Journal of Clinical and Diagnostic Research, ISSN - 0973 - 709X

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Dr Bhanu K Bhakhri

"The Journal of Clinical and Diagnostic Research (JCDR) has been in operation since almost a decade. It has contributed a huge number of peer reviewed articles, across a spectrum of medical disciplines, to the medical literature.
Its wide based indexing and open access publications attracts many authors as well as readers
For authors, the manuscripts can be uploaded online through an easily navigable portal, on other hand, reviewers appreciate the systematic handling of all manuscripts. The way JCDR has emerged as an effective medium for publishing wide array of observations in Indian context, I wish the editorial team success in their endeavour"



Dr Bhanu K Bhakhri
Faculty, Pediatric Medicine
Super Speciality Paediatric Hospital and Post Graduate Teaching Institute, Noida
On Sep 2018




Dr Mohan Z Mani

"Thank you very much for having published my article in record time.I would like to compliment you and your entire staff for your promptness, courtesy, and willingness to be customer friendly, which is quite unusual.I was given your reference by a colleague in pathology,and was able to directly phone your editorial office for clarifications.I would particularly like to thank the publication managers and the Assistant Editor who were following up my article. I would also like to thank you for adjusting the money I paid initially into payment for my modified article,and refunding the balance.
I wish all success to your journal and look forward to sending you any suitable similar article in future"



Dr Mohan Z Mani,
Professor & Head,
Department of Dematolgy,
Believers Church Medical College,
Thiruvalla, Kerala
On Sep 2018




Prof. Somashekhar Nimbalkar

"Over the last few years, we have published our research regularly in Journal of Clinical and Diagnostic Research. Having published in more than 20 high impact journals over the last five years including several high impact ones and reviewing articles for even more journals across my fields of interest, we value our published work in JCDR for their high standards in publishing scientific articles. The ease of submission, the rapid reviews in under a month, the high quality of their reviewers and keen attention to the final process of proofs and publication, ensure that there are no mistakes in the final article. We have been asked clarifications on several occasions and have been happy to provide them and it exemplifies the commitment to quality of the team at JCDR."



Prof. Somashekhar Nimbalkar
Head, Department of Pediatrics, Pramukhswami Medical College, Karamsad
Chairman, Research Group, Charutar Arogya Mandal, Karamsad
National Joint Coordinator - Advanced IAP NNF NRP Program
Ex-Member, Governing Body, National Neonatology Forum, New Delhi
Ex-President - National Neonatology Forum Gujarat State Chapter
Department of Pediatrics, Pramukhswami Medical College, Karamsad, Anand, Gujarat.
On Sep 2018




Dr. Kalyani R

"Journal of Clinical and Diagnostic Research is at present a well-known Indian originated scientific journal which started with a humble beginning. I have been associated with this journal since many years. I appreciate the Editor, Dr. Hemant Jain, for his constant effort in bringing up this journal to the present status right from the scratch. The journal is multidisciplinary. It encourages in publishing the scientific articles from postgraduates and also the beginners who start their career. At the same time the journal also caters for the high quality articles from specialty and super-specialty researchers. Hence it provides a platform for the scientist and researchers to publish. The other aspect of it is, the readers get the information regarding the most recent developments in science which can be used for teaching, research, treating patients and to some extent take preventive measures against certain diseases. The journal is contributing immensely to the society at national and international level."



Dr Kalyani R
Professor and Head
Department of Pathology
Sri Devaraj Urs Medical College
Sri Devaraj Urs Academy of Higher Education and Research , Kolar, Karnataka
On Sep 2018




Dr. Saumya Navit

"As a peer-reviewed journal, the Journal of Clinical and Diagnostic Research provides an opportunity to researchers, scientists and budding professionals to explore the developments in the field of medicine and dentistry and their varied specialities, thus extending our view on biological diversities of living species in relation to medicine.
‘Knowledge is treasure of a wise man.’ The free access of this journal provides an immense scope of learning for the both the old and the young in field of medicine and dentistry as well. The multidisciplinary nature of the journal makes it a better platform to absorb all that is being researched and developed. The publication process is systematic and professional. Online submission, publication and peer reviewing makes it a user-friendly journal.
As an experienced dentist and an academician, I proudly recommend this journal to the dental fraternity as a good quality open access platform for rapid communication of their cutting-edge research progress and discovery.
I wish JCDR a great success and I hope that journal will soar higher with the passing time."



Dr Saumya Navit
Professor and Head
Department of Pediatric Dentistry
Saraswati Dental College
Lucknow
On Sep 2018




Dr. Arunava Biswas

"My sincere attachment with JCDR as an author as well as reviewer is a learning experience . Their systematic approach in publication of article in various categories is really praiseworthy.
Their prompt and timely response to review's query and the manner in which they have set the reviewing process helps in extracting the best possible scientific writings for publication.
It's a honour and pride to be a part of the JCDR team. My very best wishes to JCDR and hope it will sparkle up above the sky as a high indexed journal in near future."



