Cause and Prevention of Central Nervous System

Injury in Neonates Undergoing Cardiac Surgery

Troy E. Dominguez, MD, Gil Wernovsky, MD, and J. William Gaynor, MD

Neurologic morbidity has been identified as increasingly problematic in neonates with

congenital heart disease as surgical mortality rates have improved. The presence of
“congenital brain disease” in patients with congenital heart disease represents a challenge
in improving long-term neurologic outcomes. Mechanisms of central nervous system injury
in infants undergoing cardiac surgery include hypoxia-ischemia, emboli, reactive oxygen
species, and inflammatory microvasculopathy. Preoperatively, the primary focus is on
preventing hypoxic-ischemic injury and thromboembolic insults. Modifiable intraoperative
factors associated with central nervous system injury include, but are not limited to, pH
management, hematocrit during cardiopulmonary bypass, regional cerebral perfusion, and
the use of deep hypothermic circulatory arrest. Postoperatively, secondary neurologic
injury may be related to post-cardiopulmonary bypass alterations in cerebral autoregulation
and additional hypoxic-ischemic insult, seizures, or other issues associated with prolonged
intensive care unit stay. In addition to prenatal and modifiable perioperative factors, genetic
and environmental factors are known to be important. Unfortunately, modifiable perioper-
ative factors may explain less of the variability in long-term outcomes than do patient-
specific factors.
Semin Thorac Cardiovasc Surg 19:269-277 © 2007 Elsevier Inc. All rights reserved.

KEYWORDS central nervous system, brain, neonate, cardiac surgery, postoperative, brain
injury, congenital heart disease, injury

W ith advances in surgical techniques and medical care

of neonates with congenital heart disease (CHD),
mortality rates have significantly declined and more effort is
being made toward preventing morbidity associated with
neonatal cardiac surgery. In particular, neurologic morbidity
has been identified to be problematic in neonates with CHD.
Although early postoperative central nervous system (CNS)
sequelae such as stroke and seizures occur in a small percent-
age of neonates with CHD,1 the importance of more subtle
neurologic findings at long-term follow-up is being increas-
ingly recognized.2-10 These findings may include fine and
gross motor impairments, speech and language delays, and
disturbances in visual-motor and visual-spatial abilities, at-
tention-deficit disorders, learning disorders, and impaired
executive functioning. Alone or in combination, these find-
Division of Cardiothoracic Surgery, The Cardiac Center at The Children’s
Hospital of Philadelphia, Philadelphia, Pennsylvania.
Address reprint requests to J. William Gaynor, MD, Division of Cardiotho-
racic Surgery, The Children’s Hospital of Philadelphia, 34th and Civic
Center Blvd, Suite 8527, Philadelphia, PA 19104. E-mail: gaynor@
email.chop.edu
ings may significantly decrease quality of life for patients and
their families, as well as result in significant costs to society.
The presence of “congenital brain disease” in patients with
CHD represents a challenge in improving long-term neuro-
logic outcomes.11 Many neonates with CHD have congenital
structural brain abnormalities and/or chromosomal abnor-
malities, as well as physiologic abnormalities that may impair
brain development. Brain abnormalities on head ultrasound
have been noted in one fifth of full-term infants undergoing
heart surgery, with half of the abnormalities being present
preoperatively.10 Limperopoulos and coworkers also noted
neurobehavioral abnormalities in more than 50% of neonates
with CHD. These abnormalities include hypertonia/hypoto-
nia, jitteriness, motor asymmetries, and absent suck reflex.12
CHD may produce abnormal fetal physiology that results
in impaired cerebral blood flow and oxygen delivery to the
developing brain. For example, in patients with left-sided
obstructive lesions, the arterial duct delivers blood flow both
cephalad and caudad. In this circumstance, the cerebral vas-
cular resistance should be lower than normal to maintain
adequate cerebral blood flow because there is flow competi-
tion with the low-resistance placenta.11

1043-0679/07/$-see front matter © 2007 Elsevier Inc. All rights reserved. 269
doi:10.1053/j.semtcvs.2007.07.005
270
Using Doppler interrogation of the middle cerebral artery,
Donofrio and coworkers and Kaltman and coworkers identi-
fied abnormal fetal cerebrovascular physiology in patients
with CHD.13,14 These authors found a lower cerebrovascular
resistance in patients with left-sided obstructive lesions and a
higher resistance in those with right-sided lesions. Addition-
ally, in the normal fetus, the most highly oxygenated blood is
preferentially streamed to the cerebral circulation and the
most desaturated blood to the placenta. In fetuses with ab-
normal arterial connections or complete intracardiac mixing
due to single ventricle, this physiology may be altered, result-
ing in lower-than-normal oxygen delivery to the developing
fetal brain. Given all of the above factors, it is not surprising
that evidence of brain injury is seen postnatally, or that inci-
dence of microcephaly is increased in patients with CHD.
