perioperative brain lesions, such as
intracranial hemorrhage, brain infarction, or osmotic demyelination
syndrome were excluded since their neurological assessment was
affected by the diseases or brain lesions. This study was conducted
in accordance with the amended Declaration of Helsinki. The insti-
tutional review board approved this study with waiver of consent in
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view of the retrospective nature of the study, and all the procedures
being performed were part of the standard care (receipt number:
1582).
2.2  |  Preoperative management
All patients with ALF were admitted to the pediatric intensive care
unit (PICU) and underwent standardized neurological examination
by pediatric neurologists. Patients with HE higher than grade II or
who had further coagulopathy deterioration were indicated for
neuro-­oriented intensive care as described elsewhere.10 Continuous
venovenous hemodiafiltration (CVVHDF) and plasma exchange
were prepared and implemented as described elsewhere.10,12
A scoring system established by the intractable Hepato-­Biliary
Disease Study Group supported by the Ministry of Health, Labour
and Welfare of Japan was referred to indicate LT. The scoring system
included six parameters and graded as 0, 1, and/or 2: the interval
between disease onset and development of hepatic encephalopathy,
prothrombin time, serum total bilirubin concentration, the ratio of
direct to total bilirubin concentration, peripheral platelet count, and
the presence of liver atrophy.13 The patient with score >5 points was
estimated to be unlikely to survive through a native liver; thus, prep-
arations for LT would proceed. If no improvements in liver function
was noted, then liver biopsy was performed 5–­7 days after intensive
care introduction. An open biopsy with minimal incision was typi-
cally performed immediately before planned LT. When histopathol-
ogy showed massive hepatic necrosis and no regeneration of hepatic
cells, LT was performed.
2.3  |  Donor selection, surgical procedures, and
postoperative management
Patients with uncontrollable encephalopathy and on renal re-
placement therapy or plasma exchange were on the waiting list
for deceased donor LT, and were given the highest priority.14
Simultaneously, the option of living-­d onor LT was discussed with
the family members because the availability of deceased donors
is limited in Japan. The donor surgery type was decided accord-
ing to the graft-­to-­p atient weight ratio, which is optimal between
1.0% and 4.0% as a guide of graft size-­matching to the recipient's
physical size. The graft type selection was followed as described
elsewhere.15 The surgical procedures for the donors and recipi-
ents were performed as described elsewhere.16 Postoperative
care was provided in the PICU at least 1 week after LT. Blood ex-
aminations and abdominal ultrasonography were performed twice
daily. The prophylactic protocol for incompatible donor LT was
described elsewhere.17 All patients <2 years of age during study
period were not indicated for B-­cell depletion therapies, and were
implemented identical post-­operative immunosuppression proto-
col of ABO-­compatible LT. The postoperative immunosuppressive
regimen consisted of tacrolimus and low-­d ose steroids, and the

