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Vol 5, No 3July 2016

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TRANSLATIONAL PEDIATRICSTRANSLATIONAL PEDIATRICSTRANSLATIONAL PEDIATRICS

Focus issue on Trends and Innovations in Caring for Patients with Congenital Heart DefectsGuest Editor: Ali Dodge-Khatami, MD, PhD, University of Mississippi Medical Center, USA

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Aims and ScopeThe Translational Pediatrics (Transl Pediatr, Print ISSN 2224-4336, Online ISSN 2224-4344) publishes articles that describe new findings in the field of translational research in pediatrics, provides current and practical information on diagnosis, prevention and clinical investigations of pediatrics. Specific areas of interest include, but not limited to, multimodality therapy, biomarkers, imaging, biology, pathology, and technical advances related to pediatrics. Contributions pertinent to pediatrics are also included from related fields such as nutrition, surgery, oncology, cardiology, urology, dentistry, public health, child health services, human genetics, basic sciences, psychology, psychiatry, education, sociology, and nursing. The aim of the Journal is to provide a forum for the dissemination of original research articles as well as review articles in all areas related to pediatrics. It has been now indexed in PubMed/PubMed Central.

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Editor-in-ChiefYu-Jia Yang, MD, PhDXiangya Hospital of Central South University, China

Deputy Editor-in-ChiefZhanhe Wu, MD, PhD, FFSc (RCPA)Western Sydney Genome Diagnostics, Western Sydney Genetic Program, The Children’s Hospital at Westmead, Sydney, Australia.

Editorial BoardStuart B. Bauer, MD Boston, USARobert J. Bollo, MDSalt Lake City, USAAndrew L. Chang, MDSan Diego, USAPatrick HY Chung, MBBS (HK), FRCSEd (Paed), FCSHK, FHKAM Hong Kong, ChinaAmanda Dixon-McIver, BMLSc, MSc, PhDAuckland, New ZealandAli Dodge-Khatami, MD, PhD, ProfessorJackson, USACiro Esposito, MD, PhD, MFAS Naples, ItalyDouglas D. Fraser, MD, PhD, FRCPCOntario, CanadaIra H Gewolb, MDEast Lansing, United StatesWalter A Hall, MD, MBASyracuse, USAMichelle Henderson, PhDRandwick, Australia

Anna Marie Kenney, PhDAtlanta, USAMartin C J Kneyber, MD, PhDGroningen, The NetherlandsHaruki KomatsuChiba, JapanShoo K. Lee, MBBS, FRCPC, FAAP, PhDToronto, CanadaGiuseppe A. Marraro, MD Milan, ItalyRajen Mody, MD, MSAnn Arbor, USAJames H. Moller, MDMinneapolis, USAKirsten K. Ness, PT, PhDMemphis, USAEnder Ödemiş, MD, Prof., Chief Istanbul, TurkeyTodd A. Ponsky, MD Akron, USAXiangming Qiu, MDEdmonton, CanadaWilliam D. Rhine, MDStanford, USAKoravangattu Sankaran, MDSaskatoon, Canada

Kris Sekar, MD, FAAPOklahoma City, USAArabella Ellie Smith, MB BS Hons II (Sydney), DipRCPath (UK), FHGSA, FRCPASydney, AustraliaChristian P. Speer, MD, FRCPEWürzburg, GermanyVarsha Tembe, MS, BSc, PhDSydney, AustraliaAmy L. Throckmorton, PhD, Associate Professor, DirectorPhiladelphia, USAHiroo Uchida, MD, PhD Nagoya, JapanChi Dung Vu, MDHanoi, VietnamShawn C. West, MD, MSCPittsburgh, USAGary Wing Kin Wong, MD, FRCPC, FHKAM, Professor Hong Kong, China Atsuyuki Yamataka (Yama), MD, PhD Tokyo, JapanTsu-Fuh Yeh, MD, PhDTaipei, Taiwan

Bing Yu, MD, PhD, FFSc (RCPA), FHGSA, FACBSCamperdown, Australia

Section EditorXicheng Deng, MD, PhD, Staff surgeon (Pediatric Cardiothoracic Surgery)Changsha, ChinaXian-Gang Yan, MD, Associate professorShanghai, ChinaZhiqun Zhang, MD (Neonatal Medicine) Zhejiang, China

Executive CopyeditorCherise Yang

Executive Typesetting EditorBella B. Chen

Production EditorEmily M. Shi

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Eunice X. XuElva S. Zheng

Science EditorsMolly J. WangMelanie C. He

Lucille L. Ye

© Translational Pediatrics. All rights reserved. Translational Pediatrics Vol 5, No 3 July 2016

Table of Contents

Editorial

109 Advances and research in congenital heart diseaseAli Dodge-Khatami

112 The battleground of the stenotic branch pulmonary arteries: the surgical approach of “less is more”Damien P. Kenny, Jonathan McGuinness, Ziyad M. Hijazi

Original Article

114 Antegrade cerebral perfusion at 25 ℃ for arch reconstruction in newborns and children preserves perioperative cerebral oxygenation and serum creatinineBhawna Gupta, Ali Dodge-Khatami, Juan Tucker, Mary B. Taylor, Douglas Maposa, Miguel Urencio, Jorge D. Salazar

125 How to set-up a program of minimally-invasive surgery for congenital heart defectsJuan-Miguel Gil-Jaurena, Ramón Pérez-Caballero, Ana Pita-Fernández, María-Teresa González-López, Jairo Sánchez, Juan-Carlos De Agustín

Review Article

134 Goal-directed-perfusion in neonatal aortic arch surgeryRobert Anton Cesnjevar, Ariawan Purbojo, Frank Muench, Joerg Juengert, André Rueffer

142 Hypoplastic left heart syndrome: current perspectivesChristopher E. Greenleaf, J. Miguel Urencio, Jorge D. Salazar, Ali Dodge-Khatami

148 Prophylactic arrhythmia surgery in association with congenital heart diseaseConstantine Mavroudis, Barbara J. Deal

160 Critical cardiac care in children: looking backward and looking forwardPaul A. Checchia

Case Report

165 Reverse Szabo technique for stenting a single major aorto-pulmonary collateral vessel in pulmonary atresia with ventricular septal defectIgor V. Polivenok, John P. Breinholt, Sri O. Rao, Olga V. Buchneva

Pediatric Epilepsy Column (Review Article)

169 Preoperative evaluation and surgical decision-making in pediatric epilepsy surgeryKatrina Ducis, Jian Guan, Michael Karsy, Robert J. Bollo

Pediatric Epilepsy Column (Editorial)

180 Surgical advancements in pediatric epilepsy surgery: from the mysterious to the minimally invasiveRobert J. Bollo

Correspondence

183 Klinefelter syndrome: fertility considerations and gaps in knowledgeLeena Nahata, Richard N. Yu, Laurie E. Cohen

© Translational Pediatrics. All rights reserved. Transl Pediatr 2016;5(3):109-111tp.amegroups.com

The fate of babies born with congenital heart disease (CHD) has dramatically changed in the last 4–5 decades, going from a universally fatal condition in the vast majority of patients in the absence of diagnosis or intervention, to an entity whose outcome, at least in terms of peri-operative/hospital stay, has improved to an expected survival of about 96%. Indeed, since the first surgical solution for any type of congenital heart defect in 1938, ligation of a patent ductus arteriosus by Dr. Robert Gross at Boston Children’s Hospital (1), followed by the pioneering work of Alfred Blalock and Helen Taussig in the palliation of “blue babies” with tetralogy of Fallot in 1944 (2), to the critical breakthrough of open heart surgery with inflow occlusion and repair of an atrial septal defect by F. John Lewis in 1952 (3), then the first operation done with the support of extracorporeal pump oxygenation by John Gibbon in 1953 (4), and cross-circulation championed by C. Walton Lillehei in 1954 (5), the field of surgical and interventional treatment and palliation for CHD has exploded into the success story we know today.

While these heroic pioneering surgical feats were necessary to break the ice, parallel developments such as cardiac catheterization and echocardiography in the 1950’s needed 2 decades to mature and become clinical mainstream in the sixties to seventies, leading to further precision in diagnosis, real-time imaging, and follow-up of the heart. With the birth of pediatric critical care in the late seventies, improvements in cardiopulmonary bypass (CPB) perfusion hardware, the advent of percutaneous catheter-based cardiac interventions and refinements in anatomical and physiological understanding of single ventricle defects, the stage has been set since the 1980’s for the current era of multidisciplinary treatment of CHD. Thus, guidelines

and milestones have been established in the treatment of virtually every single congenital cardiovascular defect encountered in nature, ranging from near 100% survival and freedom from reintervention or repeat surgery for the more simple malformations, such as atrial or ventricular septal defects, patent ductus arteriosus and coarctation, to more complex defects with correspondingly lower peri-operative survival and the need for continuous follow-up and care.

Currently, in developed countries with established programs built with the sole responsibility to care for patients with congenital heart defects, surviving any given intervention or surgical procedure is really expected by caregivers and parents alike, but really comes to taking care of what CHD really represents, which is not a cure in most instances. Indeed, outcomes are no longer only measured by survival to discharge from the hospital, or even by freedom from complications which is of course an important measure of quality of care. Now that these immediate peri-operative goals are achieved in the vast majority of patients who go on not only to survive, but to grow up and become adolescents and then adults with treated CHD, the focus has shifted towards quality of life in the mid to long-term, developmental and learning processes, and a vast array of medical and social issues relating to what it means to live with “a treated heart condition”. Tremendous technological feats at a macroscopic level which are obvious to the naked eye have already been achieved, are still being discovered, or being adapted and accordingly refined to help those patients already born and treated for CHD. More importantly, current and future focus are directed towards understanding the genesis, genetics, and corresponding earlier diagnosis with eventual new therapeutic strategies and targets at the fetal stage and/or even at the molecular level, for those

Editorial

Advances and research in congenital heart disease

Ali Dodge-Khatami

Pediatric and Congenital Heart Surgery, Children’s Heart Center, University of Mississippi Medical Center, Jackson, MS, USA

Correspondence to: Ali Dodge-Khatami, MD, PhD. Chief, Pediatric and Congenital Heart Surgery, Children’s Heart Center, University of Mississippi

Medical Center, Jackson, MS, USA. Email: [email protected].

Submitted May 19, 2016. Accepted for publication May 24, 2016.doi: 10.21037/tp.2016.05.01

View this article at: http://dx.doi.org/10.21037/tp.2016.05.01

110 Dodge-Khatami. Advances in congenital heart surgery


patients yet unborn.What are some of the future directions which research

could heavily influence? In many surgical repairs, from the newborn period to adulthood, somatic growth of the heart and vessels parallel to that of the patient must be taken into consideration. Prosthetic materials and implants are willingly avoided, with preference given to biological ones. While autologous tissue from the patient itself is the ideal material, having the advantages of being living tissue, thereby allowing for somatic growth, resisting infection, not requiring anticoagulation, and not inducing any rejection phenomenon, it is not always available in the appropriate amount or shape. The extant research and results of tissue engineering, using various combinations of biological scaffolds seeded with autologous stem or mature cells are most promising, but still have a ways to go. Although various living bio-engineered tissues have been produced and shown to function in vitro and in vivo, either in the myocardium, as valve substitutes, or as patch material, they have to date failed to endure the mechanical wear and tear of time, and therefore still need to stand the ultimate test of acceptable longevity. Furthermore, time constraints pertinent to harvesting cells from a given patient, treating and culturing them in vitro and seeding onto a scaffold which will eventually result in a functioning tissue ready for implantation back into the patient itself, make the current bio-engineered tissues unpractical, or definitely not a “real time” alternative. Ideally, such autologous bio-materials should instantly be “ready to use” in an off-the-shelf, custom-made, tailored-to-the-patient’s-size manner, which will hopefully be achieved through technological advances in the near future.

In the field of neurological development, enhanced neuro-imaging modalities have allowed better documentation of the insults, injuries and malformations, or lack thereof, in neonates with CHD. Indeed, it is increasingly becoming apparent that in utero blood flow patterns specific to certain cardiac lesions which create a relative steal of blood flow away from the brain lead to significant cerebral lesions by birth, and therefore already exist prior to any surgical or interventional procedure on the heart. Although enhanced imaging and neuro-monitoring capabilities allow for better spatio-temporal documentation of what has already happened and how it may evolve in time with follow-up, more needs to be achieved in understanding exactly what processes lead to the neurological insults, and more importantly, what can eventually be done to influence the course of events, or more ideally, even prevent any harm in the first place. Huge

research efforts are still needed to fully identify, understand and hopefully influence the patho-physiology of neurological injury and capacity for repair/regeneration in the heart-brain axis of patients with CHD.

As the various intricate and delicate stages of embryogenesis of the heart are better defined and understood, so also has advanced the bold strategy to intervene and hopefully influence certain critical key structures and blood flow patterns in the developing heart. Intrauterine intervention, either by percutaneous/trans-uteral catheter balloon dilatation or by open surgical technique, has been successfully performed, most notably on the aortic valve, in fetuses with aortic valve stenosis, hypoplasia or atresia and variants of hypoplastic left heart syndrome (6). The risk-benefit ratio should take into consideration treating two patients, the mother and the fetus, since both of the patients could potentially suffer, and only one (the fetus) benefits. Whether in-utero treatment techniques can reliably result in favour of both mother and fetus remains to be demonstrated, which is why only a few highly specialized centers are undertaking it with promising results (6).

Although major advances have been made in the field of genetics with regards to diagnosis which then influences prognosis and genetic counselling, the vast majority of the etiology of congenital heart defects remains incompletely understood or unknown (7). Roughly 30% of CHD patients have phenotypes which fit into syndromes including extracardiac manifestations. That leaves about 70% of cases in which no syndrome exists, and for whom only some have known Mendelian inheritance (dominant or recessive). This leaves a lot of room for the interplay of multifactorial etiologies such as the interactions between multiple genes, environmental factors, and spontaneous mutations, just to name a few. Therefore, currently, there is still a time-lag between the objectives of genetical testing in clinical practice with a goal to assist in diagnosis, help define prognosis and aid in parent counselling, or their value for research purposes which may lead to insights into a disease entity and potential future therapeutics targets. The future interplay between clinicians and research laboratories to bring together patterns of knowledge that fit will be of paramount value and provide additional keys to the understanding of the genesis/genetics of CHD.

In conclusion, the field of care for congenital heart defects has made tremendous strides in its young infancy. In no other field of science or medicine has so much been accomplished in so little time, with heart defects that were an unconditional death sentence 60 years ago, to

111Translational Pediatrics, Vol 5, No 3 July 2016


the current operative survival rates of more than 96% for all defects considered together. We must give tribute to bold pioneers in the early days of the 1940’s and 1950’s for taking the biggest steps, with further refinements in the 1970’s and 1980’s to reach the point where we are today. However, for certain defects, we are only scratching the surface, and short-term as well as long-term outcomes are still unsatisfactory. Owing to huge advances in perinatal care, increasingly premature babies with complex syndromes involving multiple organs are no longer subject to “natural selection” and are surviving, bringing with them an array of cardiac and associated non-cardiac malformations that confound not only cardio-pulmonary physiology, but require a more holistic approach to patient care. Furthermore, although surviving an operation or intervention for a congenital heart condition is now expected for the vast majority of patients as neonates and infants, the focus is shifting towards quality of life, long-term issues, and treatment/care algorithms for adults having survived their initial hurdles, who now represent the majority of patients with CHD, a new fast-growing population. Much collaboration, vision and innovation is still needed to tackle and understand congenital heart defects, giving providers who are privileged to be involved in the care of these patients and families challenges for many decades to come.

Acknowledgements

None.

Footnote

Conflicts of Interest: The author has no conflicts of interest to declare.

References

1. Gross RE. Surgical management of the patent ductus arteriosus: with summary of four surgically treated cases. Ann Surg 1939;110:321-56.

2. Taussig HB, Blalock A. The tetralogy of Fallot; diagnosis and indications for operation; the surgical treatment of the tetralogy of Fallot. Surgery 1947;21:145.

3. Lewis FJ, Taufic M. Closure of atrial septal defects with the aid of hypothermia; experimental accomplishments and the report of one successful case. Surgery 1953;33:52-9.

4. Gibbon JH Jr. Application of a mechanical heart and lung apparatus to cardiac surgery. Minn Med 1954;37:171-85; passim.

5. Lillehei CW, Cohen M, Warden HE, et al. The direct-vision intracardiac correction of congenital anomalies by controlled cross circulation; results in thirty-two patients with ventricular septal defects, tetralogy of Fallot, and atrioventricularis communis defects. Surgery 1955;38:11-29.

6. Freud LR, McElhinney DB, Marshall AC, et al. Fetal aortic valvuloplasty for evolving hypoplastic left heart syndrome: postnatal outcomes of the first 100 patients. Circulation 2014;130:638-45.

7. Chaix MA, Andelfinger G, Khairy P. Genetic testing in congenital heart disease: A clinical approach. World J Cardiol 2016;8:180-91.

Cite this article as: Dodge-Khatami A. Advances and research in congenital heart disease. Transl Pediatr 2016;5(3):109-111. doi: 10.21037/tp.2016.05.01


The achievements of congenital cardiac surgery over the past two decades are remarkable. However success comes at a price and occasionally the “sacrificial lamb” in this discipline are the branch pulmonary arteries. This is not to suggest intentional “sacrifice” however the necessity to provide pulmonary blood flow particularly in single ventricle palliation requires manipulation and potential distortion of the branch pulmonary arteries (BPA’s). In a large randomized trial assessing initial surgical palliation for hypoplastic left heart syndrome, although antegrade pulmonary blood flow through a Sano shunt provided an early survival benefit over a systemic arterial-pulmonary shunt, re-intervention rates on the BPA’s were significantly higher in the Sano cohort (1). The impact of pulmonary artery distortion on long-term survival in single-ventricle patients dependent on passive pulmonary blood flow is unclear, however, unlikely to be negligible. The optimal approach to relieve pulmonary artery narrowing is yet to be determined. No randomized trials comparing surgical versus transcatheter options have been published although non-randomized studies suggest that patients undergoing surgical branch pulmonary arterioplasty are more likely to require re-intervention compared to those undergoing stent placement (2). Equally it is difficult to argue that stents in their current format are the ideal long-term solution. Surgical techniques and patch material may vary and hence influence outcomes, with disappointing recent results seen with the use of a porcine extracellular matrix patch when used to patch the pulmonary arteries (3). The ideal material for surgical patching, which should be pliable and easy to handle, resistant to tearing, calcification or shrinkage, with

the potential for growth and restoration of vascular function without the induction of scar tissue may be some way off yet. In the meantime approaches to circumvent some of the consequences of suture induced scaring are required.

In this issue of Translational Pediatrics, we review a recently published novel approach to surgical reconstruction of the BPA’s in patients with congenital heart disease (4). Kim et al. described their use of “sutureless” patch angioplasty for postoperative pulmonary artery narrowing in 28 patients with a median weight of 7.3 kg, two-thirds of whom had previous palliation for hypoplastic left heart syndrome and 85% of whom had a concomitant superior cavopulmonary anastomosis. The procedure involves longitudinal opening of the stenosed BPA and enucleation of the pre-existing patch material from the surrounding fibrotic tissue. Multiple intimal incisions were made and followed by stretching the vessel manually with a dilator. In some cases the entire stenotic area was excised leaving just the perivascular fibrotic tissue intact. The patch (bovine pericardium) was then sutured to the perivascular fibrotic tissue and to the aortic wall to avoid suture mediated scaring of the intima of the pulmonary artery. Technical and operative outcomes were excellent. The procedure avoids extensive dissection of the pulmonary arteries which has previously proved challenging with retro-aortic stenosis and may also risk damage to surrounding structures. Re-intervention was required in only one patient over the medium-term, with follow-up imaging [computed tomography (CT) or angiography] demonstrating some increase in pulmonary artery dimensions at the area of sutureless patching.

Editorial

The battleground of the stenotic branch pulmonary arteries: the surgical approach of “less is more”

Damien P. Kenny1, Jonathan McGuinness1, Ziyad M. Hijazi2

1Department of Cardiology and Cardiac Surgery, Our Lady’s Children’s Hospital, Dublin, Ireland; 2Weill Cornell Medicine, Sidra Medical and

Research Center, Doha, Qatar

Correspondence to: Damien P. Kenny, MD. Department of Cardiology and Cardiac Surgery, Our Lady’s Children’s Hospital, Crumlin, Dublin 12,

Ireland. Email: [email protected].

Submitted May 06, 2016. Accepted for publication May 16, 2016.

doi: 10.21037/tp.2016.05.03




The benefit of “sutureless” techniques have evolved from pulmonary venous reconstruction surgery where exposure of the vein to suture based trauma may lead to excessive scar formation and restenosis (5). It is unclear if this approach will provide similar benefits for mitigating against branch pulmonary artery distortion in the longer-term. Some concerns have yet to be addressed. It is unclear if the absence of intimal tissue will promote true growth of the BPA’s, with only patch and scar tissue remaining. The impact of suturing to surrounding vessels, particularly the aorta may distort the vasculature with growth or increase risk of vascular compromise if further transcatheter intervention were to be required. The cause of the sudden massive hemoptysis in one patient on follow-up raises some questions about the potential for fistula formation with less integrity to the neo-pulmonary wall. It is also unclear if loss of vascular function with near complete excision of the vessel, in the setting of a circulation dependent of passive pulmonary blood flow, may have longer-term implications. No mention is made of the impact of the patch on follow-up surgeries, particularly completion of the total cavopulmonary anastomosis where distinguishing the true plane of the pulmonary artery wall with dissection may be challenging. All things considered however, this approach is certainly a welcome addition to the challenge of treating complex BPA narrowing, particularly in the context of irregular long segment stenoses where moulding a patch to the native vessel wall, often variable in diameter, is technically very difficult. It is also likely to help with accessing a retro-aortic stenosis without extensive dissection. In the end, the victor in the race to provide the optimal solution to BPA narrowing is the one most likely to provide the best long-term impact on normal vessel growth, and although this technique may provide a preferable approach in certain anatomical substrates, much work remains to be done.

Acknowledgements

None.

Footnote

Provenance: This is a Guest Editorial commissioned by the Section Editor Xicheng Deng (Department of Cardiothoracic Surgery, Hunan Children’s Hospital, Changsha, China).Conflicts of Interest: The authors have no conflicts of interest to declare.

Comment on: Kim H, Chan Sung S, Choi KH, et al. Sutureless Patch Angioplasty for Postoperative Pulmonary Artery Stenosis in Congenital Cardiac Surgeries. Ann Thorac Surg 2016;101:1031-6.

References

1. Ohye RG, Sleeper LA, Mahony L, et al. Comparison of shunt types in the Norwood procedure for single-ventricle lesions. N Engl J Med 2010;362:1980-92.

2. Patel ND, Kenny D, Gonzalez I, et al. Single-center outcome analysis comparing reintervention rates of surgical arterioplasty with stenting for branch pulmonary artery stenosis in a pediatric population. Pediatr Cardiol 2014;35:419-22.

3. Padalino MA, Quarti A, Angeli E, et al. Early and mid-term clinical experience with extracellular matrix scaffold for congenital cardiac and vascular reconstructive surgery: a multicentric Italian study. Interact Cardiovasc Thorac Surg 2015;21:40-9.

4. Kim H, Chan Sung S, Choi KH, et al. Sutureless Patch Angioplasty for Postoperative Pulmonary Artery Stenosis in Congenital Cardiac Surgeries. Ann Thorac Surg 2016;101:1031-6.

5. Yun TJ, Coles JG, Konstantinov IE, et al. Conventional and sutureless techniques for management of the pulmonary veins: Evolution of indications from postrepair pulmonary vein stenosis to primary pulmonary vein anomalies. J Thorac Cardiovasc Surg 2005;129:167-74.

Cite this article as: Kenny DP, McGuinness J, Hijazi ZM. The battleground of the stenotic branch pulmonary arteries: the surgical approach of “less is more”. Transl Pediatr 2016;5(3):112-113. doi: 10.21037/tp.2016.05.03


Original Article

Antegrade cerebral perfusion at 25 ℃ for arch reconstruction in newborns and children preserves perioperative cerebral oxygenation and serum creatinine

Bhawna Gupta1, Ali Dodge-Khatami1, Juan Tucker1, Mary B. Taylor2, Douglas Maposa3, Miguel Urencio1, Jorge D. Salazar1

1Division of Cardiothoracic Surgery, 2Divisions of Pediatric Critical Care and Pediatric Cardiology, 3Division of Pediatric Anesthesiology, The

Children’s Heart Center, The University of Mississippi Medical Center, Jackson, Mississippi, USA

Contributions: (I) Conception and design: All authors; (II) Administrative support: B Gupta, A Dodge-Khatami, JD Salazar; (III) Provision of

study materials or patients: B Gupta, A Dodge-Khatami, J Tucker, JD Salazar; (IV) Collection and assembly of data: None; (V) Data analysis and

interpretation: B Gupta, A Dodge-Khatami, J Tucker, JD Salazar; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All

authors.

Correspondence to: Jorge D. Salazar, MD. Division of Cardiothoracic Surgery, University of Mississippi Medical Center, 2500 North State Street,

Jackson, MS 39216, USA. Email: [email protected].

Background: Antegrade cerebral perfusion (ACP) typically is used with deep hypothermia for cerebral protection during aortic arch reconstructions. The impact of ACP on cerebral oxygenation and serum creatinine at a more tepid 25 ℃ was studied in newborns and children.Methods: Between 2010 and 2014, 61 newborns and children (<5 years old) underwent aortic arch reconstruction using moderate hypothermia (25.0±0.9 ℃) with ACP and a pH-stat blood gas management strategy. These included 44% Norwood-type operations, 30% isolated arch reconstructions, and 26% arch reconstructions with other major procedures. Median patient age at surgery was 9 days (range, 3 days–4.7 years). Cerebral oxygenation (NIRS) was monitored continuously perioperatively for 120 hours. Serum creatinine was monitored daily.Results: Median cardiopulmonary bypass (CPB) and cross clamp times were 181 minutes (range, 82–652 minutes) and 72 minutes (range, 10–364 minutes), respectively. ACP was performed at a mean flow rate of 46±6 mL/min/kg for a median of 48 minutes (range, 10–123 minutes). Cerebral and somatic NIRS were preserved intraoperatively and remained at baseline postoperatively during the first 120 hours. Peak postoperative serum creatinine levels averaged 0.7±0.3 mg/dL for all patients. There were 4 (6.6%) discharge mortalities. Six patients (9.8%) required ECMO support. Median postoperative length of hospital and intensive care unit (ICU) stay were 16 days(range, 4–104 days) and 9 days (range, 1–104 days), respectively. Two patients (3.3%) received short-term peritoneal dialysis for fluid removal, and none required hemodialysis. Three patients (4.9%) had an isolated seizure which resolved with medical therapy, and none had a neurologic deficit or stroke.Conclusions: ACP at 25 ℃ preserved perioperative cerebral oxygenation and serum creatinine for newborns and children undergoing arch reconstruction. Early outcomes are encouraging, and additional study is warranted to assess the impact on late outcomes.