Microcephaly may be seen in up to one quarter of the patients
and may correlate with these observed abnormalities in fetal
blood flow.10,15,16 Shillingford and coworkers have reported
the incidence of microcephaly to 18% in patients with hyp-
oplastic left heart syndrome and noted microcephaly to be
associated with a smaller size of the ascending aorta.16 In
addition, periventricular leukomalacia (PVL), thought to
arise from white-matter hypoxic-ischemic injury and com-
monly found in premature infants, has been reported in full-
term infants with CHD. Evidence of PVL has been identified
in just under 20% of newborns with CHD before surgery and
has been associated with elevated levels of brain lactate mea-
sure by magnetic resonance imagining (MRI) spectroscopy.17
Although postoperative neurodevelopmental status is sig-
nificantly correlated with preoperative status10 and evidence
of prenatal neurologic disease is not uncommon, secondary
neurologic injury can occur at any time postnatally. New,
postoperative neurologic injury may be detected clinically in
more than 10% of infants,10 and in more than 50% with more
sensitive brain imaging techniques such as MRI.17,18 Given
that new neurologic injury can occur at various times during
the neonate’s hospitalization, perioperative attention to re-
ducing known risk factors is critical. In general, mechanisms
of CNS injury in infants undergoing cardiac surgery include
hypoxia-ischemia, emboli, reactive oxygen species, and in-
flammatory microvasculopathy.19
In addition to prenatal and modifiable perioperative fac-
tors, genetic and environmental factors have recently been
shown to be important. These patient-specific factors may
not be modifiable. Varying degrees of developmental delay
are seen in patients with known genetic syndromes, such as
trisomy 21, DiGeorge syndrome, William’s syndrome, tri-
somy 13, and trisomy 18, or known associations of congen-
ital anomalies such as VACTERL and CHARGE. Genetic
polymorphisms may also increase susceptibility to neuro-
logic injury associated with infant cardiac surgery. Apoli-
poprotein E (APOE) is an important regulator of cholesterol
metabolism, and APOE-containing lipoproteins are thought
to be the primary lipid transport vehicles in the CNS. One of
the 3 APOE alleles, APOE ␧2, has been identified to be inde-
pendently associated with worse psychomotor development
index scores in patients at age 1 year after infant cardiac
surgery.20
T.E. Dominguez, G. Wernovsky, and J.W. Gaynor
Socioeconomic status is one of the strongest predictors of
neurodevelopmental outcomes. This finding has been re-
ported in several studies and is related to both environmental
and genetic factors.6,21,22 In one study of 133 individuals aged
3.7 to 41 years of age who had undergone a Fontan proce-
dure, socioeconomic status explained one sixth of the vari-
ability in intelligence quotient scores, whereas deep hypo-
thermic circulatory arrest (DHCA) and surgical variables
explained only 6.1%.21 In another study, patient-specific fac-
tors including presence of a genetic syndrome, low birth
weight, and presence of the APOE ␧2 allele were the strongest
predictors of a worse neurodevelopmental outcome at age 1
year.23 These factors were much more influential than the use
and duration of DHCA.
