Download Neurodevelopmental Outcomes in Infants with Hypoplastic Left

Neurodevelopmental Outcomes in Infants with Hypoplastic Left
Heart Syndrome after Hybrid Stage I Palliation
Dissertation
Presented in Partial Fulfillment of the Requirements for the Degree Doctor of
Philosophy in the Graduate School of The Ohio State University
By
Sharon Laneau Hill Cheatham, MSN, ACNP-BC
Graduate Program in Nursing
The Ohio State University
2012
Dissertation Committee:
Deborah Steward, RN, PhD, Advisor
Keith Yeates, PhD
Jill Heathcock, PhD
Copyright by
Sharon Laneau Cheatham
2012
Abstract
Background: Congenital heart disease (CHD) is the most common of all birth defects
and is the leading cause of infant morbidity and mortality (American Heart Association,
2010). Hypoplastic left heart syndrome (HLHS) is 100% fatal without palliation. Despite
increased survival, since a surgical strategy was developed nearly 30 years ago,
neurodevelopmental outcomes and quality of life are poor. The purpose of this study is to
examine cerebral blood flow and neurodevelopment of infants born with HLHS after
Hybrid Stage I palliation.
Methods: HLHS infants who underwent Hybrid Stage I palliation and healthy agematched control subjects underwent transcranial Doppler at baseline, 2, 4, and 6 months
of age. Systolic, diastolic, and mean velocities, as well as pulsatility index in the middle
cerebral artery was recorded. Developmental assessment was performed at 2 and 4
months, using the Test of Infant Motor Performance (TIMP), and at 6 months of age, or
prior to undergoing the second staged surgical repair, using the Bayley Scales of Infant
and Toddler Development, 3rd edition and results were compared.
Results: The HLHS group scored lower compared to controls on the TIMP at 2 months
of age (p=0.002), -1 to -2 standard deviation (SD) below the norm, and 4 months of age
(p=0.0019), within -1 SD of the norm. Motor skills were significantly lower in the HLHS
group compared with controls (p=0.049), however not significant for cognitive (p=0.29)
ii
or language (p=0.68) at 6 months. There was no significant correlation between
transcranial Doppler velocities and cognitive, language, or motor skills at 6 months of
age.
Conclusions: Infants with HLHS who undergo Hybrid Stage I palliation score lower on
standardized testing when compared to normal controls and the norm-referenced
population. Cerebral blood flow velocity did not predict neurodevelopmental outcomes.
iii
Dedication
This is dedicated to my children, Suzanne and Garrett, for their unconditional
love and support throughout my professional career. I am grateful for being blessed with
such wonderful children. For my parents, when I count my blessings, I always count them
twice. And to John, who is my rock. You inspired me to take that leap of faith, striving for
perfection, and always thinking outside the box…anything is possible. You have left
footprints on my heart forever.
iv
Acknowledgments
It is with admiration and gratitude that I acknowledge Dr. Deborah Steward as my
PhD advisor and mentor. The distinction of her academic philosophy of teaching and
mentoring far surpasses that of any other professor I have encountered over the many
years of education throughout my professional career. Her moral character and ethical
integrity, coupled with her compassion and relentless support for her students, provide
the ideal mentorship for academic and professional student development and future
success. Her guidance and leadership helped pave the way for my future as a nurse
scientist. I credit and thank her for the encouragement and support of my fellowship
training grant awarded from the National Institute of Nursing Research at the National
Institute of Health, as well as her advocacy for newborns with complex congenital heart
disease. She not only makes a difference in the academic life of all of her students, but
also indirectly for patients and families within the realm of clinical research.
I am also grateful to my dissertation committee members, Dr. KeithYeates and
Dr. Jill Heathcock for their patience and experienced guidance in congenital heart disease
research, as well as their support of families and patients with HLHS.
I would like to thank The Heart Center at Nationwide Children‘s Hospital,
particularly the staff in the cardiac catheterization suites, for their dedication to
v
improving the lives of children and adults with congenital heart disease. Dr. Mark
Galantowicz and Dr. John P. Cheatham have been instrumental in paving the way and
perfecting the Hybrid approach to treating hypoplastic left heart syndrome. Without their
support, this study would not have been possible. I also thank Dr. Pamela Lucchesi for
her encouragement and support throughout my PhD program, and Matt Sisk, RCIS for
his medical illustrations.
I would also like to acknowledge the National Institute of Health. The project
described was supported by Award Number F31NR011253 from the National Institute of
Nursing Research. The content is solely the responsibility of the author and does not
necessarily represent the official views of the National Institute of Nursing Research or
the National Institutes of Health.
vi
Vita
Education
June 1979………………………………A.S. Nursing, Massasoit Community
College
June 1989………………………………B.S. Nursing, Stonehill College
June 1998………………………………M.S. Nursing, Northeastern University
2008 to present…………………………PhD program, College of Nursing,
The Ohio State University
Professional Experience
August 2002 – present
The Heart Center at Nationwide Children‘s
Hospital, Columbus, OH
Interventional Cardiology Nurse Practitioner
Acute Care Nurse Practitioner in Cardiac
Catheterization & Interventions
May, 2001 – June 2002
The Nemours Cardiac Center, Orlando, FL
Advanced Registered Nurse Practitioner in Cardiac
Catheterization and Interventions,
Electrophysiology and Pacing.
October, 1998 – May, 2001 The Floating Hospital for Children at New England
Medical Center, Boston, MA
Nurse Practitioner Pediatric Cardiology /
Electrophysiology.
July 1993 - Sept 1998
The Floating Hospital for Children at New England
Medical Center, Boston, MA
vii
Staff Nurse Pediatric Cardiology /
Electrophysiology
June 1992- Nov.1992
The Floating Hospital for Children at New England
Medical Center, Boston, MA
Neonatal Intensive Care Unit Acting Nurse
Manager
May 1986 - July 1993
The Floating Hospital for Children at New England
Medical Center, Boston, MA
Neonatal Intensive Care Unit - Assistant Nurse
Manager
Sept. 1983 - May 1986
The Floating Hospital for Children at New England
Medical Center, Boston, MA
Neonatal Intensive Care Unit
Neonatal Staff Nurse, Neonatal Transport Nurse
June 1979 - Sept. 1983
Carney Hospital, Dorchester, MA
Staff nurse and charge nurse
Awards
National Institute of Health, National Institute of Nursing Research
Ruth L. Kirschstein National Research Service Award Individual Fellowship
(NRSA)
Neurodevelopmental Outcomes in Infants with HLHS after Hybrid Stage I
Palliation
1 F31 NR 11253-1
5 F31 NR 11253-2
5 F31 NR 11253-3
2009-2010
2010-2011
2011-2012
Intramural Research Grant 2010-2012
The Heart Center, Nationwide Children's Hospital
Transcranial Doppler and Developmental Assessment in HLHS after Hybrid
Stage I
viii
Publications
1.
Berul CI, Hill SL, Estes NAM. A teenager with pacemaker twiddler syndrome.
Journal of Pediatrics, 1997;131:496-497.
2.
Berul, CI, Hill SL, Geggel RG, Hijazi ZM, Marx GR, Rhodes J, Walsh KA,
Fulton DR. Prolonged depolarization and inhomogeneous repolarization
predicts late sudden death risk in postoperative tetralogy of Fallot. Journal of
Cardiovascular Electrophysiology, 1997;8:1349-1356.
3.
Berul CI, Sweeten TL, Hill SL, Vetter VL. Provocative testing in children with
suspect congenital long QT syndrome. Annals of Noninvasive
Electrocardiology, 1998;3:3-11
4.
Berul CI, Hill SL, Marx GR, Wang PJ, Fulton DR, Estes NAM. Neonatal
radiofrequency catheter ablation of junctional tachycardias. J. Interv Card
Electrophysiol, 1998;2:91-100.
5.
Hill SL, Evangelista JK, Pizzi AM, Mobasseleh M, Fulton DR, Berul CI.
Proarrhythmia associated with cisapride in children. Pediatrics, 1998;101:10531056
6.
Berul CI, Hill SL, Fulton DR. Coronary artery abnormalities in Kawasaki
disease are not predictable by electrocardiographic markers of repolarization.
Annals of Noninvasive Electrocardiology, 1998;3(4):334-338
7.
Link MS, Hill SL, Cliff D, Swygman C, Homoud MK, Wang PJ, Estes NAM,
Berul CI. Comparison of frequency of complications of implantable
cardioverter-defibrillators in children versus adults. American Journal of
Cardiology, 1999;83:263-266
8.
Berul CI, Michaud GF, Lee VC, Hill SL, Estes NAM, Wang PJ. A
comparison of electrical T-wave alternans and QT dispersion as noninvasive
predictors of ventricular vulnerability. Annals of Noninvasive
Electrocardiology, 1999;4(3):274-280
9.
Hill SL, Berul CI, Patel HT, Rhodes J, Supran SE, Cao QL, Hijazi ZM. Early
ECG abnormalities associated with transcatheter closure of atrial septal
defects using the Amplatzer septal occluder. J. Interv Card Electrophysiol,
Oct 2000;4(3):469-474
10.
Bruckheimer E, Berul CI, Kopf GS, Hill SL, Warner KA, Kleinman CS,
Rosenfeld LE, Nehgme RA. Recovery of surgically-induced atrioventricular
block in patients with congenital heart disease. J. Interv Card Electrophysiol,
ix
2002;(6):191-197
11.
Hill SL, Galantowicz G, Cheatham JP. Emerging Strategies in HLHS.
Pediatric Cardiology Today. 2003;1(3):1-5
12.
Fleishman CE, Fenstermaker B, Hill SL. Interventional echocardiography and
the interventional cardiac catheterization laboratory. Pediatric Ultrasound
Today, 9(9):173-192, 2004
13.
Hill SL, Mizelle K, Vellucci SM, Feltes TF, Cheatham JP. RF Perforation
and Cutting Balloon Septoplasty of Intact Atrial Septum in a Newborn with
HLHS Using Transesophageal ICE Probe Guidance. Catheter and
Cardiovasc Interv, 2004;64:214-217
14.
Ro PS, Hill SL, Cheatham JP. Congenital superior vena cava obstruction
causing anasarca and respiratory failure in a newborn: Successful transcatheter
therapy. Catheter & Cardiovasc Interv 2005;65:60-65
15.
Bacha EA, Cao QL, Galantowicz ME, Cheatham JP, Fleishman CE,
Weinstein SW, Becker PA, Hill SL, Koenig P, Alboliras E, Abdulla R, Starr
JP, Hijazi ZM: Multicenter experience with perventricular device closure of
muscular ventricular septal defects. Pediatric Cardiology, 26:169-175, 2005.
16.
Holzer RJ, Chisolm J, Hill SL, Cheatham JP. Transhepatic cardiac
catheterization in complex congenital heart disease: where there is a will,
there is a way. Congenital Cardiology Today, 3:1-7, 2005.
17.
Hill SL, Hijazii ZM, Hellenbrand WE, Cheatham JP. Evaluation of the
AMPLATZER Vascular Plug for embolization of peripheral vascular
malformations associated with congenital heart disease. Catheterization and
Cardiovascular Interventions, 2006;67:113-119
18.
Eichhorn JG, Long FR, Hill SL, Cheatham JP. Multi-slice computed tomography as an
adjunct to the management of an in-stent stenosis in
an infant with congenital heart disease – imaging for the future. Catheterization and
Cardiovascular Intervention, 2006;67:477-481
19.
20.
RJ Holzer, J Hardin, SL Hill, J Chisolm, JP Cheatham. Radiofrequency energy – a multifacetted tool for the congenital interventionist. Congenital Cardiology Today. 2006
June;4(6):1-8
Eichhorn JG, Long F, O‘Donnovan J, Chisolm JL, Hill SL, Cheatham JP. Assessment of
in-stent stenosis in small children with congenital heart disease using multi-detector
computed tomography: a validation study. Catheter Cardiovasc Interv. 2006
x
Jul;68(1):11-20.
21.
Holzer RJ, Chisolm J, Hill SL, Cheatham JP. Transcatheter devices used in the
management of patient with congenital heart disease. Expert Review Medical Devices,
3(5):603-15, 2006.
22.
Cua C, Hoffman TM, Hill SL, Turner D, Forbes T, Galantowicz M, Cheatham JP.
Palliation via hybrid procedure of 1.4kg patient with a hypoplastic left heart. Congenital
Heart Disease, 2007;2:191-193
23.
Holzer RJ, Sisk JM, Lawrence PE, Hill SL, Chisolm JL, Cheatham JP. Suture-mediated
closure of femoral venous access sites after cardiac catheterization. Congenital
Cardiology Today, 5(8):1-5, 2007.
24.
Galantowicz M, Cheatham JP, Phillips A, Cua CL, Hoffman TM, Hill SL, Rodeman R.
Hybrid approach for HLHS: Intermediate results after the learning curve. Ann Thorac
Surg 2008;85:2063-2071
25.
Fenstermaker B, Berger GE, Rowland DG, Hayes J, Hill SL, Cheatham JP, Galantowicz
M, Cua CL. Interstage echocardiographic changes in patients undergoing hybrid stage I
palliation for hypoplastic left heart syndrome. J Am Soc Echocardiogr. 2008,
21(11):1222-8.
26.
Holzer RJ, Hill SL, Chisolm J, Cheatham JP. Stenting complex aortic arch obstructions.
Catheterization and Cardiovascular Interventions, 2008;71:375-382
27.
Galantowicz M, Cheatham JP, Phillips A, Cua CL, Hoffman TM, Hill SL, Rodeman R.
Hybrid approach for HLHS: Intermediate results after the learning curve. Ann Thorac
Surg 2008 ;85:2063-2071
28.
JG Eichhorn, C Jourdan, JT Heverhagen, SL Hill, SV Raman, MV Knopp, JP Cheatham,
FR Long. CT of pediatric vascular stents used to treat congenital heart disease. Am J
Roentgenol. 2008, 190(5):1241-6
29.
JG Eichhorn, FR Long, C Jourdan, JT Heverhagen, SL Hill, SV Raman, JP Cheatham.
Usefulness of multidetector CT imaging to assess vascular stents in children with
congenital heart disease: an in vivo and in vitro study. Catheter Cardiovasc Interv
2008;72:544-55
30.
Holzer RJ, Chisolm JL, Hill SL, Olshove V, Phillips A, Cheatham JP, Galantowicz M.
"Hybrid" stent delivery in the pulmonary circulation. J Invasive Cardiol. 2008;20
(11):592-8.
31.
Holzer RJ, Wood A, Chisolm JL, Hill SL, Phillips A, Galantowicz M, Cheatham JP.
xi
Atrial septal interventions in patients with hypoplastic left heart syndrome. Catheter
Cardiovasc Interv. 2008; 72(5):696-704.
32.
Crumb SR, Cook SC, Cheatham JP, Galantowicz M, Feltes TF, Phillips A, Chan DP,
Holzer RJ, Sisk M, Olshove V, Cook LR, Hickey JC, Hill SL, Daniels CJ. Quality
outcomes of ACHD patients undergoing cardiovascular procedures and hospital
admissions in a free-standing children's hospital. Int J Cardiol. 2009.
33.
Holzer RJ, Sisk M, Chisolm JL, Hill SL, Olshove V, Phillips A, Cheatham JP,
Galantowicz M. Completion Angiography after Cardiac Surgery for Congenital Heart
Disease: Complementing the Intraoperative Imaging Modalities. Pediatr Cardiol. 2009.
34.
Holzer RJ, Green J, Bergdall V, Chisolm JL, Hill SL, Galantowicz M, Cheatham JP,
Phillips A. An Animal Model for Hybrid Stage I Palliation of Hypoplastic Left Heart
Syndrome. Pediatr Cardiol. 2009.
35.
Tsai SF, Hill SL, Cheatham JP. Treatment of aortic arch aneurysm with a NuMEDcovered stent and restoration of flow to excluded left subclavian artery: perforation and
dilation of e-PTFE can be done! Catheter Cardiovasc Interv. 2009 Feb 15;73(3):385-9.
36.
Sawdy JM, Gocha MD, Olshove V, Chisolm JL, Hill SL, Phillips A, Galantowicz M,
Cheatham JP, Holzer RJ. Radiation protection during hybrid procedures: innovation
creates new challenges. J Invasive Cardiol. 2009 Sep;21(9):437-40.