Dr. Arunava Biswas
MD, DM (Clinical Pharmacology)
Assistant Professor
Department of Pharmacology
Calcutta National Medical College & Hospital , Kolkata




Dr. C.S. Ramesh Babu
" Journal of Clinical and Diagnostic Research (JCDR) is a multi-specialty medical and dental journal publishing high quality research articles in almost all branches of medicine. The quality of printing of figures and tables is excellent and comparable to any International journal. An added advantage is nominal publication charges and monthly issue of the journal and more chances of an article being accepted for publication. Moreover being a multi-specialty journal an article concerning a particular specialty has a wider reach of readers of other related specialties also. As an author and reviewer for several years I find this Journal most suitable and highly recommend this Journal."
Best regards,
C.S. Ramesh Babu,
Associate Professor of Anatomy,
Muzaffarnagar Medical College,
Muzaffarnagar.
On Aug 2018




Dr. Arundhathi. S
"Journal of Clinical and Diagnostic Research (JCDR) is a reputed peer reviewed journal and is constantly involved in publishing high quality research articles related to medicine. Its been a great pleasure to be associated with this esteemed journal as a reviewer and as an author for a couple of years. The editorial board consists of many dedicated and reputed experts as its members and they are doing an appreciable work in guiding budding researchers. JCDR is doing a commendable job in scientific research by promoting excellent quality research & review articles and case reports & series. The reviewers provide appropriate suggestions that improve the quality of articles. I strongly recommend my fraternity to encourage JCDR by contributing their valuable research work in this widely accepted, user friendly journal. I hope my collaboration with JCDR will continue for a long time".



Dr. Arundhathi. S
MBBS, MD (Pathology),
Sanjay Gandhi institute of trauma and orthopedics,
Bengaluru.
On Aug 2018




Dr. Mamta Gupta,
"It gives me great pleasure to be associated with JCDR, since last 2-3 years. Since then I have authored, co-authored and reviewed about 25 articles in JCDR. I thank JCDR for giving me an opportunity to improve my own skills as an author and a reviewer.
It 's a multispecialty journal, publishing high quality articles. It gives a platform to the authors to publish their research work which can be available for everyone across the globe to read. The best thing about JCDR is that the full articles of all medical specialties are available as pdf/html for reading free of cost or without institutional subscription, which is not there for other journals. For those who have problem in writing manuscript or do statistical work, JCDR comes for their rescue.
The journal has a monthly publication and the articles are published quite fast. In time compared to other journals. The on-line first publication is also a great advantage and facility to review one's own articles before going to print. The response to any query and permission if required, is quite fast; this is quite commendable. I have a very good experience about seeking quick permission for quoting a photograph (Fig.) from a JCDR article for my chapter authored in an E book. I never thought it would be so easy. No hassles.
Reviewing articles is no less a pain staking process and requires in depth perception, knowledge about the topic for review. It requires time and concentration, yet I enjoy doing it. The JCDR website especially for the reviewers is quite user friendly. My suggestions for improving the journal is, more strict review process, so that only high quality articles are published. I find a a good number of articles in Obst. Gynae, hence, a new journal for this specialty titled JCDR-OG can be started. May be a bimonthly or quarterly publication to begin with. Only selected articles should find a place in it.
An yearly reward for the best article authored can also incentivize the authors. Though the process of finding the best article will be not be very easy. I do not know how reviewing process can be improved. If an article is being reviewed by two reviewers, then opinion of one can be communicated to the other or the final opinion of the editor can be communicated to the reviewer if requested for. This will help one’s reviewing skills.
My best wishes to Dr. Hemant Jain and all the editorial staff of JCDR for their untiring efforts to bring out this journal. I strongly recommend medical fraternity to publish their valuable research work in this esteemed journal, JCDR".



Dr. Mamta Gupta
Consultant
(Ex HOD Obs &Gynae, Hindu Rao Hospital and associated NDMC Medical College, Delhi)
Aug 2018




Dr. Rajendra Kumar Ghritlaharey

"I wish to thank Dr. Hemant Jain, Editor-in-Chief Journal of Clinical and Diagnostic Research (JCDR), for asking me to write up few words.
Writing is the representation of language in a textual medium i e; into the words and sentences on paper. Quality medical manuscript writing in particular, demands not only a high-quality research, but also requires accurate and concise communication of findings and conclusions, with adherence to particular journal guidelines. In medical field whether working in teaching, private, or in corporate institution, everyone wants to excel in his / her own field and get recognised by making manuscripts publication.


