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\begin{document}

\title{A Review of the Therapeutic Management of Multiple Ventricular Septal
Defects}



\author[1]{Ujjwal Chowdhury}%
\author[2]{Robert Anderson}%
\author[3]{Diane E. Spicer}%
\author[1]{Lakshmi  Sankhyan}%
\author[4]{Niwin George}%
\author[1]{Niraj Pandey}%
\author[1]{Balaji Arvind}%
\author[1]{Shikha Goja}%
\author[1]{Vishwas Malik}%
\affil[1]{All India Institute of Medical Sciences}%
\affil[2]{1Institute of Genetic Medicine, Newcastle University, Newcastle-upon-Tyne, United Kingdom Birmingham Children’s Hospital, Birmingham, United Kingdom}%
\affil[3]{Johns Hopkins All Children's Hospital}%
\affil[4]{Affiliation not available}%


\vspace{-1em}



  
  \date{May 19, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Background and Aim: We showed in our anatomical review, ventricular
septal defects existing as multiple entities can be considered in terms
of three major subsets. We address here the diagnostic challenges,
associated anomalies, the role and techniques of surgical instead of
interventional closure, and the outcomes. including reinterventions, for
each subset. Methods: We reviewed 80 published investigations, noting
radiographic findings, and the results of clinical imaging elucidating
the location, number, size of septal defects, and associated anomalies,
and the effect of severe pulmonary hypertension. Results: Overall,
perioperative mortality for treatment of residual multiple defects has
been cited to be between zero and 14.2\%, with morbidity estimated
between 6\% to 13\%. Perioperative mortality is twice as high for
perimembranous compared to muscular defects, with need for reoperation
is over four times higher. Perventricular hybrid approaches are useful
for closure of high anterior or apical defects. Overall, results have
been unsatisfactory. Pooled data reveals incidences between 2.8\% and
45\% for device-related adverse events. Currently, however, outcomes
cannot be assessed on the basis of the different anatomical sub-sets.
Conclusions: We have addressed the approaches, and the results, of
therapeutic treatment in terms of co-existing discrete defects, the
Swiss-cheese septum, and the arrangement in which a solitary apical
muscular defect gives the impression of multiple defects when viewed
from the right ventricular aspect. Treatment should vary according to
the specific combination of defects.%
\end{abstract}%



\sloppy


\textbf{A Review of the Therapeutic Management of Multiple Ventricular
Septal Defects}

\textbf{Running title: Multiple ventricular septal defects}

\textbf{Ujjwal Kumar Chowdhury, MCh, Diplomate NB\textsuperscript{3}}

\textbf{Robert H. Anderson, BSc, MD, PhD (Hon), FRCPath, FRCS Ed
(Hon)\textsuperscript{2}}

\textbf{Diane E. Spicer, BSc\textsuperscript{1}}

\textbf{Lakshmi Kumari Sankhyan, MCh\textsuperscript{4}}

\textbf{Niwin George, MCh\textsuperscript{3}}

\textbf{Niraj Nirmal Pandey, DM\textsuperscript{3}}

\textbf{Arvind Balaji, DM\textsuperscript{3}}

\textbf{Shikha Goja, MS\textsuperscript{3}}

\textbf{Vishwas Malik, DM\textsuperscript{3}}

\textsuperscript{1}Heart Institute, Johns Hopkins All Children's
Hospital, St. Petersburg, Florida, USA

and Department of Pediatric Cardiology, University of Florida,
Gainesville, Florida, USA

\textsuperscript{2}Institute of Biomedical Sciences, Newcastle
University, Newcastle-upon-Tyne, United Kingdom

\textsuperscript{3}Cardiothoracic Centre, All India Institute of Medical
Sciences, New Delhi, India

\textsuperscript{4}Department of Cardiothoracic Surgery, All India
Institute of Medical Sciences, Bilaspur, Himachal Pradesh, India

\emph{Corresponding author:}

\textbf{Dr. Ujjwal Kumar Chowdhury, M.Ch., Diplomate NB}

Professor

Department of Cardiothoracic and Vascular Surgery

AIIMS, New Delhi-110029, INDIA

Tel.: 91-11-26594835

Fax: 91-11-26588641

Email: ujjwalchowdhury@gmail.com

Orcid ID: http: //orcid.org/0000-0002-1672-1502

\textbf{Word Count:} Abstract (229), Text (7232), References (2346),
Figure Legends (444)

\textbf{Statement of human rights/ethical approval:} The authors assert
that all procedures contributing to this study comply with the ethical
standards of the relevant national guidelines on human experimentation
and with the Helsinki declaration of 1975, as revised in 2008.