37.
Hill, SL, Chisolm, JL, Cheatham, JP. Medtronic Melody transcatheter
pulmonary valve …. Improving the quality of life, Congenital Cardiology
Today. April 2010; 8(4):1-5
38.
Hill, SL, Cheatham, JP, Holzer, RJ, Phillips, A, Galantowicz, M. Hybrid
procedures: evolution of change in managing congenital heart disease,
Congenital Cardiology Today. July, 2010
39.
Holzer R, Marshall A, Kreutzer J, Hirsch R, Chisolm J, Hill S, Galantowicz
M, Phillips A, Cheatham J, Bergerson L. Hybrid Procedures: Adverse Events
and Procedural Characteristics—Results of a Multi-Institutional Registry.
Congenital Heart Disease 2010, May-Jun;5(3):233-42.
40.
Egan MJ, Hill SL, Boettner BL, Holzer RJ, Phillips AB, Galantowicz M,
Cheatham JP, Kovalchin JP. Predictors of retrograde aortic arch obstruction
after Hybrid palliation of hypoplastic left heart syndrome. Pediatr Cardiol.
2011 32:67-75
41.
Egan MJ, Trask AJ, Baker PB, Lawrence J, Ladich E, Virmani R, Hill SL,
Cheatham JP, Galantowicz M, Lucchesi PA, Kovalchin JP. Histopathologic
xii
evaluation of patent ductus arteriosus stents after Hybrid palliation. Pediatr
Cardiol. Feb. 2011 (e-print)
42.
Sawdy J, Kempton TM, Olshove V, Gocha M, Chisolm JL, Hill SL, Kirk A,
Cheatham JP, Holzer R. Use of a Dose-dependent Follow-up Protocol and
Mechanisms to Reduce Patients and Staff Radiation Exposure in Congenital
and Structural Interventions. Catheter Cardiovascular Interv. 2011;78(1):136142
43.
Roberts PA, Boudjemline Y, Cheatham JP, Eicken A, Ewert P, McElhinney
DB, Hill SL, Berger F, Khan D, Schranz D, Hess J, Ezekowitz MD,
Celermajer D, Zahn E. Percutaneous Tricuspid Valve Replacement in
Congenital and Acquired Heart Disease. J Am Coll Cardiol 2011;58:117-22
44.
Wood AM, Holzer RJ, Texter KM, Hill SL, Gest AL, Welty SE, Cheatham
JP, Yates AR. Transcatheter Elimination of Left-to-Right Shunts in Infants
with Bronchopulmonary Dysplasia is Feasible and Safe. Congenit Heart Dis.
2011 Jul;6(4):330-7. doi: 10.1111/j.1747-0803.2011.00540.x. Epub 2011 Jul 1
45.
Thrush PT, Mackman CA, Lawrence P, Naguib A, Yates AR, Cassidy SD,
Chisolm JL, Hill SL, Cheatham JP, Holzer RJ. An Institutional Approach to
Interventional Strategies for Complete Vascular Occlusions. Pediatr Cardiol.
2011 Aug;32(6):713-23. Epub 2011 Apr 10.
46.
Learn C, Phillips A, Chisolm J, Hill S, Cheatham J, Winch P, Galantowicz M,
Holzer R. Pulmonary Atresia with Ventricular Septal Defect and Multifocal
Pulmonary Blood Supply: Does an Intensive Interventional Approach
Improve the Outcome? Congenit Heart Dis. 2011 Dec 16. doi:
10.1111/j.1747-0803.2011.00590.x.
Field of Study
Major Field: Nursing
xiii
Table of Contents
Abstract ..........................................................................................................ii
Dedication ......................................................................................................iv
Acknowledgments..........................................................................................v
Vita.................................................................................................................vii
List of Tables .................................................................................................xvi
List of Figures ................................................................................................xvii
Chapter 1: Introduction and overview ..........................................................1
Chapter 2: Hypoplastic left heart syndrome: Update 2012 ...........................5
2.1 Cardiac anatomy .............................................................5
2.2 Cerebral anatomy: the operculum ...................................7
2.3 Genetic and prenatal factors............................................8
2.4 Options for surgical Stage I palliation ............................13
2.5 Norwood procedure .........................................................13
2.6 Norwood-Sano procedure ................................................15
2.7 Hybrid Stage I procedure .................................................17
2.5 Operative, post-operative, and interstage factors ............19
2.6 Stage II palliation ............................................................22
2.7 Stage III Fontan completion............................................23
xiv
2.6 Outcomes and neurodevelopment ...................................23
2.7 Conclusions .....................................................................31
Chapter 3: Neurodevelopment following Hybrid Stage I for HLHS ............33
3.1 Background ......................................................................34
3.2 Methods............................................................................41
3.3 Results ..............................................................................48
3.4 Discussion ........................................................................52
3.5 Conclusions ......................................................................55
Chapter 4: Assessment of cerebral blood flow in HLHS after
Hybrid Stage I palliation ........................................................57
4.1 Background ......................................................................57
4.2 Methods............................................................................61
4.3 Results ..............................................................................66
4.4 Discussion ........................................................................68
4.5 Limitations .......................................................................70
4.6 Conclusions ......................................................................72
References ......................................................................................................73
Appendix A : List of Abbreviations...............................................................91
xv
List of Tables
Table 1. Inclusion and exclusion criteria of HLHS and control groups .......41
Table 2. Demographic variables of HLHS and control groups ....................48
Table 3. Descriptive statistics composite scores at 6 months .......................50
Table 4. Comparison between HLHS and control subjects ..........................50
Table 5. Percent classification for language composite scores .....................51
Table 6. Percent classification for motor composite scores ..........................51
Table 7. Demographic variables ...................................................................66
Table 8. Neurodevelopment comparisonbetween HLHS and control
subjects at 6 months ........................................................................67
Table 9. Transcranial Doppler and neurodevelopment at 6 months .............67
xvi
List of Figures
Figure 1 Normal heart anatomy. ..................................................................92
Figure 2 Hypoplastic Left Heart Syndrome .................................................93
Figure 3 Norwood Stage I ............................................................................94
Figure 4 Norwood-Sano Stage I ..................................................................95
Figure 5 Hybrid Stage I................................................................................96
Figure 6 Comprehensive Stage II ................................................................97
Figure 7 Bidirectional Glenn - Stage II........................................................98
Figure 8 Extra cardiac Fontan – Stage III ....................................................99
Figure 9 Development scores in HLHS group .............................................100
Figure 10 Median transcranial Doppler cerebral velocities ...........................101
Figure 11 Median transcranial Doppler pulsatility index of HLHS and
control groups ...............................................................................102
xvii
Chapter 1
Introduction and Overview
Congenital heart disease (CHD) is the most common of all major birth defects.
The estimated incidence for babies born with CHD is 8-9 out of 1,000 live births annually
(Centers for Disease Control and Prevention, 2010; Hoffman & Kaplan, 2002; National
Institute of Health, 2012). This translates into approximately 35,000 babies each year in
the United States alone (National Institute of Health, 2012) and 1.35 million newborns
annually worldwide (van de Linde, et al., 2011). Moderate to severe forms of CHD have
been reported from 6/1000 to as high as 19/1000 live births (Lloyd-Jones, et al., 2009).
With advanced imaging and technology, and more referrals to pediatric cardiologists,
more and more minor CHD lesions are being diagnosed. Notably, at least 3 out of 1,000
babies born with CHD require either transcatheter intervention or cardiac surgery early in
life (Hoffman & Kaplan, 2002).
Compared to normal cardiac anatomy (Figure 1), hypoplastic left heart syndrome
is a severe form of CHD characterized by underdevelopment of the left ventricle and
ascending aorta, with critical stenosis or atresia of the mitral and aortic valves, a small,
undersized left ventricle, and diminutive ascending aorta (Figure 2). Up until 1980,
hypoplastic left heart syndrome was considered inoperable and a fatal diagnosis as the
patent ductus arteriosus (PDA), which provides systemic cardiac output and coronary
1
artery perfusion by backward or retrograde aortic blood flow, normally constricts and
closes within several days of birth. Traditional palliative options include three open heart
staged surgical procedures over the first few years of life. More recently a combined
surgical and transcatheter approach conducted on the beating heart, off cardiopulmonary
bypass, has become a viable option for stage I palliation, so called Hybrid Stage I
palliation (Figure 3). Over the last three decades, as staged surgical procedures,
technology, perfusion, and intensive care management has improved, the mortality rate
associated with hypoplastic left heart syndrome has decreased at many centers.
The Center for Disease Control and Prevention (CDC) reports congenital heart
defects as the main cause of death for 27,960 individuals in the United States from 1999
through 2006 with approximately half occurring during the first year of life (Centers for
Disease Control and Prevention, 2012). Additionally, the CDC and the report on neonatal
deaths attributed to CHD, hypoplastic left heart syndrome was the most common
congenital heart defect which was noted as the underlying cause of neonatal death for
white infants (480 [27%]) and black infants (126 [26%]); 38% of the neonatal deaths
were listed as "congenital malformation of heart, unspecified." From 2004 to 2006, the
adjusted national prevalence estimated hypoplastic left heart syndrome at 1 in 4,344
births with an estimated 960 annual cases and 2.3 per 10,000 live births (Centers for
Disease Control and Prevention, 2012).
As survival rates have increased with hypoplastic left heart syndrome, much of
the focus has been on outcomes, one of which being neurologic outcomes. It is well
2
documented in the literature that long-term neurodevelopmental outcomes in children
with hypoplastic left heart syndrome is less than ideal, and virtually not reported in the
literature for the hypoplastic left heart cohort who has undergone an alternative approach
to the traditional staged palliation, referred to as the Hybrid Stage I palliation, which is
hereby the foundation of this research.
The following presents the state of the science to date in treatment of hypoplastic
left heart syndrome, including review of anatomy and physiology, palliative surgical
options, outcomes, and what is known in terms of neurodevelopment. A prospective,
longitudinal, non-randomized research study is presented on a sample of hypoplastic left
heart syndrome babies who have undergone the Hybrid Stage I procedure, an alternative
strategy to the traditional first staged surgical palliation. This study is designed to
examine neurodevelopment and test the overall working hypothesis that there is a
correlation between cerebral blood flow and neurodevelopmental outcome in infants after
Hybrid Stage 1 palliation for HLHS. The following presents the aims of the study:
Aim 1: Evaluate cerebral blood flow after Hybrid Stage I palliation for HLHS
using transcranial Doppler
Hypothesis: Infants with HLHS will have decreased cerebral blood flow when
compared to healthy controls.
Aim 2: Compare neurodevelopmental outcomes between infants with HLHS and
healthy controls.
3
Hypothesis: Infants with HLHS will have lower scores on the Test of Infant
Motor Performance and Bayley Scales of Infant and Toddler Development, 3rd
edition across time when compared to healthy controls.
Aim 3: Within each group, determine whether cerebral blood flow is a predictor
of neurodevelopmental status.
Hypothesis: Within each group, cerebral blood flow will be predictive of
neurodevelopment.
Multiple measurements of variables were obtained over time, during the first six months
of life. This included transcranial Doppler ultrasound of blood flow in the middle cerebral
artery, developmental assessment, height, weight, and head circumference. Variables
were compared to normal healthy control subjects and published or norm referenced data.
Study findings were analyzed and the results are summarized in the ensuing chapters.
4
Chapter 2
Hypoplastic left heart syndrome: Update 2012
Hypoplastic left heart syndrome (HLHS) accounts for 4-8% of all congenital heart
disease (CHD) and is one of the most severe and complex forms of CHD (American
Heart Association, 2010; Morris et al., 1990; Pigula et al., 2007). This complex lesion is
100% fatal without palliation.
Cardiac anatomy
The diagnosis of HLHS consists of a complexity of left sided heart lesions: a
small and underdeveloped left ventricle, a diminutive ascending aorta, with critical mitral
and aortic valve stenosis or atresia (Figure 2). An opening between the upper chambers of
the heart, atrial septal defect, is usually present. If an atrial septal defect is not present and
the atrial septum is intact, these babies are born critically ill, quickly become extremely
acidotic, and will succumb to death almost immediately unless an opening in the atrial
septum is created immediately after birth. Otherwise, HLHS physiology is actually very
well tolerated in utero, fetuses are usually carried to full term gestation, tolerating the
stressors of birth, and are born with Apgar scores comparable to the normal newborn.
However, it is unknown whether alteration in physiology and cerebral blood flow to the
fetal brain is adequate during gestation.
5
HLHS anatomy and physiology can result in alteration in cerebral blood flow and
ultimately inadequate oxygenation to the brain. Fetal brain growth and development is
dependent upon an adequate supply of necessary nutrients and oxygenated blood flow. In
the developing embryo, intracranial circulation is visible as early as 8 weeks gestation.
Normal fetal circulation with preferential cerebral blood flow results from streaming of
highly oxygenated blood from the mother to the fetus via the ductus venosus, to the
inferior vena cava, across the foramen ovale to the left atrium, left ventricle, ascending
aorta, and delivers oxygenated blood to the brain and body. Blood flow velocity
waveforms in the middle cerebral artery in the fetus are normally highly pulsatile and
end-diastolic measurement become more prominent in gestation with 75% end-diastolic
frequencies noted in fetuses between 18-25 weeks gestation and noted in all fetuses after
34 weeks gestation (Vyas et al, 1990).
The fetus with HLHS does not have this preferential oxygenated blood flow
delivery to the brain. The majority of blood flow is via the ductus venosus to the inferior
vena cava and does not cross the foramen ovale to the left sided heart chambers. The
blood is directed from the right atrium to the right ventricle where it is ejected across the
pulmonary valve to the pulmonary artery. A very small amount of blood flow goes out to
the right and left lung for growth and development. However, with the majority of blood
flows across the patent ductus arteriosus (PDA) to the descending aorta to perfuse the
body. Antegrade blood flow from the left ventricle to the ascending aorta and head and
neck vessels may be either absent or severely diminished in fetuses and neonates with
HLHS. They are dependent upon retrograde or backward blood flow, from the PDA, to
6
the aortic arch to supply the brain, as well as backward flow to the ascending aorta to
supply the coronary arteries.
The normal fetal brain has a mechanism which autoregulates cerebral blood flow,
altering cerebral vascular resistance in accordance with changes in oxygen delivery. The
fetus with HLHS has low cerebral vascular resistance, compared to normal fetuses
(Donofrio et al., 2003; McElhinney et al., 2009). This helps to enable retrograde aortic
blood flow to the brain as previously described.
Cerebral anatomy: the operculum
The cerebral operculum refers to the area of the frontal, parietal, and temporal
lobes which overlies the insula, and with apposition of these lobes, the sylvian fissure is
formed. In the developing embryo, the operculum starts to form around 20 weeks
gestation when the cortical plate thickens and indents at the insular. The temporal and
parietal regions develop faster than the anterior region of the frontal lobe. The area folds
over covering the insula area, forming the horizontal sylvian fissure. The anterior portion
of the insula remains open until the frontal lobe covers the insula when the fetus reaches
term gestation. Opercularization has been described as the expression of functional
maturity of the brain (Chen et al., 1995; Larroche, 1977; Larroche, 1967; Guibaud et al.,
2008). The operculum covers areas of the brain involved with speech and language, as
well as the motor aspects of speech. This is Brodmann‘s areas 44, referred to as Broca‘s
area, and area 45 anteriorly, as well as area 22 and 39 posteriorly. Landmarks and
measurement of the separation of the operculum by magnetic resonance imaging (MRI)
have been reported by Tatum and colleagues (1989) as well as by Chen and colleagues
7
(1995). Tatum et al (1989) found that normal separation of the sylvian fissure should not
exceed 3mm and that an open operculum may indicate developmental arrest. Similarly,
Chen et al (1995) found the inter-opercular distance in the sylvian fissure in normal
healthy infants should not be greater than 4.5mm anteriorly and 0.5mm distance
posteriorly. The open operculum has been described in newborns with HLHS. It is an
interesting question if there is an association between the HLHS fetus with an open
operculum and cognitive outcome. This has not been studied.
Genetic and Prenatal Factors
Although recurrent congenital cardiovascular malformations in families have been
reported, the malformations are not always the same. The etiology of left ventricular
outflow tract malformations, which includes HLHS, remains unknown. A strong genetic
component for left ventricular outflow tract malformations have been reported (McBride,
et al., 2005), however gene discovery or common pathway specifically for HLHS has yet
to be determined. Connexin43 channels are intricately gated by phosphorylation.