Authors are the souls of any journal, and deserve much respect. To publish a journal manuscripts are needed from authors. Authors have a great responsibility for producing facts of their work in terms of number and results truthfully and an individual honesty is expected from authors in this regards. Both ways its true "No authors-No manuscripts-No journals" and "No journals–No manuscripts–No authors". Reviewing a manuscript is also a very responsible and important task of any peer-reviewed journal and to be taken seriously. It needs knowledge on the subject, sincerity, honesty and determination. Although the process of reviewing a manuscript is a time consuming task butit is expected to give one's best remarks within the time frame of the journal.
Salient features of the JCDR: It is a biomedical, multidisciplinary (including all medical and dental specialities), e-journal, with wide scope and extensive author support. At the same time, a free text of manuscript is available in HTML and PDF format. There is fast growing authorship and readership with JCDR as this can be judged by the number of articles published in it i e; in Feb 2007 of its first issue, it contained 5 articles only, and now in its recent volume published in April 2011, it contained 67 manuscripts. This e-journal is fulfilling the commitments and objectives sincerely, (as stated by Editor-in-chief in his preface to first edition) i e; to encourage physicians through the internet, especially from the developing countries who witness a spectrum of disease and acquire a wealth of knowledge to publish their experiences to benefit the medical community in patients care. I also feel that many of us have work of substance, newer ideas, adequate clinical materials but poor in medical writing and hesitation to submit the work and need help. JCDR provides authors help in this regards.
Timely publication of journal: Publication of manuscripts and bringing out the issue in time is one of the positive aspects of JCDR and is possible with strong support team in terms of peer reviewers, proof reading, language check, computer operators, etc. This is one of the great reasons for authors to submit their work with JCDR. Another best part of JCDR is "Online first Publications" facilities available for the authors. This facility not only provides the prompt publications of the manuscripts but at the same time also early availability of the manuscripts for the readers.
Indexation and online availability: Indexation transforms the journal in some sense from its local ownership to the worldwide professional community and to the public.JCDR is indexed with Embase & EMbiology, Google Scholar, Index Copernicus, Chemical Abstracts Service, Journal seek Database, Indian Science Abstracts, to name few of them. Manuscriptspublished in JCDR are available on major search engines ie; google, yahoo, msn.
In the era of fast growing newer technologies, and in computer and internet friendly environment the manuscripts preparation, submission, review, revision, etc and all can be done and checked with a click from all corer of the world, at any time. Of course there is always a scope for improvement in every field and none is perfect. To progress, one needs to identify the areas of one's weakness and to strengthen them.
It is well said that "happy beginning is half done" and it fits perfectly with JCDR. It has grown considerably and I feel it has already grown up from its infancy to adolescence, achieving the status of standard online e-journal form Indian continent since its inception in Feb 2007. This had been made possible due to the efforts and the hard work put in it. The way the JCDR is improving with every new volume, with good quality original manuscripts, makes it a quality journal for readers. I must thank and congratulate Dr Hemant Jain, Editor-in-Chief JCDR and his team for their sincere efforts, dedication, and determination for making JCDR a fast growing journal.
Every one of us: authors, reviewers, editors, and publisher are responsible for enhancing the stature of the journal. I wish for a great success for JCDR."



Thanking you
With sincere regards
Dr. Rajendra Kumar Ghritlaharey, M.S., M. Ch., FAIS
Associate Professor,
Department of Paediatric Surgery, Gandhi Medical College & Associated
Kamla Nehru & Hamidia Hospitals Bhopal, Madhya Pradesh 462 001 (India)
E-mail: drrajendrak1@rediffmail.com
On May 11,2011




Dr. Shankar P.R.

"On looking back through my Gmail archives after being requested by the journal to write a short editorial about my experiences of publishing with the Journal of Clinical and Diagnostic Research (JCDR), I came across an e-mail from Dr. Hemant Jain, Editor, in March 2007, which introduced the new electronic journal. The main features of the journal which were outlined in the e-mail were extensive author support, cash rewards, the peer review process, and other salient features of the journal.
Over a span of over four years, we (I and my colleagues) have published around 25 articles in the journal. In this editorial, I plan to briefly discuss my experiences of publishing with JCDR and the strengths of the journal and to finally address the areas for improvement.
My experiences of publishing with JCDR: Overall, my experiences of publishing withJCDR have been positive. The best point about the journal is that it responds to queries from the author. This may seem to be simple and not too much to ask for, but unfortunately, many journals in the subcontinent and from many developing countries do not respond or they respond with a long delay to the queries from the authors 1. The reasons could be many, including lack of optimal secretarial and other support. Another problem with many journals is the slowness of the review process. Editorial processing and peer review can take anywhere between a year to two years with some journals. Also, some journals do not keep the contributors informed about the progress of the review process. Due to the long review process, the articles can lose their relevance and topicality. A major benefit with JCDR is the timeliness and promptness of its response. In Dr Jain's e-mail which was sent to me in 2007, before the introduction of the Pre-publishing system, he had stated that he had received my submission and that he would get back to me within seven days and he did!
Most of the manuscripts are published within 3 to 4 months of their submission if they are found to be suitable after the review process. JCDR is published bimonthly and the accepted articles were usually published in the next issue. Recently, due to the increased volume of the submissions, the review process has become slower and it ?? Section can take from 4 to 6 months for the articles to be reviewed. The journal has an extensive author support system and it has recently introduced a paid expedited review process. The journal also mentions the average time for processing the manuscript under different submission systems - regular submission and expedited review.
Strengths of the journal: The journal has an online first facility in which the accepted manuscripts may be published on the website before being included in a regular issue of the journal. This cuts down the time between their acceptance and the publication. The journal is indexed in many databases, though not in PubMed. The editorial board should now take steps to index the journal in PubMed. The journal has a system of notifying readers through e-mail when a new issue is released. Also, the articles are available in both the HTML and the PDF formats. I especially like the new and colorful page format of the journal. Also, the access statistics of the articles are available. The prepublication and the manuscript tracking system are also helpful for the authors.
Areas for improvement: In certain cases, I felt that the peer review process of the manuscripts was not up to international standards and that it should be strengthened. Also, the number of manuscripts in an issue is high and it may be difficult for readers to go through all of them. The journal can consider tightening of the peer review process and increasing the quality standards for the acceptance of the manuscripts. I faced occasional problems with the online manuscript submission (Pre-publishing) system, which have to be addressed.
Overall, the publishing process with JCDR has been smooth, quick and relatively hassle free and I can recommend other authors to consider the journal as an outlet for their work."



