ARTICLE
Neurodevelopmental Outcomes After Staged
Palliation for Hypoplastic Left Heart Syndrome
Sarah Tabbutt, MD, PhDa,b, Alex S. Nord, BAc, Gail P. Jarvik, MD, PhDc, Judy Bernbaum, MDd, Gil Wernovsky, MDa,b, Marsha Gerdes, PhDe, Elaine Zackai, MDf, Robert R. Clancy, MDg, Susan C. Nicolson, MDb, Thomas L. Spray, MDh, J. William Gaynor, MDh
Department of Pediatrics, Divisions ofaCardiology,dGeneral Pediatrics,ePsychology,fGenetics, andgNeurology,bDepartment of Anesthesia and Critical Care Medicine,
andhDepartment of Surgery, Division of Cardiothoracic Surgery, Children’s Hospital of Philadelphia and University of Pennsylvania School of Medicine, Philadelphia,
Pennsylvania;cDepartment of Medicine, Division of Medical Genetics, University of Washington, Seattle, Washington
The authors have indicated they have no financial relationships relevant to this article to disclose.
ABSTRACT
OBJECTIVE.The goal was to determine the relative effects of underlying genetic factors and current management strategies on neurodevelopmental disabilities among one-year old survivors of palliation for hypoplastic left heart syndrome.
METHODS.Children who underwent staged reconstruction for hypoplastic left heart syndrome and variants were assessed at 1 year of age by using a neuromuscular examination and the Bayley Scales of Infant Development II, which provide the Mental Development Index and the Psychomotor Development Index. The effects of perioperative, operative, and genetic variables on developmental scores were eval-uated.
RESULTS.The median birth weight was 3.3 kg (range: 2.1– 4.5 kg). Eight-three patients (94%) underwent multiple operations with cardiopulmonary bypass during the first year of life (median: 2 operations). Seven patients (8%) required extracorporeal membrane oxygenation. Twenty-five patients (28%) had a confirmed or suspected genetic syndrome. At 1 year of age, the neuromuscular examination results were abnormal or suspect for 57 patients (65%). The median Mental Development Index
score was 90, and 10 patients (11%) had scores of⬍70 (2 SDs below the general
population mean). The median Psychomotor Development Index score was 73, and
42 patients (48%) had scores of⬍70. In multivariate analyses, younger gestational
age, the presence of a genetic syndrome, and the need for preoperative intubation had significant negative effects on neurodevelopmental outcomes. No association was found with operative factors, including duration of deep hypothermic circula-tory arrest.
CONCLUSIONS.At 1 year of age, there was a significant incidence of neurodevelopmental disabilities in children with hypoplastic left heart syndrome and variants; motor scores were particularly concerning. Many children had suspected or confirmed genetic syndromes, which negatively affected neurodevelopmental outcomes. Sur-gical variables did not affect neurologic outcomes.
S
URVIVAL RATES FORpatients undergoing stage 1 reconstruction (S1R) (the Norwood procedure) for hypoplasticleft heart syndrome (HLHS) and variants have improved dramatically over the past decade.1–4Prenatal diagnosis
and improved surgical strategies and perioperative care are likely important contributors. Early reports revealed a concerning incidence of significant developmental problems in patients. More-recent studies of neurodevelopmental outcomes in patients with HLHS and variants demonstrated improving outcomes but continued evidence of
developmental delays, compared with population normative values (Mahle et al5: 4 centers,n⫽48; mean age: 12
years; mean full-scale IQ: 86; Mahle et al6: single center,n⫽28; mean age: 9 years; mean full-scale IQ: 86; Goldberg
et al7: single center,n⫽51; mean age: 4.8 years; mean full-scale IQ: 93; Visconti et al8: single center,n⫽29; age:
1 year; Mental Development Index [MDI]: 88; Psychomotor Development Index [PDI]: 75). However, patient
www.pediatrics.org/cgi/doi/10.1542/ peds.2007-1282
doi:10.1542/peds.2007-1282
Key Words
developmental outcomes, hypoplastic left heart syndrome
Abbreviations
HLHS— hypoplastic left heart syndrome DHCA— deep hypothermic circulatory arrest
