A review on neurodevelopmental abnormalities in congenital heart disease: focus on minimizing the deleterious effects on patients

Abstract

Due to the surgical procedures, the longevity of congenital heart patients is dramatically increased; however, these patients suffer from concomitant neurodevelopment abnormalities, which include deficits in cognitive, executive and behavioral functions. There are more chances of seizure development and incidences of ischemic stroke in these children. Indeed, there are pathological changes in the brain, which include a reduction in the volume of the brain, metabolic alterations, alterations in the functional connectivity, dysregulation of angiogenesis and changes in the apparent axon density along with orientation dispersion. The management of neural abnormalities depends on the type of symptoms observed in these patients. There have been limited studies that have focused on identifying the interventions that may limit the impact of neurodevelopmental abnormalities. It has been reported that dexmedetomidine, α2-adrenergic receptor agonist, produces neuroprotection in infants undergoing surgery for congenital heart disease. Moreover, there have been some studies focusing on the impact of mode of feeding, anticoagulation, and effect of other anesthetics on the neurodevelopmental changes in congenital heart disease pediatrics. The present review discusses the neurodevelopment abnormalities in congenital heart disease pediatrics with a focus on different interventions that have been explored by different scientists to limit the deleterious effects on the patients.

Full text

ALL LIFE
2021, VOL. 14, NO. 1, 172–180
https://doi.org/10.1080/26895293.2021.1899992
REVIEW
A review on neurodevelopmental abnormalities in congenital heart disease:
focus on minimizing the deleterious effects on patients
Bai-hong Zhenga, Xiu-min Liub, Peng Zhaocand Ping Lid
aDepartment of Pediatrics, the Second Hospital of Jilin University, Changchun, Jilin, People’s Republic of China; bDepartment of Clinical
Laboratory, the Second Hospital of Jilin University, Changchun, People’s Republic of China; cDepartment of Anesthesiology, the Second
Hospital of Jilin University, Changchun, People’s Republic of China; dDepartment of Developmental Pediatrics, the Second Hospital of Jilin
University, Changchun, Jilin, People’s Republic of China
ABSTRACT
Due to the surgical procedures, the longevity of congenital heart patients is dramatically increased;
however, these patients suffer from concomitant neurodevelopment abnormalities, which include
deficits in cognitive, executive and behavioral functions. There are more chances of seizure develop-
ment and incidences of ischemic stroke in these children. Indeed, there are pathological changes in
the brain, which include a reduction in the volume of the brain, metabolic alterations, alterations in
the functional connectivity, dysregulation of angiogenesis and changes in the apparent axon den-
sity along with orientation dispersion. The management of neural abnormalities depends on the
type of symptoms observed in these patients. There have been limited studies that have focused on
identifying the interventions that may limit the impact of neurodevelopmental abnormalities. It has
been reported that dexmedetomidine, α2-adrenergic receptor agonist, produces neuroprotection
in infants undergoing surgery for congenital heart disease. Moreover, there have been some studies
focusing on the impact of mode of feeding, anticoagulation, and effect of other anesthetics on the
neurodevelopmental changes in congenital heart disease pediatrics. The present review discusses
the neurodevelopment abnormalities in congenital heart disease pediatrics with a focus on different
interventions that have been explored by different scientists to limit the deleterious effects on the
patients.
ARTICLE HISTORY
Received 20 July 2020
Accepted 2 March 2021
KEYWORDS
Neurodevelopment;
dexmedetomidine;
cognition; congenital heart
disease; angiogenesis;
anesthetic
1. Introduction
Congenital heart diseases are the functional and struc-
tural changes in the heart, circulatory system, or large
vessels, which develop during cardiac embryogene-
sis. Congenital heart defects are the most common
congenital anomalies, including aortic valve steno-
sis, coarctation of the aorta, patent ductus arterio-
sus, pulmonary valve stenosis, septal defects, single
ventricle defects, tetralogy of Fallot and transposition
of the great arteries (Garcia and Peddy 2018;Tassi-
nari et al. 2018).Thesedefectsaresignicantcauses
of morbidity and mortality in children worldwide.
However, with the advent of surgical procedures, the
longevity of these patients is dramatically increased.
However, these patients suer from concomitant neu-
rodevelopment abnormalities, which persist for the
whole life (Peyvandi et al. 2019). From the data of
25, 985 Swedish children and young adults with con-
CONTACT Ping Li l_ping@jlu.edu.cn Department of Developmental Pediatrics, the Second Hospital of Jilin University, 218 Ziqiang Street, Nanguan
District, Changchun, Jilin 130041
genital heart disease, it was found that patients with
congenital heart disease have about 11 fold greater
risk of development of ischemic stroke in compari-
son to the normal population (Mandalenakis et al.
2016).
Moreover, the decits in cognitive, executive, com-
munication, and behavioral functions are very com-
mon in these patients (Jakab et al. 2019;Whiteetal.
2019). The neurodevelopment abnormalities observed
in congenital heart disease patients are due to the
impairment in brain maturation (Morton et al. 2017)
andpathologicalalterationsinthebrain(Mebiusetal.
2017). These pathological changes are reduction in
the total volume of the brain, white brain and hip-
pocampus (von Rhein et al. 2014;Rollinsetal.2017);
metabolic changes (Vedovelli et al. 2019); functional
connectivity between dierent portions of the brain
(De Asis-Cruz et al. 2018)andchangesintheapparent
© 2021 The Author(s). Published by Informa UK Limited, trading as Taylor& Francis Group
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use,
distribution, and reproduction in any medium, provided the original work is properly cited.

ALL LIFE 173
axon density and orientation dispersion (Easson et al.
2020).