Dr. P. Ravi Shankar
KIST Medical College, P.O. Box 14142, Kathmandu, Nepal.
E-mail: ravi.dr.shankar@gmail.com
On April 2011

Important Notice

Original article / research
Year : 2009 | Month : June | Volume : 3 | Issue : 3 | Page : 1500 - 1509

Complex Congenital Heart Disease: Neurological And Developmental Sequela Through Early Childhood And Adolescence

GIL W*

*MD, FACC,FAAP,Interim Director,Cardiac Intensive Care Unit,Director of Program Development, Cardiac Center .The Children’s Hospital of Philadelphia,Professor in Pediatrics, University of Pennsylvania School of Medicine

Correspondence Address :
GIL Wernovsky, (MD), (FACC), (FAAP)Division of Pediatric cardiology THE Cardic Centre atThe Children’s Hospital of Philadelphia34th and Civic Center Boulevard. Philadelphia, PA 19104 (USA)E.mail:wernovsky@email.chop.edu

Abstract

This article was originally published in December 2006, Volume 1, Issue 8 of Neonatology Today. Reprinted with permission from Neonatology Today. All rights reserved. http://www.NeonatologyToday.net.

As more children with complex congenital heart disease (CHD) survive into childhood and beyond, there is a growing recognition of neurological and developmental abnormalities in some of the survivors. Over a decade ago, much emphasis was placed on the conduct of cardiopulmonary bypass and its role in neurodevelopmental disabilities. Much has been learned in the intervening years regarding the multi-factorial causes of abnormal development in school age, in particular, the role of prenatal, perioperative, socioeconomic and genetic influences. This review will highlight some of the recent advances in our understanding of the protean causes of neurological, behavioral and developmental abnormalities in children and young adults with complex forms of congenital heart disease, which in many ways is remarkably similar to that seen in survivors of prematurity.

How to cite this article :

GIL W. COMPLEX CONGENITAL HEART DISEASE: NEUROLOGICAL AND DEVELOPMENTAL SEQUELA THROUGH EARLY CHILDHOOD AND ADOLESCENCE. Journal of Clinical and Diagnostic Research [serial online] 2009 June [cited: 2019 Oct 21 ]; 3:1500-1509. Available from
http://jcdr.net/back_issues.asp?issn=0973-709x&year=2009&month=June&volume=3&issue=3&page=1500-1509&id=526

Scope Of The Problem
Prior to the early 1980s, it was uncommon for children with complex congenital heart disease to survive into later childhood. The nearly simultaneous advances in congenital heart surgery, echocardiography and intensive care were coupled with the availability of prostaglandin and the developing discipline of interventional cardiology—together these factors resulted in a dramatic fall in surgical mortality with complex repairs taking place at increasingly younger ages. At many large centers, palliative surgery followed by later repair was replaced by primary repair in infancy, and staged reconstructive surgery for various forms of univentricular heart – including hypoplastic left heart syndrome – was improving with steadily falling surgical mortality rates. As a result, the last decade has seen an increasing number of children entering primary and secondary schooling, and research into their academic and behavioral outcomes has revealed some sobering realizations about the outcomes in these surgical survivors.