CPB— cardiopulmonary bypass MDI—Mental Development Index PDI—Psychomotor Development Index ECMO— extracorporeal membrane oxygenation
LOS—length of stay S1R—stage 1 reconstruction PVL—periventricular leukomalacia mBTS—modified Blalock-Taussig shunt
Accepted for publication Aug 10, 2007
Address correspondence to Sarah Tabbutt, MD, PhD, Cardiac Intensive Care Unit, Cardiac Center, Children’s Hospital of Philadelphia, 34th Street and Civic Center Boulevard, Philadelphia, PA 19104. E-mail: tabbutt@email. chop.edu
numbers in those series were small, and comprehensive follow-up evaluation often is difficult. Neurologic com-promise may begin in utero because of diminished cerebral blood flow, which has been shown to be associated with
preoperative periventricular leukomalacia (PVL).9
Micro-cephaly is more frequent in patients with HLHS.10,11
Preop-erative brain MRI demonstrates an increased frequency of
ischemic lesions.12,13 Confirmed or suspected genetic
syn-dromes are frequent in patients with HLHS. Because early surgical palliation is necessary for survival, identifying spe-cific patient-related and preoperative risk factors for wors-ened neurodevelopmental outcomes can be difficult.
The primary aim of this study was to report the results of neurodevelopmental testing at 1 year of age in a large
cohort of patients (n⫽88) who underwent staged
pal-liation for HLHS and variants. The secondary aim was to identify risk factors for compromised outcomes.
METHODS
Patient Population
This study is a secondary analysis of a prospective trial assessing the effects of a genetic polymorphism on
neu-rodevelopmental outcomes.14Informed consent was
ob-tained from the parents or legal guardians. The study was approved by our institutional review board.
Patients born with HLHS or variants between April 1998 and March 2003 were eligible. Entry criteria in-cluded all patients with single-ventricle physiologic fea-tures and systemic outflow obstruction undergoing staged palliation. Exclusion criteria before surgical inter-vention included (1) multiple congenital anomalies, (2) recognizable chromosomal or phenotypic syndrome at birth (patients with 22q11 deletion were included in the study), and (3) non–English language primarily spoken in the home. Patients who were diagnosed as having chromosomal or phenotypic syndromes after their initial operation or at the time of 1-year neurodevelopmental testing were included. Anatomic diagnoses included (1) HLHS with a combination of mitral stenosis or atresia and aortic stenosis or atresia and (2) variants including single ventricles (right or left) with systemic outflow obstruction.
Five surgeons performed S1R during the study pe-riod. Patients were cared for by a dedicated group of cardiac anesthesiologists and recovered in a dedicated cardiac ICU. Surgical strategies included (1) deep hypo-thermic circulatory arrest (DHCA) for all patients with a
goal nasopharyngeal temperature of 18°C, (2) ␣-stat
blood gas management, and (3) use of modified ultrafil-tration. The right ventricle-pulmonary artery conduit was introduced in March 2002. Before that time, the modified Blalock-Taussig shunt (mBTS) was the shunt of preference, with a central shunt being used rarely if there was inadequate pulmonary blood flow with the mBTS. After March 2002, the choice of shunt was at the discretion of the surgeon, with 70% of shunts being the mBTS. Routine postoperative infusions were
fenta-nyl (1–2g/kg per hour), pancuronium (the first
post-operative night; 0.05– 0.1 mg/kg per hour), dopamine
(3–5 g/kg per minute), and milrinone (0.25–1 g/kg
per minute). Delayed sternal closure was not routine, and extracorporeal membrane oxygenation (ECMO) was reserved for failure to separate from cardiopulmo-nary bypass (CPB), cardiac arrest, or near-arrest. Surgi-cal data are described for the S1R and for all operations requiring CPB during the first year of life. Length of stay (LOS) was determined by the time of discharge or trans-fer. Data included in the risk factor analyses are listed in the Appendix.