Accordingly, it is suggested that there is a need for
follow-up and application of early intervention follow-
ing surgery to limit the neurodevelopment abnormal-
ities (Butler et al. 2019). The management of these
abnormalities is dependent on the type of symp-
toms observed in these patients. However, there have
been few studies that have focused on identifying
the interventions that may limit the impact of neu-
rodevelopmental abnormalities. It has been reported
that dexmedetomidine, α2-adrenergic receptor ago-
nist, produces neuroprotective eects in infants under-
going surgery for congenital heart disease (Schwartz
et al. 2016). Moreover, there have been few stud-
ies focusing on the impact of mode of feeding
(Holst et al. 2019), anticoagulation (Leijser et al.
2019) and the eect of other anesthetics (Fleck et al.
2015) on the neurodevelopmental changes in con-
genital heart disease pediatrics (Table 1). The present
review discusses the neurodevelopment abnormalities
in congenital heart disease pediatrics with a focus on
dierent interventions that have been explored by dif-
ferent scientists to limit the deleterious eects on the
patients.
Methodology
The literature to write this review was collected
using ‘PUBMED’ ‘EMBASE’ and ‘Google Scholar’
using dierent keywords including ‘congenital heart
disease’ ‘neurodevelopmental abnormalities’, ‘infants’
‘children’ ‘card i a c s u r ger y’, and ‘neuroprotection’.
Neurodevelopmental abnormalities in
congenital heart disease infants
Diverse range of abnormalities related to brain
functioning
It is very well reported that infants with congenital
heart disease exhibit a wide range of neurodevelop-
mental abnormalities, including decits in language,
executive function and behavioral abnormalities
(Peyvandi et al. 2019;Whiteetal.2019). Executive
function impairments are among the most prevalent
neurodevelopmental morbidities in youth with con-
genital heart disease (Nattel et al. 2017;Calderonetal.
2019). Children and adolescents with congenital heart
disease (CHD) are at risk for mild to moderate cog-
nitive impairments. In particular, impaired working
memory performance has been found in CHD patients
Tab le 1. Summarized findings of different interventions on neurodevelopmental abnormalities in children undergoing heart surgery.
S. No Interventions Type of study Results References
Non-Pharmacological Interventions
1. Feeding Mode Retrospective cohort study
(n=208)
Lesser neurodevelopment delay in orally fed children in
comparison to enteral tube-fed children
Holstetal.(2019)
2. Feeding Mode Retrospective cohort study
(n=194)
Infants on oral feedings developed lesser neurodevelopmental
impairment in comparison to infants on G-tube feedings
Jadcherla et al.
(2017)
Pharmacological Interventions
3. Dexmedetomidine Retrospective cohort study
(n=12,142)
Patients had improved outcomes in patients receiving
dexmedetomidine
Schwartz et al.
(2016)
Randomized, single-blind study
(n=80)
Decreased levels of neuron-specific enolase and S-100β
protein along with improvement in oxygen metabolism
suggesting reduced brain injury
Gong et al. (2019)
Retrospective study (n=256) Significant preservation of intelligence quotient and
neurodevelopment undergoing surgery
Huang et al. (2020)
4. Erythropoietin Prospective phase I/II clinical trial
(n=42)
No neurological protection from erythropoietin Andropoulos et al.
(2013)
5. Ketamine Randomized clinical study
(n=24)
No significant differences in the expression of cytokines,
chemokines, S100, and neuron-specific enolase between
ketamine-treated and placebo
Bhutta et al. (2012)
6. Dextromethorphan Randomized, placebo-controlled
trial (n=13)
Treatment with dextromethorphan exhibited fewer brain
abnormalities, however, the effects were not significantly
different in comparison to placebo
Schmitt et al.
(1997)
7. Allopurinol Single centered, randomized,
placebo-controlled, blinded trial
Ketamine produced neuroprotection in higher-risk HLHS
patients without any significant effect in lower risk,
non-HLHS infants
Clancy et al. (2001)
8. Anticoagulants Two-center, observational cohort
study (n=118)
No benefit of preventing brain injury with the use of
anticoagulation
Leijser et al. (2019)

174 B.-H. ZHENG ET AL.
of all ages (Ehrler et al. 2020). The disrupted or delayed
maturation of white matter may persist into adoles-
cence and is associated with working memory impair-
ments, particularly if present in the frontal lobe (Ehrler
et al. 2020). Furthermore, cerebral injury in the form of
arterial ischemic strokes, white matter injury, subdural
hemorrhage and intracranial hemorrhage is also com-
mon in pediatric children suering from congenital
heart disease (Kelly et al. 2019). Furthermore, children
with complex congenital heart disease experience a
high incidence of perioperative seizures (Desnous et al.
2019).
Pathological changes in the brains of newborns with
congenital heart disease
The neurodevelopment abnormalities in congenital
heart disease infants have been attributed to patholog-
icalalterationsinthebrainofthesepatients(Mebius
et al. 2017). Most of the studies have focused on the
decrease in the volume of the brain or its dierent
portions. A signicant decrease in the hippocampal
volumes in congenital heart disease patients has been
identied, which is negatively correlated with work-
ing memory and other executive functions (Fontes
et al. 2019).Therehavemorestudiesshowingasigni-
cant decline in the volume of total brain, white matter,
and cortical grey matter. The reduction in brain vol-
ume ranged from 5.3% (cortical grey matter) to 11%
(corpus callosum) (von Rhein et al. 2014). The reduc-
tion in the white matter microstructure in congenital
heart disease infants has also been reported, which was
associated with the decrease in cognitive performance
(Rollins et al. 2014).Thesamegroupofscientistsdocu-
mented that the decrease in the volume of white matter
predicts the development of language abnormalities
in congenital heart disease infants. Indeed, a reduc-
tion of approximately 54 mL in the total brain volume
andabout40mLincerebralwhitematterwasreported
in infants with congenital heart disease in compari-
son to normal infants. Moreover, this dierence in the
white matter volume was correlated to the language
development indices (Rollins et al. 2017).