As a group, patients with complex congenital heart disease – and for the remainder of this review this will include children who require cardiac surgery as neonates or young infants – have a significantly higher incidence of academic difficulties, behavioral abnormalities, fine and gross motor delays, problems with visual motor integration and executive planning, speech delays, inattention and hyperactivity. Injury to the central nervous system in infants with congenital heart disease is characterized by abnormalities of tone, feeding difficulties, delays in major motor milestones and abnormalities in speech. As these children get older, the need for special services in school is significantly increased compared to the general population. As children progress through school, low academic achievement scores, learning disabilities, behavioral problems and Attention Deficit/Hyperactivity Disorder may result in academic failure, poor classroom and social skills, low self-esteem, behavioral disinhibition and ultimate delinquency.
Depending upon a number of factors, including the underlying congenital lesion and the associated surgical management, genetic contributions, additional perinatal events such as profound hypoxia-ischemia from a delayed diagnosis, or postoperative events such as low cardiac output syndrome, the incidence of abnormalities may range from infrequent to ubiquitous. For example, in cohort studies of children with transposition of the great arteries, a small fraction may have severe developmental impairment, perhaps one-half are normal in all respects, and nearly one-half will have a combination of speech, motor, behavior or learning issues. The percentage of children with more ‘significant’ heart disease (for example, totally anomalous pulmonary venous return with obstruction, hypoplastic left heart syndrome, interruption of the aorticarch) who are developmentally ‘normal’ is significantly decreased, with perhaps only one-third of those tested having no dysfunction in any domain. While most of these abnormalities are relatively mild, and may only be determined by formal testing—they result in a so-called “high prevalence, low-severity” developmental “signature.” A schematic representation is shown in (Table/Fig 1) .

Importantly, the combined outcomes of developmental delay, academic difficulties and behavioral abnormalities – in combination – represent the single most common morbidity affecting the quality of life in school age survivors with congenital heart disease; more common than late mortality, severe exercise impairment, unplanned reoperations, bacterial endocarditis or significant arrhythmias. The later implications of these findings through adulthood are uncertain, and must continue to be a robust area of research. Our current understanding of the etiology of these findings is discussed below.

Congenital Brain Disease
Given that the central nervous and cardiovascular systems form nearly simultaneously in early gestation, it is not surprising that there is an increased incidence of structural brain abnormalities in children with structural heart abnormalities. Many children with multiple congenital anomalies or chromosomal abnormalities – many of whom have coexisting congenital heart disease – will have developmental delay as a significant component of late morbidity. In addition to genetic factors which may affect both systems from a macroscopic perspective, congenital heart disease may alter cerebral blood flow, oxygen delivery or both, and result in secondary effects of the vulnerable fetal central nervous system.

In some respects, the brain of the full term neonate with congenital heart disease structurally resembles that of a preterm neonate, and interestingly, school age survivors of complex heart surgery have developmental findings which are very similar to survivors of premature birth, suggesting a similar pathological response to injury. Serial studies of the fetal brain – utilizing ultrasound and magnetic resonance imaging – are currently underway and are increasing our understanding of the interactions between the abnormal fetal cardiovascular system and cerebral development.

Microcephaly
Head circumference at birth is a marker for brain development, and in neonates without congenital heart disease, microcephaly is independently associated with later developmental delays and academic difficulties. Multiple cohort studies have shown the incidence of microcephaly at birth is increased in children with congenital heart disease, approaching one-fourth of children in some reports, and persists into later infancy. While the causes are speculative, and most certainly multifactorial, recent work from our institution in children with Hypoplastic Left Heart Syndrome – where the median head circumference at birth is only at the 18th percentile – revealed that patients with microcephaly had significantly smaller ascending aortas than those without, suggesting that reduced flow to the brain secondary to anatomic hypoplasia of the ascending aorta may result in diminished brain growth (Shillingford AJ, in press).

The “Open Operculum”
The term operculum insulae denotes the region that covers the insulae Relie and is made up of frontal, temporal and parietal cortical convolutions. In magnetic resonance and computer tomographic imaging studies of neonates with complex congenital heart disease, underdevelopment of the operculum may be seen in nearly one-quarter of the patients, and is a marker for functional immaturity of the brain. This may be a unilateral or bilateral finding, and has been termed “underoperculinization” or an “open” operculum. The operculum is thought to be related to oral motor coordination, taste and speech-particularly expressive language. In adult patients who develop a stroke in this area of the brain (Foix-Chavany-Marie syndrome), deficits include impairment of voluntary movements such as chewing and deglutition, dysarthria and taste abnormalities. Given the high prevalence of feeding problems, expressive language delay and oral-motor apraxia in children with complex heart disease, as well as the increasing recognition of a high prevalence of an open operculum, one can speculate that some patients with these developmental disabilities may have a structural underdevelopment of the operculum as the etiology. Further research into this hypothesis is ongoing.

Periventricular Leukomalacia
White matter injury – a common finding in premature infants – has been increasingly recognized in full term neonates with congenital heart disease. Mahle and colleagues studied 24 neonates preoperatively with magnetic resonance imaging of the brain, and found periventricular leukomalacia in (4); a number which nearly tripled after cardiac surgery. Spectroscopy in this cohort revealed elevated brain lactate in slightly over half of the patients. Licht and associates have recently suggested that decreased cerebral blood flow preoperatively was significantly associated with lesions in the white matter, affecting slightly over one-quarter of the neonates. Finally, in a larger study reviewing 105 magnetic resonance imaging studies of the brain in children with congenital heart disease in the early postoperative period, periventricular leukomalacia was found in slightly over half of the neonates in the study, but rarely in older children.