Keywords: Antegrade cerebral perfusion (ACP); moderate hypothermia; circulatory arrest; infants; aortic arch

Submitted Apr 28, 2016. Accepted for publication May 26, 2015.

doi: 10.21037/tp.2016.06.03




Introduction

Complex aortic arch reconstruction in neonates and children is performed typically under deep hypothermic circulatory arrest (DHCA). This approach has enabled successful outcomes over many decades (1), with cerebral protection achieved by reducing brain metabolism and oxygen requirements. The risk of injury associated with DHCA is not clear, although long periods have been associated with seizures and choreoathetosis (2,3). Long-term neurological complications may manifest as impaired neurodevelopment, with the worst outcomes being observed in newborns with complex congenital heart lesions in need for aortic arch reconstruction under prolonged periods of DHCA (2,4-7). With the intent of maximizing cerebral protection, surgical and perfusion strategies have been developed to selectively perfuse the brain during these operations.

Antegrade cerebral perfusion (ACP) at deep hypothermia emerged as an adjunctive perfusion strategy to DHCA aiming to minimize the use of circulatory arrest and offer additional cerebral protection during arch operations. During ACP, blood flow is supplied to the brain selectively during the critical period of arch reconstruction, while at least partial somatic flow is achieved through collaterals. Somatic ischemia is theoretically lessened during arch reconstruction and the risks of neurological and cognitive deficits following operation are presumably reduced (8,9). With increased experience with ACP in the field of adult aortic arch reconstruction, a more recent evolution from deep hypothermia toward the use of warmer temperatures has occurred (10-12).

The use of tepid temperatures for ACP potentially may reduce the deleterious effects associated with deep hypothermia and rewarming (13). But this cannot be at the expense of cerebral and somatic protection. In the absence of a standardized nomenclature, a recent consensus panel categorized the temperatures into ‘deep’ for a nasopharyngeal temperature of 14.1–20 ℃, ‘moderate’ for 20.1–28 ℃ and ‘mild’ for 28.1–34 ℃ (14). Mild-moderate hypothermia with ACP is now utilized widely in adults, and although not supported by formal and prospective neurocognitive outcomes data, appears to be a safe and effective strategy for both neurological and somatic protection for periods of less than 60 minutes (10,15,16). In newborns and infants, extended end-to-end repair of coarctation is performed routinely at near-normothermia with all cerebral and systemic perfusion achieved via the

innominate artery for periods of approximately 20 minutes, without clinically significant neurological or end-organ injury (17). Notwithstanding, few reports evaluate the use of moderate hypothermia for ACP in neonates and children undergoing aortic arch reconstructions (11,12,18-20).

To this end, our specific aim was to further assess the perioperative impact of ACP at 25 ℃ on cerebral oxygenation and serum creatinine in newborns and children undergoing arch reconstructions. Herein, we report our experience and outcomes.

Methods

Institutional Review Board approval was obtained for this retrospective study and patient/parent consent was waived. Between 2010 and 2014, 61 patients less than 5 years of age underwent complex aortic arch operation using moderate hypothermia with ACP (40–60 mL/kg/min) and a pH-stat blood gas management strategy. The medical records were reviewed for demographics, preoperative diagnosis, and perioperative course. The patients were categorized into three groups: Stage I or Norwood-type operations (Stage I), isolated aortic arch reconstructions (Arch), and aortic arch reconstructions with other major cardiac procedures (Arch++). Patients with obstructed pulmonary venous return were excluded from this study.

Surgical technique

All operations were performed using a physiologic blood-prime followed by cooling with full-flow cardiopulmonary bypass (CPB) (150 mL/kg/min) using a 6 ℃ temperature gradient to moderate hypothermia (25 ℃). A pH-stat blood gas management strategy, pO2 of 150 mmHg, and hematocrit of 30% were maintained. ACP was delivered via the innominate artery or equivalent with flow rates of 40–60 mL/kg/min, maintaining a mean arterial pressure appropriate for the age of the child (25–55 mmHg). During ACP, the arch branches and descending thoracic aorta were controlled with snares or fine clamps to maintain a bloodless field and maintain cerebral and systemic perfusion pressure. Upon completion of the reconstruction, de-airing, and removal of snares or clamps, ACP was followed by re-warming with full-flow CPB at a maximum gradient of 6 ℃.

Cerebral and somatic oxygenation monitoring

Bilateral cerebral and single somatic oximetry were

116 Gupta et al. ACP at 25 ℃


monitored continuously and recorded by near-infrared spectroscopy (NIRS) (Somanetics, INVOS 5100C, Covidien) in all patients, both intraoperatively and postoperatively for 120 hours or until discharge from the intensive care unit (ICU). The non-invasive NIRS probe measures the regional oxygen saturation (rSO2) as a percentage on a scale from 15% to 95%. The probes were placed on both sides of the forehead for cerebral (left and right) readings, and over the right flank for somatic rSO2 readings. For this study, the data were recorded at the following time points: baseline (before CPB), start of CPB, cooling, aortic cross-clamping, start of ACP, during ACP, end of ACP, un-clamping, re-warming, end of CPB, and postoperatively for 120 hourly intervals.

Clinical outcomes and serum creatinine

The intraoperative variables assessed were CPB time, aortic cross-clamp time, ACP flow and time, and lactate levels. Serum creatinine and lactate levels were recorded preoperatively and postoperatively on a daily basis until hospital discharge. Postoperative variables analyzed included postoperative length of ICU and hospital stay, need for extracorporeal membrane oxygenation (ECMO), need for postoperative peritoneal dialysis or dialysis, need

for gastrostomy tube, neurological complications (seizures, neurological deficit and stroke), and discharge mortality.

Statistical analysis

Data are shown as mean ± standard deviation (SD), median and range (minimum, maximum), or N (%). Given the number of patients and low incidence of complications, additional statistical analysis was not meaningful clinically or statistically.

Results

Patient characteristics

The characteristics for all 61 patients are outlined in Table 1. Median age at surgery was 9 days, with 72% being neonates and 20% infants between 1 month and 1 year of age. Thirty-two patients were male. Among the three groups analyzed, 27 patients (44%) underwent a Norwood-type (Stage I) operation for hypoplastic left heart syndrome (HLHS) or single ventricle variants with arch hypoplasia [unbalanced atrioventricular canal, truncus arteriosus with hypoplastic arch, transposition of the great arteries (TGA) with hypoplastic arch, or interrupted arch]. Of these, 25/27 (93%) Stage I operations received a right ventricle-to-pulmonary artery shunt (Sano). In the second group, eighteen patients (30%) underwent isolated reconstruction of the aortic arch (Arch). In the third group (Arch++), sixteen (26%) patients underwent aortic arch reconstruction along with other major procedures such as a Damus-Kaye-Stansel reconstruction with bidirectional Glenn (Comprehensive stage II), subaortic resection, ventricular septal defect closure, aortic/truncal root replacement, or supravalvular aortic stenosis repair.

Operative outcomes

The operative outcomes are summarized in Table 2. All aortic arch operations were performed at a mean rectal temperature of 25.0±0.9 ℃. Mean CPB and aortic cross-clamp times for all sixty-one patients were 195±95 and 87±61 min, respectively. ACP was performed at a mean flow rate of 46±6 mL/min/kg for 52±22 minutes.

Cerebral and somatic oxygenation

The cerebral and somatic NIRS (rSO2) readings are shown

Table 1 Patient characteristics

Variable All patients (N=61)

Age at surgery

Median (range) 9 days (3 days–4.7 years)

≤1 month, N [%] 44 [72]

1–6 months, N [%] 8 [13]

6-mo–1 year, N [%] 4 [7]

1–5 years, N [%] 5 [8]

Gestational age, weeks (for ≤1 month) 38.4±1.2

Gender, male/female, N 32/29

Birth weight, kg 3.2±0.5

Prematurity <37 weeks, N 8

Birth weight <2.5 kg, N 5

Type of procedure

Stage I: Stage I or Norwood type (93% Sano), N (%)

27 [44]

Arch: isolated aortic arch reconstruction, N (%)

18 [30]

Arch++: arch plus other major, N (%) 16 [26]



in Figures 1-3. Cerebral NIRS readings stayed above baseline throughout surgery, with no clinically-significant differences in the intraoperative NIRS readings between the left and right cerebral hemispheres for all patients (Figure 1). Somatic NIRS stayed above baseline during cooling, dropped somewhat during ACP, and rebounded quickly after ACP.

Postoperatively, cerebral and somatic NIRS remained near or at baseline during the first 24 hours and beyond for all groups (Figures 2,3).

Postoperative course

The postoperative outcomes for all 61 patients and by procedure group are described in Table 3. Of the 61

patients, a total of 6 (9.8%) required ECMO. Three were in the Stage I (Norwood) group, and the other three had Arch++ procedures. Median postoperative lengths of hospital and ICU stay for all sixty-one patients were 16 days (range, 4–104 days) and 9 days (range, 1–104 days), respectively. Two patients in the Stage I group received temporary peritoneal dialysis postoperatively for fluid removal. No patient required hemodialysis. None of the patients demonstrated evidence of liver dysfunction. Three patients (4.9%) had an isolated seizure after surgery, two of which were confirmed by electroencephalogram. None persisted after initiation of medical therapy. None of the patients had a neurologic deficit or stroke. Although not the focus of this study, representative pre- and post-operative brain MRI imaging is demonstrated in Figure 4.

Table 2 Operative characteristics

Operative outcome All patients (N=61) Stage I (N=27) Arch (N=18) Arch++ (N=16)

Age at surgery, days 9 [3, 4.7 y] 7 [3, 47] 12.5 (4, 3.2 y) 131 (3, 4.7 y)

Weight at surgery, kg 3.5 [2.0, 16.0] 3.1 [2.0, 4.1] 3.8 [2.6, 14.0] 4.2 [2.0, 16.0]

Peak preoperative serum creatinine, mg/dL 0.5±0.1 0.5±0.2 0.4±0.1 0.4±0.1

Peak preoperative serum lactate, mmol/L 1.8±1.1 2.0±1.4 1.6±0.5 1.6±0.6

Cross clamp time, min 72 [10, 364] 86 [47, 184] 39 [10, 104] 107 [43, 364]

ACP time, min 48 [10, 123] 63 [32, 123] 36 [10, 62] 44 [22, 102]

ACP flow, mL/kg/min 46±6 44±5 48±6 48±5

Total CPB time, min 181 [82, 652] 205 [139, 328] 109 [82, 194] 192 [97, 652]

Peak intraoperative serum lactate, mmol/L 5.2±2.4 5.8±1.7 4.2±2.7 5.3±2.9

Creatinine, lactate and ACP flow are presented as mean ± SD. Age, weight, cross clamp time, ACP time and CPB time are presented as median and range (min, max). ACP, antegrade cerebral perfusion; CPB, cardiopulmonary bypass; SD, standard deviation.

Figure 1 Intraoperative cerebral/somatic NIRS for all patients.



Figure 2 Mean cerebral and somatic NIRS during surgery broken down into subgroups. (A) Perioperative mean cerebral and somatic NIRS for Stage I group; (B) perioperative mean cerebral and somatic NIRS for Arch group; (C) perioperative mean cerebral and somatic NIRS for Arch++ group.

A

B

C



Figure 3 (A) Perioperative mean cerebral left NIRS by reconstruction group; (B) perioperative mean cerebral right NIRS by reconstruction group; (C) perioperative mean somatic NIRS by reconstruction group.

A

B

C

Serum creatinineThe mean of the peak serum creatinine levels is shown in Figure 5. The peak creatinine for all patients averaged 0.7±0.3 mg/dL. The highest postoperative creatinine of any single patient was 1.48 mg/dL.

Discharge mortalityOverall, there were four discharge mortalities (6.6%). One patient underwent Stage I with a 3.5-mm modified Blalock-Taussig shunt. After an uneventful postoperative course and chest closure, the patient was placed on ECMO



Figure 4 Pre- and Postoperative MRI brain imaging.

Table 3 Postoperative outcomes

Postoperative outcome All patients (N=61) Stage I (N=27) Arch (N=18) Arch++ (N=16)

Discharge mortality, N (%) 4 (6.6%) 2 (7.4%) 0 2 (12.5%)

Need for ECMO, N (%) 6 (9.8%) 3 (11.1%) 0 3 (18.8%)

ICU stay, days 9 [1, 104] 12 [6, 104] 5 [1, 43] 8 [2, 63]

Postop hospital stay, days 16 [4, 104] 22 [11, 104] 11 [4, 45] 10 [4, 78]

Peak postop serum creatinine until discharge, mg/dL 0.7±0.3 0.8±0.3 0.6±0.2 0.6±0.2

Peak 24 hr postoperative serum lactate, mmol/L 3.9±2.3 5.0±2.7 2.8±1.3 3.4±1.6

Use of temporary peritoneal dialysis, N (%) 2 (3.3%) 2 (7.4%) 0 (0%) 0 (0%)

Need for G-tube, N (%) 15 (24.6%) 11 (40.0%) 3 (20.0%) 1 (6.2%)

Postoperative seizures, N (%) 3 (4.9%) 1 (3.7%) 1 (5.5%) 1 (6.2%)

Neurologic deficit/stroke, N (%) 0 (0%) 0 (0%) 0 (0%) 0 (0%)

Serum creatinine and lactate are presented as mean ± SD. ICU and postoperative hospital stay are presented as median and range (min, max). ECMO, extracorporeal membrane oxygenation; ICU, intensive care unit; Postop, postoperative; G-tube, gastrostomy tube; SD, standard deviation.

Pre-op MRI (Baby M)

Post-op MRI (Baby M)

on postoperative day (POD) 6 for respiratory distress and ultimately expired on POD 55. The second patient underwent late stage I with Sano after presenting at 6 weeks of age. Despite a favorable neurological and hemodynamic result, the child died of chronic respiratory failure on POD 104. The third patient underwent Stage I and interrupted aortic arch repair. Initially the child did well neurologically

and hemodynamically but was placed on ECMO on POD 4 for sudden cardiac arrest. During ECMO wean, the circuit clotted acutely and the child died on POD 8. The fourth patient underwent redo truncal valve replacement and arch reconstruction. The patient was placed on post-operative ECMO for bleeding and inability to separate from CPB from pulmonary dysfunction. The child separated from



ECMO but ultimately expired on POD 35.

Discussion

Deep hypothermic circulatory arrest is the traditional approach for operations involving aortic arch reconstruction in adults and children, acknowledging the potential for neurological complications including cognitive deficits. The transition from the DHCA paradigm toward ACP with deep hypothermia was aimed to maximize cerebral protection during arch operations while minimizing any morbidity. Antegrade cerebral perfusion is used now by many centers as a perfusion adjunct under deep hypothermia to minimize the use of circulatory arrest during neonatal aortic arch reconstruction (21), with the expectation of mitigating neurological and somatic morbidity. A comparison of DHCA alone versus continuous low-flow cerebral perfusion in infants has suggested more neurological perturbations and a greater likelihood of clinical seizures in the early postoperative period of the DHCA alone group (3). Other reports advocate the use of ACP over DHCA alone to not only attenuate neurological morbidity but also to achieve somatic protection during arch reconstruction (5,22-25). However, other reports question the advantage of ACP over DHCA alone, detecting no difference in the incidence of new white matter injury or cerebral ischemic lesions postoperatively, nor any benefit on psychomotor and mental development status between the two groups of ACP versus DHCA alone (26-30).

It is worth mentioning that even though ACP is used

routinely in many centers, there exist wide variations in the specific details of the perfusion strategy. ACP flow rates, blood gas temperature correction (pH versus alpha stat), time required for the repair, hematocrit, pO2, and even cannulation strategies vary significantly, making it challenging to evaluate the benefit of cerebral perfusion during arch repairs. Despite the lack of a standardized protocol for ACP and some inconsistency in the reported results, there does appear to be an increasing trend toward ACP (with deep hypothermia) over DHCA for neonatal arch reconstruction (31).

The optimal temperature for complex aortic arch reconstructions with ACP remains a topic of debate. Many adult centers have shifted toward the use of mild-to-moderate temperatures with encouraging results (10,15,32-35). While conclusive evidence is lacking, these encouraging outcomes coupled with shorter CPB times and avoiding the morbidity of deep hypothermia have led to the increasing clinical acceptance of tepid ACP for arch repair in adults. Moderate hypothermia with ACP has been explored in Europe and Asia for neonatal arch operations, although the typical practice in North America has been to use deep hypothermia with ACP or DHCA alone. Oppido et al. reported 17% early mortality and 8.5% late deaths over a follow-up of up to 50 months in a group of 70 consecutive neonates who underwent the Norwood procedure or aortic arch repair at a nasopharyngeal temperature of 25 ℃ with ACP (18). Only one patient had postoperative seizures. The authors suggested ACP to be an effective and reliable perfusion strategy that provides a longer safe period for arch repairs and minimizes neurological complications without

Figure 5 Peak perioperative creatinine for all patients.



the need for deep hypothermia. Likewise, Lim et al. (11), Dodge-Khatami et al. (12), Miyaji et al. (20) and Ly et al. (36) demonstrated in neonates and infants the effectiveness of antegrade cerebral perfusion at moderate hypothermia at preserving both cerebral and somatic tissue oxygenation.

Previously, we evaluated moderate (25 ℃) and deep (18 ℃) hypothermia with ACP in a piglet model for arch operation (37-39). These studies demonstrated improved neuroprotection at 18 and 25 ℃ with ACP as compared to DHCA alone, with shorter CPB times at 25 ℃, and laid the foundation for our clinical practice of moderate hypothermia with ACP during neonatal aortic arch repair. We have employed moderate hypothermia (25 ℃) with ACP for all aortic arch reconstructions at the University of Mississippi Medical Center since program inception in April of 2010.

The ideal flow rate for ACP is dependent on many factors and remains to be established. Although the cited literature varies widely in range for ACP from 10 to 100 mL/kg/min, studies utilizing NIRS technology or visual light spectroscopy have indicated that ACP flow rates of greater than 30 mL/kg/min are sufficient to maintain adequate cerebral and somatic oxygen saturations (12,19,40). Admittedly, these findings must be evaluated within the context of temperature and blood gas management (pH versus alpha stat) among other factors. We use ACP at a flow rate of 40–60 mL/kg/min under NIRS guidance to monitor both cerebral and somatic oxygen levels. In the current study, NIRS supports the effectiveness of ACP at 25 ℃ systemic cooling in maintaining adequate cerebral and lower body perfusion. Although somatic NIRS dropped during ACP, they remained close to baseline levels, suggesting that an ACP flow at 40–60 mL/kg/min was sufficient in maintaining adequate perfusion through collaterals to the lower body and attenuating somatic ischemia during arch operation at 25 ℃. This is further supported by favorable postoperative lactate and serum creatinine levels.

Conclusions

The present study suggests that moderate hypothermia (25 ℃) with ACP preserves perioperative cerebral oxygenation and serum creatinine in neonates, infants, and children for complex aortic arch operations.

Limitations

The study is limited by the lack of a control group with

DHCA alone or ACP at deep hypothermia. Intra-operative electroencephalogram, which does not always correlate with right and left cerebral NIRS, was not performed, and could have disclosed abnormal neurological activity undetected by NIRS. Long-term neurodevelopmental follow-up of these children is required to evaluate the late outcomes of ACP with warmer temperatures and make formal comparison with strategies at 18 ℃.

Acknowledgements

None.

Footnote

Conflicts of Interest: The authors have no conflicts of interest to declare.

Ethical Statement: Institutional Review Board (2014-0107) approval was obtained for this retrospective study and patient/parent consent was waived.

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Cite this article as: Gupta B, Dodge-Khatami A, Tucker J, Taylor MB, Maposa D, Urencio M, Salazar JD. Antegrade cerebral perfusion at 25 ℃ for arch reconstruction in newborns and children preserves perioperative cerebral oxygenation and serum creatinine. Transl Pediatr 2016;5(3):114-124. doi: 10.21037/tp.2016.06.03

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Original Article

How to set-up a program of minimally-invasive surgery for congenital heart defects

Juan-Miguel Gil-Jaurena1,2, Ramón Pérez-Caballero1,2, Ana Pita-Fernández1,2, María-Teresa González-López1,2, Jairo Sánchez3, Juan-Carlos De Agustín4

1Department of Pediatric Cardiac Surgery, Hospital Gregorio Marañón, Madrid, Spain; 2Department of Instituto de Investigación Sanitaria Gregorio

Marañón, Madrid, Spain; 3Department of Pediatric Cardiac Surgery, Instituto Cardiológico, Bucaramanga, Colombia; 4Department of Pediatric

Surgery, Hospital Gregorio Marañón, Madrid, Spain

Contributions: (I) Conception and design: JM Gil-Jaurena; (II) Administrative support: R Pérez-Caballero, JC De Agustín; (III) Provision of study

materials or patients: A Pita-Fernández , MT González-López; (IV) Collection and assembly of data: JM Gil-Jauren, MT González-López; (V) Data

analysis and interpretation: JM Gil-Jaurena, JC De Agustín; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

Correspondence to: Juan-Miguel Gil-Jaurena. Pediatric Cardiac Surgery, Hospital Gregorio Marañón, C/O´Donnell nº50, 28009, Madrid, Spain.

Email: [email protected].

Background: Mid-line sternotomy is the commonest incision for cardiac surgery. Alternative approaches are becoming fashionable in many centres, amidst some reluctance because of learning curves and overall complexity. Our recent experience in starting a new program on minimally invasive pediatric cardiac surgery is presented. The rationale for a stepwise onset and the short-medium term results for a three-year span are displayed.Methods: A three-step schedule is planned: First, an experienced surgeon (A) starts performing simple cases. Second, new surgeons (B, C, D, E) are introduced to the minimally invasive techniques according to their own proficiency and skills. Third, the new adopters are enhanced to suggest and develop further minimally invasive approaches. Two quality markers are defined: conversion rate and complications.Results: In part one, surgeon A performs sub-mammary, axillary and lower mini-sternotomy approaches for simple cardiac defects. In part two, surgeons B, C, D and E are customly introduced to such incisions. In part three, new approaches such as upper mini-sternotomy, postero-lateral thoracotomy and video-assisted mini-thoracotomy are introduced after being suggested and developed by surgeons B, C and E, as well as an algorithm to match cardiac conditions and age/weight to a given alternative approach. The conversion rate is one out of 148 patients. Two major complications were recorded, none of them related to our alternative approach. Four minor complications linked to the new incision were registered. The minimally invasive to mid-line sternotomy ratio rose from 20% in the first year to 40% in the third year.Conclusions: Minimally invasive pediatric cardiac surgery is becoming a common procedure worldwide. Our schedule to set up a program proves beneficial. The three-step approach has been successful in our experience, allowing a tailored training for every new surgeon and enhancing the enthusiasm in developing further strategies on their own. Recording conversion-rates and complications stands for quality standards. A twofold increase in minimally invasive procedures was observed in two years. The short-medium term results after three years are excellent.

Keywords: Sternotomy; minimally invasive; sub-mammary; axillary; thoracoscopy; video-assisted

Submitted Apr 19, 2016. Accepted for publication May 25, 2016.

doi: 10.21037/tp.2016.06.01

View this article at: http://dx.doi.tp/10.21037/tp.2016.06.01

126 Gil-Jaurena et al. Setting-up a congenital minimally-invasive program


Introduction

Surgical closure of cardiac defects via a full mid-line sternotomy has been considered the gold standard for over 50 years. The rise of interventional cardiology and new techniques like laparoscopy or thoracoscopy have prompted some groups to explore alternative approaches to median sternotomy (1-7). New adopters and reluctant ones have their own reasons. Added complexity, longer overall and ischemic times and even results account for the balance of the latter.

Among the most frequent alternative approaches (Figure 1) we find: lower mini-sternotomy (8-11), right sub-mammary (1,12-16), postero-lateral thoracotomy (17,18) and right axillary incisions (19-23). Main advantages are cosmesis and earlier recovery, as well as saving blood products and lower infection rates. On the other hand, a steep learning curve and technical difficulties in handling some steps (myocardial protection, de-airing maneuvers, and so on) discourage many surgeons to include these minimally invasive procedures within their routine practice.

Trying to schedule a program for starting and teaching minimally invasive pediatric cardiac surgery is a step forward. Few reports can be found in the literature on the topic, if any, except for the right mini-thoracotomy approach employed for mitral repair (23-27) in adult cardiac surgery. In the next paragraphs, we will depict our experience in developing a minimally invasive pediatric cardiac surgery program, pointing out the steps followed as well as the insights provided by the new adopters.

Methods

Upon arrival to a medium-volume centre in which approximately two hundred pump cases per year are carried out, Surgeon A is expected to develop a program of minimally-invasive pediatric cardiac surgery. He has been performing minimally invasive procedures for twelve years in two previous institutions and has produced several papers on the topic (6,16,22,23,28,29) , as well as many presentations in local meetings.

The strategy to establish a new program is split in three parts, assuming some overlapping rather than a formal schedule in a three year analysis:

(I) Performing minimally invasive cases (surgeon A) with every member of the surgical team (surgeons, anesthesiologists, perfusionists, scrub nurses) to let them become familiar and confident with the new

approaches;(II) Introducing new surgeons to minimally invasive

surgery in a stepwise and customized way, according to expertise and skills;

(III) Developing new strategies together, particularly enhanced by the young staff members.

On the other hand, some quality indicators will be measured, such as:

(I) Conversion rate. If so, was it to sternotomy or another incision?

(II) Complications. Trying to figure out whether the alternative approach is to blame for the drawback or if any other cause was responsible for it.

To begin with, a minimally invasive incision will be

A B

C D

Figure 1 Range of approaches introduced by the leading surgeon. (A) Full mid-line sternotomy; (B) lower mid-line sternotomy; (C) right sub-mammary approach; (D) right axillary incision.



defined as “surgical approach other than full mid-line sternotomy to perform open heart surgery with extracorporeal circulation”. Three main surgical approaches were introduced by surgeon A: sub-mammary, axillary and lower mini-sternotomy. A single alternative incision gives way either to cannulation maneuvers and correction, with the philosophy of “same steps, same tools, same risks, different approach”. Later in the program (as will be thoroughly displayed in Results and Discussion) several new approaches were added: upper mini-sternotomy, postero-lateral thoracotomy and video-assisted mini-thoracotomy (for which several ports were necessary). Not included in the tables, some off-pump cases

via thoracotomy and thoracoscopy were performed, as some experience was acquired by the team.