\textbf{Conflict of interest} : No potential conflicts exist

\textbf{Source of funding} : No funding was provided

\textbf{Availability of Data:} Data available in the articles cited in
references.



\textbf{Abstract}

\textbf{Background and Aim} : We showed in our anatomical review,
ventricular septal defects existing as multiple entities can be
considered in terms of three major subsets. We address here the
diagnostic challenges, associated anomalies, the role and techniques of
surgical instead of interventional closure, and the outcomes. including
reinterventions, for each subset.

\textbf{Methods:} We reviewed 80 published investigations, noting
radiographic findings, and the results of clinical imaging elucidating
the location, number, size of septal defects, and associated anomalies,
and the effect of severe pulmonary hypertension.

\textbf{Results:} Overall, perioperative mortality for treatment of
residual multiple defects has been cited to be between zero and 14.2\%,
with morbidity estimated between 6\% to 13\%. Perioperative mortality is
twice as high for perimembranous compared to muscular defects, with need
for reoperation is over four times higher. Perventricular hybrid
approaches are useful for closure of high anterior or apical defects.
Overall, results have been unsatisfactory. Pooled data reveals
incidences between 2.8\% and 45\% for device-related adverse events.
Currently, however, outcomes cannot be assessed on the basis of the
different anatomical sub-sets.

\textbf{Conclusions} : We have addressed the approaches, and the
results, of therapeutic treatment in terms of co-existing discrete
defects, the Swiss-cheese septum, and the arrangement in which a
solitary apical muscular defect gives the impression of multiple defects
when viewed from the right ventricular aspect. Treatment should vary
according to the specific combination of defects.

\textbf{Keywords:} Congenital heart disease, Muscular ventricular septal
defects, Percutaneous device closure, Perventricular hybrid device
closure, Pulmonary artery banding, Swiss-cheese ventricular septal
defects



\textbf{Introduction}

As we discussed in our anatomical review, multiple ventricular septal
defects are present when there are multiple channels within the muscular
septum, for example producing the arrangement well described as the
Swiss-cheese septum. This arrangement is different, however, from the
situation in which a muscular defect co-exists with a defect located in
the perimembranous region, or when there are multiple discrete defects
within the muscular septum. These combinations, furthermore, differ from
the arrangement in which a solitary defect within the muscular septum
can seem to be multiple when it is viewed from the right ventricle,
being crossed by apical trabeculations (Figure 1). The surgical strategy
for closure of isolated defects, even if the defect itself is large, is
now standardized. The management of multiple defects, however, remains
nebulous, the more so since as we have shown the multiple defects
themselves can be considered in terms of anatomic subsets. Our review
has revealed the wide variations in practice between centers reporting
their approach to these various sub-sets, with some of the approaches
tailored specifically to one of the sub-sets. Because of this, it is
difficult to determine the ideal operative approach. This is due, in
part due to the paucity of comparative reports. It also reflects a lack
of long-term follow-up. In this surgical part of our review, we assess
the options available for potential management of each of the sub-sets
identified subsequent to our anatomical analysis.

\textbf{Historical Background}

In terms of surgical closure of multiple defects in general, the
landmark experience was reported by Kirklin and colleagues in
1980.\textsuperscript{1} They reported hospital mortality of 14\%, and a
need for reoperation to close residual defects in 28\%. With regard to
the Swiss-cheese septum, in an attempt hermetically to close all
defects, and avoid a left ventriculotomy, Kitagawa and colleagues, in
1998, described the technique of using an oversized patch placed into
the left ventricle via the right atrium.\textsuperscript{2} As an
alternative, they also described the ``sandwich technique'', achieved by
transfixing the muscular edge of the defects to the anterior free wall
of the ventricle after transecting the moderator band and right
ventricular trabeculations to provide optimal
exposure.\textsuperscript{2} Subsequent to this account, again with
regard to the Swiss-cheese septum, Black and colleagues, in 2000,
described closure of the defects using a single large autologous
pericardial patch.\textsuperscript{3} Cetin and colleagues, in 2005, in
contrast, used a composite patch of pericardium and Dacron graft. Both
patches were placed using a right atrial
approach.\textsuperscript{4}Mace and colleagues then suggested placing
several intermediate fixation stitches to prevent septal
bulging.\textsuperscript{5} In 2001, Yamaguchi and associates had
described a ``felt sandwich technique''. This involved sandwiching the
septum itself between two polyester felt patches placed in the left and
right ventricles without need for ventriculotomy.\textsuperscript{6,7}
Brizard and associates, in 2004, reported a similar technique using
intraoperative echocardiography guidelines with excellent
results.\textsuperscript{8} In 2006, Alsoufi and colleagues described
transatrial re-endocardialization without dividing any trabeculations or
the moderator band.\textsuperscript{9}Much earlier, Stark and
associates, in 1992, had closed the defects using a fibrin seal of human
origin.\textsuperscript{10}