Periventricular Leukomalacia is believed to arise from several factors, including the high susceptibility of the immature oligodendrocyte to hypoxic ischemic injury, as well as the watershed distribution of cerebral blood flow to this area between the small arteries that penetrate from the cortex and those that arise centrally and run radially outward. This watershed area is particularly prone to ischemia during decreases in cerebral perfusion pressure. In premature infants, severe degrees of periventricular leukomalacia have been associated with cerebral palsy, while mild degrees of injury have been associated with developmental delay, motor difficulties and behavior disorders - a developmental signature remarkably similar to school-age children with congenital heart disease.

Additional Anatomical Findings At Birth
Congenital central nervous system (CNS) anomalies are known to be coincident with CHD. In a prospective study by Miller et al, head ultrasound examinations were performed on full term infants with CHD before and after surgical interventions. Brain abnormalities were noted in 27% of the infants, and nearly half of the anomalies were present before surgery (such as holoprosencephaly and agenesis of the corpus callosum)

Fetal Cerebrovascular Physiology And Oxygen Delivery
Recent ultrasound studies have revealed that cerebral vascular resistance is altered in the presence of congenital heart disease. Using Doppler interrogation of middle cerebral artery flow, both Donofrio and colleagues and Kaltman and associates have shown that fetuses with left-sided heart disease (for example, Hypoplastic Left Heart Syndrome) had decreased cerebral vascular resistance compared to normal. In patients with aortic atresia, for example, the fetal cardiac output from the ductus arteriosus must deliver blood flow cephalad to the brain as well as caudad to the low resistance placenta. It is speculated that cerebral vascular resistance must therefore be lower than normal to allow adequate blood flow to the central nervous system. Kaltman also showed that fetuses with right sided lesions (for example, Tetralogy of Fallot) had increased fetal cerebral vascular resistance. The impact of these alterations in fetal cerebral vascular resistance is unclear, but almost certainly plays a role in subsequent neurological development.

In the normal fetus, the intracirculatory patterns created by the normal fetal connections result in preferential streaming of the most highly oxygenated fetal blood to the developing brain and most desaturated blood to the placenta. When significant structural heart disease exists, these beneficial flow patterns are likely to be altered. Although not yet confirmed by fetal magnetic resonance spectroscopy (studies are underway), fetuses with transposition of the great arteries are likely to have the blood with the lowest oxygen saturation returning to the ascending aorta and brain, while blood with the highest oxygen saturation will return to the abdominal viscera and placenta – a “transposed” fetal circulation previously speculated by Naeye nearly 40 years ago as an explanation for the high incidence of macrosomia in these infants. Complete mixing lesions such as seen in univentricular hearts will have intermediate values of fetal cerebral oxygen saturation, but lower than that seen in the normal fetus.

Perioperative Contributors

Preoperative Factors
Neonates with complex congenital heart disease frequently require hospitalization immediately after birth, many to receive intravenous prostaglandin infusion, some requiring intubation, mechanical ventilation, or invasive interventions such as balloon atrial septostomy. All of these interventions carry risks to the central nervous system, especially the potential for paradoxical embolus to the brain of air or particulate matter in children with intracardiac right to left shunts. These patients also have oxygen saturations that are below normal, potentially compromising cerebral oxygen delivery.
Licht and colleagues recently reported that – in addition to diminished oxygen content – neonates with critical congenital heart disease had diminished cerebral blood flow as well. Under conditions of general anesthesia and mechanical ventilation with normocapnia, cerebral blood flow was, on average, less than half that seen in normal term newborns. The cerebral vascular response to increased inspired carbon dioxide was preserved, suggesting normal autoregulation of cerebral blood flow, at least over the short term.

Intraoperative Factors
The conduct of cardiopulmonary bypass and other support techniques during open heart surgery has received considerable attention, and has been the subject of active and gratifying research. As opposed to all of the risk factors for abnormal neurological development discussed thus far, variation in intraoperative support, such as the conduct of cardiopulmonary bypass, is one of the few modifiable risk factors which may be altered to improve long term neurological outcomes. Potential modifiable technical features of cardiopulmonary bypass are shown in (Table/Fig 2) .

Deep Hypothermic Circulatory Arrest
Much has been written on the potentially deleterious effects of prolonged circulatory arrest with profound hypothermia in neonatal and infant heart surgery. It is generally agreed that prolonged periods of uninterrupted circulatory arrest may have adverse neurological outcomes. However, upon close inspection of the data, it is increasingly clear that the effects of short durations of circulatory arrest are inconsistently related to adverse outcomes, that the effect of circulatory arrest is not a linear phenomenon, and the effects are most likely modified by other patient-related, preoperative and postoperative factors. Some reports, most in an earlier era of cardiac surgery demonstrate a detrimental effect of circulatory arrest on a variety of central nervous system outcomes, while some demonstrate either an inconsistent effect or no effect. Some practitioners have taken the stance that since the majority of studies suggest a negative effect of circulatory arrest, it should be avoided “at all costs”. Innovative and challenging bypass strategies have been designed to provide continuous cerebral perfusion during complex arch reconstruction or intracardiac repair. It must be emphasized that the avoidance of circulatory arrest by necessity requires an increased duration of cardiopulmonary bypass, which has consistently been shown to have an adverse effect on both short term and longer-term outcomes. A randomized trial of circulatory arrest and continuous cerebral perfusion has recently been completed at the University of Michigan, with short term studies soon to be reported in the literature (Ohye R, personal communication) and long term studies in the planning stages.

