Seminars in Cardiothoracic
and Vascular Anesthesia
Surrogate Markers for Neurological
Outcome in Children After Deep
Hypothermic Circulatory Arrest
Scott D. Markowitz, MD, Rebecca N. Ichord, MD, Gil Wernovsky, MD,
J. William Gaynor, MD, and Susan C. Nicolson, MD
Improved survival for infants with congenital heart disease
(CHD) has led to increased focus on the most significant
morbidities that are neurodevelopmental. Neurologic
injury in neurodevelopmental outcome may have many
causes in children with complex CHD undergoing car-
diopulmonary bypass and deep hypothermic circulatory
arrest, including genetic syndromes, abnormal blood flow
patterns, prenatal insults, and hemodynamic instability.
Although gross neurological injury can be detected in the
perinatal and postoperative period, more subtle injury may
not be identified until much later. Disabilities in speech
and language, motor skills, and attention deficit disorder
are present by school age in up to 50% of the complex CHD
population. It is imperative that the mechanisms of these
injuries be identified to enable the application of neuropro-
tective interventions. To facilitate clinical investigation,
evaluation of surrogate markers for these longer term “real”
outcomes continues. Because some abnormalities may not
A
s the survival with congenital heart disease
(CHD) has improved with advances in under-
standing, technique, and technology, increasing
focus is placed on the morbidities of CHD and the
treatment of these children. With better cardiovascular
outcomes from surgical and medical interventions and
deeper understanding of the disease course of congen-
ital heart lesions, children have been functionally able
to participate in school and other activities to a fuller
extent than ever before. This outcome increased recog-
nition of neurodevelopmental sequelae of CHD and its
From The Children’s Hospital of Philadelphia, The University of
Pennsylvania, PA.
Address correspondence to: Scott D. Markowitz, MD, Department
of Anesthesiology and Critical Care Medicine, Suite 9329, The
Children’s Hospital of Philadelphia, 34th Street and Civic Center
Boulevard, Philadelphia, Pennsylvania 19104; e-mail: markowitzs
@email.chop.edu.
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Volume 11 Number 1
March 2007 59-65
© 2007 Sage Publications
10.1177/1089253206297481
http://scv.sagepub.com
hosted at
http://online.sagepub.com
be detected for years, the evaluation of a surrogate marker
takes a long time. Thus, identification of surrogate markers
is in its infancy. Serologic proteins, seizures, magnetic res-
onance findings, cerebral oxygenation, and the neurologic
examination have all been studied. Continuing innovation
in the use of magnetic resonance imaging techniques and
the application of physiologic measures including near-
infrared spectroscopy currently pose the greatest potential
for advances. This article summarizes the state of the art
and an admission about how far we have yet to travel as we
strive to make the neurodevelopmental outcomes of
patients with CHD comparable to their healthy peers.
Keywords: congenital heart disease; deep hypothermic
circulatory arrest; neurodevelopmental outcome; surrogate
markers; near infrared spectroscopy; serological markers;
electroencephalography; magnetic resonance imaging;
magnetic resonance spectroscopy
therapy. Perhaps 50% or more of school age children
who underwent cardiac surgery as young infants have
detectable abnormalities on formal testing.1 Other
outcomes which have been or need to be addressed
include quality of life into adulthood, educability,
employability, and insurability. Research continues into
the nature of the disabilities surrounding CHDs and
their treatment, the causes, and the interventions that
may prevent some of these injuries.
Research is essential if we are to determine the
causes of these injuries and to assess preventive or
therapeutic measures. Clinical research involving the
neurologic and developmental outcome of children
who undergo cardiac interventions as neonates and
young infants is compromised by the limited predictive
validity of testing performed in the early years after
surgery. Important domains for school age children,
such as attention, behavior, visual–motor integration,
59
60 Seminars in Cardiothoracic and Vascular Anesthesia / Vol. 11, No. 1, March 2007
and executive function have no correlate in the young
infant, and no developmental tests in toddlers to date
can predict dysfunction in these domains that dramat-
ically affects quality of life. It is, therefore, prudent to
consider the important long-term outcomes (true out-
comes) and to identify short-term outcomes or mark-
ers that will enable early identification of potential
longer term problems so that appropriate interventions
can take place. In addition, identification of early
markers for late dysfunction will allow timely comple-
tion of clinical trials of neuroprotection. These short-
term markers, called surrogate outcomes, would be
clinical findings and diagnostic tests that are easily
measured and highly predictive of the true outcome
(outcome of interest).