At a much earlier date, Aaron and Lower, in 1975, had indicated that
exposure and repair could be much easier when seemingly multipl defects
were approached through the left ventricle.\textsuperscript{11} This was
because, as we showed in our anatomical review, a solitary left
ventricular opening was often viewed as multiple orifices seen from the
right ventricular aspect. As we also explained in our first part,
however, this variant is not the same as the Swiss-cheese septum. And.
although this approach can facilitate the repair, debate has continued
regarding its potential sequels of a left ventriculotomy. Surgical
exposure through a left ventriculotomy can also, at times, be
disappointing. With the problems of a left ventriculotomy in mind,
therefore, others have advocated and demonstrated the safety and
effectiveness of an apical right
ventriculotomy.\textsuperscript{12-15}Still others have proposed a
two-staged approach, with an initial band placed on the pulmonary trunk,
but this strategy has its own inherent morbidity and
mortality.\textsuperscript{16,17}

Transcatheter closure is now well recognized as an additional
therapeutic option for closure of ventricular septal defects. The option
was first reported by Lock and associates from Boston using the Rashkind
devices.\textsuperscript{18} Then, in the late 1990s, a Nitinol device
was added to the armamentarium of the
interventionist.\textsuperscript{19-21} The interventional approach may
be particularly suitable for multiple muscular septal defects located in
the mid, apical, posterior, and anterior parts of the muscular
septum.\textsuperscript{20-30} For most cardiac centers, however,
devices delivered via catheters are not recommended in neonates and
infants because of the need for a stiff guide wire. This can rupture the
mitral valve, tear the septum, or invoke ventricular arrhythmias and
cardiac arrest. In the new millennium, nonetheless, multiple groups have
reported intraoperative perventricular closure, with encouraging early
outcomes.\textsuperscript{22-28}

\textbf{Methods}

We searched the extant literature for the described instances of the
management of multiple ventricular septal defects. We then collated the
demographics, the anatomical details encountered, the indications for
surgery or intervention, and outcomes of management, including
reinterventions. The search engines employed were PubMed, Google
Scholar, Cochrane Database for Systematic Reviews, Cochrane Central
Register of Controlled Trials, Ovid Medline, ACP Journal Club, Ovid
EMBASE, and Database of Abstracts of Review of Effectiveness in all
languages.

Analysis was based initially on the individualized review of the initial
77 investigations. These were then incorporated, as far as possible,
with the results and recommendations from the Congenital Heart Surgery
Database as provided by the Society of Thoracic Surgeons. The society
has collated the findings from 116 participating centers. We also took
note of the scientific statement of the American Heart Association,
endorsed by the American Academy of Pediatrics and the Society for
Cardiovascular Angiography and Intervention.\textsuperscript{29-32} So
as to unify the divergent approaches to the description and
categorization of ventricular septal defects, we assessed the reports,
as far as was possible, on the basis of the categorization proposed for
the Eleventh Iteration of the International Classification of Disease,
as produced by the International Society for Nomenclature of Pediatric
and Congenital Heart Diseases.\textsuperscript{33,34}

Due to the limited sizes of the descriptive case series reported, and
the heterogeneity of clinical states at the time of surgical
intervention, along with the difficulties in selection of appropriate
cardiac quantifiable end points, we are unable to perform a
meta-analysis. Our analysis therefore, is based on review of case
reports, and small case series, along with incorporation of data from
the extensive series published by the Society of Thoracic Surgeons
Registry, the scientific statement of the American Heart Association,
and the report from the International Society for Nomenclature of
Pediatric and Congenital Heart Diseases.\textsuperscript{28-34}

\textbf{Results}

\textbf{Incidence}

The prevalence of multiple defects in the muscular ventricular septum is
low, occurring in less than one-fifth of patients in whom deficiency of
the ventricular septum is the main finding, and in no more than 2\% of
those with co-existing lesions such as discordant ventriculo-arterial
connections, tetralogy of Fallot, or atrioventricular septal
defect.\textsuperscript{35,36}