Modifiable Factors
in the Preoperative
Patient: Avoidance of Hypoxia,
Ischemia, and ICU Morbidity
The treatment of complex CHD in neonates often requires
multiple therapies such as intubation and mechanical venti-
lation, prostaglandin infusion, invasive monitoring, frequent
laboratory assessment, and invasive procedures such as bal-
loon atrial septostomy. Although life saving, these interven-
tions carry inherent risks of injury to the CNS. Prophylactic
intubation of patients on prostaglandin infusion may result in
hypotension due to effects of positive-pressure ventilation
and sedation. Also, excessive ventilation and high-inspired
concentrations of oxygen may reduce systemic oxygen deliv-
ery in patients with left to right shunts and single-ventricle
physiology. A reduction in systemic blood flow may be espe-
cially deleterious to neonates with critical CHD, because
these patients are hypoxemic and have been shown to have
reduced cerebral blood flow preoperatively.24 In a study by
Licht and coworkers, newborn infants with CHD were found
to have diminished cerebral blood flow (on average 40% of
what has been reported for newborns without CHD).24 In the
25 patients studied, cerebral blood flow was similar across
cardiac diagnoses and was not associated with the presence
or absence of a patent ductus arteriosus. With inspired 3%
CO2 and controlled mechanical ventilation, cerebral blood
flow doubled from baseline, demonstrating preservation of
the cerebral vascular response to CO2. Lastly, those neonates
with PVL had the lowest cerebral blood flow values in this
study.
In those patients with single-ventricle physiology with an
unbalanced circulation and inadequate systemic blood flow,
inspired CO2 may be used to improve systemic and cerebral
oxygen delivery if surgical palliation must be delayed. Tab-
butt and coworkers have demonstrated that hypercapnea and
hypoxia both lower the pulmonary-to-systemic blood flow
ratio, but oxygen delivery is unchanged with hypoxia (addi-
tion of inspired nitrogen to the inspired gas) and improves
with hypercapnea (addition of carbon dioxide to the inspired
gas).25 This same group also demonstrated an improvement
in cerebral oxygen saturations with inspired 3% CO2 com-
Neonates undergoing cardiac surgery
pared with hypoxic gas mixtures.26 In an effort to optimize
cerebral oxygen delivery preoperatively, some centers advo-
cate monitoring with near infrared spectroscopy (NIRS) of
cerebral oxyhemoglobin saturation in patients at high risk,
such as those with hypoplastic left heart syndrome.27 The
routine use of NIRS to guide therapy is controversial and will
be discussed more fully below.
Lastly, in patients with intracardiac right to left shunting,
the potential for thromboembolic complications from air,
thrombus, or particulate matter associated with lines, medi-
cation administration, or procedures exists. This issue was
recently highlighted by McQuillen and coworkers who re-
ported balloon atrial septostomy as a risk factor for focal
brain lesions identified on preoperative MRI in patients with
transposition of the great arteries.28 The issue of CNS injury
reported in this group of patients is likely multifactorial be-
cause 40% of the patients without neurologic injury also had
a septostomy; the patients who received a septostomy were
more hypoxemic; and the use of heparin was not specified.
Operative Modifiable Factors
The adverse effects of cardiopulmonary bypass (CPB) may be
greater in infants compared with larger children or adults
given their immaturity in organ function and tissues as well
as the size of the CPB circuit relative to their body size.29
However, a significant amount of research has been con-
ducted in the area of intraoperative prevention of neurologic
injury. With ongoing changes in technology and new thera-
pies, the conduct of CPB and other support techniques have
been actively under investigation. Many of these research
efforts have focused on the modifiable risk factors given in
Table 1. Several of these factors will be discussed below.
Acid-Base Management
The theoretical benefit of ␣-stat versus pH-stat blood gas
management during hypothermic CPB has been a topic of
great debate. Although the pH-stat strategy may not be opti-
mal for adults in whom the principal risk for brain injury is
microembolism, this risk is thought to be lower in infants
because of the lack of atherosclerotic disease. With pH-stat
management, the addition of CO2 to the inspired gas mixture
during cooling on CPB increases cerebral blood flow and may
improve cerebral tissue oxygenation and outcomes.
Animal models have demonstrated reduced neuropatho-
Table 1 Central Nervous System Injury and Potential Modifi-
able Intraoperative Factors
Air or particulate embolus
Rate and depth of core cooling (if utilized)
Deep hypothermic circulatory arrest (if utilized)
Reperfusion injury and inflammation
Rate of core rewarming/hyperthermia
Hyperglycemia
Hyperoxia
pH management during cardiopulmonary bypass
Hematocrit management during cardiopulmonary bypass
271
logic damage, better short-term neurologic function, and bet-
ter tissue oxygenation with the use of a pH-stat strategy.30,31
In children, Nagy and coworkers compared 2 groups of ne-
onates and older children before and after a change in pH
management strategy from ␣-stat to pH-stat.32 They found
that peak troponin levels were lower using the pH-stat strat-
egy in those patients with pulmonary hypertension, and in
those patients who required inotropic support in the operat-
ing room or who underwent DHCA. Additionally, length of
ICU stay and duration of mechanical ventilation were shorter
in the pH-stat group.