Outcomes such as stroke, seizure, physical limita-
tions, attention deficit disorders, speech and language
disabilities, and learning disabilities represent short-
and long-term outcomes, only some of which can be
measured at an early stage. Well-correlated surrogate
outcomes can reduce the cost of a clinical study by sig-
nificantly shortening the time to acquire subjects, the
follow-up period necessary to determine a difference
in outcome, and sometimes in limiting the require-
ments for other consultants or the risks of other diag-
nostic studies. Postoperative length of stay, duration of
cardiopulmonary bypass (CPB) or deep hypothermic
circulatory arrest (DHCA), and perioperative seizures
have all been investigated with some correlation to
adverse neurologic outcome.2-4 It has proven difficult
to address study design concerns in dealing with mul-
tiple interdependent predictors of outcome that can
include preoperative factors that may play a role in
determining duration of CPB or the use of DHCA,
severity of heart disease, coexisting disease, and post-
operative factors that may affect length of stay.
To date, several studies have investigated markers
that may predict neurological injury after CPB and
DHCA in infants and children. These markers fall
into broad categories: the neurologic exam, electroen-
cephalogram (EEG) abnormalities such as abnormal
background, ictal activity and burst suppression, sero-
logic markers, and neuroimaging including magnetic
resonance imaging (MRI), magnetic resonance spec-
troscopy (MRS) and near-infrared spectroscopy (NIRS).
Importantly, these signs and diagnostic tests have been
evaluated, to varying degrees, as outcome measures in
and of themselves of neurologic damage and neurode-
velopmental disability, rather than predictive surrogate
markers.
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Neurological Examination
Several studies have reported suspect or frankly abnor-
mal neurologic examination during the first postopera-
tive week in 5% to 60% of subjects.5-7 Abnormalities
include depressed level of consciousness, diffuse tone
abnormalities (mostly hypotonia), transient chorea, and
depressed neonatal reflex behaviors. Clinical neurologic
examination of an infant who has recently under-
gone surgery with CPB for CHD poses several chal-
lenges in its performance and interpretation. Findings
are confounded by recent general anesthesia and deep
hypothermia, the effects of CPB per se, and the effects
of postoperative sedatives, analgesics, and neuromuscu-
lar blocking drugs. Moreover, many infants have preop-
erative abnormalities, some related to the preoperative
cardiac lesion itself, and others related to other noncar-
diac congenital anomalies or prematurity. Evaluation of
true “cortical” function in an infant under these cir-
cumstances is limited to an assessment of conscious-
ness in an all-or-none fashion. Other truly “cortical”
functions of the very young infant, such as auditory ori-
enting or visual processing, cannot be examined. Almost
all other components of the clinical examination,
including cranial nerves, tone, limb movement, and
reflexes, are mediated by spinal cord, brainstem, and
subcortical structures. It comes as no surprise, there-
fore, that the clinical examination through the first
week of life has almost no predictive significance for
neurodevelopmental outcome.
Serologic Markers
Certain serologic markers have been examined as
markers of neurologic injury after DHCA. Serologic
markers of tissue injury can be substances that are
released from damaged cells or proteins that are
secreted in response to cellular stress. In the area of
neurologic markers, creatine kinase isoenzyme BB (CK-
BB), protein S-100 β subunit (S-100β), neuron-specific
enolase (NSE), and glial fibrillary acidic protein (GFAP)
are potential markers for neurologic injury and have to
some degree been investigated in the setting of cardiac
surgery.