\textbf{Diagnosis}

Review of the cases show that, on presentation, the great majority of
patients had evidence of congestive cardiac failure and pulmonary
hypertension in early infancy, with these features often reported in the
neonatal period when associated lesions are present. The chest
roentgenogram usually reveals a moderate increase in the cardiothoracic
ratio, along with pulmonary plethora. When present, multiple muscular
defects are more frequently diagnosed by transesophageal color coded
echocardiography, rather than transthoracic echocardiography. The
identification of the morphology, and location, of the defects is
important for selection of the appropriate therapeutic approach (Figures
2A, 2B).\textsuperscript{1-32,37-78}

Some investigators have performed ``en-face'' reconstruction of multiple
septal defects as viewed from the right ventricle, based on orthogonal
echocardiographic views, so as to plan the surgical approach, and
predict the likelihood of postoperative heart block or the occurrence of
residual defects. Features noted have included the location and
dimensions of the defects, the distance of separation between additional
defects, the relationship to various right ventricular septal
landmarks.\textsuperscript{37} Contrast-enhanced and multidetector
computed-tomographic angiocardiography in angled oblique views have also
proved helpful in ascertaining the morphology and location of the septal
defects, together with evaluation of the aortic arch and its branches
(Figures 3A-3F, 4A-4F). Cardiac catheterization and angiocardiography
may still be indicated in some circumstances for evaluation of
associated cardiac anomalies. Despite echocardiography and
angiocardiography, it can still be difficult to recognize the boundaries
of the defect, particularly in the setting of the Swiss-cheese
septum.\textsuperscript{1-32,37-73} Indeed, we found several reports
describing additional defects recognized in the intraoperative and
postoperative period, as well as at necropsy.\textsuperscript{7,13}

Associated cardiac and extracardiac anomalies were reported in one-third
to three-quarters of patients. Cardiac anomalies included common atrium,
Ebstein-like anomaly of the tricuspid valve with tricuspid stenosis or
regurgitation, endocardial fibroelastosis of the right ventricle,
pulmonary stenosis, patchy-endocardial sclerosis of the left ventricle,
downward displacement of the tricuspid valve, aneurysm of the membranous
septum, midline heart, juxtaposed right atrial appendages, double
orifice mitral valve with mitral stenosis, double outlet right
ventricle, Taussig-Bing anomaly, atrioventricular septal defect,
bilateral superior caval veins, subaortic stenosis, left superior caval
vein to coronary sinus, unroofed coronary sinus, tetralogy of Fallot,
atretic orifice of the coronary sinus, common arterial trunk, straddling
tricuspid valve, partially anomalous pulmonary venous connection,
transposition, right isomerism, pulmonary atresia, divided left atrium,
left isomerism, left ventricular outflow tract obstruction, interruption
of inferior caval vein, hypoplastic left ventricle, hypoplastic right
ventricle, congenital aortic stenosis, congenitally corrected
transposition, and criss-cross ventricles. Associated extracardiac
anomalies included patency of the arterial duct, hypoplasia of aortic
isthmus, coarctation of aorta, interrupted aortic arch, double aortic
arch, and hypoplastic aortic
arch.\textsuperscript{6-8,13-16,18,19,23,24,31,32,37}

\textbf{Surgical Approaches and Management}

There is currently no consensus regarding the management of multiple
muscular septal defects, particularly concerning the timing and type of
interventions. For those with pulmonary hypertension and congestive
cardiac failure, medical management alone is ineffective. It follows
that those diagnosed with multiple defects at an early age, with
symptoms of congestive cardiac failure and/or pulmonary hypertension,
and with volume overload of the left ventricle, should undergo surgical
or hybrid intervention to prevent ventricular dilation and dysfunction,
arrhythmias, aortic regurgitation, and ongoing pulmonary
hypertension.\textsuperscript{35,36} The urgency of intervention will be
determined primarily by the severity of presenting symptoms, and by the
associated cardiac anomalies if present. The finding of the Swiss-cheese
septum, along with major associated cardiac lesions, significantly
increases the risks of operation. Such patients are managed on an
individual basis.\textsuperscript{2-13}