Before starting any procedure, the proposed incision is drawn with a sterile pen for teaching purposes. Should an enlargement or conversion be needed, security margins are settled (e.g., lower mini-sternotomy enlargement to full sternotomy, or axillary incision conversion to postero-lateral one). Brief description of the minimally invasive approaches:

(I) Sub-mammary. Supine position with the right shoulder slightly elevated and the right arm suspended over the head. Skin incision under the right sub-mammary crease (or 6th intercostal space in children). En-block dissection of subcutaneous tissue and pectoral muscle (30,31). Cage-rib entry in the 4th intercostal space. Full cannulation and correction under cardioplegic arrest (Figures 1C,2);

(II) Axillary. Decubitus lateral position with the right arm suspended over the head. Skin incision in the axillary groove, between anterior and posterior lines. Serratus and latissimus dorsi muscles sparing (28) technique. Cage-rib entry in the 4th intercostal space. Full cannulation and correction under cardioplegic arrest (Figures 1D,3);

(III) Lower mini-sternotomy. Supine position. Skin vertical incision below an imaginary line connecting both nipples. Partial lower sternotomy. Regular spreader plus cephalad traction of the sternum. Full cannulation and correction under cardioplegic arrest (Figures 1B,4);

(IV) Upper mini-sternotomy. Supine position. Skin vertical incision above an imaginary line connecting both nipples. Partial upper sternotomy. Full cannulation and correction under cardioplegic arrest;

(V) Postero-lateral thoracotomy. Decubitus lateral position with the right arm suspended over the head. Skin incision between anterior axillary line and spine (the tip of the scapula being the mid-point). Cage-rib entry in the 4th intercostal space. Full cannulation and correction under cardioplegic arrest (Figure 3A);

(VI) Video-assisted mini-thoracotomy. Supine position with the right shoulder slightly elevated and the right arm secured below the axilla. Mini-skin incision under the right sub-mammary crease. Right jugular and right femoral (arterial and venous) cannulation to institute by-pass. Additional ports for video-assistance, aortic clamp and others.

A B

A B

Figure 2 Sub-mammary approach in an adolescent female. Note the landmarks (A) and final aesthetic result (B).

Figure 3 Right horizontal axillary incision. Note the landmarks between the nipple and the tip of the scapulla as well as the proposed conversion to a postero-lateral incision if needed (A). Final result six months later (B).



Correction under cardioplegic arrest.

Results

Part one

Surgeon A began his program with sub-mammary, axillary and lower mini-sternotomy cases alternatively, according to age/weight and cardiac condition of every patient. This way, ventricular septal defect (VSD) cases were corrected by mini-sternotomy, atrial septal defect (ASD) patients through an axillary approach, and women with well-defined sub-mammary groove were entered by a sub-mammary incision. The initial three months was time enough to get everyone in the cardiac team comfortable with the changes.

Part two

Surgeons B, C and D were sequentially introduced to

lower mini-sternotomy and sub-mammary approaches, according to their own interest and skills. Simple cases (ostium secundum ASD) were selected for this purpose to begin with, followed by VSD closure through lower mini-sternotomy in a customized pattern for every surgeon. By the end of the first year, all surgeons had already performed ASD and VSD cases through lower mini-sternotomy and some ASD closures through a sub-mammary approach.

Surgeon D moved to a different Center in another Country and was substituted by surgeon E, who took up quickly the same method of learning, following the way of surgeons B and C.

On the other hand, Surgeons B and C considered the axillary approach rather cumbersome, and suggested starting a postero-lateral one before attempting the former.

Part three

Surgeon C introduced the upper mini-sternotomy approach for aortic valve surgery with the advice of an adult cardiac surgeon.

As previously stated, the right postero-lateral thoracotomy was suggested by surgeons B and C (and surgeon E, later on) as an initial step before taking up the axillary incision.

Surgeon B suggested moving forward and attempting a thoracoscopic approach. He reviewed the literature (32-37) and contacted a pediatric surgeon with experience in the field from our own Center. After assisting him in thoracoscopic patients (pediatric surgery) and attending a specific course in minimally-invasive thoracoscopy (surgeons B and C), a new program was started.

Surgeon E displayed a sort of algorithm for case-approach, according to age/weight & cardiac defect, resulting in a tailored minimally invasive approach for any given patient.

Table 1 depicts the amount of patients operated on by a minimally invasive approach by every surgeon during the three consecutive years. When compared to the total amount of patients, the ratio of mini-invasive to total pump-cases increased twofold between 2013 and 2015. We have to take into account that 2014 was the first year for Surgeon E, which could explain why the figures are so close between 2013 (20%) and 2014 (22.5%), rather than displaying a steady progression along the three year span.

Increase in percentage of mini-invasive pump cases.(I) 2013: 40/201 (20%)(II) 2014: 40/178 (22.5%)(III) 2015: 68/166 (40%)Table 2 displays the different approaches by every

Table 1 Number of procedures performed by surgeon and year

SurgeonYear

Total2013 2014 2015

A 15 12 21 48

B 7 8 6 21

C 10 12 22 44

D 8 8

E 8 19 27

Total 40 40 68 148

Figure 4 Lower mid-line sternotomy. Full mid-line sternotomy (upper left) as compared to lower mini-sternotomy (lower left). Result at discharge on 7th postoperative day.

A

B

C



surgeon. All of us are confident with the lower mini-sternotomy and sub-mammary ones. Only surgeon A is performing the axillary incision up to now, because the remaining staff members feel more comfortable with the postero-lateral approach. The upper mini-sternotomy, introduced by surgeon C, has been taken up by surgeons B and E as well, for aortic valve patients. The video-assisted thoracotomy, led by surgeon B, is applied for ostium secundum ASD patients by surgeons B and C.

Table 3 shows the distribution of diagnosis and surgeons. Simple conditions, like ASD (ostium secundum, sinus venosus, ostium primum) and VSD have been performed by every surgeon (excepting surgeon D, who left earlier). To sum up, these simple cases account for more than 80% of the whole number of minimally-invasive pump cases. Regarding VSD’s alone, which has been approached by lower mini-sternotomy, the progression has been steady along the three years with a well-defined step up:

(I) 2013: 32/40 (80%)—12 VSD(II) 2014: 35/40 (87%)—12 VSD(III) 2015: 58/68 (82%)—20 VSDMore complex cases (complete atrio-ventricular septal

defect, subaortic myectomy (Morrow), scimitar syndrome, tricuspid valve repair) have been performed by surgeon A, expanding the indications of minimally invasive surgery as experience is gained.

Table 4 summarizes the data relating to the approach and cardiac defect, independently of the surgeon. ASD and VSD are the commonest conditions, as expected. Lower mini-sternotomy is the most prevalent approach, given its simplicity (in fact, it is the first alternative incision learned) and the wide range of cardiac defects corrected through this pathway. The sub-mammary incision has been used for any type of ASD and few others; the axillary approach for ostium secundum and sinus venosus ASD, only. At the moment, the

upper mini-sternotomy is indicated for aortic valve purposes and the video-assisted thoracotomy for ostium secundum defects.

Not included in Table 4 which describes pump cases only, some patients were operated on via left thoracotomy without cardio-pulmonary by-pass (one sling left pulmonary artery, two patients with anomalous drainage of left upper pulmonary veins) and video-assisted thoracoscopy [one pericardial window and one left atrial appendage ablation (38)

plus clip-exclusion].

Conversion rate

An axillary approach for a sinus venosus ASD had to be converted to a postero-lateral one (just enlarging the skin incision backwards and splitting the latissimus dorsi muscle). Despite the conversion, the postero-lateral approach can still be considered a minimally invasive one. No other conversion was required.

Complications

An ostium primum patient died because progression of diffuse pulmonary vein stenosis three months after repair. A VSD patch-closure developed aortic regurgitation (excessive trimming of redundant tricuspid tissue which happened to be stuck to an aortic cusp) and was re-operated two days later. A valve repair proved unsuccessful and ended up in a Ross-Konno procedure. Two patients (ASD and VSD) required revision for bleeding. The initial approach in all four cases had been via lower mini-sternotomy.

One ASD patient approached via sub-mammary incision developed transient phrenic palsy and continuous pleural effusions. An analysis of the pleural fluid showed lidocaine and, after removal of the trans-thoracic anesthetic line

Table 2 Number of procedures performed by surgeon and approach

Surgeon

Approach

TotalLower mini-sternotomy Sub-mammary Axillary

Lateral-posterior thoracotomy

Upper mini-sternotomy Thoracoscopy

A 17 6 22 3 48

B 10 4 3 1 3 21

C 25 11 2 4 2 44

D 7 1 8

E 19 4 2 2 27

Total 78 26 22 10 7 5 148



(which was dislodged), both effusion and phrenic palsy resolved. A 55-kg child developed compartment syndrome in the right leg after peripheral cannulation for a video-assisted thoracotomy ASD repair. It was the only case in whom the femoral artery was directly cannulated instead of a graft interposition.

Discussion

Many groups have shifted towards the minimally invasive surgical approaches in pediatrics (1-7). The rationale, beyond cosmesis, is offering the same results with new incisions, when catheter-based interventional procedures are also difficult or contra-indicated. Maybe the future will rely on totally robotic (32) or endoscopic (33-37) surgery, but, for the time being, offering alternative approaches is interesting. Some teams are keen on a single particular approach, whereas others prefer to be familiar with many of them (4-6). Whether this is a strategy or a matter of evolution is beyond the scope of this paper.

Currently, the range of incisions different from a full mid-line sternotomy is rich enough to provide us many options. Interestingly, among the literature reviewed, some papers underline the steps to set up programs (24-27). Particularly relevant is the publication by Bonaros et al. (32), in which the authors split every procedure in several parts and analyze them separately, so as to accurately depict anyone´s learning curve. Not only did we need to start a new program, but also to teach and enhance our young staff to develop their own ideas.

The three-step approach to introduce a program of minimally invasive surgery in a new place has proved successful for several reasons. First of all, the results are good and patients/parents are satisfied. Part one (surgeon A introducing the program) allows all members in theatre to get in touch with the novelty, and surgeon A to realize who is enthusiastic and who is reluctant. This way, approaches could be decided according to individual skills and preferences in customized patterns in part two (surgeons B, C, D and E being introduced). Most important was the honest attitude of

Table 3 Number of procedures performed by surgeon and diagnosis

SurgeonProcedure

TotalOS ASD SV ASD OP ASD VSD CAVSD Aortic Others

A 18 5 4 11 7 3 48

B 8 2 3 7 1 21

C 18 3 5 14 4 44

D 6 1 1 8

E 8 4 5 8 2 27

Total 58 14 18 41 7 7 148

ASD, atrial septal defect; OS, ostium secundum; SV, sinus venosus; OP, ostium primum; VSD, ventricular septal defect; CAVSD, complete

atrio-ventricular septal defect.

Table 4 Relationship between approach and diagnosis along the study period

ApproachProcedure

TotalOS ASD SV ASD OP ASD VSD Others

Lower mini-sternotomy 17 1 15 41 4 78

Sub-mammary 16 4 3 3 26

Axillary 17 5 22

Upper mini-sternotomy 7 7

Lat-post thoracotomy 3 4 3 10

Thoracoscopy 5 5

Total 58 14 18 41 17 148

ASD, atrial septal defect. OS, ostium secundum; SV, sinus venosus; OP, ostium primum; VSD, ventricular septal defect.



the staff, not assuming to tackle incisions considered difficult (e.g., axillary one) and suggesting new approaches (part three). As responsible of the team, surgeon A considered not to get involved in the new programs of upper mini-sternotomy for aortic valve cases and video-assisted thoracotomy for ASD patients. The rationale was to let surgeons B and D lead their own projects before incorporating new forthcoming members (E and A): pupils became teachers.

More complex cases were added as experience was gained. Thus, particularly in the last of the three years, the young surgeons were taking up simple cases while surgeon A was performing difficult ones (AVSD, scimitar). As a result, the percentage of minimally invasive cases rose to 40%, doubling the initial rate of 20% during the first year. The lesson is to couple any single patient to a surgeon who is keen either on the defect or on a particular approach, so as to match them in the algorithm of mini-invasive surgery (6,38,39).

Regarding the conversion rate, only one patient had to be switched. The take-home message in a minimally invasive program is trying to convert any patient (when needed) to another minimally invasive approach in an expeditious way. The incision was converted from axillary to postero-lateral incision (again, minimally invasive) by just prolonging posteriorly the already drawn surgical mark and severing the latissimus dorsi muscle. The new program of video-assisted mini-thoracotomy is growing-up under the readiness to convert incisions to a full sub-mammary one, if needed. To date, it has not been necessary to covert a mini-thoracotomy to full mid-line sternotomy.

Before embarking on a minimally invasive program, one has to assume that any drawback is going to be regarded as linked to the alternative approach. Whether it is true or not is irrelevant, unless invasive and minimally-invasive patients are matched. Some of the minor complications we found were definitely related to the approach, like the transient phrenic palsy and the compartment syndrome (40). We have learned how to avoid them (41) in the future.

After gathering some experience, the question is how to move forward with the program? There is no clear answer, since not all surgeons are at the same level of proficiency, or are still in their learning curve. Thinking in terms of contraindications rather than indications, as a last step of training, could be a reasonable marker. In other words, we are not expecting for the “perfect patient” to come and be an ideal candidate for a minimally invasive approach. We rather think about the contraindications, if any, for a minimally invasive procedure in every patient.

The enthusiasm showed by the team members towards

new alternative approaches was overwhelming. Not only did the young surgeons take up the new methods quickly (part two), but they quickly suggested new ones to be introduced (part three). To be honest, I had to change my mind from the aphorism “same steps, same tools, same risks, different approach” after the video-assisted mini-thoracotomy program was started. The shift from a different single incision to multi-small approaches one was not in my mind previously, but deserves all credit because it stands for a new paradigm of surgery. The more alternative approaches (5,39) we can offer, the better for the cosmesis of the patients.

Conclusions

Minimally invasive pediatric cardiac surgery is currently becoming a routine practice in many centers worldwide. The different approaches need their own learning curve, either straightforward or a steep one. Our recent experience demonstrates that a comprehensive, three-step schedule allows a safe and custom-made approach to train new surgeons in the field. and enhances enthusiasm in developing further strategies on their own.

A record of conversion-rate and complications should be used as marker of performance and quality standard. The new adopters can take their own training pace according to their level and skills. Interestingly, the wider the offer of approaches, the more ideas come up for new alternative minimally invasive methods. A twofold increase in minimally invasive procedures was observed in two years. The short-medium term results after three years are excellent.

Acknowledgements

The authors would thank the theatre staff for their patience and suggestions.

Footnote


Ethical Statement: The study was approved by our institutional ethics committee.

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Cite this article as: Gil-Jaurena JM, Pérez-Caballero R, Pita-Fernández A, González-López MT , Sánchez J, De Agustín JC. How to set-up a program of minimally-invasive surgery for congenital heart defects. Transl Pediatr 2016;5(3):125-133. doi: 10.21037/tp.2016.06.01


Introduction

Mortality and morbidity of congenital cardiac procedures have always been an issue for cardiac surgeons since the very first operation on cardiopulmonary bypass. Technical improvement in extracorporeal circulation, increased knowledge in physiology and pathophysiology of cardiopulmonary bypass and special organ protection strategies have helped to reduce the incidence of complications and death to an acceptable rate. However, they are still present and need to be tackled every day. Since Bellinger, Newburger and Jonas published their landmark studies about neurological outcomes after arterial switch operations (1-4), perfusion strategies, especially for aortic arch corrections, have been more and more modified to avoid the potential deleterious effects of deep hypothermic

circulatory arrest (DHCA) (5-9). Several alternative perfusion regimens of body and brain have been suggested and were implemented into clinical practice more or less successfully, so that we have learned a lot about possible benefits and potential new complications when mal- or hypo-perfusion of organs occur. To our opinion, monitoring and visualization of end organ oxygen supply and blood-flow is of utmost importance and not only of scientific interest.

Cerebral protection during aortic arch repair is currently performed by either deep hypothermic circulatory arrest or regional cerebral perfusion (RCP) via the innominate artery. Both completely distinct cardiopulmonary bypass techniques were unable to demonstrate a significant difference in randomized controlled trials regarding the incidence of perioperative cerebral injury or neurodevelopmental

Review Article

Goal-directed-perfusion in neonatal aortic arch surgery

Robert Anton Cesnjevar1, Ariawan Purbojo1, Frank Muench1, Joerg Juengert2, André Rueffer1

1Department of Pediatric Cardiac Surgery, 2Department of Pediatrics, University Hospital Erlangen, Friedrich Alexander University Erlangen-

Nuernberg, Erlangen, Germany

Contributions: (I) Conception and design: All authors; (II) Administrative support: RA Cesnjevar, A Rueffer; (III) Provision of study materials

or patients: All authors; (IV) Collection and assembly of data: All authors; (V) Data analysis and interpretation: RA Cesnjevar, A Rueffer; (VI)

Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

Correspondence to: Robert Cesnjevar, MD, PhD. Department of Pediatric Cardiac Surgery, University Hospital Erlangen, Friedrich Alexander

University Erlangen-Nuernberg, Loschgestraße 15, 91054 Erlangen, Germany. Email: [email protected].

Abstract: Reduction of mortality and morbidity in congenital cardiac surgery has always been and remains a major target for the complete team involved. As operative techniques are more and more standardized and refined, surgical risk and associated complication rates have constantly been reduced to an acceptable level but are both still present. Aortic arch surgery in neonates seems to be of particular interest, because perfusion techniques differ widely among institutions and an ideal form of a so called “total body perfusion (TBP)” is somewhat difficult to achieve. Thus concepts of deep hypothermic circulatory arrest (DHCA), regional cerebral perfusion (RCP/with cardioplegic cardiac arrest or on the perfused beating heart) and TBP exist in parallel and all carry an individual risk for organ damage related to perfusion management, chosen core temperature and time on bypass. Patient safety relies more and more on adequate end organ perfusion on cardiopulmonary bypass, especially sensitive organs like the brain, heart, kidney, liver and the gut, whereby on adequate tissue protection, temperature management and oxygen delivery should be visualized and monitored.

Keywords: Congenital heart disease; regional cerebral perfusion (RCP); organ protection; neonatal arch surgery

Submitted Jun 12, 2016. Accepted for publication Jul 06, 2016.

doi: 10.21037/tp.2016.07.03




outcome (10,11). Several studies suggested that longer duration of deep hypothermic circulatory arrest is associated with neurocognitive impairment (12-14), but despite the missing evidence of a clear time limit (12,15), perioperative seizures with impaired motor development (16) and brain damage evident on MRI were consistent with RCP as well (10,17,18). Nevertheless, improved outcome reports (early and late) about shorter postoperative ventilation, improved renal function and adequate time-related neurodevelopment have been subsequently published after using RCP (15,19,20).

The question of an effective distribution and ideal quantity of cerebral blood flow, particularly in the contralateral left hemisphere, is one of the main issues about RCP, and effective neuro-monitoring in addition to visualization of flow could lower this burden (21,22). The same hypothesis pertains to the amount of infra-diaphragmatic perfusion which is potentially provided via pre-existing collaterals (via subclavian and intercostal arteries to the descending aorta), which could be different in size and may not be adequate if the patient’s core temperature is kept “too warm” (Figure 1).

The level of concern in our group, especially in complex aortic arch repair with longer arch clamping times, has brought us to the concept of total body perfusion (TBP) using an additional separate arterial pump for infradiaphragmatic perfusion of the descending aorta.

Both regional cerebral oxygen saturation from the frontal

cortex (rSO2) (23,24) and time average velocity (TAV) of blood flow in the medial cerebral artery (MCA) (21,22,24-29) have been interpreted as potential surrogate indicators for cerebral perfusion during infant cardiac surgery. Low intraoperative rSO2-level may impact psychomotor development (15,30,31) and correlate with postoperative cerebral lesions diagnosed by magnetic resonance imaging (15,17,18,23,31-33). On the other hand, particularly in the context of aortic arch surgery using RCP, measuring TAV may avoid the potential dangers of excessive cerebral blood flow resulting in cerebral edema or intracranial hemorrhage (22,34).

TAV in one MCA is usually displayed continuously by transcranial Doppler ultrasonography from the temporal window. Nowadays, transfontanellar ultrasound has become routine analysis in pediatric patients whose fontanelles are not closed. It can be applied as a point-of-care method during cardiac surgery (35) and provides additional information regarding morphology of the whole brain, including detection of brain lesions, measurement of TAV and 3-dimensional (3D)-imaging of various blood vessels. It is currently our routine to investigate cerebral blood flow to both hemispheres during RCP, using combined transfontanellar/transtemporal ultrasound and bilateral frontal rSO2.

In addition, regional oxygenation below the diaphragm (rSO2) with an additional left renal somatic reflectance oximetry pad is monitored as well, but we have not yet tried to visualize renal blood flow with selective ultrasound tools (Figure 2).

This review focuses mainly on practical and theoretical

Figure 1 Somatic reflectance oximetry during RCP without descending aorta cannulation. Measurement of rSO2 (%) is performed by continuous plotting of the somatic reflectance oximetry in both frontal hemispheres [1 and 2] and subdiaphragmatic [3]. Here displayed during pure RCP (30% pump flow via the innominate artery at 25–28 ℃). rSO2, INVOS®; Somanetics Corporation, Troy, MI, USA. RCP, regional cerebral perfusion.

Figure 2 Patient monitoring. Systemic pressure is monitored in one femoral artery and the right radial artery [1 and 2]. Measurement of rSO2 (%) is performed by continuous plotting of the somatic reflectance oximetry in both frontal hemispheres [3] and subdiaphragmatic area below the left kidney [4].

136 Cesnjevar et al. Antegrade cerebral perfusion


issues on how to protect organs from ischemic or hypoxemic damage during complex aortic arch surgery by adequate monitoring of tissue oxygen supply, thus providing relatively adequate blood flow to target perfusion regions [goal-directed-perfusion (GDP)].

Methods

Monitoring

Perioperative perfusion monitoring for aortic arch repair in neonates and young infants with open fontanelles includes intraoperative combined transfontanellar/transtemporal 2D- and 3D-ultrasound imaging of both blood flow intensity in both hemispheres, and assessment of mean TAV displayed in the basilar artery (BA), bilateral internal carotid arteries (ICA), bilateral anterior cerebral arteries (ACA) and bilateral MCAs, respectively. Additionally, bilateral cerebral frontal rSO2 and subdiaphragmatic rSO2 (left kidney) are measured.

Surgical technique

After initiation of anesthesia, arterial blood pressure

monitoring lines are placed in the right radial artery and in one femoral artery. Measurement of rSO2 (%) is performed by continuous plotting of the somatic reflectance oximetry in both frontal hemispheres and subdiaphragmatic (rSO2, INVOS®; Somanetics Corporation, Troy, MI, USA). After midline sternotomy and heparinization, a 3.5-mm PTFE-tube (Gore-Tex®, Flagstaff, AZ, USA) is anastomosed to the innominate artery and cannulated with a 10F arterial cannula.

CPB is started with an estimated flow of 3.0 L/m² BSA (175–200 mL/kg) after bicaval cannulation and patients are cooled to 28 ℃ rectal temperature. The pericardium is opened posterior and to the left of the inferior vena cava (IVC). The descending aorta is identified in the left pleural space after mobilization of the lingula to the left of the esophagus. In case of ductal dependent descending aortic circulation, both pulmonary arteries are snared, distal aortic perfusion is accomplished by selective cannulation of the descending aorta above the diaphragm and connected to a second roller pump: in this way, perfusion is secured to both the head and neck vessels, as well as to the lower body vasculature below the diaphragm during isolation of the arch for reconstruction. Mean radial and femoral arterial pressures are kept in the range of 35–50 mmHg. In order to induce cerebral vasodilatation for homogenous cerebral tissue cooling, a modified alpha-stat strategy with pCO2 elevation around 50–60 mmHg is used (Figure 3).

Arch vessels and the descending aorta are clamped. Cerebral protection via RCP is commenced with 30% estimated flow (52–60 mL/kg/min). The same amount of flow is provided to the infradiaphragmatic aorta and monitored via femoral arterial pressure and somatic reflectance oximetry (Figures 4,5).

Myocardial protection is ensured by either continuous myocardial perfusion with 10% estimated flow after connecting another arterial line to the aortic root cannula (beating heart), or by cardioplegic arrest using a single shot (40 mL/kg) of cardioplegia. Arch repair includes coarctation-resection and augmentation of the aortic concavity with a patch of bovine pericardium. Patients undergoing the Norwood procedure additionally undergo atrial septectomy, division of the main pulmonary artery and Damus-Kaye-Stansel anastomosis; pulmonary perfusion is ensured by either right ventricle to pulmonary artery conduit in hypoplastic left heart syndrome or by modified Blalock-Taussig-shunt in patients with a systemic left ventricle. After the aortic and supra-aortic cross-clamps are removed, reperfusion is started until the patients are

Figure 3 Cannulation descending aorta. Selective cannulation of the descending aorta above the diaphragm. The pericardium is opened posterior and to the left of the IVC. The descending aorta is identified after opening the left pleural space to the left of the esophagus. An 8-F 135°-angled cannula (Stoeckert, Muenchen, Germany) is inserted into the vessel and connected to a separate roller pump using 30–40% flow. IVC, inferior vena cava.



Figure 4 Somatic reflectance oximetry during RCP with descending aorta cannulation. Continuous rSO2 (%) measurements during arch reconstruction with RCP (30% pump flow via the innominate artery at 25–28 ℃) and additional abdominal perfusion via the descending aorta (30–40% pump flow at 25–28 ℃). rSO2, INVOS®; Somanetics Corporation, Troy, MI, USA. RCP, regional cerebral perfusion.

Figure 5 Pressure monitoring during RCP with descending aorta cannulation. Continuous ECG monitoring during beating heart aortic arch reconstruction. Pressure monitoring in the radial [1] and femoral [2] artery during RCP (30% pump flow via the innominate artery at 28 ℃), selective myocardial perfusion (10–15% blood flow via cardioplegic system into the aortic root) and additional abdominal perfusion via descending aorta (30–40% pump flow). RCP, regional cerebral perfusion; ECG, electrocardiogram.

warmed up to 36 ℃. Weaning from CPB is performed in the usual fashion.