Neurodevelopmental Examination
The neurodevelopmental evaluation was described
pre-viously.14Children were evaluated at 1 year (⫾2 weeks;
adjusted for prematurity), by using the Bayley Scales of Infant Development II. These scales include the PDI, which assesses gross motor and fine motor skills, and the MDI, which assesses memory, problem-solving, number concepts, generalization, vocalization, language, and so-cial skills. The mean score for both tests is 100, with a SD
of 15; the lowest assigned score was 50. A score of⬍70
is⬎2 SDs below the mean. The neuromuscular
exami-nation results (active tone, passive tone, reflexes, gross motor abilities, and fine motor abilities) were classified as normal if no abnormalities affecting motor skills were noted, suspect if a moderate degree of abnormality was noted, and abnormal if functionally significant abnor-malities of tone, reflexes, or motor skills were present. At the 1-year testing, a genetic specialist evaluated every patient. Chromosomal and microdeletion testing was performed when possible. The genetic evaluation results were classified as normal, suspect (evidence of a genetic syndrome was present but chromosomal confirmation was not possible), or abnormal (a specific genetic diag-nosis was confirmed). The genetic specialist was blinded with respect to the results of the developmental testing. The familial socioeconomic status was assessed through parental report, by using the Hollingshead scale, during the visit at 1 year of age. Ethnicity was classified as Asian/Pacific Islander, black, Hispanic, Native American, other, or white, as reported by the parent.
Statistical Analyses
Continuous variables were expressed as mean⫾SD or
median (with range). Dichotomous and categorical vari-ables were presented as proportions. To identify risk factors for negative neurodevelopmental outcomes, the variables listed in the Appendix were tested in a univar-iate manner for association with MDI, PDI, and neuro-muscular examination results by using linear and logistic regression analyses. Categorical data were coded as dummy variables for the regression analyses, with the most common category being used as the reference
group, and the overall modelPvalues are reported. After
univariate analyses, variables associated with an
out-come withP⬍.1 in the univariate models were included
regres-sion models, with the most parsimonious set of signifi-cant predictors being reported in the final model for each outcome. All analyses used SPSS 10.0 for Windows (SPSS, Chicago, IL) and the R statistical software envi-ronment (R Project for Statistical Computing, Vuebba, Austria).
RESULTS
Between April 1998 and March 2003, 161 patients un-dergoing S1R for HLHS and variants were enrolled, with a hospital survival rate of 148 (92%). There were 15 deaths (9%) after hospital discharge and before 1 year of
age. Of the 133 survivors, 88 (66%) returned for 1-year neurodevelopmental evaluations and constitute the study population. Anatomic subtypes of the study group are shown in Table 1. The preoperative and intraopera-tive statistics comparing the study group with (1) the nonsurvivors and (2) the enrolled patients who survived to 1 year but did not return are shown in Table 2. Delayed sternal closure was used for 38 patients (23%), and ECMO was needed for 13 patients (8%). There was no difference in the distance of travel between the pa-tients who died (median: 102 miles; range: 1.8 –1401 miles) and the patients who returned for 1-year testing
(median: 83 miles; range: 2.9 –1041 miles; P ⫽ .14).
However, the travel distance was greater for surviving patients who did not return for testing (median: 124
miles; range: 2.9 – 4910 miles; P ⫽ .012). No research
funds were available to support travel.
The study subjects who underwent 1-year neurode-velopmental testing were primarily of the white race and had a significantly older gestational age, higher birth weight, and larger birth head circumference than did those who did not return or did not survive. In addition, the study population had a shorter postoperative LOS, compared with survivors who did not return for testing. However, all survivors who had been supported with
ECMO (n⫽7) returned for testing.
At the time of neurodevelopmental testing, the me-dian age was 1.01 years (range: 0.95–1.08 years), the
TABLE 1 HLHS and Variant Anatomic Subtypes in the Study Population
n
Total Aortic Atresia
HLHS (mitral stenosis) 31 4
HLHS (mitral atresia) 33 31
Unbalanced AVC 3 0
Single LV with arch hypoplasia (includes DILV, TA, and TGA)
11 0
Mitral stenosis or atresia with VSD (includes DORV) 8 5
Other single RV 2 0
AVC indicates atrioventricular canal; DILV, double-inlet left ventricle; DORV, double-outlet right ventricle; LV, left ventricle; RV, right ventricle; TA, tricuspid atresia; TGA, transposition of the great arteries; VSD, ventricular septal defect.