Surgical management has evolved with time. Moderately hypothermic
cardiopulmonary bypass at 32\selectlanguage{ngerman}°C, with cold cardioplegia, is now the most
popular technique. Several investigators have used deep hypothermic
circulatory arrest for patients with low body weight, complicated
anatomy, and/or associated congenital cardiac
malformations.\textsuperscript{6-8,43} The mean duration of circulation
arrest was 40 minutes, with a range of 20-60
minutes.\textsuperscript{6-8,43}

Various imaging techniques have proven their value for intraoperative
identification of the defects. Either cross-sectional or
three-dimensional color Doppler echocardiography, including
transesophageal imaging, and echocardiographic en-face reconstruction of
the right ventricular septal surface, have emerged as superior
diagnostic modalities.\textsuperscript{1-72}

While the general approach to multiple muscular septal defects is
similar to that of isolated ventricular septal defects, their presence
poses particular challenges for their identification and closure. As a
consequence, a wide range of therapeutic approaches have been described.

When multiple defects are located in the muscular septum, oozing of
blood can be demonstrated through the defects into the right ventricle
despite adequate left ventricular venting. Several maneuvers have been
used to identify the defects, including intraoperative epicardial
echocardiography. When using a transtricuspid approach, larger defects
can easily be located via the tricuspid valve. A blunt tip right angled
forceps can be placed gently through the hole, without using any force
except for the weight of the angled clamp. A DeBakey forcep is then held
in the left ventricle, either placed through the larger inlet muscular
defect, or via an atrioseptostomy. The metallic sound of two metal tips
touching each other indicates that the right angled clamp has
successfully been placed through the second defect. Either a No.3
Sutupak silk suture, or a No.8 Foley catheter, can be looped through the
additional septal defects to facilitate closure (Figures 5A-5F).

Most investigators have performed postoperative transesophageal
echocardiography and saturation determination. Large residual shunts
detected intraoperatively with a pulmonary-to-systemic blood flow ratio
of greater than 2, have been managed either by reinstitution of bypass
and reexamination of the ventricular septum, or by hybrid device
closure.\textsuperscript{7,20-24,28-32,45}

Although catheter-based techniques appear promising, they are not yet
widely used to close the entire spectrum of multiple septal defects in
all age groups. For the time being at least, surgical repair remains the
gold standard.\textsuperscript{1-26}

On the basis of our initial review, we have sought, as far as possible,
to assess the therapeutic options according to the specific anatomical
combinations of defects. Each option, of course, may further be tailored
according to the needs of the individual patient and surgeon.

\textbf{Multiple discrete muscular defects}

Several options have been suggested, although each option may be
tailored to the individual patient, and surgeon. The decision to embark
upon a one-stage repair rests with the surgeon, who must decide whether
all significant defects can safely be closed. Should the repair be
unsuccessful, leaving a residual shunt of greater than 1.5:1, after a
prolonged pump run and potential associated myocardial ischemia, a
difficult postoperative course, and death can be expected. Placement of
a band on the pulmonary trunk allows for growth before attempted
surgical or interventional closure. Ventricular hypertrophy,
furthermore, may result in closure of smaller
defects.\textsuperscript{16,17,38-40}

Separate patch closure of multiple apical defects

Many investigators have successfully used a transatrial approach when
multiple muscular defects exist cranial to the base of the anterior
papillary muscle, and in the middle part of the apical muscular septum.
These defects can reliably be closed by dividing the moderator band, and
the body of the septomarginal trabeculation. For posteroinferior and
inlet defects, the septal leaflet of the tricuspid valve may require
temporary detachment for optimal
exposure.\textsuperscript{7,12,14,38,41} A transpulmonary or an approach
via a right ventriculotomy have been described for anterosuperior
muscular defects. Knitted Dacron, and polytetrafluoroethylene synthetic
patches have been employed by various investigators, including
us.\textsuperscript{7,12,14,38,41}

Right atrial approach with a single oversized patch on the right
ventricle (the septal obliteration technique)

Black and Cetin inserted a single large autologous pericardial patch and
composite patch of Dacron lined with preserved heterologous pericardium
respectively through the transtricuspid route without dividing the
moderator band.\textsuperscript{3,4}

Seddio and associates also described this technique using a large
autologous pericardial patch after dividing the moderator
band.\textsuperscript{42} Kitagawa and associates used a
polytetrafluoroethylene patch, placed on the left ventricular side of
the septum after dividing the moderator band (Figures 6A,
6B).\textsuperscript{2,41}

These techniques are useful when multiple discrete defects are present
in the posterior and apical parts of the septum, caudal to the moderator
band.\textsuperscript{1-4,41,42} Intraoperative transesophageal
echocardiography and cardioscopy from the left side of the septum via
the aortic root have been employed for identification of the defects
from the left side by these investigators.

