0031-3998/10/6801-0001 Vol. 68, No.

1, 2010
PEDIATRIC RESEARCH Printed in U.S.A.
Copyright © 2010 International Pediatric Research Foundation, Inc.

REVIEW ARTICLE

New Approaches to Neuroprotection in Infant Heart Surgery

ERIN L. ALBERS, DAVID P. BICHELL, AND BETHANN MCLAUGHLIN

Departments of Pediatrics [E.L.A.], Cardiac Surgery [D.P.B.], Neurology [B.M.], Clinical Pharmacology [E.L.A.], and Pharmacology
[B.M.], Vanderbilt University School of Medicine, Nashville, Tennessee 37323

ABSTRACT: Advances in surgical techniques and perioperative The mechanisms contributing to CNS injury in patients
management have led to dramatic improvements in outcomes for with CHD are complex and multifactorial, occurring through-
children with complex congenital heart disease (CHD). As the num- out prenatal and perinatal life. Insults to the developing brain
ber of survivors continues to grow, clinicians are becoming increas- may occur in utero (as a result of coincident structural brain
ingly aware that adverse neurodevelopmental outcomes after surgical
malformation and/or disordered fetal circulation), in the im-
repair of CHD represent a significant cause of morbidity, with
mediate postnatal period while awaiting surgical intervention
widespread neuropsychologic deficits in as many as 50% of these
children by the time they reach school age. Modifications of intra- (related to cyanosis, perturbed cerebrovascular autoregulation,
operative management have yet to measurably impact long-term or hypoxic-ischemic injury due to ongoing hemodynamic
neurologic outcomes. However, exciting advances in our understand- instability), intraoperatively (as a consequence of cardiopul-
ing of the underlying mechanisms of cellular injury and of the events monary bypass, hypothermia, hemodilution, or cerebral em-
that mediate endogenous cellular protection have provided a variety bolic events), and during the postoperative period (because of
of new potential targets for the assessment, prevention, and treatment low cardiac output syndrome, seizures, systemic infection, or
of neurologic injury in patients with CHD. In this review, we will other complications) (3–5). Long-term neurologic functioning
discuss the unique challenges to developing neuroprotective strate- in these children is also impacted by the presence of under-
gies in children with CHD and consider how multisystem approaches
lying genetic syndromes, the influence of social and environ-
to neuroprotection, such as ischemic preconditioning, will be the
focus of ongoing efforts to develop new diagnostic tools and thera-
mental factors, and the cardiac lesion itself, which necessarily
pies. Although significant challenges remain, tremendous opportu- dictates the timing and nature of surgical intervention. There
nity exists for the development of diagnostic and therapeutic inter- is a growing body of literature that suggests that patients
ventions that can serve to limit neurologic injury and ultimately requiring surgery in the first few weeks of life have a signif-
improve outcomes for infants and children with CHD. (Pediatr Res icantly higher incidence of academic difficulties and behavior
68: 1–9, 2010) abnormalities as they reach school-age. Patients that require
several stages of palliative repair in early childhood may be
particularly vulnerable to brain injury and subsequent dis-
A dvances in surgical techniques and perioperative man-
agement have led to dramatic improvements in survival
outcomes for children with complex congenital heart disease
ability (Figs. 1 and 2) (4,6 –11).
Historical approaches to neuroprotection in this population
have focused on the most obviously modifiable factors, par-
(CHD). Indeed, children born with lesions that were fatal as
ticularly intraoperative management strategies. However, de-
recently as 30 y ago are now surviving into adolescence and
adulthood (1). With a growing population of survivors, clini- spite increasing attention to this problem, no consistent im-
cians are becoming increasingly aware that patients who have provement in long-term neurodevelopmental outcomes has
undergone life-saving open-heart surgery as infants and young been achieved in nearly two decades (12). Indeed, it has
children are facing significant neurocognitive challenges as become clear that alternative approaches to this problem are
they develop and mature. Widespread neurodevelopmental needed.1 New insights into pre- and postoperative risk factors
deficits can be identified in as many as 50% of these children that contribute to adverse neurologic outcomes in children
by the time they reach school age (2). These delays manifest with CHD, along with advances in the understanding of the
in attentional and academic problems, which ultimately result underlying mechanisms that direct cellular injury and protec-
in significant social and economic challenges to patients and tion in a variety of similar populations, can now serve as a
families. basis on which to formulate new strategies for the diagnosis,

Received December 2, 2009; accepted March 12, 2010. Abbreviations: CHD, congenital heart disease; CPB, cardiopulmonary by-
Correspondence: BethAnn McLaughlin, Ph.D., Department of Pharmacology, Vander-
bilt University School of Medicine, 465 21st Avenue South, MRB III Room 8110A,
pass; HIF, hypoxia inducible factor; HLHS, hypoplastic left heart syndrome;
Nashville, TN 37232-8548; e-mail: [email protected] IPC, ischemic preconditioning; LCOS, low cardiac output syndrome; PVL,
Supported by NIH Grants NS050396 (B.M.), GM07569 –32 (E.A.), and P30HD15052. per ventricular leukomalacia; RIPC, remote ischemic preconditioning

1
2 ALBERS ET AL.

Figure 2. Timeline of potential neurologic injury throughout staged pallia-

tion for HLHS in relation to corresponding stages of CNS development. The
top series of boxes represents timing of the normal architectural patterning in
the CNS. The bottom series of boxes indicates potential mechanisms of CNS
injury surrounding operative intervention for HLHS (which could be extrap-
olated to other forms of CHD).