IDE et al.
regimen details were described elsewhere.10 Patients were fol-
lowed up by pediatric neurologists after LT, who were consulted
when neurological abnormalities, such as seizures, encephalopa-
thy, or psychiatric symptoms, were suspected. Neuroimaging was
performed on a case-­by-­c ase basis if needed.
2.4  |  Measurements
Patients' records were manually extracted from the institutional
electronic health record database and reviewed by two investiga-
tors (K.I. and H.U.). Patients' data included patient characteristics,
laboratory evaluation, modes and duration of artificial liver support,
timing and details of LT, and outcomes. For the laboratory data, daily
peak values on consecutive days up to 2 weeks before LT and after
LT were recorded. The presence of hypoglycemic episodes (blood
sugar level < 40 mg/dL for neonates and < 60 mg/dL for infants older
than 1 month) was recorded. A PT-­INR of 10 or more was indicated
as 10. For the setting of artificial liver support, peak values before LT
were recorded. Complications regarding LT, including surgical com-
plications, or T cell-­mediated rejection, during the hospital stay were
collected.
2.5  |  Assessment and classification of NI
NI was assessed according to the status at the age of 6 years in each
patient using the six-­point PCPC score, with 1 indicating normal,
2 indicating mild disability (regular school, but grades perhaps not
age-­appropriate), 3 indicating moderate disability (age-­appropriate
independent activities of daily life, requiring special education class-
room), 4 indicating severe disability (dependent on others for daily
support because of impaired brain function), 5 indicating persistent
9
vegetative state, and 6 indicating brain death or death by any cause.
The assessment and classification were carried out by a transplant
surgeon (H.U.), a pediatric neurologist (I.H.), and a pediatric intensiv-
ist (K.I.) independently. When there were discrepancies, they were
discussed and decided upon. When the PCPC score was between 2
and 5, the patient was considered to have NI.
2.6  |  Statistical analysis
Statistical analyses were performed using R version 3.6.1 (R
Foundation for Statistical Computing, Vienna, Austria). Continuous
data were presented as the median with interquartile range and cat-
egorical data as the actual count with percentages unless stated oth-
erwise. Categorical variables were assessed using Fisher's exact test,
and continuous variables were assessed using the Mann–­Whitney
U test. Factors with a p value <.10 in the comparison between the
two groups were selected, and univariate logistic regression analysis
was performed to identify factors that might be associated with NI.
The odds ratio and its corresponding 95% confidence intervals were
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      3 of 8
presented. For the cut-­off value selection, the value corresponding
to the maximal Youden index was identified, and the sensitivity and
specificity were calculated. Each hypothesis was two-­t ailed, and a p
value <.05 was considered statistically significant.
3  |  R E S U LT S
3.1  |  Patient characteristics and perioperative
factors
A total of 62 patients with ALF underwent LT between January
2005 and December 2016. Among them, 26 patients were ana-
lyzed in this study (Figure 1). All patients had no history of perinatal
complications and no known neurological event before the onset of
ALF. Head computed tomography before LT was performed for 25
patients, and none of them showed brain edema or abnormal brain
lesion. Of the 26 patients, eight patients had NI whose PCPC scores
at 6 years were 2 (four patients) and 3 (four patients) (Table 1). They
did not have any specific brain lesions, such as brain hemorrhage or
brain infarction; however, they presented with psychomotor devel-
opmental delay, which interfered with getting age-­appropriate grade
(PCPC:2) or participating in regular class (PCPC:3). Among the survi-
vors, no patient had a PCPC score of 4 or 5.
Factors related to patient characteristics, preoperative care, and
LT were compared between the two groups (Table 2). Patients with
NI were significantly younger in age at ALF onset, and pre-­LT peak
laboratory values for total bilirubin, indirect bilirubin, and PT-­INR
were significantly higher in patients with NI. No significant differ-
ence was observed between the two groups with respect to the
peak ammonia levels and the episode of hypoglycemia. Regarding
artificial liver support and LT, no factor with a significant difference
was identified between the two groups.
A comparison of the postoperative factors is shown in Table 3.
Regarding the post-­LT peak laboratory value, no factor with a signif-
icant difference was identified between the two groups. Regarding
postoperative care, patients with NI stayed significantly longer in
the PICU after LT, although no significant differences were observed
in surgical complications during hospitalization.
3.2  |  Risk factors for NI
Table  4 shows the results of the logistic regression analysis for
NI. Pre-­LT total, indirect, and direct bilirubin and age at ALF onset
showed a statistically significant difference. Cut-­off values were
calculated as 421 μmol/L for total bilirubin (sensitivity of 75% and
specificity of 94%), 294 μmol/L for indirect bilirubin (sensitivity of
63% and specificity of 94%), and 176 μmol/L for direct bilirubin
(sensitivity of 63% and specificity of 83%). The cut-­off value for the
age of 6 months had a sensitivity and specificity of 75% and 72%,
respectively. Of the 18 patients without NI in this cohort, five pa-
tients without NI were ≤ 6 months old, three were 1 month old, and
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4 of 8       IDE et al.

F I G U R E 1  Patient flow diagram of this

study.