The controversial issue of pH management during CPB has
been addressed in a large study from Boston Children’s Hos-
pital. In this study, infants less than 9 months of age were
randomized to ␣-stat versus pH-stat during deep hypother-
mic CPB with excellent long-term follow-up.5,33 Neurodevel-
opmental outcomes were evaluated in infants undergoing
biventricular repair for a variety of cardiac defects at less than
9 months of age.
The short-term benefits identified with the pH-stat strat-
egy included a trend toward less postoperative morbidity and
shorter recovery time to first electroencephalographic activ-
ity. In patients with transposition of the great arteries, there
was a shorter duration of intubation and ICU stay.33 How-
ever, the use of either the ␣-stat or pH-stat strategies was not
consistently related to either improved or impaired neurode-
velopmental outcomes at 2- and 4-year follow-up.5 On the
Bayley Scales of Infant Development, there was no effect of
treatment assignment on the Psychomotor Development In-
dex. The Index of Mental Developmental, in contrast, varied
significantly depending on the underlying anatomical diag-
nosis. For patients with transposition of the great vessels and
tetralogy of Fallot, use of the pH-stat strategy resulted in a non-
significant, but slightly higher mental developmental index
score. However, in patients with a ventricular septal defect,
the treatment effect was opposite and significant. Cardiac
diagnosis was found to be significantly associated with out-
comes. Both scores of the Bayley examinations were signifi-
cantly higher in the patients with transposition of the great
arteries compared with the other cardiac defects. Despite the
equivocal short-term follow-up data, many centers are cur-
rently using pH-stat management during core cooling in all
neonates and infants.
Although performed in children older than 1 year of age, a
study by Sakamoto and coworkers assessed the impact of pH
management in patients with aortopulmonary collaterals.34
In the short term, the pH-stat strategy resulted in better ce-
rebral oxygenation, decreased systemic pulmonary collateral
circulation, and lower lactate level during hypothermic CPB.
The use of hyperoxia with pH-stat management during hy-
pothermic CPB has also been reported to reduce acid pro-
duction in neonates and infants after DHCA compared with
normoxia and ␣-stat management.35 No immediate postop-
erative data or longer-term outcomes are available regarding
the benefits of this technique.
Further research in this area is necessary to investigate the
long-term neurological outcomes and the effect of the poten-
tial patient-related modifiers described above.
272
Hemodilution
Hemodilution has been used during CPB to decrease homol-
ogous blood use and has been thought to improve microcir-
culatory flow by reducing blood viscosity. However, hemodi-
lution also reduces perfusion pressure, increases cerebral
blood flow, thereby potentially increasing the microembolic
load to the brain, and reduces the oxygen-carrying capacity
of blood.36 Using an animal model, Shin’oka and coworkers
found that extreme hemodilution to a hematocrit less than
10% resulted in inadequate oxygen delivery, but, with higher
hematocrit levels of 30%, there was improved cerebral recov-
ery after DHCA.37 Jonas and coworkers confirmed these find-
ings in a randomized trial with 2 hemodilution protocols
(20% vs 30% hematocrit) in infants younger than 9 months
of age.38 Developmental outcomes were assessed at follow-up
at 1 year of age with the Bayley Scales of Infant Development.
In the short term, the lower-hematocrit group had lower
nadirs of cardiac index, higher serum lactate levels 1 hour
after CPB, and a greater increase in total body water on the
first postoperative day. At 1 year of age, mental development
index scores were similar, but psychomotor development
index scores were significantly lower in the lower hematocrit
group. Also, infants in the lower hematocrit group had psy-
chomotor development scores that were 2 standard devia-
tions below the mean.