cardiopulmonary bypass (CPB) in the 1950s, surgical out-

comes after complex cardiac surgery improved dramatically
Figure 1. Staged surgical palliation for HLHS; although these interventions
(13,14). However, early experience using these techniques in
have led to improved survival, patients with HLHS remain at risk for adverse children suggested an association with both early and late
neurodevelopmental outcomes. A) HLHS includes a spectrum of defects, which neurologic complications (15–21). Subsequent efforts to min-
are characterized by the underdevelopment of left heart structures including the imize the risk of ischemic brain injury during cardiac surgery
mitral valve, left ventricle, and aorta. Decreased cerebral perfusion in utero may have focused on the development of perioperative interven-
contribute to prenatal CNS insult in this lesion. After birth, and programmed
closure of the ductus arteriosus, the hypoplastic left ventricle and aorta are unable
tions that aim to optimize cerebral blood flow, minimize
to maintain the systemic circulation, resulting in decreased coronary and cerebral cerebral oxygen demand, and prevent neuronal cell damage.
perfusion, cardiogenic shock, and death if not treated. B) Stage I palliation, the Examples of early neuroprotective strategies include the use
Norwood operation, is typically performed in the first week of life. This procedure of continuous low-flow CPB as an alternative to DHCA, the
involves reconstruction of the ascending aorta and aortic arch using the native implementation of “temperature-corrected” (pH-stat) blood
pulmonary artery. Pulmonary blood flow is achieved via a systemic to pulmonary
arterial shunt, and the right ventricle bears the workload of both the systemic and
gas management strategies during patient cooling, and the
pulmonary circulations. This physiology places a volume load on the right development of various protocols for hemodilution, hypother-
ventricle, and with significant risk for complications related to the systemic- mia, and rewarming surrounding CPB (18,22–24). Although
pulmonary shunt, it is unsuitable for long term palliation. C) Stage II palliation, many of these interventions showed promising results in
the bidirectional Glenn anastomosis, is undertaken at the age of 3 to 6 mo. short-term follow-up, no single strategy has been shown to
Systemic venous blood from the upper body is redirected to the lungs via a
superior vena cava to pulmonary artery anastomosis. The timing of this surgery
consistently and meaningfully improve long-term neurodevel-
is based on the physiologic reduction in pulmonary vascular resistance that occurs opmental outcomes in patients undergoing early repair for
over the first several weeks of life. Glenn physiology reduces the volume load on CHD (12,25).
the single right ventricle, rendering it more stable over time. However, it requires Pharmacologic interventions. Pharmacologic approaches
mixing of deoxygenated blood (venous return from the lower body) with the to neuroprotection have also historically identified the imme-
systemic output, resulting in cyanosis at baseline. D) Stage III palliation, the
Fontan completion, is performed at the age of 2– 4 y and completes the in-series
diate perioperative period as an optimal point of intervention.
circuit by directing the venous blood from the lower body into the pulmonary Agents such as volatile anesthetics, methylprednisone, apro-
circulation. With this total cavopulmonary connection, the right ventricle remains tinin, and allopurinol, among others, have been used to atten-
the single pumping chamber to the body, whereas the pulmonary circulation is uate ischemic injury in infants undergoing cardiac surgery,
driven by passive venous flow to the lungs. At this stage, there is no longer mixing based largely on experimental data that their effects may be
of oxygenated and deoxygenated blood, and systemic saturations are normal.
Arrows indicate direction of blood flow. Blue indicates deoxygenated blood, red
neuroprotective (26 –28). However, when applied clinically,
indicates oxygenated blood, purple indicates mixed oxygenated and deoxygen- none has been proven to reduce the risk of neurologic injury
ated blood. surrounding infant heart surgery. The perioperative adminis-
tration of allopurinol (an inhibitor of free radical production)
treatment, and prevention of neurologic injury in patients with was not shown to significantly reduce the risk of death or
CHD. neurologic injury surrounding surgical intervention (29), and
the use of aprotinin (an antifibrinolytic) was completely halted
Historical Approaches to Neuroprotection in Infant
after studies in adults showed an increased risk of renal failure
Heart Surgery
and end-organ damage after CPB (30), although these results
Technical modifications. After the introduction of deep have not been duplicated in pediatric studies. Other commonly
hypothermic circulatory arrest (DHCA) in the 1940s and used agents—such as isoflurane, midazolam, and methylpred-
 NEUROPROTECTION IN INFANT HEART SURGERY 3
nisone— have yet to be studied in a systematic manner in associated with PVL impairs their ability to perform develop-
patients with CHD, and many questions remain regarding their mentally required functions in CNS patterning and neurotrans-
safety and long-term effects on neurodevelopmental outcomes mission, almost certainly contributing to long-term maladap-
(31,32). tive consequences, which translate into the wide range of
neurodevelopmental deficits that have been described both in
Unique Challenges to Neuroprotection in Infant survivors of premature birth and in those requiring early
Heart Surgery surgical intervention for CHD (12,43). Recent studies report
evidence of PVL on immediate postnatal imaging in up to
Practical limitations. Many factors contribute to slow 20% of full-term infants with CHD—increasing to more than
progress in the development of effective interventions to 50% after surgery (3,8,40)—suggesting a similarly increased
improve neurocognitive outcomes in patients with CHD. One vulnerability to white matter injury and raising questions of
is that complex CHD, although a relatively common cause of delayed brain maturation in these babies (42).
childhood morbidity, remains a rare disease, affecting only 6 In addition to an underlying vulnerability to global hypoxic-
to 8 per 1000 live births (33). This limits our ability to design ischemic insult, infants and children with CHD are at risk for
and successfully enroll patients in high-powered randomized focal neurologic injury from thromboembolism or air embo-
trials, except in the largest institutions. Even multicenter trials lism, which can be related to the cardiac lesion itself or to the
are confounded by subtle differences in surgical technique and procedures required for repair or palliation. The incidence of
perioperative care. Furthermore, individual congenital heart perioperative stroke in pediatric patients undergoing open
defects demonstrate considerable variation in the unique phys- heart surgery has not yet been well defined. Risk factors such
iologic and hemodynamic alterations that contribute to inher- as type of lesion, age at surgery, perioperative hematocrit, and
ent neurologic risk, making results of even well-designed duration of CPB have been suggested, although none of these
studies difficult to generalize across the spectrum of CHD. has been consistently shown to increase the risk of embolic
Progress is further complicated by the fact that although events surrounding pediatric cardiac surgery (40,44 – 47). One
gross neurologic impairments may be easily recognized in the recent study of neonates and infants undergoing surgical
immediate postoperative period, the full extent of adverse repair for CHD demonstrated a 10% prevalence of stroke, with
neuropsychological sequelae—including academic difficul- as many as half of those events occurring preoperatively. This
ties, behavior abnormalities, motor delays, executive plan- study also reported that the majority of lesions were identified
ning, and inattention/hyperactivity (4,16,34 –39)— often do only on early postoperative MRI with no clinical evidence of
not become apparent until several years later when these neurologic deficit, suggesting that focal neurologic insults are
children reach school age. This limits the timely assessment of likely underdiagnosed in the infant population (45).
any particular intervention. Furthermore, although it is generally accepted that the
Finally, although many of the neuroprotective strategies in immature brain is more susceptible to neurologic injury
current practice have been extrapolated from experimental or caused by inflammation, oxidative stress, microemboli, and
adult studies of cardiac surgery and CPB, clinical experience hemodynamic perturbations of cerebral blood flow associated
suggests that these models may not be adequate to reproduce with CPB (48 –52), recent evidence suggests that additional
the unique circumstances that contribute to neurologic injury mechanisms of neurologic injury exist, which may be unique
in infants with CHD. Certainly, surrogate models have and to children with CHD. Subtle hemorrhagic events, as demon-
will continue to provide great insight into the mechanisms that strated by the presence of hemosiderin deposits on MRI, have
mediate neurologic injury during CPB. However, it is becom- recently been observed in a cohort of infants undergoing
ing increasingly clear that new approaches to neuroprotection 2-ventricle repair. These lesions were linked to lower Psy-
will require a more precise understanding of patient-specific chomotor Developmental Index scores at the age of 1 y.
variables and the underlying mechanisms that contribute to Importantly, such hemosiderin foci, or “microbleeds,” were
neurologic injury in children with CHD— before, during, and also associated with older age at surgery and were seen even
after surgery. in the absence of radiologic evidence of ischemic injury,
Neurologic vulnerability in infants with CHD. There now suggesting a different pathogenesis for CNS damage than has
exists a growing body of evidence to suggest that many previously been described (53).
children with complex CHD suffer from abnormal or delayed Precarious physiology. Infants and children undergoing
brain development, potentially making them more vulnerable cardiac surgery remain vulnerable to neurologic injury
to neurologic insult suffered throughout the perinatal period throughout the postoperative period—and perhaps indefi-
(3,40,41). Recent neuroimaging studies conducted in new- nitely. Low cardiac output syndrome (LCOS) refers to the
borns with CHD (before surgical intervention) demonstrate predictable fall in cardiac output, which occurs 6 –18 h after
abnormal findings similar to those seen in premature infants cardiac surgery (54,55). Because of limited myocardial re-
and those who have suffered hypoxic-ischemic injury serve, LCOS is common in pediatric patients, affecting up to
(3,12,40,41). Periventricular leukomalacia (PVL), the most 25% of neonates and young children undergoing surgical
common neuropathologic lesion identified in preterm neo- intervention for CHD (54,55). Residual cardiac lesions, par-
nates, is thought to result from enhanced vulnerability of ticularly in defects requiring staged palliation with a parallel
premyelinating oligodendrocyte precursor cells to hypoxic- circulation (such as hypoplastic left heart syndrome [HLHS];
ischemic injury (42,43). Damage to immature oligodendroglia Figs. 1 and 2), may further increase the risk of morbidity and
4 ALBERS ET AL.