Connexin subunits form a hydrophilic pore which allow cell to cell exchange of ions,
metabolites, and molecules which facilitate signaling pathways for normal heart
development (Britz-Cunningham, et al., 1995).
Mutations and polymorphisms in the connexin43 gap junction gene have been
identified as a possible factor in the development of HLHS (Dasgupta et al., 2001).
Denaturing gradient gel electrophoresis was used to separate normal and variant bands of
DNA from the connexin43 gene, coding critical sites for phosphorylation gating of
connexin43 channels. After separation, DNA underwent cycle sequencing. Results
8
demonstrated connexin43 mutations in 8 out of 14 children with HLHS and 1 with atrioventricular canal defect. However, 6 children with HLHS lacked mutations. No
mutations were found in 46 normal controls or in other forms of congenital heart defects
(Dasgupta et al., 2001).
McBride, et al, (2009) first reported on linkage analysis on families with multiple
LVOT malformations. McBride, et al. (2009) hypothesized that left ventricular outflow
tract malformation susceptibility loci, including HLHS, may be identified using a linkage
approach with multiplex families. The results of linkage analysis found evidence
suggesting linkage on chromosome 2p23.2, chromosome 12p21.2, and chromosome
16p12.2. Significant non-parametric linkage score (NPLS) in HLHS families were noted
for chromosome 2p15 (NPLS = 3.17) with additional suggestive peaks on chromosome
19q13 (NPLS=2.16) and 10q21 (NPLS=1.94) (McBride, et al, 2009). These results
showed a significant linkage signal for HLHS on 2p23.
In another study, a cohort of 91 unrelated subjects with left ventricular outflow
tract malformations, including HLHS, were analyzed and genomic DNA was screened
for mutations in NOTCH1. The mutations in NOTCH1 that alter function of the
signaling pathway were found in subjects with aortic valve stenosis, coarctation of the
aorta, and HLHS (McBride, et al., 2008). Their findings support the notion that left
ventricular outflow tract defects may have a complex genetic inheritance.
Reamon-Buettner et al. (2008) showed that transcription factor heart and neural
crest derivatives expressed 1 (Hand1) function is impaired in HLHS. Hand1 is part of
9
tissue-specific basic helix-loop-helix (bHLH) transcription factors. It is expressed in
specific regions of the pre-developed linear heart tube and becomes localized in the outer
curvature of the left ventricle and developing outflow tract as well as in the outer
curvature of the right ventricle at post-looping of the linear heart tube. Reamon-Buettner
(2008) studied hypoplastic hearts and identified a frame shift mutation in 24 out of 31
hypoplastic left or right ventricles consisting of a deletion of a G nucleotide at position
376, affecting the amino acid sequence from Alanine 126 in the bHLH domain.
In 2008, Gambetta, et al., performed gene-expression analysis and profile of the
atrial septum of children born with HLHS and compared it to age-matched controls of
children born with other congenital heart disease lesions. They identified components of
the biological pathways affected in HLHS, suggesting defects in chromatin remodeling,
cell cycle regulation, and transcriptional regulation in HLHS. Their findings help support
the concept that decreased atrial filling during fetal cardiac development may inhibit the
progression of left heart growth during fetal life (Gambetta, et al., 2008).
All of these findings are suggestive that there is a complex, sub-cellular or
molecular, genetic component to HLHS. However the etiology of HLHS is most likely
multi-faceted and remains unknown. Neural tube formation for the central nervous
system is also occurring simultaneously during cardiac development. Brain maturation
and structure has also been characterized in newborns with congenital heart disease.
High levels of prenatal stress between 16-20 weeks of gestation have been
reported to positively correlate with difficult temperament at 6 months of age in the
10
infant, but negatively correlate to scholastic achievement and behavior at 7 years of age
(Niederhofer, et al., 2000). Typically, fetal cardiac echocardiography is performed
between 18-22 weeks gestation and the fetal diagnosis of HLHS may be determined. This
may result in tremendous prenatal maternal stress which ultimately may have an adverse
effect short term on the fetus, as well as long term for the infant and child. Maternal trait
anxiety has been associated with altered distribution of fetal blood flow, lower pulsatility
index in the fetal middle cerebral artery, and small for gestational age fetuses (Sjostrom,
et al., 1997). The maternal stress effect is a complex entity for the developing fetus,
effects of which are not completely understood.
Clearly, there is a growing body of evidence suggestive that prenatal factors and
cerebral development in HLHS is abnormal in the fetus (Goldberg et al, 2000;
Limperopoulos et al, 1999; Mahle et al, 2002; Miller et al, 2007; Hinton et al, 2008).
Several studies have reported white matter injury, periventricular leukomalacia and
microcephaly in fetuses and neonates (Shillingford et al, 2007; Hinton et al, 2008; Mahle
et al, 2002; Licht et al, 2004; Glauser et al, 1990). Periventricular leukomalacia is the
result of injury to the white matter, with suspected etiology from several contributing
factors particularly hypoxic ischemic injury of immature oligodendrocytes and the
watershed area surrounding the small arteries which penetrate from the cortex. The
watershed area is highly sensitive to changes in perfusion pressure and is supplied by the
middle cerebral artery. This leads us to the focused interest in evaluating cerebral blood
flow in the middle cerebral artery, particularly in the area of the pars opercularis.
11
In searching the literature, a study by Mahle et al (2001) of 216 infants diagnosed
prenatally with HLHS was noted to have fewer intraoperative neurologic events, such as
seizures, than those diagnosed postnatally. Additionally, postnatal diagnosis of HLHS
was associated with an increased risk and severity of metabolic acidosis preoperatively.
Kern and colleagues (1998) reported that a prenatal diagnosis of HLHS in fetuses were
more stable neurologically preoperatively than those diagnosed postnatally. However,
Mahle et al, (2000) reported that there was no significant improvement in
neurodevelopmental outcome in HLHS infants who were diagnosed in utero. It seems the
results of such a study would be dependent upon individual birth centers. A prenatal
diagnosis allows for family education and careful planning for a controlled delivery in a
tertiary center with appropriate personnel to manage the neonate immediately after birth.
Although it has been suggested that post-operative lactate levels may impact outcome,
pre-operative acidosis may be just as important in terms of morbidity and outcome.
Miller et al., (2007) studied 41 term newborns with congenital heart disease, 12 of
who had single ventricle physiology, and performed MRI, magnetic resonance
spectroscopy, and diffusion tensor imaging studies preoperatively and compared to
normal term neonates. Acquired brain injury was noted in the congenital heart disease
group; preoperative stroke and white matter injury were focal in nature. All control
newborns had normal MRI scans. Impaired brain metabolism and microstructure were
identified in the congenital heart disease group, despite visible injury on MRI. These
results help support the growing evidence that brain development is impaired while in
utero. This may be due to altered cerebral perfusion and oxygenation.
12
This in turn leads us back to the question of whether there is adequate cerebral
perfusion for brain growth and development given the physiology associated with HLHS.
A correlation may exist, which may even begin in utero, between cerebral blood flow and
neurodevelopmental outcome in infants with HLHS.
Options for Surgical Stage I Palliation
Norwood Procedure
The traditional staged Norwood procedure consisted of three staged palliative
open heart surgeries during the first few years of life. This was first performed in 1980
and the first staged surgical palliation to the Fontan completion was performed by
Norwood and his colleagues and reported in 1983 (Norwood et al, 1980; Norwood et al,
1983). The stage I Norwood procedure (Figure 3) is typically performed within the first
few days of life and carries the highest mortality. This first staged procedure involves
excision of the atrial septum (atrial septectomy), ligation and division of the PDA,
division and over sewing of the main pulmonary artery trunk proximal to the bifurcation
of the left and right pulmonary arteries, reconstruction of the ascending aorta by
anastomosis of the diminutive ascending aorta to the pulmonary artery, patch
augmentation of the aortic arch, and anastomosis of a 3.5 – 4.0 mm shunt graft from the
systemic artery to pulmonary artery. Currently, the systemic to pulmonary shunt is a
referred to as a modified Blalock-Taussig shunt (mBTS), which is a Gore-Tex tube
placed between the right innominate artery and the right pulmonary artery, to augment
pulmonary blood flow. The Norwood procedure is performed utilizing deep hypothermic
13
circulatory arrest and cardiopulmonary bypass (CPB). Staged surgical palliation has
remained the gold standard for palliation of HLHS. Despite improvements in surgical
technique over the past three decades, the mortality rate associated with HLHS remains
highest of all congenital heart disease within the first year of life (Boneva et al, 2001;
Ohye et al., 2010).
Although the mortality rate for the Norwood operative procedure itself has
decreased in experienced centers, the morbidity has not. The Norwood procedure has
been associated with long-term deficits in neurodevelopment including lower full-scale
intelligence quotient (FSIQ), delayed motor development and neurologic injury ( Kern et
al,1998; Mahle & Wernovsky, 2004; Mahle et al, 2004; Mahle et al, 2006; Tabbutt et al,
2008; Rogers et al, 1995; Visconti et al, 2006; Bellinger et al, 1995; Bellinger et
al,1999). The mechanisms that account for these deficits are not fully elucidated,
however the profound effect of hypothermic circulatory arrest and prolonged CPB were
thought to play important causative roles, most likely due to the residual effects of their
influence on cerebral blood flow and perfusion (Bellinger et al, 1995; Bellinger et al,
1999; Ferry et al, 1990; Newburger et al, 1993).
Hypoxemia and reperfusion injury from prolonged CPB and deep hypothermic
circulatory arrest during the traditional Norwood procedure has been associated with
increased risk of poor neurologic outcomes ( Wypij et al, 2003). Bellinger and colleagues
have reported children who undergo deep hypothermic circulatory arrest are at a greater
risk for delayed motor development and neurologic injury (Bellinger et al, 1995;
Bellinger et al, 1999). Long-term neurologic sequelae have also been well documented
14
(Ferry et al, 1990; Newburger et al, 1993). CPB time, degree of hypothermia, selective
antegrade or retrograde cerebral perfusion, as well as time periods of circulatory arrest
vary amongst centers and individual operative procedures. Alterations in cerebral blood
flow, microembolization, and the significant inflammatory response from
cardiopulmonary bypass have also been suggested as possible etiologies for neurologic
injury (Glauser et al, 1990, Shillingford et al., 2007; Newburger et al., 1993; Dent et al.,
2006; Mahle et al., 2002). Additionally, birth weight, prematurity, and anatomical
complexity add to the risk and are significant factors in managing neonates with HLHS.
Although overall surgical survival rate after Norwood Stage I has improved, with
experienced centers reporting 70 – 90% survival, the reported 5 year survival remains
suboptimal with ranges between 40-61% (Tweddell et al, 2002; Stasik et al, 2006; Bove,
1998, 1999, 2004; Bove et al., 2004; Mahle et al, 2000; Alsoufi et al, 2007).
Norwood-Sano procedure
The Norwood-Sano procedure is a variation of the Norwood procedure. A right
ventricle to pulmonary artery (RV-PA) shunt to augment pulmonary blood flow during
the first stage palliation for HLHS was actually first performed in 1981 by Norwood
(Norwood et al, 1981). However, this was too large of a shunt, resulting in pulmonary
over circulation and failure of the right ventricle, and was abandoned for the aortopulmonary shunt or BT shunt. Modification to the RV-PA shunt using a smaller graft,
termed the Norwood-Sano or ―Sano‖ procedure (Figure 4), named after Sunji Sano, MD,
a cardiothoracic surgeon in Okayam, Japan, was first performed in 1998 and has become
popular in many centers as an alternative to the modified BT shunt. The purpose is also to
15
provide a more reliable and pulsatile blood flow to the pulmonary arteries and lungs. The
Sano modification (Figure 4) utilizes a smaller, 4-5mm RV-PA non-valved,
polytetrafluoroethylene shunt to augment pulmonary artery blood flow (Sano et al.,
2003). The Norwood-Sano operation is currently being performed in many institutions in
addition to the traditional Norwood Stage I procedure for HLHS. The Sano operation
eliminates the diastolic run-off into the pulmonary bed which is seen in with the modified
BT shunt, and decreases the ventricular volume overload (Ohye, et al., 2004). It may also
reduce complications associated with low, diastolic systemic pressure such as necrotizing
enterocolitis. However this is not proven.
The Sano operation has some reported disadvantages of right ventricle dilation
from free pulmonary shunt regurgitation, shunt obstruction, occlusion, and development
of false right ventricular aneurysm (Sano et al, 2003). Like the traditional Stage I
Norwood, the Sano operation still requires the use of CPB and circulatory arrest in the
neonatal period which again adds to the risk of developing cerebral neuronal injury from
ischemia, cerebral hemorrhage, embolization, and the neurologic effects of the systemic
inflammatory response from CPB. There is also the unknown effect of a right
ventriculotomy incision on the systemic right ventricle.
In a multi-center (15 centers) randomized clinical trial, supported by the National
Heart, Lung, and Blood Institute, comparing two different shunt types for infants
undergoing the Norwood procedure, 275 infants had a modified BT shunt, and 274
infants had a RV-PA shunt, (Ohye et al., 2010; Ohye, et al., 2008). Transplantation-free
survival at 12 months was higher for the RV-PA shunt compared to the modified BT
16
shunt (74% vs. 64%, P=0.01). However, more transcatheter interventions and
complications occurred in the RV-PA shunt group. Follow up at 32 + 11 months revealed
no significant difference between the two groups (Ohye et al, 2010). Although valuable
information was learned from this study in terms of the primary outcome of death or
cardiac transplantation at 12 months, no developmental testing was performed during this
study for comparison of two surgical strategies and developmental outcomes.
Hybrid Stage I procedure
The Hybrid Stage I palliation (Figure 5) offers an alternative management
strategy for newborns with HLHS (Galantowicz & Cheatham, 2005; Galantowicz et al,
2008; Akintuerk et al, 2002; 2007; Pill, et al., 2008; Bacha, et al., 2006; Bacha, 2008;
Chen & Parry, 2009). The rationale for performing the Hybrid procedure versus the
Norwood procedure is to completely avoid cardiopulmonary bypass, circulatory arrest,
and the associated surgical risks early in the neonatal period, and to ultimately improve
long term outcomes. The Hybrid Stage I procedure shifts the major open heart surgery,
including the risks associated with cardiopulmonary bypass, to approximately 6 months
of age and 6 kg with the idea that with maturity, cardiopulmonary bypass will be better
tolerated at a later age well beyond the neonatal period and after transitioning to extrauterine life. Prior to the Hybrid Stage I procedure, the ductus arteriosus is kept patent by
prostaglandin E1 intravenous infusion. The entire cardiac output is maintained and
dependent upon the patent ductus arteriosus (PDA).
The Hybrid Stage I palliation involves a combination of cardiothoracic surgical and
interventional techniques performed in the same setting. Hybrid Stage I palliation is
17
performed without stopping the heart and does not require cardiopulmonary bypass. This
is a great advantage for initial palliation as it helps to avoid or lessen the inflammatory
response associated with cardiopulmonary bypass. This treatment strategy involves
placing bilateral branch pulmonary artery bands and a PDA stent, through a small median
sternotomy on the beating heart, usually during the first week of life. Additionally, at a
later date, a balloon atrial septostomy is performed to create an adequate sized atrial
septal defect or opening between the left and right atrium. During the initial Hybrid Stage
I palliation, the surgeon places a 1-2mm wide Gore-Tex band around the left and right
pulmonary arteries. This is followed by placement of either a self-expandable or balloonexpandable stent in the ductus arteriosus by the interventional cardiology team through a
small sheath placed in the main pulmonary artery. The pulmonary artery bands control
blood flow to the lungs and protect the pulmonary bed from high pressure, while the PDA
stent provides a reliable means of maintaining cardiac output and retrograde aortic
perfusion to the brain and coronary arteries. Once the PDA stent is in place, prostaglandin
E1 infusion is discontinued immediately. Cardiac catheterization is performed at a
separate setting prior to discharge or when the atrial septal defect becomes restrictive of
blood flow from the left atrium. At that time a balloon atrial septostomy is performed in
order to allow unobstructed blood flow from the left atrium to the right atrium, thus
completing Stage I palliation.