Creatinine Kinase
The BB isoenzyme of creatine kinase is present in
astrocytes as well as intestine, lung, and prostate.8

There have also been measurements of CK-BB in
myocardium at autopsy study.9 Because of the lack
of specificity for neuronal tissues, no published
pediatric studies have shown promise for the use of
this marker to predict brain injury after surgery for
CHD. In fact, Newburger et al identified a higher
CK-BB in patients having undergone DHCA com-
pared with low-flow CPB; however, this difference
did not predict outcome at later examination.10-13
NSE
NSE is a glycolytic enzyme that has been used to pre-
dict long-term neurologic outcome after cardiac arrest
in adults. In pediatric patients, NSE is used as a tumor
marker for certain neuroendocrine malignancies. NSE
is located in the cytoplasm of neurons, as well as in red
blood cells and platelets. NSE increases proportionate
to the degree of neurologic injury after cardiac arrest,
but is confounded by hemolysis during and after extra-
corporeal circulation, making the use of this marker
after neonatal heart surgery of questionable value.14 In
a study intended to compare neurologic outcome
markers after normothermic versus DHCA in pediatric
patients undergoing surgery for CHD, all patients had
increased levels of NSE, and no difference was seen
between the two groups.15 In their study, Rasmussen
et al measured NSE at 12 and 24 hours after CPB.
Because the estimated plasma half-life of NSE is 48
hours, it may be possible to revisit this marker in a
delayed measurement after bleeding and hemolysis
have stabilized. No such studies have been published
in the neonatal literature.
β Protein
S-100β
The αβ and ββ isoforms of the S-100 proteins are
found in astroglial cells and have a short plasma half-
life. Neonates and infants have an increased serum
concentration of these proteins compared with adults,
which may represent increased permeability of the
blood–brain barrier. Additionally, newborns have the
highest serum levels. Infants with CHD, especially
those with lesions obstructive to antegrade aortic flow,
have increased preoperative S-100β, which have been
hypothesized to be markers of preoperative cerebral
injury. The biological half-life of S-100β is 133 min-
utes, and the protein is metabolized in the kidney and
excreted in the urine.16
Protein S-100β has been shown to be a spe-
cific marker for traumatic or ischemic brain injury in
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Surrogate Markers / Markowitz et al. 61
adults,17,18 and investigators have examined S-100β as a
marker for perioperative neurologic injury after CPB
and DHCA in infants. Lindberg et al found the protein
to be elevated in relation to increasing perfusion time
and the use of DHCA and inversely to age, although
they failed to find a relationship to weight, temperature,
or trisomy 21 status (the β subunit of S-100 is found on
chromosome 21, and children with Down’s syndrome
have more intracranial cells that contain S-100).18,19
Jensen et al also found a correlation with duration of
bypass, but found the postoperative increase to be tran-
sient.20 Neither study correlated the change to neuro-
logic injury or seizures. Bokesch et al compared the
S-100β levels at 24-hours postoperatively to preopera-
tive values and found that postoperative increases did
not correlate with 30 day mortality.21 Erb et al and
Lardner et al both examined the application of a delayed
or persistent elevation of the protein as a marker for
neurological injury. Erb et al identified two children
with postoperative neurologic injury who did not have
an increased S-100β level, but did identify a 7-day
delayed rise in S-100β associated with new-onset
seizure activity in one subject, suggesting that S-100β
can be a screening tool for postoperative seizures that
can be difficult to detect clinically in the early postop-
erative period.22 Lardner hypothesized that because
S-100β was also present in thymic and adipose tissue
this would confound the post-CPB assays because
these tissues would introduce the protein into the car-
diotomy suction; therefore, a delayed assay at 48 hours
would be a better time to identify a rise in S-100β solely
on the basis of neurologic injury. In their study, Lardner
et al found a strong association between a rise in S-
100β at 48 hours and neurologic injury, although they
did not specify the nature of the injury nor the method
of diagnosis.23 Importantly, no published studies after
neonatal and infant heart surgery have demonstrated a
correlation with long-term neurologic findings. Although
S-100β may have clinical utility if measured 24 hours
after CPB, a study to correlate the findings to early and
late clinical neurologic outcomes is needed. The CK-
BB and NSE have not been shown to produce consis-
tent results that could be used to study their predictive
value in neonates after CPB and DHCA.
GFAP
The GFAP is only found in the astroglial cells of the
central nervous system. Currently, no studies have
examined the utility of GFAP serum levels after CPB
or DHCA in infants.