TA B L E 1  Characteristics of the patients with NI.

Laboratory data (pre-­LT peak value)

Age at
ALF Total Indirect Post-­LT PCPC at
onset Year Ammonia bilirubin bilirubin MV days days in 6 years
No. (month) at LT Sex Etiology (μmol/L) (μmol/L) (μmol/L) PT-­INR after LT PICU old

1 1 2010 Female Viral infection 228 566 344 10 4 11 2

2 1 2014 Female Indeterminate 93 470 294 10 13 21 2
3 1 2016 Female Hemochromatosis 88 708 359 3.1 8 35 3
a
4 2 2012 Male Indeterminate 224 506 378 10 83 83 2
5 6 2006 Male Indeterminate 168 662 583 5.7 12 15 3
6 6 2007 Male Indeterminate 81 421 162 4.4 5 42 3
7 7 2011 Female Indeterminate 122 221 130 8.8 4 16 3
8 9 2008 Male Indeterminate 71 183 60 4.1 6 20 2

Abbreviations: ALF, acute liver failure; LT, liver transplantation; MV, mechanical ventilation; NI, neurological impairment; PCPC, Pediatric Cerebral
Performance Category; PICU, pediatric intensive care unit; PT-­INR, prothrombin time/international normalization ratio.
a
The patient underwent a tracheostomy.

two were 6 months old, and none of them had total bilirubin of
≥421 μmol/L.
4  |  D I S C U S S I O N
A total of 26 infants with ALF who subsequently underwent LT and
survived until 6 years of age were examined. Unclassified NI was ob-
served in 31% (8/26). Patients with NI were significantly younger in
age, had significantly higher pre-­LT bilirubin and pre-­LT PT-­INR, and
stayed significantly longer in the PICU after LT. This study showed
that high pre-­LT peak bilirubin value and younger age at ALF onset
can be perioperative risk factors for NI after LT in infantile ALF.
However, pre-­LT peak ammonia value was not significantly different
between patients with NI and without NI.
Hyperammonemia was reported to be a risk factor for HE and
mortality in pediatric and adult ALF.8,18–­20 However, no significant
difference was observed between the two groups with respect to
the peak ammonia values, and it did not seem to be a risk factor for
NI in our cohort. Ozanne et al.8 examined children with ALF and re-
ported that peak ammonia >200 μmol/L within the first 48 h was an
independent risk factor for mortality. In our cohort, the median peak
ammonia values, 119 μmol/L in patients without NI and 108 μmol/L
in patients with NI, were relatively lower than those in the previous
report (Table 2). Furthermore, there were only two patients with a
peak ammonia value >200 μmol/L, even in patients with NI (Table 1).
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IDE et al.       5 of 8

TA B L E 2  Patient characteristics and

Patients without NI Patients with
perioperative care.
(n = 18) unclassified NI (n = 8) p value

Characteristics
Age at ALF onset (months) 7.5 (6.3–­9.8) 4.0 (1.0–­6.3) .037
Sex (male) 10 (56%) 4 (50%) 1.00
Days between onset and coma 8 (2–­11) 5 (3–­7 ) .11
Etiology .36
Indeterminate 16 (89%) 6 (75%)
Viral infection 1 (6%) 1 (13%)
Hemochromatosis 1 (6%) 1 (13%)
Laboratory data (pre-­LT peak value)
Ammonia (μmol/L) 119 (94–­145) 108 (86–­182) .89
Total bilirubin (μmol/L) 236 (210–­318) 489 (371–­590) .015
Direct bilirubin (μmol/L) 140 (109–­156) 181 (128–­262) .071
Indirect bilirubin (μmol/L) 103 (70–­198) 320 (156–­364) .035
Albumin (g/L)* 24 (23–­25) 27 (25–­28) .16
PT-­INR 3.9 (3.0–­4.4) 7.3 (4.3–­10) .044
Hypoglycemia 6 (33%) 5 (63%) .22
Artificial liver support
Duration of CVVHDF (days) 6 (5–­8) 5.5 (5–­9) .91
Dialysate rate (mL/kg/h) 493 (418–­518) 440 (270–­567) .98
Filtration rate (mL/kg/h) 83 (75–­100) 76 (35–­90) .18
Course of plasma exchange 6 (5–­8) 5 (5–­8) .61
LT
Days between coma and LT 5 (5–­8) 7.5 (5–­16) .36
Days between admission and 6 (5–­6) 4.5 (4–­8) .76
LT
Live donor 17 (94%) 8 (100%) 1.00
Incompatible donor 5 (28%) 1 (13%) .63
Graft-­to-­recipient weight 3.0 (2.7–­3.6) 3.3 (2.9–­3.7) .47
ratio (%)
Duration of operation (min) 526 (441–­580) 519 (438–­586) .72
Blood loss (mL/kg) 91.2 (54.0–­159) 90.1 (63.7–­203) .72