18
Operative, post-operative, and interstage factors
The human body normally has a protective mechanism to initiate an inflammatory
response to destroy what it recognizes as foreign and ―not self.‖ A systemic inflammatory
response syndrome can occur from cardiopulmonary bypass as a result of surgical trauma
itself, blood coming in contact with non-physiological surfaces such as the bypass circuit,
or ischemia and endotoxins (Kats et al, 2010). Multiple factors contribute to the systemic
inflammatory response as a result of cardiopulmonary bypass including activation of the
coagulation cascade, both intrinsic and extrinsic pathways, along with increased
fibrinolytic activity, activation of the complement system, leukocyte activation including
pro-inflammatory cytokines, endothelial cell activation, and platelet activation. The end
products of the complement system activation may contribute to tissue injury due to proinflammatory effects. Studies have shown administering glucocorticoid can help
decrease pro-inflammatory cytokines including tumor necrosis factor alpha (TNF- )
interleukin (IL) -6, and IL-8, as well as increase IL-10, an anti-inflammatory cytokine
(Kats et al., 2010). Endotoxin come from gram negative bacteria cell walls and is
produced by intestinal flora. However, when endotoxin is in the circulation it binds to
various receptor sites and leads to cytokine production and an inflammatory response
(Kats et al, 2010). Studies have found endotoxins to be present in the cardioplegia
solution, priming fluid for the cardiopulmonary bypass circuit, contaminated
extracorporeal circuits, pulmonary artery catheters, intravenous fluids and banked blood
product used for transfusion, drugs, and surgical instruments (Andersen et al, 1987;
Nilsson et al, 1990; Miller & Levy, 1997; Kats et al, 2010). The overall systemic
19
inflammatory response following cardiopulmonary bypass contributes to post-operative
management of patients with HLHS who have undergone the Norwood procedure.
Complications from the systemic inflammatory response may ultimately affect major
organ systems, such as cardiac, respiratory, renal, and in particular the brain and
neurologic function (Paparella et al, 2002; Kats et al, 2010).
A variety of management strategies have been investigated to eliminate the
inflammatory response from cardiopulmonary bypass. From a pharmacologic approach,
corticosteroids have been used prophylactically before and during cardiopulmonary
bypass, however routine use is controversial. Selective digestive decontamination by
pharyngeal and gastric application of non-absorbable antibiotics has been reported in
adult coronary artery bypass graft and valvular surgery patients (Martinez-Pellus et al,
1993). Results showed lower endotoxin levels in the treated group compared to the
control group, however there was no difference in clinical outcomes. Other strategies
that have been employed include off-pump versus on-pump technique, pulsatile versus
nonpulsatile flow, and normothermia versus hypothermia, as well as pharmacologic
therapies to reduce the inflammatory response (Day & Taylor, 2005; Hill et al., 1995;
Mongero et al., 2001; Engelman et al., 1995). The fact remains that despite decreased
endotoxin and lactate levels, the body still elicits an inflammatory response to the
surgical trauma itself and manipulation of the heart.
In the immediate post-operative period following the Norwood or Norwood Sano
procedure, the cardiothoracic intensive care management team needs to be adept at
closely monitoring and treating lactate levels. The effects of cardiopulmonary bypass and
20
the systemic inflammatory response can alter multiple organ systems, resulting in postoperative complications. At times, the neonate will have difficulty being separated from
cardiopulmonary bypass and will require extracorporeal membrane oxygenation
(ECMO). Frequently, before transfer to the cardiothoracic intensive care unit, it is not
possible to close the chest in the immediate postoperative period for the Norwood or
Norwood-Sano patient, which adds another source of morbidity and surgical procedure.
Inotropic support in these patients is common.
Unlike the immediate post-operative outcomes in the Norwood or Norwood-Sano
patient, the post-operative care after Hybrid Stage I is remarkably different. In 40 HLHS
patients, after Hybrid Stage I palliation, with a median weight of 3.2kg, Galantowicz et al
(2008) reported 52% of Hybrid patients are extubated in the operating room, while 85%
are extubated within 24 hours. Inotropic support was not required in any patient and 79%
of patients were feeding within 24 hours. No patient required ECMO support or delayed
sternal closure. There was a reported 97.5% hospital survival to discharge with the
average length of stay 4.5 days in the cardiothoracic intensive care unit (CTICU) and the
average postoperative length of stay in the hospital was 13 days (Galantowicz et al,
2008). Although the Hybrid patients appear to do better post-operatively compared to the
Norwood patients with shorter time to extubation, initiation of enteral feeds, shorter
CTICU and hospital length of stay, there is uncertainty regarding oxygenation and
perfusion to the brain due to the anatomy of the persistent retrograde aortic blood flow.
More importantly, neurocognitive development and deficits are unknown at this time and
to date there is only one study reported in the literature (Knirsch, et al., 2012).
21
The interstage period between Stage I and Comprehensive Stage II surgical
palliation for HLHS is a vulnerable period in terms of infants reaching their nadir with
hematocrit and hemoglobin levels, as well as their immune system and protection from
maternal antibodies. The Hybrid patients are at some degree of risk for developing
intimal proliferation within the stented ductus as the nature of the ductal tissue wants to
close, with the risk of creating retrograde arch obstruction, recoarctation at the distal
PDA stent, decreased RV function. Hybrid Stage I palliation is independent of patient
size unlike the Norwood or Norwood-Sano palliation; babies as small as 1 kg have been
successfully palliated (Galantowicz et al., 2008; Cua et al., 2004). These extreme preterm
babies are at risk for other comorbidities such as interventricular hemorrhage and
necrotizing enterocolitis. Any of these events can lead to hospitalization, cardiorespiratory support, and cardiac catheterization with interventional therapy. These infants
need to be closely monitored with echocardiograms and electrocardiograms as
outpatients. Many centers have incorporated a home monitoring program for recording
daily intake for caloric monitoring, daily weight, and oxygen saturation monitoring.
Stage II palliation
The second staged reconstruction for HLHS after the Norwood procedure is
performed at approximately 6 months of age and consists of a cavopulmonary
anastomosis of the superior vena cava to the right pulmonary artery and takedown of the
Blalock-Taussig shunt by ligation and division. This second surgery is a bidirectional
Glenn shunt or hemi-Fontan (Figure 6). Both will have the same physiology. The
difference between the bidirectional Glenn and the hemi-Fontan is the transected cardiac
22
side of the superior vena cava from the right atrium is anastomosed to the undersurface of
the right pulmonary artery and a patch applied. This will decrease the amount of
cardiopulmonary bypass time at the final Fontan completion.
The second staged reconstruction after Hybrid Stage I palliation is termed the
Comprehensive Stage II procedure (Figure 7). This is considered the big open heart
surgery for staged palliation for HLHS. This incorporates removal of the PDA stent and
pulmonary artery bands, removal of the atrial septum, anastomosis of the diminutive
ascending aorta to the main pulmonary artery, and anastomosis of the diminutive
ascending aorta to the pulmonary artery and augmentation of the transverse aortic arch.
Stage III – Fontan completion
The third and final stage of reconstruction, the Fontan, is normally completed
around 18-24 months of age. This is the total cavopulmonary connection where the
inferior vena cava is now anastomosed to the pulmonary artery via an extra cardiac
pericardial baffle, completing the circuit (Figure 8). A small 4-5mm fenestration may be
performed to act as a pressure ―pop-off‖ allowing a small amount of ―blue‖ blood to
shunt across to the ―red‖ blood side. This may increase the risk of an embolic event,
therefore anticoagulation therapy is usually recommended. Fenestrations may be closed
non-surgically using a device in the cardiac catheterization suite at a later age.
Outcomes and neurodevelopment
When comparing cohorts of HLHS patients between surgical eras, different
surgical palliation strategies, and neurodevelopmental outcomes, it will be important to
23
compare a cohort of patients with uniform risk. This will require excluding babies who
have HLHS with intact atrial septum, who present with cyanosis and acidosis, and require
emergent creation of an atrial septal defect at birth. These patients are known to be at
higher risk for mortality and morbidity. Additionally, babies with severe prematurity and
HLHS are also identified as a higher risk group, as are those with genetic syndromes,
right ventricle dysfunction with significant tricuspid regurgitation due to perinatal
asphyxia, and those babies born with HLHS who were not identified prenatally, were
discharged home and the PDA closes resulting in cardiovascular collapse.
Mahle and colleagues (2002) compared serial brain MRI studies in 24 neonates
with complex CHD who underwent open heart surgery. Studies were performed preoperatively, early post-operatively (between 5-12 days) and late post-operatively between
3-6 months. Diagnoses included 13 neonates with single ventricle physiology; 8 of which
had HLHS. From a structural standpoint, 4 subjects were noted to have an open
operculum. Pre-operatively, 6 out of 24 (25%) were found to have ischemic lesions; 4
with periventricular leukomalacia (PVL) and 2 with small infarcts. In the early postoperative scan, (n=21) new or worsened lesions were noted in 14 subjects (67%); this
included 9 subjects with new PVL, 4 subjects with significant infarcts. New or worsened
lesions were noted in 7 of 12 (58%) patients who underwent the Norwood procedure
(figure 2). In the late post-operative scan, only 1 subject developed a new infarct. PVL
from early scans resolved in all subjects. Preoperatively 53% of subjects had increased
white matter lactate levels consistent with ischemia.
24
In another study by Dent and colleagues (2006) pre- and post-surgical brain MRI
studies were performed after the Norwood procedure using regional cerebral perfusion.
Ischemic lesions were noted in 5 out of 22 patients (23%) compared to new or worsened
lesions in 11 out of 15 (73%) patients. Neonates with HLHS undergoing a Norwood
procedure who had prolonged (>180 minutes) postoperative regional cerebral oxygen
saturation of 45% or lower, had new or worsened ischemia on early postoperative MRI
(Dent et al, 2006). What is considered a ―safe‖ threshold for hypoxia and cerebral
ischemia is yet to be determined for neonates undergoing open heart surgery. Multiple
variables can influence this threshold including shorter deep hypothermic cardiac arrest
and cross clamp time (Goldberg et al, 2007; Hanley, 2005), utilization of regional low
flow perfusion, as well as perfusion flow rate (Ohye et al, 2009; Goldberg et al 2007),
and oxygen saturation variability (Fenton et al, 2005; Kurth et al, 2001).
In a five year study by Glauser and colleagues (1990), findings at neonatal
autopsy reported one-third of HLHS infants had central nervous system anomalies and/or
were microcephalic. In another study, aortic morphometry and microcephaly was
evaluated in 129 term neonates with HLHS with a median head circumference at the 18th
percentile at birth (Shillingford et al, 2007). The mean birth weight was 3.2 + 0.5 kg. The
average head circumference + standard deviation (SD) was 33.9 cm + 1.6 cm, with
average percentile 26.5 + 20 percent. Mean and SD of the ascending aortic diameter was
3.2 + 1.5mm. Head circumferences were found to be disproportionately smaller than
birth weight and length, with 12% microcephaly noted. They noted a significant
correlation between those with microcephaly and a smaller ascending aortic diameter.
25
All of these studies suggest that having a diminutive ascending aorta with an atretic or
severely stenotic aortic valve, may result in abnormal cerebral development in the HLHS
fetus.
Not all children with HLHS have neurocognitive deficits and in fact, most have a
normal IQ and fall within the normal range for standardized testing. Goldberg and
colleagues (2007) showed that the average FSIQ score for 19 subjects with HLHS was
97.9 after the third and final stage with Fontan palliation. Wernovsky et al, (2000)
reported on a large series of HLHS patients after completing the third staged palliation,
the Fontan procedure. After undergoing a battery of developmental testing and adjusting
for socioeconomic status, statistically significant lower IQ was associated with deep
hypothermic circulatory arrest in HLHS patients. Mean FSIQ was 95.7 + 17.4 (p<0.006
compared to normal) and 10 patients had FSIQ scores <70 (p=0.001). Wernovsky (2000)
concluded that Fontan patients who received palliation in the 1980‘s have cognitive and
academic function within normal range; however, overall lower than the general
population. However, other studies reported major developmental disabilities during the
same era (Rogers, et al 1995).
A later study by Mahle et al., (2000) reported neurocognitive outcomes on 28
HLHS patients who had undergone the Norwood procedure. The findings showed a
median FSIQ of 86, 18% of these patients had significant mental retardation (FSIQ < 70).
This study demonstrated that only preoperative seizures significantly correlated with
lower FSIQ. Kern, et.al. (1998) reported moderate neurocognitive impairment, with
26
medians scores for FSIQ, verbal IQ, and performance IQ of 88, 91 and 83, respectively,
in HLHS patients after the Norwood procedure in 14 preschool subjects ages 3-6 years
and compared to family controls. In a study by Tabbutt, et al. (2008) 88 children with
HLHS were tested at 1 year of age, using the Bayley Scales of Infant Development,
second edition (BSD II) (Bayley, 1993) for Psychomotor Developmental Index (PDI) and
Mental Developmental Index (MDI). Although the median MDI was 90, 11% of children
had scores <70, 2 standard deviations (SD) below the normative population.
Interestingly, PDI scores were more adversely affected with a median score of 73, and
48% of children scoring <70, again 2 SD below the norm. These results are similar to
findings by Goldberg et al, (2007) with PDI scores lower than MDI scores, both before
second staged surgery (P < .0001) and at 1 year (P < .0001). Similarly, in a study by
Visconti et al (2006), 29 infants with HLHS did not perform well on the BSD II at one
year of age. Results showed median MDI and PDI scores of 87.7 and 75.2, demonstrating
a low average and mild delay respectively. Mental development and motor development
are both impacted, with motor development being more affected. Deficits in
neurodevelopment continue to be prevalent well into school-age. Neuropsychological
testing demonstrates that school-age children were well below normative values (Mahle
et al, 2006).
Wernovsky et al., (2000) found mean FSIQ was significantly lower compared
with the normal population and 7.8% of test subjects had FSIQ scores <70. After
controlling for socioeconomic status, lower IQ and independent risk factors for low
achievement scores was associated with HLHS and deep hypothermic circulatory arrest.
27
Previous studies examined children with single ventricle physiology who underwent the
Fontan operation (third and final staged palliation) and found IQ scores were lower
compared to the normal population, however intelligence scores were within 1 SD of the
norm (Uzark et al., 1998; Goldberg et al., 2000). Goldberg et al (2000) compared HLHS
and non-HLHS patients who under Fontan completion between 1989 and 1994. The
overall mean scores were within normal range however the HLHS group scored lower
than the non-HLHS group. Socioeconomic status, cardiac arrest and perioperative
seizures were associated with lower neurodevelopmental outcome. Visuomotor and
visuospatial skills, as well as language proficiency have also been reported below
expected norms (Mahle et al., 2006). Based upon neurologic examination, Mahle et al
(2000) reported 67% of HLHS patients met screening criteria for attention deficit
hyperactivity disorder, 18% had attention problems, 18% had behavior problems, and
20% of scores were identified for concerns of anxiety and depression. Shillingford et al
(2008) also reported clinically significant scores for inattention and hyperactivity in
school aged children with complex CHD, almost half of which had staged reconstruction
for HLHS and single ventricle.
In a more recent prospective study, a Finland group evaluated 22 patients with
HLHS and 14 with univentricular heart (single ventricle physiology) and compared them
with 42 healthy control children at a median age of 30.2 months (Sarajuuri et al., 2010).
The children were evaluated using the BSD II. The results showed a mean MDI score
was significantly lower (89.9) in patients with HLHS compared to control subjects
(105.5, P < .001), whereas there was no difference between patients with other single
28
ventricle lesions (98.5) and control subjects. The mean PDI score in the HLHS group
(80.7, P < .001), as well as in the univentricular heart group (94.5, P = .016),
demonstrated a statistically significant lower score compared with control subjects
(105.3) (Sarajuuri et al., 2010).
In a similar study, Atallah et al (2008) performed standardized developmental
testing using the BSD II on 94 children with HLHS comparing different surgical
strategies in different eras. The Norwood modified Blalock Taussig Shunt (NorwoodmBTS) era was from 1996-2002 (n=62) and the Norwood Right Ventricle to Pulmonary
Artery (Norwood-RVPA) (Figure 4) era was from 2002-2005 (n=32). Early and 2-year
mortality rates were 23% and 52% respectively in the mBTS era, and 6% and 19% in the
RVPA era. The mean MDI scores were not significantly different between groups. The
mean PDI scores were significantly higher and the incidence of psychomotor delay <70
was significantly lower for the RVPA group. High serum lactate levels were identified as
an independent predictor of 2-year mortality for both groups. As with many of these
studies, this study did not reach statistical power to show a statistical difference in the 2
groups for early mortality.