Ultrasound imaging

Transfontanellar ultrasonography is investigated with a multifrequent sector probe S 4–10 (7MHz), 3D/4D curved array probe RNA 5-9-D (8MHz) and transtemporal Doppler ultrasound uses a M5S sector probe (3 MHz).

Transfontanellar examination includes B-mode scan, 2D and 3D Power- or Color-Doppler ultrasound of both hemispheres. Two-D Power- and Color-Doppler ultrasound visualizes the intensity of vessel perfusion of the main blood vessels and illustrates a functioning communication in the Circle of Willis. 3D Power- and Color-Doppler via the anterior fontanelle allows 0.5 mm cerebral tomography, and glass-body rendering of the main cerebral vessels. Pulsed-wave (Pw)-Doppler is used to measure mean TAV for intervals of 3–5 seconds. The probes are placed over the anterior fontanelle or over the right and left temporal area. The positioning and measurement with the best Color Doppler signal is selected. Ultrasound imaging with the above mentioned techniques is currently not applicable for monitoring infradiaphragmatic perfusion.

Collected data at given standard time points are compared between hemispheres (left vs. right), and between two perfusion time points (FF versus RCP) in each ipsilateral hemisphere.

Observations

Patient characteristic and outcome

Fourteen patients were monitored with a complete data-set as specified above. One patient out of this group died after the procedure; all other patients were discharged home without clinical signs of impaired neurologic function.

Cerebral sonography

Two-D and 3D Color/Power-Doppler ultrasound showed regular anatomy with a communicating Circle of Willis in all infants, with near symmetric distribution of blood flow intensity in vessels of both hemispheres during both RCP and TBP.

Comparing TAVs in contralateral vessels during both TBP and RCP, no significant differences between hemispheres were calculated, except for higher TAV in right ICA during TBP. Comparing TAVs in each vessel depending on perfusion methods, no significant differences between FF and RCP were observed. Comparison of contralateral mean levels of rSO2 did not reveal significant differences between both hemispheres, regardless of the perfusion method. Comparing rSO2 in each hemisphere between perfusion methods, there was a significant difference regarding rSO2

measured in the right frontal cortex, with higher levels



during TBP when compared to RCP.

Discussion

The main concern regarding the efficiency of RCP is about adequate perfusion of the left hemisphere and the quality of subdiaphragmatic perfusion. We are one of the first groups to publish a prospective study evaluating combined transtemporal/transfontanellar ultrasound in an intraoperative setting during aortic arch repair, showing a functioning Circle of Willis for all studied patients, pointing to symmetric distribution of blood flow intensity to both cerebral hemispheres during both TBP and RCP. This impression was confirmed by bilateral comparison of cerebral TAVs and rSO2.

An exception was found for ICA-flow during TBP, which was substantiated by significantly higher TAVs in the right vessel when compared to the left. Divergent blood flow directions between patients indicate that the left ICA is being supplied from both sites, either antegrade via the hypoplastic aortic arch, or retrograde via the Circle of Willis, which is probably related to the size of the transverse arch by reflecting the amount of antegrade aortic flow. Therefore, calculated difference in TAV between both contralateral ICAs during TBP may be a result of counteracting blood flow directions in the left ICA, leading to reduction or flow signal extinction for TAV.

Difference between contralateral TAVs in both carotid arteries was evident even during RCP, however, without reaching statistical significance and with an exclusively retrograde flow-direction in the left ICA at this time point. As an explanation for that difference in flow intensity, it should be kept in mind, that even with an effective perfusion of the left hemisphere during RCP, the left ICA, when perfused from the right via Circle of Willis, presents the end of the cerebral vasculature with a “blind end” due to proximal clamping at its origin from the aortic arch, and limited run-off into the left external carotid, BA and ophthalmic artery.

Changes in direction of blood flow in the ICA following occlusion of the ipsilateral common carotid artery have been reported previously (36,37). Divergent flow-directions in the left ICA during both TBP and RCP may mirror the non-physiologic perfusion of blood vessels originating from the distal aortic arch in neonates with aortic arch hypoplasia and ductal-dependent lower body perfusion even as an inherent phenomenon. We have performed transfontanellar ultrasound sporadically in our cohort in the perioperative

context and could verify a normalization of flow velocity in the left ICA and changing flow-direction in left the vertebral artery after surgery in one infant.

Assessment of bilateral SO2 did not reveal a significant difference when compared between hemispheres. Both, increased rSO2 in the right frontal cortex by comparing both methods of perfusion, and higher TAV in the right ICA by contralateral comparison during TBP, raises suspicion of increased blood flow to the right hemisphere especially during TBP. The potential dangers of excessive cerebral blood flow include cerebral edema and intracranial hemorrhage (22,25). We believe that initiation of “full-flow” bypass over the innominate artery might be responsible for early hyper-perfusion especially of the right hemisphere, which may explain why an alpha stat strategy with limitation of cerebral vasodilatation is beneficial in these patients to avoid excessive overflow. Initial “overperfusion” of the right hemisphere seems to persist during cooling despite introduction of distal aortic perfusion and adjustment of TBP between both arterial lines.

With regard to infradiaphragmatic perfusion and oxygen supply it is difficult to support statements that conclude that RCP provides adequate somatic perfusion via native collaterals, as suggested by some authors (9). After more than 15 years’ experience (including animal lab experiment and subsequent later patient observation), it is even more difficult to believe that this holds true and has been questioned by us in the past (5). A special subset of patients with large intercostal arteries may be well perfused on both sites of the diaphragm by RCP, but we would not rely on them, especially if surgery is performed under warmer conditions of moderate hypothermia around 28 ℃. If you do not follow an effective strategy to perfuse the lower body with bypass, some patients will suffer from postoperative renal failure or mesenteric ischemia. We therefore rely on regional saturation plotting and femoral artery pressure monitoring during RCP, and feel very safe since we have introduced our infradiaphragmatic cannulation technique.

It is our personal bias that continuous rSO2-monitoring (NIRS) as a point of care measurement of tissue oxygenation has given us a substantial surplus in procedure safety. In analogy to our anesthesiology colleagues, we think that NIRS has become the pulse oximetry of perfusionists and cardiac surgeons.

One limitation to our observations is that TAV is only a surrogate indicator for perfusion, considering a fixed diameter of cerebral vessels during measurements. Further, the technique of transfontanellar ultrasound is investigator-



dependent, and can be affected by suboptimal positioning or covering of the patient. This variation in color distribution can depend on the direction of the vessel and corresponding blood flow direction regarding the position to the probe. If the blood flow is vertical to the ultrasonic waves, a movement of blood cannot be detected. It remains unclear whether our results can be extrapolated to other RCP strategies including “real” pH-stat regime and deep hypothermia (10,12,14,15,19,22,34). A superiority to other modes of RCP or neuroprotective strategies as deep hypothermic circulatory arrest cannot be derived from our experience to date, but may become likely when gathering data from an increasing number of patients. To date, postoperative transfontanellar morphologic cerebral evaluation in five of our patients did not reveal side-dependent structural abnormalities, and did not show evidence of hyper- and/or hypo-perfusion-related injury.

In conclusion, the hypothesis of a homogenous distribution of cerebral blood flow to both hemispheres during RCP is being strengthened, using a combined transfontanellar/transtemporal approach, with 2D and 3D Color- and Power-Doppler ultrasound to visualize the Circle of Willis and the intensity of cerebral vessel perfusion during aortic arch repair. By indirect and non-invasive estimations of effective cerebral blood flow using the transcranial ultrasound methods described in our study, and regional cerebral tissue oxygenation with NIRS, it is hoped to make arch reconstruction using cardiopulmonary bypass even safer.

Acknowledgements

Most of the data and figures are related to the work by the interdisciplinary research group of Andre Rueffer and colleagues.

Footnote

Conflict of Interest: The authors have no conflicts of interest to declare.

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Cite this article as: Cesnjevar RA, Purbojo A, Muench F, Juengert J, Rueffer A. Goal-directed-perfusion in neonatal aortic arch surgery. Transl Pediatr 2016;5(3):134-141. doi: 10.21037/tp.2016.07.03


Hypoplastic left heart syndrome (HLHS): current perspective

The term HLHS describes a heterogeneous group of diagnoses that encompass a wide array of pathophysiology. The term potentially pertains to any malformation that involves underdevelopment of the left sided cardiac structures from aortic stenosis and coarctation of the aorta to the other extreme of aortic atresia, mitral atresia, and hypoplasia of the ascending aorta. The Congenital Heart Surgery Nomenclature and Database Committee (1) attempted to precisely define those abnormalities. The proposed definition is that “HLHS is a spectrum of cardiac malformations, characterized by a severe underdevelopment of the left heart-aorta complex, consisting of aortic and/or mitral valve atresia, stenosis, or hypoplasia with marked hypoplasia or absence of the LV, and hypoplasia of ascending aorta and of the aortic arch.” The treatment options for these malformations are discussed in this manuscript.

It is estimated that each year about 960 babies in the United States are born with HLHS (2). Since the first successful intervention for HLHS was undertaken by Norwood in 1983 (3), there have been many advancements

in the pre-, intra-, and postoperative care. Just 25 years ago, this diagnosis would certainly be a fatal one. Currently there are five options and paths of treatment for these neonates. The potential interventions include staged palliation that starts with a Norwood procedure, a hybrid treatment strategy, a hybrid-bridge-to-Norwood, transplant, or compassionate care.

There is a subset of HLHS patients who have a mild form and could potentially undergo a biventricular repair. This complex decision-making process is out of the scope of the current manuscript.

Norwood procedure

The goal of staged palliation for HLHS is to end up with a Fontan circulation, also known as a total cavo-pulmonary connection (TCPC). This is typically done in three stages. The three stages include the Norwood stage I procedure, the middle stage is a partial cavo-pulmonary connection (PCPC), also known as a bidirectional Glenn anastomosis or Hemi-Fontan, and the final stage is a TCPC. The goal of the Norwood procedure is to relieve systemic ventricular outflow obstruction, have unrestricted pulmonary venous

Review Article

Hypoplastic left heart syndrome: current perspectives

Christopher E. Greenleaf, J. Miguel Urencio, Jorge D. Salazar, Ali Dodge-Khatami

University of Mississippi Medical Center, 2500 North State Street, Jackson MS 39216, USA

Contributions: (I) Conception and design: CE Greenleaf, A Dodge-Khatami; (II) Administrative support: CE Greenleaf, A Dodge-Khatami; (III)

Provision of study materials or patients: CE Greenleaf, A Dodge-Khatami; (IV) Collection and assembly of data: CE Greenleaf, A Dodge-Khatami; (V)

Data analysis and interpretation: CE Greenleaf, A Dodge-Khatami; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

Correspondence to: Ali Dodge-Khatami, MD, PhD. Chief, Pediatric and Congenital Heart Surgery, Children’s Heart Center; Professor of Surgery,

University of Mississippi Medical Center, 2500 North State Street, Room S345, Jackson MS 39216, USA. Email: [email protected].

Abstract: Since the first successful intervention for hypoplastic left heart syndrome (HLHS) was undertaken by Norwood in 1983, there have been many advancements in the pre-, intra-, and postoperative care of these children for a diagnosis that just 25 years ago was almost certainly a fatal one. This paper aims to describe the most recent trends and perspectives on the treatment of HLHS. In particular, we will discuss the five current options for HLHS, including Norwood stage I as the beginning to 3-stage palliation, transplant, true hybrid, hybrid-bridge-to-Norwood, and compassionate care.

Keywords: Hypoplastic left heart syndrome (HLHS); single ventricle; congenital cardiac anomalies

Submitted May 23, 2016. Accepted for publication May 25, 2016.doi: 10.21037/tp.2016.05.04




return, and controlled pulmonary arterial perfusion. This is accomplished with a Damus-Kaye-Stansel (DKS) procedure, an ascending arch aortoplasty, an atrial septectomy, and a source of pulmonary blood flow (PBF), either a systemic to pulmonary artery shunt or a right ventricle-pulmonary artery (RV-PA) conduit.

The source of PBF initially used and still used frequently today is the modified Blalock-Taussig (MBT) shunt, which is a Gore-Tex graft between the innominate artery and the right pulmonary artery. This was the predominant shunt until Sano revived the RV-PA modification, initially described by Norwood, but long ignored (4). The RV-PA conduit has seen a dramatic revival in popularity since its reintroduction, and the choice between the two sources of PBF is currently surgeon/institution-dependent. There have been multiple retrospective, single-center studies comparing the outcomes between the two shunts (5-7), with contradictory results, and no definitive advantage of one technique versus the other. The MBT shunt gives continuous flow to the right pulmonary artery from the innominate artery even during diastole. The concern is for diastolic runoff leading to coronary steal that could potentially cause death during the initial hospitalization or in the interstage period. The RV-PA shunt requires a right ventriculotomy which could potentially lead to ventricular dysfunction in an already stressed univentricular heart.

The Pediatric Heart Network published a multicenter, randomized trial on infants with HLHS undergoing the Norwood procedure, known as the Single Ventricle Reconstruction (SVR) trial (8). Infants were randomized to either a MBT shunt or an RV-PA conduit. Between May 2005 and July 2008, 555 patients were enrolled in the study. The primary outcome was the rate of death or cardiac transplantation 12 months after randomization. There were 72 deaths or cardiac transplants in the RV-PA shunt group, and 100 deaths or cardiac transplants in the MBT shunt group. On the basis of the data, the RV-PA shunt as compared to the MBT was associated with an improved transplantation free-survival at 12 months. When using all available data and not stopping at the pre-specified 12 months end point, the primary outcome approached but did not cross statistical significance (P=0.06). After 12 months, 10 deaths and 6 transplantations occurred in the RV-PA shunt group, as compared with 7 deaths and 0 transplantations in the MBT shunt group.

A study that investigated complications after the Norwood stage I used the Society of Thoracic Surgeons database to find preoperative risk factors that led to

postoperative complications (9). These risk factors were relatively uniform across multiple studies and included weight less than 2.5 kg, preoperative shock, non-cardiac/genetic abnormality, and preoperative mechanical ventilator or circulatory support. Two studies from the Pediatric Heart Network Investigators described in hospital and inter-stage mortality associated with the Norwood procedure. The hospital mortality rate during the Norwood stage I was 16%, irrespective of shunt type. The inter-stage mortality between stages I and II was 6% for the RV-PA conduit, and 18% for the MBT shunt. The 3-year follow-up to the SVR trial was published in 2014 (10). Transplantation-free survival did not differ by shunt type.

In the largest and most recent study from the Congenital Heart Surgeons’ Society (11) propensity scores were used to match 169 RV-PA conduit patients with 169 MBT shunt patients. Six year survival was better after RV-PA conduit (70%) versus the MBT shunt (55%). In contradistinction to the SVR trial, there was also more moderate or severe atrioventricular valvular regurgitation and right ventricular dysfunction and lower transplant-free survival in the MBT shunt group.

The Norwood procedure is undertaken during a time when the pulmonary vascular resistance is too elevated to allow a cavo-pulmonary anastomosis. The second stage is usually undertaken between 4–6 months of age. The goal of the second stage is to unload the right ventricle. This is accomplished with either a bidirectional Glenn or a Hemi-Fontan. The advantages of the bidirectional Glenn is that it can potentially be performed off-pump and is an easier connection. The Hemi-Fontan makes the final stage more straightforward.

This second stage originally was proposed as an interim palliation only for high risk babies before undergoing the Fontan operation (12,13), instead of proceeding directly from a shunted physiology to TCPC in one step, which is a huge physiological change associated with high risk of failure. After staged palliation with an interim Glenn operation, breaking the adaptation to new cardio-pulmonary flows into two lower-risk steps with better results, the Glenn operation became a standard staging procedure even in babies with a low-risk profile, leading to the current 3-stage approach. The goal is to unload the ventricle as early as possible, minimize potential steal from coronary blood flow, and limit the amount of time the pulmonary vasculature is exposed to systemic pressures before the baby can tolerate a Fontan (14).

Traditionally, the bidirectional Glenn anastomosis was between the superior vena cava and the pulmonary arteries.

144 Greenleaf et al. HLHS: current perspectives


The inferior vena cava to pulmonary artery anastomosis was abandoned in the animal lab by Dr. Glenn after repeated failure in an animal model. In patients with unfavorable upper body systemic venous anatomy, the SVC-PA connection is suboptimal or not feasible, and an alternative is needed to unload the heart. We have found that this subset of patients can benefit from a primary IVC-PA connection, the “Southern Glenn”, which we have performed successfully in two patients (15).

The Fontan operation typically connects the IVC to the RPA leading to a total cavopulmonary connection so that all PBF is achieved passively. In-series circulation is restored and saturations achieve near-normal levels. This typically happens between 24 and 48 months of age. There is a wide breadth of single-institution series looking at short and long-term outcomes and predictors of mortality and morbidity after Fontan completion (16-18). The consistent predictors of poor outcome across multiple studies are longer cross-clamp times, longer length of hospital stays, heterotaxy, and atrioventricular valve anomaly.

Despite studies showing the success of either type of PBF, MBT or RVPA conduit for the Norwood stage I, the majority of centers have not changed their practice. Those centers that have solid technical and postoperative results with either the RV-PA conduit or the MBT shunt have continued to palliate the patients in the same way they always have. Current expected benchmark results for Norwood stage I palliation, as harvested by the STS congenital heart surgery database, is 85.1% in-hospital survival (19).

The “true” hybrid approach

Concerns about placing a neonate on cardiopulmonary bypass wi th s igni f icant cardiac and non-cardiac comorbidities, especially neurological ones, which could lead to intracranial hemorrhage, led to the advent of hybrid approaches to the HLHS baby. High risk factors included weight less than 2.5 kg, preoperative shock, non-cardiac/genetic abnormality, preoperative mechanical ventilator or circulatory support, small ascending aorta, intact/restrictive interatrial septum, and the variant of HLHS with aortic atresia and mitral stenosis. The goals of the first stage are the same as the standard Norwood procedure including securing adequate systemic perfusion, unrestricted pulmonary venous return, and controlling PBF; relief of systemic ventricular outflow obstruction with a DKS, which requires cardiopulmonary bypass, is not performed. Using

a conjunction of catheter-based intervention and surgery without cardiopulmonary bypass, systemic perfusion is maintained with a ductal arteriosus stent, unrestricted pulmonary venous return is accomplished with a balloon atrial septostomy if needed and controlled (diminished) PBF is accomplished with bilateral PA bands. The concern with this approach is that the ductal stent could potentially limit retrograde blood flow into the ascending aorta, leading to coronary compromise and myocardial ischemia.

After the inter-stage period, the comprehensive stage I + II includes removal of the PA bands, removal of the ductal stent, connecting the ascending aorta with the pulmonary valve (DKS), and repair of the aortic arch and pulmonary arteries. Removing the ductal stent is probably the most challenging. It takes a technique similar to an endarterectomy to safely extract the stent without injuring the descending thoracic aorta. Initially, the hybrid approach was used for high risk infants. With formal or relative contraindications to a Norwood stage I operation, single center studies showed the feasibility of the approach, and others started using it on standard risk patients as an alternative to the Norwood stage I procedure (20,21).

Pioneering work by Galantowicz and colleagues (22) has been very illustrative in what can be accomplished with the hybrid approach for HLHS. Sixty-two patients underwent a hybrid stage I procedure between 2002 and 2007. High risk patients were excluded from their study so that the cohort of patients would have a more typical risk profile to the usual HLHS patient. The results are impressive, with a hospital survival after the hybrid stage I reaching 97.5%. The interstage I–II interval had two deaths. The hospital survival during the comprehensive stage I + II was 92%. The most important point from this early experience is that in certain patients with unfavorable anatomy, namely those with aortic atresia and no antegrade flow to the coronary arteries, jailing by the ductal stent may create stenosis of the retrograde orifice to the transverse arch. These patients should be identified before intervention, because a ductal stent can acutely lead to head vessel and/or coronary artery flow compromise, potentially leading to death from myocardial infarction and circulatory collapse. The options are to offer these patients a standard Norwood procedure or to stent the retrograde orifice at the time of the PDA stent (23).

The group in Giessen recently described 182 babies that underwent this hybrid strategy (24,25). At 10 years, the probability of survival is 77.8%. Aortic arch reinterventions were only needed in 16.7% of patients. A benefit of this approach is that several of the patients were able to be



transitioned to a biventricular repair after the hybrid approach instead of the single ventricle palliation.

The hybrid approach is theoretically attractive by reducing the early insult to an already stressed neonate while limiting pulmonary overcirculation and securing systemic perfusion. Uneven results in other centers and concerns with the technical aspects of the comprehensive stage I + II have kept the true hybrid approach from garnering widespread support for low to intermediate risk patients.

Hybrid-bridge-to-Norwood

In the above study by Galantowicz there were 12 reinterventions in the catheterization lab during the interstage I to II interval. The majority (n=7) dealt with issues with regards to the position of the ductal stent to improve antegrade systemic flow, and four were placed to relieve retrograde stenosis into the transverse aortic arch. Despite the need for reintervention, all patients went on to a comprehensive stage I + II. The need for more catheterizations and the concerns with removing the stent during the comprehensive stage I + II has led to the revival of another sequence of operations once described by Dr. Norwood, coined the hybrid-bridge-to-Norwood or the “salvage-bridge-to-Norwood” (26).

In high-risk HLHS neonates with concomitant cardiac and non-cardiac comorbidities, in whom an initial Norwood stage I operation is deemed prohibitive, the sequence starts with bilateral pulmonary artery bands in the early period after birth. The ductus is kept open with prostaglandins, instead of a mechanical stent. The Norwood stage I is then performed after the baby is stabilized, typically at about 2 weeks. We described our experience with 47 consecutive babies with HLHS between April 2010 and June 2014. Nine of these patients had a hybrid-bridge-to-Norwood. Seven of these high-risk patients had significant preoperative cardiac and non-cardiac comorbidities, including severe seizure disorders with cerebral infarction, and great vessel arrangements that precluded ductal stenting. Two patients were salvaged intraoperatively with the hybrid-bridge-to-Norwood: one had severe abdominal distension and suspected sepsis with total anomalous pulmonary venous return, and another baby with standard risk HLHS had hemo-pericardium and tamponade upon sternal entry. Seven of the patients required extracorporeal membrane oxygenation support postoperatively. Eight patients went on to a deferred Norwood stage I at a mean of 14.3 days. Six survived to hospital discharge.

The Great Ormond Street group had 17 of 147 patients between January 2006 and October 2011 who underwent what they label as the “rapid 2-stage Norwood strategy” (27). These patients were defined as high risk by having multiple risk factors, including age >2 weeks, weight <2.5 kg, prolonged mechanical ventilation, systemic sepsis, necrotizing enterocolitis, cardiac, renal or hepatic failure, coagulopathy, pulmonary edema, sustained hypotension, significant inotropic requirements, generalized edema, and previous cardiac arrest. Five patients died after the bilateral PA bands. The other 12 patients underwent a Norwood stage I procedure.

The “hybrid-bridge-to-Norwood” or “salvage-to-Norwood” approach gives the baby time to recover and allows time for the surgeon to undertake the Norwood stage I at a more advantageous moment. Although the in-hospital mortality with the “salvage-to-Norwood” approach is high compared to other approaches in neonates with HLHS, it is the only alternative to certain death in an otherwise very high-risk and unstable situation.

Cardiac transplantation

Cardiac transplantation is an attractive option in the sense that there is a dramatic change in the patient’s physiology to that of a normal one. The downsides are the use of an organ in short supply for a disease that has other options, life-long immunosuppression, a 20% mortality rate while on the waiting list, and the almost inevitable prospect of future retransplantation beyond the first one to two decades of life. If transplantation is undertaken after staged palliation, the outcomes are similar to those who undergo transplantation as their primary therapy (28).

Despite these hurdles, since Bailey’s first description in 1986 (29), cardiac transplantation remains a valid option for some patients with HLHS. The main difference between transplantation of a heart into a patient with HLHS and other pathologic conditions is that the donor arch and proximal descending aorta must be procured to reconstruct the recipient’s arch past the isthmus. The 5-year survival is comparable between staged palliation and cardiac transplantation. As mentioned, cardiac transplantation has an upfront cost due to the shortage of available organs and potential attrition while on the waiting list. This has led some centers to palliate these patients with pulmonary artery bands to allow a more stable and safe waiting period.

The Loma Linda group has probably published the most on the subject of primary transplantation (30). In their series, only 64% of patients listed for transplantation

146 Greenleaf et al. HLHS: current perspectives


completed and survived through transplantation. The risk factors for mortality with transplantation are pretransplant circulatory support, posttransplant mechanical circulatory support, and donor heart cross-clamp time.

Given the shortage of organs required for this age and size of patients and the high mortality while waiting for an organ, most centers have abandoned this approach. It is now offered in only a handful of highly specialized and geographically centralized high-volume referral centers in the world.

Compassionate care

With the advent of multiple options for these complex patients, the decision “to do nothing” has been a less frequently sought option, making this line of parent counseling rarer for the majority of practitioners. When other major, uncorrectable genetic, anatomic, or physiologic cardiac or non-cardiac malformations preclude a satisfactory final outcome, comfort care may be an option. If no intervention is chosen, the mortality is about 98% in the first 6 weeks of life. The keys to this discussion should encompass counseling, facts, and ultimately letting the family decide.

Conclusions

Before 1980, HLHS was a uniformly fatal diagnosis. There have been great advancements with the treatment of these patients, which have led to an initial survival rate of 90–92% in the neonatal period for standard-risk patients undergoing surgery. There are now four viable pathways for these patients to become long-term survivors. The future holds refinement of surgical techniques, lessening of risks, catheter-based advancements, and improved perioperative care with a better understanding of the physiology. Factors influencing the long-term prognosis of these patients after successfully undergoing all three stages of palliation remain to be determined.

Acknowledgements

None.

Footnote


References

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3. Norwood WI, Lang P, Hansen DD. Physiologic repair of aortic atresia-hypoplastic left heart syndrome. N Engl J Med 1983;308:23-6.

4. Sano S, Ishino K, Kado H, et al. Outcome of right ventricle-to-pulmonary artery shunt in first-stage palliation of hypoplastic left heart syndrome: a multi-institutional study. Ann Thorac Surg 2004;78:1951-7; discussion 1957-8.

5. Pizarro C, Malec E, Maher KO, et al. Right ventricle to pulmonary artery conduit improves outcome after stage I Norwood for hypoplastic left heart syndrome. Circulation 2003;108 Suppl 1:II155-60.

6. Ghanayem NS, Jaquiss RD, Cava JR, et al. Right ventricle-to-pulmonary artery conduit versus Blalock-Taussig shunt: a hemodynamic comparison. Ann Thorac Surg 2006;82:1603-9; discussion 1609-10.