TABLE 2 Preoperative and Operative Statistics Comparing the Study Group With the Enrolled Surviving Patients Who Did Not Return for Neurodevelopmental Testing and With the Enrolled Patients Who Did Not Survive to 1 Year
Enrolled Patients Who Returned for Testing (n⫽88)
Enrolled Patients Who Did Not Return (n⫽45)
Enrolled Patients Who Did Not Survive (n⫽28)
Parameter P Parameter P
Baseline characteristics
Female gender,n(%) 35 (40) 20 (44) .72 10 (36) .91
Race,n(%) .002a .001a
White 73 (83) 25 (56) 12 (43)
Nonwhite 15 (17) 20 (44) ⬍.001b 16 (57) ⬍.001b
Black 8 (9) 17 (38) 10 (36)
Hispanic 2 (2) 1 (2) 2 (7)
Other 5 (6) 2 (4) 4 (14)
Gestational age, median (range), wk 39 (34–42) 38 (31–40) .007 38 (32–40) .002 Birth weight, median (range), kg 3.3 (2.1–4.5) 3.1 (1.3–4.6) .005 2.7 (1.6–4.1) ⬍.001 Head circumference, median (range), cm 34.5 (29.5–41) 34 (28–37.5) .014 32.8 (27.5–36.5) .003
Preoperative intubation,n(%) 40 (45) 16 (36) .73 11 (39)
Diagnosis of HLHS,n(%) 64 (72) 30 (67) .99 23 (82) .71
S1R operative data
Age at surgery, median (range), d 3 (0–25) 3 (1–69) .24 4 (1–99) .61
DHCA, median (range), min 42 (5–92) 42 (1–97) .45 51 (20–90) .09
CPB, median (range), min 44 (37–175) 42 (34–120) .66 51 (37–166) .13
Delayed sternal closure,n(%) 19 (22) 8 (18) .8 11 (39) .1
ECMO/VAD,n(%) 7 (8) 0 ⬍.001 6 (21) .1
Hospital LOS, median (range), d 14 (8–96) 15 (7–119) .26 26 (2–216) .01
Total operative data
No. of operations (with CPB), median (range) 2 (1–4) 2 (1–4) .88
DHCA, median (range), min 65 (5–127) 63 (1–150) .88
CPB, median (range), min 83 (38–429) 82 (38–307) .7
VAD indicates ventricular assist device.Pvalues are for comparisons with enrolled patients who returned for testing. aPfor2test for race.
median weight was 8.5 kg (range: 6.1–11 kg), and the median head circumference was 45.8 cm (range: 40.5– 49 cm). At the time of 1-year follow-up evalua-tion, a genetic syndrome or chromosomal abnormality was found or suspected for 31 patients (35%). Chromo-somal abnormalities in those tested included balanced translocation 13:14 (1 case), X-linked immunodefi-ciency (1 case), 11p deletion (1 case), and partial Turner syndrome (1 case). Diagnosed syndromes included Ka-buki syndrome (1 case) and syndromic but undefined (3 cases). Patients with definite or suspected genetic con-ditions were not significantly different with respect to birth weight, birth head circumference, gestational age, preoperative intubation, use of ECMO, use of delayed sternal closure, and length of DHCA or CPB. They did, however, have a longer postoperative LOS after their
S1R (22⫾19 vs 13⫾9.5 days;P⫽.02).
Abnormal or suspect neuromuscular examination re-sults were found for 56 patients (64%), with no
signif-icant difference between those without genetic
syn-dromes (n⫽35; 59%) and those with known (n ⫽6;
100%; P ⫽.08) or suspected (n ⫽ 13; 72%;P ⫽.41)
genetic syndromes. In multivariate analyses, patients with a longer postoperative LOS for the S1R were more likely to have abnormal or suspect neuromuscular
ex-amination results (⫽0.091; 95% confidence interval:
0.02– 0.21; SE: 0.046;P⫽.05), and patients of black race
were less likely to have abnormal or suspect
neuromus-cular examination results (⫽ ⫺2.57; 95% confidence
interval:⫺5.21 to⫺0.73; SE: 1.07; P⫽.017).