mortality associated with LCOS (55–58). Hemodynamic in- days, the CNS is only capable of inducing the late form of IPC
stability associated with LCOS in the postoperative period (63– 65).
leads to global hypoperfusion and can be associated with The early cardiac IPC event has been associated with
neurologic and other end-organ injury (55). Pharmacologic activation of the opioid and bradykinin receptor pathways (via
interventions to prevent LCOS have been associated with PI3-kinase and ERK/Akt signaling), stimulation of the G-
improved outcomes after surgery for CHD (55,58). Although protein coupled adenosine (A1) receptor, and the production
these agents might be considered an indirect approach to of reactive oxygen species (ROS) in the mitochondria. Under
neuroprotection, their specific effects on long-term neurode- the appropriate stimulus, all of these converge to activate
velopment have not been formally studied. protein kinase C (PKC), which acts as a final common path-
Finally, it must be remembered that many patients with way in the “trigger” phase of IPC (66). On reperfusion, PKC
CHD remain at risk for ongoing neurologic complications, is primed to initiate a second round of activation of PI3-
well beyond the immediate perioperative period. Unfavorable kinase/Akt and MEK/ERK cell survival pathways to confer
hemodynamics, residual right-to-left intracardiac shunts, hy- the protective effects of IPC (Fig. 3) (66,67).
percoagulability, and arrhythmias can all contribute to in- The neural kinase pathways associated with CNS precon-
creased risk for thromboembolic events and subsequent CNS ditioning protection are far less well appreciated. The conver-
injury, with certain lesions known to be at significant risk over gence of stress signaling at the level of the mitochondria
a lifetime (59,60). In addition, chronic cyanosis associated seems to be essential, and hallmark features of neuronal
with many palliated lesions is most likely associated with poor preconditioning include requirement for new protein synthe-
long-term neurodevelopmental outcomes. In light of these sis, activation of heat shock proteins (HSPs), and opening of
complex issues, perhaps new strategies for neuroprotection ATP-dependent potassium channels (67,68). The redox sensi-
should consider a multisystem approach. tive pathways activated by preconditioning ischemia and
reperfusion likely alter metabolic tone at the time of secondary
stress, but the activation of this form of protection is much
Ischemic Preconditioning: A Lesson in Neuroprotection

Multisystem applications of ischemic preconditioning. An

elegant illustration of the kind of multidisciplinary approach
needed to support ongoing advances in neuroprotection sur-
rounding pediatric cardiac surgery is that of ischemic precon-
ditioning (IPC). IPC refers to a phenomenon in which prior
exposure to a series of sublethal insults results in the up-
regulation of endogenous defense mechanisms, which then
provide robust protection from subsequent lethal insults (61).
IPC was first described in the mid-1980s in a model of
myocardial infarction (62), and it has since been observed in
extracardiac tissues including the brain, liver, and kidney.
Subsequent investigations into the mechanisms that mediate
the protection conferred by IPC in the heart and the brain have
led to important advances in our understanding of numerous Figure 3. Signaling pathways involved in IPC. Focal ischemic insults result
in initiation of cell stress pathways and rapid release of adenosine, acetyl-
pathways that mediate cell fate in response to acute stress.
choline, glutamate, and other neurotransmitters, which activate receptors
Signaling pathways in IPC: the heart and the brain are including bradykinin (BK) and opioid (OP) receptors. These proteins are
not the same. Both neurons and cardiomyocytes are highly coupled to more general changes in kinase activation via phosphatidylinositol
metabolically active and have tremendously limited prolifer- phosphatase-3 (PIP3), phosphoinositide 3-kinase (PI3-K), and mitogen-
ative mechanisms. Therefore, in the context of providing activated protein kinase (MAPK) signaling. The kinase-regulated signaling
then signals secondary oxidative stress by stimulating NO production via
neuroprotection during cardiac surgery, identification of the
endothelial NOS. Nitrosylative and oxidative stress activate mitochondrial
activator and effector molecules that are dually activated in the ATP-dependent potassium channels (KATP) and PKC. The oxidative stress
CNS and the heart is essential to provide therapies that target signaling is initiated by loss of glucose and oxygen when cells experience
both the systems in a protective way. However, although hypoxia, which initiates mitochondrial dysfunction, ROS production, ATP
neurons and cardiomyocytes share many characteristics, im- depletion, and p66shc activation, which potentiates the activation of the mitochon-
drial KATP channels. Cell stress signaling is dampened as oxygen is returned, and
portant differences in metabolic and cellular signaling path-
energetic and oxidative tone is restored. Additional levels of paracrine signaling
ways exist that are crucial to understanding the mechanisms are initiated by activation of innate immunity pathways via the redox-sensitive
by which each organ can elicit endogenous protection. transcription factors including NF␬B and hypoxia inducible factor 1 (HIF1).
One of the most dramatic differences between cardiac and Activation of NF␬B favors production of proteins, which participate in cellular
neuronal preconditioning is the lack of an early protective protection such as HSP 70, cytokines, and modulators of oxidant stress. These
molecules and endogenous proinflammatory molecules are thought to act on
window for CNS models of ischemia. Unlike cardiomyocytes,
toll-like receptors (TLR) and TNF-␣ receptors to potentiate MAPK signaling
which, on brief exposure to hypoxia and ischemia, induce a pathways. Activation of HIF promotes expression of genes, which mediate
near immediate but short-lived protective period followed by cellular adaption to hypoxia (inducible NOS, erythropoietin [EPO], VEGF,
a second protective period observed after hours and lasting for glucose receptors [GlcR], among others).
 NEUROPROTECTION IN INFANT HEART SURGERY 5
slower than cardiac preconditioning and can take hours to protection (73). An alternate, or perhaps complimentary, pos-
