Single Ventricle—A Comprehensive Review

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Review Single Ventricle—A Comprehensive Review

P. Syamasundar Rao

McGovern Medical School, University of Texas-Houston, Children’s Memorial Hermann Hospital, 6410 Fannin Street, UTPB Suite # 425, Houston, TX 77030, USA; [email protected] or [email protected]; Tel.: +1-713-500-5738; Fax: +1-713-500-5751

Abstract: In this paper, the author enumerates cardiac defects with a functionally single ventricle, summarizes single ventricle physiology, presents a summary of management strategies to address the single ventricle defects, goes over the steps of staged total cavo-pulmonary connection, cites the prevalence of inter-stage mortality, names the causes of inter-stage mortality, discusses strategies to address the inter-stage mortality, reviews post-Fontan issues, and introduces alternative approaches to Fontan circulation.

Keywords: single ventricle; double-inlet left ventricle; hypoplastic left heart syndrome; tricuspid atresia; unbalanced atrioventricular septal defect; mitral atresia with normal aortic root; heterotaxy syndromes; Down syndrome; Fontan circulation; biventricular repair

1. Introduction The term “single ventricle” is generally utilized to describe any congenital heart defect (CHD) with one functioning ventricle, and these are: double-inlet left ventricle (DILV), single ventricle, common ventricle, and univentricular atrio-ventricular (AV) connection [1]. Other lesions, namely hypoplastic left heart syndrome (HLHS), tricuspid atresia, unbal- Citation: Rao, P.S. Single anced AV septal defect, mitral atresia with normal aortic root, and heterotaxy syndromes Ventricle—A Comprehensive Review. with one functioning ventricle may now be added to this group. The objectives of this Children 2021, 8, 441. https:// paper are to specify congenital heart defects with one functioning ventricle, describe single doi.org/10.3390/children8060441 ventricle physiology, present management strategies to address the single ventricle defects, cite the prevalence of and name the causes of inter-stage mortality, discuss strategies to Academic Editor: Bibhuti B. Das address the inter-stage mortality, review post-Fontan issues, and to introduce alternative approaches to Fontan palliation. Received: 28 April 2021 Accepted: 21 May 2021 2. Cardiac Defects with Functionally Single Ventricle Published: 24 May 2021 As mentioned above, there are number of cardiac defects that have a functionally single ventricle and are candidates for single ventricle/Fontan repair. These will be described Publisher’s Note: MDPI stays neutral briefly. The order of presentation is arbitrary. with regard to jurisdictional claims in published maps and institutional affil- 2.1. Hypoplastic Left Heart Syndrome iations. The phrase “HLHS” was first suggested by Noonan and Nadas [2] to characterize a very small left ventricle with poorly developed aortic and mitral valves. The left ventricle (LV) is usually a slit-like cavity (Figure1) with thick muscle, especially when mitral atresia co-exists. The aortic valve is atretic or markedly narrowed with annular hypoplasia. Copyright: © 2021 by the author. Similarly, the mitral valve is markedly stenotic, hypoplastic or atretic (Figure1). The LV Licensee MDPI, Basel, Switzerland. is very small when the mitral valve is open. Endocardial fibroelastosis is often present. This article is an open access article Hypoplasia of the ascending aorta is present, and its diameter is usually 2–3 mm (Figure2). distributed under the terms and However, it is adequate to supply ample coronary blood flow retrogradely. The left atrium conditions of the Creative Commons is very small (Figure1). The interatrial septum is usually thickened with a small patent Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ foramen ovale (PFO) and rarely the atrial septum is intact. A patent ductus arteriosus 4.0/). (PDA) is classically present and is necessary for the baby to survive [3–5].

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Children 2021, 8, 441 2 of 31 small patent foramen ovale (PFO) and rarely the atrial septum is intact. A patent ductus small patent foramen ovale (PFO) and rarely the atrial septum is intact. A patent ductus arteriosus (PDA) is classically present and is necessary for the baby to survive [3–5]. arteriosus (PDA) is classically present and is necessary for the baby to survive [3–5].

FigureFigure 1. 1.Echocardiogram Echocardiogram in anin an apical apical 4-chamber 4-chamber view view of a babyof a baby with hypoplasticwith hypoplastic left heart left syn- heart syn- Figure 1. Echocardiogram in an apical 4-chamber view of a baby with hypoplastic left heart syndrome,drome, showing showing a strikingly a strikingly small, small, slit-like slit- (thicklike (thick arrow) arrow) left ventricle left ventricle (LV), obviously (LV), obviously enlarged andenlarged and drome, showing a strikingly small, slit-like (thick arrow) left ventricle (LV), obviously enlarged and hypertrophiedhypertrophied right right ventricle ventricle (RV), (RV), and and a dilated a dilated right right atrium atrium (RA). The(RA). atretic The atretic mitral valvemitral (MV) valve (MV) hypertrophied right ventricle (RV), and a dilated right atrium (RA). The atretic mitral valve (MV) (thin(thin arrow) arrow) and and hypoplastic hypoplastic left atriumleft atrium (LA) are(LA) also are seen. also seen. (thin arrow) and hypoplastic left atrium (LA) are also seen.

Figure 2. Echocardiogram in a parasternal long short axis view of a baby with hypoplastic left heart FiguresyndromeFigure 2. 2.Echocardiogram Echocardiogram illustrates a small in a in parasternal lefta parasternal ventricle long (LV), shortlong axisashort severely view axis of viewhypoplastic a baby of witha baby hypoplasticaorta with (Ao) hypoplastic left(arrow heart), andleft heartan syndromeenlargedsyndrome illustratesright illustrates ventricle a small a small (RV). left left ventricleLA, ventricle left atrium. (LV), (LV), a severely a severely hypoplastic hypoplastic aorta (Ao) aorta (arrow), (Ao) (arrow and an), and an enlargedenlarged right right ventricle ventricle (RV). (RV). LA, leftLA, atrium. left atrium. 2.2. Tricuspid Atresia 2.2.2.2. Tricuspid Tricuspid Atresia Atresia Tricuspid atresia (TA) is a cyanotic CHD and is characterized as a congenital ab- TricuspidTricuspid atresia atresia (TA) (TA) is a cyanotic is a cyanotic CHD and CHD is characterized and is characterized as a congenital as a absence congenital ab- orsence agenesis or agenesis of the morphologic of the morphologic tricuspid valvetricuspid [6,7]. valve The right [6,7]. atrium The right is dilated atrium and is thedilated and sence or agenesis of the morphologic tricuspid valve [6,7]. The right atrium is dilated and tricuspidthe tricuspid valve is valve atretic is (Figure atretic3). (Figure In the most 3). common In the most muscular common variety, muscular atretic tricuspid variety, atretic the tricuspid valve is atretic (Figure 3). In the most common muscular variety, atretic valvetricuspid is seen valve as a localizedis seen as ﬁbrous a localized thickening fibrous or a dimple thickening in the or ﬂoor a dimple of the right in the atrium floor of the tricuspid valve is seen as a localized fibrous thickening or a dimple in the floor of the atright the anticipatedatrium at the site anticipated of the tricuspid site valveof the [ 8tricuspid–12]. An atrialvalve septal[8–12]. defect An atrial is necessary septal defect is right atrium at the anticipated site of the tricuspid valve [8–12]. An atrial septal defect is fornecessary survival for and survival is typically and a stretchedis typically PFO. a stretched The mitral PFO. valve The is usually mitral bicuspid valve is and usually bi- morphologicallynecessary for survival a mitral valve. and is The typically LV is evidently a stretched a morphological PFO. The LV,mitral but it valve is enlarged is usually bicuspid and morphologically a mitral valve. The LV is evidently a morphological LV, but cuspid and morphologically a mitral valve. The LV is evidently a morphological LV, but it is enlarged and hypertrophied [8–12]. Usually, a ventricular septal defect (VSD) is it is enlarged and hypertrophied [8–12]. Usually, a ventricular septal defect (VSD) is present. The VSD is most commonly in the muscular ventricular septum [13,14]. The present. The VSD is most commonly in the muscular ventricular septum [13,14]. The

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and hypertrophied [8–12]. Usually, a ventricular septal defect (VSD) is present. The VSD is most commonly in the muscular ventricular septum [13,14]. The right ventricle (RV) isright hypoplastic ventricle and (RV) is not is hypoplastic sufﬁciently large and inis not size sufficiently to support pulmonary large in size circulation. to support The pulmo- originnary ofcirculation. great arteries The is origin variable of andgreat on arteries the basis is ofvariable which aand classiﬁcation on the basis of this of which disease a clas- entitysification was developed of this disease [6]: Type entity I, normally was developed related great [6]: Type arteries; I, normally Type II, d-transposition related great arteries; of theType great II, arteries; d-transposition Type III, malpositions of the great of arteries; the great Type arteries III, other malpositions than d-transposition; of the great and arteries Typeother IV, than truncus d-transposition; arteriosus [6]. and Some Type of the IV, echocardiographic truncus arteriosus features [6]. Some are demonstratedof the echocardio- ingraphic Figure3 features. are demonstrated in Figure 3.

FigureFigure 3. 3.Echocardiograms Echocardiograms in apicalin apical four-chamber four-chamber views views of an of infant an infant with with tricuspid tricuspid atresia atresia demonstratingdemonstrating a dilated a left dilated ventricle left (LV),ventricle a small (LV), right a small ventricle right (RV), ventricle and a (RV dense), and band a dense of echoes band at theof echoes at the site where the tricuspid valve echo should be (ATV; thick arrow). Images with closed (A) and site where the tricuspid valve echo should be (ATV; thick arrow). Images with closed (A) and open open (B) mitral valve are shown; the tricuspid valve remains closed in both situations. A ventricu- (B) mitral valve are shown; the tricuspid valve remains closed in both situations. A ventricular septal lar septal defect (VSD; thin arrow) is also shown. LA, Left atrium; RA, Right atrium. defect (VSD; thin arrow) is also shown. LA, Left atrium; RA, Right atrium.

2.3.2.3. Double-Inlet Double-Inlet Left Left Ventricle Ventricle InIn DILV, DILV, the the ventricle ventricle most most frequently frequently has has LV LVmorphology, morphology, although although RV, mixed, RV, mixed, indeterminate,indeterminate, or or undifferentiated undifferentiated morphologies morphologies have have been been reported reported [1,15 ]. [1,15]. The main The main ventricleventricle is is largely largely a a morphological morphological LV LV with with an an outlet outlet chamber chamber connected connected to to it it which which has hasa RV a RV morphology. morphology. The The AV AV valves valves may may be be normal (Figure4 4),), or or one one of of them them may may be be hy- hypoplastic,poplastic, stenotic, stenotic, or or even even atretic. atretic. The The great arteries areare mostmost frequentlyfrequently transposed transposed and andthe theaorta aorta arises arises from from the the hypoplastic hypoplastic RV, RV, and and the the pulmonary pulmonary artery artery comes comes off off the main main LV chamber. L-transposition happens more often than d-transposition. The great LV chamber. L-transposition happens more often than d-transposition. The great vessels vessels are normally related in 30% of cases. Double-outlet RV may be seen, in which both are normally related in 30% of cases. Double-outlet RV may be seen, in which both great great vessels arise from the rudimentary RV. Pulmonary stenosis is present in two thirds of patientsvessels and arise such from stenosis the rudimentary is seen irrespective RV. Pulmonary of the great arterystenosis relationship. is present Thein two stenosis thirds of maypatients be at and the valvarsuch stenosis or subvalvar is seen level, irrespective or the pulmonary of the great valve/artery artery relationship. may be atretic. The steno- Subaorticsis may obstructionbe at the valvar maybe or present subvalvar in patients level, or with the transposition pulmonary ofvalve/art the greatery arteries may andbe atretic. isSubaortic due to the obstruction stenosis of may the VSD be present or, more in accurately,patients with bulbo-ventricular transposition of foramen. the great Patients arteries and withis due subaortic to the obstructionstenosis of the often VSD have or, associated more accurately, aortic coarctation bulbo-ventricular [1,15]. foramen. Patients with subaortic obstruction often have associated aortic coarctation [1,15].