62 Seminars in Cardiothoracic and Vascular Anesthesia / Vol. 11, No. 1, March 2007
Seizures and EEG Abnormalities
Two large prospective studies of perioperative EEG
findings in infants undergoing open-heart surgery have
been published. In the Boston Circulatory Arrest study,
134 infants underwent continuous EEG monitoring
for 48 hours after arterial switch operations for trans-
position of the great arteries.24 Electrographic seizures
occurred in 20% and were associated with an increased
risk of abnormal brain MRI and lower Psychomotor
Developmental Index scores on the Bayley Scales of
infant development at 1 year and with increased risk of
abnormal neurologic exam and lower intelligence quo-
tient at age 4 years. In contrast, Gaynor et al reported
that postoperative electrographic seizures affected only
11% of a larger cohort, which included a variety of
heart lesions and did not affect the risk of a lower
Bayley score at 1 year.25 Differences that may explain
the discrepancy in results include advances in care over
the 10 years separating the two studies, differences in
underlying heart lesions, and universal treatment of
seizures in the cohort studied by Gaynor et al. Several
smaller studies have reported on the significance of
EEG background abnormalities. Limperopoulos et al
conducted the only one of three studies with a positive
relationship, showing that background slowing or
amplitude suppression were common in the first post-
operative week (50% to 75%). They reported that a nor-
mal background predicted a normal neurological status
at follow-up, whereas severe background suppression
was associated with death or severe disability.26 Other
studies have not observed this kind of association.
NIRS and Systemic Venous
Oxygen Saturation
NIRS is a noninvasive method using the measure-
ment of the wavelength-specific absorption of light to
determine the concentration of specific chromophores
in tissue. Typically, NIRS can be used to measure
oxyhemoglobin and deoxyhemoglobin and oxidized
cytochrome a,a3 (CytOx). Animal studies have sug-
gested that the use of NIRS during and after DHCA
can predict neurologic injury with a correlation in min-
imum CytOx level to the amount of histologic brain
injury in piglets.27 In a study in rabbits, Abdul-Khaliq
et al suggested that hemoglobin saturation and CytOx
using NIRS were important for monitoring delivery and
receipt of oxygen to the brain, respectively.28 Sakamoto
et al used NIRS to identify a “safe” period of DHCA to
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be dependent on hematocrit and temperature.29 In this
and other studies using NIRS during DHCA, the
hemoglobin saturation decreases and plateaus early in
the DHCA phase, and in the cases where it has been
examined, the CytOx continues to decrease throughout
the early phases of DHCA, indicating continued metab-
olism using oxygen and inadequate oxygen delivery even
during deep hypothermia. Several studies have identi-
fied a delay in recovery of baseline oxygen metabolism
that is dependent on minimal temperature and dura-
tion of DHCA.30,31
The use of postoperative physiological parame-
ters to predict long-term outcomes has shown some
utility in the case of children after the stage I oper-
ation for hypoplastic left heart syndrome. In a neu-
rodevelopmental outcome study, 13 neonates having
undergone the stage I operation and then neurode-
velopmental testing at age 4 showed that lower post-
operative systemic venous oxygen saturation was a
significant risk factor for later abnormalities in
motor, visual–motor integrative, and composite neu-
rodevelopmental scores (including cognitive, motor,
behavioral, and visual–motor integrative outcomes).
Magnetic Resonance
MRI can detect structural abnormalities and stroke-
type injuries to the brain. MRS can determine the
presence or relative level of certain substances
in the brain tissue. Because these techniques require
immobility of the subject, sometimes for a prolonged
period, the young patients usually require general
anesthesia to accomplish these scans. The use of
MRI/MRS to study perioperative infants with heart
disease poses challenges to the design of a clinical
trial and the timing of cardiac surgery and has impor-
tant implications to the practice of the anesthesiolo-
gist. With patient safety of paramount importance,
research trials have been limited to centers with a sig-
nificant experience with anesthetizing this patient
population. With the limited published studies avail-
able, generalization is difficult, but we have identified
pre-existing brain injury that will confound the deter-
mination of the additional effect of extracorporeal cir-
culation, with or without DHCA, on the neurologic
outcome in these children.
In a study by Miller et al examining 10 infants pre-
operatively and postoperatively from surgical correction
of transposition of the great arteries, the investigators
found a 40% incidence of abnormalities preoperatively.