days to reveal itself. sibility is that of a systemic pathway in which RIPC induces
Although activation of kinase pathways is necessary for organism-wide changes in gene expression, metabolism, and
IPC in both the heart and the brain, it is not sufficient for signaling, which serve to augment the local protective envi-
induction of protection. The protection observed in cardiac ronment. In support of this, microarray analyses of precondi-
and neural cells hours after nonlethal priming stress requires tioned tissue have demonstrated up-regulation of multiple
new protein transcription, including up-regulation of HSPs anti-inflammatory and antiapoptotic pathways after RIPC
and hypoxia inducible factor (HIF), among others (63). HSPs (74 –76).
are cellular chaperones that act intracellularly to direct protein Although there is still much to be learned about the precise
degradation or refolding in response to cell stress (61). Up- mechanisms that underlie the protection conferred by RIPC,
regulation of these molecules in response to a preconditioning several clinical applications of RIPC are currently being
stress is required for protein salvage and enhanced cell sur- tested. These include therapeutic remote pre- and postcondi-
vival in the face of subsequent otherwise lethal insults (69). tioning after acute myocardial infarction, stroke, and even
HIF is a transcription factor that regulates the induction of surrounding cardiac surgery. One randomized controlled study
hundreds of genes in response to cellular hypoxia, including has shown evidence of myocardial protection (decreased tro-
those regulating endothelial NO production, erythropoietin ponin and decreased need for postoperative inotropic support)
synthesis, expression of multiple glucose transporters and in children undergoing repair of CHD (77). Although there
glycolytic enzymes, and angiogenesis. HIF is known to be an have been no studies examining the effects of RIPC on
essential mediator of preconditioning-induced cellular protec- neurologic injury surrounding cardiac surgery, it certainly has
tion, presumably via stimulation of anaerobic glycolysis and exciting potential to be an inexpensive, well-tolerated neuro-
preservation of mitochondrial function (65) (Fig. 3). The protective therapy for patients undergoing CPB.
complexity of these adaptations is enormous, as each activated
protein has a unique set of effector molecules, which regulate The Future of Neuroprotection in Infant Heart Surgery
gene transcription, cell membrane channel properties, and
metabolic function, the full effects of which we are only Despite limited progress in the improvement of neurode-
beginning to appreciate. velopmental outcomes for children undergoing repair of CHD
From laboratory to clinic: therapeutic implications of over the last 20 y, remarkable advances in molecular science
IPC. Continued advances in our understanding of the path- and technology have provided us with a better understanding
ways that mediate IPC now offer a number of possible ther- of the mechanisms that underlie neuropathology in a variety of
apeutic targets that allow us to capitalize on the cell’s endog- models, thus offering new and innovative approaches to the
enous protective mechanisms to limit injury from acute diagnosis and prevention of neurologic injury in patients with
ischemic insult. A promising example of the therapeutic po- CHD (Table 1).
tential of IPC is the discovery of remote ischemic precondi- Preoperative considerations. Early and accurate prenatal
tioning (RIPC), a phenomenon whereby the application of a diagnosis of complex CHD by fetal echocardiography now
preconditioning stimulus at a remote site, such as the inflation allows for planned delivery in an advanced nursery setting
of a blood pressure cuff around an arm or leg, confers IPC-like where prompt initiation of medical therapy can minimize the
protection at a distant target (such as the heart and/or brain). risk for early hemodynamic compromise, potentially contrib-
First described in the mid-1990s in a model of myocardial uting to improved neurologic outcomes in some groups
infarction (70,71), the protective effects of RIPC have been (78,79). In select cases, prenatal diagnosis also offers the
observed in various other tissues, including the brain. opportunity for highly specialized fetal cardiac intervention,
The exact mechanisms through which RIPC exerts its dis- which— by optimizing fetal hemodynamics— has the poten-
tant effects remain unknown, but ongoing preclinical investi- tial to not only improve cardiovascular outcomes but also to
gations suggest that multiple pathways may be involved. One restore physiologic cerebral circulation, theoretically promot-
proposed model of RIPC is that of a humoral pathway in ing normal CNS development. Although one recent study
which substances released at the site of a remote precondi- showed no significant change in cerebral blood flow after fetal
tioning stimulus circulate to their target organs to initiate intervention for aortic stenosis (80), continued modification
cell-protective pathways. Convincing evidence in support of a and ongoing study of these relatively new techniques will be
humoral pathway was provided by an experimental model of required to assess any impact on long-term neurodevelopmen-
heart transplantation in which RIPC applied to the recipient of tal outcomes.
a transplanted heart led to reduced myocardial infarct size in Other antenatal therapies that may be of benefit in cases of
the donor heart (72). Another proposed mechanism is that of prenatally diagnosed CHD include those currently being de-
a neural pathway in which an endogenous substance released veloped to prevent PVL and associated long-term brain injury
at the remote site of preconditioning activates afferent nerve in premature infants, such as maternal administration of free
fibers, which in turn stimulate IPC signaling pathways in the radical scavengers such as vitamin E and anti-inflammatory
target organ. This model is supported by studies in which and anticytokine agents (43). Although future study is needed,
ganglion blockade or nerve dissection in the remote limb leads continued advances in the understanding of the common
to complete block of IPC effect in the target organ, suggesting pathways that participate in the development of PVL, such as
that intact neural pathways are required for RIPC-induced ischemia-reperfusion and free-radical injury, can propel the
6 ALBERS ET AL.