It has been reported that there is a reduced regional
functional connectivity involving critical brain regions
in newborns with congenital heart disease, which
may be responsible for early-life brain dysfunction
and neurodevelopmental impairments (De Asis-Cruz
et al. 2018). In a very recent study, the changes in
the apparent axon density and orientation dispersion
in the white matter of newborns with congenital
heart disease have been reported. Using brain mag-
netic resonance imaging, the comparison between the
axon density and neurite orientation dispersion within
white matter was made between normal and congen-
ital heart disease infants. The average neurite den-
sity index was much lower, particularly within long
association tracts and in regions of the corpus callo-
sum in congenital heart disease infants. Along with
it, smaller white matter tract volumes and clusters of
lower fractional anisotropy was also reported, with-
out any signicant dierences in orientation disper-
sion index. It suggests that the decrease in the density
of axonal packing, but not altered axonal orientation,
is the important microstructural change in the white
matter in infants born with congenital heart disease
(Easson et al. 2020). Apart from well-dened patho-
logical alterations in the brain, there are changes in the
metabolic proles in congenital heart disease patients,
including higher levels of accumulation of citric acid
cycle intermediates and glucose, which has been sug-
gested due to switching to anaerobic metabolism. The
presence of these metabolic changes has been cor-
related with the adverse neurodevelopment pattern
(Vedovelli et al. 2019).
Dysregulation of angiogenesis
It has been proposed that there is an overall dysreg-
ulation of angiogenesis i.e. an increase in the expres-
sion of antiangiogenic and decrease in the angiogenic
factors in the brains of fetuses with congenital heart
disease. An experimental study identied the changes
in the expression of angiogenesis regulating genes in
the cerebral tissues obtained from 15 fetuses with con-
genital heart disease that had undergone termination
of pregnancy. Real-time polymerase chain reaction
(RT–PCR) revealed the higher expression of soluble
fms-like tyrosine kinase-1 (sFlt-1), a tyrosine kinase
protein with antiangiogenic properties, in the frontal
cortex and basal ganglia of fetuses. There was also
ariseinthelevelsofangiogenesispromotingpro-
teins including, VEGF-A and hypoxia-inducible fac-
tor 2-alpha in the frontal cortex and basal ganglia.
However, the net balance was towards the antiangio-
genic factors, which suggested that fetuses with con-
genitalheartdiseasehaveimpairedangiogenesisthat
may be responsible for impaired brain perfusion and
abnormal neurological development (Sánchez et al.
2018).

ALL LIFE 175
An earlier study reported a similar pattern of
changes including an increase in sFlt-1 and angiogen-
esis promoting proteins and suggested that the imbal-
ance in angiogenic-antiangiogenic factors is associ-
ated with developmental defects of the human heart
(Llurba et al. 2014). However, these ndings are not in
linewithastudyraisingthepossibilityofanincreasein
bloodperfusioninthewhitematterofnewbornswith
congenital heart disease. Indeed, the extent of blood
perfusion was compared in one newborn with con-
genital heart disease before surgery and three healthy
newborns. The cerebral blood ow was increased in
the white matter of a newborn with congenital heart
diseases. Moreover, there was the overexpression of
vascular endothelial growth factor in the injured white
matter of the newborn with congenital heart disease
(Wintermark et al. 2015). The studies of Wintermark
et al. (2015) and Sánchez et al. (2018)reportthe
opposite results, however, both reported the increase
in the expression of vascular endothelial growth fac-
tor in the brain of congenital heart disease children.
Sánchez et al proposed that an increase in the shift
to anti-angiogenesis factors may decrease the cerebral
blood ow, which may contribute to neurodevelop-
mental abnormalities. There have been several studies
supporting that decrease in cerebral oxygen supply or
utilization is responsible for reduced brain size and
neurodevelopmental abnormalities (Sun et al. 2015).
On the other hand, Wintermark et al proposed that
an increase in angiogenesis may contribute to cerebral
injury and this hypothesis was based on the studies
showing that an increase in angiogenesis is responsible
for macular injury and retinopathy (Hartnett 2014).
Accordingly, more detailed studies are required to fully
elucidate the role of angiogenesis regulating factors in
the neurodevelopmental abnormalities in congenital
heart disease.
Studies focusing on the impact of different
interventions on neurodevelopment
abnormalities
Non-Pharmacological
Impact of the feeding mode on the neurodevelopment
changes
A signicant impact of the mode of feeding has been
identied on the outcome of neurodevelopment in
congenital heart disease infants. A retrospective cohort
study performed by Holst et al on 208 children with
congenital heart disease reported that the children on
enteral feeding tubes had signicantly lower develop-
mental quotient scores in cognition, communication,
and motor function in comparison to orally fed chil-
dren. The developmental delay was much more signif-
icant in enteral tube-fed children with the same-aged
infants, kept on oral feed (Holst et al. 2019). Another
study involving retrospective cohorts of 194 neonates
reported the impact of the mode of feeding on the neu-
rodevelopment outcomes. It was reported that infants
(60%, n=117) discharged on oral feedings remained
on an oral diet and presented with lesser long-term
neurodevelopmental impairment. On the other hand,
the remaining infants (40%, n=77) discharged on
G-tube feedings had lower cognitive, communication,
and motor composite scores. It further emphasizes the
importance of oral feeding in reducing neurodevelop-
ment alterations in congenital heart disease patients
(Jadcherla et al. 2017).