In a more recent study, Mahle, et al. (2012) studied the subjects from the Single
Ventricle Reconstruction Trial (Ohye, et al., 2010) and used a classification and
regression tree analysis model to predict severe neurodevelopment impairment, defined
as the PDI score of less than 70. Using the BSD II, 138 out of 313 (44%) scored less than
70. Predictors identified included intensive care unit length of stay greater than 46 days,
29
birth weight less than 2.7 kilograms, genetic syndromes and other anomalies, additional
cardiac procedures, and the use of at least 5 medications at hospital discharge. The model
correctly identified 75% of infants with a PDI score less than 70 (Mahle, et al., 2012).
HLHS from the Single Ventricle Reconstruction Trial were also assessed at 14.3
+ 1.1 months of age for psychomotor and mental development using the BSD II. Scores
were compared to norm referenced data. PDI and MDI scores were significantly
decreased compared to age matched controls. Independent predictors for low scores
included the institution, birth weight less than 2.5 kilograms, length of hospital stay,
complications, genetic syndrome, and lower maternal education for MDI (Newburger, et
al., 2012). Furthermore, the study concluded that ―impaired neurodevelopment‖ was
related to ―innate factors‖ and overall morbidity during infancy, versus intra-operative
management (Newburger, et al., 2012). This suggests that in order to improve
neurodevelopmental outcomes, the focus should not be related to surgical management in
the operating room, but perhaps in early interventions in neurodevelopment.
The first report comparing outcomes between the Norwood procedure and the
Hybrid procedure in 31 HLHS and other univentricular hearts showed no difference in
mortality at 1 year of age (31% in the Hybrid group versus 39% in the Norwood group,
p=.71) (Knirsch, et al., 2012). Surgical treatment strategy had no effect on outcomes.
Mortality was associated with low birth weight, older age at initial surgical palliation, and
a smaller diameter of the ascending aorta. Median PDI scores were significantly lower
than the norm (PDI 57, range 49–99, P < 0.001). Predictors of lower motor scores
30
included hospital length of stay and lower weight at the second staged surgery. Median
MDI scores were also lower than the norm-referenced data. The MDI scores were
associated with longer mechanical ventilation, longer intensive care and overall hospital
length of stay. This raises the question whether supplementary developmental
interventions can be performed while hospitalized.
Conclusions
The Hybrid Stage I procedure offers advantages over the Norwood and NorwoodSano procedures as the Hybrid does not require deep hypothermic circulatory arrest or
cardiopulmonary bypass (Galantowicz & Cheatham, 2005; Galantowicz et al., 2008). The
physiology however, remains the same, or similar to fetal physiology for retrograde aortic
arch blood flow to the brain and perfusion of the coronary arteries. After the Hybrid
procedure and up until the second staged surgical palliation, the Comprehensive Stage II
procedure performed at approximately 6 months of age, blood flow to the brain is
maintained through the PDA and is dependent upon retrograde flow of blood to the aortic
arch vessels and ultimately the vessels that perfuse the brain. It is presumed that there is
an adequate supply of oxygenated blood to the brain to prevent neurologic injury and
promote growth and development of the central nervous system. What is unknown is the
impact of the Hybrid procedure on short and long term neurodevelopmental outcomes,
although the first study to report developmental outcomes comparing the Norwood to the
Hybrid shows no difference. The Comprehensive Stage II procedure is considered the big
open heart surgical repair for those who underwent Hybrid Stage I. This is a long
31
complicated surgery, essentially incorporating part of the traditional Stage I palliation, as
well as the second stage of palliation, with the philosophy that the 5-6 month old infant is
more mature to tolerate cardiopulmonary bypass and circulatory arrest.
Now that the Hybrid Stage I is an accepted and practiced management strategy,
there is an ethical obligation to investigate in a scientific and systematic way, the
neurodevelopmental outcomes in HLHS infants who undergo Hybrid Stage I palliation
and ultimately compare them with infants who have had Norwood Stage I, as well as the
Norwood-Sano procedure. However, it will be difficult to perform a multi-center,
randomized clinical trial, with all three surgical strategies given the difference in surgical
technique, experience, or preference by cardiothoracic surgeons. Decisions are often
collaborative between the surgeon, cardiologist, and family on which strategy would
provide the best outcome. However, institution to institution neurodevelopmental
outcomes can be studied and compared using standardized testing methods, regardless of
the initial choice of Stage I palliation. The following chapter presents an initial
investigation into the development of infants born with HLHS, who undergo the Hybrid
Stage I palliation.
32
Chapter 3
Neurodevelopment following Hybrid Stage I for HLHS
Introduction
Hypoplastic left heart syndrome (HLHS) is a complex form of congenital heart
disease which requires three open heart surgeries during the first few years of life. HLHS
was a fatal diagnosis, the only option being comfort care, up until 1980. The first staged
open heart surgical procedure was first reported in the early 1980s (Norwood, et al.,
1981; Norwood, et al., 1983). During the ensuing years morbidity and mortality were
high and neurodevelopmental outcomes were not favorable. A variety of factors may
collectively contribute to the neurodevelopmental outcome in neonates who are born with
HLHS including genetic and epigenetic factors, prenatal cerebral blood flow effecting
brain growth and development, and open heart surgery in the newborn period. Over the
recent decades morbidity and mortality have improved. Advances in surgical technique,
pre- and post-operative management, cerebral oxygen monitoring particularly during
surgery, as well as advancement in bypass circuits and perfusion technique may all have
contributed to increased survival. However, despite these improvements and increased
survival, HLHS continues to have the worst neurodevelopmental outcomes compared to
other forms of congenital heart disease. To date, very little is known on
33
neurodevelopmental outcomes in children with HLHS who have undergone Hybrid Stage
I, Comprehensive Stage II, and Fontan completion. The following report describes
neurodevelopmental outcomes in infants with HLHS after Hybrid Stage I palliation.
Background
Neurodevelopmental outcome studies have been reported in children with HLHS
who have undergone the traditional staged Norwood palliation showing a lower level of
mental and psychomotor deficits compared to other forms of congenital heart disease, as
well as normal controls (Sarajuuri et al., 2010; Sarajuuri et al., 2009; Atallah et al., 2008;
Tabbutt et al., 2008; Visconti et al., 2006; Goldberg et al., 2007; Goldberg et al., 2000).
Rogers, et al (1995) examined neurodevelopment after palliative surgery for
HLHS, in a small cohort of 11 patients and reported 7 of these children (64%) had major
developmental disabilities. Kern, et al. (1998) reported moderate neurocognitive
impairment, with medians scores for full scale intelligence quotient (FSIQ), verbal
intelligence quotient (IQ), and performance IQ of 88, 91 and 83, respectively, in HLHS
patients after the Norwood procedure in 14 preschool subjects ages 3-6 years and
compared to family controls. A study of 88 children with HLHS, who underwent staged
reconstruction, were tested at 1 year of age, using the Bayley Scales of Infant
Development, second edition (BSD II) (Bayley, 1993) for Psychomotor Developmental
Index (PDI) and Mental Developmental Index (MDI). The median MDI was 90, however
11% of children had scores <70, 2 standard deviations (SD) below the normative
population. Interestingly, PDI scores were more adversely affected with a median PDI
score of 73, with 48% of children scoring <70, again 2 SD below the norm. Years later,
34
these results are similar to findings by Goldberg et al, (2007) with PDI scores lower than
MDI scores both before second staged surgery (P < .0001) and at 1 year (P < .0001).
Similarly, in a study by Visconti et al (2006), 29 infants with HLHS did not perform well
on the BSD II at one year of age. Results showed median MDI and PDI scores of 87.7
and 75.2, demonstrating a low average and mild delay respectively.
Not all children born with HLHS have neurocognitive deficits. In fact, HLHS is a
heterogeneous group and most have a normal IQ and fall within the normal range for
standardized testing. Goldberg and colleagues (2007) showed that the average FSIQ
score for 19 subjects with HLHS was 97.9 after the third and final stage with Fontan
palliation. Wernovsky et al, (2000) reported on a large series of HLHS patients after
Fontan completion. After undergoing a battery of developmental testing for overall preacademic and academic function, and adjusting for socioeconomic status, statistically
significant lower IQ was associated with deep hypothermic cardiac arrest in HLHS
patients. Mean FSIQ was 95.7 + 17.4 (p<0.006 compared to normal) and 10 patients had
FSIQ scores <70 (p=0.001). Wernovsky (2000) concluded that Fontan patients who
received palliation in the 1970‘s-1980‘s have cognitive and academic function within
normal range, however overall lower than the general population.
Contrary to this study, Mahle et al., (2000) reported neurocognitive outcomes on
28 HLHS patients who had undergone the Norwood procedure. The findings showed a
median FSIQ of 86, 18% of these patients had significant mental retardation (FSIQ < 70).
This study revealed that only preoperative seizures significantly correlated with lower
35
FSIQ. Deficits in neurodevelopment continue to be prevalent well into school-age.
Neuropsychologic testing demonstrated that school-age children were well below
normative values (Mahle et al, 2006).
In a select cohort of children with single ventricle who underwent the Fontan
operation, standardized testing for FSIQ and achievement testing was performed at a
median age of 11.1 years (Wernovsky et al., 2000). Mean FSIQ was significantly lower
compared with the normal population and 7.8% of test subjects had FSIQ scores <70.
After controlling for socioeconomic status, lower IQ and independent risk factors for low
achievement scores was associated with HLHS and deep hypothermic circulatory arrest.
Previous studies examined children with single ventricle physiology who underwent the
Fontan operation (third and final staged palliation) and found IQ scores were lower
compared to the normal population. However, intelligence scores were within 1 SD of the
norm (Uzark et al., 1998; Goldberg et al., 2000; Forbess et al., 2001). Goldberg et al.
(2000) compared HLHS and non-HLHS patients who under Fontan completion between
1989 and 1994. The overall mean scores were within normal range, however the HLHS
group scored lower than the non-HLHS group. Socioeconomic status, cardiac arrest and
perioperative seizures were associated with lower neurodevelopmental outcome.
Visuomotor and visuospatial skills, as well as language proficiency have also
been reported below expected norms (Mahle et al., 2006). Based upon neurologic
examination, Mahle et al (2000) reported 67% of HLHS patients met screening criteria
for attention deficit hyperactivity disorder. The investigators found 18% of children had
36
attention problems, 18% had behavior problems, and 20% of scores were identified for
concerns of anxiety and depression. Shillingford et al. (2008) also reported clinically
significant scores for inattention and hyperactivity in school aged children with complex
congenital heart disease, almost half of which had staged reconstruction for HLHS and
single ventricle physiology.
A Canadian group studied early childhood neurodevelopment and
compared the results to preschool neurocognitive results in children with complex
congenital heart disease who initially underwent cardiac surgery under 6 weeks of age
(Creighton et al., 2007). Developmental assessments were performed at a mean age of 22
months using the BSD II, and compared with the 5 year assessment. The subscales
included the MDI and the PDI. Out of the 85 children studied, 14 had HLHS and
underwent the Norwood procedure. For this subset of patients with HLHS, 5 year
survival was only 54%. The study reported a correlation between the MDI at 2 years and
the FSIQ at 5 years (r=0.9197; p< .001). Additionally, non-HLHS complex forms of
congenital heart disease scored higher than the Norwood HLHS group on PDI,
performance IQ, and visual motor integration. This showed a high correlation between
the two time intervals of testing, early childhood development to preschool, and a high
negative predictive value was reported within categories of intelligence.
In a similar study, Atallah et al (2008) performed standardized developmental
testing using the BSD II on 94 children with HLHS comparing different surgical
strategies in different eras. The Norwood modified Blalock Taussig Shunt (Norwood37
mBTS, figure 3) era was from 1996-2002 (n=62) and the Norwood Right Ventricle to
Pulmonary Artery (Norwood-RVPA), described in previous chapters (figure 4), era was
from 2002-2005 (n=32). Early and 2-year mortality rates were 23% and 52%
respectively in the mBTS era, and 6% and 19% in the RVPA era. The mean MDI scores
were not significantly different between groups. The mean PDI scores were significantly
higher and the incidence of psychomotor delay <70 was significantly lower for the RVPA
group. High serum lactate levels were identified as an independent predictor of 2-year
mortality for both groups. As with many of these studies, this study did not reach
statistical power to show a statistical difference in the 2 groups for early mortality.
In 2008, Tabbutt et al. reported on 83 children who underwent staged
reconstruction for HLHS and variants of single ventricle physiology who were tested at
one year of age using the BSD II. The median birth weight was 3.3 kg (range 2.1-4.5 kg).
Twenty-five patients (28%) had a confirmed or suspected genetic syndrome. Results for
the neuromuscular assessment were abnormal in 57 patients (65%). A median MDI score
was 90. Ten patients (11%) scored <70 which represents 2 standard deviations below the
mean for the general population. The median PDI score was 73. A total of 42 patients
(48%) scored <70. Contrary to other studies, there was no association between deep
hypothermic circulatory arrest and neurodevelopmental outcomes. Gestational ages
varied from 32 – 40 weeks. However, younger gestational age, the presence of a genetic
syndrome, and the need for preoperative intubation were identified as significant risk
factors associated with negative neurodevelopmental outcomes.
38
In a more recent prospective study, a Finland group evaluated 22 patients with
HLHS and 14 with univentricular heart (single ventricle physiology) and compared them
with 42 healthy control children at a median age of 30.2 months (Sarajuuri et al., 2010).
The children were evaluated using the BSD II. The results showed the mean MDI was
significantly lower (89.9) in patients with HLHS than in control subjects (105.5, P <
.001), whereas there was no difference between patients with non-HLHS single ventricle
(98.5) and control subjects. The mean PDI in the HLHS group (80.7, P < .001) as well as
in the single ventricle group (94.5, P = .016) demonstrated a statistically significant lower
score compared with control subjects (105.3) (Sarajuuri et al., 2010).
In a more contemporary study, Mahle, et al. (2012) studied the subjects from the
Single Ventricle Reconstruction Trial and used a classification and regression tree
analysis model to predict severe neurodevelopment impairment as defined as the
psychomotor development index score of less than 70. Using the BSD II, 138 out of 313
(44%) scored less than 70. Predictors identified included intensive care unit length of stay
greater than 46 days, birth weight less than 2.7 kilograms, genetic syndromes and other
anomalies, additional cardiac procedures, and the use of at least 5 medications at hospital
discharge. The model correctly identified 75% of infants with a PDI score less than 70
(Mahle, et al., 2012).
HLHS subjects from the Single Ventricle Reconstruction trial were also assessed
at 14.3 + 1.1 months of age for psychomotor and mental development, also using the
BSD II. Scores were compared to norm referenced data. PDI and MDI scores were
39
significantly decreased compared to age matched controls. Independent predictors for
low scores included the institution, birth weight less than 2.5 kilograms, length of
hospital stay, complications, genetic syndrome, and lower maternal education for MDI
(Newburger, et al., 2012). Furthermore, the study concluded that ―impaired
neurodevelopment‖ was related to ―innate factors‖ and overall morbidity during infancy,
versus intra-operative management (Newburger, et al., 2012). This suggests that in order
to improve neurodevelopmental outcomes, the focus should not be related to surgical
management in the operating room. Early interventions are needed in these infants. It is
important to note, all of these studies were performed on children with HLHS who have
undergone the traditional Norwood staged palliation.
The first published study on neurodevelopmental outcomes in infants with HLHS
and other univentricular hearts who underwent Hybrid Stage I palliation versus the
Norwood procedure was reported recently (Knirsch, et al., 2012). Results showed no
significant difference in 1 year mortality. Additionally, the PDI and MDI scores were
comparable in both groups (Hybrid n=9 and Norwood n=11), although significantly
lower than the norm at 1 year of age. Similar to previous development studies on
Norwood subjects, motor impairment was high. This study, like others, is limited to the
small sample size in a single institution without randomization.
The purpose of this research study is to compare neurodevelopmental outcomes in
HLHS infants after Hybrid Stage I palliation, with age-matched, normal healthy infants.