7. Ballweg JA, Dominguez TE, Ravishankar C, et al. A contemporary comparison of the effect of shunt type in hypoplastic left heart syndrome on the hemodynamics and outcome at Fontan completion. J Thorac Cardiovasc Surg 2010;140:537-44.

8. Ohye RG, Sleeper LA, Mahony L, et al. Comparison of shunt types in the Norwood procedure for single-ventricle lesions. N Engl J Med 2010;362:1980-92.

9. Hornik CP, He X, Jacobs JP, et al. Complications after the Norwood operation: an analysis of The Society of Thoracic Surgeons Congenital Heart Surgery Database. Ann Thorac Surg 2011;92:1734-40.

10. Newburger JW, Sleeper LA, Frommelt PC, et al. Transplantation-free survival and interventions at 3 years in the single ventricle reconstruction trial. Circulation 2014;129:2013-20.

11. Wilder TJ, McCrindle BW, Phillips AB, et al. Survival and right ventricular performance for matched children after stage-1 Norwood: Modified Blalock-Taussig shunt versus right-ventricle-to-pulmonary-artery conduit. J Thorac Cardiovasc Surg 2015;150:1440-50, 1452.e1-8; discussion 1450-2.

12. Bridges ND, Jonas RA, Mayer JE, et al. Bidirectional cavopulmonary anastomosis as interim palliation for



high-risk Fontan candidates. Early results. Circulation 1990;82:IV170-6.

13. Pridjian AK, Mendelsohn AM, Lupinetti FM, et al. Usefulness of the bidirectional Glenn procedure as staged reconstruction for the functional single ventricle. Am J Cardiol 1993;71:959-62.

14. Jaquiss RD, Ghanayem NS, Hoffman GM, et al. Early cavopulmonary anastomosis in very young infants after the Norwood procedure: impact on oxygenation, resource utilization, and mortality. J Thorac Cardiovasc Surg 2004;127:982-9.

15. Dodge-Khatami A, Aggarwal A, Taylor MB, et al. When the bi-directional Glenn is an unfavourable option: primary extracardiac inferior cavopulmonary connection as an alternative palliation. Cardiol Young 2015;28:1-3. [Epub ahead of print]

16. Gentles TL, Mayer JE Jr, Gauvreau K, et al. Fontan operation in five hundred consecutive patients: factors influencing early and late outcome. J Thorac Cardiovasc Surg 1997;114:376-91.

17. Stamm C, Friehs I, Mayer JE Jr, et al. Long-term results of the lateral tunnel Fontan operation. J Thorac Cardiovasc Surg 2001;121:28-41.

18. Mosca RS, Kulik TJ, Goldberg CS, et al. Early results of the fontan procedure in one hundred consecutive patients with hypoplastic left heart syndrome. J Thorac Cardiovasc Surg 2000;119:1110-8.

19. Data Analyses of the Society of Thoracic Surgeons Congenital Surgery Database. 2015.

20. Bacha EA, Daves S, Hardin J, et al. Single-ventricle palliation for high-risk neonates: the emergence of an alternative hybrid stage I strategy. J Thorac Cardiovasc Surg 2006;131:163-171.e2.

21. Pizarro C, Murdison KA. Off pump palliation for hypoplastic left heart syndrome: surgical approach. Semin Thorac Cardiovasc Surg Pediatr Card Surg Annu 2005:66-71.

22. Galantowicz M, Cheatham JP, Phillips A, et al. Hybrid

approach for hypoplastic left heart syndrome: intermediate results after the learning curve. Ann Thorac Surg 2008;85:2063-70; discussion 2070-1.

23. Akintuerk H, Michel-Behnke I, Valeske K, et al. Stenting of the arterial duct and banding of the pulmonary arteries: basis for combined Norwood stage I and II repair in hypoplastic left heart. Circulation 2002;105:1099-103.

24. Yerebakan C, Valeske K, Elmontaser H, et al. Hybrid therapy for hypoplastic left heart syndrome: Myth, alternative, or standard? J Thorac Cardiovasc Surg 2016;151:1112-1123.e5.

25. Michel-Behnke I, Akintuerk H, Marquardt I, et al. Stenting of the ductus arteriosus and banding of the pulmonary arteries: basis for various surgical strategies in newborns with multiple left heart obstructive lesions. Heart 2003;89:645-50.

26. Dodge-Khatami A, Chancellor WZ, Gupta B, et al. Achieving Benchmark Results for Neonatal Palliation of Hypoplastic Left Heart Syndrome and Related Anomalies in an Emerging Program. World J Pediatr Congenit Heart Surg 2015;6:393-400.

27. Gomide M, Furci B, Mimic B, et al. Rapid 2-stage Norwood I for high-risk hypoplastic left heart syndrome and variants. J Thorac Cardiovasc Surg 2013;146:1146-51; discussion 1151-2.

28. Alsoufi B, Mahle WT, Manlhiot C, et al. Outcomes of heart transplantation in children with hypoplastic left heart syndrome previously palliated with the Norwood procedure. J Thorac Cardiovasc Surg 2016;151:167-74, 175.e1-2.

29. Bailey LL, Nehlsen-Cannarella SL, Doroshow RW, et al. Cardiac allotransplantation in newborns as therapy for hypoplastic left heart syndrome. N Engl J Med 1986;315:949-51.

30. Bailey LL. Transplantation is the best treatment for hypoplastic left heart syndrome. Cardiol Young 2004;14 Suppl 1:109-11; discussion 112-4.

Cite this article as: Greenleaf CE, Urencio JM, Salazar JD, Dodge-Khatami A. Hypoplastic left heart syndrome: current perspectives. Transl Pediatr 2016;5(3):142-147. doi: 10.21037/tp.2016.05.04


Introduction

The idea that prophylactic arrhythmia surgery should be incorporated into reparative open heart procedures stems from the reality that many patients with specific congenital cardiac anatomic substrates are subject to atrial arrhythmia development in the course of their lives, which will impact negatively on ventricular function, physical well being, and long-term survival (1-3). Patients presenting later in life with any form of atrial septal defect (ASD) have a 30% to 50% incidence of atrial arrhythmias [mostly atrial fibrillation (AF)] with or without operative repair (4-8). Patients with Ebstein anomaly of the tricuspid valve and

patients undergoing repeat surgery for tetralogy of Fallot (TOF) are at significantly increased risk of atrial arrhythmia development (9-11). Patients who have had staged procedures en route to Fontan physiology also have a high incidence of atrial arrhythmias whether the connections be atriopulmonary, total cavopulmonary, or extracardiac/lateral tunnel (12-15). Others with complex atrial baffles such as atrial switch procedures in association with arterial switch (double switch for congenitally corrected transposition of the great arteries) are associated with a predictable incidence of atrial arrhythmias, which theoretically can be ameliorated or neutralized (mitigated) by a prophylactic maze procedure.

Review Article

Prophylactic arrhythmia surgery in association with congenital heart disease

Constantine Mavroudis1, Barbara J. Deal2

1Johns Hopkins Children’s Heart Surgery, Florida Hospital for Children, Orlando, Florida, USA; 2Ann & Robert H Lurie Children’s Hospital of

Chicago, Chicago, Illinois, USA

Contributions: (I) Conception and design: All authors; (II) Administrative support: All authors; (III) Provision of study materials or patients: None;

(IV) Collection and assembly of data: All authors; (V) Data analysis and interpretation: All authors; (VI) Manuscript writing: All authors; (VII) Final

approval of manuscript: All authors.

Correspondence to: Constantine Mavroudis, MD. Professor of Surgery, Johns Hopkins University Medical School; Site Director, Johns Hopkins

Children’s Heart Surgery, Florida Hospital for Children, 2501 N Orange Ave, Suite 540, Orlando, Florida 32804, USA.


Abstract: Certain congenital heart anomalies make patients more susceptible to arrhythmia development throughout their lives. This poses the question whether prophylactic arrhythmia surgery should be incorporated into reparative open heart procedures for congenital heart disease. There is currently no consensus on what constitutes a standard prophylactic procedure, owing to the questions that remain regarding lesions to be performed; energy sources to use; proximity of energy source or incisions to coronary arteries, sinoatrial node, atrioventricular node; circumstances for right atrial, left atrial, or biatrial appendectomy; and whether to perform a right, left, or biatrial maze procedure. These considerations are important because prophylactic arrhythmia procedures are performed without knowing if the patient will actually develop an arrhythmia in his or her lifetime. By reviewing and summarizing the literature, congenital heart disease patients who are at risk for developing atrial arrhythmias can be identified and lesion sets can be suggested in an effort to standardize experimental protocols for prophylactic arrhythmia surgery.

Keywords: Atrial fibrillation (AF); atrial flutter (AFL); atrial septal defect (ASD); Ebstein anomaly; univentricular

physiology

Submitted May 05, 2016. Accepted for publication Jun 01, 2016.

doi: 10.21037/tp.2016.06.04 View this article at: http://dx.doi.org/10.21037/tp.2016.06.04



Presently, there is emerging consensus regarding indications for prophylactic arrhythmia surgery in congenital heart disease (16). The surgical community has not reached unanimity of opinion as to what constitutes a standard prophylactic maze procedure (1,17-21). While the operation was conceived to be complication-free owing to the lesions being placed in areas that theoretically do not interfere with normal sinus rhythm mechanism and one-to-one conduction, the reality is that there have been reported cases of sinus node dysfunction resulting in nodal rhythm following maze procedures (21,22). Understandably, one must approach such a conundrum with a rationale as to which forms of heart disease are associated with sufficiently high risk of developing arrhythmia (Table 1) (16) to warrant consideration for prophylactic arrhythmia surgery, as well as clarity regarding the set of prophylactic lesions to be performed, the appropriate lesion sets, and techniques. These considerations are important in light of the fact that prophylactic arrhythmia therapy may be performed without advanced knowledge that the patient in question will actually develop an arrhythmia during the course of his or her life. Invocation of bioethical principles of non-maleficence, beneficence, patient autonomy, and justice all come to mind and apply (1,23-25). The idea is to establish the historic incidence of these arrhythmias, identify the arrhythmia (right-sided, left-sided, both right and left sided) and offer a safe, effective, and complication-free prophylactic procedure (4,22,26-28).

The aim of this review is to identify preoperative

congenital heart surgery patients who are at risk for developing future atrial arrhythmias, assess the efficacy of techniques of arrhythmia surgery in treating the specific arrhythmia substrate, and assess the risk/benefit of prophylactic arrhythmia surgery. Concomitant prophylactic arrhythmia surgery in association with reparative procedures is discussed based on a literature review and considered application of safe lesion sets for standardization and future interprogram comparisons.

Arrhythmias and congenital heart disease

The natural history of unrepaired and repaired congenital heart disease is fraught with late arrhythmogenic complications and therefore is an important field of inquiry. As the complexity of types of congenital heart disease undergoing surgery advanced, the recognition of associated arrhythmia development as a significant source of late morbidity evolved. The marked improvement in survival among patients with congenital heart disease has been associated with the recognition that late arrhythmias and heart failure account for over half of late deaths (29,30). Among adults with congenital heart disease, the development of atrial arrhythmias is associated with a 50% increase in early mortality, a two-fold increase in stroke and congestive heart failure, and a three-fold increase in the need for cardiac interventions (31). Lesions associated with the highest prevalence of supraventricular tachycardia (SVT) include Ebstein anomaly, atrial repairs of transposition of

Table 1 Reoperation rates and estimated prevalence of arrhythmias in adults with congenital heart disease

Congenital heart disease lesion Reoperation Atrial arrhythmias Ventricular tachycardia

Ebstein anomaly 30–50% 33–60% >2%

Single ventricle >25% 40–60% >5%

Tetralogy of Fallot 26–50% 15–25% 10–15%

Transposition of the great arteries, atrial switch 15–27% 26–50% 7–9%

Transposition of the great arteries, arterial l switch 12–20% <2% 1–2%

Congenitally corrected transposition of the great arteries 25–35% >30% >2%

Truncus arteriosus 55–89% >25% >2%

Atrioventricular septal defect 19–26% 5–10% <2%

Atrial septal defect <2% 16–28% <2%

Reproduced with permission from Khairy P, et al. PACES/HRS Expert Consensus Statement on the Recognition and Management of Arrhythmias in Adult Congenital Heart Disease. Heart Rhythm 2014;11:e102-e165. Copyright © 2014 with permission from Elsevier (16).

150 Mavroudis and Deal. Prophylactic arrhythmia surgery for CHD


the great arteries, univentricular hearts, ASDs, and right heart obstructive lesions such as TOF and double outlet right ventricle (31). Of these defects, more than 25% of patients with right heart obstructive lesions, Ebstein anomaly, and univentricular hearts undergo reoperations (10,32). Patients with ASDs may present for intervention in adulthood (1,6,8). Clearly, a surgical intervention that reduces the risk of later arrhythmia development by the inclusion of successful prophylactic arrhythmia surgery should result in improved quality of life for a significant number of patients (1).

ASDs, although technically straightforward substrates for surgical repair, are associated with late atrial flutter (AFL) and AF in as many as 20% to 35% of patients (6,26,33). In 1990, Murphy et al. studied 123 patients with ostium secundum or sinus venosus ASD in an effort to determine the natural history of surgically corrected ASDs, 27 to 32 years following the repair (6). Patients repaired before age 25 had excellent prognosis; patients aged 25 to 41 had good survival but less than age matched controls; and patients greater than 41 years had poor survival and more frequent late cardiac failure, stroke, and AF. Their results indicate “that age at operation is the most powerful independent predictor of long-term survival”. The idea that ASD closure after 40 years of age is associated with increased risk of late complications and arrhythmias was heralded by this study (6). Gatzoulis and associates [1999] from Toronto retrospectively identified 213 adults who underwent surgical ASD closure owing to symptoms or substantial left-to-right shunt (ratio of pulmonary to systemic blood flow >1.5:1), or both (26). In comparison with patients who did not have preoperative AF or AFL, the 40 patients with AF or AFL were older and had higher pulmonary artery pressure, and 24 of the 40 patients (60%) continued with AF or AFL after mean follow-up of 3.8 years. New onset AF or AFL was found at follow up at greater frequency in patients who were older than 40 years at the time of surgery, echoing Murphy’s 1990 report (6). The authors concluded via multivariate analysis that older age at time of surgery (>40 years; P=0.001); presence of preoperative AF or AFL; and presence of postoperative AF, AFL, or junctional rhythm were predictive of late postoperative AF or AFL in adults with ASD (26). In Belgium, 155 patients who underwent ASD closure were selected from 3 databases (33). All patients were 18 years or older; 24 were surgically repaired, and 131 underwent transcatheter device closure (33). Over a median follow-

up of 25 months (range, 1–289 months), 25% developed atrial arrhythmia. Risk factors for arrhythmia development were preoperative or early postoperative atrial tachycardia, female gender, and mean pulmonary artery pressure ≥25 Torr (33).

Arrhythmia development following surgical repair of TOF was initially focused on the risk of ventricular tachycardia, related to ventriculotomy, fibrosis, scarring and ventricular dilatation and hypertrophy. Subsequently, as surgical techniques evolved and repairs were performed at younger ages, atrial arrhythmias were recognized in over 40% of patients, which contributed to important morbidity and hospitalizations (11). Ebstein anomaly of the tricuspid valve is associated with SVT in 20% to 50% of patients, related to accessory connections as well as AF and AFL (9,19,34). Perhaps the most challenging patients are those with postoperative Fontan complications who develop atrial arrhythmias with increasing incidence over time which can be as high as 50% (32,35). Oftentimes, these patients present with gigantic right atria, atrial reentry tachycardia, AF, and hemodynamically important lesions requiring surgery such as: venous and arterial pathway obstructions, valvar insufficiency, aneurysms, and intracavitary clot formation. Modification of the Fontan operation has decreased the incidence of late atrial tachycardia to approximately 8% to 15% in extracardiac connections, 13% to 60% in lateral tunnel connections, and over 60% in the earlier atriopulmonary connection repairs (36). Incidence of late arrhythmias in patients with modified connections can be expected to rise with longer follow-up. Catheter ablation in the Fontan patient has acute success rates of about 50% with at least 70% recurrence of tachycardia within two years (37,38). Catheter access to the right atrium in patients with extracardiac connections is limited to the transhepatic or transthoracic approach with potential morbidity. Certainly patients with prior Fontan surgery undergoing reoperations should be considered for prophylactic lesion sets, taking on greater importance in light of limited transcatheter access.

Arrhythmia surgery

The historic record of arrhythmia surgery has been mostly confined to therapeutic application of specific lesion sets developed to treat existing refractory arrhythmias with or without associated intracardiac repair. Sealy and Cox originated the descriptions of surgical treatment of accessory connections and successfully applied the techniques to hundreds of patients (39). Guiradon et al. extended surgical



therapy to patients with AFL by developing the isthmus lesion from the coronary sinus to the inferior vena cava (IVC) (40). Theodoro and colleagues applied the techniques of the right sided maze as described by Cox to patients with congenital heart disease and atrial arrhythmias (21). Mavroudis extended the application of surgical treatment of both AFL and AF to patients with congenital heart disease of all ages and to patients with prior Fontan surgeries (1,15,41-43). During preoperative electrophysiologic studies the recognition of three dominant reentrant circuits for atrial tachycardia in Fontan patients led to the development of the modified right atrial maze, which included an isthmus lesion that was not part of the Cox right atrial maze (12,15). Multiple centers have successfully applied these various operative arrhythmia techniques to patients with congenital heart lesions.

In 2006, Karamlou and colleagues have demonstrated efficacy of concomitant atrial arrhythmia surgery in TOF patients with preexisting atrial arrhythmias who were undergoing pulmonary valve surgery and or tricuspid valve repair (44). In patients without arrhythmia by 18 years of age, reported SVT prevalence during long-term follow-up was over 15% (3). Giamberti and colleagues published their cumulative experience of 50 adults with congenital heart disease in 2006 (8) and 2008 (45). Patients underwent irrigated radiofrequency ablation concomitantly (31 right-sided maze procedures; 13 Cox-maze III procedures; 6 right ventricular ablations; and additional 14 pacemakers). Two patients died from causes not related to intraoperative ablation. During average follow up of 28 months, 48 patients were alive and in New York Heart Association class I or II. All patients were discharged with antiarrhythmic medication for 3 months. Forty three patients were still in sinus rhythm, 2 were in sinus rhythm and taking permanent antiarrhythmic medication for recurrent AF, 2 were in stable AF, and 1 was in pacemaker rhythm at the time of publication (45). The authors found irrigated radiofrequency ablation to be effective to control arrhythmias in adults with congenital heart disease (45).

Recognizing the increasing contribution of arrhythmias to long-term morbidity, three recent groups have published recommendations for concomitant arrhythmia surgery in patients with existing arrhythmias undergoing planned surgical repairs (Table 2) (16,46). The 2015 American College of Cardiology/American Heart Association/Heart Rhythm Society guidelines for the management of SVT in adults include a class I recommendation for assessment of associated hemodynamic abnormalities for potential repair in adults with congenital heart disease as part of therapy for

SVT (46). In the consensus statement for management of arrhythmias in adults with congenital heart disease, surgical ablation of associated atrial tachycardia is recommended in patients undergoing planned surgical repair, and a left atrial Cox-maze III procedure with right atrial cavotricuspid isthmus ablation is recommended for adults with congenital heart disease and AF. Guidelines for the management of AF in adults consider it reasonable to perform surgical ablation for AF in select patients undergoing cardiac surgery for other indications. These guidelines were made in recognition of the efficacy of surgical techniques for treating AFL and AF, as well as SVT related to accessory connections (16,46).

Arrhythmia surgery techniques

AF

The original maze procedures for AF were characterized as Cox-maze I, II, and III (47-49). Because original lesion sets were designed as “cut and sew”, energy ablative sources were introduced to shorten the procedure and limit bleeding complications, termed the Cox-maze IV. Lesion sets were designed to isolate left atrial macro and micro-reentry and prevent AF, while preserving conduction from the sinoatrial node to the atrioventricular node to maintain atrioventricular synchrony, preserve left atrial transport function, and reduce thromboembolism. The left atrial maze procedure is effective owing to the specific lesions designed to encircle the pulmonary veins and to limit reentry circuits that would occur in the left atrioventricular valve isthmus, reentry via the coronary sinus, and reentry via Bachmann’s bundle in the dome of the left atrium (1). Originally, the Cox-maze procedure included left atrial appendectomy and an incision to the confluence of pulmonary vein encircling lesion(s). Resection of the left atrial appendage was thought to remove the source of thrombi known to occur in AF; it is not clear whether the left atrial appendectomy plays a role in arrhythmia ablation.

Cox articulated the following observations regarding AFL/AF and the maze procedure (50):

(I) The local effective refractory periods of the left atrium are shorter than in the right atrium;

(II) AFL most likely occurs on the basis of reentry in the right atrium (longer effective refractory periods and larger reentrant circuits);

(III) AF likely occurs on the basis of reentry in the left atrium (shorter effective refractory periods and smaller reentrant circuits);



Table 2 2014 ACC/AHA/HRS Guidelines and Consensus Statements

Class of recommendation

Level of evidence

Recommendation

2014 Guidelines for arrhythmia management in adult congenital heart disease

I B A modified right atrial maze procedure is indicated in adults undergoing Fontan conversion with symptomatic right atrial IART

A modified right atrial maze procedure in addition to a left atrial Cox maze III procedure is indicated in patients undergoing Fontan conversion with documented AF

IIa B Concomitant atrial arrhythmia surgery should be considered in adults with Ebstein anomaly undergoing cardiac surgery

A (modified) right atrial maze procedure can be useful in adults with CHD and clinical episodes of sustained typical or atypical right atrial flutter

A left atrial Cox maze III procedure with right atrial cavotricuspid isthmus ablation can be beneficial in adults with CHD and AF

2014 Guidelines for the management of AF in adult congenital heart disease

IIa C An AF surgical ablation procedure is reasonable for selected patients with AF undergoing cardiac surgery for other indications

2015 Guidelines for the management of SVT in adult congenital heart disease

I C-LD Assessment of associated hemodynamic abnormalities for potential repair of structural defects is recommended in ACHD patients as part of therapy for SVT

IIa B-NR Preoperative catheter ablation or intraoperative surgical ablation of accessory pathways or AT is reasonable in patients with SVT who are undergoing surgical repair of Ebstein anomaly

Surgical ablation of AT or atrial flutter can be effective in ACHD patients undergoing planned surgical repair

Recommendations for prophylactic arrhythmia surgery in adult congenital heart disease

IIa B A modified right atrial maze procedure should be considered in adults undergoing Fontan conversion or revision surgery without documented atrial arrhythmias

Concomitant atrial arrhythmia surgery should be considered in adults with Ebstein anomaly undergoing cardiac surgery

IIb B Adults with CHD and inducible typical or atypical right atrial flutter without documented clinical sustained atrial tachycardia may be considered for (modified) right atrial maze surgery or cavotricuspid isthmus ablation

C Adults with CHD undergoing surgery to correct a structural heart defect associated with atrial dilatation may be considered for prophylactic atrial arrhythmia surgery

Adults with CHD and left-sided valvar heart disease with severe left atrial dilatation or limitations of venous access may be considered for left atrial maze surgery in the absence of documented or inducible atrial tachycardia

Closure of the left atrial appendage may be considered in adults with CHD undergoing atrial arrhythmia surgery

III C Prophylactic arrhythmia surgery is not indicated in adults with CHD at increased risk of surgical mortality from ventricular dysfunction or major co-morbidities, in whom prolongation of cardiopulmonary bypass or cross clamp times owing to arrhythmia surgery might negatively impact outcomes

Empiric ventricular arrhythmia surgery is not indicated in adults with CHD and no clinical or inducible sustained VT

Reproduced with permission from Khairy P, et al. PACES/HRS Expert Consensus Statement on the Recognition and Management of Arrhythmias in Adult Congenital Heart Disease. Heart Rhythm 2014;11:e102-e165. Copyright © 2014 with permission from Elsevier (16) and Page RL, et al. 2015 ACC/AHA/HRS Guideline for the Management of Adult Patients With Supraventricular Tachycardia: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2016:67;e27-e115. Copyright © 2016 with permisson from Elsevier (46). ACC, American College of Cardiology; AHA, American Heart Association; HRS, Heart Rhythm Society; IART, intra-atrial reentrant tachycardia; AF, atrial fibrillation; CHD, congenital heart disease; SVT, supraventricular tachycardia; LD, limited data; NR, nonrandomized; ACHD, adult congenital heart disease; AT, atrial tachycardia; VT, ventricular tachychardia.



(IV) Maze incisions confined to the left atrium are likely to ablate AF but not AFL (50).

Subsequent modifications to the maze procedure, all developed to shorten the operation, allow epicardial approaches without cardiopulmonary bypass and facilitate a transcatheter ablation (1,51,52). Further, because AF typically originates in the left atrium, potential exclusion of the right-sided lesions was introduced (50,51). Subsequent efforts to minimize the pulmonary vein and left atrial lesions resulted in procedures labeled as mini-maze, “modified” maze, “right atrial” maze, ”left atrial” maze, and “biatrial” maze. “Maze” became synonymous with any modified lesion set that was applied to the atria as therapy for reentrant atrial arrhythmias.

The original “cut and sew” Cox-maze III procedure resulted in long-term freedom from AF in greater than 97% of patients (1,49,53). All subsequent modifications have achieved varying degrees of efficacy, approaching 93% (1,54-56). The superiority of a biatrial maze procedure for AF prevention has been demonstrated in several studies (1,17,55,56). In a review of many different lesion sets for AF, Barnett and Ad [2006] reviewed 69 studies and 5,885 patients who underwent surgical ablation (67% biatrial and 33% left atrial) for AF lasting >6 or 12 months (56). Survival rates were similar for both procedures, however, the biatrial maze ablation demonstrated superior long-term freedom from AF at all time points.

AFL

The classic “cut and sew” right-sided maze procedure (49) involves a linear incision from the superior vena cava (SVC) to the IVC, right atrial appendectomy, incision from the base of the resected right atrial appendage to the midpoint of the right atrial anterior wall not in communication with the SVC-IVC incision, an incision posteriorly from the base of the right atrial appendage to the anterior tricuspid valve annulus, and a communicating incision from the SVC-IVC incision to the posterior tricuspid valve annulus (1). It is important to recognize that these lesions were developed from animal models without congenital heart disease or previous operations.

Subsequent electrophysiology studies have demonstrated the key role played by the right atrial isthmus in typical right AFL (isthmus dependent right atrial macroreentry) (1,57-60). The right atrial isthmus is considered the area between the tricuspid valve annulus and the coronary sinus and the IVC. Targeted ablation of this isthmus region

transforms the area of “slow conduction” to an area of “no conduction” and effectively terminates typical AFL (1,61).