Right atrial approach with a single large patch on the right ventricle
and intermediate fixation

In 1996, Mace and associates used a right atrial approach and inserted a
single large patch to cover the right side of the apical muscular
septum, adding intermediate fixation stitches at the junction between
the septum and anterior right ventricular free wall to prevent septal
bulging (Figures 7A, 7B).\textsuperscript{5}

Intraoperative echocardiography and double-patch device sandwiching the
septum

In 2004, Brizard and associates developed a unique technique in which
the discrete defects were located with intraoperative epicardial
echocardiography and transfixed with a guide wire inserted directly
through the right ventricular free wall.\textsuperscript{8} The multiple
ventricular septal defects were then sandwiched with custom made
multilayered double patches from both sides of the ventricular septum
under cardioplegic arrest via a right atriotomy. Multiple patches were
used for distantly located ventricular septal defects. For closely
related ventricular septal defects, oversized patches were used for
collective closure of the septal defects.\textsuperscript{8}

Device closure of multiple midmuscular septal defects

In cases of multiple septal defects separated by a moderate margin,
double and triple devices have been inserted, either by a hybrid
approach or percutaneously. in select
institutions.\textsuperscript{21-28,52-55}

\textbf{Combined perimembranous and inlet muscular septal defects}

Black and associates used a standard patch to close the perimembranous
defect, and inserted a pericardial patch to obliterate the associated
muscular ventricular septal defect.\textsuperscript{3} Serraf and
associates also used a patch to close the perimembraneous defect, but
used pledget-reinforced mattress sutures for the smaller muscular
defect.\textsuperscript{43} Alsoufi and associates used separate patches
to close combined perimembranous and muscular defects, but used Dacron
patches to close large apical defects located underneath the moderator
band.\textsuperscript{9} These latter authors employed a strategy of
re-endocardialization for associated smaller septal defects without
dividing any major trabeculations. using double-layered suturing of the
septal trabeculations with fine, superficial, subendocardial running
sutures.\textsuperscript{9} Yashimura and associates closed the
perimembranous defects using a Dacron polyester patch. Like Serraf and
colleagues, they used pledget reinforced mattress sutures for the
muscular defects, or re-endocardialisation using 6-0
prolene.\textsuperscript{44} Closure of these ventricular septal defects
using separate patches, however, entails the risks of surgical complete
heart block, since the conduction axis runs in between two ventricular
septal defects.\textsuperscript{38,43} Because of this, closure has been
recommended and practiced using a single patch. Another option is to
temporize by banding the pulmonary trunk, as described above,
anticipating that growth will facilitate the placement of separate
patches (see below).

Patch closure of perimembranous defect and device closure of muscular
defects

A combination of hybrid transcatheter closure of the muscular defect,
followed by surgical closure of the perimembranous defect, has been
described in cases of locations deemed surgically inaccessible, this
avoiding ventriculotomy, reducing the need for extensive septal
suturing, and decreasing the bypass time.\textsuperscript{29-32,45}

Device closure of perimembranous and outlet septal defects

Although not approved by Food, Drug and Administration, USA, several
institutions have performed interventional closure of associated
perimembranous and outlet septal defects using perimembranous Amplatzer
device in anatomically suitable patients weighing more than 8
kilograms.\textsuperscript{54,55,66,67,73-78}

Staged approach with an initial banding of the pulmonary trunk

As suggested above, in small infants with combined perimembranous and
inlet muscular defects separated by a thin muscle bundle, some
investigators have preferred initial banding of the pulmonary trunk,
thus promoting growth of the muscle bar containing the conduction axis
which separates the defects.\textsuperscript{14,16,17,43} The hope is
that the passage of time will permit growth of the muscle bar
interposing between perimembranous and muscular defects, thus allowing
placement of sutures to secure separate patches at the time of
second-stage surgery.\textsuperscript{16,17,38-40} This strategy is
helpful in preventing iatrogenic heart block.