For the overall study group, the median MDI score was 90 (range: 50 –129), and 10 (11%) had scores of
⬍70 (2 SDs below the mean for the general
popula-tion). The median PDI score was 73 (range: 50 –117),
and 42 (48%) had scores of ⬍70 (Fig 1). Significant
univariate and multivariate risk factors for lower scores are shown in Table 3. Multivariate risk factors for lower MDI score were younger gestational age
(P⫽.011), abnormal (P⫽.001) or suspect (P⫽.011)
genetic evaluation results at 1 year of age,
preopera-tive endotracheal intubation (P⫽.002), and younger
gestational age (P⫽.011). Multivariate risk factors for
lower PDI score were abnormal (P⫽.005) or suspect
(P⫽ .011) genetic evaluation results at 1 year of age
and preoperative intubation (0.002) (Fig 2).
Patients were evenly divided between earlier (April
1998 through January 2001;n⫽44) and later (January
2001 through March 2003; n⫽44) eras of S1R. There
were no significant differences between the eras of sur-gery in the perioperative and surgical parameters mea-sured, with the following exceptions: (1) lower
hemat-ocrit levels on CPB in the earlier era (26 ⫾ 2.8% vs
0 5 10 15 20 25 30 35
40 MDI
PDI
50–59 60–69 70–79 80–89 90–99 100–109 >110
FIGURE 1
Frequency of PDI and MDI scores among all patients tested at 1 year. The mean score for normal children is 100 (dashed line); a score of 70 is 2 SDs below the mean.
TABLE 3 Statistically Significant Risk Factors Affecting 1-Year Neurodevelopmental Testing Results Univariate Analysis Multivariate Analysis
 SE P  95% CI SE P
PDI
Abnormal genetic testing result ⫺21.5 6.7 .002 ⫺18.7 ⫺31.7 to⫺5.8 6.5 .005 Suspected genetic abnormality ⫺10.5 4.5 .022 ⫺10 ⫺18.8 to⫺1.2 4.4 .027
Gestational age 3.0 1.2 .015
Preoperative intubation ⫺8.9 3.7 .018 ⫺8 ⫺15.1 to⫺8.9 3.6 .028 Postoperative LOS (S1R) ⫺0.28 0.13 .041
LOS (S1R) ⫺0.27 0.13 .045
Length of CPB (S1R) ⫺5.4 2.6 .043 Delayed sternal closure ⫺9.0 4.5 .05 MDI
Abnormal genetic testing result ⫺23.7 5.8 ⬍.001 ⫺18.7 ⫺29.1 to⫺8.4 5.2 .001 Preoperative intubation ⫺12.1 3.2 ⬍.001 ⫺9.1 ⫺14.9 to⫺3.4 2.9 .002
Gestational age 3.7 1.1 .001 2.4 0.57 to 4.3 .93 .011
Birth weight 0.008 0.003 .001
Postoperative LOS (S1R) ⫺0.31 0.12 .011
LOS (S1R) ⫺0.31 0.12 .011
Suspected genetic abnormality ⫺10 3.9 .013 ⫺9.3 ⫺16.5 to⫺2.2 3.6 .011 Use of ECMO or VAD ⫺17.8 6.1 .018
Weight at testing (1 y) 5.7 2.7 .039 Head circumference at testing 2.1 1.0 .048 Birth head circumference 1.9 0.90 .049
Era of surgery 6.2 3.4 .068
30.7 ⫾ 3.3%; P ⬍ .0001), (2) more-frequent use of preoperative intubation in the earlier era (26 of 44
pa-tients [59%] vs 14 of 44 papa-tients [32%];P⫽.018), (3)
longer preoperative LOS in the earlier era (2.9 ⫾ 1.7
days vs 2.0⫾1.2 days;P⫽.004), and (4) more-frequent
diagnosis of HLHS in the later era (29 of 44 patients
[66%] vs 39 of 44 patients [88%];P⫽.02). However,
there were trends in the later era toward improved MDI
scores (85.2 ⫾17.0 vs 91.5⫾15.6;P⫽.079) and PDI
scores (67.2⫾17 vs 73.7⫾18;P⫽.084).