Note: Values are presented as median (interquartile range) or number (%). * The peak value
indicates the lowest value.
Abbreviations: ALF, acute liver failure; CVVHDF, continuous venovenous hemodiafiltration;
LT, liver transplantation; NI, neurological impairment; PT-­INR, prothrombin time/international
normalization ratio.

One of the reasons for lower ammonia values in our cohort may be
the implementation of CVVHDF. CVVHDF was implemented for
patients with HE higher than grade II, and the dialysate flow rate
10
was increased to maintain an ammonia value <90 μmol/L.
cohort, all patients were treated with CVVHDF. Cardoso et al.
ported that continuous renal replacement therapy was associated
with a reduction in serum ammonia level and an improvement in
transplant-­free survival in adult ALF. CVVHDF implementation re-
duced serum ammonia and might have affected the outcomes.
Hyperbilirubinemia can cause bilirubin neurotoxicity, present-
ing as acute bilirubin encephalopathy or kernicterus. 21,22 Bilirubin
neurotoxicity is known to affect the basal part of the brain in
kernicterus, and it may also affect cortical neurons and cause clum-
siness, memory deficit, hearing deficit, language impairment, autism
spectrum disorders, or attention deficit hyperactivity disorder. 21–­23
In this Bilirubin neurotoxicity is caused by a high level of unbound unconju-
18
re- gated bilirubin that is unbound to albumin since albumin-­bound bil-
irubin probably does not cross an intact blood–­brain barrier. 21,22,24
Although there is no research on unbound unconjugated bilirubin in
ALF to the best of our knowledge, Lin et al. 25 reported that the un-
conjugated bilirubin-­albumin ratio constitutes the most powerful risk
factor in the occurrence of HE in adult ALF. In this study, peak serum
bilirubin level was significantly higher in patients with NI. Thus, hy-
perbilirubinemia might cause acute bilirubin encephalopathy and
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6 of 8       IDE et al.

TA B L E 3  Clinical course after liver

Patients without Patients with
transplantation.
NI (n = 18) unclassified NI (n = 8) p value

Laboratory data (post-­LT peak value)

Ammonia (μmol/L) 48 (42–­57) 58 (53–­68) .067
Total bilirubin (μmol/L) 79 (58–­97) 87 (62–­140) .52
Direct bilirubin (μmol/L) 39 (26–­48) 48 (27–­87) .39
Indirect bilirubin (μmol/L) 38 (27–­4 4) 41 (36–­60) .37
PT-­INR 1.7 (1.5–­2.2) 2.0 (1.8–­2.2) .20
Hypoglycemia 1 (6%) 0 1.00
MV days after LT 4.5 (3–­7 ) 7 (5–­12) .079
Post-­LT days in PICU 12.5 (10–­16) 20.5 (16–­37) .021
Post-­LT days in hospital 70 (56–­86) 62.5 (47–­94) .58
Surgical complications during hospitalization
Portal vein 0 1 (13%) .31
Hepatic artery 0 0
Hepatic vein 1 (6%) 0 1.00
Bile duct 1 (6%) 1 (13%) .53
Relaparotomy 2 (11%) 1 (13%) 1
TCMR (rejection activity index 11 (61%) 2 (25%) .20
≥4) during hospital stay

Note: Values are presented as median (interquartile range) or number (%).