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Figure 4. Echocardiograms in apical four-chamber views of a baby with double inlet left ventricle Figure 4. Echocardiograms in apical four-chamber views of a baby with double inlet left ventricle Figure(DILV) 4. withEchocardiograms closed (A) and in open apical (B) four-chamber atrioventricular views valves ofa (arrows). baby with The double outlet inlet chamber left ventricle is not (DILV) with closed (A) and open (B) atrioventricular valves (arrows). The outlet chamber is not (DILV)visualized with in closed this view. (A) and LA, openleft atrium; (B) atrioventricular RA, right atrium. valves Reproduced (arrows). from The outletreference chamber [15]. is not visualized in this view. LA, left atrium; RA, right atrium. Reproduced from reference [15]. visualized in this view. LA, left atrium; RA, right atrium. Reproduced from Reference [15]. 2.4. Unbalanced Atrioventricular Septal Defect 2.4. Unbalanced Atrioventricular Septal Defect 2.4. UnbalancedDefects in Atrioventricular the atrial and ventricular Septal Defect septae, together with defects in one or both AV valves,DefectsDefects described in in the the in atrial atrial the and pastand ventricular asventricular common septae, septae,AV canal together together or complete withwith defectsdefects endocardial inin oneone orcushionor both both AV AVde- valves,fectvalves, [16], described described are now in generallyin thethe pastpast called asas common common AV septal AVAV defects canal canal or or(AVSDs). complete complete In endocardial theendocardial complete cushion cushion form, there de-de- fectisfect usually [ 16[16],], are are a now largenow generally generallyinlet VSD called called contiguous AV AV septal septal with defects defects a primum (AVSDs). (AVSDs). atrial In theInseptal the complete complete defect form, (ASD), form, there and there is a usuallycommonis usually a large AV a large valve inlet inlet VSDwith VSD contiguousa single contiguous valve with a nnulus.with a primum a primum A variant atrial atrial septal of this, septal defect called defect (ASD), the (ASD),intermediate and a com-and a monform,common AV has valve AV the valve with same awith single features a single valve but annulus.valve with a distinctnnulus. A variant A and variant of separate this, of called this, right thecalled and intermediate the left intermediate AV valves. form, hasTransitionalform, the hassame the featuresand same partial but features forms with distinct butare also with and described, distinct separate and and right separateare and similar left right AVto or valves. and the leftsame Transitional AV as valves.ostium andprimumTransitional partial ASDs. forms and areCompletepartial also forms described, AVSDs are also andare described, are also similar categorized and to or are the basedsimilar same as on to ostium or the the ventricular primumsame as ostium ASDs. sizes, Completenamelyprimum balanced AVSDsASDs. Complete are and also unbalanced categorized AVSDs (Figureare based also on5) categorized[17]. the ventricular Unbalanced based sizes, AVSDs on namely the comprise ventricular balanced 10 sizes,– and15% unbalancedofnamely all complete balanced (Figure AVSDs. and5)[ 17unbalanced The]. Unbalanced unbalanced (Figure AVSDs types 5) [17]. may comprise Unbalanced be LV 10–15%-dominant AVSDs of all with completecomprise a large AVSDs. 10LV– 15%and Thesmallof all unbalanced completeRV, or RV typesAVSDs.-dominant may The be with unbalanced LV-dominant a large R typesV withand may small a large be LV LV (Figure- anddominant small 5). RV RV,with-dominant or a RV-dominant large LVAVSDs and witharesmall more a largeRV, frequently or RV RV and-dominant small seen LV [17]. with (Figure a large5). RV-dominant RV and small AVSDs LV (Figure are more 5). RV frequently-dominant seen AVSDs [ 17]. are more frequently seen [17].

FigureFigure 5. 5.Echocardiograms Echocardiograms in in apical apical four-chamber four-chamber views views of of an an infant infant with with complete complete atrioventricular atrioventricu- larFigure septal 5. Echocardiogramsdefect with marked in hypoplasiaapical four- ofchamber the left views ventricle of an (LV). infant LV with in diastole complete (A) atrioventricu- and in systole septal defect with marked hypoplasia of the left ventricle (LV). LV in diastole (A) and in systole (B) (B)lar septalare shown. defect LA, with left marked atrium; hypoplasia RA, right atrium; of the left RV, ventricle right ventricle. (LV). LV in diastole (A) and in systole are(B) shown. are shown. LA, leftLA, atrium;left atrium; RA, rightRA, right atrium; atrium; RV, rightRV, right ventricle. ventricle. 2.5.2.5. Mitral Mitral Atresia Atresia with with Normal Normal Aortic Aortic Root Root 2.5. Mitral Atresia with Normal Aortic Root MitralMitral atresia atresia may may be be seen seen with with aortic aortic atresia atresia or or a a normal normal aortic aortic root; root; the the former former is is Mitral atresia may be seen with aortic atresia or a normal aortic root; the former is generallygenerally characterized characterized as as HLHS HLHS which which was was discussed discussed in in a a preceding preceding section. section. In In this this generally characterized as HLHS which was discussed in a preceding section. In this segment,segment, mitralmitral atresia atresia with with normal normal aortic aortic root root will will be be reviewed. reviewed. While While this this division division is is arbitrary,arbitrary,segment, it mitralit is is considered considered atresia with appropriate appropriate normal [aortic 18[18]] because because root will of of the bethe differencesreviewed. differences While in in therapy therapy this division for for these these is arbitrary, it is considered appropriate [18] because of the differences in therapy for these

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twotwo defects, defects, in in that that HLHS HLHS babies babies almost almost always always require require the the Norwood Norwood procedure procedure [19 ,20[19,20]] in thein the neonatal neonatal period, period, while while babies babies with with mitral mitral atresia atresia with normalwith normal aortic aortic root need root differentneed dif- typesferent of types intervention of intervention at different at different ages based ages on based the associated on the associated cardiac defectscardiac [defects18]. Mitral [18]. atresiaMitral withatresia normal with aorticnormal root aortic is an root uncommon is an uncommon complex complex CHD and CHD is usually and is associatedusually as- withsociated several with other several defects. other The defects. atretic The mitral atretic valve mitral may bevalve an absent may be AV an connection absent AV or con- an imperforatenection or an valve imperforate membrane. valve The membrane. left atrium The (LA) left is hypoplasticatrium (LA) or is smallhypoplastic (Figure or6) andsmall the(Figure right 6) atrium and the is enlarged right atrium and is hypertrophied. enlarged and Ahypertrophied. PFO or ASD isA generally PFO or ASD seen; is agenerally PFO in 2/3rdsseen; a of PFO patients in 2/3rds and anof ASDpatients in 1/3rd. and an A ASD restrictive in 1/3rd. atrial A septalrestrictive defect atrial may septal be present defect and,may rarely, be present atrial and, septum rarely, is intact; atrial in septum such cases is intact; the levoatriocardinal in such cases the vein levoatriocardinal may help to decompressvein may help the LA.to decompress A single ventricle the LA. is mostA single commonly ventricle associated is most commonly ventricular associated anatomy, althoughventricular in aanatomy, few cases although there are in two a few ventricles. cases there If two are ventriclestwo ventricles. are present, If two theventricles LV is smallare present, and communicates the LV is small with and the RVcommunicates via a VSD which with the is usually RV via small a VSD (Figure which6). is The usually RV issm alwaysall (Figure enlarged 6). and The hypertrophied. RV is always enlargedTransposition and of hypertrophied. the great vessels Transposition is frequently of seen. the Double-outletgreat vessels is right frequently ventricle seen. is present Double in-outlet some right babies. ventricle In most is present patients in the some pulmonary babies. In valvemost ispatients normal the and pulmonary not stenotic. valve However, is normal in 25–30% and not of stenotic cases valvar. However, and/or in subvalvar25–30% of stenosiscases valvar or atresia and/or is subvalvar seen. The stenosis aortic valve or atresia and aorticis seen. root The are aortic near valve normal and inaortic size root by deﬁnition.are near normal Coarctation in size of by the definition. aorta or interrupted Coarctation aortic of the arch aorta is seenor interrupted in nearly 30% aortic of arch cases. is Such aortic obstruction is seen only in subjects with a normal pulmonary valve. PDA is seen in nearly 30% of cases. Such aortic obstruction is seen only in subjects with a normal seen in nearly 80% of patients [15,18]. pulmonary valve. PDA is seen in nearly 80% of patients [15,18].

FigureFigure 6. 6. Echocardiograms in in modified modiﬁed four four-chamber-chamber views views of oftwo two infants infants with with mitral mitral atresia, atresia, demonstrating atretic mitral valves (AMV), indicated by thick arrows. A small left atrium (LA) and demonstrating atretic mitral valves (AMV), indicated by thick arrows. A small left atrium (LA) left ventricle (LV) and a large right ventricle (RV) are also seen. The thin arrow in (B) shows a re- and left ventricle (LV) and a large right ventricle (RV) are also seen. The thin arrow in (B) shows a strictive patent foramen ovale (PFO). All four chambers were shown in A while B focuses on the restrictiveatria. Reproduced patent foramen from referen ovalece (PFO). [15]. All four chambers were shown in (A) while (B) focuses on the atria. Reproduced from Reference [15].

2.6.2.6. Other Other Heart Heart Defects Defects with with Single Single Ventricle Ventricle Physiology Physiology ThereThere are are other other cardiac cardiac defects defect thats that may may have have functionally functionally one one ventricle. ventricle. These These will will be briefed.be briefed.

2.6.1.2.6.1. Pulmonary Pulmonary Atresia Atresia with with Intact Intact Ventricular Ventricular Septum Septum SomeSome children children with with pulmonary pulmonary atresia atresia with with intact intact ventricular ventricular septum septum have have severe severe hypoplasiahypoplasia of of the the RV, RV, infudibular infudibular atresia atresia or RV-dependantor RV-dependant coronary coronary circulation circulation and become and be- candidatescome candidates for single for ventriclesingle ventricle repair [repair21–24 ].[21 Similarly,–24]. Similarly, patients patients who end-up who end with-up very with smallvery RVssmall despite RVs despite transcatheter transcatheter and/or and/or surgical surgical procedures procedures to improve to improve the RV the size RV will size alsowill join also this join group this group [21–24 [21]. –24].

2.6.2.2.6.2. Ebstein’s Ebstein’s Anomaly Anomaly of of the the Tricuspid Tricuspid Valve Valve SomeSome severe severe forms forms of of Ebstein’s Ebstein’s anomaly anomaly of of the the tricuspid tricuspid valve valve have have extremely extremely small small RVs,RVs, unable unable to to support support pulmonary pulmonary circulation, circulation, are are also also candidates candidates for for single single ventricle ventricle repairrepair [ 25[25––2727].].

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2.6.3.2.6.3. Heterotaxy Heterotaxy Syndromes Syndromes SomeSome patients patients with with asplenia asplenia and and polysplenia polysplenia syndromes syndromes have have only only one one functioning functioning ventricleventricle [ 28[28,29],29] and and become become candidates candidates for for single single ventricle ventricle repair repair consideration. consideration.

3.3. Single Single Ventricle Ventricle Physiology Physiology InIn normal normal subjects subjects the the circulation circulation is in is series in series (Figure (Figure7); the vena 7); the caval vena blood caval is emptied blood is intoemptied the right into atriumthe right (RA), atrium and (RA), from thereand from is passed there onis topassed the RV, on andto the pulmonary RV, and pulmo- artery (PA)nary and artery is transported (PA) and is into transported the lungs into for the oxygenation. lungs for oxy Fromgenation. there, it From is returned there, it to is the re- LA,turned LV, andto the aorta LA, and LV,is and passed aorta on and to theis passed body foron deliveryto the body ofoxygen for delivery and nutrients. of oxygen The and ≥ resultantnutrients. systemic The resultant arterial systemic saturation arterial is 96%. saturation The blood is ≥96%. is returned The blood back is to returned the vena back cavae to andthe thevena cycle cavae is repeatedand the cycle (Figure is repeated7). (Figure 7).

Normal oxygen saturation ≥ 96%

Figure 7. Diagram illustrating normal circulation in series (see the text) resulting systemic arterial Figure 7. Diagram illustrating normal circulation in series (see the text) resulting systemic arterial oxygen saturation of ≥96%. oxygen saturation of ≥96%.

ByBy contrast, contrast, in in babies babies with with single single ventricle, ventricle, the the systemic systemic (SBF) (SBF) and and pulmonary pulmonary (PBF) (PBF) bloodblood ﬂow flow returns returns mix mix with with each each other other in in the the single single functioning functioning ventricle ventricle (Figure (Figure8) 8 with) with consequentconsequent lower lower systemic systemic oxygen oxygen saturations saturations [30 ]. [30]. The The single single ventricle ventricle then provides then pro bothvides theboth SBF the and SBF PBF and (Figure PBF (8Figure). This 8 admixture). This admixture in the single in the ventricle single ventricle causes systemic causes arterialsystemic arterial oxygen desaturation. The O2 saturations vary between 75% and 85%, depending oxygen desaturation. The O2 saturations vary between 75% and 85%, depending upon the quantityupon the of quantity PBF and of pulmonary PBF and pulmonary to systemic to ﬂow systemic ratio (Qp:Qs).flow ratio (Qp:Qs).