It seems imprudent to change practice based upon studies with only short term developmental assessment, as it is clear that developmental studies in infants have very limited predictive validity for long term outcomes, both in patients with and without congenital heart disease. Perhaps the best conducted study in this regard-which emphasizes this point-is the Boston Circulatory Arrest Study, with multiple reports from Bellinger, Newburger, Jonas and colleagues. In this cohort, 171 children with transposition of the great arteries were randomly assigned an intraoperative support strategy of predominantly deep hypothermic circulatory arrest or predominantly low flow cardiopulmonary bypass during the arterial switch operation. Earlier reports suggested that the group as a whole was performing below expectations in many aspects of evaluation, with worse outcomes for the circulatory arrest group in the areas of postoperative seizures, motor skills at one year of age, as well as behavior, speech and language at age 4 years. Mean Intelligence Quotient at age 4 was lower than expected at 93, with no difference across treatment assignment. Many centers began avoiding even short periods of circulatory arrest based upon these and other reports.

However, in 2003, quality of life assessments and detailed standardized testing were reported in this group. Neurodevelopmental analyses of this cohort at 8 years of age revealed that the Intelligence Quotient scores for the cohort as a whole are now closer to normal (98 versus the population mean of 100). However, the group demonstrated significant deficits in visual-spatial and visual-memory skills, as well as in components of executive functioning such as working memory, hypothesis generation, sustained attention, and higher-order language skills. In other words, the children had difficulty coordinating skills in order to perform complex operations. The circulatory arrest group scored worse on motor and speech functioning, while the low-flow bypass group demonstrated worse scores for impulsivity and behavior. When compared to a normative sample, parents of the entire cohort reported significantly higher frequencies of attention problems, developmental delay, learning problems, and speech problems. More than a third of the population received remedial school services, and one in ten had repeated a grade. Thus, in this population of patients who underwent the arterial switch operation between 1988 and 1992, there appears to be a correlation between congenital heart disease and its surgical repair with later speech and language difficulty, behavioral difficulties and execution planning in childhood. Whether current modifications of support techniques will improve the long term outcomes remains the subject of ongoing study.

This well-designed trial with superb follow-up compliance enrolled neonates with transposition of the great arteries, with or without a ventricular septal defect, who were planned to undergo an arterial switch operation between 1988 and 1992. The results, thus, reflect the perioperative care delivered in that era, and thus may not be generalizable to the current era, or other congenital heart lesions. In addition, those patients randomized to predominantly continuous bypass did undergo a brief period of circulatory arrest; thus, the study does not compare use of circulatory arrest to no circulatory arrest. Nonetheless, the results serve to show the multiple factors which influence developmental outcome at school age, and that factors related to poorer outcome such as deep hypothermic circulatory arrest, which seem apparent and significant on early testing may be attenuated or even abolished during longer term follow-up, as other factors assume a more important role.

Postoperative Factors
It has long been recognized that systemic blood flow is reduced in the first 24-48 hours following cardiac surgery, typically reaching a nadir in the first night after cardiac surgery. At this time, the central nervous system may be especially vulnerable to secondary insults of decreased oxygen delivery, particularly after circulatory arrest. Currently, close attention to cardiac output, oxygen delivery and oxygen consumption seems warranted from a central nervous system perspective, however, bedside techniques for quantitative assessment of these parameters is limited, particularly if there are residual intracardiac shunts.

Following cardiopulmonary bypass, with or without circulatory arrest, autoregulation of cerebral blood flow may be impaired, making the neonate and infant particularly vulnerable to periods of low cardiac output and/or hypoxemia. Although many studies in laboratory animals demonstrated various factors that adversely affect cerebral blood flow following cardiopulmonary bypass, it has been previously difficult to reproduce these studies in postoperative neonates and infants. However, recently, Bassan and colleagues utilized transcranial Doppler and cerebral near-infrared spectroscopy to study cerebral blood flow in the cardiac intensive care unit in 43 neonates and infants following biventricular repair. In this study cohort, approximately one in six patients demonstrated bnormalities of cerebrovascular pressure autoregulation, with risk factors including hypercapnia higher mean arterial pressure during the time of the measurements. To date, the potentially deleterious effects of significant hypocapnia—which decreases total cerebral blood flow – and hypotension (for ethical reasons) have not been reported in postoperative neonates. Further research is mandatory to determine the combined effects of cardiac output, mechanical entilation, and cerebral blood flow, especially in the immediate postoperative period.

