Advances in Cardiothoracic Surgery
Advances in Cardiothoracic Surgery
Chapter 4
Recent Advances in Neonatal Cardiac
Surgery
Vicki L Mahan
Department of Surgery, Division of Pediatric Cardiothoracic Surgery, Drexel University College of Medicine, St.
Christopher’s Hospital for Children, USA
Corresponding Author: Vicki L Mahan, Department of
Surgery, Division of Pediatric Cardiothoracic Surgery,
Drexel University College of Medicine, St. Christopher’s
Hospital for Children, USA, Email: Vicki.Mahan@tenethealth.com
*
First Published December 16, 2015
Copyright: © 2015 Vicki L Mahan.
This article is distributed under the terms of the Creative
Commons Attribution 4.0 International License
(http://creativecommons.org/licenses/by/4.0/), which
permits unrestricted use, distribution, and reproduction
in any medium, provided you give appropriate credit to
the original author(s) and the source.
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Neonates with complex congenital heart disease may
require surgical intervention in the first few days of life.
The overall operative risk has decreased to 3 to 5% in most
high volume centers. Morbidity has decreased as well and
equally important is the improvement in quality of life.
Long term normal psychomotor development is achievable in the majority of patients and need for re-operation
for residual lesions has declined. Improvement in short
and long term outcomes are attributed to several factors
during preoperative, perioperative, and postoperative
care. While decisions may be difficult, advances in neonatal cardiac surgery has resulted in our ability to offer hope
to families with a high risk newborn with complex congenital heart disease (CHD) and complicated physiology.
Preoperative Advances
Fetal Diagnosis
Prenatal diagnosis of CHD may lead to benefits in early postnatal status and outcomes in certain critical forms
of CHD [1,2]. The cardiac fetal screening examination
during the second-trimester scan is designed to maximize
the detection of heart anomalies [3] and is usually done
between 18 and 22 weeks gestational age. As a minimum,
the four-chamber view and outflow tract views should be
included in the screening examination [4-7]. The fourchamber view can be done in 95% to 98% of pregnancies
and theoretically detects > 50% of serious cardiac malformations when performed in midgestation. The three-vessel view and three vessels and trachea view are desirable
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[8, 9]. Addition of the outflow tracts and three-vessel with
trachea view increases the sensitivity to as high as 90%.
Indications for fetal echocardiography include chamber
asymmetry, altered cardiac axis, altered position of the
fetal heart, enlarged fetal heart, fetal arrhythmia on the
routine scan, maternal diabetes, congenital heart disease
in the mother, assisted reproduction technology, use of
drugs by the mother, autoimmune disorders in the mother, history of a sibling with a cardiac anomaly, prominent
nuchal translucency or increased nuchal fold thickness,
structural defect in other systems, fetal infections, and
IUGR in the mid-trimester [10,11]. Earlier fetal echocardiography (< 18 weeks gestational age) may be done
earlier – the indication that has yielded the greatest number of fetal cardiac diagnosis is the finding of an increased
nuchal translucency [12].
The fetal echocardiogram includes detailed 2D/
gray-scale imaging of all cardiovascular structures, color
Doppler interrogation of all valves, veins, arteries, and
atrial and ventricular septae, and assessment of cardiac
rhythm and function. Additional studies that may be
needed are cardiac biometry, additional pulsed Doppler
measure and quantitative evaluation of cardiac function.
Basic fetal biometric measurements and evaluation for
presence of pleural and pericardial effusions, ascites, and
integumentary edema may be assessed as well. Followup studies are frequently needed – fetal heart disease may
progress. Advanced techniques to further evaluate the fetal cardiac structure, function, and rhythm include three-
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dimensional and four dimensional ultrasound, cardiovascular MRI, tissue Doppler imaging, strain and strain
rate imaging, fetal electrocardiography, and fetal magnetocardiography. Assessment of extracardiac anomalies
in fetuses with CHD helps with pregnancy and postnatal
management. Presence may have a profound impact on
neonatal care [13].
Fetal Interventions
Fetal therapy is indicated and available for fetal arrhythmias and cardiac lesions amenable to fetal intervention –aortic stenosis with evolving hypoplastic left heart
syndrome (HLHS), HLHS with restrictive/intact atrial
septum, dilated left ventricle with severe mitral regurgitation/aortic stenosis/restrictive or intact atrial septum, and
pulmonary atresia/intact ventricular septum (PA/IVS).
Optimal techniques for open surgical repair of CHD before birth have not been developed and appropriate candidates have not been identified. Two patients are affected,
mother and fetus. The current strategies include administration of medication to the mother with transplacental
transfer to the fetus, minimally invasive fetoscopic-guided
techniques, and invasive open uterine fetal surgery.
Fetal arrhythmia management for fetal bradycardia
and tachycardia and fetal congestive heart failure are common. With antiarrhythmics, high doses are required during the second and third trimesters because maternal circulating blood volume and renal clearance are increased.
Direct treatment of the fetus by intracordal or intramuswww.avidscience.com
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cular injections may more rapidly restore sinus rhythm in
the hydropic fetus. Drugs that have been used for management of fetal tachycardias include digoxin, flecainide,
sotalol, amiodarone, magnesium, lidocaine, propranol,
mexiletine, and dexamethasone. A pediatric cardiologist
with knowledge and expertise in managing fetal arrhythmias is needed to manage these patients.
Success of fetal cardiac catheter intervention does
not always translate into clinical success after birth. The
natural history of the malformation is important. Severe
aortic stenosis in early gestation and midgestation evolves
into HLHS at birth. Fetal intervention with in utero balloon dilation of the aortic valve is done to improve left
ventricular function, improve flow through the left heart,
reverse the ongoing damage to the left heart structures,
and to promote left heart growth [14,15]. HLHS with restrictive or intact atrial septum has a high mortality and
morbidity after delivery. Opening of the atrial septum in
utero using puncture and tearing with a balloon, and stent
placement have been done to limit the development of
pulmonary vasculopathy [16,17). In patients with mitral
valve dysplasia syndrome with mitral regurgitation and
aortic stenosis, fetal intervention to open the aortic valve
[18] or opening of the atrial septum [19] have been suggested. Fetal intervention in PA/IVS is more difficult than
that for the aortic valve [20]. The benefit is uncertain.
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Delivery
Care of the fetus with CHD must be coordinated between obstetric, neonatal, cardiology, and cardiothoracic
surgery services. The majority of newborns with CHD do
not need special care at delivery. Neonatal condition and
surgical outcomes, however, are improved by delivery in
close proximity to a center with the resources needed to
provide medical and surgical interventions for newborns
with specific major cardiac defects [1,2,13]. Level of care
(LOC) assignment with delivery recommendations are as
follows: LOC P – CHD in which palliative care is planned
– normal delivery at local hospital; LOC 1 – CHD without
predicted risk of hemodynamic instability in the delivery
room or first days of life – normal delivery at local hospital; LOC 2 – CHD with minimal risk of hemodynamic
instability in delivery room but requiring postnatal catheterization/surgery – delivery at hospital with neonatologist and accessible cardiology consult; LOC 3 – CHD with
likely hemodynamic instability in delivery room requiring immediate specialty care for stabilization – delivery
at hospital that can execute rapid care including stabilizing/lifesaving procedures; LOC 4 – CHD with expected
hemodynamic instability with placental separation requiring immediate catheterization and/or surgery in delivery
room to improve chance of survival – cesarean section in
cardiac facility with necessary specialists in the delivery
room usually at 38 to 39 weeks gestation; and LOC 5 CHD in which cardiac transplantation is planned – list
after 35 weeks of gestation, cesarean section when heart
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is available [21]. Elective delivery after 39 weeks gestation
improve neonatal outcomes [22]. However, waiting beyond 42 weeks is detrimental [23]. The method of delivery, spontaneous vaginal delivery versus cesarean section,
has not been resolved.
Prostaglandin
Prostaglandin E1 (PGE1) has been routinely used to
maintain ductal patency in patients with CHD who are
ductal dependent. The usual initial dose is around 50100 ng/kg/minute, but apnea, respiratory distress, hypotension, fever, and diarrhea are not uncommon with this
high initial PGE1 dose. Lower doses maintain adequate
patent ductus arteriosus (PDA) flows in newborns with
CHD and PDA-dependent pulmonary circulation and result in fewer complications. A lower initial dose of 20 ng/
kg/minute and a maintenance dose of 10 ng/kg/minute
has been recommended [24,25]. Long-term infusion of
PGE1 before discontinuation result in side effects which
are manageable [26,27]. Intravenous use has also been
used to treat pulmonary arterial hypertension [28,29]
and PGE1 inhalation is also associated with reduction in
pulmonary arterial pressure and improvement in arterial
blood oxygen levels in pediatric patients with pulmonary
arterial hypertension and has been suggested as treatment
for postoperative pulmonary hypertension [30].
Nitric Oxide
Selective pulmonary vasodilation by inhalation of nitric oxide (iNO) prompted clinical application and FDA
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approval of iNO for treating hypoxemia in term neonates
[31]. In term and near-term neonates, iNO decreased pulmonary vascular resistance, diminished the need for extracorporeal membrane oxygenation (ECMO), and its actions are facilitated with HFOV [32]. Use as rescue therapy
for the very ill ventilated preterm infant does not appear
effective [33]. When used for the postoperative management of pulmonary hypertension in infants and children
with CHD, there were no differences with the use of iNO
as compared with control [34]. In routine cardiac surgery,
postcardiotomy right ventricular dysfunction/failure in
the setting of increased pulmonary vascular resistance is
the most common indications for starting iNO. Clinical
practice guidelines on its use have been based on small
observational or single center randomized trials. The few
multicenter trials have not provided strong evidence base.
The high price tag associated with iNO therapy and lack
of clinical evidence requires large retrospective studies as
well as prospective studies [35]. Standardized initiation
and weaning guidelines for iNO is successful in reducing
variation in iNO use and intensive care unit utilization
while maintaining quality of care [36,37]. Sildenafil may
facilitate the withdrawal of iNO and prevent rebound pulmonary hypertension in patients with CHD [38].
Hypoxic/Hypercarbic Ventilation
Blood flow is inversely proportional to resistance –
when resistance decreases, blood flow increases. Balancing of systemic and pulmonary blood flow is important
in patients with ductal-dependent CHD. After birth, pulwww.avidscience.com
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monary vascular resistance (PVR) decreases. Steal from
the systemic circuit results and poor perfusion, metabolic
acidosis, and oliguria may be clinically observed. An increase in PVR may result in hypoxemia. Adjusting the
carbon dioxide (CO2) level using mechanical ventilation
and/or sedation limits pulmonary blood flow – elevated
CO2 in the range of 45-50 mm Hg increases PVR [39,40].
Lowering the CO2 level decreases PVR. Hypoxic gas mixtures may also be used to increase PVR [41]. Addition of
nitrogen gas to the inspired gas through the endotracheal tube or hood results in a < 21% gas mixture [42,43].
Higher oxygen levels decrease PVR. The use of CO2 and
hypoxic gas have been proven to be clinically helpful in
optimizing shunting by increasing PVR, but their use is
controversial.
Routine Use of Pulse Oximetry
Critical congenital heart diseases (CCHD) are potentially life-threatening cardiac abnormalities where the systemic or pulmonary circulation is dependent on a patent
ductus arteriosus and include those with duct-dependent
pulmonary blood flow, inter-circulatory mixing, and systemic hypoperfusion. The seven main CCHD screening
targets for neonatal pulse oximetry are hypoplastic left
heart syndrome, pulmonary atresia (with intact ventricular septum), Tetralogy of Fallot, total anomalous pulmonary venous return, transposition of the great arteries,
tricuspid atresia, and truncus arteriosus. Early diagnosis
improves outcomes. Systematic review and meta-analysis
of pulse oximetry screening for critical congenital heart
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defects in asymptomatic newborn babies revealed that the
overall sensitivity was 76.5% and specificity was 99.9%.