In the congenital heart disease population, additional right atrial macroreentrant circuits have been identified commonly referred to as “non-isthmus” dependent tachycardia (1,62). These circuits may involve reentry around prior incisions (“incisional tachycardia”) or prosthetic material such as ASD patches. The lateral right atrial wall at the inferior aspect of the crista terminalis is often an area of unexcitable atrial tissue with low voltage electrograms and is labeled as “scar”. This area of “slow conduction” or scar can contribute to an additional macroreentrant circuit. Elimination of the isthmus of slow conduction between these incisions, patches, or electrical scars forms the basis of ablation strategies for non-isthmus-dependent right atrial tachycardia. These alternative lesion sets are referred to as “modified right atrial maze procedures” and appear to be responsible for elimination of right atrial tachycardia in the setting of complex congenital heart disease (14,62). The lesion sets of the modified right atrial maze (Figures 1,2) (1,63) may not be appropriate to employ as prophylactic lesion sets as the evidence for first time arrhythmia occurrence favors an isthmus-dependent circuit. In light of the accumulated retrospective studies, we favor an isthmus lesion (Figure 1) for right atrial arrhythmia prophylaxis (1,63).

Energy sources

Technical concerns relative to the “cut and sew” maze include the length of the procedure and risk of perioperative bleeding (1). Energy sources have been developed to minimize the need for incisions and subsequent bleeding complications (1,8,48-51,53,64).

Khargi and colleagues [2005] compared alternative sources of energy (radiofrequency-microwave and cryoablation; group I) for treating AF with a classic cut and sew Cox-maze III (group II), which claims 97% to 99% sinus rhythm success rate (1,65). Forty eight studies were reviewed with 3,832 patients (2,279 in group I and 1,553 in group II). There was no difference in mean duration of preoperative AF, left atrial diameter and left ventricular ejection fraction. Freedom from AF was 78% (group I), 85% (group II), and not statistically significant, implying no significant difference in the two sources of energy (1). Schuessler et al. [2009] summarized their experience in porcine models with 9 different unidirectional devices to create continuous transmural lines of ablation from the



atrial epicardium and thereby replace the cut and sew lesions with lines of ablation and perform the procedure without cardiopulmonary bypass (66). The devices included radiofrequency, microwave, lasers, and a cryothermia device. The maximum penetration of any device was 8.3 mm and therefore all devices except one (a radiofrequency device) failed to penetrate 2.0 mm in some non-transmural sections.

It appears that depth of lesions by whatever means is more important than the energy sources/incisions that are used to achieve the result. Patients with congenital heart disease have varying degrees of atrial thickness owing to the specific heart defect and the adaptive mechanisms over a lifetime of perturbed hemodynamics. For example, patients with tricuspid atresia have thick atrial walls, while patients with double inlet left ventricle tend to have thin atrial walls. These anatomic variances become important when a transmural lesion needs to be accomplished.

What we know about lesion sets for atrial tachycardia

The right-sided maze procedure as described by Cox et al. [1991] has a number of lesion sets that are performed by the classic “cut and sew” technique (47). The traditional surgical lesions in the classical right atrial maze include right atrial appendectomy, a lesion between the amputated right atrial appendage and the anterior tricuspid annulus, and the lesion from the SVC to the IVC (63). In particular, the lesion between the SVC and the IVC is similar to the incision that is oftentimes performed to repair a sinus venosus ASD (63). This incision is commenced in the upper third of the right atrial free wall and extends through the area of the sinoatrial node into the SVC. This repair, when performed in this manner has a high incidence of sinus node dysfunction, resulting in nodal rhythm.

Subsequent development of the modified right atrial

Figure 1 A right atrial view of potential prophylactic ablative lesions after aortobicaval cardiopulmonary bypass and cardioplegic arrest. The two cryoablation lines (cryoablation or radiofrequency ablation) connect the coronary sinus with the os of the inferior vena cava and the tricuspid annulus with the os of the inferior vena cava, respectively. Reproduced with permission from Mavroudis C, et al. Prophylactic atrial arrhythmia surgical procedures with congenital heart operations: review and recommendations. Ann Thorac Surg 2015;99:352-59. Copyright © 2015 with permission from Elsevier (1).

Figure 2 Right and left atrial views of potential prophylactic ablative lesions after aortobicaval cardiopulmonary bypass and cardioplegic arrest. Added to the lesion set in Figure 1 are the lesion sets that comprise the left sided maze procedure without performing a left atrial appendectomy. Shown in the left atrium are circumferential isolation of the pulmonary vein confluence, connection of the pulmonary vein confluence with the P3 location of the posterior mitral valve annulus, and connection of the pulmonary vein confluence with the base of the left atrial appendage. Reproduced with permission from Mavroudis C, et al. Prophylactic atrial arrhythmia surgical procedures with congenital heart operations: review and recommendations. Ann Thorac Surg 2015;99:352-59. Copyright © 2015 with permission from Elsevier (1).



maze includes lesions between the IVC and the tricuspid valve, the coronary sinus and the tricuspid valve, and between the IVC and the coronary sinus. The right atrial cavotricuspid isthmus represents areas of “slow conduction” which together with an area of unidirectional block contribute to atrial reentry tachycardia (1,61,63). Converting these locations from areas of slow conduction to areas of no conduction using transcatheter radiofrequency ablation techniques can be effective. This area at the so-called “isthmus” is usually the first set of applied radiofrequency lesions that are delivered by transcatheter techniques in a hierarchical series that includes the area between the fossa ovalis and the lateral wall crista terminalis, the base of the atrial appendage and the tricuspid annulus, as well as other areas of slow conduction that are identified by electrophysiologic mapping.

Because of the severity of the tachycardia in patients with complex congenital heart disease such as Fontan patients, arrhythmia ablation tends to be more important than the risk of nodal rhythm, which can be treated by pacemaker therapy (63). In addition, surgical ablation in these populations does not lend itself to a step wise hierarchical treatment plan because access to the anatomic areas of interest often require extending the cross clamp time under some type of systemic hypothermia. Separation from cardiopulmonary bypass, remapping and recommencement of cardiopulmonary bypass/aortic cross clamp to ablate the next area of interest increases the risks of myocardial ischemia, systemic inflammation, and air embolism (63). As a result, surgeons are more likely to ascribe to the axioms “more is better” and “getting it right the first time”. These tenets are not operative, however, when considering simple cases of atrial tachycardia or recent onset of AF in patients with two ventricles and congenital heart disease. This is especially true when considering prophylactic arrhythmia surgery, which raises the tenet of “do no harm”.

In light of evidence of sinus node dysfunction following the classic right atrial maze in the ASD population, it seems unwise to include the lesion between the SVC to IVC to prevent atrial tachycardia as a prophylactic procedure, especially because there is little proof as to the validity of this lesion when compared with the isthmus ablation line. The same is true for the lesion that is sometimes placed from the fossa ovalis to the posterior atrial flap of the atriotomy, when an atriotomy is required for right atrial access. While this lesion might be indicated for treatment of incessant atrial tachycardia, there is very little evidence that such a lesion might be effective as a prophylactic measure.

Proposed lesions sets for prophylactic arrhythmia surgery

Prophylactic arrhythmia surgery in humans with congenital heart disease has not been tested by a prospective, randomized, clinical study owing to non-standardized lesion sets, variable patient populations, and lack of unanimity for the need of this additive procedure, which requires a measurable amount of cardiopulmonary bypass and cross-clamp times (1). In addition to these impediments are the paucity of retrospective clinical studies, which can help to define various approaches to certain patient populations and can form the basis for clinical equipoise and the need for an organized multi-institutional study (1).

There have been very few studies that have applied therapeutic lesion sets as prophylactic measures in humans (1,5,17,21). Based on animal studies that induce atrial tachycardia and lysis with one incision, Collins and associates applied a single incision in the anterior atrial flap to the anterior tricuspid annulus in Fontan patients (67). The idea was that this lesion would mitigate against the incidence of atrial tachycardia. The short-term results failed to show efficacy, which was perhaps related to the small number of patients with limited follow up or alternatively related to a lesion set that did not address the right atrial cavotricuspid isthmus (1).

Based on the limited clinical studies, retrospective surgical and transcatheter ablation results, and the debated opinion of surgeons, prophylactic arrhythmia lesion sets are offered for diagnostic subsets with predictive arrhythmia occurrence that are undergoing a primary or secondary therapeutic anatomic surgical intervention (Table 3, Figures 1,2) (1,63). Based on the historic data regarding populations with the highest incidence of atrial arrhythmia development, targeted populations for prophylactic arrhythmia surgery in the right atrium include patients with unrepaired ASDs presenting over 40 years of age (1,5), patients with Ebstein anomaly (1), tetralogy patients presenting for pulmonary valve insertion (1,68,69), and single-ventricle patients who present for Fontan operations (1,16,32,70-72). Prophylactic surgery for AF would be considered for patients with significant left-sided atrioventricular disease and severe left atrial dilatation undergoing planned surgery, with lesions including left atrial maze and right-sided cavotricuspid isthmus ablation (16).

Figure 1 shows a lesion set that interrupts the potential areas of slow conduction at the “isthmus” (1,63). This is the first area that is approached for therapeutic transcatheter radiofrequency ablation in patients with atrial reentry



tachycardia, which is successful in 75% of cases. The area of interest is easy to locate, easy to ablate and has minimal risks. Figure 2 shows the lesion set for prevention of AF.

Lesion sets should be standardized not only for therapeutic measures but also for prophylactic applications for patients with congenital heart disease undergoing repair. The principles of prophylactic procedures should be preserved, namely that the prophylactic procedure should be simple to perform, should be attended by a minimum of complications, and be supportive of potential problems that can cause significant hemodynamic problems to the patient over the long term.

Acknowledgements

None.

Footnote


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Table 3 Suggested prophylactic lesion sets for patients with congenital heart disease

Congenital heart disease

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Prophylactic lesion set Timing of procedure

Ebstein anomaly ART, large right atrium See Figure 1 (1,63) Primary repair in patients without arrhythmias; most reparative operations performed in adolescents and adults

ART, large right and left atria

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Univentricular hearts ART See Figure 1 (1,63) Primary repair Fontan operation in patients without arrhythmias

Atrial septal defect Atrial fibrillation See Figures 1,2 (1,63) Patients >40 years without arrhythmias

Tetralogy of Fallot ART See Figure 1 (1,63) Reoperation for older patients without arrhythmias

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Cite this article as: Mavroudis C, Deal BJ. Prophylactic arrhythmia surgery in association with congenital heart disease. Transl Pediatr 2016;5(3):148-159. doi: 10.21037/tp.2016.06.04


Introduction

Pediatric Cardiovascular Intensive Care has become increasingly organized as a subspecialty over the past two decades. The pediatric cardiac intensivist plays a central role in the critical care of these patients, as well as continuous quality improvement and family centered care. This growth of the subspecialty comes in response to the explosion of knowledge and research in the patient with critical cardiac disease, the increasing complexity of cardiac lesions and procedures to treat them, and the growing numbers of patients of a younger age requiring cardiac intensive care. Indeed an international subspecialty society, the Pediatric Cardiac Intensive Care Society, was organized in 2003 to address the issues facing practitioners.

Within this review, we take the opportunity to examine the subspecialty’s past accomplishments with pride, take stock in its current state, and look forward with excitement to its future. Additionally, it gives the opportunity to applaud those who attempt to innovate in order to radically improve the future care of these children.

Looking backward

It is clear that we have had rapid advancement in all outcome

measures (1). However, the danger of always looking backward is that we are subject to either positive or negative revisionist history. Additionally, hindsight is always 20/20. The reality is, as with all history, truth is found somewhere in the middle ground between the superlative and stupidity. We were never as good, nor as bad, as we think.

An interesting conceptual framework that is important in medicine is that throughout the history of care, at the time and in the present, we were convinced that we were doing the right thing for our patients. However, many of these truths have subsequently proved to be false. In the modern world facts change all of the time, according to Samuel Arbesman, author of The Half-Life of Facts: Why Everything We Know Has an Expiration Date (2). Since scientific knowledge is still growing by a factor of ten every 50 years, it should not be surprising that many of the facts people learned in school and universities have been overturned and are now out of date. But at what rate do former facts disappear? Applying the concept of half-life to facts, Arbesman cites research that looked into the decay in the truth of clinical knowledge about cirrhosis and hepatitis. “The half-life of truth was 45 years,” reported the researchers.

An example of the changing “truth” occurred in relation to George Washington, the former President and senior leader of our nascent country. On December 12, 1799,

Review Article

Critical cardiac care in children: looking backward and looking forward

Paul A. Checchia

Pediatric Cardiovascular Intensive Care, Texas Children’s Hospital, Baylor College of Medicine, Houston, Texas, USA

Correspondence to: Paul A. Checchia, MD, FCCM, FACC, Professor, Director. Pediatric Critical Care Medicine and Cardiology, Pediatric Cardiovascular

Intensive Care, Texas Children’s Hospital, Baylor College of Medicine, 6621 Fannin st. W6006, Houston, Texas 77030, USA. Email: [email protected].

Abstract: The growth of Pediatric Cardiovascular Intensive Care as a subspecialty has been incredible. Outcomes have improved, care delivery has matured, and research has made advances. Within this review, we take the opportunity to examine the subspecialty’s past accomplishments with pride, take stock in its current state, and look forward with excitement to its future. While outcomes in general have improved dramatically, we must always be aware of the outcomes that matter to families and patients. Additionally, we must constantly ask ourselves to improve. Research into neuroprotection and individual therapeutic strategies based in genomic medicine provide the next opportunity for the subspecialty to improve.

Keywords: Pediatric; cardiac; congenital heart disease (CHD); outcomes

Submitted Jun 16, 2016. Accepted for publication Jun 24, 2016.doi: 10.21037/tp.2016.06.07




Washington suffered from an upper respiratory infection (3). His physicians applied a painful “blister of cantharides”, better known as “Spanish fly”, to Washington’s throat to cause “counter-irritation”. They justified the removal of more than 80 ounces of his blood (2.365 liters or 40 percent of his total blood volume) over a 12-hour period in order to reduce the massive inflammation of his windpipe and constrict the blood vessels in the region.

Of course, this is seen as ridiculous in today’s scientific understanding. However, as stated, in their present it was the most justifiable approach. So with this as background, what are some of the “truths” in the care of critically ill children with cardiac disease that will be questioned in the future. I propose discussion pertaining to three present day “truths”. First, we think surgeons actually matter. Second, we think doctors actually matter. Finally, we think we know which outcomes matter.

We examined the influence of surgical volume on outcome in a recent investigation of the Norwood procedure (4). Lower mortality following the Norwood procedure was associated with high institutional volume. However, lower mortality was not associated with the number of cases performed by a surgeon. We concluded that a well-experienced surgeon was necessary but insufficient to truly impact positive outcomes. The impact of the institution, the team, had a greater influence on outcomes.

Ultimately, cardiovascular critical care is a team sport. Every participant has a role in the care of each child. Everyone from physicians, to nurses, to therapists, to family members, all influence the success of complex care. However, there is a struggle within this team concept. The team is important, but ultimately the individual is accountable for their performance. As stated by former coach Phil Jackson, “The strength of the team is each individual member...the strength of each member is the team”. It is incumbent on the specialty as a whole to develop care models that enhance teamwork while maintaining a culture of individual skill, pride and accountability.

Another team member that is viewed as important in today’s truth construct is the physician. I would contend that doctors are not as important as we believe ourselves to be in today’s cardiovascular intensive care unit. The most important member of today’s unit team is the bedside nurse.

While we continually rely on technology in the form of monitors, diagnostic imaging, and laboratory surveillance, all data gained from monitors must be integrated with the information gained by physical exam. An experienced clinician must accomplish this integration. While

technology can serve to aid in the care of the patient, nothing can replace the experience of a clinician. Bernard Lown, writing in Scientific American, outlined such a balance over 40 years ago. “Neither monitors nor the most complicated electronic gear makes a coronary care unit. The fundamental ingredient is a properly indoctrinated nursing staff. The reason for this is obvious. The nurse is usually the only trained medical professional at the bedside during important clinical events. The time for effective action is brief and does not usually allow delay for the arrival of a physician. The nurse is trained in the recognition of arrhythmias and is delegated the authority for enacting the entire repertory of lifesaving techniques In fact, many well-functioning coronary care units have been successful because of the elite spirit and competence of the nursing staff.” (5).

As was apparent in the infancy of cardiac critical care, the presence at the bedside by experienced clinicians was paramount to success. However, this paradigm is currently under attack. We are forced to limit the experience gained by trainees and bedside nurses. While we profess the desire to avoid monitors acting as a replacement to experienced clinicians, we are forced to re-examine their utility when faced with shifts covered by residents and fellows who are restricted by work hours, and young nurses who have just graduated nursing school. This represents a new challenge to the continued growth and success of our care delivery models.

Finally, we think we know the outcomes that matter. Boneva et al. (1) reviewed population-based mortality data of congenital heart disease (CHD) from 1979–1997, from the Center for Disease Control and Prevention (CDC). Overall mortality decreased 39%. Yet there was a smaller decline in HLHS—7.5%, and TOF—10%. The decrease for TGV was 40.6% in infants <1 year and 74.4% in children 1–4 years of age. In fact, our center has reported overall outcomes of surgical procedures improved to <1% mortality. While individual lesions, risk categories, and co-morbid conditions impact this low mortality leading to variations within risk subcategories, the improvement is obvious. We are not alone in this staggering improvement. It is safe to say that, as a community, we have moved CHD from an expected mortality to an expected survival. However, this creates risks, opportunities, and consequences, not the least of which is a loss of perspective of meaningful outcome.

In 1986, Lillehei et al. reported long term follow up on his first operations conducted from 1954 to 1960 (6). Of course, he was proud of an actuarial survival at 30 years of 77%. However, he also went on to highlight other outcomes. In his

162 Checchia. Critical cardiac care: looking backward and forward


cohort of patients, 32% completed college, ten completed graduate school, 40 patients had children with 93% of those being live births, and 7.3% with cardiac defects. He understood that these are the outcomes that truly matter. This pre-dates the latest attention to neurodevelopmental outcomes.

Ever since Alfred Blalock reported how successful the original interventions were at improving quality of life (7), we, as a community, thought we were great. However, that greatness was short lived. Ignorance, it seems, truly was bliss. As these children aged, we realized the impact of CHD, surgical interventions, cardiopulmonary bypass (CPB), and medications on the neurodevelopmental outcomes of these children (8). Our historical success has allowed us to realize that the road to an adult survivor of CHD is one that is far from linear. It is now incumbent on our entire field to cooperate, coordinate, and collaborate to determine how best to protect the neurologic status of our patients, and allow them to become the type of adult survivor we hope for when we first meet with families.

Looking forward

This easily transitions to looking forward in our subspecialty. Where do we go from here? How do we improve? The path to improvement in care involves education, research, and innovation. It is through the combined work of the committees and the Board of Directors of the PCICS that will soon yield training pathways for physicians and nurses seeking additional experience in cardiac critical care, international quality improvement initiatives, online journal clubs, and a research structure that will provide robust collaboration and mentorship opportunities. Innovation requires pushing boundaries, changing perspective on current problems, and taking risks. Three areas that have promise to do just that involve protection during CPB, data management, and the promise of individualized medicine.

In a recent study, we evaluated the impact of delivery of the gas nitric oxide (gNO) to the membrane oxygenator of the CPB circuit on postoperative outcome measures in children undergoing cardiac surgery for CHD (9). Children who received gNO during CPB had an improved postoperative course, as demonstrated by significantly reduced myocardial injury and shortened duration of mechanical ventilation and length of stay in the pediatric CICU. This has been reproduced by colleagues in Australia (10). Our premise is that NO added to the circuit has effect distal to the entry site. This is a novel concept and one that fits the requirement of

pushing boundaries for innovation. It is possible that through this type of novel, innovative application of existing drugs or therapies, we may impact outcomes in ways not previously realized.

Innovation is also necessary to adequately capture and interpret the ever-expanding wealth of data generated by each individual patient or event within a critical care hospitalization. Ultimately, data equals power. Data gives us the power to do the right thing well, at the right time and with the minimum of resources. Do it well, once, and with no complications.

For example, monitoring patients allows us to gauge the effectiveness of our efforts. Our goal is to monitor, and then intervene, in order to avoid progression to a decompensated shock state. It is the cornerstone of modern critical care medicine that intervening prior to the development of end-organ dysfunction or damage yields improved outcomes for the patients in our care. While monitoring can guide intervention, one effect of this approach is the generation of increasing volumes of data. As an intensivist, we must manage an enormous amount of information each moment we care for patients. These data must ultimately guide interventions. Yet with the growing volume of data, how do we know what information is meaningful? How do we separate the wheat from the chafe? This is the role of effective monitoring and effective data management in a modern ICU setting.

The second challenge for innovation comes in the integration of the overwhelming amount of data presented in a modern pediatric cardiac intensive care setting. We not only manage patients, we manage data. We need to develop the means to adequately monitor trends and pick up a signal when one is present. Monitoring in the pediatric cardiac intensive care environment should be an intuitive and analytic process. As noted above, there are numerous monitoring modalities available, both physiologic and laboratory based. The clinician at the bedside needs to be able to integrate this information to track the trajectory of the patient, and decide on interventions when necessary. Further, we do not know the impact of specific monitoring on patient recovery and outcome, on cost effectiveness and on the longer term quality of life; we assume we are monitoring the right predictors of outcome and that the target ranges are correct as well.

We have assumed that more is better although there are clear problems with fixation on specific abnormal results that deflect critical decisions. We now work in very complex environments. There is a huge amount of information



coming to the clinicians from physiologic and laboratory data, yet we do not collect, store and analyze this data in real time. In addition, there are multiple distractions at the bedside with continual interruptions to workflow. In short, we have not leveraged information systems to our benefit, and have not leveraged our common knowledge within the field and between institutions to standardize care and resource utilization. We need to leverage monitoring data to move away from the traditional “chain-of-event” analysis following adverse outcomes, which focuses primarily on patient characteristics and human error, and also move away from a “failure to rescue” analysis which focuses on unit-based team structure and function. Rather, we should focus on “failure to predict” an evolving clinical picture, which really evaluates systems characteristics and data integration. We need to understand how we function as a system and leverage the information systems to support our workflow.

In addition to information systems and data management, there has been an explosion of genetic data and power in the past two decades. We now have the ability, through whole genome informatics, to analyze the information found in literally thousands of genes within minutes. Data from investigators such as Hector Wong and Perren Cobb (11,12), to name but two, indicate that blood transcriptional and proteomic profiles can distinguish between host responses to different types of injuries in different age groups. They are demonstrating that information at the genome (DNA) level provides information about predisposition to a given outcome, while data at the transcriptome (RNA) (13) and proteome (protein) levels can be harnessed to make diagnoses, and finally gauge the response to therapy (prognoses). The promise of this line of investigation is that these patterns of change in gene and protein expression, in effect, become new, genomic “vital signs” (14). Additionally, we now have the computational power to not only analyze these data at a single point in the time course of a patient, but also across the time spectrum of the entire disease and healing trajectory (15,16). Through these discoveries, we finally have the potential for truly personalized diagnosis and intervention. Within these lines of investigation lies the opportunity for providing the right care to the right person at the exact right time. What if we applied this approach and this technology to other outcome questions such as sedation and analgesia postoperatively, nutrition, and neurodevelopmental outcomes?

Conclusions

There have been incredible advances in the care of

children with cardiac disease. We should all take pause and recognize the advancements that have been made. I would contend that there are very few areas of medicine that have achieved the same degree of success over the past 50 years. However, it is now incumbent on each of us in the field to build upon these advances so that the next generation of practitioners will be just as proud to look back on our latest accomplishments.

Acknowledgements

None.

Footnote


References

1. Boneva RS, Botto LD, Moore CA, et al. Mortality associated with congenital heart defects in the United States: trends and racial disparities, 1979-1997. Circulation 2001;103:2376-81.

2. Arbesman S. The half-life of facts: why everything we know has an expiration date. New York: Current, 2012.

3. Witt CB Jr. The health and controversial death of George Washington. Ear Nose Throat J 2001;80:102-5.

4. Checchia PA, McCollegan J, Daher N, et al. The effect of surgical case volume on outcome after the Norwood procedure. J Thorac Cardiovasc Surg 2005;129:754-9.

5. Lown B. Intensive heart care. Sci Am 1968;219:19-27.6. Lillehei CW, Varco RL, Cohen M, et al. The first open

heart corrections of tetralogy of Fallot. A 26-31 year follow-up of 106 patients. Ann Surg 1986;204:490-502.

7. Taussig H, Blalock A. Surgery of congenital heart disease. Br Med J 1947;2:462.

8. Marino BS. New concepts in predicting, evaluating, and managing neurodevelopmental outcomes in children with congenital heart disease. Curr Opin Pediatr 2013;25:574-84.

9. Checchia PA, Bronicki RA, Muenzer JT, et al. Nitric oxide delivery during cardiopulmonary bypass reduces postoperative morbidity in children--a randomized trial. J Thorac Cardiovasc Surg 2013;146:530-6.

10. James CS, Horton S, Brizard C, et al. Abstract 14827: Nitric Oxide During Cardiopulmonary Bypass Improves Clinical Outcome: A Blinded, Randomized Controlled Trial. Circulation 2015;132:A14827.

164 Checchia. Critical cardiac care: looking backward and forward


11. Chung TP, Laramie JM, Province M, et al. Functional genomics of critical illness and injury. Crit Care Med 2002;30:S51-7.

12. Wong HR. Genetics and genomics in pediatric septic shock. Crit Care Med 2012;40:1618-26.

13. McDunn JE, Muenzer JT, Rachdi L, et al. Peptide-mediated activation of Akt and extracellular regulated kinase signaling prevents lymphocyte apoptosis. FASEB J 2008;22:561-8.

14. Cobb JP, Brownstein BH, Watson MA, et al. Injury in the

era of genomics. Shock 2001;15:165-70.15. Wong HR, Cvijanovich N, Allen GL, et al. Genomic

expression profiling across the pediatric systemic inflammatory response syndrome, sepsis, and septic shock spectrum. Crit Care Med 2009;37:1558-66.

16. McDunn JE, Husain KD, Polpitiya AD, et al. Plasticity of the systemic inflammatory response to acute infection during critical illness: development of the riboleukogram. PLoS One 2008;3:e1564.