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Figure 8. Diagrammatic portrayal of single ventricle circulation; the blood from both the lungs and Figure 8. Diagrammatic portrayal of single ventricle circulation; the blood from both the lungs and body return to the single ventricle; this mixed blood is redistributed to the lungs (Qp) and body body return to the single ventricle; this mixed blood is redistributed to the lungs (Qp) and body (Qs). (Qs). Reproduced with permission from reference [30]. Reproduced with permission from Reference [30]. The PBF is either derived from the pulmonary artery (PA) coming off of the single The PBF is either derived from the pulmonary artery (PA) coming off of the single ventricle or from the level of the great vessels (patent ductus arteriosus, surgically placed ventricle or from the level of the great vessels (patent ductus arteriosus, surgically placed aorta-pulmonaryaorta-pulmonary artery artery shunt shunt (or (or RV RV to to PA PA non-valved non-valved conduit), conduit), or or aorto-pulmonary aorto-pulmonary collateralcollateral vessels). vessels). The The SBF SBF is is either either unobstructed unobstructed or or obstructed. obstructed. BasedBased on on such such a thought,a thought, these these patients patients may may be grouped be grouped into theinto following the following subsets subsets [30]; this[30]; classification this classification is helpful is helpful in determining in determining the type the of type therapy of therapy that a given that patienta given needs.patient needs. Group 1: Unobstructed Systemic Blood Flow Group 1: Unobstructed Systemic Blood Flow 1A: Unobstructed SBF with unobstructed PBF 1B:1A: Unobstructed Unobstructed SBF SBF with with moderately unobstructed obstructed PBF PBF 1C:1B: Unobstructed Unobstructed SBF SBF with with severely moderately obstructed obstructed (or atretic) PBF PBF 1C: Unobstructed SBF with severely obstructed (or atretic) PBF Group 2: Obstructed Systemic Blood Flow Group 2: Obstructed Systemic Blood Flow In summary, the systemic and pulmonary blood flow returns mix with each other with In summary, the systemic and pulmonary blood flow returns mix with each other consequent lower systemic oxygen saturations (75–85%—Normal ≥96%). The systemic with consequent lower systemic oxygen saturations (75–85%—Normal ≥96%). The sys- and pulmonary circuits work in-parallel rather than normal in-series circulation. Markedly temic and pulmonary circuits work in-parallel rather than normal in-series circulation. increased PBF results in systemic hypo-perfusion and severely decreased PBF creates severe Markedly increased PBF results in systemic hypo-perfusion and severely decreased PBF hypoxemia. Therefore, a delicate balance of the blood flows between the two circulations creates severe hypoxemia. Therefore, a delicate balance of the blood flows between the should be preserved. two circulations should be preserved. 4. Management Strategies to Address the Single Ventricle Defects 4. Management Strategies to Address the Single Ventricle Defects Since there is only one functioning ventricle, the overall objective is to allow the func- tioningSince ventricle there (whether is only omorphologicallyne functioning rightventricle, or left) the to overall supply objective the systemic is to circulation allow the andfunctioning to connect ventricle the systemic (whether veins morphologically directly to the PAs right (Fontan or left) circulation—single to supply the systemic ventricle cir- repair).culation This and procedure to connect can’t the systemic be done inveins the directly neonate to since the PAPAs pressure (Fontan andcirculation resistance—single are high.ventricle Consequently, repair). This it isprocedure performed can’t by stagedbe done procedures. in the neonate The since types PA of procedurespressure and and re- theirsistance timing are havehigh. evolvedConsequently, over the it years,is performed as reviewed by staged elsewhere procedures [10,31. –T34he], types since of their pro- originalcedures description and their timing by Fontan, have evolved Kruetzer over and the their years, associates as reviewed [35,36 elsewhere]. Currently, [10,31 this–34 is], since their original description by Fontan, Kruetzer and their associates [35,36]. Cur- rently, this is accomplished by staged total cavo-pulmonary connection (TCPC), devised

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by de Leval and associates [37]. This TCPC is undertaken in three stages: Stages I, II, and accomplished by staged total cavo-pulmonary connection (TCPC), devised by de Leval III. and associates [37]. This TCPC is undertaken in three stages: Stages I, II, and III.

4.1.4.1. StageStage I—ManagementI—Management at at the the Time Time of of Initial Initial Presentation Presentation TheThe managementmanagement atat initialinitial presentation,presentation, typicallytypically inin the the neonatal neonatal period, period, depends depends uponupon thethe pathophysiologypathophysiology ofof thethe defectdefect itselfitself plusplus thethe associated associated cardiaccardiac abnormalities, abnormalities, namelynamely the the status status of of PBF, PBF, the the presence presence of of obstruction obstruction to to SBF, SBF, and and other other cardiac cardiac defects. defects.

4.1.1.4.1.1. StatusStatus ofof PulmonaryPulmonary Blood Blood Flow Flow TheThe PBF PBF may may be be decreased, decreased, increased, increased, or or the the PBF PBF is is adequate. adequate.

ReducedReduced Pulmonary Pulmonary Blood Blood Flow Flow (Group (Group 1C 1C above) above) InIn patients patients withwith reducedreduced PBF,PBF, the the ductus ductus arteriosus arteriosus shouldshould bebe keptkept patentpatent byby intra-intra- venousvenous infusion infusion of of prostaglandinprostaglandin EE11 (PGE(PGE11) at a dose of 0.05 0.05–0.1–0.1 mcg/kg/min. mcg/kg/min. After After the the O2 Osaturation2 saturation gets gets better, better, the the dose dose of of PGE PGE11 isis slowly, stepwise, stepwise, decreased decreased to to 0.02–0.025 0.02–0.025 mcg/kg/minmcg/kg/min to l lessenessen the adverse effects ofof thethe prostaglandins.prostaglandins. SubsequentSubsequent to to achieving achieving a a stablestable baby baby and and studies studies needed needed to to firm firm up up the the diagnosis, diagnosis, a more a more stable stable way way of supplying of supplying the PBFthe shouldPBF should be undertaken. be undertaken. Several Several methods methods of augmenting of augmenting PBF havePBF have been been utilized utilized in the in past,the pas as reviewedt, as reviewed elsewhere elsewhere [38]. Of [38]. these, Of these, modified modified Blalock–Taussig Blalock–Taussig (BT) shunt (BT) [39 shunt], ductal [39], stentingductal stenting [22,40,41 [22,40,41]], balloon, valvuloplastyballoon valvuloplasty of the pulmonary of the pulmonary valve (if thevalve major (if the obstruction major ob- isstruction at the level is at of the pulmonary level of pulmonary valve) [42– 44valve)], and [42 most–44 recently], and most connection recently of connection the RV outflow of the tractRV outflow with the tract PA with via athe non-valved PA via a non Gore-Tex-valved tube Gore [-45Tex] are tube currently [45] are availablecurrently available options. However,options. However, most surgeons most usesurgeons a modified use a BTmodified shunt byBT placingshunt by of placing a Gore-Tex of a graftGore- betweenTex graft thebetween subclavian the subclavian artery and artery the PA and on thethe samePA on side the [ 39same] (Figure side 9[39]) to (Figure address 9) pulmonary to address oligemia.pulmonary oligemia.

Figure 9. Cine-angiograms demonstrating patent Gore-Tex grafts (GG) following modified Figure 9. Cine-angiograms demonstrating patent Gore-Tex grafts (GG) following modiﬁed Blalock- Blalock-Taussig (BT) shunt surgery in two patients. Note wide-open BT shunts with good visuali- Taussig (BT) shunt surgery in two patients. Note wide-open BT shunts with good visualization of the zation of the pulmonary artery (PA) in (A) of the right (RPA) and left (LPA) pulmonary arteries in pulmonary(B). artery (PA) in (A) of the right (RPA) and left (LPA) pulmonary arteries in (B). Increased Pulmonary Blood Flow (Group 1A above) Increased Pulmonary Blood Flow (Group 1A above) A markedly elevated PBF produces congestive heart failure (CHF). These infants are initiallyA markedly stabilized withelevated anticongestive PBF produces therapy congestive [46]. This heart should failure be (CHF). followed These by banding infants are of theinitially PA [47 stabilized] (Figure 10with), irrespective anticongestive of control therapy of CHF.[46]. This should be followed by banding of the PA [47] (Figure 10), irrespective of control of CHF. Adequate Pulmonary Blood Flow (Group 1B above)

Babies with a mildly increased or near normal PBF with O2 saturations in the low 80s do not exhibit signiﬁcant symptoms and, are less cyanotic than babies with pulmonary oligemia and do not require any treatment and may be followed until Stage II.

Children 2021, 8, 441 9 of 31 Children 2021, 8, x FOR PEER REVIEW 9 of 32

FigureFigure 10.10. ((AA)) DiagrammaticDiagrammatic portrayal portrayal of of pulmonary pulmonary artery artery banding banding (PB) (PB) for for infants infants with with mark- markedly elevatededly elevated pulmonary pulmonary blood blood ﬂow andflow congestive and congestive heart heart failure. failure. (B) Selected(B) Selected cine cine frame frame form form pulmonary pulmonary artery cineangiogram in straight lateral view demonstrating constriction of the pul- artery cineangiogram in straight lateral view demonstrating constriction of the pulmonary artery monary artery (PB; arrow) in an infant who had the banding procedure. C, catheter; LPA, left (PB;pulmonary arrow) inartery; an infant NG, nasogastric who had thetube; banding PG, pig procedure.tail catheter; C, RPA, catheter; right pulmonary LPA, left pulmonary artery. artery; NG, nasogastric tube; PG, pigtail catheter; RPA, right pulmonary artery. 4.1.2.Adequate Obstructed Pulmonary Systemic Blood Blood Flow Flow(Group (Group 1B above) 2 above) Babies with a mildly increased or near normal PBF with O2 saturations in the low 80s The majority of these babies belong to HLHS syndrome or its variants and require do not exhibit significant symptoms and, are less cyanotic than babies with pulmonary Children 2021, 8, x FOR PEER REVIEWNorwood operation [19,20] with either Modiﬁed BT [39] or Sano [48,49] shunt (Figure10 of 32 11). oligemia and do not require any treatment and may be followed until Stage II. In some institutions, cardiac transplantation [50] is employed to address this lesion. 4.1.2. Obstructed Systemic Blood Flow (Group 2 above) The majority of these babies belong to HLHS syndrome or its variants and require Norwood operation [19,20] with either Modified BT [39] or Sano [48,49] shunt (Figure 11). In some institutions, cardiac transplantation [50] is employed to address this lesion.

Figure 11. Cineangiogrames demonstrating the Norwood procedure, showing the neoaorta (NAo) Figure 11. Cineangiogrames demonstrating the Norwood procedure, showing the neoaorta (NAo) and hypoplastic old aorta (HAo). The latter supplies the coronary arteries (CAs) as shown in (a). A and hypoplastic old aorta (HAo). The latter supplies the coronary arteries (CAs) as shown in (a). Blalock-Taussig (BT) shunt in seen in (b) and a Sano shunt in (c) from two other babies are also Ashown. Blalock-Taussig This is Stage (BT) I ofshunt the Fontan in seen procedure in (b) and for ainfants Sano shuntwith hypoplastic in (c) from left two heart other syndrome. babies are also shown.LPA, left This pulmonary is Stage Iartery; of the RPA, Fontan right procedure pulmonary for infantsartery. Reproduced with hypoplastic from leftreference heart syndrome.[33]. LPA, left pulmonary artery; RPA, right pulmonary artery. Reproduced from Reference [33]. 4.1.3. Other Cardiac Abnormalities Some of the babies may have other cardiac abnormalities such as intra-cardiac obstruction, aortic arch obstruction, or atrioventricular valve insufficiency at presentation or may develop such abnormalities during the succeeding period. These will be reviewed.

Intra-Cardiac Obstruction Intra-cardiac obstruction may take place either at the atrial or at the ventricular level.

Inter-Atrial Obstruction The total systemic or pulmonary venous return must pass through the PFO in babies with atretic atrioventricular valves and/or atretic semi-lunar valves. These defects are listed in Table 1.

Table 1. Inter-atrial Obstruction.

1 Pulmonary atresia 2 Tricuspid atresia 3 Mitral atresia 4 Hypoplastic left heart syndrome Modified from reference [51].

There is a tendency for the PFO to remain open because of a persistence of fetal flow patterns. However, sometimes the PFO becomes obstructed. Evidence for obstructed PFO may be present either with systemic or pulmonary venous congestion and is confirmed by a small-sized PFO by 2-dimentional echo and high velocity flow across it by Doppler studies. The PFO may be enlarged by balloon atrial septostomy (Figure 12) [52].

Children 2021, 8, 441 10 of 31

4.1.3. Other Cardiac Abnormalities Some of the babies may have other cardiac abnormalities such as intra-cardiac obstruction, aortic arch obstruction, or atrioventricular valve insufﬁciency at presentation or may develop such abnormalities during the succeeding period. These will be reviewed.

Intra-Cardiac Obstruction Intra-cardiac obstruction may take place either at the atrial or at the ventricular level.

Table 1. Inter-atrial Obstruction.