\textbf{Apical ventricular septal defects}

The ``Felt Sandwich Technique''

Several authors have described this technique, approaching the septum
through the transtricuspid route for multiple muscular defects located
just underneath the moderator band or at the apex of the heart, where it
is difficult to place sutures, and hence making the defects unsuitable
for direct closure.\textsuperscript{7,44,79} A 3F Nelaton catheter
(Bard, Haverhill, Mass) was railroaded through the septal defect. The
Nelaton catheter led an oversized circular polyester felt patch mounted
on a 4-0 braided polyester suture. The suture ends were then passed
through a slightly smaller polyester felt patch on the right ventricular
side of the septum. The braided polyester suture was then tied, thereby
sandwiching the septum between two polyester felt patches (Figure
8).\textsuperscript{7,44,79}

Modified Sandwich technique

Kitagawa and associates modified the ``sandwich'' technique for multiple
small anterior muscular septal defects. Using the transtricuspid route,
they passed mattress sutures through the septum, continuing through the
anterior wall of the ventricle away from the anterior interventricular
coronary artery, and finally through a felt buttress effectively to
close the defects by ``sandwiching'' them against the anterior wall of
the heart (Figure 9).\textsuperscript{2,41}

Apical right ventriculotomy approach

This approach has been described when multiple ventricular septal
defects are located between the left and right ventricular apex,
antero-inferior to the moderator band. Surgical closure has been
accomplished through a small right ventricular incision of approximately
2 cm using a sandwich technique under bypass and hypothermic
cardioplegic arrest (Figures 10A-10C).\textsuperscript{12-15}

Device closure

Apical multiple septal defects have been closed using a Clampshell
device via percutaneous and hybrid perventricular
approaches.\textsuperscript{21-28,51-55}

\textbf{Spurious multiple ventricular septal defects}

Limited apical left ventriculotomy approach

This approach has been employed for multiple apical muscular defects
inaccessible through the transtricuspid route. When viewed from the left
side of the septum, of course, a single discrete defect is
observed.\textsuperscript{11,46-49} A short ``fish-mouth'' incision
about 1 cm long is made at the apex of the left ventricle away from, and
parallel to the interventricular coronary arteries on a non-vented heart
filled with cardioplegia solution, avoiding injury to the anterior
papillary muscles of the mitral valve. The recommended incision is
usually smaller than the size of the defect. The ventriculotomy is
closed by a double layer of continuous polypropylene suture, sandwiching
a portion of the patch used to close the septal defect without injuring
the coronary arteries (Figure 11).\textsuperscript{2,11,41,43,46-50}

Apical right ventriculotomy

This approach has also been employed in diagnosed cases of the large
muscular defects that seem to be multiple because of the overlying right
ventricular apical septal trabculations.\textsuperscript{12-15}When a
large acute marginal branch is present, a small right ventriculotomy of
approximately 2 cm is performed 4 mm lateral to the left anterior
interventricular coronary artery. When the acute marginal branch is less
prominent, a transverse incision is made above the acute margin of the
heart. Trabeculations overlying the margins of the septal defect were
taken down sharply to expose the edge of the defect. 5-0 polypropylene
sutures are placed full thickness at the superior margin of the defect,
maintaining pledgets on the left ventricular side. The ventricular
septal defect was closed with a Dacron patch (Figures
10A-10C).\textsuperscript{12-15}

\emph{\textbf{Device closure}}

For defects with multiple right ventricular openings, and a single left
ventricular opening, the Amplatzer delivery system should be positioned
through the largest right ventricular opening to avoid compression of
the device. For those defects with so-called ``wind sock type''
morphology, with a large left ventricular orifice and smaller right
ventricular sites of exit, the device should be placed within the wind
sock to avoid interference with the conduction system and/or aortic
valve. Since patients with previous banding of the pulmonary trunk may
not exhibit shunting across the multiple defects, it is crucial to
deband prior to any attempted hybrid closure. It is always desirable to
cross the largest defect first and subsequently cross the smaller
defects.\textsuperscript{21-28,51-55}

\textbf{Swiss-cheese defects}

The ``septal obliteration technique'' using a single oversized patch on
the right ventricle

In patients with the true Swiss-cheese septum, adequate closure of the
multiple defects essentially requires ventricular septation. An
oversized composite patch of Dacron lined with preserved heterologous
pericardium with multiple points of intermediate fixation was used by
Cetin and other investigators with satisfactory short-term
results.\textsuperscript{4} Their outcome may be complicated by abnormal
ventricular function, and may require cardiac
transplantation.\textsuperscript{4,8,42,48,49,56-61} This technique has
also been described for multiple discrete muscular defects located in
the posterior, and apical part of the septum caudal to the moderator
band.