Pharmacological Interventions
Dexmedetomidine as an anesthetic in congenital
heart disease infants
Safety and ecacy of dexmedetomidine as an anes-
thetic in infants with heart diseases. Dexmedeto-
midine is an α2-adrenergic receptor agonist, which
is FDA approved for sedation and analgesia in the
intensive care unit (ICU) (Phan and Nahata 2008;
Afonso and Reis 2012). As a pre-anesthetic medica-
tion, dexmedetomidine produces arousable sedation
and anxiolysis, while as an intraoperative adjunctive
agent, it provides balanced anesthesia and reduces the
neuro-humoral stress response. Moreover, its clinical
usehasbeenfoundtosparetheuseofopioidsand
prevent the risk of postoperative delirium or agitation
(Kiski et al. 2019). There have been several studies
showing the ecacy and safety of dexmedetomidine
in infants with cardiac diseases (Chrysostomou et al.
2009). Moreover, its safety persists beyond 24 h, with-
out the emergence of rebound eects after its discon-
tinuation (Guinter and Kristeller 2010). A retrospec-
tive observational study conducted in the cardiovas-
cular intensive care unit has reported that critically ill
neonates and infants with heart disease remain hemo-
dynamicallystableinresponsetodexmedetomidine
infusion during surgery. Moreover, it was shown to

176 B.-H. ZHENG ET AL.
reduce the concomitant dose of opioid and benzo-
diazepine agents (Lam et al. 2012). There has been
another retrospective study showing the ecacy and
safety of dexmedetomidine in critically ill infants and
children with congenital or acquired heart disease
who received dexmedetomidine for more than 96 h. It
was shown that the duration and amount of midazo-
lam and morphine infusions were signicantly lower
in the dexmedetomidine-administered infants (Gupta
et al. 2012). The retrospective observational study con-
ducted by Lam et al also reported the safety and
ecacy of dexmedetomidine in children with heart
failure. Dexmedetomidine was administered in 21
patients, and it was reported that there was no sig-
nicant eect on the heart rate, blood pressure, or
inotropic score at the termination of infusion. It also
led to a reduction in the dose of midazolam. Moreover,
the numbers of sedation and analgesic rescue were sig-
nicantly lower in the dexmedetomidine group, sug-
gesting that the administration of dexmedetomidine
in children with heart failure appears to be safe (Lam
et al. 2012). Moreover, dexmedetomidine is eective
in reducing the length of stay and time to extubation
in critically ill ICU patients. However, a relative risk of
bradycardia has been identied among patients treated
with dexmedetomidine (Cruickshank et al. 2016).
Neuroprotective eects of dexmedetomidine. Apart
from a simple anesthetic agent, the employment of
dexmedetomidine has produced favorable eects on
the brain in congenital heart disease infants under-
going surgery. Schwartz et al analyzed the data from
the Congenital Cardiac Anesthesia Society-Society of
Thoracic Surgeons Congenital Heart Disease Database
to study the role of perioperative use of dexmedeto-
midine in pediatric patients with congenital heart
disease. The data of 12,142 patients, in which 3600
received perioperative dexmedetomidine and 8542
did not receive the drug, was collected from 2010
to 2013. The results revealed that children receiving
dexmedetomidine had improved outcomes as com-
pared to patients who did not receive dexmedetomi-
dine (Schwartz et al. 2016). A randomized, single-
blind controlled study involving pediatric patients
(n=80) with congenital heart disease explored the
neuroprotective potential of dexmedetomidine during
surgery. The study revealed that the administration of
dexmedetomidine signicantly attenuated brain injury
as assessed by decreased levels of neuron-specic eno-
lase (NES) and S-100βprotein. Moreover, dexmedeto-
midine treatment during surgery improved the oxygen
metabolism in brain tissues suggesting the neuropro-
tective actions of dexmedetomidine during surgery
of congenital heart disease pediatric patients (Gong
et al. 2019). Another retrospective study on pediatric
patients (n=256) with heart disease undergoing tho-
racic surgery revealed the signicance of dexmedeto-
midine. The results showed that there was a signi-
cant preservation of intelligence quotient scores and
neurodevelopment evaluation scores in infants receiv-
ing dexmedetomidine in comparison to patients not
receiving dexmedetomidine. However, there was no
signicant dierence in overall mortality, duration
of mechanical ventilation, or length of stay. There-
fore,itmaybesuggestedthattheadministrationof
dexmedetomidine may improve neural development
in infants with congenital heart disease undergoing
surgery (Huang et al. 2020).
Erythropoietin as neuroprotective drug
Erythropoietin has been shown to exert neuro-
protective eects due to its anti-apoptotic, anti-
inammatory, and antiexcitatory eects (Fischer et al.
2017). Therefore scientists have employed the use of
erythropoietin as a neuroprotectant in patients under-
going heart surgery. There have been mixed reports
regarding the use of erythropoietin as neuroprotec-
tive agents in older patients undergoing cardiac injury
(Lakič et al. 2010,2016). However, in a prospective
phase, I/II clinical trial involving 22 neonates under-
going cardiac surgery did not get neurological pro-
tection from erythropoietin administration and results
were not statistically dierent from the placebo group
(n=20) (Andropoulos et al. 2013).
N-methyl-D-aspartate receptor antagonists as
neuroprotective drugs
Ketamine. Ketamine is an NMDA receptor antago-
nist and serves as a dissociative anesthetic. There have
been preclinical (Wang et al. 2019)aswellasclin-
ical studies (Nagels et al. 2004)showingtheneuro-
protective eects of ketamine. The employment of
ketamine has been shown to attenuate post-operative
cognitive dysfunction after cardiac surgery (Hudetz
et al. 2009). Based on these reported benecial eects
of ketamine, a randomized clinical trial explored
the neuroprotective potential of ketamine in infants

ALL LIFE 177
(n=13) undergoing cardiopulmonary bypass surgery
for repair of ventricular septal defects in comparison
to placebo (n=11).Theresultsfoundnosignicant
dierences in the expression of cytokines, chemokines,
S100, and neuron-specic enolase between ketamine-
treated and placebo. It suggested that ketamine failed
to exhibit neuroprotective eects in infants with con-
genital heart disease (Bhutta et al. 2012).