The false-positive rate was low when it was done after 24
hours from birth [44]. The American Heart Association
and the American Academy of Pediatrics suggest that routine pulse oximetry done on asymptomatic newborns after 24 hours of life but before discharge may detect critical
CHD, incurs very low cost, and there is a low risk of harm
[45]. European studies suggest that screening is cost-effective in identifying newborns with CCHD [46,47]. Over
half of babies discharged with CHD detected in the first
year of life were discharged from the hospital with a normal routine neonatal examination and the 6 week exam
missed one-third of the patients [48]. In many countries,
births are not attended and infants are discharged within
hours of birth without medical evaluation by a qualified
practioner. CCHD will go undetected in this setting.
The screening study is done on the child in the well
baby nursery at 24 to 48 hours of age or shortly before discharge if < 24 hours of age. The screen is done by a qualified screener using a pulse oximeter and probes calibrated
for the newborn’s right hand and either foot. A negative
screen is defined as an O2 saturation ≥ 95% in the right
hand or foot and ≤ 3% difference between the right hand
and foot. If the O2 saturation is 90% to < 95% in the right
hand and foot or > 3% difference in saturation between
the right hand and foot, the screen is repeated in 1 hour. A
negative screen is again defined as an O2 saturation ≥ 95%
in the right hand or foot and ≤ 3% difference between the
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right hand and foot. If the screen again shows that the O2
saturation is 90% to < 95% in the right hand and foot or
> 3% difference in saturation between the right hand and
foot, the screen is again repeated in 1 hour and a negative
screen is again defined as an O2 saturation ≥ 95% in the
right hand or foot and ≤ 3% difference between the right
hand and foot. A positive screen requires further evaluation to determine if the findings are respiratory related or
cardiac related.
The local situation is key. Cardiac services are standard of care in many countries and are becoming more
common in developing countries. As undetected CCHD
is a cause of sudden neonatal death with patients dying at
home or in the emergency department [49], early detection improves the survival of neonates and infants and improves long-term quality and quantity of life for patients
identified early in life. Missing the diagnosis or detecting
CCHD at an advanced stage portends poor outcomes.
Implementation of the screening program in developing countries not having access to comprehensive primary healthcare services may magnify the discrepancies
in management and outcomes of congenital heart disease.
However, early detection may improve overall neonatal
care and outcomes, provide basic medical care, and foster
an independent approach to diagnosis and management
of CCHD acceptable to the population served.
The Newborn Foundation is working with global
health agencies, clinicians, nongovernmental organiza-
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tions (NGOs) and the medtech industry to implement the
BORN (Birth Oximetry Routine for Newborns) Project.
The project is aligned with the World Health Organization’s Safe Childbirth Checklist and was presented at the
International Conference on Birth Defects in the Developing World in 2013. The education-and-implementation
model will provide clinical education, data, and a screening framework for accurate measurements of hypoxemia
in newborns. The inaugural pilot project in Sichuan Province China will evaluate nearly 50.000 newborns at county
and village birth facilities. In its efforts to reduce neonatal
mortality and to trigger additional NGOs and international health bodies to support pulse oximetry evaluation
as a standard practice for all newborns regardless of geography, the Newborn Foundation joined with the Every
Newborn Action Plan (ENAP) and newborn pulse oximetry screening is being implemented in a growing number
of countries around the world. Evidence shows that using
pulse oximetry and having reliable oxygen sources in district and provincial hospitals in developing countries can
reduce infection-related newborn death rates by as much
as 35%. A growing number of countries are implementing
newborn pulse oximetry screening with the goal of reducing newborn mortality throughout the world.
Implementation of newborn pulse oximetry on a
worldwide level should improve referral of the high risk
newborn to facilities able to evaluate and manage CCHD.
Newborn screening by pulse oximetry is an invaluable
tool to improve overall newborn mortality rates, diagnose
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CCHD, and to help communities decide on the care patients with CCHD may need. Many of these patients may
be able to undergo interventional or surgical correction of
their CHD and lead a normal life and be able to contribute
to their families and communities. Delay in diagnosis
may result in early death or development of irreversible
lung and/or cardiac disease. Early diagnosis will help the
family and community make an informed decision regarding treatment of the newborn with CCHD.
Perioperative Advances
Cardiopulmonary Bypass Circuit
The ideal neonatal cardiopulmonary bypass (CPB)
circuit should combine low foreign surface area with reliable mass transfer, low priming volume, and optimal
hemocompatibility. Small oxygenators, reservoirs, and
filters are available – total priming volume is dependent
on oxygenator position, use of vacuum-assisted return,
and the correct choice of diameter and length of tubing.
Miniaturization of the circuit has allowed bloodless open
heart surgery to be performed in selected pediatric patients [50]. However, bloodless prime does not necessarily mean bloodless CPB or bloodless open heart surgery.
Small diameter arterial tubing decreases total CPB priming volume, but is associated with higher circuit pressure,
higher pressure drop, and more hemodynamic energy loss
across the CPB circuit [51]. Neonates operated on using
the smallest circuits spent less time in the ICU and were
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cuits [52]. Reduction in surface area and prime volume, a
perfusion strategy to avoid cardiac arrest, and warm perfusion help to blunt the systemic inflammatory response
of CPB. Minimizing hemodilution reduces the inflammatory response as well [53]. CPB priming with a high
colloid osmotic pressures results in a lesser extent of fluid
overload by the end of CPB and priming with albumin is
more appropriate in neonates than priming with crystalloids [54,55]. Adding fresh frozen plasma to CPB priming
decreases postoperative blood loss [56]. Use of autologous
umbilical cord blood achieves adequate end-organ oxygen
delivery [57]. This is rich in HbF, platelets and other cellular constituents and induces minimal immune reaction
[58]. Further studies are needed before routine clinical
use of autologous umbilical cord blood in the CPB circuit.
Alpha Stat Versus pH Stat Management for Deep Hypothermic Circulatory
Arrest
Optimal acid-base management strategy during hypothermic cardiopulmonary bypass has still not been
clearly defined. Hypothermia results in an alkaline shift
of blood pH. With alpha-stat strategy, CO2 is not added to
maintain a normal pH. In the pH-stat strategy, 3-5% CO2
is added to the oxygenator gas flow to maintain a temperature-corrected blood pCO2 of 40 mmHg and a pH of 7.40.
Alpha-stat management is preferred for optimal myocardial function. The pH-stat strategy may result in loss of
autoregulation of the brain and lead to cerebral microem-
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bolisation and intracranial hypertension [59]. In a piglet
model of deep hypothermic bypass, pH-stat management
increases tissue oxygenation during deep hypothermic
bypass and after circulatory arrest [60]. In another piglet
study, the maximal safe duration of hypothermic circulatory arrest was found to be dependent on the temperature, hematocrit, and pH management strategy with the
pH-stat strategy protecting the brain more effectively than
the alpha-stat strategy [61]. Clinical studies suggest that
pH-stat management in the paediatric patients results in
better outcomes [62-65].
Hematocrit
A prospective randomized trial of 2 hemodilution
strategies was shut down by the Data and Safety Monitoring Board of the National Institutes of Health because
of a strongly positive outcome – infants who had a mean
hematocrit of 27% had better motor skills at 1 year old
relative to patients with a lowest hematocrit of 21.5%. A
greater percentage of patients at 1 year of age were also
classified as developmentally delayed with respect to motor skills in the lower hematocrit group [66]. A randomized trial of hemodilution to a hematocrit value of 25%
versus 35% during hypothermic cardiopulmonary bypass
in infants undergoing 2-ventricle repairs without aortic
arch obstruction had no major benefits or risks between
the two groups [67]. A hematocrit of 24% or higher at the
onset of low-flow cardiopulmonary bypass is associated
with higher Psychomotor Development Index scores and
reduced lactate levels [68]. Current recommendations
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are that the hematocrit not be diluted below 24% in the
newborn undergoing cardiopulmonary bypass for CHD.
An inverse relationship between hematocrit and cerebral
blood flow velocity during deep hypothermic cardiopulmonary bypass in neonates and infants may correlate with
cerebral metabolism of oxygen, oxygen use by NIRS, and
long-term neurologic outcome [68]. This is being further
evaluated.
Extracoporeal Membrane Oxygenation
The Maquet Cardiohelp System, a portable miniaturized extracorporeal membrane oxygenaton system
(ECMO), is the world’s smallest heart-lung support system, is fully integrated, offers simple setup and priming
techniques, and provides safe and reliable support for
adult patients on ECMO during interhospital patient
transport as compared to the standard circuit [69-71].
The system is intended to be used to provide circulatory
and/or pulmonary support during procedures requiring
CPB, to provide circulatory and/or pulmonary support
during procedures not requiring CPB, to be used within
and outside the hospital environment, and to be used in
extracorporeal circulation during CPB in cardiac surgery.
ECMO settings and oxygenator performance are similar
between the Cardiohelp and standard groups [72]. Use in
neonates has been limited and long-term outcome studies are required. Ex utero intrapartum therapy to ECMO
has been used in late-term fetuses with expected respira-
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tory and/or cardiac failure at birth, but indications have
not been defined and effectiveness is not clear [73]. The
artificial placenta recreates the intrauterine environment
with ECMO instead of mechanical ventilation. Umbilical
vessels are cannulated, mechanical ventilation is not required, and a low partial pressure of oxygen is used. These
are in the developmental stage and have limited clinical
availability [73,74]. The Hemolung RAS for respiratory
dialysis is a simple, minimally invasive technique providing extracorporeal carbon dioxide removal for patients
with acute hypercapnic respiratory failure, requires low
blood flow rates, and uses a small veno-venous catheter.
This technology is not yet available for neonates [75].
Berlin Heart
Patient selection and timing for implantation of ventricular assist devices (VAD) are not well defined. A multivariable logistic regression model predicting the likelihood of death or need for mechanical circulatory support
within 60 days based on listings without mechanical circulatory support for isolated pediatric heart transplant has
been developed. A simplified score (PedsMCS score) to
predict the need for mechanical circulatory support based
on risk factors present at listing has been developed and
validated. This score is determined by the patient’s clinical
condition at listing and should improve clinical decisionmaking [76].
The Berlin Heart Investigational device exemption
(IDE) trial divided study participants into 2 cohorts based
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on body surface area with 24 participants in each cohort.
The control group was selected from the Extracorporeal
Life Support Organization (ELSO) registry [77]. For children with a BSA < 0.7 m2, the median duration of support
was 28 days and the primary end point (time to death or
weaning from the device with an unacceptable neurologic outcome) had not been reached at 174 days [78]. The
U.S. Food and Drug Administration granted Humanitarian Device Exemption approval of the Berlin Heart EXCOR Pediatric VAD on December 16, 2011. For patients
with a BSA <0.7, this devices is currently the only option
for long-term ventricular assist device support [79]. The
EXCOR VAD provides circulatory support for patients as
small as 2.5 kg. Neurologic complications are the major
cause of mortality for infants < 5 kg [80].
Although several other devices are being developed,
it will be years before the devices are tested in clinical trials. In 2004, the National Heart, Lung and Blood Institute
(NHLBI) established the Pediatric Circulatory Support
Program and awarded five contracts toward the development of pediatric circulatory support devices – the PediaFlow VAD, the PediPump, the Pediatric Cardiopulmonary
Assist System, the Pediatric Jarvik 2000, and the Pediatric
VAD. NHLBI subsequently established the PumpKIN
(Pumps for Kids, Infants, and Neonates) program to provide financial support for preclinical testing of the most
promising devices. NHLBI has made a national commitment to making pediatric-specific VADs clinically available [81,82].