Abbreviations: LT, liver transplantation; NI, neurological impairment; MV, mechanical ventilation;
PICU, pediatric intensive care unit; PT-­INR, prothrombin time-­international normalization ratio;
TCMR, T cell-­mediated rejection.

TA B L E 4  Risk factors for NI. babies with clinical instability, 402 μmol/L (23.5 mg/dL), 26 or the
threshold identifying 90% of infants with bilirubin encephalopathy,
Odds
434 μmol/L (25.4 mg/dL). 27 However, only eight patients had NI in
Factors ratio 95% CI p value
this study. Thus, we do not think we can use the cut-­off value as a
Total bilirubin (pre-­LT) 1.12a 1.02–­1.22 .012
treatment threshold. Further investigations are needed for bilirubin
(μmol/L)
toxicity in ALF.
Indirect bilirubin (pre-­LT) 1.10a 1.01–­1.20 .025
(μmol/L) In this study, younger age at ALF onset was considered a poten-
tial risk factor for NI in infantile ALF. Infants less than 12 months
Direct bilirubin (pre-­LT) 1.22a 1.01–­1.47 .040
(μmol/L) old with ALF were reported to have a high risk of mortality.28,29

Age at ALF onset (months) 0.76 0.58–­ .049 HE and cerebral edema were the main causes of death in patients
0.999 with ALF.1 Thus, patients with a poor prognosis may have poor neu-
PT-­INR (pre-­LT) 1.34 0.99–­1.82 .063 rological outcomes, even if they survive. Also, brain development
Ammonia (post-­LT) (μmol/L) 1.04 0.995–­1.08 .089 in younger children may be affected by repeated or lengthy use

Post-­LT days in PICU 1.05 0.99–­1.12 .10

MV days after LT 1.09 0.91–­1.30
Note: High pre-­LT peak bilirubin value and younger age at ALF onset
can be perioperative risk factors for neurological impairment after LT in
infantile ALF.
Abbreviations: ALF, acute liver failure; CI, confidence interval; LT,
liver transplantation; MV, mechanical ventilation; NI, neurological
impairment; PICU, pediatric intensive care unit; PT-­INR, prothrombin
time-­international normalization ratio.
a
Per 10 μmol/L change.
contribute to NI in infants with ALF. Regarding the cut-­off value for
total bilirubin, a 421 μmol/L in this study was similar to the thresh-
old for exchange transfusion in neonatal hyperbilirubinemia in term
of general anesthetics and sedatives, as reported in the Food and
Drug Administration “Drug Safety Communications” (www.fda.gov/
.34
Drugs/​DrugS​afety/​ucm53​2356.htm). In this study, patients with NI
were on mechanical ventilation for a median of 4.5 days before LT
(Table 3) and a median of 7 days after LT (Table 4). The lengthy use
of sedatives during mechanical ventilation may affect the vulnerable
infant brain. Furthermore, there may be an age-­related susceptibility
to hyperbilirubinemia. Regarding bilirubin toxicity, immaturity is one
of the known risk factors associated with reduced albumin binding
and increased vulnerability.22
There are various factors in the perioperative period that have
complex effects on the neurological outcome.1,2 To the best of
our knowledge, this is the first study that examined the periop-
erative risk factors for NI in infants with ALF following LT and