Dextromethorphan. Dextromethorphan is a non-
competitive antagonist and it has also been shown to
exhibit neuroprotection (Pu et al. 2015).Inaclinical
study involving thirteen children (age 3–36 months)
undergoing cardiac surgery with cardiopulmonary
bypass, the ecacy of dextromethorphan in attenu-
ating brain injury was explored. The results found
that children with dextromethorphan exhibited fewer
abnormalities in electroencephalography and MRI,
however, the eects were not signicantly dierent in
comparison to placebo (Schmitt et al. 1997).
Allopurinol as a neuroprotective drug
Allopurinol is a xanthine oxidase inhibitor and apart
from its typical anti-hyperuricemic actions, it has been
shown to produce neuroprotective eects in animal
studiesaswellinneonates(Anninketal.2017). The
neuroprotective eects of allopurinol may be due to
inhibition of superoxide formation and directly scav-
enging free radicals (Yıldız et al. 2017). A single-
center, randomized, placebo-controlled, blinded trial
explored the neuroprotective potential of allopuri-
nol in infants undergoing heart surgery. The authors
divided the patients into two categories i.e. hypoplas-
tic left heart syndrome (HLHS) and all other forms
of congenital heart disease (non-HLHS). It was found
that treatment with ketamine led to signicant neu-
roprotection in higher-risk HLHS patients without
any signicant eect in lower-risk, non-HLHS infants
(Clancy et al. 2001).
Anticoagulants
The use of anticoagulants is recommended for the pre-
vention of the development of stroke in patients with
atrial brillation and valvular defects. A two-center,
observational cohort study of 118 term-born neonates
with congenital heart diseases (TGA, n=83 and SVP,
n=35) studied the eectiveness of anticoagulation
therapyonbraininjuryinneonatesundergoingcar-
diopulmonary bypass surgery. The results revealed
the more signicant postoperative parenchymal brain
injury (stroke) in SVP neonates with the use of antico-
agulants as compared to without anticoagulation (31%
vs 5%). In neonates with the incidence of preoperative
stroke, there was more frequent development of new
subdural hemorrhage as compared to without anti-
coagulation (36% vs 0%). Accordingly, it was stated
that there was no anticipated benet of preventing
brain injury with the use of anticoagulation during
cardiopulmonary bypass surgery (Leijser et al. 2019).
Impact of propofol
Propofol is widely used in procedural sedation in chil-
dren during surgeries. Indeed, intravenous propofol is
used for the induction of anesthesia, and thereafter,
anesthesia is maintained with propofol-remifentanil.
Propofol is well known to decrease systemic vascu-
lar resistance and arterial blood pressure. Therefore,
it has been speculated that due to a decrease in sys-
temic perfusion, the employment of propofol may
potentially result in a reduction in cerebral blood ow
and oxygenation. A study was performed to mea-
sure the changes in the cerebral blood in congeni-
tal heart disease children (n=32, median age =49
months) undergoing heart surgery using propofol as
an anesthetic agent. Propofol was shown to decrease
the mean arterial pressure (79 ±16 vs. 67 ±12 mmHg)
and cardiac index (3.2 ±0.8 vs. 2.9 ±0.6 ml/min/m2).
However, the cerebral tissue oxygenation index was
increased (57 ±11 to 59 ±10%) despite a decrease
in cardiac index and arterial blood pressure, which
may be possibly due to decreased oxygen consump-
tion by the sedated brain with an intact cerebral auto-
regulation. Accordingly, it was suggested that the use of
propofol as an anesthetic agent does not reduce cere-
bral blood ow and oxygenation during surgery (Fleck
et al. 2015).
Future directions
At present, there are limited options to attenuate
brain injury during cardiac surgery for the repair of
congenital heart disease. There has been extensive
research on the use of stem cells for the repair of con-
genital heart disease and success has been achieved
in many experimental studies. However, the impact
of stem cells in preventing brain may need further
research.

178 B.-H. ZHENG ET AL.
Conclusion
There have been very few studies that have focused on
the reduction in neuronal damage in congenital heart
disease patients. Amongst the pharmacological inter-
ventions, dexmedetomidine, α2-adrenergic receptor
agonist, has been reported to impart neuroprotection
and limit the impact of surgery on neurodevelopment.
However, the employment of anticoagulants has not
been reported to produce benecial eects in these
patients. The non-pharmacological intervention i.e.
oral mode of feeding, has also been found to produce
benecial eects. Nevertheless, there is a need for more
studies to identify the interventions that may attenuate
the deleterious impact of congenital heart disease on
the brain.
Data availability statement
Thedatawillbeavailableonrequest.
Disclosure statement
No potential conict of interest was reported by the author(s).
Funding
This work was supported by Appropriate Health Techniques
For Poverty Alleviation Program of Health Commission of Jilin
Province: [Grant Number 2018FP044].
References
Afonso J, Reis F. 2012. Dexmedetomidine: current role in anes-
thesia and intensive care. Rev Bras Anestesiol. 62:118–133.
doi:10.1016/S0034-7094(12)70110-1.