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Myocardial Protection
Myocardial protection requires reduction of metabolic requirements by hypothermia and/or arrest of the
contractile myocardium by depolarization of the membrane potential using high potassium blood cardioplegia
[83,84]. Hypothermia is the mainstay of protection – oxygen consumption is decreased by 45% and arterial oxygen saturation increases or remains the same at 32°C and
no adverse effects on the organism have been detected in
the absence of cardiac fibrillation [85,86]. It is not clear
whether cardioplegia is superior to hypothermia alone
although cardioplegia is the gold standard of myocardial
protection in neonates undergoing cardiac surgery. Physiologic differences between neonatal and adult myocardium increasing ischemia tolerance include use of glucose
as the preferred substrate for adenosine triphosphate production, high glycogen content, and low 5’ nucleotidase.
The benefit of cardioplegia over hypothermia alone is
substantial with increase in temperature [87]. Warm surgery with low prime bypass and intermittent warm blood
cardioplegia is an alternative to hypothermic perfusion
with cold cardioplegia using a larger priming volume and
a more physiologic ATP steady state is observed with intermittent warm blood cardioplegia [88,89]. For cyanotic
patients, cold blood cardioplegia with a hot shot reduces
metabolic injury compared with cold crystalloid cardioplegia [90]. Meta-analysis of 34 randomised trials found
a lower incidence of low cardiac output symdrome and
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CK-MK release with blood cardioplegia when compared
with asanguinous solutions in adult patients [91]. It is not
clear if this is also true in neonates.
Circulatory Arrest Versus Low Flow
CPB
Prolonged deep hypothermic circulatory arrest
(DHCA) is associated with brain injury – the safe duration of circulatory arrest is unknown. In neonates undergoing repair of transposition of the great arteries, neonates
repaired during DHCA showed significant developmental
deficits at 1 year when compared with children repaired
during low-flow CPB [92]. Persistent deficits in motor
skills were seen at 4 years of age in these same patients
[93]. Further evaluation of these data suggests that the
neurologic outcomes were affected only if the duration of
DHCA exceeded 41 minutes [94]. In a randomized trial
of regional cerebral perfusion (RCP) versus DHCA in
newborns with functional single ventricle, RCP was not
associated with improved neurodevelopmental outcomes
when compared with DHCA [95]. High-flow selective
cerebral perfusion leads to cerebral edema with no change
in metabolic rate [96]. Management of low-flow CPB is
not well–defined and cerebral vascular resistance is dynamic. Changes in requirements of flow during CPB and
constituents of the perfusate for neuroprotection are being evaluated.
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Attenuation of Inflammatory Responses
Systemic inflammatory response syndrome (SIRS)
is induced by CPB and is more pronounced in pediatric
patients – pediatric patients are immunologically immature and the organs, coagulation systems, and endocrine
systems are developing. Neonates have high numbers of
TH cells expressing CD4 and CD8, but these cells do not
produce TH specific cytokines [97,98]. Biphasic cytokine
response is less than that seen in older patients after CPB
[99,100]. The clinical benefits of steroids in neonates undergoing repair of CHD on CPB is unclear [101] and is
being further evaluated. Opiods enhance the anti-imflammatory effect after CPB – a greater effect is seen with
fentanyl compared with morphine [102]. Heparin has
both proinflammatory activation of complement during
CPB and anti-inflammatory effect on neutrophils [102].
Propofol, thiopental, and sufentanil affect lymphocyte
function in vitro [103], but in vivo effects are not clear.The
allopurinol neurocardiac protection trial in 350 neonates
who had congenital heart surgery and required cardiac
surgery as a newborn did not reduce the risk of death, but
did provide protection in the higher-risk HLHS survivors
[104]. Topiramate and caffeine are beinag evalaued as
neuroprotective strategies during CPB in newborns.
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Ultrafiltration
In newborns, hemodilution by CPB priming results
in significant complications with CPB. Ultrafiltration to
remove excess water has been used to counteract these adverse effects. Conventional ultrafiltration (CUF) is carried
out while CPB is running and offers limited filtration efficiency. Modified ultrafiltration (MUF), performed immediately after the termination of CPB, removes excess fluid
with greater efficiency than CUF. Analysis of available
evidence from several randomized controlled trials and
retrospective studies showed that MUF reduces excess total body water with a clinical improvement in cardiac and
pulmonary function after CPB in infants and children in
the postoperative period, corrects dilutional coagulopathy, and modifies the systemic inflammatory response
[105]. MUF after separation from CPB improves pulmonary compliance and alveolar gas exchange, is associated
with lower red blood cell transfusion, and is safe and reliable [106]. Meta-analysis of randomized controlled trials
that examined clinical benefits of MUF over CUF in pediatric cardiac surgery indicated that MUF resulted in higher postbypass hematocrit levels and mean arterial blood
pressure, but did not show improvement in postoperative
blood loss, ventilator time, and ICU time [107]. Ultrafiltration and peritoneal dialysis are effective in removing
proinflammatory interleukins and are renoprotective in
newborns and infants undergoing cardiopulmonary bypass surgery [108]. Filter type is important as filtration
profiles vary and impact the removal of inflammatory
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mediators in pediatric heart surgery [109]. Comparison
of MUF groups with non-MUF groups in which the CPB
circuit is simplified will help determine if miniaturization
of the circuit eliminates the need for MUF [110].
Liothyronine
In neonates, a reduction of triiodothyronine (T3),
thyroxine (T4), and thyroid-stimulating hormone (TSH)
after CPB is associated with increased morbidity, prolonged postoperative course, greater use of inotropes
and diuretics, and longer time on mechanical ventilator
support [111-113]. The Triiodothyronine for Infants and
Children Undergoing CPB (TRICC) showed a significant
reduction in time to extubation, less use of inotropic support, and better cardiac function with T3 supplementation in patients under 5 months old [114]. Young patients
with complex operations and long bypass times might
benefit most from T3 supplementation [115]. Use of intravenous T3 is commonly used in this patient population
in the United States, but cost constraints and availability
limits its use in many countries. Oral T3 (0.5 µg/kg to a
maximum of 10 µg) starting on induction of anesthesia
and then every 12 hours afterward prevents a decline in
T3 [116]. Oral T3 is less expensive than the intravenous
route, is not accompanied by rapid increase of peak serum
level after intravenous administration, and maintains T3
levels in a stable manner [117]. Clinical trials are needed
to further evaluate oral T3 use in neonates undergoing
open heart surgery.
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Postoperative Advances
Management of Low Cardiac Output
One quarter of newborns will decrease their index to
< 2.0 L/min/m2 after CPB. Myocardial dysfunction after
CPB for congenital heart surgery has been attributed to
the inflammatory response to CPB, effects of myocardial
ischemia after cross-clamping, hypothermia, reperfusion
injury, inadequate myocardial protection and ventriculotomy. Excluding residual disease is important. There is
usually a time delay before low cardiac output syndrome is
seen. In newborns undergoing the arterial switch procedure for D-TGA, the maximum decrease in cardiac index
occurred 6 to 12 hours after separation from CPB in 32%
of patients. This varies [118]. Anticipation of low cardiac
output syndrome and preemptive intervention can reduce
morbidity. Preload, afterload, myocardial contractility,
heart rate and rhythm must be assessed in these patients.
Preload must be optimized and ventricular responses to
atrial pressure evaluated [119]. Allowance of right-to-left
shunting at the atrial level may be helpful in patients with
right ventricular dysfunction. Atrio-biventricular pacing
may be useful. Atrio-ventricular sequential pacing is important for arrhythmias. Pharmacologic support may be
needed to increase systemic vascular resistance or for afterload reduction. Prolonged high-dose epinephrine after
CPB in neonates is associated with myocardial infarction
and diastolic dysfunction. Effectiveness of prophylactic
milrinone in preventing death or low cardiac output syn-
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Advances in Cardiothoracic Surgery
drome in newborns undergoing surgery for CHD is not
clear. No differences have been shown between milrinone,
levosimendan, or dobutamine in the immediate post-operative period [120]. An increase in cardiac index is seen
in newborns treated with levosimendan after open-heart
surgery when compared to milrinone, but multicenter trials are needed [121]. Nitric oxide reduces afterload on
the right heart. Positive pressure ventrilation decreases left
ventricular afterload but also decreases preload. Negative
pressure ventilation augments right heart function. Lowering of core body temperature for patients with low cardiac output states may reduce oxygen consumption and
optimize oxygen delivery. Anti-inflammatory drugs are
being used to prevent and protect organs from ischemic
injury occurring during CPB and reperfusion injury. Mechanical support using ECMO or ventricular assist devices are used when other therapies fail [122].
Ventilation/Extubation
Weaning from mechanical ventilation is normally
performed with pressure support ventilation (PSV) [123],
but this conventional ventilation is not adequate in providing patient-ventilatory synchrony in infants [124].
Neurally adjusted ventilator assist (NAVA) improves the
match between the patient’s needs and the assistance delivered by the ventilator – the pressure is proportional
to the integral of the electrical activity of the diaphragm
(EAdi) [125,126]. Use of EAdi to trigger the respiratory
cycle and to deliver proportional assist with the patient’s
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neural drive on a breath-to-breath basis improves patientventilator synchrony. The number of asynchronies in
NAVA is lower than that of pressure support ventilation
[127-129]. In very low birth weight infants, NAVA allows
neonates to use physiologic feedback to control ventilation
[130,131]. NAVA is being used in newborns undergoing
surgery for CHD for weaning. Long-term outcomes are
not yet available. All mechanically ventilated patients able
to sustain spontaneous assisted ventilation with an intact
neural ventilator drive and who can undergo placement of
a nasogastric tube may benefit from NAVA [125].
Blood Products
Blood product transfusion in adults is associated with
increased morbidity and mortality after cardiac surgery.
In pediatric patients, the amount of blood transfusion is
not associated with mortality [132] but is associated with
prolonged duration of mechanical ventilation and infection [132,133]. The absolute hemoglobin requiring transfusion in neonates with CHD has not been determined
[132]. Predictors of blood transfusion are patient-related,
procedure-related, and process-related. Neonates require
a higher volume for the priming circuit [134] Coagulation studies are more likely to be abnormal in newborns
with CHD and polycythemia worsens the coagulation
profile [135]. Cyanotic patients with a hematocrit greater
than 50% have prolonged coagulation time, a decreased
level of fibrinogen, and thrombocytopenia [136] and are
frequently on platelet inhibitors. Platelet count during
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Advances in Cardiothoracic Surgery
cardiopulmonary bypass (CPB) is the variable most significantly associated with blood loss [137]. Deep hypothermic circulatory arrest, hypothermia, hemodilution,
long duration of CPB or a combination are related to postoperative bleeding [134,135,138] Transfusion of < 48
hours old whole blood is associated with significantly less
post-op blood loss than transfusion of packed red blood
cells, fresh frozen plasma, and platelets in children under 2 years old who underwent complex cardiac surgery
[139]. Prophylactic use of aprotinin is not associated with
need for blood product transfusions and short-term outcome in neonates and infants [140]. Washing red blood
cells and platelets reduces inflammatory biomarkers,
number of transfusions, and donor exposures in patients
under 17 years old undergoing cardiac surgery with CPB
[141]. ε-Aminocaproic acid and tranexamic acid have
been found to be equally effective with respect to perioperative transfusion requirements in newborns undergoing
cardiac surgery [142]. Three-factor prothrombin complex
concentrate exerts procoagulant activity compared with
recombinant activated factor VII ex vivo and requires further clinical study [143]. Recombinant factor VIIa is efficient and safe in correcting hemostasis in children after
CPB when other means fail [144]. The use of autologous
umbilical cord blood for blood transfusion in neonates
during open-heart surgery maintains a leftward shift of the
HbO2 dissociation curve during hypothermic CPB when
compared to neonates who received HBa blood transfusion, but tissue oxygen delivery appears to be preserved
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[145]. Transfusion of blood products for survival, brain
protection, and decreased morbidity in newborns with
CHD needs prospective randomized studies. Outcomes
will reflect the efficacy of the blood products in achieving physiologic goals resulting in improved survival with
limited complications.