Deep Hypothermic Circulatory Arrest
The potentially deleterious effects of prolonged DHCA in
infants and neonates are well described. In general, it is
agreed that very prolonged periods of uninterrupted DHCA
may have adverse neurological outcomes. However, there is
considerable disagreement if a “safe” period of DHCA exists
and whether patient-specific, procedure-specific, or postop-
erative management strategies may attenuate or promote
CNS damage from DHCA. There are reports of detrimental
effects of DHCA on a variety of outcomes regarding the
CNS21,39-42, whereas others report either an inconsistent ef-
fect or no effect.43-45 Three issues have become clear over
time: 1) the effects of short durations of DHCA are inconsis-
tently related to adverse outcomes, 2) the effect of DHCA is
not a linear phenomenon, and 3) the effects are most likely
modified by other patient-related, preoperative, and postop-
erative factors.3,46 Because many studies suggest a negative
effect, some surgeons have developed innovative and chal-
lenging strategies to provide continuous cerebral perfusion
during complex reconstruction of the aortic arch or intracar-
diac repair to avoid or minimize the use of DHCA. It should
be emphasized that by avoiding DHCA, the duration of CPB
is necessarily lengthened, and longer durations of CPB have
been shown to adversely effect both short-term and long-
term outcomes.47,48 The relative risks and benefits of longer
CPB versus less (or no) DHCA remain a subject of continued
controversy.
Because many studies investigating DHCA have only
short-term developmental follow-up, it may be premature to
change practice based on these results because developmen-
tal studies performed in infants have suggested limited pre-
T.E. Dominguez, G. Wernovsky, and J.W. Gaynor
dictive validity for long-term outcomes.46,49 An illustration of
this point is seen in a series of articles from the Boston Cir-
culatory Arrest Study. In this cohort of children, 171 neo-
nates with transposition of the great arteries who underwent
an arterial switch operation were randomly assigned an in-
traoperative support strategy of predominantly DHCA or
low-flow CPB. The initial reports suggested that the group as
a whole was performing below expectations in many areas of
evaluation with a lower-than-expected mental intelligence
quotient of 93 at age 4 years. Although the mental intelli-
gence quotient at 4 years was similar in both groups, worse
outcomes were seen in the DHCA group in terms of postop-
erative seizures,50 motor skills at 1 year of age,6 as well as
behavior, speech, and language at age 4 years.3,51 Given these
findings and other reports, many centers began avoiding
even short periods of DHCA. The most recent follow-up for
this group at 8 years of age demonstrates that the intelligence
quotient scores for the cohort are now closer to normal, at 98
versus the population mean of 100.2 Although no differences
were identified in terms of intelligence measures, both strat-
egies were associated with neurodevelopmental abnormali-
ties. Deficits were seen in visual-spatial and visual-memory
skills, as well as in components of executive functioning such
as working memory, hypothesis generation, sustained atten-
tion, and higher-order language skills. However, those as-
signed to DHCA scored worse on tests of motor and speech
function, whereas the patients submitted to low-flow CPB
demonstrated more impulsive responses and worse behavior
as rated by teachers. In comparison with children without
heart disease, parental reporting identified reported higher
frequencies of problems with attention, learning, and speech
in this cohort. More than one third of the population received
remedial school services, and 1 in 10 had repeated a grade.
Overall, the diagnosis of complex CHD and necessary sur-
gical treatments are correlated with later speech and language
difficulty, behavioral difficulties and execution planning in
childhood.2,2,46,52,53 However, these results may not be gen-
eralizable to other forms of congenital heart disease or even to
the present era given other improvements in perioperative
care. In addition, the study does not compare use of DHCA to
no DHCA because even the patients who received continu-
ous cardiopulmonary underwent a period of DHCA. How-
ever, the results highlight the importance of multiple factors
that influence developmental outcome at school age in addition
to intraoperative interventions. In the Boston Circulatory Arrest
Study, DHCA explained only 0.3% of the variation in neurode-
velopmental scores at 8 years of age, whereas in another study,
DHCA explained only 1% of the variation.23 Studies assessing
the benefits of different support are continuing.
Regional Cerebral Perfusion
In efforts to study these newer strategies, 2 recent studies
have evaluated the technique of regional cerebral perfusion.
In 1 nonrandomized study from Boston, Visconti and co-
workers followed up 29 infants who underwent a stage I
palliation, 9 of whom received regional cerebral perfusion at
30 to 40 mL/kg/min.54 The authors reported no difference in
Neonates undergoing cardiac surgery
mental or psychomotor developmental indices at 1 year of
age between the regional cerebral perfusion group and those
who received DHCA as a primary strategy. The group from
the University of Michigan has recently published a larger,
randomized trial of DHCA ⫾ regional cerebral perfusion at
20 mL/kg/min in patients with functional single ventricle,
with long-term studies that are in the planning stages.55 A
total of 77 patients were enrolled with similar survival to
hospital discharge (88%) and at 1-year follow-up (75%). No
significant difference was seen in either the psychomotor
development index or mental development index scores be-
tween the 2 groups at any time, although the scores tended to
be lower in the regional cerebral perfusion group.