Andropoulos DB, Easley RB, Brady K, McKenzie ED, Heinle
JS, Dickerson HA, Shekerdemian LS, Meador M, Eisen-
manC,HunterJV,etal.2013. Neurodevelopmental out-
comes after regional cerebral perfusion with neuromoni-
toring for neonatal aortic arch reconstruction. Ann Thorac
Surg. 95:648–655. doi:10.1016/j.athoracsur.2012.04.070.
Annink KV, Franz AR, Derks JB, Rüdiger M, Bel FV, Ben-
ders M. 2017. Allopurinol: old drug, new indication in
neonates? Curr Pharm Design. 23:5935–5942. doi:10.2174/
1381612823666170918123307.
BhuttaAT,SchmitzML,SwearingenC,JamesLP,Wardbeg-
noche WL, Lindquist DM, Glasier CM, Tuzcu V, Prodhan
P, Dyamenahalli U, et al. 2012. Ketamine as a neuropro-
tective and anti-inammatory agent in children undergoing
surgery on cardiopulmonary bypass: a pilot randomized,
double-blind, placebo-controlled trial. Pediatr Crit Care
Med. 13:328–337. doi:10.1097/PCC.0b013e31822f18f9.
Butler SC, Sadhwani A, Stopp C, Singer J, Wypij D, Dunbar-
MastersonC,WareJ,NewburgerJW.2019.Neurodevel-
opmental assessment of infants with congenital heart dis-
ease in the early postoperative period. Congenit Heart Dis.
14:236–245. doi:10.1111/chd.12686.
Calderon J, Bellinger DC, Hartigan C, Lord A, Stopp C, Wypij
D, Newburger JW. 2019.Improvingneurodevelopmental
outcomes in children with congenital heart disease: proto-
col for a randomised controlled trial of working memory
training. BMJ Open. 9:e023304. doi:10.1136/bmjopen-2018-
023304.
ChrysostomouC,SanchezDeToledoJ,AvolioT,MotoaMV,
BerryD,MorellVO,OrrR,MunozR.2009.Dexmedeto-
midine use in a pediatric cardiac intensive care unit: can we
use it in infants after cardiac surgery? Pediatr Crit Care Med.
10:654–660. doi:10.1097/PCC.0b013e3181a00b7a.
Clancy RR, McGaurn SA, Goin JE, Hirtz DG, Norwood
WI,GaynorJW,JacobsML,WernovskyG,MahleWT,
Murphy JD, et al. 2001. Allopurinol neurocardiac pro-
tection trial in infants undergoing heart surgery using
deep hypothermic circulatory arrest. Pediatr. 108:61–70.
doi:10.1542/peds.108.1.61.
Cruickshank M, Henderson L, MacLennan G, Fraser C, Camp-
bell M, Blackwood B, Gordon A, Brazzelli M. 2016.Alpha-2
agonists for sedation of mechanically ventilated adults in
intensivecareunits:asystematicreview.HealthTechnol
Assess. 20:v–xx;1–117. doi:10.3310/hta20250.
De Asis-Cruz J, Donofrio MT, Vezina G, Limperopoulos C.
2018. Aberrant brain functional connectivity in newborns
with congenital heart disease before cardiac surgery. Neu-
roimage Clin. 17:31–42. doi:10.1016/j.nicl.2017.09.020.
DesnousB,LenoirM,DoussauA,MarandyukB,Beaulieu-
Genest L, Poirier N, Carmant L, Birca A, CINC multi-
disciplinary team. 2019. Epilepsy and seizures in children
withcongenitalheartdisease:aprospectivestudy.Seizure.
64:50–53. doi:10.1016/j.seizure.2018.11.011.
Easson K, Rohlicek CV, Houde J-C, Gilbert G, Saint-Martin C,
Fontes K, Majnemer A, Marelli A, Wintermark P, Descoteaux
M, Brossard-Racine M. 2020. Quantication of apparent
axon density and orientation dispersion in the white mat-
ter of youth born with congenital heart disease. Neuroimage.
205:116255. doi:10.1016/j.neuroimage.2019.116255.
EhrlerM,LatalB,KretschmarO,vonRheinM,O’Gorman
Tuura R. 2020. Altered frontal white matter microstruc-
ture is associated with working memory impairments
in adolescents with congenital heart disease: a diu-
sion tensor imaging study. Neuroimage Clin. 25:102123.
doi:10.1016/j.nicl.2019.102123.
Fischer HS, Reibel NJ, Buhrer C, Dame C. 2017.Prophylactic
early erythropoietin for neuroprotection in preterm infants:
a meta-analysis. Pediatr. 139. doi:10.1542/peds.2016-4317.
FleckT,SchubertS,EwertP,StillerB,NagdymanN,Berger
F. 2015. Propofol eect on cerebral oxygenation in children
with congenital heart disease. Pediatr Cardiol. 36:543–549.
doi:10.1007/s00246-014-1047-7.
Fontes K, Rohlicek CV, Saint-Martin C, Gilbert G, Easson K,
Majnemer A, Marelli A, Chakravarty MM, Brossard-Racine

ALL LIFE 179
M. 2019. Hippocampal alterations and functional correlates
in adolescents and young adults with congenital heart dis-
ease. Hum Brain Mapp. 40:3548–3560. doi:10.1002/hbm.24615.
Garcia RU, Peddy SB. 2018.Heartdiseaseinchildren.Prim
Care. 45:143–154. doi:10.1016/j.pop.2017.10.005.
GongJ,ZhangR,ShenL,XieY,LiX.2019.Thebrainpro-
tective eect of dexmedetomidine during surgery for pae-
diatric patients with congenital heart disease. J Int Med Res.
47:1677–1684. doi:10.1177/0300060518821272.
Guinter JR, Kristeller JL. 2010.Prolongedinfusionsof
dexmedetomidine in criticallyillpatients.AmJHealthSyst
Pharm. 67:1246–1253. doi:10.2146/ajhp090300.