Special Cases
Hypoplastic Left Heart Syndrome
Almost 70% of patients with HLHS will survive into
adulthood [146]. The role of fetal aortic balloon valvuloplasty and decompression of the left atrium in utero are
not well-defined, but are being evaluated [147]. While
prematurity, low birth weight, and genetic/extracardiac
anomalies continue to adversely affect survival of newborns with HLHS, advances in surgical and perioperative
management strategies have reduced the impact of the
specific anatomies on survival [148-150]. The “classical”
Norwood utilizing the Blalock-Taussig shunt results in diastolic run-off and can result in hemodynamic instability
and coronary steal. Use of the right ventricle to pulmonary artery (RV-PA) conduit maintains diastolic pressure
with a more stable postoperative course [151]. Improved
pulmonary growth is also seen with the Norwood operation using a RV-PA nonvalved conduit [152]. An alternative initial procedure to the Norwood procedure for
HLHS and its variants, the hybrid procedure, avoids circulatory arrest and shifts the major surgical stage to later
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Advances in Cardiothoracic Surgery
in life [145]. Mortality is low and midterm survival is good
[153,154]. However, the need for catheter and/or surgical
interventions and the slow growth of the branch pulmonary arteries pre-Fontan require further solutions [155].
Neurodevelopmental outcomes in these patients have
improved as well and are reflective of changes in surgical
techniques and perioperative management [156,157].
Left Ventricular Outflow Tract Rehabilitation
Single-ventricle palliation (SVP) results in 10-year
survival rates ranging from 50% to 70% [158]. These
patients are predisposed to protein-losing enteropathy,
plastic bronchitis, thromboembolism, arrhythmias, and
may need to undergo cardiac transplantation [159]. Patients with borderline left heart structures present a clinical challenge and a decision must be made regarding
SVP or biventricular repair. Left ventricular salvage to
maintain biventricular circulation in patients with highrisk anatomy (variants of hypoplastic left heart syndrome
and Shone’s complex, coarctation with ventricular septal defect, and unbalanced atrioventricular canal defect)
is dependent on the growth potential of the left heart
structures if appropriate flow and loading conditions are
present. Presence of mitral or aortic atresia in patients
with intact ventricular septum is considered a contraindication to biventricular repair, but hypoplasia of left heart
structures is not. Left heart rehabilitation may result in
growth of left heart structures and permit biventricular
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repair. Surgical techniques include resection of endocardial fibroelastosis, mitral valvuloplasty to include division
of tethering secondary or accessory chordae, separation of
fused papillary muscles, chordal elongation of shortened
primary chorda, commissurotomy for commissural fusion, augmentation of deficient leaflets, and debridement
of thickened leaflet tissue, redistribution of atrioventricular valve tissue, aortic valvuloplasty to include commissurotomy, debridement of thickened aortic valve leaflets,
and augmentation of deficient leaflets, atrial septal defect
restriction, transcatheter interventions, and addition of
accessory pulmonary blood flow [160]. Primary left ventricular recruitment may be useful in patients with variations of Shone’s complex or borderline HLHS and surgery addresses aortic and/or mitral valve outflow tract
obstruction, coarctation, and endocardial fibroelastosis
[161]. Staged recruitment in patients initially considered
for or who are at high risk for biventricular repair undergo
SVP and simultaneous procedures to rehabilitate the left
ventricle [162]. Biventricular conversion with takedown
of the aortopulmonary anastomosis and re-establishment
of separate left and right ventricle outflow tract continuity
has been applied to patients with HLHS and unbalanced
complete atrioventricular canal and borderline left heart
with acceptable short-term results [163].
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Tetralogy of Fallot, Pulmonary Atresia, Major Aortopulmonary Collaterals
PA/IVS with major aortopulmonary collateral arteries (MAPCAs) is a complex lesion including a tetralogy
of fallot type of ventricular septal defect, atresia of the
pulmonary valve, and pulmonary blood flow arising from
systemic arterial collateral vessels. The natural history is
poor and less than 50% of patients survive beyond 2 years
old without intervention. Earlier surgery has been recommended to improve survival and outcomes and a staged
procedure to increase pulmonary blood flow to stimulate
growth of the pulmonary arteries followed by unifocalization has been the standard of care [164,165]. A modified
Blalock-Taussig shunt has been the mainstay of palliation. Long-term outcomes using this strategy have been
poor. The use of a right ventricle to pulmonary artery homograft in neonates has resulted in rapid and balanced
growth of central pulmonary arteries allowing complete
repair in most patients [166]. Staged repair is still required. In some patients with functional single ventricle
and MAPCAs, unifocalization may increase venous flow
to the pulmonary vascular bed and decrease cardiac volume load with resultant increase in life expectancy [167].
Early unifocalization of all important collaterals and early
establishment of a low-pressure pulmonary arterial bed
has resulted in improved outcomes and a protocol-based
individualized approach is now recommended. Angiography defines the arborization of the pulmonary arteries.
In those patients with MAPCAs having segmental level
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stenosis, staged unifocalization followed by staged intracardiac repair is recommended. Midline complete unifocalization is one if MAPCAs do not have segmental level
stenosis. Simultaneous intracardiac repair is done in the
newborns with low pulmonary artery pressures and staged
intracardiac repair is done if pulmonary artery pressures
are high [168,169].
Congenitally Corrected Transposition
of the Great Arteries
Physiologic repair of congenitally corrected transposition of the great arteries (ccTGA) (atrioventricular and
ventriculoarterial discordance) restores normal physiology, does not address ventriculoarterial discordance,
places the morphologic right ventricle in the systemic
position, and results in suboptimal long-term outcomes.
Progressive deterioration of right ventricular function,
tricuspid regurgitation, and the high rate of reintervention led to the concept of the anatomic repair. The latter procedure includes a venous and arterial switch and
utilizes the left ventricle as the systemic ventricle. Clinical outcomes suggest that the repair is associated with a
low operative mortality rate, superior survival, and lower
New York Heart Association functional class [170,171].
In the double switch operation, the Mustard procedure is
preferable – it conforms better to the unusual anatomy of
the atrial septum, is more versatile, allows more optimal
suture line placement, and has a lower incidence of reintervention and late death [172-174]. In those patients with
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left ventricular outflow tract obstruction (LVOTO), the
venous switch operation is performed in conjunction with
a modified Rastelli procedure [171]. An unprepared left
ventricle requires left ventricular training . Early pulmonary artery banding (< 2 years old) followed by anatomic
repair has low short-term mortality and favorable left ventricular and neoaortic valve function [175-177]. Late left
ventricular dysfunction after anatomic repair of ccTGA is
common and occurs most often in older patients and in
those requiring pacing [178,179].
Pulmonary Atresia with Intact Ventricular Septum
Treatment strategies for pulmonary atresia with intact
ventricular septum (PAIVS) depend on the type of atresia,
right ventricular anatomy, tricuspid valve size and function, and presence or absence of right ventricle-to-coronary artery fistula. Group A patients have valvar or “membranous” atresia with a well-developed infundibulum
and mild right ventricular hypoplasia. Patients are usually treated with radiofrequency valvotomy and balloon
dilation and long-term outcomes are excellent. Group
C patients have the most severe form of PA/IVS and the
right ventricle is severely hypoplastic and heavily musclebound, major right ventricle-coronary arterial connections with or without stenosis/interruptions are common,
the tricuspid valve is usually competent and the right ventricle systolic pressure is often suprastemic. These patients
have a duct dependent pulmonary circulation and a shunt
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is usually placed in the newborn period. These patients
follow the SVP pathway. Long-term outcomes are similar
to patients with tricuspid atresia. The intermediate Group
B patients have borderline right ventricular size, the pulmonary atresia is of the valvar or membranous type, the
infundibulum may be smaller than those in Group A, the
pulmonary valve annulus may be small, there may be a
fixed right ventricular outflow tract obstruction with suboptimal right ventricle decompression after an interventional procedure, major right ventricle-coronary artery
connections are less common than in Group C patients
but minor sinusoids are common, and varying degrees of
tricuspid regurgitation is present. Individualized management is required for this group of patients and is determined by morphologic characteristics [180-182]. In these
patients, right ventricular growth and function is difficult
to predict. Catheter-based interventions to include the
use of stiff wire, lasers, and radiofrequency and percutaneous perforation and balloon valvuloplasty rarely avoid
the need for surgical therapy [183]. Classification based
on the right ventricle hypoplasia (mild, moderate or severe hypoplasia of the right ventricle and its components)
has been helpful in determining treatment. Management
is usually staged with the initial goal of improving systemic arterial oxygenation and establishing forward flow
through the right ventricle [184,185]. The hybrid procedure in patients not having major right ventricular-tocoronary artery communications allow decompression of
the right ventricular outflow tract. The procedure is done
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through a median sternotomy approach and needle perforation of the atretic plate and dilation of the pulmonary
valve is performed. Simultaneous procedures - modified
Blalock-Taussig shunt, bidirectional Glenn, etc. – may be
performed and are dependent on the patient’s age, oxygen saturation, response to opening of the biventricular
outflow tract, and the z-score of the tricuspid valve. All
newborn patients have a modified Blalock-Taussig shunt
placed at the the of the right ventricular outflow tract
augmentation. Biventricular repair has been possible in
greater than 80% of patients [186,187].
Summary
Complex CHD diagnosed in the fetus and newborn
is now being medically and surgically managed with improved immediate and long-term outcomes. In utero interventions with the goal of preventing the more complex
pathologies are still being evaluated and are not yet standard of care. Fetal diagnosis requires that the obstetrician,
neonatologist, cardiologist, and cardiothoracic surgeon
are involved in the care of the fetal patient before delivery and that plans are made for the best care of the newborn upon delivery. Preoperative advances have allowed
for more stable newborns with complex CHD to undergo
complicated procedures with good outcomes. Postoperative care has resulted in improved morbidities and reduced
mortalities as well in these high risk patients.
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References
1. Tworetzky W, McElhinney DB, Reddy VM,
Brook MM, Hanley FL. Improved surgical outcome after fetal diagnosis of hypoplastic left heart
syndrome. Circulation. 2001; 103: 1269-1273.
2. Bonnet D, Coltri A, Butera G, Fermont L, Le Bidois J. Detection of transposition of the great arteries in fetuses reduces neonatal morbidity and
mortality. Circulation. 1999; 99: 916-918.
3. Donofrio MT, Moon-Grady AJ, Hornberger LK,
Copel JA, Sklansky MS, et al; American Heart Association Adults With Congenital Heart Disease
Joint Committee of the Council on Cardiovascular Disease in the Young and Council on Clinical
Cardiology, Council on Cardiovascular Surgery
and Anesthesia, and Council on Cardiovascular
and Stroke Nursing. Diagnosis and treatment of
fetal cardiac disease: a scientific statement from
the American Heart Association. 2014; 129: 21832242.
4. International Society of Ultrasound in Obstetrics
and Gynecology, Carvalho JS, Allan LD, Chaoui
R, Copel JA, et al. ISUOG Practice Guidelines
(updated): sonographic screening examination of
the fetal heart.. 2013; 41: 348-359.