Table 1. Multidisciplinary approaches to diagnosis, monitoring, and prevention of neurologic injury throughout the perioperative period
Preoperative Intraoperative Postoperative
Tools for diagnosis/monitoring Imaging (ultrasound, MRI) NIRS Imaging (ultrasound, MRI)
EEG, ERP Biomarkers NIRS
Genetic analysis, risk stratification Biomarkers
Biomarkers EEG, ERP
Strategies for neuroprotection Fetal intervention for CHD Modified perfusion techniques (RLFP, Postconditioning therapies
(improved cerebral blood flow) new circuits, etc.)
Prenatal therapy for PVL Modified cooling/rewarming protocols Afterload reduction (avoid
LCOS)
Preconditioning therapies
RIPC
Pharmacologic
ERP, evoked response potential; NIRS, near-infrared-spectroscopy; CHD, congenital heart disease; LCOS, low cardiac output syndrome; PVL, per ventricular
leukomalacia; RIPC, remote ischemic preconditioning.

development of neuroprotection strategies, which may be on the planned nature of the ischemic injury caused by cardiac
effective in both of these vulnerable populations. surgery by developing therapies aimed at enhancing endoge-
Finally, improved understanding of the genetic and molec- nous cellular protective mechanisms. One such novel therapy
ular basis of CHD over recent years has led to the identifica- was recently described using siRNA to inhibit translation of
tion of multiple genes that participate in the development of a the prolyl-hydroxylase (PHD) enzymes, which act to target
variety of congenital heart lesions, and the genetic heritability HIF-1␣ (a subunit of the HIF complex) for proteasomal
of some forms of CHD has now been well described (81). degradation under normal conditions. In a murine model of
Similarly, genetic influences on abnormal neurologic devel- myocardial infarction, treatment with these siRNA PHD in-
opment in patients with CHD are also being explored. Gaynor hibitors allowed for the activation of HIF and subsequent
et al. (82,83) have described that polymorphisms in the Apo-E protection from ischemia, similar to that seen in precondi-
allele may correlate with poor neurologic outcome. As knowl- tioned cells (92). Other studies have shown that the molecular
edge in this area continues to grow, genetic factors will chaperone HSP70, which is essential for intracellular precon-
become extremely important as predictors of neurologic risk, ditioning protection, may also exert neuroprotective effects
and a more patient-specific approach to risk-stratification and when released extracellularly, and that exogenous administra-
intervention will be required. tion of HSP70 may induce preconditioning-like neuroprotec-
Intraoperative considerations. Intraoperative management tion. Certainly, clinical applications of these and other pre-
strategies remain important modifiable factors, which will conditioning therapies, such as RIPC, are intriguing and
continue to evolve in attempts to improve neurodevelopmental require further collaborative study.
outcomes. Emerging modifications in surgical technologies, Postoperative considerations. An important challenge to
including the development of hybrid strategies in the repair of the clinical management of potential adverse neurologic out-
HLHS and the use of regional low-flow cerebral perfusion comes in infants with CHD is lack of tools that can aid in the
(RLFP) (84), and more advanced monitoring of cerebral ox- timely assessment of neurologic deficits. This would be helped
ygen saturation using near-infrared-spectroscopy (NIRS), are by the development of an accurate and specific biomarker of
currently being studied; however, long-term outcomes have neurologic injury. Candidate biomarkers such as HSPs, IL-6,
not yet been determined (31). C-reactive protein, S-100b, neuron specific enolase (50), se-
In addition, modified perfusion strategies such as the use of rum calcium (93), and activin A (94) are being investigated in
coated CPB circuitry and leukocyte filtration strategies (85), studies of CPB and multiple other models of neurologic
modified ultrafiltration (86), miniaturized circuits using re- injury, and we await studies assessing the value of these
duced or asanguinous blood prime (87– 89), and newer nor- markers as indices of long-term outcomes.
mothermic and normoxic perfusion protocols (90,91) are cur- We are keenly interested in developing peripheral biomar-
rently in varying stages of development and testing, with kers of CNS stress, which may be useful in a variety of clinical
long-term results still pending. Although unique pediatric settings. Isoprostanes (IsoPs), prostaglandin-like molecules
issues remain, close collaboration with our adult and basic formed in vivo via the free radical-mediated oxidation of
science counterparts should allow better understanding of arachidonic acid, have been demonstrated to be formed in
CPB-related complications, which will help target pathways increased amounts in the brains of patients with various
for prevention and treatment of multiorgan dysfunction in neurodegenerative diseases (95,96). Widely considered the
both adults and children requiring cardiac surgery. “gold standard” for quantification of oxidative stress, F2-IsoP
The operative period also remains an attractive target for formation is currently being studied in a variety of patient
neuroprotective pharmacotherapy. Further study of currently populations, but there are limited published data in neonatal
used perioperative medications including steroids and anes- models of hypoxia or in children with CHD. Similar free
thetic agents is essential and ongoing. Moreover, as the path- radical-mediated oxidation of docosahexaenoic acid (DHA)—
ways which mediate the protective effects of IPC are further the predominant fatty acid found in neurons of normal human
elucidated, clinicians and scientists are seeking to capitalize brain—leads to the formation of neuroprostanes (NPs), which
 NEUROPROTECTION IN INFANT HEART SURGERY 7
may serve as a more sensitive biomarker of oxidative injury 2. Markowitz SD, Ichord RN, Wernovsky G, Gaynor JW, Nicolson SC 2007 Surrogate
markers for neurological outcome in children after deep hypothermic circulatory
specific to the brain (97,98). Studies of IsoP and NP formation arrest. Semin Cardiothorac Vasc Anesth 11:59 – 65
surrounding pediatric cardiac surgery are underway and may 3. Miller SP, McQuillen PS, Hamrick S, Xu D, Glidden DV, Charlton N, Karl T,
Azakie A, Ferriero DM, Barkovich AJ, Vigneron DB 2007 Abnormal brain devel-
provide insights into the timing and extent of oxidative injury opment in newborns with congenital heart disease. N Engl J Med 357:1928 –1938
during and after surgical intervention for CHD. 4. Ballweg JA, Wernovsky G, Gaynor JW 2007 Neurodevelopmental outcomes fol-
lowing congenital heart surgery. Pediatr Cardiol 28:126 –133
Overcoming obstacles: a combined effort. There remain a 5. Dominguez TE, Wernovsky G, Gaynor JW 2007 Cause and prevention of central
number of clinical and practical issues that contribute to the nervous system injury in neonates undergoing cardiac surgery. Semin Thorac
Cardiovasc Surg 19:269 –277
slow progress toward achieving measurable improvements in 6. Dittrich H, Buhrer C, Grimmer I, Dittrich S, Abdul-Khaliq H, Lange PE 2003
neurodevelopmental outcomes in patients with CHD. Faced Neurodevelopment at 1 year of age in infants with congenital heart disease. Heart
89:436 – 441
with small sample sizes, time constraints, resource limitations,