Neuromonitoring
Numerous intraoperative techniques have been used for
monitoring the brain to prevent secondary brain injury due
to hypoxia, ischemia, emboli, and electrophysiological de-
rangements. These have primarily included the following 3
modalities in isolation or combination: NIRS to provide a
measure of venous-weighted, tissue oxyhemoglobin saturation;
transcranial Doppler to measure arterial flow and resistance;
and electroencephalography (EEG) to assess perfusion-related
changes in cortical activity.27 Transcranial Doppler has been
primarily used for research purposes in infants and allows de-
tection of venous or arterial flow abnormalities and the detection
of microemboli.56 EEG monitoring allows detection of ischemia
or recognition of an adequate decrease in cerebral metabolic
activity during hypothermia before DHCA. However, cerebral
NIRS is the most widely used of the 3 modalities, but its use is
highly center specific.27,57-60
Centers with excellent outcomes may report “never” or
“always” using NIRS during the perioperative care of neo-
nates with CHD. Given that cerebral NIRS values have been
shown to correlate with jugular venous bulb saturations, the
interest in using NIRS as a way to noninvasively assess oxy-
gen delivery to the brain is sensible.61 Austin and coworkers
have reported the value of monitoring cerebral NIRS intraop-
eratively. The authors noted that cerebral oxyhemoglobin
desaturation accounted for the majority of neurophysiologic
abnormalities during multimodality neuromonitoring using
NIRS, transcranial Doppler, and EEG.57 Over two thirds of
the patients in their study had detectable neuromonitoring
events, and a similar percentage of these events required
intervention by the perfusionist, surgeon, or anesthesiologist.
Surgical interventions, such as cannula repositioning, were
performed in one quarter of the events, and the perfusionist
intervened in more than one half of the events. The incidence
of postoperative neurological sequelae was also higher in
those patients who had untreated events. During some spe-
cific surgical techniques, such as regional cerebral perfusion,
NIRS monitoring has also been reported to be of benefit in
guiding intraoperative care.55,62 However, no studies have yet
shown that use of NIRS in the postoperative period is asso-
ciated with improved neurodevelopmental outcomes.
273
Modifiable Factors in
the Postoperative Period
Although a neonate’s cardiovascular physiology may be im-
proved through surgical palliation or repair, after separation
from CPB the neonatal brain is considerably vulnerable to
injury. For example, preoperative PVL is seen in approxi-
mately 20% of neonates on MRI; more than 50% have this
finding postoperatively, which suggests neurologic intraop-
erative and/or early postoperative insults.17,60Targeted man-
agement to prevent further injury includes improving cardiac
output, as well as preventing hypoxia, hyperthermia, hypo-
tension, and excessive hypocarbia, and reducing emboliza-
tion risks.
Low Cardiac Output Syndrome
The occurrence and time course of low cardiac output syn-
drome (LCOS) are well known. LCOS occurs in 20% to 30%
of infants after cardiac surgery, and markers of LCOS have
been associated with mortality.47,63-67 Although LCOS has
not been found to be associated with abnormal neurologic
testing at follow-up,63 other hemodynamic variables have
been found to be important. In a study by Galli and cowork-
ers, in which they looked at risk factors for PVL after infant
cardiac surgery, a lower minimum diastolic blood pressure
and neonatal age were independent risk factors for PVL.18 In
those patients with a minimum diastolic blood pressure of
ⱕ35 mm Hg, PVL was seen in at least 45%. Although not an
independent risk factor in neonates, more than 50% of the
patients with a partial pressure of oxygen ⱕ40 mm Hg had
evidence of PVL. To minimize the risk of the deleterious
effects of LCOS and prevent secondary neurologic insults,
Ungerleider and colleagues have suggested the routine use of
a ventricular assist device postoperatively in patients at high
risk.68 Neurodevelopmental follow-up of this cohort is ongo-
ing (R. Ungerleider, personal communication, 2007).