5. Copel JA, Pilu G, Green J, Hobbins JC, Kleinman
CS. Fetal echocardiographic screening for conwww.avidscience.com
37
Advances in Cardiothoracic Surgery
Advances in Cardiothoracic Surgery
genital heart disease: the importance of the fourchamber view. Am J Obstet Gynecol. 1987; 157:
648-655.
6. DeVore GR. The aortic and pulmonary outflow
tract screening examination in the human fetus. J
Ultrasound Med. 1992; 11: 345-348.
7. Achiron R, Glaser J, Gelernter I, Hegesh J, Yagel
S. Extended fetal echocardiographic examination
for detecting cardiac malformations in low risk
pregnancies. BMJ. 1992; 304: 671-674.
8. Yoo SJ, Lee YH, Kim ES, Ryu HM, Kim MY, et
al. Three-vessel View of the Fetal Upper Mediastinum: An Easy Means of Detecting Abnormalities
of the Ventricular Outflow Tracts and Great Arterties During Obstretric Screening. Ultrasound
Obstet Gynecol. 1997; 9: 173-182.
9. Viñals F, Heredia F, Giuliano A. The role of the
three vessels and trachea view (3VT) in the diagnosis of congenital heart defects. Ultrasound Obstet Gynecol. 2003; 22: 358-367.
10.Jone PN, Schowengerdt KO Jr. Prenatal diagnosis
of congenital heart disease. Pediatr Clin North
Am. 2009; 56: 709-715, Table of Contents.
11.Cohen MS1. Fetal diagnosis and management of
congenital heart disease. Clin Perinatol. 2001; 28:
11-29, v-vi.
38
www.avidscience.com
12.Pike JI, Krishnan A, Donofrio MT. Early Fetal
Echocardiography: Congenital Heart Disease Detection and Diagnositic Accuracy in the Hands of
an Experienced Fetal Cardiology Program. Prenat
Diagn. 2014; 34: 790-796.
13.Verheijen PM, Lisowski LA, Stoutenbeek P, Hitchcock JF, Brenner JI. Prenatal diagnosis of congenital heart disease affects preoperative acidosis in
the newborn patient. J Thorac Cardiovasc Surg.
2001; 121: 798-803.
14.McElhinney DB, Marshall AC, Wilkins-Haug LE,
Brown DW, Benson CB. Predictors of technical
success and postnatal biventricular outcome after in utero aortic valvuloplasty for aortic stenosis with evolving hypoplastic left heart syndrome.
Circulation. 2009; 120: 1482-1490.
15.Simpson JM, Sharland GK. Natural history and
outcome of aortic stenosis diagnosed prenatally.
Heart. 1997; 77: 205-210.
16.Michelfelder E, Gomez C, Border W, Gottliebson
W, Franklin C. Predictive value of fetal pulmonary
venous flow patterns in identifying the need for
atrial septoplasty in the newborn with hypoplastic
left ventricle. Circulation. 2005; 112: 2974-2979.
17.Marshall AC, Levine J, Morash D, Silva V, Lock
JE. Results of in utero atrial septoplasty in fetuses
www.avidscience.com
39
Advances in Cardiothoracic Surgery
Advances in Cardiothoracic Surgery
with hypoplastic left heart syndrome. Prenat Diagn. 2008; 28: 1023-1028.
18.Vogel M, McElhinney DB, Wilkins-Haug LE,
Marshall AC, Benson CB. Aortic stenosis and
severe mitral regurgitation in the fetus resulting
in giant left atrium and hydrops: pathophysiology, outcomes, and preliminary experience with
pre-natal cardiac intervention. J Am Coll Cardiol.
2011; 57: 348-355.
24.Huang FK, Lin CC, Huang TC, Weng KP, Liu
PY. Reappraisal of the prostaglandin E1 dose for
early newborns with patent ductus arteriosus-dependent pulmonary circulation. Pediatr Neonatol.
2013; 54: 102-106.
19.Rogers LS, Peterson AL, Gaynor JW, Rome JJ,
Weinberg PM. Mitral valve dysplasia syndrome:
a unique form of left-sided heart disease. J Thorac
Cardiovasc Surg. 2011; 142: 1381-1387.
25.Kramer HH, Sommer M, Rammos S, Krogmann
O. Evaluation of low dose prostaglandin E1 treatment for ductus dependent congenital heart disease. Eur J Pediatr. 1995; 154: 700-707.
20.Tworetzky W, McElhinney DB, Marx GR, Benson
CB, Brusseau R. In utero valvuloplasty for pulmonary atresia with hypoplastic right ventricle:
techniques and outcomes. Pediatrics. 2009; 124:
e510-518.
26.Aykanat A, Yavuz T, Özalkaya E, Topçuoğlu S,
Ovalı F, et al. Long-Term Prostaglandin E1 Infusion for Newborns with Critical Congenital Heart
Disease. Pediatr Cardiol. 2015;.
21.Donofrio MT, Levy RJ, Schuette JJ, Skurow-Todd
K, Sten M, et al. Specialized Delivery Room Planning for Fetuses with Critical Congenital Heart
Disease. Am J Cardiol. 2012; 111: 737-747.
22.Tita AT, Landon MB, Spong CY, Lai Y, Leveno KJ,
et al; Eunice Kennedy Shriver NICHD MaternalFetal Medicine Units Network. Timing of Elective
Repeat Cesarean Delivery at Term and Neonatal
Outcomes. N Eng J Med. 2009; 360; 111-120.
40
23.Hilder L, Costeloe K, Thilaganathan B. Prolonged
pregnancy: evaluating gestation-specific risks of
fetal and infant mortality. Br J Obstet Gynaecol.
1998; 105: 169-173.
www.avidscience.com
27.Tálosi G, Katona M, Túri S. Side-effects of longterm prostaglandin E(1) treatment in neonates.
Pediatr Int. 2007; 49: 335-340.
28.Kermode J, Butt W, Shann F. Comparison between
prostaglandin E1 and epoprostenol (prostacyclin)
in infants after heart surgery. Br Heart J. 1991; 66:
175-178.
29.Serra W, Musiari L, Ardissino D, Gherli T, Montanari A. Benefit of prostaglandin infusion in severe heart failure: preliminary clinical experience
www.avidscience.com
41
Advances in Cardiothoracic Surgery
Advances in Cardiothoracic Surgery
of repetitive administration. Int J Cardiol. 2011;
146: e10-15.
ing variation in the use of inhaled nitric oxide.
Pediatrics. 2014; 133: e1753-1758.
30.Zhang CY, Ma ZS, Ma LL, Wang LX. Effect of prostaglandin E1 inhalation on pulmonary hypertension following corrective surgery for congenital
heart disease. Exp Clin Cardiol. 2013; 18: 13-16.
37.Todd Tzanetos DR, Housley JJ, Barr FE, May WL,
Landers CD. Implementation of an inhaled nitric
oxide protocol decreases direct cost associated
with its use. Respir Care. 2015; 60: 644-650.
31.[No authors listed]. American Academy of Pediatrics. Committee on Fetus and Newborn. Use of
inhaled nitric oxide. Pediatrics. 2000; 106: 344345.
38.Lee JE, Hillier SC, Knoderer CA. Use of sildenafil
to facilitate weaning from inhaled nitric oxide in
children with pulmonary hypertension following
surgery for congenital heart disease. J Intensive
Care Med. 2008; 23: 329-334.
32.Kinsella JP, Abman SH. Inhaled nitric oxide: current and future uses in neonates. Semin Perinatol.
2000; 24: 387-395.
33.Barrington KJ, Finer NN. Inhaled Nitric Oxide for
Respiratory Failure in Preterm Infants. Cochrane
Database Syst Rev. 2007; 18: CD000509.
34.Bizzarro M, Gross I. Inhaled Nitric Oxide for the
Postoperative Management of Pulmonary Hypertension in Infants and Children with Congenital
Heart Disease. Cochrane Database Syst Rev. 2005;
19: CD005055.
35.Benedetto M, Romano R, Baca G, Sarridou D,
Fischer A. Inhaled nitric oxide in cardiac surgery:
Evidence or tradition? Nitric Oxide. 2015; 49: 6779.
36.Simsic JM, Harrison S, Evans L, McClead R, Teske
D; Institute of Healthcare Improvement. Reduc42
www.avidscience.com
39.Morray JP, Lynn AM, Mansfield PB. Effect of pH
and PCO2 on pulmonary and systemic hemodynamics after surgery in children with congenital heart disease and pulmonary hypertension. J
Pediatr. 1988; 113: 474-479.
40.Mora GA, Pizarro C, Jacobs ML, Norwood WI.
Experimental model of single ventricle. Influence
of carbon dioxide on pulmonary vascular dynamics. Circulation. 1994; 90: II43-46.
41.Myers TR1. Therapeutic gases for neonatal and
pediatric respiratory care. Respir Care. 2003; 48:
399-422.
42.Day RW, Tani LY, Minich LL, Shaddy RE, Orsmond GS, et al. Congenital Heart Disease With
Ductal-Dependent Systemic Perfusion: Doppler
Ultransonography Flow Velocities Are Altered
www.avidscience.com
43
Advances in Cardiothoracic Surgery
Advances in Cardiothoracic Surgery
by Changes in the Fraction of Inspired Oxygen. J
Heart Lung Transplant. 1995; 14: 718-725.
43.Day RW, Barton AJ, Pysher TJ, Shaddy RE. Pulmonary vascular resistance of children treated
with nitrogen during early infancy. Ann Thorac
Surg. 1998; 65: 1400-1404.
44.Thangaratinam S, Brown K, Zamora J, Khan KS,
Ewer AK. Pulse Oximetry Screening for Critical
Congenital Heart Defects in Asymptomatic Newborn Babies: A Systematic Review and Meta-analysis. Lancet. 2012; 379: 2459-2464.
45.Mahle WT, Newburger JW, Matherne GP, Smith
FC, Hoke TR, et al. Role of Pulse Oximetry in Examining Newborns for Congenital Heart Disease:
A Scientific Statement from the American Heart
Association and American Academy of Pediatrics.
Circulation. 2009; 120: 447-458.
46.de-Wahl Granelli A, Wennergren M, Sanberg K,
Mellander M, Bejlum C, et al. Impact of Pulse
Oximetry Screening on the Detection of Duct
Dependent Congenital Heart Disease: A Swedish Prospective Screeening Study in 39,821 Newborns. BMJ. 2009; 338: a3037.
47.Roberts TE, Barton PM, Auguste PE, Middleton
LJ, Furmston AT. Pulse oximetry as a screening
test for congenital heart defects in newborn infants: a cost-effectiveness analysis. Arch Dis Child.
44
www.avidscience.com
2012; 97: 221-226.
48.Wren C, Richmond S, Donaldson L. Presentation
of congenital heart disease in infancy: implications for routine examination. Arch Dis Child Fetal Neonatal Ed. 1999; 80: F49-53.
49.Chang RK, Gurvitz M, Rodriguez S. Missed diagnosis of critical congenital heart disease. Arch
Pediatr Adolesc Med. 2008; 162: 969-974.
50.Durandy Y. Usefulness of low prime perfusion
pediatric circuit in decreasing blood transfusion.
ASAIO J. 2007; 53: 659-661.
51.Golab HD, Bogers JJ. Small, smaller, smallest.
Steps towards bloodless neonatal and infant cardiopulmonary bypass. Perfusion. 2009; 24: 239-242.
52.Wang S, Rosenthal T, Kunselman AR, Ãœndar A.
Evaluation of Different Diameter Arterial Tubing
and Arterial Cannulae in Simulated Neonatal/
Pediatric Cardiopulmonary Bypass Circuits. Artific Org. 2015; 39: 43-52.