1 Pulmonary atresia 2 Tricuspid atresia 3 Mitral atresia 4 Hypoplastic left heart syndrome Modiﬁed from Reference [51].

There is a tendency for the PFO to remain open because of a persistence of fetal flow patterns. However, sometimes the PFO becomes obstructed. Evidence for obstructed PFO may be present either with systemic or pulmonary venous congestion and is confirmed by a small-sized PFO by 2-dimentional echo and high velocity flow across it by Doppler studies. The PFO may be enlarged by balloon atrial septostomy (Figure 12)[52]. Such a procedure is usually successful, especially in the early neonatal period, because the septum primum (lower margin of the PFO) is thin and flail and can be ruptured by balloon septostomy. When PFO obstruction develops during the later part of the neonatal period or in older infants, balloon atrial septostomy is unlikely to be successful, and in such situations, alternative methods such as blade atrial septostomy [53], static balloon dilatation [54,55], or stent placement [56–58] may have to be used to accomplish the relief of inter-atrial obstruction. If transcatheter methods are not feasible or not successful, surgical atrial septectomy is necessary. If there is no PFO and the atrial septum is intact, the atrial septum may be perforated either by Brockenbrough technique [59] or radiofrequency perforation [60]. This should be followed by static dilatation [54,55] or stent placement across the atrial septum [56–58]. For a detailed discussion of these transcatheter techniques, the interested reader may review the author’s previous publications [58,61]. In babies with single ventricle and mitral atresia, inter-atrial obstruction is frequently present [62,63]. In such infants, predictable fall in pulmonary vascular resistance (PVR) takes place after relief of atrial obstruction either by balloon septostomy or surgery [63]. Therefore, banding of the PA should be performed without hesitation at the time of alleviating the atrial septal obstruction in order to reduce the probability for CHF, reduce the PVR and PA pressure, prevent pulmonary vascular obstructive disease (PVOD), and pave the way for Fontan circulation [62,63]. Children 2021, 8, x FOR PEER REVIEW 11 of 32

Children 2021, 8, 441 Such a procedure is usually successful, especially in the early neonatal period, because11 of 31 the septum primum (lower margin of the PFO) is thin and flail and can be ruptured by balloon septostomy.

FigureFigure 12. 12.Cinfluroscopic Cinfluroscopic framesframes demonstratingdemonstrating the procedure of Rashkind’s balloon balloon septostomy. septostomy. Initially the balloon is inflated in the left atrium (A). The balloon septostomy catheter (BSC) is Initially the balloon is inflated in the left atrium (A). The balloon septostomy catheter (BSC) is rapidly and forcefully pulled into the right atrium (B) and inferior vena cava (C,D) and quickly rapidly and forcefully pulled into the right atrium (B) and inferior vena cava (C,D) and quickly advanced back into the right atrium (E,F). The entire procedure is done as one single motion. Rapid E F advancedadvancement back of into the the BSC right into atrium the right ( , atrium). The entire(E,F) is procedure done in order is done to asavoid one inadvertent single motion. occlusion Rapid advancementof the inferior of vena the BSCcava into if failure the right to deflate atrium the (E, Fballoon) is done occurs in order (this to is avoid quite inadvertent rare). At about occlusion the same of thetime inferior the balloon vena cavais deflated. if failure ET, to en deflatedotracheal the balloon tube; NG, occurs nasogastric (this is quitetube; rare).UAC, Atumbilical about the arterial same timecatheter; the balloon UVC, umbilical is deflated. venous ET, endotracheal catheter. tube; NG, nasogastric tube; UAC, umbilical arterial catheter; UVC, umbilical venous catheter. When PFO obstruction develops during the later part of the neonatal period or in Inter-Ventricularolder infants, balloon Obstruction atrial septostomy is unlikely to be successful, and in such situa- tionsIn, alternative some complex methods cardiac such defects, as blade namely, atrial tricuspid septostomy atresia, [53], double-inlet static balloon left ventricle,dilatation and[54,55], double-outlet or stent placement right (or left)[56– ventricle,58] may have the VSD to be or used bulbo-ventricular to accomplish foramen, the relief as of the in- caseter-atrial may obstruction. be, is very smallIf transcatheter and obstructive methods at are presentation not feasible in or the not neonatal successful, period surgical or spontaneouslyatrial septectomy becomes is necessary. smaller If with there time is no [13 PFO,14,64 and,65]. the Such atrial a reduction septum is in intact, the size the of atrial the VSDseptum or bulbo-ventricular may be perforated foramen either causes by Brockenbrough sub-pulmonary technique obstruction, [59] producing or radiofrequency reduced pulmonaryperforation blood [60]. flowThis orshould subaortic be followed narrowing, by s resultingtatic dilatation in obstruction [54,55] or to systemicstent placement blood flowacross (Table the2 atrial). septum [56–58]. For a detailed discussion of these transcatheter techniques, the interested reader may review the author’s previous publications [58,61]. Table 2. Inter-Ventricular Obstruction. In babies with single ventricle and mitral atresia, inter-atrial obstruction is frequently present [62,63].1 In such infants, predictable Tricuspid fall atresia in pulmonary vascular resistance (PVR) takes place after relief of atrial obstruction either by balloon septostomy or surgery 2 Double-inlet left ventricle [63]. Therefore, banding3 of the PA should be Double-outletperformed without right (or hesitation left) ventricle at the time of Modifiedalleviating from the Reference atrial [ 51septal]. obstruction in order to reduce the probability for CHF, reduce the PVR and PA pressure, prevent pulmonary vascular obstructive disease (PVOD), and paveIf the such way a closurefor Fontan produces circulation diminished [62,63]. pulmonary blood flow, the management is similar to that discussed in the “Decreased Pulmonary Blood Flow” section above (PGE1 andInter modified-Ventricular BT Obstruction shunt). If the VSD/bulbo-ventricular foramen closure results in ob- structionIn some to SBF, complex the narrowing cardiac defects, is either namely, relieved tricuspid directly atresia, by enlarging double- theinlet VSD left orventri- the obstructioncle, and double is bypassed-outlet right by the (or Damus–Kaye–Stansel left) ventricle, the VSD (DKS) or procedurebulbo-ventricular (anastomosis foramen, of the as dividedthe case pulmonary may be, is artery very small to the and ascending obstructive aorta eitherat presentation directly or in via the a prostheticneonatal period conduct) or (Figure 13)[14,66]. Most commonly DKS is performed instead of directly enlarging the VSD. However, it should be noted that the development of a significant inter-ventricular obstruction that requires intervention in the neonate is infrequent. Children 2021, 8, x FOR PEER REVIEW 12 of 32

spontaneously becomes smaller with time [13,14,64,65]. Such a reduction in the size of the VSD or bulbo-ventricular foramen causes sub-pulmonary obstruction, producing reduced pulmonary blood flow or subaortic narrowing, resulting in obstruction to systemic blood flow (Table 2).

Table 2. Inter-Ventricular Obstruction.

1 Tricuspid atresia 2 Double-inlet left ventricle 3 Double-outlet right (or left) ventricle Modified from reference [51].

If such a closure produces diminished pulmonary blood flow, the management is similar to that discussed in the “Decreased Pulmonary Blood Flow” section above (PGE1 and modified BT shunt). If the VSD/bulbo-ventricular foramen closure results in obstruction to SBF, the narrowing is either relieved directly by enlarging the VSD or the obstruction is bypassed by the Damus–Kaye–Stansel (DKS) procedure (anastomosis of the divided pulmonary artery to the ascending aorta either directly or via a prosthetic Children 2021, 8, 441 conduct) (Figure 13) [14,66]. Most commonly DKS is performed instead of directly12 of en- 31 larging the VSD. However, it should be noted that the development of a significant inter-ventricular obstruction that requires intervention in the neonate is infrequent.

FigureFigure 13. 13.A A. Line Line drawing drawing illustratingillustrating Damus-Kaye-StanselDamus-Kaye-Stansel procedure. The The left left ventricular ventricular (LV) (LV) blood flows via the ventricular septal defect (circle) and right ventricle (RV) into the aorta (Ao). If blood ﬂows via the ventricular septal defect (circle) and right ventricle (RV) into the aorta (Ao). If the the VSD is small and restrictive, causing “subaortic” obstruction, this obstruction may be circum- VSD is small and restrictive, causing “subaortic” obstruction, this obstruction may be circumvented vented by connecting the proximal stump of the divided pulmonary artery to the Ao directly or a byvia connecting a non-valved the conduit. proximal The stump pulmonary of the divided arteries pulmonaryare supplied artery with a to Blalock the Ao-Taussig directly shunt. or a via a non-valvedConcept derived conduit. from The reference pulmonarys [13,14]. arteries are supplied with a Blalock-Taussig shunt. Concept derived from References [13,14].

Aortic Obstruction Aortic arch obstruction may occur in the form of aortic coarctation or interrupted aortic arch. Both will be brieﬂy reviewed.

Aortic Coarctation Aortic coarctation is a descending aortic abnormality with constriction of the aortic arch distal to the left subclavian artery at about the level of ductal insertion [67]. In the neonate, it is frequently associated with other defects such as PDA, VSD and other complex CHDs such as tricuspid atresia with transposition of the great arteries and DILV with transposition of the great arteries. Initial medical management by infusion of PGE1 to bypass the coarctation and anti-congestive treatment, if CHF is present, is suggested. In most institutions the neonatal coarctations are addressed by surgery. Although the immediate success rate following balloon angioplasty is good [68–70], because of a high recurrence rate [70–72] associated with balloon therapy in the neonate, surgery is preferred. However, in special circumstances when surgical risk is high or contraindicated, balloon dilatation may be used as an initial treatment option [68–70,73].

Interrupted Aortic Arch In aortic arch interruption, there is a total loss of luminal continuity between the arch of the aorta and the descending aorta [74] and the condition is classiﬁed into types A, B, and C [75] depending upon the site of interruption. The initial management is by PGE1 infusion to allow the ductus to open and restore systemic perfusion. Then, end-to-end anastomosis after removal of the ductal tissue is performed. In cases where the aortic arch Children 2021, 8, 441 13 of 31

can’t be mobilized, an interposition Gore-Tex graft is inserted to bridge the gap. In any baby with interrupted aortic arch, especially in association with single ventricle physiology, arch repair should be promptly performed.

Atrio-Ventricular Valve Insufficiency Mild AV valve insufficiency does not require any treatment. However, moderate to severe AV valve insufficiency (tricuspid, mitral or common AV valve) should be addressed promptly. Initially medical management with angiotensin-converting-enzyme (ACE) inhibitors (Captopril/Enalopril) may be used. If no adequate improvement with medical therapy is seen, surgical valvuloplasty or valve replacement may become necessary.

4.2. Stage II—Bidirectional Glenn Independent of the nature of palliative intervention during the neonatal period, bidirectional Glenn operation [76] by anastomosis of the superior vena cava (SVC) to the right PA, end-to-side (Figure 14) is undertaken at an approximate age of six months. If a prior BT or Sano shunt is present, it is ligated at the time of bidirectional Glenn. While performing Children 2021, 8, x FOR PEER REVIEWthe procedure at six months is commonly accepted, the Glenn can be performed as early14 of as 32

three months subject to demonstrating normal PA pressures and anatomy.

Figure 14. Cineangiographic frames illustrating bidirectional Glenn procedure, i.e., anastomosis of Figure 14. Cineangiographic frames illustrating bidirectional Glenn procedure, i.e., anastomosis of the superior vena cava (SVC) to the right pulmonary artery (RPA)] in two different children is the superior vena cava (SVC) to the right pulmonary artery (RPA)] in two different children is shown shown in (a,b) (Stage II). Unobstructed blood flow from the SVC to the right (RPA) and left (LPA) in (a,b) (Stage II). Unobstructed blood ﬂow from the SVC to the right (RPA) and left (LPA) pulmonary pulmonary arteries is seen. Reproduced from reference [33]. arteries is seen. Reproduced from Reference [33].

In babies who have persistent left SVC, bilateral bidirectional Glenn (Figure 15) is performed particularly in patients with a small or absent left innominate vein. A bidirectional Glenn procedure may also be undertaken for patients with infrahepatic interruption of the IVC with azygos or hemiazygos continuation, and such a procedure may be called the Kawashima procedure. Prior to undertaking the bidirectional Glenn procedure, it must be ensured that the PA pressures are normal and the branch PAs are adequate in size. This is most often accomplished by cardiac catheterization and cineangiography. However, some institutions employ echocardiogrms or other imaging studies such as magnetic resonance imaging (MRI) or computed tomography (CT) to accomplish this goal. If stenosis of the PAs is present, it may be relieved with balloon angioplasty or stent placement, as appropriate, or it may be repaired while performing the bidirectional Glenn procedure. If atrioventricular valveFigure regurgitation, 15. Cineangiographic aortic coarctation,frames demonstrating subaortic a obstruction,bilateral bidirectional and other Glenn abnormalities procedure (Stage are present,II). In (a) they, angiogram should of also the besuperior repaired vena at cava the time(SVC) of illustrates bidirectional opacification Glenn of surgery. the right pulmonary artery (RPA). The arrow in (a) shows the unopacified blood from a persistent left superior vena cava (PLSVC). In (b), an injection into the PLSVC illustrates opacification of the left pulmonary artery (LPA). The arrow in (b) shows the unopacified blood from the right SVC. Unobstructed flow from the respective SVCs into the pulmonary arteries is clearly seen. Reproduced from reference [33].

Prior to undertaking the bidirectional Glenn procedure, it must be ensured that the PA pressures are normal and the branch PAs are adequate in size. This is most often accomplished by cardiac catheterization and cineangiography. However, some institutions employ echocardiogrms or other imaging studies such as magnetic resonance imaging (MRI) or computed tomography (CT) to accomplish this goal. If stenosis of the PAs is present, it may be relieved with balloon angioplasty or stent placement, as appropriate, or it may be repaired while performing the bidirectional Glenn procedure. If atrioventricular valve regurgitation, aortic coarctation, subaortic obstruction, and other abnormalities are present, they should also be repaired at the time of bidirectional Glenn surgery.