Cerebral Autoregulation
After DHCA, there is a period of time where the cerebrovas-
cular resistance remains high,62,69 and cerebral metabolism is
maintained through high oxygen and glucose extraction. Ad-
ditional stress during this interval could result in cerebral
hypoxic-ischemic injury.69 In addition, autoregulation of ce-
rebral blood flow may be impaired after CPB with or without
DHCA,70-72 further increasing this risk. With the use of cere-
bral NIRS and transcranial Doppler, Bassan and coworkers,
in a recent study, demonstrated abnormal cerebrovascular
autoregulation in one seventh of the neonates in the ICU after
open-heart surgery.73 Pressure-passive cerebral blood flow
was more likely to be seen in conditions of fluctuating mean
arterial pressures and partial pressure of carbon dioxide ⱖ40
mm Hg.73 Because of these findings, there is some concern
that hypercarbia may reduce autoregulation and render the
infant more vulnerable to cerebral injury during periods of
blood pressure instability. In contrast, at centers that com-
monly use cerebral NIRS, hypercarbia has been suggested as
274
a way to improve cerebral oxygen delivery after CPB in con-
ditions of elevated cerebrovascular resistance.62
Surrogate Markers of Cardiac Output
Several studies have demonstrated an association between
monitoring markers of oxygen delivery (mixed venous satu-
ration and blood lactate) and mortality.65-67 However, the
association between neuromonitoring, subsequent interven-
tion, and the reduction of neurologic injury remains elusive.
In a group of patients with hypoplastic left heart syndrome,
Hoffman and coworkers performed neurodevelopmental
testing at a mean age of 4.5 years and evaluated risk factors
for adverse neurologic outcomes from perioperative data ac-
quired after stage I palliation. They found that 38% of the
patients in the cohort had abnormal outcomes, and, in this
group of patients, mixed venous saturations were lower than
those with normal outcomes. In addition, an increasing du-
ration of a mixed venous oxygen saturation of less than 40%
was a predictor of adverse neurodevelopmental outcome in
survivors.74 In addition to cerebral NIRS monitoring, post-
operative monitoring of regional cutaneous saturations with
NIRS is becoming increasingly popular. With regards to
making inferences about regional oxygen delivery to the
brain with cerebral NIRS postoperatively, there are limited
short-term data and no long-term data at this time. Given the
desire to improve outcomes in groups of patients at high risk,
several centers are routinely using cerebral and somatic NIRS
perioperatively.58,60,62,75 In a study of 22 infants with hypo-
plastic left heart syndrome, prolonged low postoperative ce-
rebral oximetry (⬍45% for ⬎180 minutes) was associated
with the development of new or worsened ischemia on post-
operative MRI.60
Seizures
Clinical seizures occur at a significantly lower frequency than
electroencephalographic seizures. Depending on the method
of detection, the reported incidence may be as high as 20%.
The occurrence of seizures is thought to multifactorial, with
seizures being more prevalent in neonates, in patients with
longer DHCA times (⬎40 minutes), and in patients with CNS
abnormalities.33,76-79 Perioperative seizures are thought to be
a marker for early CNS injury.77 In the Boston Circulatory
Arrest Study, seizures were associated with lower scores on
later developmental testing.3,4,6,79 More recent data have sug-
gested that the occurrence of seizures after neonatal cardiac
surgery is not associated with a worse developmental out-
come at 1 year of age.77 It is unknown if seizure treatment or
general improvements in care over time account for the dif-
ferences in outcome seen in the most recent study.
Hyperthermia
A large amount of evidence exists supporting the notion that
hyperthermia is detrimental after all types of brain injury.27,80
Animal models of DHCA suggest that even mild postischemic
hyperthermia after DHCA exacerbates functional and struc-
tural neuronal injury.81,82 Additionally, hyperthermia is com-
mon after periods of cerebral ischemia.80,83 In a study by
T.E. Dominguez, G. Wernovsky, and J.W. Gaynor
Cottrell and coworkers,84 the relationship between postoper-
ative temperature and neurodevelopmental outcomes was
assessed in patients at 1 and 4 years of age after infant cardiac
surgery. In this study, however, the authors did attempt to
control temperature during the postoperative period. No as-
sociation was identified between temperature and neurode-
velopmental outcomes; however, less than 0.5% of the tem-
peratures recorded were above 39.0°C, making the
assessment of a harmful effect difficult. Tabbutt and cowork-
ers found that the incidence of postoperative hyperthermia in
infants was relatively low with conventional measures, but a
peak in measured temperatures was seen at postoperative
hour 4 to 6.85 By tracking core temperature with an intracar-
diac thermister catheter, one half of the patients were identi-
fied to have postoperative hyperthermia. This study high-
lights the fact that during future trials that aim to assess the
effect of temperature on later neurodevelopmental outcome,
consideration must be given to the site of measurement, since
intracardiac temperatures were considerably higher than rec-
tal or axillary temperatures.