Cite this article as: Checchia PA. Critical cardiac care in children: looking backward and looking forward. Transl Pediatr 2016;5(3):160-164. doi: 10.21037/tp.2016.06.07


Introduction

Pulmonary atresia with ventricular septal defect (PA-VSD) is a complex heart lesion, occurring 2% of all congenital malformations (1,2). Management of patients with PA-VSD in the neonatal period presents numerous challenges (3). The primary aim of intervention for these patients is to provide reliable pulmonary blood flow in order to prevent life-threatening desaturation and promote further growth of the pulmonary arteries. The traditional approach includes a prostaglandin E infusion started shortly after birth with subsequent surgical systemic-to-pulmonary artery shunting. However, in 25% of cases with this lesion, the source of pulmonary blood supply are collateral vessels, either single or multiple, instead of the ductus arteriosus. These collateral vessels are typically not amenable to the effects of prostaglandin, and tend to be stenotic, making conservative management of such patients fairly unpredictable.

In addition, application of an aorto-pulmonary shunt, particularly in the setting of right aortic arch, which occurs in 40% of patients with PA-VSD, is technically more challenging, often requires a sternotomy with cardiopulmonary bypass, and could create significant PA

distortion (1,4).Recently, endovascular stenting of the ductus arteriosus

or of a collateral vessel in ductal-dependent pulmonary circulation as an alternative to the BT-shunt has become increasingly popular (5-7). In PA-VSD, the pulmonary trunk is usually absent or severely hypoplastic. This results in changing the pulmonary artery bifurcation geometry, which makes positioning of the distal end of the stent particularly difficult without the risk to compromise blood flow in to the PA branches.

We describe the reverse Szabo (anchor-wire) technique, which is used for precise proximal stent positioning at the main branch in bifurcation coronary stenting (8,9). In the available literature, we found only a very limited description of the similar technique in congenital heart defects, by Girona et al., describing a similar concept but with a slightly different modification (10).

Case presentation

Patient M., 2 days of age, 2.5 kg, with a prenatal diagnosis of “Tetralogy of Fallot” and without any significant

Case Report

Reverse Szabo technique for stenting a single major aorto-pulmonary collateral vessel in pulmonary atresia with ventricular septal defect

Igor V. Polivenok1,2, John P. Breinholt3, Sri O. Rao2, Olga V. Buchneva1

1Zaitcev Institute for General and Urgent Surgery NAMS of Ukraine, Kharkiv, Ukraine; 2William Novick Global Cardiac Alliance, Memphis, TN,

USA; 3University of Texas Health Science Center at Houston, TX, USA

Correspondence to: Igor V. Polivenok, MD, FSCAI. Zaitcev Institute for General and Urgent Surgery NAMS of Ukraine, 1 Balakireva entr., 61103,

Kharkiv, Ukraine. Email: [email protected].

Abstract: Management of pulmonary atresia with ventricular septal defect (PA-VSD) in the neonatal period presents numerous challenges. Endovascular stenting of the ductus arteriosus or of a collateral vessel in ductal-dependent pulmonary circulation as an alternative to the Blalock-Taussig (BT) shunt has become increasingly popular in the last decades. The utilization of the reverse Szabo (anchor-wire) technique for single collateral vessel stenting in a case of PA-VSD is described.

Keywords: Congenital heart disease, pediatrics; stenting technique; pediatric intervention

Submitted Jun 01, 2016. Accepted for publication Jun 24, 2016.doi: 10.21037/tp.2016.07.02


166 Polivenok et al. Reverse Szabo technique for PDA stenting


comorbidities, was referred from the neonatal hospital in clinically stable condition with saturation of 90%. Transthoracic echocardiography revealed pulmonary atresia with ventricular septal defect, and a continuous infusion 20 ng/kg/min of PGE1 was started. During the following 10 days the patient’s condition remained stable, but the saturations gradually decreased to 70% without significant response on to increased prostaglandins.

On the 12th day of l i fe, the baby was taken for catheterization, which confirmed PA-VSD, single major aorto-pulmonary collateral artery (MAPCA) and, right-sided aortic arch (Figure 1). No other significant sources of pulmonary flow were found.

Venous access was obtained via the right common femoral vein with a 4 Fr introducer sheath (Terumo, Tokyo, Japan) and IV Heparin 100 IU/kg was administered. A 4-Fr JR catheter over 0.035'' hydrophilic angled guide wire (Radifocus, Terumo, Tokyo, Japan) was advanced through the VSD into the ascending aorta. A 0.018'' guide wire (V-18, Boston Scientific, Marlborough, MA, USA) was then inserted into the descending aorta, after which the 4-Fr introducer sheath was exchanged for a long 4-Fr sheath (Cook Medical, Bloomington, IN, USA) positioning the tip in the ascending aorta opposite the innominate artery. The innominate artery was engaged by rotating of the sheath, and the 0.018'' guide wire was advanced through the collateral vessel into the distal pulmonary artery followed by the sheath, deeper to the ostium of the collateral vessel. To facilitate further insertion of the sheath further and establish a more stable position, we used the “mother and child” technique by introducing the 4-Fr JR catheter through the sheath deeper into the collateral vessel. Then

the pulmonary arteries were wired with two 0.014’’ guide wires (Runthrough NS, Terumo, Tokyo, Japan) as distally as possible, in order to achieve a stable position of the assembly (Figure 2). After measuring collateral vessel length and considering patient weight, the coronary bare metal stent 3.5×22 mm2 was selected (Integrity, Medtronic, Santa Rosa, CA, USA).

The proximal end of the right pulmonary artery guide wire was introduced into the lumen of the balloon. Then the protective tube over the stent was slightly withdrawn to uncover two rows of stent cells. The balloon was gently inflated to expand the most distal rows of stent cells (Figure 3A). The second left pulmonary artery guide wire (anchor wire) was inserted through the most distal, expanded stent cell (Figure 3B) and the stent was manually crimped over the balloon again (Figure 3C). The stent was then advanced to the branch pulmonary artery bifurcation (Figure 2B) and, after confirming its location with angiography, deployed at nominal pressure (Figure 2C).

With this technique, the anchor wire delivers the distal position of the stent at the bifurcation precisely and prevents undesired distal sliding of the stent during inflation (Figure 2D). At the same time, we can safely apply continuous forward force on the whole assembly to prevent the stent from missing the bifurcation, which typically is the most stenotic segment.

The post-intervention course was without complications. After the procedure, the patient developed moderate pulmonary over-circulation with saturations of 96%, which were easily controlled with conservative medical management. The patient was extubated the following morning, his condition was stable with saturations of 88–90% without heart failure or systemic hypoperfusion. Two days after the procedure, he was transferred to the neonatal hospital on Aspirin 5 mg/kg per day.

Discussion

The anchor-wire technique, originally described by Szabo, was used in coronary stenting for precise positioning of the stent in the ostium of the main vessel (8). The Reverse Szabo technique at V-stenting of the coronary arteries was described by Lo and Kern (9). Nonetheless, the use of anchor-wire technique for stenting in congenital heart diseases has been limited. Only Girone et al. described the use of an extended anchor-wire concept in the treatment of congenital malformations (10). However, in their original description, to anchor the distal end of the stent, the

Figure 1 Angiography of PA-VSD, a single collateral vessel takes off from a right-sided aortic arch with pulmonary trunk hypoplasia.



anchor wire was passed through the entire stent. In our modification, the anchoring wire was passed through the most distal stent cell. As this is a pre-mounted assembly, we were able to minimize the risk of the stent sliding from the balloon while advancing.

Conclusions

The utilization of the described technique for PDA/collateral vessel stenting has the following advantages over the traditional approach: (I) precise positioning of the distal end of the stent exactly at the bifurcation without the risk of stent protrusion into the one of the branch pulmonary arteries; (II) minimization of the risk of missing the usual stenosis at the insertion of the vessel at the pulmonary artery bifurcation by allowing safe continuous forward pressure application on the stent-balloon assembly before

Figure 2 Reverse Szabo technique of single collateral vessel stenting: (A) 0.014’’ guide wires in both PAs; (B) stent-balloon assembly advanced to the desired position. The anchor wire fixes the distal end of the stent exactly at the carina level; (C) stent deployment; (D) final position of the stent.

Figure 3 Stent preparation: (A) gentle inflation of the balloon to expand the most distal rows of the stent cells; (B) insertion of the proximal end of anchor guide wire through a most distal stent cell; (C) stent crimped again over the balloon and anchor guide wire.

A

B

C

C

A

D

B

168 Polivenok et al. Reverse Szabo technique for PDA stenting


and during deployment; (III) and facilitate advancement of the stent-balloon assembly due to the presence of a buddy-wire.

Acknowledgements

None.

Footnote


Informed Consent: Written informed consent was obtained from the patient for publication of this mauscript and any accompanying images.

References

1. O'Leary PW, William D, Edwards WD, et al. Pulmonary Atresia and Ventricular Septal Defect. In: Moss and Adams' Heart Disease in Infants, Children, and Adolescents: Including the Fetus and Young Adult. Vol. 2. Chapter 42. Philadelphia: Wolters Kluwer Health / Lippincott Williams & Wilkins, 2008.

2. Haas NA, Kleideiter U. Pulmonary Atresia with Ventrical Septal Defect. In: Haas NA, Kleideiter U. Pediatric cardiology: symptoms, diagnosis, treatment. Stuttgart:

Thieme 2015:51-4.3. Lofland GK. The management of pulmonary atresia,

ventricular septal defect, and multiple aorta pulmonary collateral arteries by definitive single stage repair in early infancy. Eur J Cardiothorac Surg 2000;18:480-6.

4. Muralidhar K. Modified Blalock Taussig shunt: comparison between neonates, infants and older children. Ann Card Anaesth 2014;17:197-9.

5. Alwi M. Stenting the ductus arteriosus: Case selection, technique and possible complications. Ann Pediatr Cardiol 2008;1:38-45.

6. Alwi M, Choo KK, Latiff HA, et al. Initial results and medium-term follow-up of stent implantation of patent ductus arteriosus in duct-dependent pulmonary circulation. J Am Coll Cardiol 2004;44:438-45.

7. Okubo M, Benson LN. Intravascular and intracardiac stents used in congenital heart disease. Curr Opin Cardiol 2001;16:84-91.

8. Szabo S, Abramowits B, Vaitkuts PT. New technique for aorto-ostial stent placement (Abstr) Am J Cardiol 2005;96:212 H.

9. Lo H, Kern MJ. Use of a branch wire to anchor stents for exact placement proximal to bifurcation stents: the reverse Szabo technique. Catheter Cardiovasc Interv 2006;67:904-7.

10. Girona J, Martí G, Betrian P, et al. Extended Szabo (anchor-wire) technique concept for stent implantation in congenital heart lesions. Pediatr Cardiol 2012;33:1089-96.

Cite this article as: Polivenok IV, Breinholt JP, Rao SO, Buchneva OV. Reverse Szabo technique for stenting a single major aorto-pulmonary collateral vessel in pulmonary atresia with ventricular septal defect. Transl Pediatr 2016;5(3):165-168. doi:10.21037/tp.2016.07.02


Introduction

Epilepsy is a common yet rarely discussed chronic disease. In the United States, 5.1 million individuals carry the diagnosis of a seizure disorder or epilepsy (1-3). In 2012, direct medical cost of epilepsy treatment amounted to $9.6 billion (4); the cost of community services, lost wages of individuals and caregivers, and immense social stress of patients and their families add to the toll. The age of onset of epilepsy is bimodal. Of the 5.1 million Americans with a seizure disorder or epilepsy, 460,000 are age 17 or younger and are actively undergoing epilepsy treatment (2,3). Underlying etiologies of epilepsy include neonatal hypoxia, congenital anomalies, traumatic brain injury, meningitis,

brain tumor, and stroke. Frequently, however, an underlying cause is never identified.

Several modalities for epilepsy treatment exist. Medical management in the form of antiepileptic drugs (AEDs) is the first line of treatment and is successful in seizure control in 60–80% of cases (5). At present, the United States Food and Drug Administration (FDA) lists 18 AEDs, with several drugs having short-acting and extended-release preparations. Drug-resistant epilepsy (DRE) is defined by the International League Against Epilepsy (ILAE) as an adequate trial of two or more appropriately selected AEDs, alone or in combination, with failure of treatment resulting in continued seizures or intolerable side effects (6).

Pediatric Epilepsy Column (Review Article)

Preoperative evaluation and surgical decision-making in pediatric epilepsy surgery

Katrina Ducis1,2, Jian Guan2, Michael Karsy2, Robert J. Bollo2,3

1Department of Neurosurgery, University of Vermont School of Medicine, Burlington, VT, USA; 2Department of Neurosurgery, University of Utah

School of Medicine, Salt Lake City, UT, USA; 3Division of Pediatric Neurosurgery, Primary Children’s Hospital, Salt Lake City, UT, USA

Contributions: (I) Concept and design: RJ Bollo, K Ducis; (II) Administrative support: All authors; (III) Provision of study materials: None; (IV)

Collection and assembly of data: None; (V) Data analysis and interpretation: None; (VI) Manuscript writing: All authors; (VII) Final approval of

manuscript: All authors.

Correspondence to: Robert J. Bollo. Department of Neurosurgery, University of Utah, Primary Children’s Hospital, 100 Mario Capecchi Drive, Salt

Lake City, UT 84113, USA. Email: [email protected].

Abstract: Epilepsy is a common disease in the pediatric population, and the majority of cases are controlled with medications and lifestyle modification. For the children whose seizures are pharmacoresistant, continued epileptic activity can have a severely detrimental impact on cognitive development. Early referral of children with drug-resistant seizures to a pediatric epilepsy surgery center for evaluation is critical to achieving optimal patient outcomes. There are several components to a thorough presurgical evaluation, including a detailed medical history and physical examination, noninvasive testing including electroencephalogram, magnetic resonance imaging (MRI) of the brain, and often metabolic imaging. When necessary, invasive diagnostic testing using intracranial monitoring can be used. The identification of an epileptic focus may allow resection or disconnection from normal brain structures, with the ultimate goal of complete seizure remission. Additional operative measures can decrease seizure frequency and/or intensity if a clear epileptic focus cannot be identified. In this review, we will discuss the nuances of presurgical evaluation and decision-making in the management of children with drug-resistant epilepsy (DRE).

Keywords: Drug-resistant; epilepsy; seizure focus; pediatric; surgery


doi: 10.21037/tp.2016.06.02


170 Ducis et al. Preoperative evaluation and decision-making in epilepsy


Uncontrolled seizures represent an important public health problem. A recent study published by Berg et al. (7) prospectively analyzed 198 children based on age of first seizure, pharmacoresistance, and cognitive outcomes. Patients with DRE had statistically worse processing speed and verbal comprehension scores, freedom from distractibility, and overall intelligence quotients (IQs). Furthermore, among children with DRE, younger age of seizure onset correlated negatively with IQ. As these children age, continued epileptic activity can prevent reaching major social milestones, including driving and living independently.

Options for the treatment of DRE include lifestyle modification and surgery. The ketogenic diet, consisting of a combination of high fat and low carbohydrate content, has been used to treat DRE with some success. It is the first-line treatment for patients with glucose transporter type 1 and pyruvate dehydrogenate complex deficiencies (8,9). The ketogenic diet’s success depends on the ability of the patient to maintain it. Among 59 patients initially enrolled in a recent study, only 24 were able to maintain the ketogenic diet for 12 months. Although only a minority of patients were able to sustain the diet for the entire study, 21 of those 24 children experienced at least a 50% reduction in seizure frequency.

Independent of the ketogenic diet, children with persistent seizures (due to failure to control seizures or intolerable medication side effects) should be referred for surgical evaluation as soon as they meet ILAE criteria for DRE (10). Timing is critical because of the impact of persistent seizures on the developing brain and because of the greater neuroplasticity in younger children. If surgical intervention necessitates resection or disconnection of eloquent areas of brain and loss of function, potential for reorganization is optimal at younger ages. Furthermore, continued epileptic activity can lead to the spread of seizure activity to previously normal areas of brain, an effect called “kindling”, leading to further neurologic deficit and multifocal epilepsy, which may be less amenable to surgical cure. Early patient assessment is critical, especially in patients with developmental delay. The factor most consistently associated with seizure freedom is the ability to completely remove the epileptogenic zone (11-13), which can often be identified through precise preoperative planning.

Preoperative evaluation

There are several components to a thorough presurgical evaluation. The core components include a detailed medical history, physical examination, electroencephalography

(EEG), and structural brain magnetic resonance imaging (MRI). Other noninvasive tests including magnetoencephalography (MEG) and metabolic studies are often complementary. In the context of discordant data from noninvasive studies, epileptic foci near eloquent cortex, or in patients with a normal structural MRI, intracranial EEG recordings with subdural electrode arrays and depth electrodes may also be required.

Electroencephalography

Ictal scalp EEG can be useful for localization of an epileptic zone as it is widely available and relatively cost effective. Among children with DRE and normal structural findings MRI, EEG is critical for localization of the epileptic zone or at least hemispheric lateralization. Scalp EEG is less sensitive for epileptic foci located in the interhemispheric, basal, or mesial temporal locations. In addition, although interictal signal abnormalities may exist either remote from a cortical lesion or in a multifocal pattern, this should not influence eligibility or extent of resection if a solitary structural lesion is demonstrated by MRI (14-16). Video EEG is also useful in capturing and verifying auras. For example, forced turning of the head and eyes with neck extension localizes to the contralateral frontal eye fields and can be the first indication of frontal lobe epilepsy (17). Video EEG is also helpful in confirming whether stereotypic, episodic behaviors are a manifestation of seizure activity or are nonepileptic. If rapid seizure spread is present, localization of the initial epileptic zone may be limited, and additional modalities may be necessary to augment localization. In specific regard to infantile spasms, video EEG should be of sufficient length to capture wakefulness, sleep, and wakening (18); 24-hour video EEG monitoring has the best chance of capturing epileptic spasms and detecting hypsarrhythmia (19).

Magnetic resonance imaging

The Pediatric Epilepsy Surgery Task Force created by the ILAE recently published guidelines for evaluation of surgical candidates. Of all the proposed testing, only two modalities were uniformly agreed-upon core tests: scalp EEG and MRI. A single lesion on MRI corresponding to an EEG epileptogenic focus is a common situation with a potentially straightforward surgical plan, but more complex scenarios are frequently encountered. For example, in patients with tuberous sclerosis complex, several cortical



tubers may be present on imaging, making it more difficult to determine the epileptogenic lesion noninvasively. In addition, adult patterns of myelination do not appear until 18 months of age (20), and it is often difficult to resolve subtle abnormalities including focal cortical dysplasia in infants. Finally, while MRI is a widely available diagnostic modality, barriers do exist. Strict contraindications include cochlear implants and cardiac pacemakers, and images can be degraded by presence of dental braces, ventricular shunts, and any patient motion. Any image degradation can be detrimental when attempting to detect subtle abnormalities on high-resolution scans.

Functional MRI (fMRI) is another tool frequently employed in the evaluation of patients with epilepsy. Classically, fMRI has been used to map motor, speech, auditory, and visual areas with the goal of avoiding them during surgical resection. Areas of activation are identified by blood-oxygen-level-dependent (BOLD) response or increased blood flow to an identified region while performing a specific task. It is critical that the specific tasks used during fMRI are appropriate to the age and education level of the patient, as responses are partially dependent on this (21) and responses may be attenuated by tasks that are too simple or too complex (22,23). Functional MRI is limited in terms of seizure localization, as only a few case reports exist of patients incidentally having a seizure while undergoing BOLD sequence imaging. More commonly, reflexive seizures, those that occur following a stimulus, such as flashing lights or excessive heat, can be provoked during imaging for localization purposes, as increased blood flow will be present to the epileptogenic region. The simultaneous use of scalp EEG and fMRI to localize interictal discharges was successful in identifying the epileptogenic region in 60% of cases in one report (24).

Magnetoencephalography

MEG is a more recent noninvasive method of epileptic focus identification. This imaging modality detects magnetic fields produced by the brain’s electrical activity. The signal is created by cortical dendrites and is best detected when oriented tangentially to the skull’s surface; signals from deeper structures are not detected as well as those from more superficial cortical regions. This modality is limited by regional availability and cost, but has some advantages in comparison to EEG. First, MEG is more sensitive than EEG in detecting smaller epileptic foci, with a threshold of 4–8 vs. 10–15 cm2 for scalp EEG (25). Interictal MEG

epileptiform discharges, including activity from insular cortex (26-28), may be seen in approximately 50% of patients without detectable interictal epileptiform discharges on scalp EEG (29-31), which makes MEG particularly useful in guiding the placement of intracranial electrodes in patients without a structural lesion detectable by MRI. It is also advantageous compared with scalp EEG recordings for the detection and lateralization of interhemispheric epileptiform activity (32-34) and can detect interictal mesial temporal lobe discharges in as many as 85% of patients with mesial temporal lobe epilepsy (35). In summary, MEG may provide critical noninvasive localizing data when this cannot be done with EEG and MRI alone (36).

Positron emission tomography (PET)

PET using fluorine 18 fluorodeoxyglucose (FDG) is a study of brain metabolism and has a role in epileptogenic focus localization, especially when structural MRI is unrevealing. The brain’s primary energy source is glucose, and the labeled glucose may reveal areas of relative hypo- or hyper-metabolism with PET imaging. Hypometabolism occurs at an epileptic focus in an interictal state and is the result of neuronal loss, decreased synaptic activity, or decreased activity of blood–brain barrier glucose transport receptors (37-39). Because of the typical infrequency of seizure activity, the test is typically performed in an interictal state, but EEG is usually performed concurrently to determine whether seizure activity occurs during the examination. If a seizure occurs during the study, the EEG can correlate areas of possible glucose hypermetabolism and the epileptic focus. One limitation of FDG-PET imaging is that the area of glucose hypometabolism, or functional deficit zone, is often larger than the focal epileptic zone (40). PET localization plays the greatest role in MRI-occult epilepsy or in children with discordant noninvasive data between MRI and EEG studies. It is critical to note that regions of hypometabolism cannot differentiate the primary epileptogenic zone from secondary foci (41).

Single-photon emission computed tomography (SPECT)

SPECT is a noninvasive, metabolic imaging study similar to PET, with the distinction that it can be performed peri-ictally. Ictal SPECT is completed by injection of a radioisotope at the time of seizure onset. To conduct the study, children are admitted to the hospital, and long-term video EEG is placed. A seizure is confirmed by EEG and



at that time the radioisotope is injected, and imaging is completed within subsequent hours. Interictal imaging is completed at a separate time for digital subtraction to identify areas of hypermetabolism during seizure onset. If SPECT and PET localization are concordant with EEG and MRI results, seizure freedom after surgery is more likely than if these studies are discordant (42). However, technical details may confound interpretation of the results, including the length of time between seizure onset and radioisotope administration, during which propagation of the seizure may occur. Children with focal cortical dysplasia, including those with a “normal” structural MRI, have higher rates of seizure freedom with complete resection of the perfusion abnormality identified by SPECT (43).

Intracranial electroencephalography (EEG)

Intracranial EEG is an invasive measure to identify an epileptic zone that incorporates subdural EEG strip, grid, and depth electrode placement via craniotomy and stereotactic depth electrode insertion (Figure 1). Intracranial EEG is often required if lateralization or localization of an epileptic focus has not been identified using noninvasive methods and also facilitates cortical stimulation mapping of functionally eloquent cortex. Although this modality is the gold standard of epileptic focus localization, limitations exist. For example, general anesthesia, the definitive treatment of status epilepticus, is required for intracranial electrode placement and has a variable impact on seizure activity (44).

Stereo EEG (SEEG), which involves the placement of multiple (often bilateral) depth electrodes, is commonly used in children in whom accurate lateralization or localization cannot be achieved with noninvasive diagnostic means. In one report from a single institution, 18 children underwent depth electrode placement because scalp EEG results were unclear or indicated discordant localization of an epileptic focus. An epileptic zone was identified in 15/18 patients, and resection of an area encompassing the epileptic zone plus 5 mm in all directions was undertaken without further electrocorticography. All patients who underwent resection were seizure-free at the one-year time point (45). Subdural strip electrodes have a similar goal of lateralization or localization but can be placed through burr holes only. Regardless of the technique, intracranial surveys often require subsequent craniotomy and grid placement for more precise localization once regional seizure onset is

identified. Craniotomy with insertion of large subdural electrode

arrays requires general localization of the epileptic zone, either based on concordant noninvasive data or from a previous intracranial survey operation. Various electrode combinations are available, including dense grid electrodes (5 mm between platinum contacts) or double-sided interhemispheric grid electrodes. In certain cases, interictal recordings under total intravenous anesthesia in the operating room are sufficient to make surgical decisions. Frequently, however, staged craniotomy with long-term seizure monitoring to capture ictal onset and allow cortical stimulation mapping of functional eloquent cortex is required (46,47). Nearly two decades ago, Davies and colleagues described their experience using MRI to evaluate subdural and depth electrodes without complication (48). At our institution, an MRI is completed on postoperative day 1 to verify grid location and to identify possible surgical complications including hemorrhage or ischemia (Figure 1).

The advantages to grid placement include dense electrode coverage in the absence of a structural lesion identified by MRI, resolution of discordant noninvasive testing, evaluating the relationship of a structural lesion to an epileptic zone, evaluation of patients with dual pathology or multifocal epilepsy, and extraoperative awake cortical stimulation mapping to identify primary cortex and map eloquent function (49). The risks of staged craniotomy and placing large electrode arrays include intracranial hemorrhage, compression of cortical vascular structures causing cerebral edema and ischemia, as well as cerebrospinal fluid leak and meningitis. Large single-center series report complication rates between 10% and 20% (50,51).

Surgical decision-making

Epilepsy surgery requires a multidisciplinary team including a pediatric epileptologist, a pediatric neurosurgeon, and a neuropsychologist. Pediatric neuroradiologists, critical care specialists, behavioral health specialists, and a program coordinator are extremely valuable adjuncts. Dedicated pediatric epilepsy surgery conferences for detailed review of all component tests of the presurgical evaluation together with multidisciplinary clinics facilitate optimizing surgical decisions and communication with patients and families. Prior to surgical intervention, neuropsychological evaluation is mandatory. Neuropsychologists provide objective, baseline testing to identify individual cognitive



strengths and deficits, anticipate postoperative deficits, and provide information regarding postoperative rehabilitation and education (25).

Because the primary goal of epilepsy surgery in children is seizure freedom, the previous section concentrated on methods for localizing an epileptic focus in patients with partial seizures with the goal of resection of the epileptogenic zone. Secondary goals of epilepsy surgery include palliation by decreasing seizure frequency and improving quality of life, cognitive development, and functional independence.