4.3. Stage III—Fontan/Kruetzer Procedure Although the author prefers the term “Fontan/Kruetzer Procedure” because of the simultaneous description of the procedure by both groups [35,36], it is more commonly referred to as “Fontan Procedure” in the literature and therefore, it will be so used in the rest of the presentation. During the final stage, the IVC blood flow is rerouted into the

Children 2021, 8, x FOR PEER REVIEW 14 of 32

Figure 14. Cineangiographic frames illustrating bidirectional Glenn procedure, i.e., anastomosis of Children 2021, 8, 441 the superior vena cava (SVC) to the right pulmonary artery (RPA)] in two different children14 is of 31 shown in (a,b) (Stage II). Unobstructed blood flow from the SVC to the right (RPA) and left (LPA) pulmonary arteries is seen. Reproduced from reference [33].

FigureFigure 15. 15.Cineangiographic Cineangiographic frames frames demonstrating demonstrating a a bilateral bilateral bidirectional bidirectional Glenn Glenn procedure procedure (Stage (Stage II). In (a), angiogram of the superior vena cava (SVC) illustrates opacification of the right pulmo- II). In (a), angiogram of the superior vena cava (SVC) illustrates opacification of the right pulmonary nary artery (RPA). The arrow in (a) shows the unopacified blood from a persistent left superior artery (RPA). The arrow in (a) shows the unopacified blood from a persistent left superior vena cava vena cava (PLSVC). In (b), an injection into the PLSVC illustrates opacification of the left pulmo- (PLSVC).nary artery In (LPA). (b), an The injection arrow into in (b the) shows PLSVC the illustrates unopacified opacification blood from of the the right left SVC. pulmonary Unobstructed artery (LPA).flow from The arrowthe respective in (b) shows SVCs the into unopacified the pulmonary blood arteries from theis clearly right SVC. seen. Unobstructed Reproduced from flow ref- from theerence respective [33]. SVCs into the pulmonary arteries is clearly seen. Reproduced from Reference [33]. 4.3. Stage III—Fontan/Kruetzer Procedure Prior to undertaking the bidirectional Glenn procedure, it must be ensured that the PA pressuresAlthough are the normal author prefersand the thebranch term PAs “Fontan/Kruetzer are adequate in Procedure” size. This is because most often of the ac- simultaneouscomplished by description cardiac catheterization of the procedure and bycineangiography. both groups [35 However,,36], it is moresome commonlyinstitutions referredemploy toechocardiogrms as “Fontan Procedure” or other inimaging the literature studies and such therefore, as magnetic it will resonance be so used imaging in the rest(MRI) of theor computed presentation. tomography During the (CT) final to stage,accomplish the IVC this blood goal. flow If stenosis is rerouted of the into PAs the is PA.present, At the it samemay be time relieved a fenestration with balloon between angioplasty the conduit or stent and placement, the atrial mass as appropriate, is created. Arbitraryor it may division be repaired of these whil procedurese performing into the Stage bidirectional IIIA (diversion Glenn of procedure. IVC into the If PA)atrioven- and Stagetricular IIIB valve (closure regurgitation, of the fenestration) aortic coarctation, [33,34] may subaortic be undertaken. obstruction, and other abnormalities are present, they should also be repaired at the time of bidirectional Glenn sur- 4.3.1. Stage IIIA gery. In the Stage IIIA, the TCPC may be accomplished by redirecting the IVC blood flow into4.3. theStage PA III either—Fontan/Kruetzer by a lateral tunnelProcedure [77 ,78] or by an extra-cardiac, non-valved conduit (Figure 16)[79,80]. This surgery is typically carried out anytime from one to two years of Although the author prefers the term “Fontan/Kruetzer Procedure” because of the age, frequently one year after the bidirectional Glenn. At the present time, the majority of surgeonssimultaneous favor description an extra-cardiac of the conduit procedure to achieve by both the groups final stage [35,36], of Fontan. it is more It also commonly appears thatreferred most to surgeons as “Fontan create Procedure a fenestration,” in the 4–6 literature mm in size, and betweentherefore, the it conduitwill be so and used the in atria the (Figurerest of 16the)[ 81presentation.]. Whereas creationDuring ofthe fenestration final stage, during the IVC the blood Fontan flow surgery is rerouted was originally into the suggested for patients with high-risk [81,82], most surgeons and pediatric intensivists appear to opt for fenestration, because the creation of fenestration during the Fontan decreases mortality rate and lessens the morbidity during the immediate postoperative period [33]. Children 2021, 8, x FOR PEER REVIEW 15 of 32

PA. At the same time a fenestration between the conduit and the atrial mass is created. Arbitrary division of these procedures into Stage IIIA (diversion of IVC into the PA) and Stage IIIB (closure of the fenestration) [33,34] may be undertaken.

4.3.1. Stage IIIA In the Stage IIIA, the TCPC may be accomplished by redirecting the IVC blood flow into the PA either by a lateral tunnel [77,78] or by an extra-cardiac, non-valved conduit (Figure 16) [79,80]. This surgery is typically carried out anytime from one to two years of age, frequently one year after the bidirectional Glenn. At the present time, the majority of surgeons favor an extra-cardiac conduit to achieve the final stage of Fontan. It also appears that most surgeons create a fenestration, 4–6 mm in size, between the conduit and the atria (Figure 16) [81]. Whereas creation of fenestration during the Fontan surgery was originally suggested for patients with high-risk [81,82], most surgeons and pediatric in- Children 2021, 8, 441 tensivists appear to opt for fenestration, because the creation of fenestration during15 of the 31 Fontan decreases mortality rate and lessens the morbidity during the immediate postoperative period [33].

Figure 16. Cineangiographic frames in postero-anterior (a) and lateral (b) projections, illustrating Figure 16. Cineangiographic frames in postero-anterior (a) and lateral (b) projections, illustrating Stage IIIA of the Fontan procedure in which the inferior vena caval (IVC) blood flow is diverted Stage IIIA of the Fontan procedure in which the inferior vena caval (IVC) blood flow is diverted into into the pulmonary arteries via a non-valve conduit (Cond). The flow via the fenestration (Fen) is theshown pulmonary by the arrows arteries in via a aand non-valve b. HV, hepatic conduit veins; (Cond). LPA, The left flow pulmonary via the fenestration artery; PG, (Fen)pigtail is catheter shown byin thethe arrowsdescending in a andaorta; b. RPA, HV, hepatic right pulmonary veins; LPA, artery. left pulmonary Modified from artery; reference PG, pigtail [33]. catheter in the descending aorta; RPA, right pulmonary artery. Modified from Reference [33]. 4.3.2. Stage IIIB 4.3.2. Stage IIIB During the Stage IIIB, the fenestration is occluded (Figure 17) by transcatheter During the Stage IIIB, the fenestration is occluded (Figure 17) by transcatheter meth- odsmetho [33,ds81 ,[33,81,8383–85], usually–85], usually 6–12 months 6–12 months following following Stage Stage IIIA Fontan. IIIA Fontan. In the In past, the allpast, pre- all viouslypreviously available available ASD ASD occluding occluding devices devices [81,83 [81,83–85]– were85] were used used for fenestration for fenestration closure. clo- However,sure. However, at the present at the present time, Amplatzer time, Amplatzer Septal Occluders Septal Occluders are the most are regularlythe most usedregularly de- Children 2021, 8, x FOR PEER REVIEWvicesus ed to devices accomplish to accomplish fenestration fenestration closures. Any closures. other Any residual other shunts residual may shunts also be may addressed 16also of be32

byaddressed device closure. by device closure.

FigureFigure 17. 17.( a()a.).Cineangiogram Cineangiogram in in antero-posterior antero-posterior view, view, illustrating illustrating Stage Stage IIIA IIIA of the of Fontanthe Fontan operation, operation, diverting the inferior vena caval (IVC) blood flow into the pulmonary arteries via a non-valve diverting the inferior vena caval (IVC) blood ﬂow into the pulmonary arteries via a non-valve conduit conduit (Cond). Fenestration (Fen) is shown by the arrow in (a). The Fen is occluded with an Am- (Cond). Fenestration (Fen) is shown by the arrow in (a). The Fen is occluded with an Amplatzer platzer device (D), shown by the arrow in (b) (Stage IIIB). HV, hepatic veins; LPA, left pulmonary deviceartery; (D), RPA, shown right bypulmonary the arrow artery. in (b) Reproduced (Stage IIIB). from HV, hepaticreference veins; [33]. LPA, left pulmonary artery; RPA, right pulmonary artery. Reproduced from Reference [33].

5.5. Inter-Stage Inter-Stage Mortality Mortality AsAs mentioned mentioned above, above, in in babies babies who who have have single single ventricle ventricle physiology, physiology, the systemic the systemic and pulmonaryand pulmonary circulations circulations function function in-parallel in-parallel instead instead of the usualof the in-seriesusual in circulation-series circulation and a delicateand a delicate equilibrium equilibrium between between the two circulationsthe two circulations must be maintained must be maintained such that sufﬁcientsuch that systemicsufficient and systemic pulmonary and pulmonary perfusions perfusions are preserved. are preserved. Inability toInability maintain to suchmaintain balance such maybalance result may in result morbidity in morbidity and even and mortality even mortality in these vulnerablein these vulnerable babies. Ababies. substantial A substantial inter-stage mortality, ranging from 5% to 15%, has been documented [33,34,86,87]. Some investigators have identified the reason for inter-stage mortality; these are restrictive atrial septal defect, obstructed aortic arch, distorted pulmonary arteries, AV valve regurgitation, shunt blockage, and inter-current illnesses [86,88]. The inter-stage mortality is seen more often between Stages I and II than between Stages II and III. Strategies to address the inter-stage mortality include periodic clinical evaluation, as well as echo-Doppler and other imaging studies to detect the above described abnormalities and provide adequate relief of detected problems in order to prevent/reduce the mortality.

5.1. Restrictive Atrial Communication Obstruction of PFO/ASD may manifest either as systemic venous or pulmonary venous congestion, depending upon the lesion. The obstruction may be confirmed by a small-sized PFO by 2-dimentional echo and high velocity flow across it by Doppler. Once it is detected, it should be promptly relieved. In the majority of babies, Rashkind balloon atrial septostomy [52,58,61] (Figure 12) is successful in relieving the interatrial obstruction. Rashkind septostomy may not be feasible in some patients either because of thick atrial septal tissue and/or small left atria. In such situations, atrial septal restriction may be relieved by static balloon dilatation [54,55] (Figure 18) or stent implantation [55–58,61,89] (Figures 19 and 20). If transcatheter methods are not feasible or not successful, surgical septostomy becomes necessary.

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inter-stage mortality, ranging from 5% to 15%, has been documented [33,34,86,87]. Some investigators have identiﬁed the reason for inter-stage mortality; these are restrictive atrial septal defect, obstructed aortic arch, distorted pulmonary arteries, AV valve regurgitation, shunt blockage, and inter-current illnesses [86,88]. The inter-stage mortality is seen more often between Stages I and II than between Stages II and III. Strategies to address the inter-stage mortality include periodic clinical evaluation, as well as echo-Doppler and other imaging studies to detect the above described abnormalities and provide adequate relief of detected problems in order to prevent/reduce the mortality.

5.1. Restrictive Atrial Communication Obstruction of PFO/ASD may manifest either as systemic venous or pulmonary venous congestion, depending upon the lesion. The obstruction may be conﬁrmed by a small-sized PFO by 2-dimentional echo and high velocity ﬂow across it by Doppler. Once it is detected, it should be promptly relieved. In the majority of babies, Rashkind balloon atrial septostomy [52,58,61] (Figure 12) is successful in relieving the interatrial obstruction. Rashkind septostomy may not be feasible in some patients either because of thick atrial septal tissue and/or small left atria. In such situations, atrial septal restriction may be relieved by static balloon dilatation [54,55] (Figure 18) or stent implantation [55–58,61,89] Children 2021, 8, x FOR PEER REVIEW(Figures 19 and 20). If transcatheter methods are not feasible or not successful, surgical17 of 32

septostomy becomes necessary.

FigureFigure 18. 18.Cineradiographic Cineradiographic framesframes demonstrating balloon balloon angioplasty angioplasty procedures procedures to to widen widen the the patent foramen ovale. Inflated balloons in lateral (A,B) and posterior-anterior (C,D) projections in patent foramen ovale. Inﬂated balloons in lateral (A,B) and posterior-anterior (C,D) projections in two different neonates, illustrating the waisting of the balloons (arrows in A,C) during the initial two different neonates, illustrating the waisting of the balloons (arrows in A,C) during the initial phases of balloon angioplasty. The waisting was fully abolished on further inflation of the balloons phases(B,D). ofReproduced balloon angioplasty. from Reference The waisting [89]. was fully abolished on further inﬂation of the balloons (B,D). Reproduced from Reference [89].

Figure 19. Selected cine (A) and video (B) frames demonstrating the location of the stent (St) across the atrial septum following St deployment. LA, left atrium; RA, right atrium; PG, pigtail catheter in the descending aorta. Reproduced from Reference [89].