Gupta P, Whiteside W, Sabati A, Tesoro TM, Gossett JM,
Tobias JD, R o t h S J. 2012. Safety and ecacy of pro-
longed dexmedetomidine use in critically ill children
with heart disease∗. Pediatr Crit Care Med. 13:660–666.
doi:10.1097/PCC.0b013e318253c7f1.
Hartnett ME. 2014. Vascular endothelial growth factor antag-
onist therapy for retinopathy of prematurity. Clin Perinatol.
41:925–943. doi:10.1016/j.clp.2014.08.011.
HolstLM,SerranoF,ShekerdemianL,RavnHB,GueyD,
Ghanayem NS, Monteiro S. 2019. Impact of feeding mode on
neurodevelopmental outcome in infants and children with
congenital heart disease. Congenit Heart Dis. 14:1207–1213.
doi:10.1111/chd.12827.
Huang J, Gou B, Rong F, Wang W. 2020. Dexmedetomidine
improves neurodevelopment and cognitive impairment in
infants with congenital heart disease. Per Med. 17:33–41.
doi:10.2217/pme-2019-0003.
HudetzJA,IqbalZ,GandhiSD,PattersonKM,ByrneAJ,
Hudetz AG, Pagel PS, Warltier DC. 2009. Ketamine atten-
uates post-operative cognitive dysfunction after cardiac
surgery. Acta Anaesth Scand. 53:864–872. doi:10.1111/
j.1399-6576.2009.01978.x.
JadcherlaSR,KhotT,MooreR,MalkarM,GulatiIK,
Slaughter JL. 2017. Feeding methods at discharge predict
long-term feeding and neurodevelopmental outcomes in
preterm infants referred for gastrostomy evaluation. J. Pedi-
atr. 181:125–130.e1. doi:10.1016/j.jpeds.2016.10.065.
JakabA,MeuwlyE,FeldmannM,RheinMV,KottkeR,
O’Gorman Tuura R, Latal B, Knirsch W, Research Group
Heart and Brain. 2019. Left temporal plane growth pre-
dicts language development in newborns with congeni-
tal heart disease. Brain. 142:1270–1281. doi:10.1093/brain/
awz067.
Kelly CJ, Arulkumaran S, Tristão Pereira C, Cordero-Grande
L, Hughes EJ, Teixeira RPAG, Steinweg JK, Victor S, Push-
parajah K, Hajnal JV, et al. 2019. Neuroimaging ndings in
newborns with congenital heart disease prior to surgery:
an observational study. Arch Dis Child. 104:1042–1048.
doi:10.1136/archdischild-2018-314822.
Kiski D, Malec E, Schmidt C. 2019. Use of dexmedetomi-
dine in pediatric cardiac anesthesia. Curr Opin Anaesthesiol.
32:334–342. doi:10.1097/ACO.0000000000000731.
Lakič N, Mrak M, Šušteršič M, Rakovec P, Bunc M. 2016.Peri-
operative erythropoietin protects the CNS against ischemic
lesions in patients after open heart surgery. Wiener klinis-
che Wochenschrift. 128:875–881. doi:10.1007/s00508-016-
1063-0.
LakičN,ŠurlanK,JerinA,MegličB,CurkN,BuncM.2010.
Importance of erythropoietin in brain protection after car-
diac surgery: a pilot study. Heart Surg Forum. 13:E185–E189.
doi:10.1532/HSF98.20091150.
Lam F, Bhutta AT, Tobias JD, Gossett JM, Morales L, Gupta
P. 2012. Hemodynamic eects of dexmedetomidine in crit-
ically ill neonates and infants with heart disease. Pediatr
Cardiol. 33:1069–1077. doi:10.1007/s00246-012-0227-6.
Leijser LM, Chau V, Seed M, Poskitt KJ, Synnes A, Blaser
S, Au-Young SH, Hickey EJ, Campbell A, McQuillen PS,
Miller SP. 2019. Anticoagulation therapy and the risk of
perioperativebraininjuryinneonateswithcongenital
heart disease. J Thorac Cardiovasc Surg. 157:2406–2413.e2.
doi:10.1016/j.jtcvs.2019.02.029.
Llurba E, Sanchez O, Ferrer Q, Nicolaides KH, Ruiz A,
Dominguez C, Sanchez-de-Toledo J, Garcia-Garcia B, Soro
G, Arevalo S, et al. 2014. Maternal and foetal angio-
genic imbalance in congenital heart defects. Eur Heart J.
35:701–707. doi:10.1093/eurheartj/eht389.
MandalenakisZ,RosengrenA,LappasG,ErikssonP,Hans-
son P-O, Dellborg M. 2016.Ischemicstrokeinchildren
and young adults with congenital heart disease. J Am Heart
Assoc. 5. doi:10.1161/JAHA.115.003071.
Mebius MJ, Kooi EMW, Bilardo CM, Bos AF. 2017. Brain injury
and neurodevelopmental outcome in congenital heart dis-
ease: a systematic review. Pediatr. 140. doi:10.1542/peds.
2016-4055.
Morton PD, Ishibashi N, Jonas RA. 2017. Neurodevelop-
mental abnormalities and congenital heart disease: insights
into altered brain maturation. Circ Res. 120(6):960–977.
doi:10.1161/CIRCRESAHA.116.309048.
Nagels W, Demeyere R, Van Hemelrijck J, Vandenbussche E,
Gijbels K, Vandermeersch E. 2004.Evaluationoftheneu-
roprotective eects of S(+)-ketamine during open-heart
surgery. Anesth Analg. 98:1595–1603. doi:10.1213/01.ane.
0000117227.00820.0c.