53.Yoshizumi K, Ishino K, Ugaki S, Ebishima H, Kotani Y. Effect of a miniaturized cardiopulmonary
bypass system on the inflammatory response and
cardiac function in neonatal piglets. Artif Organs.
2009; 33: 941-946.
54.Loeffelbein F, Zirell U, Benk C, Schlensak C,
Dittrich S. High colloid oncotic pressure primwww.avidscience.com
45
Advances in Cardiothoracic Surgery
Advances in Cardiothoracic Surgery
ing of cardiopulmonary bypass in neonates and
infants: implications on haemofiltration, weight
gain and renal function. Eur J Cardiothorac Surg.
2008; 34: 648-652.
Stamm C. Effects of pH management during deep
hypothermic bypass on cerebral microcirculation:
alpha-stat versus pH-stat. Circulation. 2002; 106:
I103-108.
55.Riegger LQ, Voepel-Lewis T, Kulik TJ, Malviya S,
Tait AR. Albumin versus crystalloid prime solution for cardiopulmonary bypass in young children. Crit Care Med. 2002; 30: 2649-2654.
61.Sakamoto T, Zurakowski D, Duebener LF, Lidov
HG, Holmes GL. Interaction of temperature with
hematocrit level and pH determines safe duration
of hypothermic circulatory arrest. J Thorac Cardiovasc Surg. 2004; 128: 220-232.
56.Oliver WC Jr, Beynen FM, Nuttall GA, Schroeder
DR, Ereth MH. Blood loss in infants and children
for open heart operations: albumin 5% versus
fresh-frozen plasma in the prime. Ann Thorac
Surg. 2003; 75: 1506-1512.
57.Chasovskyi K, Fedevych O, McMullan DM, Mykychak Y, Vorobiova G. Tissue perfusion in neonates
undergoing open-heart surgery using autologous
umbilical cord blood or donor blood components.
Perfusion. 2015; 30: 499-506.
58.Armstrong DH, Schroeder WA, Fenninger WD. A
comparison of the percentage of fetal hemoglobin
in human umbilical cord blood as determined
by chromatography and by alkali denaturation.
Blood. 1963; 22: 554-565.
59.Kofstad J. Blood gases and hypothermia: some
theoretical and practical considerations. Scand J
Clin Lab Invest Suppl. 1996; 224: 21-26.
60.Duebener LF, Hagino I, Sakamoto T, Mime LB,
46
www.avidscience.com
62.Sakamoto T, Kurosawa H, Shin’oka T, Aoki M, Isomatsu Y. The influence of pH Strategy on Cerebral
and Collateral Circulation During Hypothermic
Cardiopulmnary Bypass in Cyanotic Patients
With Heart Disease: Results of a Randomized Trial and Real-time Monitoring. J Thorac Cardiovasc
Surg. 2004; 127: 12-19.
63.Bellinger DC, Wypij D, du Plessis AJ, Rappaport
LA, Riviello J. Developmental and neurologic effects of alpha-stat versus pH-stat strategies for
deep hypothermic cardiopulmonary bypass in
infants. J Thorac Cardiovasc Surg. 2001; 121: 374383.
64.du Plessis AJ, Jonas RA, Wypij D, Hickey PR,
Riviello J. Perioperative effects of alpha-stat versus
pH-stat strategies for deep hypothermic cardiopulmonary bypass in infants. J Thorac Cardiovasc
Surg. 1997; 114: 991-1000.
www.avidscience.com
47
Advances in Cardiothoracic Surgery
Advances in Cardiothoracic Surgery
65.Abdul Aziz KA, Meduoye A. Is pH-stat or alphastat the best technique to follow in patients undergoing deep hypothermic circulatory arrest? Interact Cardiovasc Thorac Surg. 2010; 10: 271-282.
tracorporeal Membrane Oxygenation Systems for
H!N!-related Severe Acute Respiratory Distress
Syndrome: A Case Series. J Crit Care. 2012; 27:
454-463.
66.Jonas RA, Wypij D, Roth SJ, Bellinger DC, Visconti KJ. The influence of hemodilution on outcome after hypothermic cardiopulmonary bypass:
results of a randomized trial in infants. J Thorac
Cardiovasc Surg. 2003; 126: 1765-1774.
71.Alwardt CM, Wilson DS, Alore ML, Lanza LA,
Devaleria PA. Performance and Safety of an Integrated Portable Extracorporeal Life Support System for Adults. J Extra Corpor Technol. 2015; 47:
38-43.
67.Newburger JW, Jonas RA, Soul J, Kussman BD,
Bellinger DC. Randomized trial of hematocrit
25% versus 35% during hypothermic cardiopulmonary bypass in infant heart surgery. J Thorac
Cardiovasc Surg. 2008; 135: 347-354, 354.
72.Schmid C, Philipp A, Mueller T, Hilker M. Extracorporeal life support - systems, indications, and
limitations. Thorac Cardiovasc Surg. 2009; 57:
449-454.
68.Wypij D, Jonas RA, Bellinger DC, Del Nido PJ,
Mayer JE Jr. The effect of hematocrit during hypothermic cardiopulmonary bypass in infant heart
surgery: results from the combined Boston hematocrit trials. J Thorac Cardiovasc Surg. 2008; 135:
355-360.
69.Philipp A, Arlt M, Amann M, Lunz D, Müller T,
et al. First Experience With the Ultra Compact
Mobile Extracorporeal Membrane Oxygenation
System Cardiohelp in Interhospital Transport. Interact Cardiovasc Thorac Surg. 2011; 12: 978-981.
70.Roncon-Albuquerque R, Basiol C, Figueiredo P,
Silva S, Alves C, et al. Portable Miniaturized Ex48
www.avidscience.com
73.Gray BW, Shaffer AW, Mychaliska GB. Advances
in neonatal extracorporeal support: the role of extracorporeal membrane oxygenation and the artificial placenta. Clin Perinatol. 2012; 39: 311-329.
74.Bryner BS, Mychaliska GB2. ECLS for preemies:
the artificial placenta. Semin Perinatol. 2014; 38:
122-129.
75.Hemolun RAS/ALung Technologies.
76.Davies RR, Haldeman S, McCulloch MA, Pizarro
C. Creation of a quantitative score to predict the
need for mechanical support in children awaiting
heart transplant. Ann Thorac Surg. 2014; 98: 675682.
www.avidscience.com
49
Advances in Cardiothoracic Surgery
Advances in Cardiothoracic Surgery
77.Extracorporeal Life Support Organization.
78.Fraser CD Jr, Jaquiss RD, Rosenthal DN, Humpl T,
Canter CE, et al; Berlin Heart Study Investigators.
Prospective Trial of a Pediatric Ventricular Assist
Device. N Engl J Med. 2012; 367: 532-541.
79.Adachi I, Fraser CD Jr. Berlin Heart EXCOR Food
and Drug Administration Investigational Device
Exemption Trial. Semin Thorac Cardiovasc Surg.
2013; 25: 100-106.
80.Kirklin JK, Bennett Pearce F, Dabal RJ, Carlo WF.
Mechanical circulatory support: strategies and
outcomes in pediatric congenital heart disease.
Semin Thorac Cardiovasc Surg Pediatr Card Surg
Annu. 2014; 17: 62-68.
81.Baldwin JT, Borovetz HS, Duncan BW, Gartner
MJ, Jarvik RK, et al. The National Heart, Lung,
and Blood Institute Pediatric Circulatory Support
Program. Circulation. 2006; 113: 147-155.
82.Callahan KA, Panter TM, Hall TM, Slemmons M.
Peak flow monitoring in pediatric asthma management: a clinical practice column submission. J
Pediatr Nurs. 2010; 25: 12-17.
83.Hearse D, Braimbridge M, Jynge P. Protection of
the Ischemic Myocardium: Cardioplegia. New
York: Raven Press. 1981.
84.Preusse CJ, Gebhard MM, Bretschneider HJ. My-
50
www.avidscience.com
ocardial “Equilibration Processes” and Myocardial Energy Turnover during Initiation of Artificial
Cardiac Arrest with Cardioplegic Solution - Reasons for a Sufficiently Long Cardioplegic Perfusion. Thorac Cardiovasc Surg. 1981; 29: 71-76.
85.Litasova EE and Lomivorotov VN. Hypothermic
Protection (26-25 Degrees C) Without Perfusion
Cooling for Surgery of Congenital Cardial Defects Using Prolonged Occlusion. Thorax. 1988;
43: 201-211.
86.Bigelow WG, Mustard WT, Evans JG. Some physiologic concepts of hypothermia and their applications to cardiac surgery. J Thorac Surg. 1954; 28:
463-480.
87.Doenst T, Schlensak C, Beyersdorf F. Cardioplegia in pediatric cardiac surgery: do we believe in
magic? Ann Thorac Surg. 2003; 75: 1668-1677.
88.Durandy Y1. Pediatric myocardial protection.
Curr Opin Cardiol. 2008; 23: 85-90.
89.Poncelet AJ, van Steenberghe M, Moniotte S, Detaille T, Beauloye C, et al. Cardiac and Neurological Assessment of Normothermia/Warm Blood
Cardioplegia Vs Hypothermia/Cold Crystalloid
Cardioplegia in Pediatric Cardiac Surgery: Insight
From a Prospective Randomized Trial. Eur J Cardiothorac Surg. 2011; 49: 1384-1391.
90.Modi P, Suleiman MS, Reeves B, Pawade A, Parry
www.avidscience.com
51
Advances in Cardiothoracic Surgery
Advances in Cardiothoracic Surgery
AJ. Myocardial metabolic changes during pediatric cardiac surgery: a randomized study of 3 cardioplegic techniques. J Thorac Cardiovasc Surg.
2004; 128: 67-75.
al cerebral perfusion versus deep hypothermic
circulatory arrest: outcomes for infants with functional single ventricle. J Thorac Cardiovasc Surg.
2007; 133: 880-887.
91.Jacob S, Kallikourdis A, Sellke F, Dunning J. Is
blood cardioplegia superior to crystalloid cardioplegia? Interact Cardiovasc Thorac Surg. 2008; 7:
491-498.
96.Haldenwang PL, Strauch JT, Amann I, Klein T,
Sterner-Kock A. Impact of pump flow rate during
selective cerebral perfusion on cerebral hemodynamics and metabolism. Ann Thorac Surg. 2010;
90: 1975-1984.
92.Bellinger DC, Jonas RA, Rappaport LA, Wypij
D, Wernovsky G. Developmental and neurologic
status of children after heart surgery with hypothermic circulatory arrest or low-flow cardiopulmonary bypass. N Engl J Med. 1995; 332: 549-555.
93.Bellinger DC, Wypij D, Kuban KC, Rappaport LA,
Hickey PR. Developmental and neurological status of children at 4 years of age after heart surgery
with hypothermic circulatory arrest or low-flow
cardiopulmonary bypass. Circulation. 1999; 100:
526-532.
94.Wypij D, Newburger JW, Rappaport LA, duPlessis
AJ, Jonas RA. The effect of duration of deep hypothermic circulatory arrest in infant heart surgery
on late neurodevelopment: the Boston Circulatory Arrest Trial. J Thorac Cardiovasc Surg. 2003;
126: 1397-1403.
95.Goldberg CS, Bove EL, Devaney EJ, Mollen E,
Schwartz E. A randomized clinical trial of region52
www.avidscience.com
97.Chipeta J, Komada Y, Zhang XL, Deguchi T, Sugiyama K. CD4+ and CD8+ cell cytokine profiles in
neonates, older children, and adults: increasing T
helper type 1 and T cytotoxic type 1 cell populations with age. Cell Immunol. 1998; 183: 149-156.