Twenty-eight of the 89 patients who returned for testing underwent their initial palliative surgery after March 1, 2002, when the right ventricle-pulmonary ar-tery conduit was introduced; the right ventricle-pulmo-nary artery conduit was used for 10 patients and the mBTS for 18 patients. There was no significant differ-ence in MDI (right ventricle-pulmonary artery conduit: median: 94.5; range: 77-105; mBTS: median: 97.5;
range: 64-129;P⫽.53) and PDI (right
ventricle-pulmo-nary artery conduit: median: 87; range: 69-105; mBTS:
median: 87; range: 55-117; P ⫽ .73) scores between
shunt types.
DISCUSSION
Reported risk factors for death in patients with HLHS
include low birth weight,1–4,15,16preoperative shock,2
sin-gle right ventricle (compared with left ventricle),4
ob-struction to pulmonary venous return,2severe
ventric-ular dysfunction,2,4,16genetic syndrome,3and size of the
ascending aorta.1,4 The current study identified similar
patient-specific risk factors (gestational age, genetic syn-dromes, and ethnicity), rather than operative variables, as risk factors for worse neurodevelopmental outcomes. Although these patient-related risk factors cannot be modified, there exist surgical and perioperative manage-ment strategies that likely affect long-term morbidities, including suboptimal neurologic outcomes.
Studies showed that neonates with HLHS have evi-dence of preoperative factors that likely compromise
neurologic outcomes. Dent et al12performed
preopera-tive brain MRI in term infants (n⫽22) without
hemo-dynamic decompensation or genetic syndromes and found that 23% of patients had ischemic lesions or areas of small hemorrhage and only 50% of patients had completely normal study results. Metabolic acidosis (base deficit: median: 4 mmol/L; range: 1–7.5) was the only identified preoperative risk factor to affect MRI
findings (P⫽.024). These preoperative MRI findings are
similar to those reported previously for newborns with
complex congenital heart disease.13 Microcephaly is
more common in patients with HLHS, compared with both normal infants and other newborns with complex heart disease, and may result from abnormal in utero
physiologic features and cerebral blood flow.10,11
Preop-erative cerebral blood flow, as measured by MRI, is
decreased9and is associated with increased incidence of
PVL.
Early postoperative neurologic evaluations have de-40
60 80 100 120
40 60 80 100 120 140
MDI
PDI
40 60 80 100 120
40 60 80 100 120 140
MDI
PDI
<2 risk factors
≥2 risk factors
FIGURE 2
tected abnormalities, but the impact on long-term neuro-logic outcomes remains uncertain. Postoperative brain MRI demonstrated new or enlarged ischemic injury, including
PVL, in 73% of patients with HLHS (11 of 15 patients).12
Operative variables were not found to affect the incidence of MRI abnormalities in this small series. Prolonged
(cho-sen as⬎3 cumulative hours) low (⬍45%) cerebral oxygen
saturation, as measured with a near-infrared spectroscopy
surface probe, was associated with MRI abnormalities.12
Postoperative hypoxemia and low diastolic blood pressure were shown to be associated with an increased incidence of
PVL on postoperative MRI scans.17Authors at the
Univer-sity of Michigan compared MRI results and
neurodevelop-mental scores in patients after Fontan palliation (n⫽29;
age of testing: 4.8 years) and were unable to show a sig-nificant correlation between ischemia or infarction and lower test scores.7
Several small series reported neurodevelopmental follow-up data for patients with HLHS. Some of those series examined perioperative factors to determine how they affected outcomes. Investigators at Children’s Hos-pital of Wisconsin found that lower systemic venous oxygen saturation in the immediate postoperative period
negatively affected neurodevelopmental outcomes (n⫽
13; mean age at testing: 4.5 years).18 Investigators at
Boston Children’s Hospital studied patients treated
dur-ing their S1R with DHCA (44.3 ⫾ 15 minutes),
com-pared with regional low-flow perfusion with a shorter