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Figure 18. Cineradiographic frames demonstrating balloon angioplasty procedures to widen the patent foramen ovale. Inflated balloons in lateral (A,B) and posterior-anterior (C,D) projections in Children 2021, 8, 441 two different neonates, illustrating the waisting of the balloons (arrows in A,C) during the initial17 of 31 phases of balloon angioplasty. The waisting was fully abolished on further inflation of the balloons (B,D). Reproduced from Reference [89].

FigureFigure 19. 19.Selected Selected cine cine ( A(A)) and and video video ( B(B)) frames frames demonstrating demonstrating the the location location of of the the stent stent (St) (St) across across the atrial septum following St deployment. LA, left atrium; RA, right atrium; PG, pigtail catheter in Children 2021, 8, x FOR PEER REVIEWthe atrial septum following St deployment. LA, left atrium; RA, right atrium; PG, pigtail catheter18 of in32 the descending aorta. Reproduced from Reference [89]. the descending aorta. Reproduced from Reference [89].

FigureFigure 20. 20.Video Video frame frame of of the the stent stent (St) (St) (short (short arrows) arrows) demonstrates demonstrates laminar laminar ﬂow flow (LF) (LF) (long (long arrow) arrow) across it. LA, left atrium; RA, right atrium. Reproduced from Reference [89]. across it. LA, left atrium; RA, right atrium. Reproduced from Reference [89].

5.2.5.2. ObstructionObstruction ofof the the Aortic Aortic Arch Arch AorticAortic coarctationcoarctation maymay developdevelop oror aamissed missed neonatalneonatal diagnosisdiagnosis maymay manifestmanifest sub-sub- sequentsequent toto StageStage II palliation,palliation, oror aorticaortic recoarctationrecoarctation maymay occuroccur followingfollowing priorprior surgery.surgery. TheseThese may may be be detected detected by by physical physical examination examination (decreased (decreased and/or and/or delayed delayed femoral femoral arterial arte- pulsesrial pu andlses higherand higher systolic systolic blood blood pressure pressure in the in arm the than arm leg) than or leg) imaging or imaging studies studies such assuch echocardiogram as echocardiogram or MRI/CT. or MRI/CT. The indicationsThe indications for intervention for intervention are CHFare CHF or hyperten- or hyper- siontension along along with with a peak a peak systolic systolic gradient gradient higher higher than than 20 20 mmHg. mmHg. At At this this stage, stage, balloon balloon angioplastyangioplasty [ 69[69,70,72,90],70,72,90] (Figure (Figure 21 21)) may may be be carried carried out. out.

Figure 21. Cineradiographic frames in 200 left anterior oblique view demonstrating a balloon angioplasty catheter placed across the aortic coarctation. Note waisting (arrow) of the balloon (A) during the initial phases of balloon inflation, which was abolished (B) on further inflation of the balloon. AAo, ascending aorta; DAo, descending aorta; ET, endotracheal tube; GW, guide wire; NG, nasogastric tube. Modified from reference [90].

Good results may be expected with both native [67–70,72,73] (Figures 22 and 23) and post-surgical aortic recoarctations [89–94] (Figures 24 and 25).

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Figure 20. Video frame of the stent (St) (short arrows) demonstrates laminar flow (LF) (long arrow) across it. LA, left atrium; RA, right atrium. Reproduced from Reference [89].

5.2. Obstruction of the Aortic Arch Aortic coarctation may develop or a missed neonatal diagnosis may manifest subsequent to Stage I palliation, or aortic recoarctation may occur following prior surgery. These may be detected by physical examination (decreased and/or delayed femoral arterial pulses and higher systolic blood pressure in the arm than leg) or imaging studies Children 2021, 8, 441 such as echocardiogram or MRI/CT. The indications for intervention are CHF18 or of 31hyper- tension along with a peak systolic gradient higher than 20 mmHg. At this stage, balloon angioplasty [69,70,72,90] (Figure 21) may be carried out.

0 FigureFigure 21. 21. CineradiographicCineradiographic framesframes inin 2020◦ left anterior anterior oblique oblique view view demonstrating demonstrating a a balloon balloon an- angioplastygioplasty catheter catheter placed placed across across the aortic coarctation. NoteNote waistingwaisting (arrow) (arrow) of of the the balloon balloon (A ()A) during the initial phases of balloon inflation, which was abolished (B) on further inflation of the during the initial phases of balloon inflation, which was abolished (B) on further inflation of the balloon. AAo, ascending aorta; DAo, descending aorta; ET, endotracheal tube; GW, guide wire; balloon. AAo, ascending aorta; DAo, descending aorta; ET, endotracheal tube; GW, guide wire; NG, NG, nasogastric tube. Modified from reference [90]. nasogastric tube. Modified from Reference [90].

Children 2021, 8, x FOR PEER REVIEW GoodGood results results may may be be expected expected with with both both native native [67– [6770,–7270,72,73,73] (Figures] (Figures 22 and 2223 and19) and of 23) 32 and

post-surgicalpost-surgical aortic aortic recoarctations recoarctations [89 –[8994–]94 (Figures] (Figures 24 and 24 and25). 25).

FigureFigure 22. 22.Bar Bar graph graph illustrating illustrating the the fall fall (p (p< < 0.001) 0.001) of of the the peak-to peak-to peak peak systolic systolic pressure pressure gradients gradients (in (in mmHg) across the aortic coarctation following balloon angioplasty. The reduction in the gra- mmHg) across the aortic coarctation following balloon angioplasty. The reduction in the gradients dients was seen for all the infant group (left panel) and for all the three subgroups: Balloon angio- was seen for all the infant group (left panel) and for all the three subgroups: Balloon angioplasty plasty via trans-umbilical arterial (UA), trans-femoral arterial (FA), and trans-femoral venous an- viaterograde trans-umbilical (FVA) routes. arterial The (UA), mean trans-femoral and standard arterial deviation (FA), (SD) and trans-femoralare marked. N venous represents anterograde the (FVA)number routes. of subjects The mean in each and standardgroup. Modified deviation from (SD) reference are marked. [70]. N represents the number of subjects in each group. Modiﬁed from Reference [70].

Figure 23. Cineangiographic frames from aortic arch angiograms in a 200 left anterior oblique views, illustrating a narrowed (coarcted) aortic segment (arrow) priot to balloon angioplasty (A) which improved following balloon angioplasty (B). Note mild hypoplasia of the distal transverse aortic arch and isthmus. AAo, ascending aorta; DAo, descending aorta; LCC, left common carotid artery; LSA, left subclavian artery; NG, nasogastric tube; PG, pigtail catheter; RInn. right innominate artery. Modified from reference [90].

Children 2021, 8, x FOR PEER REVIEW 19 of 32

Figure 22. Bar graph illustrating the fall (p < 0.001) of the peak-to peak systolic pressure gradients (in mmHg) across the aortic coarctation following balloon angioplasty. The reduction in the gradients was seen for all the infant group (left panel) and for all the three subgroups: Balloon angio- Children 2021, 8, 441 plasty via trans-umbilical arterial (UA), trans-femoral arterial (FA), and trans-femoral venous19 ofan- 31 terograde (FVA) routes. The mean and standard deviation (SD) are marked. N represents the number of subjects in each group. Modified from reference [70].

0 FigureFigure 23. 23.Cineangiographic Cineangiographic frames frames from from aortic aortic arch arch angiograms angiograms in in a 20a 20◦ left left anterior anterior oblique oblique views, views, illustrating a narrowed (coarcted) aortic segment (arrow) priot to balloon angioplasty (A) illustrating a narrowed (coarcted) aortic segment (arrow) priot to balloon angioplasty (A) which which improved following balloon angioplasty (B). Note mild hypoplasia of the distal transverse improved following balloon angioplasty (B). Note mild hypoplasia of the distal transverse aortic aortic arch and isthmus. AAo, ascending aorta; DAo, descending aorta; LCC, left common carotid archartery; and LSA, isthmus. left subclavian AAo, ascending artery; aorta;NG, nasogastric DAo, descending tube; PG, aorta; pigtail LCC, catheter; left common RInn. right carotid innomi- artery; Children 2021, 8, x FOR PEER REVIEWLSA, left subclavian artery; NG, nasogastric tube; PG, pigtail catheter; RInn. right innominate20 artery. of 32 nate artery. Modified from reference [90]. Modiﬁed from Reference [90].

Figure 24. Cineangiographic frames from aortic arch angiograms in 200 left anterior oblique pro- Figure 24. Cineangiographic frames from aortic arch angiograms in 20◦ left anterior oblique projection, illustrating a coarcted aortic segment (white arrow) prior to balloon angioplasty (A) which jection, illustrating a coarcted aortic segment (white arrow) prior to balloon angioplasty (A) which widened (black arrow) following balloon angioplasty (B) in a neonate who had had the Norwood B widenedprocedure (black earlier. arrow) DAo, following descending balloon aorta; angioplasty LCC, left ( common) in a neonate carotid who artery; had hadLSA, the left Norwood subclavian pro- cedureartery; earlier. PG, pigtail DAo, catheter; descending RCC, aorta; right LCC, common left common carotid artery; carotid RInn, artery; right LSA, innominate left subclavian artery. artery; Re- PG,produced pigtail catheter;from Reference RCC, right [58]. common carotid artery; RInn, right innominate artery. Reproduced from Reference [58].

However, if there is long-segment coarctation or associated transverse aortic arch hypoplasia, surgical therapy to address the aortic obstruction should be considered.

Figure 25. Cineangiographic frames from aortic arch angiograms in straight lateral projection showing a post-surgical recoarcted aortic segment (arrow) priot to balloon angioplasty (A) which improved (arrow) following balloon dilatation (B), in a neonate who developed recoarctation at three weeks of age after neonatal surgical repair of coarctation. DAo, descending aorta; LSA, left subclavian artery; NG, nasogastric tube. Reproduced from Reference [58].

However, if there is long-segment coarctation or associated transverse aortic arch hypoplasia, surgical therapy to address the aortic obstruction should be considered.

5.3. Distortion/Stenosis of the Pulmonary Arteries If distortion or stenosis of the branch PAs is detected, balloon angioplasty for discrete obstruction and stents [95–99] for long segment or diffuse narrowing may be indicated (Figure 26). Again, surgery is reserved for situations that can’t be addressed by transcatheter approaches.

Children 2021, 8, x FOR PEER REVIEW 20 of 32

Figure 24. Cineangiographic frames from aortic arch angiograms in 200 left anterior oblique projection, illustrating a coarcted aortic segment (white arrow) prior to balloon angioplasty (A) which widened (black arrow) following balloon angioplasty (B) in a neonate who had had the Norwood Children 2021, 8, 441 procedure earlier. DAo, descending aorta; LCC, left common carotid artery; LSA, left subclavian20 of 31 artery; PG, pigtail catheter; RCC, right common carotid artery; RInn, right innominate artery. Re- produced from Reference [58].

FigureFigure 25.25. CineangiographicCineangiographic frames frames from from aortic aortic arch arch angiograms angiograms in straight in straight lateral lateral projection projection showing a post-surgical recoarcted aortic segment (arrow) priot to balloon angioplasty (A) which showing a post-surgical recoarcted aortic segment (arrow) priot to balloon angioplasty (A) which improved (arrow) following balloon dilatation (B), in a neonate who developed recoarctation at improvedthree weeks (arrow) of age following after neonatal balloon surgical dilatation repair (ofB ),coarctation. in a neonate DAo, who descending developed aorta; recoarctation LSA, left at threesubclavian weeks artery; of age NG, after nasogastric neonatal surgical tube. Reproduced repair of coarctation. from Reference DAo, [58]. descending aorta; LSA, left subclavian artery; NG, nasogastric tube. Reproduced from Reference [58]. 5.3. Distortion/StenosisHowever, if there of is the long Pulmonary-segment Arteries coarctation or associated transverse aortic arch hypoplasia, surgical therapy to address the aortic obstruction should be considered. If distortion or stenosis of the branch PAs is detected, balloon angioplasty for discrete obstruction5.3. Distortion/Stenosis and stents of [95 the–99 Pulmonary] for long Arteries segment or diffuse narrowing may be indicated Children 2021, 8, x FOR PEER REVIEW(Figure 26). Again, surgery is reserved for situations that can’t be addressed by transcatheter21 of 32 If distortion or stenosis of the branch PAs is detected, balloon angioplasty for dis- approaches. crete obstruction and stents [95–99] for long segment or diffuse narrowing may be indicated (Figure 26). Again, surgery is reserved for situations that can’t be addressed by transcatheter approaches.

Figure 26. (A). Cineangiographic frames in a 300 right anterior oblique view illustrating Figure 26. (A). Cineangiographic frames in a 30◦ right anterior oblique view illustrating long-segment long-segment right pulmonary artery (RPA) stenosis (arrow) before implantation of stent (St). The right pulmonary artery (RPA) stenosis (arrow) before implantation of stent (St). The position of the position of the St prior to (B) and following (C) balloon inflation to implant the St are shown. (D). StAngiography prior to (B )following and following St implantation (C) balloon shows inﬂation improvement. to implant Note the trivial St are residual shown. (narrowingD). Angiography (top followingarrow) in St(D implantation). C, catheter; showsLPA St, improvement. left pulmonary Note artery trivial stent residual implanted narrowing just prior (top to RPA arrow) stent in (D). C,implantation. catheter; LPA Sh, St, sheath; left pulmonary PIG, pigtail artery catheter. stent Reproduced implanted from just prior reference to RPA [98]. stent implantation. Sh, sheath; PIG, pigtail catheter. Reproduced from Reference [98]. 5.4. Atrio-Ventricular Valve Insufficiency Atrio-ventricular valve insufficiency may be addressed by administration of afterload reducing agents (ACE inhibitors {Captopril/Enalopril}), surgical valvuloplasty or valve replacement, as appropriate.