Focal lesions

In the context of a discrete lesion on MRI with a corresponding epileptic focus on EEG, the goal is typically gross total resection of the lesion. If suspicion exists that the ictal focus may extend beyond the borders of the MRI abnormality, further testing with intracranial EEG is possible. This may also be desirable if the lesion is near eloquent cortex. Noninvasive functional mapping such as fMRI is often useful to localize eloquent function preoperatively and determine whether cortical

Figure 1 Intracranial eletroencephalography in two patients. (A) Intraoperative photograph before closure after right craniotomy and placement of intracranial electrodes for long-term seizure monitoring in a 15-month-old girl showing a dense central 64-contact grid electrode with 5 mm between contacts (arrow). This “mini-grid” is frequently used near eloquent cortex to optimize extraoperative cortical stimulation mapping of motor function in very young children with immature myelination; (B) axial and (C) coronal T1-weighted spoiled gradient (SPGR) MR images for patient in A on postoperative day 1; (D) intraoperative photograph before closure after right craniotomy and placement of intracranial electrodes for seizure monitoring in a 17-year-old girl showing 32-contact double-sided interhemispheric electrode array (arrows); (E) coronal and (F) sagittal T1-weighted SPGR MR images for patient in B on postoperative day 1.

A B C

D E F



stimulation mapping is required. In younger children, task-based fMRI may be especially challenging. A wide range of heterogeneous pathology may represent the ictal substrate in the setting of a solitary structural lesion such as focal cortical dysplasia, brain tumors including World Health Organization grade 1 developmental tumors such as ganglioglioma or dysembryoplastic neuroepithelial tumors (DNET), vascular lesions including cavernous malformations and arteriovenous malformations, and postinfectious etiologies and perinatal insults (25,52-55).

Hypothalamic hamartomas , which are usua l ly characterized clinically as gelastic seizures, are other discrete lesions encountered in children with DRE. EEG may demonstrate different patterns of focal or generalized seizure onset, but disconnection or resection of the hamartoma usually confers seizure freedom regardless of the patterns on the EEG. Previous microsurgical and endoscopic treatments for hypothalamic hamartoma have carried high morbidity, but over the past several years, the combination of laser ablation and disconnection with real-time MR thermography has emerged as a minimally invasive treatment option associated with excellent preliminary results (56).

Lobar lesions

Mesial temporal sclerosis is a frequent cause of DRE in adults, but less commonly identified in children. When it occurs in the pediatric population, it is most frequently in older children and adolescents (57-59). In younger children, temporal lesions including cortical dysplasia and developmental tumors like ganglioma and DNET are more common. When younger children present with mesial temporal sclerosis, dual pathology should be suspected and carefully investigated (25). In patients with a larger, more diffuse epileptogenic zone, including poorly defined cortical dysplasia as well as DRE with a normal MRI, larger regions of resection may be considered, including a lobar resection extending to the borders of primary cortex. This poses minimal risk beyond simple lesion removal if the anterior temporal and frontal lobes are involved, especially in the nondominant hemisphere. Careful functional and seizure mapping is mandatory when eloquent areas, including primary vision, language, or motor cortex, are adjacent to the ictal onset zone or possibly involved (25).

Hemispheric and multifocal lesions

Disease affecting an entire cerebral hemisphere requires

special consideration. Many patients present with catastrophic epilepsy, developmental delay, and focal neurologic deficits including hemiparesis and hemianopsia. Disconnection of the dysfunctional hemisphere will prevent further seizure propagation and allow for stable and possibly improved function of the contralateral hemisphere. Hemispheric dysplasia such as hemimegalencephaly, encephalomalacia in the context of remote middle cerebral artery infarction, Sturge-Weber syndrome, and Rasmussen encephalitis are common causes of DRE that may require hemispherectomy (60,61). Patients with pre-existing focal manifestations of hemispheric dysfunction, including hemiplegia and hemianopia, may not need additional testing if scalp EEG and MRI are convincing of a dysfunctional hemisphere, especially if it is the nondominant hemisphere. Extensive presurgical evaluation should be conducted in patients with less severe neurologic deficits, and preoperative functional mapping of language function is mandatory, especially in older children with DRE localized to the left hemisphere.

Vagus nerve stimulation (VNS)

VNS is currently FDA-approved in children 12 years and older to decrease seizure frequency. VNS is considered a second-line treatment as it is not does not produce seizure freedom but does result in a reduction of seizures. Its use is indicated in patients with DRE who are not candidates for resection or disconnection procedures. In 2011, a single-center retrospective study from New York University reviewed 141 consecutive patients who underwent VNS, 61% under the age of 12 years, with a minimum of one-year follow-up (mean, 5 years) (62). Seizure frequency was reduced by at least 50% in 64.8% of patients and was reduced by 75% in 41.4% of patients. The complication rate was 6.4%, and two-third of complications were minor. Despite the successful reduction in seizure frequency, the number of seizure medications (average 3) was not reduced (62). VNS therapy is an excellent palliative therapy in all children, including those under 12 years, who have persistent seizures after surgery or who are not candidates for focal resection with curative intent.

Corpus callosotomy

The corpus callosum, the largest white matter tract connecting the two cerebral hemispheres, allows rapid seizure propagation. Children with atonic seizures or



“drop attacks” often fall, which may lead to severe brain injury and bodily harm. Atonic seizures are a frequent component of Lennox-Gastaut syndrome and other epileptic encephalopathies (63,64). Callosotomy of the anterior two-thirds or complete corpus callosum is a surgical option for children with pharmacoresistant drop seizures who have failed or are not candidates for focal resection and who have failed a trial of VNS therapy (65,66). Corpus callosotomy has also been successful in patients with recurrent or medically refractory status epilepticus (67). Preservation of the splenium, especially in older children with good language skills, may prevent a disconnection syndrome, characterized by temporary or permanent language and memory deficits.

A recent study conducted in Sweden prospectively analyzed 31 patients with DRE treated with corpus callosotomy (68). The mean age at surgery was 13.3 years, and only one patient had no clear neurologic deficit preoperatively. Twenty-five (81%) patients had two or more different seizure types, and 18 patients suffered from atonic seizures. All patients were monitored for at least two years, and 20 patients had follow-up for more than ten years. For all seizure types, nearly half (15/31) of the patients had at least a 50% reduction in seizure frequency at two years, with three patients experiencing worsening seizures. This benefit was durable, with a mean overall reduction in seizure frequency of 68% ten years after surgery. One third of the 18 patients with atonic or drop seizures experienced complete remission at two years, while two thirds of the remaining 12 patients had at least a 50% reduction. Ten years after surgery, 10/18 (56%) patients with atonic seizures had complete resolution, 6/18 (33%) had at least 50% improvement in atonic seizure frequency, and two patients were lost to follow-up (68).

Special considerations: infants

Rates of epilepsy are highest in the infant age group (69-77), with an estimated incidence of 70.1 per 100,000 (77). Furthermore, in one third of children presenting at less than 36 months of age, the epilepsy will become drug resistant (78). As surgical and anesthetic techniques continue to improve, surgery for DRE in infants has become safer. Thus, given the natural history of DRE with seizure onset in infancy (7), early surgical intervention is preferred, including relatively large resections or disconnections when indicated. In addition to seizure remission, it may be possible to avoid the financial burden and potentially harmful side effects of antiepileptic medications during early brain development (79-84). Early

surgery also takes advantage of increased neuroplasticity in infants, which rapidly decreases with age.

A recent prospective cohort study of 47 children with a history of DRE who had epilepsy surgery before the age of four analyzed clinical outcomes at 2 and 10 years a f ter surgery ; 68% of pat ients had preoperat ive neurodevelopmental impairment. The mean age of seizure onset was 15 months, and the mean frequency was 150 seizures per month. The mean age at surgery was 25 months. The most common operations included frontal lobectomy, temporal lobectomy, and hemispherectomy (12 each); eight of the 47 patients ultimately required additional epilepsy surgery. The most common pathological substrates were malformations of cortical development. The complication rate was low: one child had an epidural abscess, one patient had pneumonia, and two children who underwent hemispherectomy required cerebrospinal fluid diversion with a shunt. Seventy percent of children (33/47) experienced a decrease of at least 75% in seizure frequency, and 21 (45%) achieved complete remission. Four children had worsening seizures. The best outcomes were seen in patients who underwent temporal lobectomy or hemispherectomy. In long-term follow-up, two children achieved late remission and four had late seizure recurrence (85).

Conclusions

DRE is a significant public health issue, with extremely high direct and indirect costs. Early age of seizure onset and DRE are major risk factors for poor cognitive development (7). Children with DRE face barriers to social integration and living independently, including driving and employment. Dedicated multidisciplinary teams of pediatric subspecialists are necessary to evaluate and treat these patients early in the course of their disease to optimize outcome. Seizure localization is important because it offers the best opportunity for complete lesion removal and seizure freedom. In patients in whom noninvasive methods of seizure localization fail to indicate a seizure focus, invasive methods can provide more detailed information. Once an epileptic focus is identified, resection or disconnection of the lesion from normal brain structures may help achieve the ultimate goal of complete seizure remission.

Acknowledgements

We thank Kristin Kraus, MSc, for her critical editorial



assistance with this paper.

Footnote


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72. Camfield CS, Camfield PR, Gordon K, et al. Incidence of epilepsy in childhood and adolescence: a population-based study in Nova Scotia from 1977 to 1985. Epilepsia 1996;37:19-23.

73. Kurtz Z, Tookey P, Ross E. Epilepsy in young people: 23 year follow up of the British national child development study. BMJ 1998;316:339-42.

74. Freitag CM, May TW, Pfafflin M, et al. Incidence of epilepsies and epileptic syndromes in children and adolescents: a population-based prospective study in Germany. Epilepsia 2001;42:979-85.

75. Olafsson E, Ludvigsson P, Gudmundsson G, et al. Incidence of unprovoked seizures and epilepsy in Iceland and assessment of the epilepsy syndrome classification: a prospective study. Lancet Neurol 2005;4:627-34.

76. Durá-Travé T, Yoldi-Petri ME, Gallinas-Victoriano F. Incidence of epilepsies and epileptic syndromes among children in Navarre, Spain: 2002 through 2005. J Child Neurol 2008;23:878-82.

77. Eltze CM, Chong WK, Cox T, et al. A population-based study of newly diagnosed epilepsy in infants. Epilepsia 2013;54:437-45.

78. Wirrell E, Wong-Kisiel L, Mandrekar J, et al. Predictors and course of medically intractable epilepsy in young children presenting before 36 months of age: a retrospective, population-based study. Epilepsia 2012;53:1563-9.

79. Jonas R, Nguyen S, Hu B, et al. Cerebral hemispherectomy: hospital course, seizure, developmental, language, and motor outcomes. Neurology 2004;62:1712-21.

80. Jonas R, Asarnow RF, LoPresti C, et al. Surgery for symptomatic infant-onset epileptic encephalopathy with and without infantile spasms. Neurology 2005;64:746-50.

81. Freitag H, Tuxhorn I. Cognitive function in preschool children after epilepsy surgery: rationale for early



Cite this article as: Ducis K, Guan J, Karsy M, Bollo RJ. Preoperative evaluation and surgical decision-making in pediatric epilepsy surgery. Transl Pediatr 2016;5(3):169-179. doi: 10.21037/tp.2016.06.02

intervention. Epilepsia 2005;46:561-7. 82. Loddenkemper T, Holland KD, Stanford LD, et al.

Developmental outcome after epilepsy surgery in infancy. Pediatrics 2007;119:930-5.

83. Skirrow C, Cross JH, Cormack F, et al. Long-term intellectual outcome after temporal lobe surgery in childhood. Neurology 2011;76:1330-7.

84. Viggedal G, Olsson I, Carlsson G, et al. Intelligence two years after epilepsy surgery in children. Epilepsy Behav 2013;29:565-70.

85. Reinholdson J, Olsson I, Edelvik A, et al. Long-term follow-up after epilepsy surgery in infancy and early childhood--a prospective population based observational study. Seizure 2015;30:83-9.


“Men regard its nature and cause as divine from ignorance and wonder, because it is not at all like to other diseases. And this notion of its divinity is kept up by their inability to comprehend it.”—Hippocrates, On the Sacred Disease, 400 BC

Nearly two and a half millennia ago, Hippocrates described epilepsy as “the sacred disease.” His hypothesis that seizures arose from an organic, physical substrate that was not understood, rather than from the divine or supernatural, was ahead of his time. Yet, despite centuries of research and innovation, superstitions about epilepsy remain deeply embedded in local cultural traditions and belief systems throughout much of the world (1). More than 50 million people worldwide have epilepsy, making it the most prevalent serious chronic neurological disorder. Seizures disproportionately affect children: the incidence is higher in infancy compared with any other age group (1,2).

Our understanding of the pathogenesis of epilepsy and its impact on the developing brain as well as our armamentarium of anti-epileptic medications to treat seizures continue to evolve. Despite profound advancements, one fifth to one third of patients have disease that remains drug resistant. Seizures that persist despite trials of two properly selected medications are deemed by the International League Against Epilepsy criteria as drug-resistant epilepsy (DRE). Once these criteria are met, it is critical that children are referred for surgical evaluation because, at that point, the likelihood of medical control is extremely low (3). Further, early age of seizure onset and pharmacoresistance are risk factors for poor cognitive development (4), and seizure freedom after surgery is

likely to rescue that downward trajectory. Unfortunately, at this time, most children with DRE still endure years of seizures before surgical evaluation, and epilepsy surgery remains among the most under-utilized therapies in modern medicine (5).

Recent advancements in the diagnosis and treatment of epilepsy are creating a paradigm shift in the surgical management of children with DRE and opening the door to a future of minimally invasive surgical therapy. High-resolution structural magnetic resonance imaging (MRI) and voxel-based morphometry algorithms allow quantitative analysis of brain structure to better identify malformations of cortical development (6). Resting-state functional MRI allows the identification of functional brain circuits and the analysis of connectivity without performing tasks. Through these techniques and many more, modern neuroimaging is rapidly evolving to identify previously undetectable lesions and map functionally eloquent neuronal circuits (6,7). The use of minimally invasive intracranial electroencephalography (EEG) recordings using stereotactic depth electrode placement, or stereo EEG (SEEG), facilitated by newly developed robotic technology to allow the efficient, accurate placement of multiple bilateral electrodes, is replacing large craniotomies for intracranial EEG recordings. Simultaneously, new computational algorithms are being developed to model three-dimensional epileptic networks based on interictal EEG data, potentially limiting the duration of electrode recordings required to map the epileptogenic zone (8,9).

Large subdural electrode arrays are still often required for cortical stimulation mapping of eloquent brain tissue,

Pediatric Epilepsy Column (Editorial)

Surgical advancements in pediatric epilepsy surgery: from the mysterious to the minimally invasive

Robert J. Bollo

Division of Pediatric Neurosurgery, Department of Neurosurgery, Primary Children’s Hospital, University of Utah School of Medicine, Salt Lake

City, UT, USA

Correspondence to: Robert J. Bollo, MD. Division of Pediatric Neurosurgery, Department of Neurosurgery, Primary Children’s Hospital, University of

Utah School of Medicine, Salt Lake City, UT, USA. Email: [email protected].


doi: 10.21037/tp.2016.05.02




especially in children who may not be able to tolerate task-based functional MRI. This is often the case in patients with epileptic lesions that border motor and language cortex, as well as for anatomic resections extending to primary cortex in non-lesional epilepsy. However, recent advancements in transcranial magnetic stimulation (TMS) are now facilitating mapping outside the operating room on an outpatient basis. TMS allows cortical stimulation mapping through the scalp, and functional maps may be imported into neuronavigation equipment in the operating room. These advances have the potential to significantly decrease the number of patients in whom multi-stage craniotomies are required for functional mapping of eloquent cortex (10,11).

Finally, the advent of MRI-guided laser interstitial thermal therapy (LITT) is quickly revolutionizing the surgical management of DRE in children. The stereotactic placement of cooled lasers of different sizes, followed by ablation of the epileptogenic zone monitored in real-time using MR thermography, has demonstrated promising efficacy in the management of deep epileptic foci in children such as hypothalamic hamartomas (12). LITT is now being used to treat a variety of epileptic lesions in children (13). Previously, minimally invasive diagnostics like SEEG were uncoupled with minimally invasive treatment approaches such as LITT. Many patients requiring SEEG have MRI-negative disease, and multi-stage craniotomies with cortical stimulation mapping and large anatomic resections were required to achieve seizure freedom.

It is easy to see how LITT and SEEG may be used together in children with multifocal epilepsy, such as tuberous sclerosis complex. Leveraging multiple new technologies—including quantitative neuroimaging, robotic-assisted SEEG, outpatient functional mapping of eloquent cortex via TMS, and minimally invasive ablation with LITT—has the potential to usher in a new era of minimally invasive surgical treatment, with the result of shorter hospital stays and decreased morbidity. Through this series of articles on the evaluation, treatment paradigms, and emerging tools in the surgical management of pediatric epilepsy, we hope readers of Translational Pediatrics (TP) come to share not simply our passion about the power of surgery to cure epilepsy, but also our excitement about the future of the field. It is our hope that continued surgical innovation will change surgical treatment strategies for more and more children from large operations and brain resections to minimally invasive therapy. Undoubtedly,

such innovation will help change the stigma associated with epilepsy surgery, allowing more children to realize a life without seizures, reach their full cognitive potential, and achieve functional independence.

Acknowledgements

The author thanks Kristin Kraus, MSc, for editorial assistance with this paper.

Footnote


References

1. Perucca E, Covanis A, Dua T. Commentary: Epilepsy is a global problem. Epilepsia 2014;55:1326-8.

2. Wilmshurst JM, Gaillard WD, Vinayan KP, et al. Summary of recommendations for the management of infantile seizures: Task Force Report for the ILAE Commission of Pediatrics. Epilepsia 2015;56:1185-97.

3. Kwan P, Arzimanoglou A, Berg AT, et al. Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia 2010;51:1069-77.

4. Berg AT, Zelko FA, Levy SR, et al. Age at onset of epilepsy, pharmacoresistance, and cognitive outcomes: a prospective cohort study. Neurology 2012;79:1384-91.

5. Engel J Jr. Why is there still doubt to cut it out? Epilepsy Curr 2013;13:198-204.

6. Kini LG, Gee JC, Litt B. Computational analysis in epilepsy neuroimaging: A survey of features and methods. Neuroimage Clin 2016;11:515-29.

7. Vadivelu S, Wolf VL, Bollo RJ, et al. Resting-state functional MRI in pediatric epilepsy surgery. Pediatr Neurosurg 2013;49:261-73.

8. Boido D, Kapetis D, Gnatkovsky V, et al. Stimulus-evoked potentials contribute to map the epileptogenic zone during stereo-EEG presurgical monitoring. Hum Brain Mapp 2014;35:4267-81.

9. Rummel C, Abela E, Andrzejak RG, et al. Resected brain tissue, seizure onset zone and quantitative EEG measures: towards prediction of post-surgical seizure control. PLoS One 2015;10:e0141023.

10. Narayana S, Rezaie R, McAfee SS, et al. Assessing motor

182 Bollo. Surgical advancements in pediatric epilepsy surgery


function in young children with transcranial magnetic stimulation. Pediatr Neurol 2015;52:94-103.

11. Babajani-Feremi A, Narayana S, Rezaie R, et al. Language mapping using high gamma electrocorticography, fMRI, and TMS versus electrocortical stimulation. Clin Neurophysiol 2016;127:1822-36.

12. Lewis EC, Weil AG, Duchowny M, et al. MR-guided laser interstitial thermal therapy for pediatric drug-resistant lesional epilepsy. Epilepsia 2015;56:1590-8.

13. Wilfong AA, Curry DJ. Hypothalamic hamartomas: optimal approach to clinical evaluation and diagnosis. Epilepsia 2013;54 Suppl 9:109-14.

Cite this article as: Bollo RJ. Surgical advancements in pediatric epilepsy surgery: from the mysterious to the minimally invasive. Transl Pediatr 2016;5(3):180-182. doi: 10.21037/tp.2016.05.02


To the Editor:

We would like to thank Drs. Rogol and Skakkebaek for their timely and insightful commentary about medical and ethical issues with regard to sperm retrieval in adolescents with Klinefelter syndrome (KS) (1); the authors present key points discussed at the recent International Workshop on Klinefelter syndrome, in addition to summarizing our pilot clinical trial investigating sperm retrieval rates in adolescents and young adults with KS published in The Journal of Pediatrics (2,3). As was acknowledged in the original manuscript, Drs. Rogol and Skakkebaek emphasize potential selection bias in the study, as the sample size was small and many of the eligible subjects declined to participate due to “lack of psychological readiness to focus on fertility”; additionally, none of the patients had been treated with testosterone, indicating a “milder” end of the spectrum (1,2). The potential impact of prior testosterone therapy and other agents on sperm retrieval in this population was identified as a necessary issue for investigation (1,4).

Prospective studies in this area have been limited due to the rarity of making the KS diagnosis early in life, in addition to challenges associated with recruiting adolescents and young adults with KS for fertility related research. According to a 2011 study by Maiburg et al., adults with KS were interested in fathering children and were willing to undergo testicular sperm extraction (TESE) (5). Recent research, however, demonstrates a discrepancy between attitudes of parents and physicians versus those of younger individuals with KS; while most parents of children with KS and pediatricians favored pursuing TESE in a pubertal minor, adolescents with KS reported a lack of interest in fertility and required at least three medical consultations

prior to becoming involved in fertility preservation (6,7). Thus, in order to successfully complete prospective studies to investigate predictors of successful TESE and the impact of exogenous testosterone or other treatments on sperm retrieval, reproductive priorities and potential barriers to acceptance of fertility preservation procedures need to be better understood in this particular population.

Most of the pediatric literature with regard to fertility has been done in oncology, where many males are able to produce an ejaculate for sperm cryopreservation. It is notable that this is generally not an option for individuals with KS, which is in itself, a potential barrier. Additionally, neurocognitive dysfunction is common in KS, and studies have shown lower quality of life and self-esteem, all of which could impact attitudes about reproductive health and willingness to participate in research studies (8). Thus, validated surveys and qualitative methodology should be implemented to further explore key factors such as reproductive concerns, romantic relationships, sexual function, and psychosocial well-being among adolescents and young adults with KS at different ages/developmental stages.

Based on current literature, the recommended age range to consider sperm retrieval among individuals with KS is 15–30 years (3,9,10). Medical professionals who care for individuals with KS have a responsibility to become educated on this topic and offer referrals to fertility specialists to (I) provide comprehensive counseling about the current options along with acknowledging their experimental nature; and (II) consider potential ethical implications in each individual case (6,11). As Drs. Rogol and Skakkebaek point out, many questions remain unanswered, including the viability and quality of sperm

Correspondence

Klinefelter syndrome: fertility considerations and gaps in knowledge

Leena Nahata1, Richard N. Yu2, Laurie E. Cohen3

1Division of Endocrinology, Nationwide Children’s Hospital, 700 Children’s Dr, Columbus, USA; 2Department of Urology, 3Division of

Endocrinology, Boston Children’s Hospital, Boston, MA, USA

Correspondence to: Leena Nahata, MD. Division of Endocrinology, Nationwide Children’s Hospital, 700 Children’s Dr, Columbus, USA.


Submitted Jun 08, 2016. Accepted for publication Jun 17, 2016.

doi: 10.21037/tp.2016.06.06


184 Nahata et al. Knowledge of Klinefelter syndrome


retrieved from this patient population after many years of freezing (1). Opportunities for early diagnosis of KS will likely increase due to increasing use of prenatal testing, and more patients and families may inquire about the potential risks/benefits of cryopreservation of sperm. Thus, longitudinal follow-up to assess utilization of the frozen sperm, pregnancy rates, and outcomes, will be critical for informing future research and clinical care.

Acknowledgements

None.

Footnote

Conflict of Interest: The original research (published in Journal of Pediatrics) was partially supported by the 2012 Boston Children’s Hospital House Officer Development Award.

Response to: Rogol AD, Skakkebaek NE. Sperm retrieval in adolescent males with Klinefelter syndrome: medical and ethical issues. Transl Pediatr 2016;5:104-6.

References

1. Rogol AD, Skakkebaek NE. Sperm retrieval in adolescent males with Klinefelter syndrome: medical and ethical issues. Transl Pediatr 2016;5:104-6.

2. Nahata L, Yu RN, Paltiel HJ, et al. Sperm Retrieval in Adolescents and Young Adults with Klinefelter Syndrome: A Prospective, Pilot Study. J Pediatr 2016;170:260-5.e1-2.

3. Nieschlag E, Ferlin A, Gravholt CH, et al. The Klinefelter

syndrome: current management and research challenges. Andrology 2016;4:545-9.

4. Mehta A, Bolyakov A, Roosma J, et al. Successful testicular sperm retrieval in adolescents with Klinefelter syndrome treated with at least 1 year of topical testosterone and aromatase inhibitor. Fertil Steril 2013;100:970-4.

5. Maiburg MC, Hoppenbrouwers AC, van Stel HF, et al. Attitudes of Klinefelter men and their relatives towards TESE-ICSI. J Assist Reprod Genet 2011;28:809-14.

6. Gies I, Tournaye H, De Schepper J. Attitudes of parents of Klinefelter boys and pediatricians towards neonatal screening and fertility preservation techniques in Klinefelter syndrome. Eur J Pediatr 2016;175:399-404.

7. Rives N, Milazzo JP, Perdrix A, et al. The feasibility of fertility preservation in adolescents with Klinefelter syndrome. Hum Reprod 2013;28:1468-79.

8. Close S, Fennoy I, Smaldone A, et al. Phenotype and Adverse Quality of Life in Boys with Klinefelter Syndrome. J Pediatr 2015;167:650-7.

9. Plotton I, Giscard d'Estaing S, Cuzin B, et al. Preliminary results of a prospective study of testicular sperm extraction in young versus adult patients with nonmosaic 47,XXY Klinefelter syndrome. J Clin Endocrinol Metab 2015;100:961-7.

10. Rohayem J, Fricke R, Czeloth K, et al. Age and markers of Leydig cell function, but not of Sertoli cell function predict the success of sperm retrieval in adolescents and adults with Klinefelter's syndrome. Andrology 2015;3:868-75.

11. Gies I, Oates R, De Schepper J, et al. Testicular biopsy and cryopreservation for fertility preservation of prepubertal boys with Klinefelter syndrome: a pro/con debate. Fertil Steril 2016;105:249-55.

Cite this article as: Nahata L, Yu RN, Cohen LE. Klinefelter syndrome: fertility considerations and gaps in knowledge. Transl Pediatr 2016;5(3):183-184. doi: 10.21037/tp.2016.06.06

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