period of DHCA (23.5 ⫾ 13 minutes), and found no
significance in neurodevelopmental outcomes (n⫽29;
age at testing: 1 year). They did find that intraoperative
temperature of⬍16°C and birth order (younger sibling)
negatively affected MDI score and older age at S1R and birth order (younger sibling) negatively affected PDI
score.8Using a prospective, randomized strategy,
inves-tigators at the University of Michigan also compared the
use of DHCA (41⫾10 minutes) with the use of regional
cerebral perfusion (mean DHCA time: 5.7 minutes) and also found no statistical difference in developmental
testing results (n⫽50; age at testing: 1 year).19Similarly,
they found the PDI (score: 77⫾20) to be significantly
more affected than the MDI (92⫾21;P⬍.0001). They
found no statistical difference between patients in the
regional cerebral perfusion group (PDI: 74 ⫾20; MDI:
88.9⫾22) and patients in the DHCA group (PDI: 79.6⫾
21;P⫽.34; MDI: 94.1⫾20;P⫽.39). The MDI and PDI
scores in that study were very similar to those in the
current study. Mahle et al5 evaluated survivors with
HLHS from 4 centers, comparing the S1R with primary
heart transplant (n⫽48; age at testing: 12 years), and
found that surgical approach was not associated with neurodevelopmental test scores. Multivariate analyses of many patient- and procedure-related risk factors found only longer LOS to affect test scores negatively. Neuro-developmental testing after repair or palliation of
neo-natal heart disease demonstrated that clinical7but not
electrographic20 seizures affected neurodevelopmental
outcomes.
In this study, we report the 1-year neurodevelopmen-tal testing results for a significantly larger cohort of
pa-tients (n⫽88) than reported previously, with a
second-ary aim of identifying patient-related and perioperative risk factors for compromised outcomes. Perioperative information was collected prospectively. In addition, perioperative and surgical data included all operations before the age of testing in the risk analyses. Similar to the smaller series of patients with HLHS reported from
Boston Children’s Hospital8and from the University of
Michigan,19we found the PDI to be more seriously
af-fected than the MDI, a finding that is consistent across many other diagnostic groups studied to date. Despite a fairly exhaustive list of patient-related and perioperative risk factors, multivariate analyses identified few risk fac-tors for worsened neurodevelopmental testing results. The neuromuscular examination results were worse for patients with a longer S1R LOS and improved for pa-tients of black race. These findings of higher motor scores for black patients, compared with other ethnic
groups, have been reported previously.21 Suspected or
confirmed genetic syndrome and earlier gestational age affected PDI scores negatively. These same risk factors, in addition to the need for preoperative intubation, affected MDI scores negatively. Interestingly, although there was a wide range of CPB and DHCA times, operative vari-ables, including the duration of DHCA, were not associ-ated with better or worse outcomes. Most concerning
was the subgroup with ⱖ2 statistically significant risk
factors, in which no patient had a PDI score of⬎100 and
only 3 patients had MDI scores of ⬎100 (mean for
normal populations). In fact, in the entire cohort, only 2
patients had both MDI and PDI scores of⬎100.
Comparisons of the earlier (1998 –2001) and later (2001–2003) eras of surgery revealed only 2 expected differences in perioperative and surgical parameters, re-flecting changes in practice. There was a higher hemat-ocrit level during CPB and fewer preoperative endotra-cheal intubations in the later era. The change in hematocrit levels reflected a response to the intraoper-ative hemodilution study performed at Boston Chil-dren’s Hospital (1996 –2000), which demonstrated worsened outcome measures at lower hematocrit
lev-els.22In the multivariate analyses, however, higher
course of the study period reinforces caution regarding the use of historical control data.