5.5. Shunt Blockage Some of the babies with one functioning ventricle may have had palliation with a modified BT [39] or a Sano [48,49] shunt. Both these shunts may become occluded either completely or partially, producing acute or chronic hypoxemia, respectively. If such an obstruction develops before a planned bidirectional Glenn procedure in single-ventricle physiology patients, further surgery such as a shunt revision may be needed, further increasing the risk of inter-stage mortality and/or morbidity. In almost all of these babies the shunt is the sole source of PBF. Therefore, prompt assessment, diagnosis, and treatment are critical to guarantee a successful result. Babies with a completely obstructed shunt manifest with marked cyanosis and res- piratory distress. A continuous murmur of the shunt that was present previously is no longer heard on auscultation or is markedly decreased in intensity. The management of an obstructed shunt includes use of principles of basic life support, namely, the airway, breathing, and circulation (or circulation, airway, breathing as per the new protocol) with intubation, as necessary, and starting cardiopulmonary resuscitation. In babies with suspected shunt blockage, heparin should be administered to prevent futher progression of the thrombus. Concurrently, stat echocardiogram should be performed, and pediatric cardiology and cardiovascular surgical consultation should be obtained promptly. Transcatheter recanalization of the shunt (Figure 27) in an urgent manner is feasible by interventional pediatric cardiologists [58,87,100] or the shunt may be revised, or the baby placed on ECMO by pediatric cardiovascular surgeons, depending upon the baby’s clinical status and institutional preference. The shunt thrombosis appears to occur, though

Children 2021, 8, 441 21 of 31

5.4. Atrio-Ventricular Valve Insufﬁciency Atrio-ventricular valve insufﬁciency may be addressed by administration of afterload reducing agents (ACE inhibitors {Captopril/Enalopril}), surgical valvuloplasty or valve replacement, as appropriate.

5.5. Shunt Blockage Some of the babies with one functioning ventricle may have had palliation with a modiﬁed BT [39] or a Sano [48,49] shunt. Both these shunts may become occluded either completely or partially, producing acute or chronic hypoxemia, respectively. If such an obstruction develops before a planned bidirectional Glenn procedure in single-ventricle physiology patients, further surgery such as a shunt revision may be needed, further increasing the risk of inter-stage mortality and/or morbidity. In almost all of these babies the shunt is the sole source of PBF. Therefore, prompt assessment, diagnosis, and treatment are critical to guarantee a successful result. Babies with a completely obstructed shunt manifest with marked cyanosis and res- piratory distress. A continuous murmur of the shunt that was present previously is no longer heard on auscultation or is markedly decreased in intensity. The management of an obstructed shunt includes use of principles of basic life support, namely, the airway, breathing, and circulation (or circulation, airway, breathing as per the new protocol) with intubation, as necessary, and starting cardiopulmonary resuscitation. In babies with suspected shunt blockage, heparin should be administered to prevent futher progression of the thrombus. Concurrently, stat echocardiogram should be performed, and pediatric cardiology and cardiovascular surgical consultation should be obtained promptly. Transcatheter recanalization of the shunt (Figure 27) in an urgent manner is feasible by interventional Children 2021, 8, x FOR PEER REVIEWpediatric cardiologists [58,87,100] or the shunt may be revised, or the baby placed22 of on 32

ECMO by pediatric cardiovascular surgeons, depending upon the baby’s clinical status and institutional preference. The shunt thrombosis appears to occur, though infrequently, despite the routine use of platelet inhibiting drugs such as aspirin in an attempt to avert infrequently, despite the routine use of platelet inhibiting drugs such as aspirin in an at- such a problem. tempt to avert such a problem.

FigureFigure 27. 27.Selected Selected cineangiographic cineangiographic frame frame demonstrating demonstrating clotted clotted Blalock-Taussig Blalock-Taussig (CBT) (CBT) shunt shunt ( A(A).). After unsuccessful recanalization with mechanical thrombolysis and balloon angioplasty, a stent After unsuccessful recanalization with mechanical thrombolysis and balloon angioplasty, a stent (St) (St) was implanted (B). Angiography with tip of the catheter (C) in the proximal portion of the stent was implanted (B). Angiography with tip of the catheter (C) in the proximal portion of the stent showed complete opening of the BT shunt with visualization of right (RPA) and left (LPA) pul- showedmonary complete arteries. openingLSA, left of subclavian the BT shunt artery. with Reproduced visualization from of right reference (RPA) and[61]. left (LPA) pulmonary arteries. LSA, left subclavian artery. Reproduced from Reference [61]. Stenotic shunts without acute symptoms may undergo electives balloon angioplasty Stenotic shunts without acute symptoms may undergo electives balloon angioplasty or stent implantation across the stenotic BT or Sano shunts (Figures 28 and 29). or stent implantation across the stenotic BT or Sano shunts (Figures 28 and 29).

Figure 28. (A) Selected cine frame in a postero-anterior view, demonstrating discrete narrowing (arrow) of a modified Blalock-Taussig (MBT) shunt. (B). Following stent implantation, this site is wide open (arrow in (B)). DAo, descending aorta; LPA, left pulmonary artery; RPA, right pulmonary artery. Reproduced from Reference [58].

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infrequently, despite the routine use of platelet inhibiting drugs such as aspirin in an attempt to avert such a problem.

Figure 27. Selected cineangiographic frame demonstrating clotted Blalock-Taussig (CBT) shunt (A). After unsuccessful recanalization with mechanical thrombolysis and balloon angioplasty, a stent (St) was implanted (B). Angiography with tip of the catheter (C) in the proximal portion of the stent showed complete opening of the BT shunt with visualization of right (RPA) and left (LPA) pulmonary arteries. LSA, left subclavian artery. Reproduced from reference [61]. Children 2021, 8, 441 22 of 31 Stenotic shunts without acute symptoms may undergo electives balloon angioplasty or stent implantation across the stenotic BT or Sano shunts (Figures 28 and 29).

FigureFigure 28. 28.( (AA)) SelectedSelected cinecine frame in in a a postero postero-anterior-anterior view, view, demonstrating demonstrating discrete discrete narrowing narrowing (arrow) of a modified Blalock-Taussig (MBT) shunt. (B). Following stent implantation, this site is (arrow) of a modiﬁed Blalock-Taussig (MBT) shunt. (B). Following stent implantation, this site is wide open (arrow in (B)). DAo, descending aorta; LPA, left pulmonary artery; RPA, right pulmo- Children 2021, 8, x FOR PEER REVIEWwide open (arrow in (B)). DAo, descending aorta; LPA, left pulmonary artery; RPA, right pulmonary23 of 32 nary artery. Reproduced from Reference [58]. artery. Reproduced from Reference [58].

Figure 29. (A). Cineangiographic frame in a caudal angulation, demonstrating a narrowed (arrow) Figure 29. (A). Cineangiographic frame in a caudal angulation, demonstrating a narrowed (arrow) Sano shunt in a baby with hypoplastic left heart syndrome. (B). A stent (St) catheter is placed across Sano shunt in a baby with hypoplastic left heart syndrome. (B). A stent (St) catheter is placed across the narrowed site with the guide wire positioned deep into the right pulmonary artery (RPA). (C). theNote narrowed the wide site-open with (arrow) the guide Sano wire shunt positioned after the deepstent intowas theimplanted right pulmonary across the arterynarrowed (RPA). seg- (C). Notement. the LPA, wide-open left pulmonary (arrow) Sanoartery; shunt PG, afterpigtail the catheter. stent was Reproduced implanted from across Reference the narrowed [58]. segment. LPA, left pulmonary artery; PG, pigtail catheter. Reproduced from Reference [58]. As discussed above, timely medical, trans-catheter or surgical treatment as appro- As discussed above, timely medical, trans-catheter or surgical treatment as appropriate priate should be undertaken in an attempt to prevent mortality and reduce morbidity. should be undertaken in an attempt to prevent mortality and reduce morbidity.

5.6.5.6. Inter-Current Inter-Current Illnesses Illnesses Inter-currentInter-current illnesses illnesses that that produce produce dehydration, dehydration, acidosis, acidosis, or or high high fever fever may may disturb disturb thethe equilibrium equilibrium between between the the pulmonary pulmonary and and systemic systemic circulations circulations and and the the infant infant may may becomebecome critically critically ill ill [86 [86,87].,87]. Indeed, Indeed, these these inter-current inter-current illnesses illnesses result result in significantin significant inter- in- stageter-stage mortality mortality [86]. [86]. Consequently, Consequently, even even minor minor illnesses illnesses must must be be addressed addressed promptly. promptly. AnyAny baby baby with with high high temperature, temperature, diarrhea, diarrhea, vomiting, vomiting, or or reduced reduced fluid fluid intake intake should should be be watchedwatched until until the the fever fever subsides subsides for for at leastat least 24 h.24 IVh. fluidsIV fluids should sho beuld administered be administered until until the vomiting,the vomiting, or diarrhea or diarrhea resolves, resolves, or until or oral until intake oral intake normalizes. normalizes. Therefore, Therefore, intense intense attention at- intention managing in managing these patients these shouldpatients be should continued be continued by the caregiver by the caregiver [86,87]. Even[86,87] minor. Even illnessesminor illnesses must be must aggressively be aggressively monitored monitored and addressed and add asressed deemed as deemed appropriate. appropriate.

6. Post-Fontan Issues Following completion of Fontan, periodic follow-up is necessary, namely assessment at one, six, and twelve months following Stage IIIB, and once a year thereafter is suggested. Inotropic and/or diuretic therapy is provided as deemed appropriate. Reduc- tion of afterload with an angiotensin-converting enzyme inhibitor (Captopril or Enalo- pril) is instituted by most cardiologists. Anticoagulation with platelet-inhibiting doses of aspirin (2–5 mg/kg/day) in infants and children or clopidogrel (75 mg/day) in adults to prevent thrombo-embolism is a routine for most patients. The results of older types of Fontan (RA-to-PA or RA-to-RV anastomosis either directly or via valved or non-valved conduits) indicated high initial mortality rates varying from 10% to 26% [31,32,101,102]. In addition, the postoperative stay in the intensive care unit (ICU) was long. The initial mortality following staged TCPC without fenestration decreased remarkably with rates ranging from 8% to 10.5% [103–105]. There was a further reduction in mortality rates to 4.5% to 7.5% when TCPC with fenestration was employed [106–108]. A number of complications were detected during follow-up: arrhythmias, obstructed Fontan pathways, persistent shunts, thrombo-embolism, development of cerebro-vascular accidents (CVA), cyanosis, systemic venous to pulmonary venous collateral vessels, and systemic venous congestion including protein-losing enteropathy [10,33,109]. The complications seem to occur more often with earlier types of Fontan than with the current staged TCPC with extra-cardiac conduit and fenestration. When such

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6. Post-Fontan Issues Following completion of Fontan, periodic follow-up is necessary, namely assessment at one, six, and twelve months following Stage IIIB, and once a year thereafter is suggested. Inotropic and/or diuretic therapy is provided as deemed appropriate. Reduction of afterload with an angiotensin-converting enzyme inhibitor (Captopril or Enalopril) is instituted by most cardiologists. Anticoagulation with platelet-inhibiting doses of aspirin (2–5 mg/kg/day) in infants and children or clopidogrel (75 mg/day) in adults to prevent thrombo-embolism is a routine for most patients. The results of older types of Fontan (RA-to-PA or RA-to-RV anastomosis either directly or via valved or non-valved conduits) indicated high initial mortality rates varying from 10% to 26% [31,32,101,102]. In addition, the postoperative stay in the intensive care unit (ICU) was long. The initial mortality following staged TCPC without fenestration decreased remarkably with rates ranging from 8% to 10.5% [103–105]. There was a further reduction in mortality rates to 4.5% to 7.5% when TCPC with fenestration was employed [106–108]. A number of complications were detected during follow-up: arrhythmias, obstructed Fontan pathways, persistent shunts, thrombo-embolism, development of cerebro-vascular accidents (CVA), cyanosis, systemic venous to pulmonary venous collateral vessels, and systemic venous congestion including protein-losing enteropathy [10,33,109]. The complications seem to occur more often with earlier types of Fontan than with the current staged TCPC with extra-cardiac conduit and fenestration. When such complications are detected, they should be quickly investigated and treatment provided as detailed elsewhere [33,34,109].

7. Alternative Approaches to Fontan Circulation Despite improvement in mortality rates with staged TCPC, there is a signiﬁcant morbidity with Fontan. Poor outcomes are seen in children with Down syndrome, heterotaxy syndromes, young age at surgery, high mean PA pressure (>15 mmHg), AV valve insufﬁ- ciency, a morphologic tricuspid valve as systemic AV valve, distorted PAs, poor ventricular function, non-sinus rhythm, presence of a pacemaker, an atrio-pulmonary type of Fontan, no Fontan fenestration, and long cardiopulmonary bypass time [107,110–115]. Therefore, alternative approaches to Fontan are being entertained and these include, one and one-half ventricle repair, primary biventricular repair, staged biventricular repair, and conversion from single-ventricle (SV) to two-ventricle (TV) repair.