7. Majnemer A, Limperopoulos C, Shevell MI, Rohlicek C, Rosenblatt B, Tchervenkov
and the very important logistical and ethical considerations of C 2009 A new look at outcomes of infants with congenital heart disease. Pediatr
conducting research in this vulnerable population, individual Neurol 40:197–204
8. Galli KK, Zimmerman RA, Jarvik GP, Wernovsky G, Kuypers MK, Clancy RR,
institutions are often unable to conduct the kind of high- Montenegro LM, Mahle WT, Newman MF, Saunders AM, Nicolson SC, Spray TL,
impact studies needed to answer important questions regard- Gaynor JW 2004 Periventricular leukomalacia is common after neonatal cardiac
surgery. J Thorac Cardiovasc Surg 127:692–704
ing the safety and efficacy of new and emerging neuroprotec- 9. Limperopoulos C, Majnemer A, Shevell MI, Rohlicek C, Rosenblatt B, Tchervenkov
tive strategies. However, the recent and ongoing development C, Darwish HZ 2002 Predictors of developmental disabilities after open heart
surgery in young children with congenital heart defects. J Pediatr 141:51–58
of several multi-institutional collaborations, such as the Pedi- 10. Limperopoulos C, Majnemer A, Shevell MI, Rosenblatt B, Rohlicek C, Tchervenkov
atric Heart Network (PHN) and the Joint Council on Congen- C 2000 Neurodevelopmental status of newborns and infants with congenital heart
defects before and after open heart surgery. J Pediatr 137:638 – 645
ital Heart Disease (JCCHD), provide promise for future im- 11. Trittenwein G, Nardi A, Pansi H, Golej J, Burda G, Hermon M, Boigner H,
plementation of large-scale trials and quality-improvement Wollenek G 2003 Early postoperative prediction of cerebral damage after pediatric
cardiac surgery. Ann Thorac Surg 76:576 –580
efforts. Moreover, ongoing multidisciplinary collaborations 12. Clancy RR 2008 Neuroprotection in infant heart surgery. Clin Perinatol 35:809 –
between pediatric and adult cardiologists, cardiac surgeons, 821 viii
neonatologists, neurologists, developmental specialists, and 13. Amir G, Ramamoorthy C, Riemer RK, Reddy VM, Hanley FL 2005 Neonatal brain
protection and deep hypothermic circulatory arrest: pathophysiology of ischemic
basic scientists will be essential to our continued progress, neuronal injury and protective strategies. Ann Thorac Surg 80:1955–1964
as contributions from each area of expertise can be inte- 14. Stoney WS 2009 Evolution of cardiopulmonary bypass. Circulation 119:2844 –2853
15. Bellinger DC, Jonas RA, Rappaport LA, Wypij D, Wernovsky G, Kuban KC, Barnes
grated to help answer mutual questions with applications PD, Holmes GL, Hickey PR, Strand RD, Walsh AZ, Helmers SL, Constantinou JE,
across disciplines. Carrazana EJ, Mayer JE, Hanley FL, Castaneda AR, Ware JH, Newburger JW 1995
Developmental and neurologic status of children after heart surgery with hypother-
mic circulatory arrest or low-flow cardiopulmonary bypass. N Engl J Med 332:549 –
CONCLUSIONS 555
16. Bellinger DC, Wypij D, duDuplessis AJ, Rappaport LA, Jonas RA, Wernovsky G,
Adverse neurodevelopmental outcomes after early surgical Newburger JW 2003 Neurodevelopmental status at eight years in children with
dextro-transposition of the great arteries: the Boston Circulatory Arrest Trial.
repair of CHD represent a significant cause of morbidity in a J Thorac Cardiovasc Surg 126:1385–1396
growing number of survivors. Historical approaches toward 17. Bellinger DC, Wypij D, Kuban KC, Rappaport LA, Hickey PR, Wernovsky G, Jonas
RA, Newburger JW 1999 Developmental and neurological status of children at 4
modification of intraoperative management strategies have not years of age after heart surgery with hypothermic circulatory arrest or low-flow
been shown to impact long-term outcomes. Although children cardiopulmonary bypass. Circulation 100:526 –532
18. Newburger JW, Jonas RA, Wernovsky G, Wypij D, Hickey PR, Kuban KC, Farrell
with CHD remain a specialized population with a unique set DM, Holmes GL, Helmers SL, Constantinou J, Carrazana E, Barlow JK, Walsh AZ,
of risk factors, investigations in other models of neurologic Lucius KC, Share JC, Wessel DL, Hanley FL, Mayer JE, Castaneda AR, Ware JH
1993 A comparison of the perioperative neurologic effects of hypothermic circula-
injury have led to dramatic advances in our understanding of tory arrest versus low-flow cardiopulmonary bypass in infant heart surgery. N Engl
the intricate processes that direct cellular injury and adaption J Med 329:1057–1064
in response to stress, providing a variety of new potential 19. Wypij D, Newburger JW, Rappaport LA, duPlessis AJ, Jonas RA, Wernovsky G,
Lin M, Bellinger DC 2003 The effect of duration of deep hypothermic circulatory
targets for the prevention and treatment of neurologic injury. arrest in infant heart surgery on late neurodevelopment: the Boston Circulatory
As our understanding of the genetic and molecular basis of Arrest Trial. J Thorac Cardiovasc Surg 126:1397–1403
20. Brunberg JA, Doty DB, Reilly EL 1974 Choreoathetosis in infants following cardiac
CHD expands, patient-specific variables will become central surgery with deep hypothermia and circulatory arrest. J Pediatr 84:232–235
to the formulation of unique strategies for risk stratification 21. du Plessis AJ, Bellinger DC, Gauvreau K, Plumb C, Newburger JW, Jonas RA,
Wessel DL 2002 Neurologic outcome of choreoathetoid encephalopathy after car-
and management. Although challenges remain, it is clear that diac surgery. Pediatr Neurol 27:9 –17
through continued study and collaboration, there exists tre- 22. Bellinger DC, Wypij D, du Plessis AJ, Rappaport LA, Riviello J, Jonas RA,
Newburger JW 2001 Developmental and neurologic effects of alpha-stat versus
mendous opportunity for the development of diagnostic and pH-stat strategies for deep hypothermic cardiopulmonary bypass in infants. J Thorac
therapeutic interventions that can serve to limit neurologic Cardiovasc Surg 121:374 –383
23. Jonas RA, Wypij D, Roth SJ, Bellinger DC, Visconti KJ, du Plessis AJ, Goodkin H,
sequelae and ultimately improve outcomes for patients with Laussen PC, Farrell DM, Bartlett J, McGrath E, Rappaport LJ, Bacha EA, Forbess
CHD. JM, del Nido PJ, Mayer JE Jr, Newburger JW 2003 The influence of hemodilution
on outcome after hypothermic cardiopulmonary bypass: results of a randomized trial
in infants. J Thorac Cardiovasc Surg 126:1765–1774
Acknowledgments. We thank Drs. Judy Aschner, Gregg 24. Newburger JW, Jonas RA, Soul J, Kussman BD, Bellinger DC, Laussen PC,
Robertson R, Mayer JE Jr, del Nido PJ, Bacha EA, Forbess JM, Pigula F, Roth SJ,
Stanwood, Ann Kavanaugh-McHugh, and Jonathon Soslow Visconti KJ, du Plessis AJ, Farrell DM, McGrath E, Rappaport LA, Wypij D 2008
for their advice and editorial assistance. Graphic support was Randomized trial of hematocrit 25% versus 35% during hypothermic cardiopulmo-
nary bypass in infant heart surgery. J Thorac Cardiovasc Surg 135:347–354,
provided by Kylie Beck at the Vanderbilt Kennedy Center. 354.e1–354.e4
25. Wernovsky G, Shillingford AJ, Gaynor JW 2005 Central nervous system outcomes
REFERENCES in children with complex congenital heart disease. Curr Opin Cardiol 20:94 –99
26. Langley SM, Chai PJ, Jaggers JJ, Ungerleider RM 2000 Preoperative high dose
1. Khairy P, Poirier N, Mercier LA 2007 Univentricular heart. Circulation 115:800 – methylprednisolone attenuates the cerebral response to deep hypothermic circulatory
812 arrest. Eur J Cardiothorac Surg 17:279 –286
8 ALBERS ET AL.