ICU Length of Stay
Reducing ICU morbidity may also improve long-term out-
comes, given that longer lengths of ICU stay have been re-
ported to be independently associated with lower verbal,
performance, and full-scale IQ scores in separate populations
of patients.86,87 In the study by Newburger and coworkers,
differences in IQ scores between the first and fourth quartiles
of ICU length of stay were on average 6 to 7 points different,
but no differences were seen between quartiles of hospital
length of stay. A multicenter study by Mahle and coworkers
sought to determine the influence of primary heart transplan-
tation versus stage I palliation on neurodevelopmental out-
comes at school age in patients with hypoplastic left heart
syndrome. In this study, longer ICU length of stay was asso-
ciated with lower verbal, performance, and full-scale IQ
scores, and there was no association between these scores
and surgical strategy.86,87 The mechanism for this finding is
unclear and likely multifactorial. Prolonged ICU stay may be
a marker for severity of illness or other morbidity. Postulated
etiologies include the influence of ICU therapies, such as
mechanical ventilation or inotropic therapy, adversely affect-
ing a disturbed cerebrovascular autoregulation; a more pro-
nounced inflammatory response after CPB causing neuro-
logic and end-organ dysfunction leading to a prolonged ICU
stay; and unrecognized neurohormonal or congenital CNS
abnormalities. Further investigations into these potential
mechanisms are warranted.
Hyperglycemia
An additional modifiable factor that has been identified in
critically ill patients undergoing cardiac surgery is hypergly-
cemia. In adults, hyperglycemia and impaired glucose con-
trol have been associated with worse outcomes after myocar-
dial infarction and acute coronary syndromes, stroke, and
postoperative wound infections, and it has recently been rec-
ognized as a problem in children.88 Less is currently known
Neonates undergoing cardiac surgery
about the impact of hyperglycemia after neonatal and infant
cardiac surgery. Data analysis from the Boston Circulatory
Arrest Study found no relationship between intraoperative
hyperglycemia and neurodevelopmental outcome after the
arterial switch operation.89 Interestingly, one study in infants
who underwent open heart surgery found postoperative hy-
perglycemia was associated with more end-organ dysfunc-
tion and mortality.90 However, this association was unad-
justed and likely a marker of severity of illness. A recent,
longer-term study in infants by Ballweg and coworkers did
not find any relationship between postoperative glucose lev-
els and neurodevelopmental scores at 1 year of age.91 In this
study, hyperglycemia was common with almost 90% of the
patients having a blood glucose ⬎200 mg/dL during the hos-
pitalization. With the adult data suggesting worse outcomes
with untreated hyperglycemia and critical illness, there is
temptation to treat postoperative hyperglycemia in infants.
Given that the most common neuropathologic finding after
neonatal cardiac surgery is injury to the periventricular white
matter,18 this may not be the appropriate intervention be-
cause there is evidence that hypoxic injury to developing glial
cells can be decreased by elevated glucose levels.92 Thus, it is
likely there are different effects of hyperglycemia on brain
injury between adults and children undergoing cardiac sur-
gery. These maturational differences in glucose metabolism
and susceptibility to hypoxic injury deserve further study.
Conclusion
Despite the improvements in mortality over time, there is an
increasing body of literature drawing attention to the neuro-
logic morbidity in children who have undergone surgical
repair or palliation of their congenital heart disease. Many of
the risk factors such as cardiac diagnosis, abnormalities in
fetal circulation, length of ICU stay, hypoxemia, method of
CPB support, and reoperations are all interrelated, and there
is great difficultly identifying which variables, if any, explain
the outcomes. This has been particularly true in studies ex-
amining the CNS effects of CPB. Before major changes in
intraoperative support strategies are made, long-term fol-
low-up is necessary, given the poor predictive validity of the
infant examination compared with long-term assessments.
Future studies should address ways to reduce the widely
prevalent neurodevelopmental issues that affect quality of life
in this patient population.
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