7.1. One and One-Half Ventricle Repair In one and one-half ventricle repair, a bidirectional Glenn procedure is undertaken and allows the small RV to handle the reduced volume. The ASD/PFO is closed. Babies with pulmonary atresia with intact ventricular septum whose RVs have not grown ade- quately to support pulmonary circulation are candidates for this approach. In extreme forms of Ebstein’s anomaly with a minimal functional right ventricle, bidirectional Glenn anastomosis may help to improve the hemodynamic outcome. Anecdotal experiences show favorable results, but no organized studies or long-term results are available at this time.

7.2. Primary Biventricular Repair In primary biventricular repair, the AV valves are reconstructed so that nearly similar- sized AV valves are produced and the ASD is closed. The VSD is closed with a patch to create nearly equal-sized ventricles; the patch is relocated to the right in RV-dominant AVSDs and to the left in the LV-dominant AVSDs. Inflow and outflow obstructions, if present, are relieved. and endocardial fibroelastosis resected. The criteria used for selection of patients for primary biventricular repair are not clearly established. A number of echocardiographic, MRI, and cine-angiographic criteria have been examined as reviewed elsewhere [17,116]. A combination of LV Z scores and LV volumes seems to help decide on such a selection. Children 2021, 8, 441 24 of 31

7.3. Staged Biventricular Repair In staged biventricular repair, the ASD and VSD are partly closed at the time of the initial operation, relief of inflow and outflow obstruction, if present, is provided; endocardial fibroelastosis, if present, is resected; and additional Glenn/BT shunt are created to promote blood flow into the left atrium and ventricle. The ASD and VSD are completely closed at the time of a second surgery after the growth of the hypoplastic ventricle is verified. Any other residual abnormalities are also taken care of at the time of second operation.

7.4. Results of Biventricular Repair The data of the results of biventricular repair are limited. The mortality rates ranged between 10.4% and 18% [117–119]. Survival at long-term was excellent and varied between 88% and 90% [117,118,120]. However, the requirement for operative (17.4–34%) and transcatheter (13.4%) re-interventions was high [117,118,120]. Nevertheless, an increase in AV valve Z-scores (−2.8 to −7.4 vs. −0.6 to −2.7) [118], ventricular size Z-scores (−1.0 to −7.5 vs. −2.0 to +1.8) [118], and LV end-diastolic volume Z-scores (from a median of −3.15 to +0.42) [117] was seen at follow-up.

7.5. Conversion from Single-Ventricle to Two-Ventricle Repair During conversion from SV to TV repair, relief of inflow and outflow tract obstructions and restriction of the atrial defect to promote flow through the LV were undertaken in an attempt to rehabilitate the LV. If endocardial fibroelastosis is present, it is also resected. The mortality after conversion from SV to TV is low (1–11%) [117,121] However, operative and catheter re-interventions were needed during follow-up in 19% and 38% patients respectively [121]. While the initial LV Z-scores before Stage I SV palliation were similar, the Z-scores of the LV increased significantly in the SV to TV conversion group and the Z scores decreased in the SV palliation group who have not had SV to TV conversion [122]. Improvement of LV end-diastolic volume by echo from 28.1 to 58.5 mL/m2 was also demonstrated in a limited number of the unbalanced AVSD patients after SV to TV conversion [123].

7.6. Comparison of Various Methods of Intervention When mid-term results of primary, staged biventricular repair, and SV to TV conversion of unbalanced complete AVSDs were examined, there was low morbidity and mortality, but surgical and/or catheter re-interventions were required in 52% of patients [124]. Nathan and her associates evaluated the results of patient subsets who underwent SV palliation, biventricular repair, and SV to TV conversion [117]. The biventricular repair and SV to TV conversion cohorts had similar mortality and the necessity for heart transplantation but these rates were lower than those seen with the SV palliation cohort at a mean follow-up of 35 months [117]. While the need for operative re-interventions was similar in the three cohorts, the need for catheter re-interventions was lower in the biventricular repair cohort than in the other two cohorts. These authors conclude that biventricular repair and SV to TV conversion may be performed with relatively lower mortality and morbidity rates in children with unbalanced AVSDs. SV to TV conversion and biventricular recruitment appear to be a vital option for children with Down syndrome and heterotaxy syndrome because of anatomic and physiologic reasons. Babies with Down syndrome tolerate SV physiology poorly [115]. Children with heterotaxy syndrome have intricate and abnormal AV valve anatomy and require complicated and innovative repair methods. These patients tolerate AV valve insufﬁciency poorly when SV palliation is opted for. Children 2021, 8, 441 25 of 31

8. Other Issues 8.1. Role of Socioeconomic Status, Racial Classification, and Geographical Location in the Management of Single Ventricle Patients The author has practiced pediatric cardiology in five academic centers for the last 50 years and has not discovered significant adverse influence of these factors in the management of CHD patients in general and single ventricle patients in particular. The sole exception is a baby with HLHS whose parents declined to care for their baby (secondary to socioeconomic issues), but the hospital’s Social Service Department rapidly identified adoptive parents so that appropriate care could be provided by the medical staff. However, how much the lack of access to medical care by some of these groups [125] will influence the pediatric cardiac care has not been thoroughly investigated.

8.2. Is There a Need for Centralization of Surgical Care of Complex CHD The available data, though sparse, indicate a slightly better surgical outcomes in larger-volume institutions than in smaller-volume programs. Requiring patients to be transferred to selected centers will impose substantial burden to the parents in addition Children 2021, 8, x FOR PEER REVIEW 26 of 32 to medical insurance coverage issues. Whether such an approach is desirable is at best marginal, given the minor better outcome advantage at large-volume institutions.

8.3.8.3. HybridHybrid ApproachApproach forfor HLHSHLHS InIn HLHS HLHS patients patients with with high high risk risk for for Norwood Norwood surgery, surgery, particularly particularly in in premature premature babies,babies, a a hybrid hybrid approach approach has has been been utilized. utilized. In In the the ﬁrst first stage stage of thisof this procedure, procedure, banding banding of bothof both branch branch pulmonary pulmonary arteries arteries through through median median sternotomy sternotomy and stentand stent implantation implantation into theinto ductus the ductus arteriosus arteriosus via pulmonary via pulmonary arteriotomy arteriotomy (Figures (Figures 30 and 3031 ),and originally 31), originally described de- byscribed Akintuerk by Akintuerk and associates and associates [126], are [126], performed are performed simultaneously simultaneously [126–129]. [126 This– becomes129]. This Stagebecomes I. Stage I.

FigureFigure 30. 30.Selected Selected cine cine frames frames in in postero-anterior postero-anterior (A (A),), lateral lateral (B (B) and) and sitting-up sitting-up (C ()C views,) views, showing showing the position of a stent (St) placed within the ductus via a purse-string suture in the pulmonary the position of a stent (St) placed within the ductus via a purse-string suture in the pulmonary artery in a premature neonate with hypoplastic left heart syndrome during a hybrid procedure. artery in a premature neonate with hypoplastic left heart syndrome during a hybrid procedure. NG, NG, naso-gastric tube; RHC, right heart catheter. Sternal wires are seen. Reproduced from Refer- naso-gastricence [58]. tube; RHC, right heart catheter. Sternal wires are seen. Reproduced from Reference [58]. During stage II, aortic arch reconstruction, atrial septectomy, and a bidirectional Glenn shunt are performed. This is followed by a Fontan conversion (Stage III). It would appear that there is a reduction of early mortality when this approach is used, but some of it is transferred to Stage II. A careful comparison of the hybrid approach with the conventional Norwood procedure did not reveal an improvement in outcome following the hybrid procedure [128]. In addition, a lower systemic and cerebral oxygen delivery with the hybrid procedure than with the Norwood procedure [129] is of concern. It appears that the majority of institutions are reverting to a conventional Norwood procedure with a Sano shunt. Our own personal preference is to reserve the hybrid procedure for premature

Figure 31. Selected cine frames in sitting-up (A) and right anterior oblique (B) views from a right ventricular (RV) angiogram, demonstrating the position of a stent (STENT) placed within the ductus via a purse-string suture in the pulmonary artery during a hybrid procedure, in a premature infant with hypoplastic left heart syndrome shown in Figure 30. Note the opacification of the descending aorta (DAo) via the stent. Bands placed during the hybrid procedure around the right (RPA) (in B) and left (LPA) (in A) pulmonary arteries are seen. ARCH, aortic arch opacified retrogradely via the STENT. NG, naso-gastric tube.

Children 2021, 8, x FOR PEER REVIEW 26 of 32

8.3. Hybrid Approach for HLHS In HLHS patients with high risk for Norwood surgery, particularly in premature babies, a hybrid approach has been utilized. In the first stage of this procedure, banding of both branch pulmonary arteries through median sternotomy and stent implantation into the ductus arteriosus via pulmonary arteriotomy (Figures 30 and 31), originally described by Akintuerk and associates [126], are performed simultaneously [126–129]. This becomes Stage I.

Children 2021, 8, 441 26 of 31 Figure 30. Selected cine frames in postero-anterior (A), lateral (B) and sitting-up (C) views, showing the position of a stent (St) placed within the ductus via a purse-string suture in the pulmonary artery in a premature neonate with hypoplastic left heart syndrome during a hybrid procedure. babies with HLHS and those that have other co-morbidities that preclude safe Norwood NG, naso-gastric tube; RHC, right heart catheter. Sternal wires are seen. Reproduced from Refer- palliation. ence [58].

FigureFigure 31. 31.Selected Selected cinecine framesframes inin sitting-upsitting-up (A)) and right anterior oblique oblique ( (BB)) views views from from a a right right ventricular (RV) angiogram, demonstrating the position of a stent (STENT) placed within the ventricular (RV) angiogram, demonstrating the position of a stent (STENT) placed within the ductus ductus via a purse-string suture in the pulmonary artery during a hybrid procedure, in a prema- via a purse-string suture in the pulmonary artery during a hybrid procedure, in a premature infant ture infant with hypoplastic left heart syndrome shown in Figure 30. Note the opacification of the withdescending hypoplastic aorta left (DAo) heart via syndrome the stent. shown Bandsin placed Figure during 30. Note the thehybrid opaciﬁcation procedure of around the descending the right aorta(RPA) (DAo) (in B via) and the left stent. (LPA) Bands (in A placed) pulmonary during arteries the hybrid are seen. procedure ARCH, around aorticthe arch right opacified (RPA) retro- (in B) andgradely left (LPA) via the (in STENT.A) pulmonary NG, naso arteries-gastric are tube. seen. ARCH, aortic arch opaciﬁed retrogradely via the STENT. NG, naso-gastric tube.

8.4. Cardiac Transplantation Transplantation of the heart is another available surgical alternative [50] for patients with HLHS and other complex CHD in the neonate. Following the report of Bailey and

associates [50], several institutions have applied this procedure to address HLHS. However, because of scarcity of donor hearts, most institutions have reverted back to Norwood. At the present time, cardiac transplantation is employed in patients with failed Fontan. However, since these patients, having been exposed to cardiopulmonary bypass and blood products, may develop HLA antibodies, which increases their risk of antibody mediated rejection following transplantation.

9. Summary and Conclusions Several cardiac defects have functionally single ventricle; notable of these are: hypoplastic left heart syndrome, tricuspid atresia, single ventricle (DILV), unbalanced AV septal defect, mitral atresia, and others. Single ventricle physiology is dissimilar from that of biventricular physiology and a fragile balance of the blood ﬂows between the pulmonary and systemic circulations should be preserved. These babies are generally man- aged by staged total cavo-pulmonary connection (Fontan) in three stages. The prevalence of inter-stage mortality is high (5–15%). It is more frequent between Stages I and II than between Stages II and III. The inter-stage mortality is largely associated with: restrictive atrial communication, obstruction of the aortic arch, distortion/stenosis of the pulmonary arteries, AV valve insufﬁciency, shunt blockage, and inter-current illnesses. Periodic clinical evaluation and echocardiographic or other imaging studies to detect these abnormalities Children 2021, 8, 441 27 of 31

should be systematically undertaken and when identiﬁed, they should be promptly treated. Even minor inter-current illnesses must be addressed aggressively. Post-Fontan complications decreased remarkably following the introduction of staged TCPC with extracardiac conduit and fenestration with succeeding catheter-based fenestration occlusion. Because of the problems identiﬁed with single ventricle (Fontan) repair, alternative methods, namely one and one-half ventricle repair, primary biventricular repair, staged biventricular repair, and conversion from SV to TV repair, are being considered.

Funding: This research received no external funding. Institutional Review Board Statement: Institutional Review Boards approved the respective studies. Informed Consent Statement: Informed consent was obtained from all subjects involved in the respective studies. Data Availability Statement: Not applicable. Conﬂicts of Interest: The author declares no conﬂict of interest.

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