98.Sack U, Burkhardt U, Borte M, Schädlich H, Berg
K. Age-dependent levels of select immunological
mediators in sera of healthy children. Clin Diagn
Lab Immunol. 1998; 5: 28-32.
99.de Jong PR, Schadenberg AW, van den Broek T,
Beekman JM, van Wijk F, et al. Stat3 Regulates
Monocyte TNF-alpha Production in Systemic Inflammation Caused by Cardiac Surgery With Cardiopulmonary Bypass. PLoS One. 2012; 7: e35070.
100.
Wang W, Huang HM, Zhu DM, Chen H,
Su ZK. Modified ultrafiltration in paediatric cardiopulmonary bypass. Perfusion. 1998; 13: 304310.
www.avidscience.com
53
Advances in Cardiothoracic Surgery
Advances in Cardiothoracic Surgery
101.
Robertson-Malt S, Afrane B, El Barbary
M. Prophylactic steroids for pediatric open heart
surgery. Cochrane Database Syst Rev. 2007; :
CD005550.
102.
Kapitein B, van Saet AW, Golab HD, de
Hoog M, de Wildt S. Does pharmacotherapy influence the inflammatory responses during cardiopulmonary bypass in children? J Cardiovasc
Pharmacol. 2014; 64: 191-197.
103.
Schneemilch CE, Ittenson A, Ansorge S,
Hachenberg T, Bank U. Effect of 2 anesthetic techniques on the postoperative proinflammatory and
anti-inflammatory cytokine response and cellular
immune function to minor surgery. J Clin Anesth.
2005; 17: 517-527.
104.
Clancy RR1. Neuroprotection in infant
heart surgery. Clin Perinatol. 2008; 35: 809-82,
viii.
105.
Raja SG, Yousufuddin S, Rasool F, Nubi A,
Danton M. Impact of modified ultrafiltration on
morbidity after pediatric cardiac surgery. Asian
Cardiovasc Thorac Ann. 2006; 14: 341-350.
106.
Ziyaeifard M, Alizadehasl A, Massoumi
G. Modified ultrafiltration during cardiopulmonary bypass and postoperative course of pediatric cardiac surgery. Res Cardiovasc Med. 2014; 3:
e17830.
54
www.avidscience.com
107.
Kuratani N, Bunsangjaroen P, Srimueang
T, Masaki E, Suzuki T. Modified versus conventional ultrafiltration in pediatric cardiac surgery:
a meta-analysis of randomized controlled trials
comparing clinical outcome parameters. J Thorac
Cardiovasc Surg. 2011; 142: 861-867.
108.
Dittrich S, Aktuerk D, Seitz S, Mehwald
P, Schulte-Mönting J, et al. Effects of Ultrafiltration and Peritoneal Dialysis on Proinflammatory
Cytokines During Cardiopulmonary Bypass Surgery in Newborns and Infants. Eur J Cardiothorac
Surg. 2004; 25: 935-940.
109.
Berdat PA, Eichenberger E, Ebell J, Pfammatter JP, Pavlovic M. Elimination of proinflammatory cytokines in pediatric cardiac surgery:
analysis of ultrafiltration method and filter type.
J Thorac Cardiovasc Surg. 2004; 127: 1688-1696.
110.
McRobb CM, Mejak BL, Ellis WC, Lawson
DS, Twite MD. Recent Advances in Pediatric Cardiopulmonary Bypass. Semin Cardiothorac Vasc
Anesth. 2014; 18: 153-160.
111.
Talwar S, Khadgawat R, Sandeep JA,
Sreenivas V, Choudhary SK, et al. Cardiopulmonary Bypass and Serum Thyroid Hormone Profile
in Pediatric Patients with Congenital Heart Disease. Congenital Heart Disease. 2012; 7: 33-440.
112.
Mackie AS, Booth KL, Newburger JW,
www.avidscience.com
55
Advances in Cardiothoracic Surgery
Advances in Cardiothoracic Surgery
Gauvreau K, Huang SA. A randomized, doubleblind, placebo-controlled pilot trial of triiodothyronine in neonatal heart surgery. J Thorac Cardiovasc Surg. 2005; 130: 810-816.
113.
Bettendorf M, Schmidt KG, Grulich-Henn
J, Ulmer HE, Heinrich UE. Tri-iodothyronine
treatment in children after cardiac surgery: a double-blind, randomised, placebo-controlled study.
Lancet. 2000; 356: 529-534.
114.
Portman MA, Slee A, Olson AK, Cohen
G, Karl T. Triiodothyronine Supplementation in
Infants and Children Undergoing Cardiopulmonary Bypass (TRICC): a multicenter placebo-controlled randomized trial: age analysis. Circulation.
2010; 122: S224-233.
115.
Plumpton K, Haas NA. Identifying infants
at risk of marked thyroid suppression post-cardiopulmonary bypass. Intensive Care Med. 2005;
31: 581-587.
116.
Marwali EM, Boom CE, Sakidjan I, Santoso A, Fakhri D, et al. Oral Triiodothyronine Normalizes Triiodothyronine Levels After Surgery for
Pediatric Congenital Heart Disease. Pediatr Crit
Care Med. 2013; 14: 701-708.
117.
Choi YS, Kwak YL, Kim JC, Chun DH,
Hong SW. Peri-operative oral triiodothyronine
replacement therapy to prevent postoperative low
56
www.avidscience.com
triiodothyronine state following valvular heart
surgery. Anaesthesia. 2009; 64: 871-877.
118.
Wernovsky G, Wypij D, Jonas RA, Mayer
JE Jr, Hanley FL, et al. Post-operative Course and
Hemodynamic Profile After the Arterial Switch
Operation in Neonates and Infants: A Comparison of Low-flow Cardiopulmonary Bypass Versus
Circulatory Arrest. Circulation. 1995: 92: 22262235.
119.
Friedman WF, George BL. Treatment of
congestive heart failure by altering loading conditions of the heart. J Pediatr. 1985; 106: 697-706.
120.
Burkhardt BE, Rücker G, Stiller B. Prophylactic Milrinone for the Prevention of Low Cardiac Output Syndrome and Mortality in Children
Undergoing Surgery for Congenital Heart Disease
(Review.) Cochrane Database Syst Rev. 2015; 25:
CD009515.
121.
Lechner E, Hofer A, Leitner-Peneder G,
Freynschlag R, Mair R. Levosimendan versus
milrinone in neonates and infants after corrective open-heart surgery: a pilot study. Pediatr Crit
Care Med. 2012; 13: 542-548.
122.
Wessel DL1. Managing low cardiac output syndrome after congenital heart surgery. Crit
Care Med. 2001; 29: S220-230.
123.
Esteban A, Ferguson ND, Meade MO, Fru-
www.avidscience.com
57
Advances in Cardiothoracic Surgery
Advances in Cardiothoracic Surgery
tos-Vivar F, Apezteguia C, et al; VENTILA Group.
Am J Respir Crit Care Med. 2008; 177: 170-177.
124.
Beck J, Tucci M, Emeriaud G, Lacroix J,
Sinderby C. Prolonged neural expiratory time induced by mechanical ventilation in infants. Pediatr Res. 2004; 55: 747-754.
125.
Verbrugghe W, Jorens PG. Neurally adjusted ventilatory assist: a ventilation tool or a ventilation toy? Respir Care. 2011; 56: 327-335.
126.
Terzi N, Piquilloud L, Rozé H, Mercat A,
Lofaso F. Clinical review: Update on neurally adjusted ventilatory assist--report of a round-table
conference. Crit Care. 2012; 16: 225.
127.
Yonis H, Crognier L, Conil J, Serres I,
Rouget A, et al. Patient-ventilator Synchrony in
Neurally Adjusted Ventilatory Assist (NAVA) and
Pressure Support Ventilation (PSV): A Prospective Observational Study. BMC Anesth. 2015; 15:
117.
128.
Coisel Y, Chanques G, Jung B, Constantin
JM, Capdevila X. Neurally adjusted ventilatory assist in critically ill postoperative patients: a crossover randomized study. Anesthesiology. 2010; 113:
925-935.
129.
Spahija J, de Marchie M, Albert M, Bellemare P, Delisle S. Patient-ventilator interaction
58
www.avidscience.com
during pressure support ventilation and neurally
adjusted ventilatory assist. Crit Care Med. 2010;
38: 518-526.
130.
Narchi H, Chedid F. Neurally adjusted
ventilator assist in very low birth weight infants:
Current status. World J Methodol. 2015; 5: 62-67.
131.
Beck J, Reilly M, Grasselli G, Mirabella L,
Slutsky AS. Patient-ventilator interaction during
neurally adjusted ventilatory assist in low birth
weight infants. Pediatr Res. 2009; 65: 663-668.
132.
Székely A, Cserép Z, Sápi E, Breuer T, Nagy
CA. Risks and predictors of blood transfusion in
pediatric patients undergoing open heart operations. Ann Thorac Surg. 2009; 87: 187-197.
133.
Kipps AK, Wypiz D, Thiagarajan RR, Bacha EA, Newburger JW. Blood Transfusion is Associated With Prolonged Duration of Mechanical Ventilation in Infants Undergoing Reparative
Cardiac Surgery. Pediatr Crit Care Med. 2011; 12:
52-56.
134.
Petäjä J, Lundström U, Leijala M, Peltola K,
Siimes MA. Bleeding and use of blood products
after heart operations in infants. J Thorac Cardiovasc Surg. 1995; 109: 524-529.
135.
Williams GD, Bratton SL, Ramamoorthy
C. Factors associated with blood loss and blood
www.avidscience.com
59
Advances in Cardiothoracic Surgery
Advances in Cardiothoracic Surgery
product transfusions: a multivariate analysis in
children after open-heart surgery. Anesth Analg.
1999; 89: 57-64.
136.
Sambasivan A, Tibble A, Donahue BS. Low
arterial saturation is associated with increased
sensitivity to activated protein C in children with
congenital heart disease. J Cardiothorac Vasc Anesth. 2006; 20: 38-42.
141.
Cholette JM, Henrichs KF, Alfieris GM,
Powers KS, Phipps R, et al. Washing Red Blood
Cells and Platelets Transfused in Cardiac Surgery
Reduces Post-operative Inflammation and Number of Transfusions: Results of a Prospective, Randomized, Controlled Clinical Trial. Pediatr Crit
Care Med. 2012; 13: 1-22.
137.
Williams GD, Bratton SL, Riley EC, Ramamoorthy C. Coagulation Tests During Cardiopulmonary Bypass Correlate With Blood Loss in
Children Undergoing Cardiac Surgery. J Cardiothor Vasc Anesth. 1999: 13: 398-404.
142.
Martin K, Gertler R, Sterner A, MacGuill
M, Schreiber C. Comparison of blood-sparing
efficacy of ε-aminocaproic acid and tranexamic
acid in newborns undergoing cardiac surgery.
Thorac Cardiovasc Surg. 2011; 59: 276-280.
138.
Manno CS, Hedberg KW, Kim HC, Bunin
GR, Nicolson S. Comparison of the hemostatic
effects of fresh whole blood, stored whole blood,
and components after open heart surgery in children. Blood. 1991; 77: 930-936.
143.
Guzzetta NA, Szlam F, Kiser AS, Fernandez JD, Szlam AD. Augmentation of thrombin
generation in neonates undergoing cardiopulmonary bypass. Br J Anaesth. 2014; 112: 319-327.
139.
Manno CS, Hedberg KW, Kim HC, Bunin
GR, Nicolson S. Comparison of the hemostatic
effects of fresh whole blood, stored whole blood,
and components after open heart surgery in children. Blood. 1991; 77: 930-936.
140.