Nattel SN, Adrianzen L, Kessler EC, Andelnger G, Dehaes
M, Côté-Corriveau G, Trelles MP. 2017.Congenitalheart
disease and neurodevelopment: clinical manifestations,
genetics, mechanisms, and implications. Can J Cardiol.
33:1543–1555. doi:10.1016/j.cjca.2017.09.020.
Peyvandi S, Latal B, Miller SP, McQuillen PS. 2019.Theneona-
tal brain in critical congenital heart disease: insights and
future directions. Neuroimage. 185:776–782. doi:10.1016/j.
neuroimage.2018.05.045.
Phan H, Nahata MC. 2008.Clinicalusesofdexmedeto-
midine in pediatric patients. Paediatr Drugs. 10:49–69.
doi:10.2165/00148581-200810010-00006.
PuB,XueY,WangQ,HuaC,LiX.2015. Dextromethorphan
provides neuroprotection via anti-inammatory and anti-
excitotoxicity eects in the cortex following traumatic brain
injury. Mol Med Rep. 12:3704–3710. doi:10.3892/mmr.2015.
3830.

180 B.-H. ZHENG ET AL.
Rollins CK, Asaro LA, Akhondi-Asl A, Kussman BD, Rivkin
MJ, Bellinger DC, Wareld SK, Wypij D, Newburger JW,
Soul JS. 2017. White matter volume predicts language devel-
opment in congenital heart disease. J Pediatr. 181:42–48.e2.
doi:10.1016/j.jpeds.2016.09.070.
RollinsCK,WatsonCG,AsaroLA,WypijD,VajapeyamS,
Bellinger DC, DeMaso DR, Robertson RL, Newburger JW,
Rivkin MJ. 2014. White matter microstructure and cogni-
tion in adolescents with congenital heart disease. J Pediatr.
165:936–944.e1–2. doi:10.1016/j.jpeds.2014.07.028.
Sánchez O, Ruiz-Romero A, Domínguez C, Ferrer Q, Ribera
I, Rodríguez-Sureda V, Alijotas J, Arévalo S, Carreras E,
Cabero L, Llurba E. 2018. Brain angiogenic gene expression
in fetuses with congenital heart disease. Ultrasound Obstet
Gynecol. 52:734–738. doi:10.1002/uog.18977.
Schmitt B, Bauersfeld U, Fanconi S, Wohlrab G, Huisman TA,
Bandtlow C, Baumann P, Superti-Furga A, Martin E, Arbenz
U, et a l. 1997. The eect of the N-methyl-D-aspartate recep-
tor antagonist dextromethorphan on perioperative brain
injury in children undergoing cardiac surgery with car-
diopulmonary bypass: results of a pilot study. Neuropedi-
atrics. 28:191–197. doi:10.1055/s-2007-973699.
Schwartz LI, Twite M, Gulack B, Hill K, Kim S, Vener DF.
2016. The perioperative use of dexmedetomidine in pedi-
atric patients with congenital heart disease: an analysis from
the congenital cardiac anesthesia society-society of thoracic
surgeons congenital heart disease database. Anesth Analg.
123:715–721. doi:10.1213/ANE.0000000000001314.
SunL,MacgowanCK,SledJG,YooSJ,ManlhiotC,Porayette
P,Grosse-WortmannL,JaeggiE,McCrindleBW,King-
dom J, et al. 2015. Reduced fetal cerebral oxygen con-
sumption is associated with smaller brain size in fetuses
with congenital heart disease. Circulation. 131:1313–1323.
doi:10.1161/CIRCULATIONAHA.114.013051.
Tassinari S, Martínez-Vernaza S, Erazo-Morera N, Pinzón-
Arciniegas MC, Gracia G, Zarante I. 2018. Epidemiology of
congenital heart diseases in Bogotá, Colombia, from 2001
to 2014: improved surveillance or increased prevalence?
Biomedica. 38:148–155. doi:10.7705/biomedica.v38i0.3381.
Vedovelli L, Cogo P, Cainelli E, Suppiej A, Padalino M,
Tassini M, Simonato M, Stellin G, Carnielli VP, Buono-
core G, Longini M. 2019. Pre-surgery urine metabolomics
may predict late neurodevelopmental outcome in chil-
dren with congenital heart disease. Heliyon. 5:e02547.
doi:10.1016/j.heliyon.2019.e02547.
von Rhein M, Buchmann A, Hagmann C, Huber R, Klaver P,
Knirsch W, Latal B. 2014.Brainvolumespredictneurode-
velopment in adolescents after surgery for congenital heart
disease. Brain. 137:268–276. doi:10.1093/brain/awt322.
Wang R, Zhang Z, Kumar M, Xu G, Zhang M. 2019.
Neuroprotective potential of ketamine prevents develop-
ing brain structure impairment and alteration of neu-
rocognitive function induced via isourane through the
PI3K/AKT/GSK-3beta pathway. Drug Des. 13:501–512.
doi:10.2147/DDDT.S188636.
White BR, Rogers LS, Kirschen MP. 2019.Recentadvances
in our understanding of neurodevelopmental outcomes in
congenital heart disease. Curr. Opin. Pediatr. 31:783–788.
doi:10.1097/MOP.0000000000000829.
Wintermark P, Lechpammer M, Kosaras B, Jensen FE, Wareld
SK. 2015. Brain perfusion is increased at term in the white
matter of very preterm newborns and newborns with con-
genital heart disease: does this reect activated angiogenesis?
Neuropediatrics. 46:344–351. doi:10.1055/s-0035-1563533.
Yıldız EP, Ekici B, Tatlı B. 2017. Neonatal hypoxic ischemic
encephalopathy: an update on disease pathogenesis and
treatment. Expert Rev Neurother. 17:449–459. doi:10.1080/
14737175.2017.1259567.