IDE et al.
showed hyperbilirubinemia as a potential risk factor. However,
this study has several limitations. First, this was a single-­center
retrospective cohort study with a small sample size, which lim-
its generalizability. Also, the study period was relatively long as
11 years. Thus, practice changes, such as establishment of graft
15
type selection, during the study period may affect the outcome
although the patients with NI were observed evenly. Second, we
included patients less than 1 year old. Thus, it is unclear whether
this can be generalized to patients older than 1 year. Third, neuro-
logical evaluation was performed using the PCPC. Although the
PCPC is useful for assessing overall functional morbidity, 30 neuro-
cognitive function tests, such as the Wechsler Intelligence Scales
for Children, and health-­related quality of life assessments, such
as PedsQL4.0 Generic Core Scales, may provide precise and ex-
tensive information. Therefore, further investigations using these
neurological evaluation methods are needed. Fourth, the patient's
PCPC score was assessed according to the status at the age of
6 years. Patients who died by 6 years were excluded, which can
cause bias. Furthermore, long-­term immunosuppressive therapy
or graft failure requiring repeat LT can cause complications. In ad-
dition, readmission to the hospital or prolonged hospital stay and
administration of medicines may affect the mental development.
However, those effects have not been fully investigated in this
study. Fifth, we did not evaluate the prognostic value of the coma
status during intensive care and at the time of LT since it was dif-
ficult to accurately assess the coma status for infants under me-
chanical ventilation. As coma status may be important in predicting
clinical factors, further investigations are needed. Sixth, PT-­INR,
one of the indicator of liver function and liver regeneration, was
not a statistically significant predictor for NI in this study. PE or
fresh frozen plasma improved the value and affected the result.
Seventh, the odds ratio for bilirubin was calculated per 10 μmol/L
change, thus, it should be interpreted with caution. Eighth, un-
bound unconjugated bilirubin was not measured, although it plays
an important role in neonatal bilirubin encephalopathy. 21,22 Also,
the effect of hyperbilirubinemia on head image findings identified
in cases of kernicterus was not examined. Thus, further investiga-
tions are needed to examine the perioperative risk factors, includ-
ing bilirubin toxicity, in patients with ALF. Furthermore, a larger
multicenter cohort, such as a prospective registry of ALF children,
is needed.
5  |   CO N C LU S I O N S
A total of 26 infants with ALF who subsequently underwent LT and
survived until 6 years of age were examined. The results revealed
that unclassified NI was observed in 31% (8/26). The high pre-­LT peak
bilirubin value and younger age at ALF onset can be perioperative
risk factors for NI after LT in infantile ALF. Further investigations are
needed to examine the perioperative risk factors, including bilirubin
toxicity, in patients with ALF.
|
13993046, 2023, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/petr.14524 by Universidad Nacional Autonoma De Mexico, Wiley Online Library on [25/06/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
      7 of 8
AU T H O R C O N T R I B U T I O N S
KI reviewed and extracted data from the electronic health records
and wrote the manuscript. HU and IH reviewed the electronic health
records with KI to access the NI. SS, SN, and MK conceptualized
and designed the study. TK and SI supervised data analysis. All the
authors read and approved the final article.
AC K N OW L E D G M E N T S
This work was supported by the National Center for Child Health and
Development (grants 2021A-­2 and 2022C-­11). The authors would
like to thank the medical editor from the Division of Postgraduate
Education and Training, National Center for Child Health and
Development, for editing this manuscript.
C O N F L I C T O F I N T E R E S T S TAT E M E N T
The authors declare no conflicts of interest associated with this
manuscript.
DATA AVA I L A B I L I T Y S TAT E M E N T
The data used to support the findings of this study are available from
the corresponding author, KI, upon reasonable request.
ORCID
Kentaro Ide  https://orcid.org/0000-0003-3142-0764
Hajime Uchida  https://orcid.org/0000-0003-2441-5158
Seisuke Sakamoto  https://orcid.org/0000-0003-3031-7319
Itaru Hayakawa  https://orcid.org/0000-0002-6384-0205
Tohru Kobayashi  https://orcid.org/0000-0002-7630-5367
Mureo Kasahara  https://orcid.org/0000-0002-1651-0430
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How to cite this article: Ide K, Uchida H, Sakamoto S, et al.
Perioperative risk factors for neurological impairment in
infants with acute liver failure following liver transplantation.
Pediatric Transplantation. 2023;27:e014524. doi:10.1111/
petr.14524