Bojan M, Boulat C, Peperstraete H, Pouard
P. High-dose aprotinin, blood product transfusions, and short-term outcome in neonates and
infants: a pediatric cardiac surgery center experi60
ence. Paediatr Anaesth. 2012; 22: 818-825.
www.avidscience.com
144.
Razon Y, Erez E, Vidne B, Birk E, Katz J.
Recombinant factor VIIa (NovoSeven) as a hemostatic agent after surgery for congenital heart disease. Paediatr Anaesth. 2005; 15: 235-240.
145.
Chasovskyi K, Fedevych O, McMullan
DM, Mykychak Y, Vorobiova G. Tissue perfusion
in neonates undergoing open-heart surgery using
autologous umbilical cord blood or donor blood
components. Perfusion. 2015; 30: 499-506.
www.avidscience.com
61
Advances in Cardiothoracic Surgery
Advances in Cardiothoracic Surgery
146.
Feinstein JA, Benson DW, Dubin AM, Cohen MS, Maxey DM. Hypoplastic left heart syndrome: current considerations and expectations. J
Am Coll Cardiol. 2012; 59: S1-42.
147.
Frommelt MA1. Challenges and controversies in fetal diagnosis and treatment: hypoplastic left heart syndrome. Clin Perinatol. 2014; 41:
787-798.
148.
Alsoufi B, Mori M, Gillespie S, Schlosser B,
Slesnick T. Impact of Patient Characteristics and
Anatomy on Results of Norwood Operation for
Hypoplastic Left Heart Syndrome. Ann Thorac
Surg. 2015; 100: 591-598.
149.
Ghanayem NS, Allen KR, Tabbutt S, Atz
AM, Clabby ML. Interstage mortality after the
Norwood procedure: Results of the multicenter
Single Ventricle Reconstruction trial. J Thorac
Cardiovasc Surg. 2012; 144: 896-906.
150.
Ohye RG, Schonbeck JV, Eghtesady P,
Laussen PC, Pizarro C. Cause, timing, and location of death in the Single Ventricle Reconstruction trial. J Thorac Cardiovasc Surg. 2012; 144:
907-914.
151.
Barron DJ. The Norwood procedure: in
favor of the RV-PA conduit. Semin Thorac Cardiovasc Surg Pediatr Card Surg Annu. 2013; 16:
52-58.
62
www.avidscience.com
152.
Fiore AC, Tobin C, Jureidini S, Rahimi M,
Kim ES. A comparison of the modified BlalockTaussig shunt with the right ventricle-to-pulmonary artery conduit. Ann Thorac Surg. 2011; 91:
1479-1484.
153.
Galantowicz M, Cheatham JP, Phillips A,
Cua CL, Hoffman TM. Hybrid approach for hypoplastic left heart syndrome: intermediate results
after the learning curve. Ann Thorac Surg. 2008;
85: 2063-2070.
154.
Murphy MO, Bellsham-Revell H, Morgan
GJ, Krasemann T, Rosenthal E. Hybrid Procedure
for Neonates With Hypoplastic Left Heart Syndrome at High-Risk for Norwood: Midterm Outcomes. Ann Thorac Surg. 2015;.
155.
Dave H, Rosser B, Knirsch W, Hübler M,
Prêtre R. Hybrid approach for hypoplastic left
heart syndrome and its variants: the fate of the
pulmonary arteries. Eur J Cardiothorac Surg.
2014; 46: 14-19.
156.
Sistino JJ, Bonilha HS. Improvements in
survival and neurodevelopmental outcomes in
surgical treatment of hypoplastic left heart syndrome: a meta-analytic review. J Extra Corpor
Technol. 2012; 44: 216-223.
157.
Shillingford AJ, Glanzman MM, Ittenbach RF, Clancy RR, Gaynor JW, et al. Inattenwww.avidscience.com
63
Advances in Cardiothoracic Surgery
Advances in Cardiothoracic Surgery
tion, Hyperactivity, and School Performanc in a
Population of School-age Children With Complex
Congenital Heart Disease. Pediatrics. 2008; 121:
759-767.
158.
d’Udekem Y, Iyengar AJ, Cochrane AD,
Grigg LE, Ramsay JM. The Fontan procedure:
contemporary techniques have improved longterm outcomes. Circulation. 2007; 116: I157-164.
159.
Tweddell JS, Nersesian M, Mussatto KA,
Nugent M, Simpson P. Fontan palliation in the
modern era: factors impacting mortality and
morbidity. Ann Thorac Surg. 2009; 88: 1291-1299.
160.
Emani SM, del Nido PJ. Strategies to maintain biventricular circulation in patients with
high-risk anatomy. Semin Thorac Cardiovasc
Surg Pediatr Card Surg Annu. 2013; 16: 37-42.
161.
Emani SM, Bacha EA, McElhinney DB,
Marx GR, Tworetzky W. Primary left ventricular rehabilitation is effective in maintaining twoventricle physiology in the borderline left heart.
J Thorac Cardiovasc Surg. 2009; 138: 1276-1282.
162.
Emani SM, McElhinney DB, Tworetzky
W, Myers PO, Schroeder B. Staged left ventricular
recruitment after single-ventricle palliation in patients with borderline left heart hypoplasia. J Am
Coll Cardiol. 2012; 60: 1966-1974.
64
www.avidscience.com
163.
Kalish BT, Banka P, Lafranchi T, Tworetzky W, Del Nido P. Biventricular conversion after
single ventricle palliation in patients with small
left heart structures: short-term outcomes. Ann
Thorac Surg. 2013; 96: 1406-1412.
164.
Purmut LC, Laks H. Surgical Management
of Pulmonary Atresia With Ventricular Septal
Defect and Multiple Aortopumonary Collaterals.
Adv Card Surg. 1994; 5: 75-95.
165.
Rome JJ, Mayer JE, Castaneda AR, Lock
JE. Tetralogy of Fallot with pulmonary atresia.
Rehabilitation of diminutive pulmonary arteries.
Circulation. 1993; 88: 1691-1698.
166.
Hibino N, He D, Yuan F, Yu JH, Jonas R.
Growth of diminutive central pulmonary arteries after right ventricle to pulmonary artery homograft implantation. Ann Thorac Surg. 2014; 97:
2129-2133.
167.
Reinhartz O, Reddy VM, Petrossian E,
Suleman S, Mainwaring RD. Unifocalization of
major aortopulmonary collaterals in single-ventricle patients. Ann Thorac Surg. 2006; 82: 934938.
168.
Malhotra SP, Hanley FL. Surgical Management of Pulmonary Atresia With Ventricular
Septal Defect and Major Aortopulmonary Collaterals: A Protocol-Based Approach. Semin Thorac
www.avidscience.com
65
Advances in Cardiothoracic Surgery
Advances in Cardiothoracic Surgery
Cardiovasc Surg Pediatr Card Surg Ann. 2009;
12:145-151.
169.
Farouk A, Zahka K, Siwik E, Erenberg F,
Al-Khatib Y. Individualized approach to the surgical treatment of tetralogy of Fallot with pulmonary atresia. Cardiol Young. 2009; 19: 76-85.
170.
Duncn B. Results of the Double Switch
Operation for Congenitally Corrected Transposition of the Great Arteries. Eur J Cardiothorac
Surg. 2003; 24: 11-20.
171.
Sharma R, Talwar S, Marwah A, Shah S,
Maheshwari S. Anatomic repair for congenitally
corrected transposition of the great arteries. J
Thorac Cardiovasc Surg. 2009; 137: 404-412.
172.
Wells WJ, Blackstone E. Intermediate outcome after Mustard and Senning procedures: A
study by the Congenital Heart Surgeons Society.
Semin Thorac Cardiovasc Surg Pediatr Card Surg
Annu. 2000; 3: 186-197.
173.
El-Zein C, Subramanian S, Ilbawi M.
Evolution of the surgical approach to congenitally corrected transposition of the great arteries.
Semin Thorac Cardiovasc Surg Pediatr Card Surg
Annu. 2015; 18: 25-33.
174.
Barron DJ, Jones TJ, Brawn WJ. The Senning procedure as part of the double-switch oper-
66
www.avidscience.com
ations for congenitally corrected transposition of
the great arteries. Semin Thorac Cardiovasc Surg
Pediatr Card Surg Annu. 2011; 14: 109-115.
175.
Myers PO, del Nido PJ, Geva T, BautistaHernandez V, Chen P. Impact of age and duration
of banding on left ventricular preparation before
anatomic repair for congenitally corrected transposition of the great arteries. Ann Thorac Surg.
2013; 96: 603-610.
176.
Metton O, Gaudin R, Ou P, Gerelli S,
Mussa S, et al. Early Propylactic Pulmonary Artery Banding in Isolated Congenitally Corrected
Transposition of the Great Arteries. Eur J Cardiothorac Surg. 2010; 38: 728-734.
177.
Bautista-Hernandez V, Serrano F, Palacios
JM, Caffarena JM. Successful neonatal double
switch in symptomatic patients with congenitally
corrected transposition of the great arteries. Ann
Thorac Surg. 2008; 85: e1-2.
178.
Bautista-Hernandez V, Myers PO, Cecchin
F, Marx GR, Del Nido PJ. Late left ventricular dysfunction after anatomic repair of congenitally corrected transposition of the great arteries. J Thorac
Cardiovasc Surg. 2014; 148: 254-258.
179.
Huhta JC, Maloney JD, Ritter DG, Ilstrup
DM, Feldt RH. Complete atrioventricular block in
patients with atrioventricular discordance. Circuwww.avidscience.com
67
Advances in Cardiothoracic Surgery
Advances in Cardiothoracic Surgery
lation. 1983; 67: 1374-1377.
180.
Alwi M1. Management algorithm in pulmonary atresia with intact ventricular septum.
Catheter Cardiovasc Interv. 2006; 67: 679-686.
181.
Daubeney PE, Wang D, Delany DJ, Keeton
BR, Anderson RH. Pulmonary atresia with intact
ventricular septum: predictors of early and medium-term outcome in a population-based study. J
Thorac Cardiovasc Surg. 2005; 130: 1071.
182.
Alwi M, Geetha K, Choo KK, Bilkis AA,
Hasri S, et al. Risk Factors for Augmentation of
the Flow of Blood to the Lungs in Pulmonary
Atresia With Intact Ventricular Septum After Radiofrequency Valvotomy. Cardiol Young. 2005;
15: 141-157.
of the Right Ventricle in Patients With Pulmonary
Atresia and Intact Ventricular Septa. J Thorac
Cardiovasc Surg. 2009; 138: 1160-1166.
186.
Lin MC, Wei HJ, Fu YC, Jan SL. A novel
hybrid therapy for pulmonary atresia with intact
ventricular septum. Int J Cardiol. 2010; 144: 438439.
187.
Zampi JD, Hirsch-Romano JC, Goldstein
BH, Shaya JA, Armstrong AK. Hybrid Approach
for Pulmonary Atresia With Intact Ventricular
Septum: Early Single Center Results and Comparison to the Standard Surgical Approach. Catheter
Cardiovasc Interv. 2014; 83: 753-761.
183.
Li S, Chen W, Zhang Y, Zhang H, Hua Z.
Hybrid therapy for pulmonary atresia with intact
ventricular septum. Ann Thorac Surg. 2011; 91:
1467-1471.
184.
Schneider AW, Blom NA, Bruggemans EF,
Hazekamp MG. More than 25 years of experience
in managing pulmonary atresia with intact ventricular septum. Ann Thorac Surg. 2014; 98: 16801686.
185.
Huang S, Ishino K, Kasahara S, Ko Y, Kotani Y, et al. The Potential of Disproportionate
Growth of Tricuspid Valve After Decompression
68
www.avidscience.com
www.avidscience.com
69