Specifically, the investigators seek to understand how the early motor, language, and
40
intellectual development of infants with HLHS who have undergone the Hybrid Stage I
procedure compares to that of healthy babies. The working hypothesis is infants with
HLHS will have lower developmental scores across time when compared to healthy
controls.
Methods
Study Design
The study is a longitudinal, repeated measures design, descriptive and prospective
in nature. Institutional Review Board approval was obtained prior to initiation of the
study. Between 2010 and 2012, all neonates admitted to Nationwide Children's Hospital
with a diagnosis of HLHS were screened for meeting inclusion/exclusion criteria
recruitment (Table 1). Those families who chose to have Hybrid Stage I palliation and
met the criteria for this procedure, were approached for study recruitment and potential
enrollment.
HLHS
Inclusion
Criteria
Exclusion
Criteria
Control
>36 weeks gestation
Planned Hybrid Stage I
Willing to follow up
Healthy newborns
>36 weeks gestation
Willing to follow up
<36 weeks gestation
Chromosomal
abnormality
Known central nervous
system injury, or
paralysis
Maternal history of drug
or alcohol abuse during
pregnancy
< 36 weeks gestation
Birth asphyxia
Apgar score <5 @ 5 minutes
Resuscitation at birth
Congenital heart disease, medical
diagnosis, central nervous system injury,
paralysis, seizures, active infection
Chromosome abnormality
Maternal history of drug or alcohol
abuse during pregnancy
Table 1. Inclusion and exclusion criteria of HLHS and control groups
Attempts to recruit normal healthy control subjects were performed through hand
delivery of letters to post-partum mothers of normal full term newborns at The Ohio State
41
University, Columbus, Ohio and advertising emails to employees at Nationwide
Children‘s Hospital, Columbus, Ohio, as well as screening the appointment roster for
newborn visits in the out-patient ambulatory clinic at Nationwide Children‘s Hospital,
and word of mouth. Subjects were screened to meet the inclusion/exclusion criteria.
Informed consent was obtained on all subjects prior to enrollment in the study.
Incentives were used to help retain enrolled study participants included paid parking, as
well as gift cards to a local department store, $20 at the 2 month visit, $25 at the 4 month
visit, and $30 at the 6 month visit.
The standardized tools used for measures of developmental assessment were the
Test of Infant Motor Performance (TIMP) (Campbell, 2007) and the Bayley Scales of
Infant and Toddler Development, 3rd edition (Bayley, 2006). Three domains within the
Bayley Scales were utilized for assessment: cognitive, language, and motor, with subscales
of receptive and expressive language, and gross and fine motor scales. Composite scores in
the HLHS group will be compared with corresponding scores in the control group as well
as norm-referenced data. A score of 100 + 15 defines the mean + SD of the normative
sampled population.
Test of Infant Motor Performance
The TIMP has been normed on a United States national sample of 990 infants
selected to reflect the racial/ethnic distribution of low birth weight infants (Campbell,
2005). It is used to diagnosis developmental delay in gross motor skills. The TIMP tests
the observed and elicited motor behavior in infants between the ages of 34 weeks postconceptional age and 4 months post-term to predict motor performance at 12 months.
42
The tool is a 42-item assessment of observed items of postural control and active
movement, and from elicited items tested by positioning in space and with visual and
auditory stimuli. The testing takes approximately 30 - 45 minutes. Test-retest reliability
has been performed and shows that infant scores are stable across a 3 day period
(Campbell et al., 2005). Therefore, a single test can be used for clinical decisions if the
infant‘s status allowed for optimal performance.
Construct validity testing of the TIMP has been performed and the 3 month
sensitivity and specificity of the TIMP exceeds many other developmental tests at a
similar age (Campbell et al., 2002). At 3 months of age the percent of accurately
predicting the outcome of an infant's motor performance using the TIMP is 87% (Kolobe
et al., 2004). This indicates that those infants who performed poorly at 3 months will
continue to do so at preschool age and those infants who performed well at 3 months can
be expected (91% probability) to continue to perform well at preschool age.
Age standards and scores for performance on the TIMP are reported starting at 34
weeks post conceptual age through 17 weeks post term (Campbell, 2002). The TIMP is
reliable and valid only up until 4 months of age, thereafter a change in the assessment
tool is required.
Bayley Scales of Infant and Toddler Development, Third Edition
The Bayley Scales of Infant and Toddler Development, Third Edition (BSD III)
(Bayley, 2006), is an individually administered instrument that assesses the
developmental functioning of infants and young children between 1 and 42 months of
age. This assessment tool is norm-referenced and covers all core developmental
43
domains. The purpose of this tool is to diagnose developmental delays within the three
administered domains: cognitive, language, and motor. The last two domains, socialemotional and adaptive behavior are questionnaires. For the trained healthcare
professional or therapist administering the tool, the average assessment takes
approximately 45 minutes for infants under 12 months of age. Scoring bbegins at the
letter that corresponds to the correct age and items are scored 0 or 1, based on whether
the skill was achieved. The basal is established with three passes in a row and scoring is
performed until a ceiling is reached which are five failures in a row. The raw scores are
added and converted to scaled scores (1-19; mean=10, SD=3) using a conversion table.
Scaled scores can be converted to composite scores and percentile ranks can be
determined.
Validity
Confirmatory Factor Analysis was performed for Cognitive, Language, and Motor
Scales. There is a relatively high correlation between BSID III Cognitive and Language
composites and the Wechsler Preschool and Primary Scale of Intelligence-Third Ed.
(r=.71-.83). Moderate correlations were demonstrated between BSID III Language
composite and Preschool Language Scale 4th ed. Auditory comprehension and expressive
communication was moderate (r = .51-.71). Moderate correlations between BSID III
Motor composite and Peabody Developmental Motor Skills 2nd edition (r = .49-.70). No
long-term predictive validity is available.
While the Bayley Scales covers all core developmental domains and is normreferenced for ages 1-42 months, the reliability was lowest (r =.71) for the 1-5 month age
44
group. Additionally, the test-retest reliability was as low as r = .67 in the 2-4 month
range. In order to assess motor, cognitive, and language domains using a reliable
measure, the BSID-III was chosen, starting at 6 months of age.
Reliability
Reliability of the BSID-III is high, particularly in children over 6 months of age,
demonstrated by internal consistency reliability with correlation for cognitive r = .91,
language r = .93, fine motor r = .86, expressive communication and gross motor r =
0.91. The lowest reliability reported is r =.71 in receptive and expressive communication
subtests for infants in the age group of 1-5 months.
The BSID-III has good test-retest reliability. The average test-retest reliability
correlation is r =.80 or higher across all ages, however ranging as low as r =.67 - .80 for
2-4 months and higher, r =.83 - .94, for ages 33-42 months.
Developmental assessment was performed on all subjects using standardized
developmental assessment tools. Infant motor skills were assessed using the TIMP at two
and four months of age. Subscales of the BSD III were used for assessing gross and fine
motor skills, expressive and receptive language, and cognitive skills at six months of age.
Although these assessment tools are standardized and norm-referenced for the general
population, a normal healthy control group was used for comparison to infants born with
HLHS. Including a normal healthy control group for comparison may be important to
distinguish mild behavior or developmental differences that otherwise may not be
identified using only the published norm-referenced data.
45
In order to control for experimenter bias, all study subject evaluations for
developmental testing were performed by an experienced therapist, adept at using both
tools. Attempts were made to keep testing conditions the same including the examination
room, lighting, noise level, free from distractions, and for the baby to be in a calm, awake
state. Evaluations were performed within a 2 week window at the designated time
intervals at 2, 4, and 6 months of age. All testing was performed prior to HLHS infants
undergoing the second staged open heart surgery and if clinical status allowed during the
testing period.
Scoring
Raw scores were obtained using both assessment tools. The TIMP included 13
observed items while the infant was laying supine, starting with the head in the midline
position. Midline is defined to include 15 degrees to either side of the midline. The baby
was observed; the infant was credited with 1 point for yes, and 0 points for no, or not
being observed. Items 18 through 42 are elicited items. Verbal and visual prompts may be
used, however no more than three trials are allowed for each elicited test item. Items
which test right and left are scored individually. Depending on the elicited item, scoring
is from 1-6. Observed and elicited items are totaled and compared to age standards and
scores for performance on the TIMP. Mean + SD and range of raw scores are reported
and are categorized as average (+ 1SD), low average (+ -.5 and -1SD), below average (+ 1 and -2SD), and far below average (-2SD below the mean).
For the BSD III, the starting point was determined by chronological age. Scoring
was performed according to the administration manual. A score of 1 is awarded if the
46
item is performed, and 0 if the item is not accomplished by the infant. Once the ceiling is
reached, the raw scores are totaled, and converted to scaled scores according to the tables
presented in the administration manual. Scaled scores range from 1-19, mean of 10 and a
SD of 3. Based on the scaled scores, composite scores and percentile ranks with
confidence intervals at the 95% level were determined for cognitive, language, and motor
skills. Composite scores are based on the sums of the subtest scaled scores, ranging from
40-160, mean of 100, and a SD of 15. A total of 68% of the population falls between 85
and 115 (+ 1 SD). The 95% confidence interval more accurately represents a range where
the true score for the child may fall. A score <70, >2 SD below the expected mean, will
be considered severely delayed.
Other variables collected included anthropometric measures for growth
parameters. Head circumference and weight gain will serve as a marker for brain growth
and development.
Statistical Analysis
Descriptive statistics were provided for all variables. Mean and standard deviation
were calculated for continuous variables. For continuous variables, two samples t-test or
Mann-Whitney U-test where appropriate for point group comparisons, while using
paired-t test or Wilcoxon signed-rank test for matched pairs was used. For repeated
measurement, a mixed model analysis of variance was used, which reduces the error
term, increases the power of analysis, and is powerful to deal with missing data. A power
analysis was performed a-priori. Using an alpha of .05, at 80% power, with a moderate
47
effect size, for a single group with 3 repeated measures, 14 subjects are needed in each
group. P<0.05 will be considered as statistically significant. Statistical analysis was
performed using SAS version 9.2 (SAS Institute, Inc., Cary, NC).
Results
A total of 22 newborns with HLHS were screened and 18 subjects were enrolled.
A total of 110 normal newborns were screened, however recruitment yielded only 6
enrollments as control subjects. Demographic variables are presented in Table 2. Weight,
height, and head circumference were lower in the HLHS group. The median head
circumference at birth in the control group was 36.1 centimeters (cm) (range 34.3 - 39cm)
compared to 33.5cm (range 30.5 - 36.5cm) in the HLHS group (p=0.0036). This places
the HLHS group in the 15% versus the control group in the 97% for head circumference
based on the World Health Organization standards.
Variable
HLHS n=18
Controls
n=6
P value
39
40
0.0277*
Apgar score (1, 5 min)
8, 9
8, 9
0.1506/0.5801
Birth weight (kg)
3.16
3.99
0.2712
Birth height (cm)
50
53
0.7381
Head circumference (cm)
33.5
36.2
0.0036*
Male / female
11 / 7
2/4
0.3572
Gestation in weeks
Table 2. Demographic variables of subjects in HLHS group vs. control group displayed as
median. Significant at p<.05*
48
During the study period there were 9 infants who had a cardiac arrest requiring
resuscitative measures. There were 4 deaths in the HLHS group. Two patients‘ clinical
status was critical and assessment was not performed at 4 months. One patient went on to
orthotopic heart transplant, 1 patient was clinically unstable for testing, and 1 patient
went to an early stage II surgical repair, therefore these patients did not undergo 6 month
assessment.
The median age for 2 month testing (n=14) was 62 days, 4 month testing (n=12)
was 117 days, and 6 month testing (n=11) was 170 days of age in the HLHS group. The
median age at testing in the control group (n=6) was 62, 120, and 181 days respectively.
Overall TIMP scores (HLHS and controls) were higher at 4 months than 2 months (p=
<0.0001). The HLHS group scored significantly lower compared to controls on the TIMP
at 2 months of age (p=0.002), and at 4 months of age (p=0.0019). The mean TIMP score
at 2 months was 63.9 + 18.1, median score 61.5 (range 30 - 98), in the HLHS group,
placing them -1 to -2 SD below the norm. Control subjects scored a mean of 94.5 + 10,
median 91 (range 85 - 112), which places them just above the mean for norm referenced
data. At 4 months of age, the mean TIMP score was 108.3 + 14.9, median score 111
(range 83-127) in the HLHS group, and mean of 133 + 4, median 133 (range 128-138) in
the control group. This placed the HLHS group -.5 to -1 SD below the norm referenced
mean, and the control group within 1 SD above the norm referenced mean.
At 6 months of age, a mean composite score in the HLHS group of 78.9 + 16.4
was obtained on the standardized measure of motor development, the mean composite
score of 88.5 + 12.4 on the standardized measure of language development, and the mean
49
score of 90.5 + 16 on the standardized measure of cognitive assessment, all relative to
infants of comparable age. Individual scores for the HLHS group are presented in Figure
9. There was a statistically significant difference between the HLHS group and the
control group in motor (fine and gross) skills (p=0.049). However, there was no
significant difference for cognitive (p=0.29) and language (receptive and expressive)
skills (p=0.68) at 6 months. All scores are displayed in Table 3 and results are displayed
in Table 4. Motor skills were significantly lower in the HLHS group at 6 months of age
compared to control subjects.
N
Group Obs
Variable
N
Mean
Median Minimum Maximum
HLHS
18 Cognitive
Language
Motor
11
11
11
90.4
88.5
78.9
95.0
89.0
74.0
55.0
62.0
46.0
110
106
103
Control
6 Cognitive
Language
Motor
6
6
6
99.7
88.8
97.8
102.5
94
107
84
58
68
115
118
110
Table 3. Descriptive statistics composite scores at 6 months
Variable
6 month Bayley
Cognitive
0.2883
6 month Bayley Language
6 month Bayley
Motor
0.0489*
0.6849
p-value
Table 4. Comparison between HLHS and Control Subjects at 6 months, significant at .05*
Descriptive classifications by level of performance for composite language scores
are presented in Table 5 for the HLHS group and normative population (Bayley, 2006).
Descriptive classifications by motor skill level of performance are presented in Table 6
50
for the HLHS group compared to the normative population (Bayley, 2006). Although the
majority of HLHS subjects fall within the average to borderline classification, a small
group of HLHS scores are classified as extremely low.
*Composite
Language Score
>130
*Classification
*Sample% (N=1700)
HLHS % (N=11)
Very Superior
2.0
0
120-129
Superior
7.9
0
110-119
High Average
14.2
0
90-109
Average
51.4
45.4
80-89
Low Average
14.4
36.4
70-79
Borderline
7.6
9.1
< 69
Extremely Low
2.4
9.1
Table 5. Percent Classification of Language Composite Scores vs. Normative Data
*(Bayley Scales of Infant and Toddler Development, third ed, Bayley, 2006)
*Composite
Motor Score
>130
*Classification
*Sample % (N=1700)
HLHS %
(N=11)
Very Superior
2.0
0
120-129
Superior
7.9
0
110-119
High Average
14.2
0
90-109
Average
51.4
36.4
80-89
Low Average
14.4
9.1
70-79
Borderline
7.6
36.4
< 69
Extremely Low
2.4
18.2
Table 6. Percent Classification of Motor Composite Scores vs. Normative Data
*(Bayley Scales of Infant and Toddler Development, third ed, Bayley, 2006)
51
Discussion
The Hybrid approach to HLHS is a viable option in the initial palliation of babies
with this disease. Studies assessing neurodevelopment in HLHS demonstrate significantly
lower development scores or intelligence scores compared to the normal age-matched
population (Mahle, et al., 2002; Wernovsky, et al., 2000; Goldberg, et al., 2007; Tabbutt,
et al., 2008; Newburger, et al., 2012; Knirsch, et al, 2012). Cognitive development in
HLHS is also impaired compared with controls, however, does not appear to be as
effected.