These findings were felt to suggest abnormal brain
metabolism in these subjects before surgical interven-
tion and CPB/DHCA, and only one new injury was
identified postoperatively.32
Mahle et al evaluated 24 infants with CHD by
MRI/MRS before and after surgery with CPB and
found an elevated brain lactate in 53% of the patients
studied, as well as tissue loss (infarction) in 8% and
periventricular leukomalacia (PVL) in 16%.33 Postoper-
atively, 48% of subjects had new PVL; 19% had new
areas of infarction, and there was new parenchymal
hemorrhage in 33% of subjects, suggesting that intra-
operative and postoperative factors play a greater role
than previously suggested in Miller et al’s study. No
comments on neurologic deficit or developmental
abnormalities were made in this study, which followed
subjects up to 7 months postoperatively. In longitudinal
studies of premature infants found to have PVL,
the pattern of school-age disabilities is similar to that
reported in CHD, suggesting a similar response to
injury. PVL may thus be a reasonable predictor surro-
gate variable, but as mentioned previously here, acqui-
sition of adequate imaging requires considerable
resources and coordinated logistics to ensure patient
safety.
More recently, Galli et al identified a very high inci-
dence of PVL in postoperative patients, whereas in a
study of preoperative patients, Licht et al using pulsed-
arterial spin label perfusion identified severe impair-
ment of cerebral blood flow of a similar patient
population.34-36 The implication of these findings is that
these patients are at increased vulnerability for periop-
erative neurologic injury and that aspects of preopera-
tive and postoperative management, in addition to
intraoperative management, can potentially have signif-
icant influence in the neurodevelopmental outcome of
these patients. Although the correlation between PVL
and neurodevelopmental outcome in CHD patients has
not yet been established, it warrants the attention of
researchers.
A recent article by McQuillen et al identified bal-
loon atrial septostomy (BAS) as a major risk factor for
preoperative focal brain injury in babies with dextro-
transposition of the great arteries. In this study of 29
neonates, 12 of 19 who underwent BAS were diag-
nosed by MRI with preoperative brain injury; none of
the neonates who did not undergo BAS had preopera-
tive brain injury.37 In earlier work, the incidence of
MRI lesions in patients 1 year after correction of dex-
trotransposition of the great arteries was 14% of 142
patients, all having undergone preoperative BAS.12
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Surrogate Markers / Markowitz et al. 63
Additionally, Dent et al recently confirmed a 23% pre-
operative incidence of ischemic MRI lesions in babies
with hypoplastic left heart syndrome.38 Also, the inci-
dence of postoperative cerebral injury in this study is
similar to that found by Mahle et al despite the former
using regional low flow perfusion instead of DHCA.33
Using MRS to identify the n-acetylaspartate, crea-
tine compounds, and lactate in the brains of nine
infants who had undergone surgical correction for
CHD and who had been diagnosed with severe central
nervous system insults, mostly as a result of cardiac
arrest, Ashwal et al found that those with both a
n-acetylaspartate/creatine compound ratio reduced by
at least 50% and positive lactate had severely impaired
neurologic outcome at 6 and 12 months by the Glasgow
Outcome Score.39 Although the Glasgow Outcome
Score is a gross tool for the identification of more sub-
tle neurologic outcomes, the study shows that there are
degrees of severity identifiable by the MRS technology
and suggests further studies are warranted.
Conclusion
The high incidence of neurodevelopmental abnormal-
ities in the current school-age survivors of neonatal
and infant heart surgery is concerning. It is important
to recognize that intraoperative and perioperative
techniques have changed considerably in the past
decade, and children repaired in the current era may
have considerably different outcomes. Nonetheless,
modifying the long-term neurodevelopment of patients
is a major focus of research. It is highly impractical
to enroll newborns in clinical trials—either random-
ized trials of neuroprotection strategies or registries
used to track long-term outcomes—and wait 8 to 15
years to determine the effects of our current manage-
ment strategies. The identification of surrogate vari-
ables, measured in the early postoperative period, is
essential.
A combination of structural and functional meas-
ures is likely to assume increasing importance in the
coming years, including the use of MRI/MRS, bedside
EEG, and NIRS. The recent use of MRI, MRS, and
other advanced magnetic resonance techniques have
offered insight into the preoperative and postoperative
state of the brain in the neonate with CHD and have
identified potential markers that may predict longer
term developmental outcomes. Bedside techniques
such as signal-averaged EEG and NIRS show promise,
but further studies to validate the predictive ability for
longer term function will need to be accomplished
64 Seminars in Cardiothoracic and Vascular Anesthesia / Vol. 11, No. 1, March 2007
before these tools are ready to be used in the evalua-
tion of therapeutic interventions.
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