Although our study population nearly doubles the next largest trial, risk factor analyses remain limited by statistical power. In addition, risk factor analyses are limited to the extensive but most likely incomplete list of factors measured prospectively in this trial. Because of the tertiary referral patterns, a substantial number of patients were unable to participate in the neurodevel-opmental follow-up evaluation. Patients who returned for evaluation were disproportionately of white race, had greater gestational age and birth weight, and had shorter postoperative LOS. Therefore, the study popula-tion might have had better neurodevelopmental out-come scores than the entire cohort, had it been tested. The socioeconomic status was determined at the 1-year follow-up evaluation, which limited our ability to com-pare evaluated and nonevaluated patients. Our designa-tion of suspected or confirmed genetic syndrome was determined through evaluation by a geneticist at 1 year of age. Genetic studies were ordered only when clinically indicated. Ideally, genetic testing of the entire cohort, with a combination of complete chromosome, telomere, and comparative genomic hybridization testing, might have improved our accuracy in identification of genetic syndromes. Finally, 1-year neurodevelopmental evalu-ations have limited predictive validity for longer-term neurologic and developmental outcomes. The cohort currently is undergoing developmental testing at 4 years of age.
CONCLUSIONS
Patients with HLHS demonstrate deficiencies in 1-year neurodevelopmental testing results, with motor scores (PDI) being more affected than cognitive scores (MDI). Multivariate analyses identified suspected or confirmed genetic syndrome and younger gestational age as risk factors negatively affecting outcomes, with no identifi-able impact of intraopertative variidentifi-ables such as duration of DHCA or CPB. However, even among patients with no more than 1 significant risk factor, only 3 patients had PDI scores above the mean for normal control sub-jects (score: 100) and only 2 patients had both MDI and
PDI scores of⬎100. Later era of surgery trended toward
positively affecting both MDI and PDI scores. With little change in operative strategies, the lack of impact of intraoperative support techniques on 1-year outcomes suggests that future research should continue to focus on the role of perioperative management and postdischarge early interventions. Longer-term developmental fol-low-up evaluation of these patients is of utmost impor-tance and currently is underway in this patient popula-tion. In addition, continued investigation to identify modifiable risk factors in this high-risk group of infants must be supported.
ACKNOWLEDGMENTS
This work was supported by an American Heart Associ-ation nAssoci-ational grant-in-aid (grant 9950480N, to Dr Gaynor), the Pew Biomedical Scholar Program (Dr Jar-vik), and the Fannie E. Rippel Foundation (Dr Gaynor).
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APPENDIX Risk Factors Analyzed Patient-related
Race Gender
Diagnosis (HLHS vs other) Aortic atresia vs aortic stenosis Right ventricle vs left ventricle Gestational age
Birth weight Birth length
Birth head circumference Apgar scores (1 and 5 min) Multiple gestation Preoperative intubation Vaginal vs cesarean section Abnormal genetic syndrome Suspected genetic syndrome Age at testing
Weight at testing Height at testing
Head circumference at testing Socioeconomic status MDI score
PDI score
Neuromuscular score Operative variables
Surgical era Surgeon Age at S1R Weight at S1R Time of DHCA at S1R Time of CPB at S1R Total support time at S1R Time of cooling at S1R
Lowest nasopharyngeal temperature at S1R Lowest hematocrit level at S1R
mBTS vs right ventricle-pulmonary artery conduit No. of cardiac operations before testing No. of cardiac operations with CPB before testing No. of periods of DCHA before testing No. of aortic cross-clamp periods before testing Total DHCA time for all operations before testing Total CPB time for all operations before testing
Total circulatory support time for all operations before testing Perioperative variables
Delayed sternal closure ECMO
Preoperative LOS at S1R Postoperative LOS at S1R Death
DOI: 10.1542/peds.2007-1282
2008;121;476
Pediatrics
William Gaynor
Gerdes, Elaine Zackai, Robert R. Clancy, Susan C. Nicolson, Thomas L. Spray and J.
Sarah Tabbutt, Alex S. Nord, Gail P. Jarvik, Judy Bernbaum, Gil Wernovsky, Marsha
Heart Syndrome
Neurodevelopmental Outcomes After Staged Palliation for Hypoplastic Left
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DOI: 10.1542/peds.2007-1282
2008;121;476
Pediatrics
William Gaynor
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Sarah Tabbutt, Alex S. Nord, Gail P. Jarvik, Judy Bernbaum, Gil Wernovsky, Marsha
Heart Syndrome
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