The landmark multicenter study by Ohye and colleagues (2010) is the first
surgical study randomizing patients to Norwood versus Norwood-Sano palliation for
staged surgical repair for HLHS. Newburger (2012) found no difference in
developmental outcomes based on either of these surgical techniques in this same cohort
of HLHS children at approximately 14 months of age. PDI and MDI scores were both
well below the norm with PDI <70 in 44% and MDI <70 in 16%. The question remains if
the Hybrid technique will yield similar results. Only one study to date has been presented
in the literature focusing on neurodevelopmental outcomes in this cohort of HLHS
patients following Hybrid Stage I palliation. Although this adds to the literature, it is
difficult to generalize results to all HLHS undergoing Hybrid Stage I palliation based on
a Hybrid sample of 9 subjects. Therefore, short and long term neurodevelopmental
outcomes still remain unknown.
Based on the results of this study, neurodevelopment appears to lag behind
normal controls from the time of initial assessment at 2 months of age and continues
52
through 5-6 months of age, at the second staged surgical procedure. The median
composite motor score of 74 (range 46 – 103) was approaching the level of being
considered severely delayed and warrants referral for intervention. This places this
specific study cohort in the median 4th percentile rank, and mean 17th percentile, for
motor development. However, these are basically theoretical values based on the normal
distribution. The findings in this study, along with previously reported more recent
studies, supports the growing evidence that neurodevelopment is impaired during fetal
life. Demographic results in the current study are consistent with other studies. Smaller
head circumference and weight in the HLHS group possibly suggests stunted brain
growth and development.
Most other neurodevelopment studies have used an earlier (2nd) edition of the
Bayley Scales. The third edition, used in the current study, is a revision of the Bayley
Scales of Infant Development, 2nd edition. The third edition was designed with five
domains to meet the federal and state guidelines for assessing development in infants and
children. Normative data was updated using a sample representing the United States
census from 2004. Psychometric properties were strengthened. New items were added to
encompass a greater floor and ceiling within each scale, while other items which were
difficult to administer or score were removed. Despite there being no universal definition
of developmental delay, the Bayley Scales of Infant and Toddler Development, third
edition can aid in diagnosing developmental delay comparing scores to the normative
population.
53
Up until recently no good practice guidelines were in place for evaluating patients
with CHD for developmental delay or identifying patients at risk for neurocognitive
impairment. Recently, the American Heart Association Congenital Heart Defects
Committee of the Council on Cardiovascular Disease in the Young, Council on
Cardiovascular Nursing, and Stroke Council published a scientific statement on
neurodevelopmental outcomes in children with CHD (Marino, et al., 2012). Infants with
HLHS are considered high risk for developmental delay and the committee recommends
frequent and routine assessment in the medical home (Marino, et al., 2012).
Limitations
The major limitation of the study is the biased, small sample size, particularly not
having an equal number of subjects in each group, and not reaching statistical power for
testing despite the total number of subjects enrolled in the HLHS group. Attrition through
death, readmissions for hemodynamic instability requiring resuscitation efforts and
prolonged mechanical ventilation, as well as early Comprehensive Stage II open heart
surgery, contributed to missing data points and not reaching power. Fifty percent of
HLHS subjects suffered a cardiac arrest which required intubation and resuscitation
during the study period. A total of 78% underwent an additional unplanned cardiac
catheterization, 50% of whom required some form of interventional procedure during the
catheterization, i.e. placing a stent in the retrograde aortic arch, or creating a larger atrial
septal defect. Some infants‘ clinical status was too critical to undergo developmental
testing. This is a vulnerable period, between Hybrid Stage I palliation and
Comprehensive Stage II, for this at-risk group. Multiple uncontrolled variables most
54
likely contributed to the motor function delays, including mechanical ventilation,
prolonged intensive care and hospital length of stay, cardiac output and oxygen
saturation, hemoglobin levels for oxygen carrying capacity, level of maternal education,
and even socio-economic status. The convenience sample adds bias to the sample
population and due to the study design, randomization was not possible.
Conclusions
A multi-center randomized clinical study evaluating HLHS patients who undergo
all three surgical strategies, Norwood, Norwood-Sano, and Hybrid, is necessary to
compare long terms outcomes in the current era. Ideally, the study protocol needs to
standardize post-operative care management and perform pre- and post-operative brain
imaging studies, such as MRI, as well as use standardized norm-referenced
developmental assessment tools, and compare the results to normal healthy controls. In
the interim, short term, interstage assessment using standardized assessment evaluation
tools, as well as careful monitoring for adequate cerebral blood flow for growth and
development, are crucial prior to undergoing the second and final staged open heart
surgical repair.
Early developmental screening utilizing norm-referenced assessment tools such as
the Bayley Scales of Infant and Toddler Development, Third Edition, should be
recommended as a standard of care in children with HLHS. Providing developmental
screening can help identify children at risk and provide developmental support for gross
and fine motor skills, as well as receptive and expressive language development.
55
Developmental assessment, support and intervention needs to begin in the newborn
period and continue throughout childhood.
56
Chapter 4
Assessment of Cerebral Blood Flow in HLHS after Hybrid Stage I Palliation
Background
Measurement of cerebral blood flow by Doppler ultrasound is gaining interest for
several reasons, including potential alterations in cerebral blood flow during fetal
development, evidence of brain tissue changes at birth, and smaller head circumference
prior to any intervention. In addition, there is beginning evidence of alterations in
cerebral blood flow after birth. Because of the concern over neurodevelopmental
outcomes for infants with hypoplastic left heart syndrome (HLHS), researchers have
begun to examine brain development during fetal life.
Fetal brain development depends upon oxygenated blood distribution and
obstruction. Alteration in cerebral blood flow patterns may affect normal brain
development and studies have shown that fetuses with HLHS have white matter injury on
neuropathology examination (Glauser, et al., 1990; Hinton, et al., 2008; Mahle, et al.,
2002).
Cerebral blood flow velocity in the circle of Willis, first measured in 1982
(Aaslid, et al.1982), remains fairly constant by autoregulation. Cerebral blood flow is
defined as cerebral perfusion pressure divided by cerebral vascular resistance of the
arterioles. When cerebral perfusion pressure drops, the resistance vessels dilate to
57
decrease the resistance, versus when cerebral perfusion pressure increases, the vessels
constrict to increase vascular resistance, keeping the cerebral blood flow constant.
Doppler ultrasound has been performed in normal fetuses as well as fetuses with
intrauterine growth retardation. A finding of increased cerebral diastolic blood flow in
the latter group has been suggestive of a compensatory autoregulation mechanism for
increased flow to the brain (Arbeille et al., 1997; Mari & Deter, 1992; Donofrio et al.,
2003). Fetuses with HLHS have been noted to have the lowest cerebral-placental
resistance ratio by Doppler, decreased weight, and smaller head circumference (Donofrio
et al., 2003; Kaltman et al., 2005). Abnormal cerebral blood flow in neonates with
congenital heart disease have been reported (Limperopoulos, et al., 2000; Te Pas, et al.,
2005). Normally, cerebral blood flow velocity increases throughout infancy and can be
measured in the middle and anterior cerebral artery non-invasively using transcranial
Doppler sonography (Ilves et al., 2008).
In the only study in which cerebral blood flow was examined prior to the first
surgical repair, newborn infants with HLHS had decreased cerebral blood flow (Licht et
al., 2004). In addition, there was a significant correlation between cerebral blood flow
and white matter injury. At present, there have been no reported evaluations of cerebral
blood flow in HLHS patients who have undergone Hybrid Stage 1 palliation. It is only
presumed that these infants have adequate cerebral blood flow and are developing
normally during the interstage period between Hybrid Stage I and the Comprehensive
Stage II. This is a vulnerable and critical time for this high risk group.
58
Magnetic resonance imaging (MRI) studies have shown white matter injury
preoperatively, as well as an increased number of new lesions postoperatively in HLHS
(Hinton, et al., 2007). Earlier studies indicate deep hypothermic circulatory arrest and
cardiopulmonary bypass required with the Norwood and Norwood-Sano Stage I
procedures have a negative correlation on neurodevelopmental outcomes (Wypij, et al.,
2003; Limperopoulos, et al., 2001; Andropoulis, et al., 2012; Bellinger, et al., 2003;
1999). This suggests that a relationship exists between deep hypothermic circulatory
arrest and neurologic injury. Contrary to this and despite these findings in these earlier
studies, a recent report by Newburger, et al. (2012) found no significant correlation
between operative factors such as cardiopulmonary bypass, deep hypothermic cardiac
arrest, and regional cerebral perfusion.
MRI has been the gold standard for brain imaging, however is not always possible
to obtain in HLHS patients. Transcranial Doppler (TCD) technology is an alternative
imaging modality, which can assist in evaluating cerebral hemodynamics. Using the
temporal bony window, TCD offers non-invasive, excellent resolution and is robust for
measuring peak systolic, diastolic, and mean pressures, pulsatility index, and calculating
cerebral resistance, particularly in the middle cerebral artery (Bode and Wais, 1988;
Polito, et al., 2006). TCD has been performed in normal, small for gestational age, and
intrauterine growth retarded fetuses (Arduini & Rizzo, 1990; Kaltman, et al., 2004; Mari,
et al., 1989; Mari & Deter, 1992; Mari, et al., 1994; Mari, et al, 2005; Mari, et al., 2007),
preterm (van Bel, et al., 1989) and term infants (Ilves, et al., 2008), as well as HLHS
(Donofrio, et al., 2003; 2011) and fetuses with right and left sided heart obstructive
59
lesions including 14 fetuses with HLHS (Kaltman, et al., 2005). Arduini and Rizzo
(1990) studied 1556 normal fetuses using transcranial Doppler to provide pulsatility
index values as reference limits. The findings of this large population study have been
used for normative data in healthy fetuses and compared to pulsatility index
measurements converted into Z-scores in other studies (Kaltman, et al., 2005).
Transcranial Doppler is able to detect cerebral blood flow during open heart
surgery with deep hypothermic circulatory arrest and cardiopulmonary bypass in
neonates with flow rates as low as 10 ml/kg per minute (Zimmerman, et al., 1997).
Normative values and what is considered adequate cerebral blood flow for growth and
development without risk of neural injury in patients with HLHS who undergo Hybrid
Stage I palliation is yet to be determined. Performing TCD measurements in HLHS
patients and comparing them to a normal healthy control group and associated
neurodevelopment, may help answer this question.
Bode (1988) studied cerebral blood flow velocity changes in response to
hypocapnia and hypercapnia in premature infants. The reported correlation between mean
velocity and transcutaneous carbon dioxide was poor (r = 0.42). Carbon dioxide
reactivity was absent in patients with interventricular hemorrhage and a patent ductus
arteriosus. The age and arousal state of the infant can have an effect on the velocity.
Blood flow velocity can change in response to vessel diameter change even though blood
flow is constant. It is unclear what velocity is needed for adequate cerebral blood flow in
HLHS babies after Hybrid Stage I palliation and during the interstage period.
60
The purpose of this study is to assess cerebral blood flow velocity in the middle
cerebral artery over time in babies with HLHS who undergo Hybrid Stage I palliation,
and compare findings with normal healthy age-matched controls. In addition, the study
seeks to evaluate whether there is a relationship between cerebral blood flow velocity and
neurodevelopmental outcomes in HLHS infants who undergo Hybrid Stage I palliation.
Methods
Study Design
The study is a prospective, case comparison, mixed model design with repeated
measures which will allow the subjects to be their own controls in this biased
convenience sample. A repeated measures design is the examination of data
longitudinally and assessment of change over time. The time interval for collecting data
points is the same for all subjects. Data points will be collected at baseline, 2, 4, and 6
months.
Institutional Review Board approval was obtained prior to initiation of the study.
Between April 2010 and November 2012, all neonates admitted to Nationwide Children‘s
Hospital with a diagnosis of HLHS were screened for recruitment. Parents of newborns
with HLHS undergoing Hybrid Stage I palliation were approached for recruitment and
potential enrollment.
Normal healthy newborns were recruited as control subjects. Recruitment was
through hand delivery of letters to post-partum mothers of normal full term newborns at
The Ohio State University, Columbus, Ohio and advertising emails to employees at
61
Nationwide Children‘s Hospital, Columbus, Ohio, as well as screening the appointment
roster for newborn visits in the out-patient ambulatory clinic at Nationwide Children‘s
Hospital, and word of mouth. Subjects were screened to meet the inclusion and exclusion
criteria.
Inclusion Criteria
The inclusion criteria for control subjects included age matched healthy
newborns, gestational age greater than or equal to 36 weeks, no known medical
diagnosis, illness or disease, no genetic or chromosomal abnormality, and willingness to
participate in follow up assessment. Inclusion criteria in the HLHS group included
neonates born greater than or equal to 36 weeks gestation with a diagnosis of HLHS or a
variant of HLHS, admitted to Nationwide Children‘s Hospital, and planned Hybrid Stage
I procedure, and willingness to participate in follow up.
Exclusion Criteria
The purpose of the exclusion criteria in the control group is to specifically
exclude any variable which may have impacted fetal brain growth and development, or
variables which may be the result of injury to the brain, such as hypoxic-ischemic insult
resulting in a low Apgar score, seizure activity or hydrocephalus. Any central nervous
system injury involving the spinal cord or paralysis will be excluded. Fevers in neonates
under 1 month of age are often treated with intravenous antibiotics to cover sepsis.
Systemic infection can affect any organ system, including the brain, and could potentially
be life threatening if not treated accordingly. Finally, any maternal history of drug or
alcohol abuse during the pregnancy could have impacted normal embryologic
62
development, or caused fetal brain injury which may result in abnormal
neurodevelopment or long term neurologic sequelae. Therefore, exclusions in the control
group will include gestational age < 36 weeks, history of birth asphyxia, Apgar scores
less than 5 at 5 minutes or requiring resuscitation after birth, congenital heart disease,
history of seizures, hydrocephalus, any genetic syndrome or chromosomal abnormality,
spinal cord injury, paralysis or partial paralysis including brachial plexus injury, febrile
illness or active infection, and maternal history of drug or alcohol abuse during
pregnancy. Exclusion criteria in the HLHS group includes prematurity less than 36 weeks
gestation, known genetic or chromosomal abnormality, central nervous system injury,
spinal cord paralysis, and maternal history for drug or alcohol abuse.
Informed consent was obtained on all subjects prior to enrollment in the study. To
maintain anonymity and protect health information, patient identifiers were removed and
all study information was stored in a password protected computer, and/or in a locked
cabinet in a locked office within the institution. Being a longitudinal study, incentives
were used to help retain enrolled study participants. A parking voucher was provided at
each visit, as well as a gift card to a local department store, $20 gift card at the 2 month
visit, $25 at the 4 month visit, and $30 at the 6 month visit.
Technical imaging
A Pediatric Neurologist, trained in TCD and brain imaging studies, provided
training for a standard protocol for imaging cerebral blood flow using the TCD machine.
Inter-rater reliability was demonstrated through a training protocol of the investigator
63
with repeat simulation. All TCD measures were obtained by either the Pediatric
Neurologist or the principal investigator.
Transcranial Doppler (TCD) sonography and a 2 megahertz (MHz) Doppler probe
was used to assess the middle cerebral artery in all study subjects in the HLHS group, as
well as the control group. The anatomical bifurcation of the middle cerebral artery served
as the reference point for within-subjects, thereby minimizing measurement error.
Cerebral blood flow velocity is the rate of blood flow over time through cerebral vessels.
The highest (peak), lowest (end-diastolic), and average (mean) blood flow velocities are
based on the systolic and diastolic phases of the cardiac cycle. These values are used to
calculate an index for variability of the pulsatile flow.
Insonation is performed through the bilateral bony temporal window in each
subject using a conventional transcranial Doppler machine with 2-Mhz transducer
(Viasys, Companion III, Madison, WI). The Doppler probe is placed approximately 1
centimeter in front of the external auditory meatus and 1-2 cm above the zygomatic arch
to direct the ultrasound beam. Gate depths are adjusted until the bifurcation of the middle
cerebral artery and anterior cerebral artery is identified. While maintaining transducer
position and angulation, blood-flow parameters were recorded including maximum mean
blood flow velocity (MV), peak systolic velocity (PV), end-diastolic velocity (EDV), and
pulsatility index (PI). Gosling‘s formula (Gosling & King, 1975) was used to calculate
the pulsatility index (PV–EDV/MV). The blood flow direction and waveform shape
recorded is an electronic spectral image of cerebral blood flow. The relative depths from
the reference bifurcation depth will remain consistent between study subjects and
64
between exams in the same subjects. All examinations are performed while the subject is
in a stable or quiet state. Variables recorded included peak systolic velocity, end-diastolic
velocity, mean velocity, and pulsatility index measured in cm/second. In order to improve
reliability measures for TCD and help reduce the standard error of measurement, 3
measurements were recorded and averaged. Variables were measured at baseline, and at
2, 4, and 6 months of age and results were compared between groups.