27. Lodge AJ, Chai PJ, Daggett CW, Ungerleider RM, Jaggers J 1999 Methylpred- 54. Hoffman TM, Wernovsky G, Atz AM, Bailey JM, Akbary A, Kocsis JF, Nelson DP,
nisolone reduces the inflammatory response to cardiopulmonary bypass in neonatal Chang AC, Kulik TJ, Spray TL, Wessel DL 2002 Prophylactic Intravenous Use of
piglets: timing of dose is important. J Thorac Cardiovasc Surg 117:515–522 Milrinone After Cardiac Operation in Pediatrics (PRIMACORP) study. Prophylactic
28. Kurth CD, Priestley M, Watzman HM, McCann J, Golden J 2001 Desflurane confers intravenous use of milrinone after cardiac operation in pediatrics. Am Heart J
neurologic protection for deep hypothermic circulatory arrest in newborn pigs. 143:15–21
Anesthesiology 95:959 –964 55. Hoffman TM, Wernovsky G, Atz AM, Kulik TJ, Nelson DP, Chang AC, Bailey JM,
29. Clancy RR, McGaurn SA, Goin JE, Hirtz DG, Norwood WI, Gaynor JW, Jacobs Akbary A, Kocsis JF, Kaczmarek R, Spray TL, Wessel DL 2003 Efficacy and safety
ML, Wernovsky G, Mahle WT, Murphy JD, Nicolson SC, Steven JM, Spray TL of milrinone in preventing low cardiac output syndrome in infants and children after
2001 Allopurinol neurocardiac protection trial in infants undergoing heart surgery corrective surgery for congenital heart disease. Circulation 107:996 –1002
using deep hypothermic circulatory arrest. Pediatrics 108:61–70 56. Guzzetta NA 2007 Phenoxybenzamine in the treatment of hypoplastic left heart
30. Mangano DT, Tudor IC, Dietzel C 2006 The risk associated with aprotinin in cardiac syndrome: a core review. Anesth Analg 105:312–315
surgery. N Engl J Med 354:353–365 57. Hoffman GM, Tweddell JS, Ghanayem NS, Mussatto KA, Stuth EA, Jaquis RD,
31. Massaro AN, El-Dib M, Glass P, Aly H 2008 Factors associated with adverse Berger S 2004 Alteration of the critical arteriovenous oxygen saturation relationship
neurodevelopmental outcomes in infants with congenital heart disease. Brain Dev by sustained afterload reduction after the Norwood procedure. J Thorac Cardiovasc
30:437– 446 Surg 127:738 –745
32. Istaphanous GK, Loepke AW 2009 General anesthetics and the developing brain. 58. Tweddell JS, Hoffman GM, Fedderly RT, Berger S, Thomas JP Jr, Ghanayem NS,
Curr Opin Anaesthesiol 22:368 –373 Kessel MW, Litwin SB 1999 Phenoxybenzamine improves systemic oxygen deliv-
33. Hoffman JI, Kaplan S 2002 The incidence of congenital heart disease. J Am Coll ery after the Norwood procedure. Ann Thorac Surg 67:161–167; discussion 167–168
Cardiol 39:1890 –1900 59. du Plessis AJ, Chang AC, Wessel DL, Lock JE, Wernovsky G, Newburger JW,
34. Forbess JM, Visconti KJ, Hancock-Friesen C, Howe RC, Bellinger DC, Jonas RA Mayer JE Jr 1995 Cerebrovascular accidents following the Fontan operation. Pediatr
2002 Neurodevelopmental outcome after congenital heart surgery: results from an Neurol 12:230 –236
institutional registry. Circulation 106:I95–I102 60. Rosenthal DN, Friedman AH, Kleinman CS, Kopf GS, Rosenfeld LE, Hellenbrand
35. Limperopoulos C, Majnemer A, Shevell MI, Rosenblatt B, Rohlicek C, Tchervenkov WE 1995 Thromboembolic complications after Fontan operations. Circulation
C, Darwish HZ 2001 Functional limitations in young children with congenital heart 92:II287–II293
defects after cardiac surgery. Pediatrics 108:1325–1331 61. O’Duffy AE, Bordelon YM, McLaughlin B 2007 Killer proteases and little strokes—
36. Majnemer A, Limperopoulos C, Shevell M, Rosenblatt B, Rohlicek C, Tchervenkov how the things that do not kill you make you stronger. J Cereb Blood Flow Metab
C 2006 Long-term neuromotor outcome at school entry of infants with congenital 27:655– 668
heart defects requiring open-heart surgery. J Pediatr 148:72–77 62. Murry CE, Jennings RB, Reimer KA 1986 Preconditioning with ischemia: a delay
37. Miatton M, De Wolf D, Francois K, Thiery E, Vingerhoets G 2007 Neuropsycho- of lethal cell injury in ischemic myocardium. Circulation 74:1124 –1136
logical performance in school-aged children with surgically corrected congenital 63. Barone FC 2005 Endogenous brain protection—models, gene expression, and
heart disease. J Pediatr 151:73–78, 78.e71 mechanisms. In: Read SJ, Virley D (eds) Stroke Genomics: Methods and Reviews.
38. Shillingford AJ, Glanzman MM, Ittenbach RF, Clancy RR, Gaynor JW, Wernovsky Humana Press, Totowa, pp 105–184
G 2008 Inattention, hyperactivity, and school performance in a population of 64. Dave KR, DeFazio RA, Raval AP, Torraco A, Saul I, Barrientos A, Perez-Pinzon
school-age children with complex congenital heart disease. Pediatrics 121:e759 – MA 2008 Ischemic preconditioning targets the respiration of synaptic mitochondria
e767 via Protein Kinase C. J Neurosci 28:4172– 4182
39. Wernovsky G 2006 Current insights regarding neurological and developmental 65. Yenari M, Kitagawa K, Lyden P, Perez-Pinzon M 2008 Metabolic downregulation:
abnormalities in children and young adults with complex congenital cardiac disease. a key to successful neuroprotection? Stroke 39:2910 –2917
Cardiol Young 16:92–104 66. Downey JM, Davis AM, Cohen MV 2007 Signaling pathways in ischemic precon-
40. Mahle WT, Tavani F, Zimmerman RA, Nicolson SC, Galli KK, Gaynor JW, Clancy ditioning. Heart Fail Rev 12:181–188
RR, Montenegro LM, Spray TL, Chiavacci RM, Wernovsky G, Kurth CD 2002 An 67. Gidday JM 2006 Cerebral preconditioning and ischaemic tolerance. Nat Rev Neu-
MRI study of neurological injury before and after congenital heart surgery. rosci 7:437– 448
Circulation 106:I109 –I114 68. Obrenovitch TP 2008 Molecular physiology of preconditioning-induced brain tol-
41. Miller G, Vogel H 1999 Structural evidence of injury or malformation in the brains erance to ischemia. Physiol Rev 88:211–247
of children with congenital heart disease. Semin Pediatr Neurol 6:20 –26 69. McLaughlin B, Hartnett KA, Erhardt JA, Legos JJ, White RF, Barone FC, Aizenman
42. Licht DJ, Shera DM, Clancy RR, Wernovsky G, Montenegro LM, Nicolson SC, E 2003 Caspase 3 activation is essential for neuroprotection in preconditioning. Proc
Zimmerman RA, Spray TL, Gaynor JW, Vossough A 2009 Brain maturation is Natl Acad Sci USA 100:715–720
delayed in infants with complex congenital heart defects. J Thorac Cardiovasc Surg 70. Gho BC, Schoemaker RG, van den Doel MA, Duncker DJ, Verdouw PD 1996
137:529 –537 Myocardial protection by brief ischemia in noncardiac tissue. Circulation 94:2193–
43. Volpe JJ 2001 Neurobiology of periventricular leukomalacia in the premature infant. 2200
Pediatr Res 50:553–562 71. Przyklenk K, Bauer B, Ovize M, Kloner RA, Whittaker P 1993 Regional ischemic
44. Beca J, Gunn J, Coleman L, Hope A, Whelan LC, Gentles T, Inder T, Hunt R, ‘preconditioning’ protects remote virgin myocardium from subsequent sustained
Shekerdemian L 2009 Pre-operative brain injury in newborn infants with transpo- coronary occlusion. Circulation 87:893– 899
sition of the great arteries occurs at rates similar to other complex congenital heart 72. Konstantinov IE, Li J, Cheung MM, Shimizu M, Stokoe J, Kharbanda RK, Reding-
disease and is not related to balloon atrial septostomy. J Am Coll Cardiol 53:1807– ton AN 2005 Remote ischemic preconditioning of the recipient reduces myocardial
1811 ischemia-reperfusion injury of the denervated donor heart via a Katp channel-
45. Chen J, Zimmerman RA, Jarvik GP, Nord AS, Clancy RR, Wernovsky G, Mon- dependent mechanism. Transplantation 79:1691–1695
tenegro LM, Hartman DM, Nicolson SC, Spray TL, Gaynor JW, Ichord R 2009 73. Dong JH, Liu YX, Ji ES, He RR 2004 [Limb ischemic preconditioning reduces