Seizures occur in the immediate postoperative period in up to 20% of neonates, depending upon the detection method; clinical seizures are significantly less prevalent than those detected on continuous electroencephalographic monitoring. The etiology is most-likely multifactorial, but is likely to be more prevalent in younger patients, those with prolonged periods of circulatory arrest, or those with coexisting central nervous system abnormalities.

In addition to the identified factors above, the immediate post operative period typically requires invasive monitoring, mechanical ventilation and significant medical support, especially in the neonate and young infant. While these therapies have resulted in significant improvements in mortality, they increase the risk of factors which may adversely affect the central nervous system, including paradoxical embolus of air or particulate matter from peripheral or central intravenous access, fever, hyperglycemia and swings in cerebral blood flow brought on by acute changes in mechanical ventilation. Newburger and colleagues have recently demonstrated in the Boston Circulatory Arrest cohort that longer hospital and intensive care unit length of stay in the newborn period was associated with worse developmental outcomes at age 8 years. These effects were significant, even when controlling for other factors known to adversely affect long-term outcome, such as seizures, intraoperative support duration, reoperations and other postoperative events. Children with transposition whose length of stay was in the fourth quartile had mean intelligence quotients 7.6 points lower than those in the first quartile. Further investigation into the multiple potential mechanisms of central nervous system injury in the intensive care environment must continue.

Following hospital discharge, some neonates remain at risk for ongoing central nervous system injury. Chronic hypoxemia, as a result of ongoing palliation and/or intentional intracardiac right to left shunting, may result in neurodevelopmental impairment. In children with transposition, older age at repair, as a surrogate for duration of hypoxemia, has been associated with worse outcomes during follow-up. Cohort studies -many from a much earlier era of cardiac surgery when delayed repair was common – consistently show lower scores in children with “cyanotic” lesions compared to “acyanotic” lesions. However, simple comparisons of heart disease with and without associated hypoxemia are confounded by the multiple factors present in children with “cyanotic” heart disease, including earlier age at repair and exposure to bypass, more complex surgical procedures, abnormal fetal flow patterns, and many of the factors mentioned in this review. In children with structurally normal hearts and hypoxemia from other causes (for example, chronic lung disease, sleep disordered breathing, high altitude), chronic or intermittent hypoxemia has been associated with adverse effects on development, behavior and academic achievement. The presence of hypoxemia undoubtedly plays some role in patients with congenital heart disease, but is most likely modified by other factors and is difficult to measure the effect of hypoxemia in isolation.

Genetic and Environmental Factors
Socioeconomic status is perhaps the strongest predictor of eventual neurodevelopmental outcome, and is a reflection of both the child’s environment and the genetic factors for development inherited from his or her parents. Multiple studies have shown the relationship between socioeconomic status and/or parental intelligence and outcome in children with congenital heart disease. Children with identified genetic syndromes with known chromosomal abnormalities (e.g., Down, Williams and DiGeorge syndromes, Trisomy 13 and 18, etc.) as well as multiple ongenital anomaly associations (e.g., CHARGE and VACTERL associations) frequently have coexisting CHD; in total perhaps 1/3 of all children with CHD have additional abnormalities besides their heart disease. Sub-chromosomal gene abnormalities are being discovered with increasing frequency in this patient population, and most studies report worse outcome in children with associated congenital anomalies compared to children with the same lesion without additional anomalies.

Future Directions
While advances in the medical and surgical fields have allowed the ability to ‘mend’ children born with congenital heart disease, the increasing number of survivors has created a growing cohort of children with potential academic difficulties. The causes are clearly multifactorial, additive and incompletely understood. Much has been learned about cardiopulmonary bypass and the short period of time these children spend in surgery; much more work needs to be done to understand the modifiable risk factors in the perioperative period, the influences of the timing of surgery and whether or not improved monitoring of the central nervous system in the intensive care unit setting will improve neurological and developmental outcomes.

Summary
(Table/Fig 3) represents some of the current understanding regarding the multiple factors which may adversely affect the central nervous system in children with complex congenital heart disease – a remarkably similar “phenotype” as that seen in school-age children who were born prematurely. There is a growing body of literature showing suboptimal outcomes in school age children, particularly with respect to attention, behavior, higher-order executive function, handwriting and school performance. Many of the risk factors for adverse outcomes are co-linear, such as abnormalities of the fetal circulation, the need for prolonged intensive care, complex operations with cardiopulmonary bypass with or without deep hypothermia and circulatory arrest, prolonged hypoxemia and multiple reoperations. Thus, it is difficult to conclude which, if any, are most explanatory. Many of the reports on the effects of cerebral consequences of cardiopulmonary bypass, in particular, are conflicting, and there is a need for ongoing laboratory experiments and controlled clinical trials before sweeping changes to intraoperative management are undertaken, with particular attention to long-term outcomes in school-age children. Neurodevelopmental abnormalities are widely prevalent and are major contributors to adverse health-related quality of life outcomes. Further research must continue, in the laboratory, inpatient, and outpatient settings.





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