Cognitive, language, and motor skill domains were also tested at 6 months of age
using the Bayley Scales of Infant and Toddler Development, 3rd edition (Bayley, 2006).
The overall findings of the TCD variables over time were then compared to the scores of
developmental testing for cognitive, language, and motor skills.
Statistical analysis
Descriptive statistics were provided for all variables. Mean and standard deviation
were calculated for continuous variables. Two samples t-test or Mann-Whitney U-test,
where appropriate, for point group comparisons, while paired-t test or Wilcoxon signedrank test for matched pairs were used for continuous variables. Pearson product-moment
correlation coefficient and Spearman rho rank order correlation coefficient were used to
examine the extent to which TCD scores were associated with neurodevelopment scores.
For repeated measurement, a mixed model analysis was used, which reduces the error
term, increases the power of analysis, and is powerful to deal with missing data. A power
analysis was performed a-priori. Using an alpha of .05, at 80% power, with a moderate
effect size, for a single group with 4 repeated measures, 13 subjects will be needed in
65
each group. P<0.05 will be considered as statistically significant. Statistical analysis was
performed using SAS version 9.2 (SAS Institute, Inc., Cary, NC).
Results
A total of 22 newborns with HLHS were screened and 18 HLHS who met criteria
were enrolled. A total of 110 normal newborns were screened and recruited for
enrollment, however only 6 normal newborn control subjects were enrolled.
Demographic variables are reported in Table 6.
HLHS
n=18
Control
n=6
p value
39
40
0.0277*
Apgar score (1, 5 min)
8, 9
8, 9
0.1506/0.5801
Birth weight (kg)
3.16
3.99
0.2712
Birth height (cm)
50
53
0.7381
Head circumference (cm)
33.5
36.2
0.0036*
Male / female
11 / 7
2/4
0.3572
Variable
Gestation in weeks
Table 7. Demographic variables displayed as median. Statistically significant at p<0.05*
66
TCD measures were performed at 4 points in time, at a median age of 5 days, 62
days, 117 days, and 170 days in the HLHS group and 11 days, 62 days, 120 days, and
181 days in the control group. Overall, there was a significant difference in peak systolic
velocity (p= 0.0031), end-diastolic velocity (p<0.0001), mean velocity (p<0.0001) (Table
8) and pulsatility index (p=0.0011) (Table 9) between the HLHS group and the control
group. A significant trend in change over time increase was noted for peak systolic
velocity (p<0.0016) and mean velocity (p<0.0046).
The HLHS group scored lower than controls in all three domains of development,
however only motor skills were significantly different (p=0.0489) (Table 7). There was
no significant correlation between TCD variables and cognitive, language, and motor
skills, as performed using the Bayley Scales of Infant and Toddler Development, 3rd
edition (Bayley, 2006), at 6 months of age (Table 8).
Variable
p-value
Bayley
Cognitive
0.2883
Bayley
Language
0.6849
Bayley Motor
0.0489*
Table 8. Neurodevelopment comparison between HLHS and Control Subjects
at 6 months, significant at .05*
Cognitive
correlation p value
Language
correlation p value
Motor
correlation p value
PI
r= -0.128
p= 0.6237
r= 0.114 p=0.6621
r= -0.124 p =0.6360
mean
r= 0.286
p=0.2658
r= 0.226 p =0.3841
r= 0.356 p =0.1616
EDV
r= 0.114
p=0.6627
r= 0.013 p =0.9586
r= 0.07
PSV
r= 0.087
p=0.7383
r= 0.068 p =0.7953
r= 0.296 p =0.2494
p =0.7852
Table 9. Transcranial Doppler and neurodevelopment scores compared at 6 months of age
67
Discussion
Single ventricle anatomy may be comprised of a variety of anatomical diagnoses
in congenital heart disease (CHD) abnormalities including hypoplastic right ventricle,
unbalanced atrioventricular canal with either a dominant right or left ventricle, or
hypoplastic left heart syndrome (HLHS) which involves a constellation of left sided
abnormalities. HLHS and HLHS variants involve hypoplasia and underdevelopment of
the left ventricle, aortic valve atresia or stenosis, mitral valve atresia or stenosis, and a
diminutive ascending aorta. The surgical management strategies with three staged
surgical palliative surgeries are Norwood, Norwood-Sano or Hybrid Stage I, Stage II
(Bidirectional Glenn cavopulmonary anastomosis) or Comprehensive Stage II, and the
final stage III completion, the Fontan operation. Although all single ventricle physiology
infants undergo staged palliation, not all have the same risk of morbidity and mortality,
especially when it comes to neurodevelopmental outcomes. Single ventricle physiology
of a hypoplastic right ventricle has fetal cerebral blood flow similar to normal newborns
but quite unlike those with HLHS where cerebral blood flow is dependent upon
retrograde or backward flow across the ductus arteriosus to the aortic arch to perfuse the
brain and the coronary arteries.
Head circumference serves as an indirect measure of adequate brain growth. For
infants born with HLHS, head circumference measurements at birth that are below
average suggest inadequate brain development (Shillingford, et al., 2007). Newborn
infants with HLHS have been found to have smaller head circumferences when compared
to healthy controls (Hinton, et al., 2008; Manzar, et al., 2005; Shillingford, et al., 2007),
68
which was also present in this study cohort of HLHS subjects. It is worrisome that the
smaller head circumferences were not proportionate to measures of weight and length,
and that a smaller head circumference at birth is most likely reflective of alterations in
cerebral blood flow (Hinton, et al., 2008; Shillingford, et al., 2007).
The method used for obtaining TCD measures is operator dependent. The imaging
requires a high level of skill to acquire quality images of cerebral blood flow in the
cerebral arteries, in particularly if an infant is not being cooperative. Transcranial
Doppler has been used as a screening tool in infants undergoing cardiac surgery to
evaluate cerebral blood flow and as an alternative to non-invasive infrared spectroscopy,
which measures regional cerebral oxygenation (Fraser & Andropoulos, 2008).
Transcranial Doppler may detect alterations in cerebral perfusion which may lead to
cerebral tissue ischemia and ultimately neurologic injury. Early detection and prevention
of cerebral ischemia and hypoxemia is crucial for prevention of long term neurologic
sequelae. Doppler mean pressures may not be capable of detecting small changes in
pressure. Taking multiple measures in a single subject may provide a value which is
closer to the true measure. TCD has been used to measure the pulsatility index serially as
a noninvasive measure associated with cerebral perfusion pressure and intracranial
pressure (Bellner, et al., 2004). Although a correlation between these variables was
reported, this is not a true measure.
This is the first study to evaluate cerebral blood flow velocities in HLHS infants
who undergo Hybrid Stage I palliation. Based on the findings in the current study, overall
TCD measures are lower compared to normal age-matched controls. This may be due to
69
variables such as mechanical ventilation, medication, hemoglobin and hematocrit, or
intensive care and hospital length of stay, which were not controlled for. However, in
comparing baseline TCD results in the current study to published reference values of
flow velocities in the middle cerebral artery at 0-1 month of age (Bode, 1988), results are
very similar. Comparing TCD results in the current study, at a median age of 170 days or
5.6 months, to published reference values for 5-6 month old normal infants (Bode, 1988)
all measures are lower in the HLHS group. For example, reference values of the flow
velocity in the middle cerebral artery for a 5-6 month old: peak systolic velocity 109,
end-diastolic velocity 45, mean velocity 71, with a calculated pulsatility index of 0.9;
compared with corresponding median measures in the HLHS group of: 86, 17, 49, and
1.5 respectively. When comparing overall group difference of change with time, there is a
significant trend noted in the peak systolic and mean velocity. However, this is expected
as normally blood pressure parameters increase from the neonatal period.
Limitations
The greatest weakness of this study, being non-experimental in nature, is the lack
of control over the independent variable of cerebral blood flow, as it is inherently not
manipulable. The independent variable cannot be manipulated and although the sample
selection is a biased convenience sample, the researcher has no control over the cerebral
blood flow, even if an interaction exists. Technology dependent devices are subject to
calibration and error in measurement which can be a limitation for interpreting study
results. The limitations of this measurement include lack of machine calibration for TCD
70
which can alter output data and the use of two different TCD machines due to machine
failure, although they were from the same company.
Threats to internal and external validity
Significant events that may impact the testing of variables and results for HLHS
babies included additional hospital admissions, prolonged intensive care and hospital
length of stay, additional interventional or surgical procedures, particularly those
performed under anesthesia, and cardiac arrest requiring resuscitation. Age-matched
controls helped eliminate the maturation threat in this longitudinal study.
Attrition, particularly related to mortality, was expected during the course of the
study in the HLHS group. Additionally, although control subjects did not drop out,
missing data points resulted from study appointment cancelations. Selection bias is a
noted threat to the internal validity. Given the nature of the disease with HLHS,
randomization was not an option. Matching with control subjects, in addition to having
an adequate sample size helped control for this.
The sampling of the HLHS population is limited based on the incidence of the
disease. Although a small sample size is a threat to external validity and generalizing to
the overall population, reaching statistical power would strengthen the results of the
study. Another possible threat to external validity is the sampling of infants from the
same geographic location. Although this is true in the control group, the HLHS infants
came from a variety of geographic locations outside the Columbus area, as well as
outside the state of Ohio.
71
Sources of measurement error in relation to the accuracy and precision of TCD
for systematic error may be from the portable TCD system, including the Doppler
display, measures of depth range, measures of standard test parameters, color resolution
display, or the 2 MHz Doppler probe.
Conclusions
Transcranial Doppler is a safe, non-invasive method for monitoring cerebral
blood flow velocity using serial measurements. Although no significant correlation
between TCD and neurodevelopmental outcome measures of cognitive, language, and
motor skills were noted in this study, this is still an important finding. Transcranial
Doppler values, in 5-6 month old infants with HLHS who undergo Hybrid Stage I
palliation, are lower than the values in normal age-matched infants. Unfortunately, the
inability to control variables effecting these values does not allow satisfactory
comparison, but may show a trend. The alternative management strategy for HLHS using
Hybrid Stage I palliation, which relies on retrograde cerebral perfusion, does not appear
to have any worse adverse effects on neurodevelopmental outcomes scores when
compared to the traditional Norwood Stage I as reported in previous chapters. A larger
sample size may allow for statistically significant TCD findings to be more predictive of
neurodevelopmental outcomes in this high risk patient population.
72
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Appendix A: List of Abbreviations
Ao
bHLH
BSD II
BSD III
CHD
cm
cm/sec
CPB
CTICU
EDV
FSIQ
HLHS
IVC
kg
LA
LPA
LV
mBTS
MDI
MPA
MRI
MV
NPLS
PDA
PDI
PI
PSV
PVL
RA
RPA
RV
RV-PA
SD
SVC
TIMP
aorta
basic helix loop helix
Bayley Scales of Infant Development, 2nd edition
Bayley Scales of Infant and Toddler Development, 3rd edition
congenital heart disease
centimeter
centimeter per second
cardiopulmonary bypass
cardiothoracic intensive care unit
end-diastolic velocity
full scale intelligence quotient
hypoplastic left heart syndrome
inferior vena cava
kilogram
left atrium
left pulmonary artery
left ventricle
modified Blalock-Taussig
mental development index
main pulmonary artery
magnetic resonance imaging
mean velocity
non-parametric linkage score
patent ductus arteriosus
psychomotor development index
pulsatility index
peak systolic velocity
periventricular leukomalacia
right atrium
right pulmonary artery
right ventricle
right ventricle to pulmonary artery
standard deviation
superior vena cava
Test of Infant Motor Performance
91
Figure 1 Normal heart anatomy with patent ductus arteriosus (A&B) Arrows depict
direction of normal blood flow (B) (Sisk, M., 2012, reprinted with permission)
A
B
PDA
SVC
RPA
LPA
Ao
MPA
RA
PV
LA
LV
RV
IVC
SVC superior vena cava
RPA right pulmonary artery
IVC inferior vena cava
LPA left pulmonary artery
RA right atrium
PV pulmonary veins
RV right ventricle
LA left atrium
MPA main pulmonary artery
LV left ventricle
PDA patent ductus arteriosus
Ao aorta
92
Figure 2 Hypoplastic left heart syndrome (HLHS) with arrows showing direction of
blood flow. (Sisk, M., 2012, reprinted with permission)
SVC
Ao
PDA
RPA
LPA
PV
MPA
LA
RA
LV
RV
IVC
SVC superior vena cava
RPA right pulmonary artery
IVC inferior vena cava
LPA left pulmonary artery
RA right atrium
PV pulmonary veins
RV right ventricle
LA left atrium
MPA main pulmonary artery
LV left ventricle
PDA patent ductus arteriosus
Ao aorta
93
Figure 3 Norwood stage I palliation for HLHS (close up and unroofed view)
The pulmonary artery has been transected at its bifurcation and the distal end over sewn.
Pulmonary blood flow is provided through a modified Blalock-Taussig shunt. The aortic
arch is augmented with a patch and connected to the proximal main pulmonary artery.
The atrial septum is also removed for unrestricted blood flow from the left atrium to the
right atrium (not shown). (Sisk, M., 2012, reprinted with permission)
Modified BT shunt
94
Figure 4 Norwood –Sano Stage I for HLHS
The pulmonary artery has been transected at its bifurcation and the distal end over sewn.
Pulmonary blood flow is provided through a right ventricle to pulmonary artery (RV-PA)
shunt. The aortic arch is augmented with a patch and connected to the proximal main
pulmonary artery. The atrial septum is also removed for unrestricted blood flow from the
left atrium to the right atrium (not shown). (Sisk, M., 2012, reprinted with permission)
RV-PA shunt
95
Figure 5 Hybrid Stage I palliation for HLHS
Pulmonary artery bands are placed around the left and right pulmonary arteries (LPA,
RPA), a bare metal stent is placed in the patent ductus arteriosus (PDA), and balloon
atrial septostomy is performed to create an opening between the upper heart chambers to
allow unobstructed blood flow returning from the left atrium to the right atrium. (copyright
Nationwide Children‘s Hospital, reprinted with permission)
PDA stent
RPA Band
LPA Band
Balloon Atrial Septostomy
96
Figure 6 Comprehensive Stage II palliation
The patent ductus arteriosus (PDA) stent and the right and left pulmonary artery bands
are removed, the main pulmonary artery is divided and over sewn, and the small
ascending aorta is anastomosed to the pulmonary artery with patch augmentation of the
transverse aortic arch. The superior vena cava (SVC) is divided and over sewn on the
cardiac side, and anastomosed to the right pulmonary artery for venous return from the
SVC out to both lungs. (copyright Nationwide Children‘s Hospital, reprinted with permission)
Superior vena cava
Augmented aortic arch
97
Figure 7 Bidirectional Glenn – Stage II repair for HLHS
Cavopulmonary anastomosis of superior vena cava to the right pulmonary artery and
takedown of the Blalock-Taussig shunt. ―Blue‖ blood from upper body returns to lungs
through the superior vena cava anastomosis. ―Blue‖ blood from lower body returns to
heart from the inferior vena cava and is pumped out the ―neoaorta‖ across augmented
aortic arch, mixing unoxygenated blood with oxygenated blood results in lower oxygen
saturations. (Sisk, M., 2012, reprinted with permission)
Superior vena cava
Neoaorta & Augmented aortic arch
98
Figure 8 Extra cardiac Fontan – 3rd and final stage for HLHS palliation
Total cavo-pulmonary connection – the inferior vena cava and superior vena cava
connect to the pulmonary artery allowing all venous blood to flow to the lungs. (Sisk, M.,
2012, reprinted with permission)
Cavo-pulmonary
connection
99
Figure 9 Development Scores in HLHS group
Scatter plot demonstrating composite scores for developmental testing at 6 months
Developmental Scores in HLHS
120
Composite Score
100
80
HLHS Cognitive
60
HLHS Language
40
HLHS Motor
20
0
0
2
4
6
8
10
Subject
12
100
14
16
18
Figure 10 Median transcranial Doppler cerebral velocities
101
Figure 11 Median transcranial Doppler pulsatility index of HLHS and control groups
Overall group difference P=0.0011
102