Perioperative stroke in infants undergoing open heart operations for congenital heart infarct size following myocardial ischemia-reperfusion in rats]. Sheng Li Xue Bao
disease. Ann Thorac Surg 88:823– 829 56:41– 46
46. Domi T, Edgell DS, McCrindle BW, Williams WG, Chan AK, MacGregor DL, 74. Dhodda VK, Sailor KA, Bowen KK, Vemuganti R 2004 Putative endogenous
Kirton A, deVeber GA 2008 Frequency, predictors, and neurologic outcomes of mediators of preconditioning-induced ischemic tolerance in rat brain identified by
vaso-occlusive strokes associated with cardiac surgery in children. Pediatrics genomic and proteomic analysis. J Neurochem 89:73– 89
122:1292–1298 75. Stenzel-Poore MP, Stevens SL, Simon RP 2004 Genomics of preconditioning.
47. Miller G, Mamourian AC, Tesman JR, Baylen BG, Myers JL 1994 Long-term MRI Stroke 35:2683–2686
changes in brain after pediatric open heart surgery. J Child Neurol 9:390 –397 76. Hausenloy DJ, Yellon DM 2008 Remote ischaemic preconditioning: underlying
48. Cavalca V, Sisillo E, Veglia F, Tremoli E, Cighetti G, Salvi L, Sola A, Mussoni L, mechanisms and clinical application. Cardiovasc Res 79:377–386
Biglioli P, Folco G, Sala A, Parolari A 2006 Isoprostanes and oxidative stress in 77. Cheung MM, Kharbanda RK, Konstantinov IE, Shimizu M, Frndova H, Li J, Holtby
off-pump and on-pump coronary bypass surgery. Ann Thorac Surg 81:562–567 HM, Cox PN, Smallhorn JF, Van Arsdell GS, Redington AN 2006 Randomized
49. Dybdahl B, Wahba A, Lien E, Flo TH, Waage A, Qureshi N, Sellevold OF, Espevik controlled trial of the effects of remote ischemic preconditioning on children
T, Sundan A 2002 Inflammatory response after open heart surgery: release of undergoing cardiac surgery: first clinical application in humans. J Am Coll Cardiol
heat-shock protein 70 and signaling through toll-like receptor-4. Circulation 47:2277–2282
105:685– 690 78. Mahle WT, Clancy RR, McGaurn SP, Goin JE, Clark BJ 2001 Impact of prenatal
50. Ramlawi B, Rudolph JL, Mieno S, Khabbaz K, Sodha NR, Boodhwani M, Levkoff diagnosis on survival and early neurologic morbidity in neonates with the hypoplas-
SE, Marcantonio ER, Sellke FW 2006 Serologic markers of brain injury and tic left heart syndrome. Pediatrics 107:1277–1282
cognitive function after cardiopulmonary bypass. Ann Surg 244:593– 601 79. Eapen RS, Rowland DG, Franklin WH 1998 Effect of prenatal diagnosis of critical
51. Ulus AT, Aksoyek A, Ozkan M, Katircioglu SF, Basu S 2003 Cardiopulmonary left heart obstruction on perinatal morbidity and mortality. Am J Perinatol 15:237–
bypass as a cause of free radical-induced oxidative stress and enhanced blood-borne 242
isoprostanes in humans. Free Radic Biol Med 34:911–917 80. McElhinney DB, Benson CB, Brown DW, Wilkins-Haug LE, Marshall AC, Zac-
52. Sherlock RL, McQuillen PS, Miller SP 2009 Preventing brain injury in newborns cagnini L, Tworetzky W 2010 Cerebral blood flow characteristics and biometry in
with congenital heart disease: brain imaging and innovative trial designs. Stroke fetuses undergoing prenatal intervention for aortic stenosis with evolving hypoplas-
40:327–332 tic left heart syndrome. Ultrasound Med Biol 36:29 –37
53. Soul JS, Robertson RL, Wypij D, Bellinger DC, Visconti KJ, du Plessis AJ, 81. Sander TL, Klinkner DB, Tomita-Mitchell A, Mitchell ME 2006 Molecular and
Kussman BD, Scoppettuolo LA, Pigula F, Jonas RA, Newburger JW 2009 Subtle cellular basis of congenital heart disease. Pediatr Clin North Am 53:989 –1009
hemorrhagic brain injury is associated with neurodevelopmental impairment in 82. Gaynor JW, Gerdes M, Zackai EH, Bernbaum J, Wernovsky G, Clancy RR,
infants with repaired congenital heart disease. J Thorac Cardiovasc Surg 138:374 – Newman MF, Saunders AM, Heagerty PJ, D’Agostino JA, McDonald-McGinn D,
381 Nicolson SC, Spray TL, Jarvik GP 2003 Apolipoprotein E genotype and neurode-
 NEUROPROTECTION IN INFANT HEART SURGERY 9
velopmental sequelae of infant cardiac surgery. J Thorac Cardiovasc Surg 90. Caputo M, Mokhtari A, Rogers CA, Panayiotou N, Chen Q, Ghorbel MT, Angelini
126:1736 –1745 GD, Parry AJ 2009 The effects of normoxic versus hyperoxic cardiopulmonary
83. Gaynor JW, Wernovsky G, Jarvik GP, Bernbaum J, Gerdes M, Zackai E, Nord AS, bypass on oxidative stress and inflammatory response in cyanotic pediatric patients
Clancy RR, Nicolson SC, Spray TL 2007 Patient characteristics are important undergoing open cardiac surgery: a randomized controlled trial. J Thorac Cardiovasc
determinants of neurodevelopmental outcome at one year of age after neonatal and Surg 138:206 –214
infant cardiac surgery. J Thorac Cardiovasc Surg 133:1344 –1353, 1353.e1–1353.e3 91. Durandy YD, Younes M, Mahut B 2008 Pediatric warm open heart surgery and
84. Chock VY, Amir G, Davis CR, Ramamoorthy C, Riemer RK, Ray D, Giffard RG, prolonged cross-clamp time. Ann Thorac Surg 86:1941–1947
Reddy VM 2006 Antegrade cerebral perfusion reduces apoptotic neuronal injury in 92. Eckle T, Kohler D, Lehmann R, El Kasmi K, Eltzschig HK 2008 Hypoxia-inducible
a neonatal piglet model of cardiopulmonary bypass. J Thorac Cardiovasc Surg factor-1 is central to cardioprotection: a new paradigm for ischemic preconditioning.
131:659 – 665 Circulation 118:166 –175
85. Warren O, Alexiou C, Massey R, Leff D, Purkayastha S, Kinross J, Darzi A, 93. Ovbiagele B, Starkman S, Teal P, Lyden P, Kaste M, Davis SM, Hacke W, Fierus
Athanasiou T 2007 The effects of various leukocyte filtration strategies in cardiac M, Saver JL 2008 Serum calcium as prognosticator in ischemic stroke. Stroke
surgery. Eur J Cardiothorac Surg 31:665– 676 39:2231–2236
94. Florio P, Abella RF, de la Torre T, Giamberti A, Luisi S, Butera G, Cazzaniga A,
86. Gaynor JW 2003 The effect of modified ultrafiltration on the postoperative course in Frigiola A, Petraglia F, Gazzolo D 2007 Perioperative activin A concentrations as a
patients with congenital heart disease. Semin Thorac Cardiovasc Surg Pediatr Card predictive marker of neurologic abnormalities in children after open heart surgery.
Surg Annu 6:128 –139 Clin Chem 53:982–985
87. Hickey E, Karamlou T, You J, Ungerleider RM 2006 Effects of circuit miniaturiza- 95. Montine KS, Quinn JF, Zhang J, Fessel JP, Roberts LJ II, Morrow JD, Montine TJ
tion in reducing inflammatory response to infant cardiopulmonary bypass by elim- 2004 Isoprostanes and related products of lipid peroxidation in neurodegenerative
ination of allogeneic blood products. Ann Thorac Surg 81:S2367–S2372 diseases. Chem Phys Lipids 128:117–124
88. Hickey E, Karamlou T, You XM, Komanapalli C, Person T, Wehrley K, Ungerleider 96. Montine TJ, Neely MD, Quinn JF, Beal MF, Markesbery WR, Roberts LJ, Morrow
R 2007 The use of a miniaturized circuit and bloodless prime to avoid cerebral JD 2002 Lipid peroxidation in aging brain and Alzheimer’s disease. Free Radic Biol
no-reflow after neonatal cardiopulmonary bypass. Ann Thorac Surg 83:895–901 Med 33:620 – 626
89. Karamlou T, Schultz JM, Silliman C, Sandquist C, You J, Shen I, Ungerleider RM 97. Arneson KO, Roberts LJ II 2007 Measurement of products of docosahexaenoic acid
2005 Using a miniaturized circuit and an asanguineous prime to reduce neutrophil- peroxidation, neuroprostanes, and neurofurans. Methods Enzymol 433:127–143
mediated organ dysfunction following infant cardiopulmonary bypass. Ann Thorac 98. Roberts LJ II, Fessel JP 2004 The biochemistry of the isoprostane, neuroprostane,
Surg 80:6 –14 and isofuran pathways of lipid peroxidation. Chem Phys Lipids 128:173–186