Conventional, absorbable, and telemetric adjustable FloWatch banding
techniques

Conventional, absorbable, or telemetrically adjustable bands placed on
the pulmonary trunk have been employed in several institutions as
initial palliation in premature infants with low body weight having
either multiple muscular defects, or alternatively the true Swiss-cheese
septum. This protocol has also been employed in cases of multiple septal
defects having anatomical peculiarities predisposing to postoperative
heart block, and residual defects in a small
infant.\textsuperscript{14,16,17,43}

Two-patch and right ventricle apex exclusion technique

Wu and Perez-Negueruela developed this technique of closing either
multiple large apical muscular or the Swiss-cheese septum using a
procedure that involved exclusion of the right ventricular apex through
the tricuspid route. Associated septal defects were closed
separately.\textsuperscript{50,62} A 10-Fr Foley catheter was railroaded
through a defect to facilitate visualization of the overall arrangement
by applying gentle traction. Two patches of bovine pericardium were used
to close the defects, excluding the apex of the right ventricle (Figure
12).\textsuperscript{62} The first bovine pericardial patch was sutured
at the upper edge of the deficient septum and moderator band using a 6-0
polypropylene suture. A second pericardial patch was used to close the
defects present between the moderator band and anterior free wall of the
right ventricle. Some investigators have used a 5-0 polypropylene purse
string suture to exclude the apical portion of the right ventricle,
thereby occluding multiple defects between the trabeculations of the
right ventricle.\textsuperscript{50,62}

Repair of the Swiss-cheese septum using biologic glue

In 1992, Stark and associates developed this technique using fibrin seal
of human origin (Tissucal, Immuno-France, Orly, France). Fibrin seal
consists of concentrated lyophilized fibrinogen enriched with factor
XIII and fibronectin. An aprotinin solution warmed to 37°C was added to
the fibrinogen.\textsuperscript{10} After closing any larger defects
either using a pericardial or composite Dacron fabric lined with
pericardium, and direct pledget supported sutures, the fibrin seal was
injected into a dry operating field. Precautions were taken to avoid too
deep an insertion into the left ventricle. Other authors subsequently
reported good results with fibrin glue.\textsuperscript{10,63}

Transcatheter closure

Percutaneous closure of such defects with catheter-delivered devices has
been extensively explored in select
institutions.\textsuperscript{19-21}Delivery in the catheterization
laboratory by percutaneous femoral exposure is generally limited to
older children weighing more than 5-10 kg, to minimize femoral vessel
injury. The size of the Amplatzer muscular defect occlude ranges in size
from 4-18 mm.\textsuperscript{19-28} Depending on the location, number,
and size of the muscular defects, several technical details need to be
taken into account. The proximity of the tricuspid valve for defects
located below the moderator band may cause entrapment of the sheath in
the chordal apparatus.

Hybrid closure of multiple apical muscular septal defects

Hybrid, perventricular delivery of the device involves direct access to
the right ventricle via a surgical incision, which may be median
sternotomy, or a limited subxiphoid, parasternal or infra-axillary
incision.\textsuperscript{23-25,51-55,69} The procedure is performed on
a beating heart without fluoroscopy using continuous transesophageal or
epicardial echocardiographic guidance. The approach to device delivery
include direct puncture into the right ventricle, direct transthoracic
puncture, and placement with the heart open under cardiopulmonary
bypass.\textsuperscript{55,68} In some institutions, device closure is
the treatment of choice if the defect is difficult to access, such as in
the apical or anterior muscular septum, and in the setting of the
Swiss-cheese septum.\textsuperscript{19-28,51-55}

Orthotopic cardiac transplantation

Cardiac transplantation has been recommended for extremely large apical
septal defects with severe biventricular dysplasia, and persistent
ventricular dysfunction following closure of Swiss-cheese septal defects
through apical left
ventriculotomy.\textsuperscript{6,8,29-32,41,42,47,56-60}

\textbf{Short- and long-term outcomes}

The overall reported perioperative mortality for patients undergoing
conventional repair of multiple septal defects, including the
Swiss-cheese variety, has been cited to be between zero and
14.2\%.\textsuperscript{1-15,29-62} The causes of death were due to
intractable pulmonary hypertensive crises, residual defects, and
congestive cardiac failure. The requirement of reoperation for residual
defects has been between 6 and13\%, with a reoperative mortality of
around 33\%.\textsuperscript{1-15,29-62} The STS Congenital Heart
Surgery Spring 2017 Database provides results from 116 participating
centers on 7322 operations for ventricular septal defects over 4 years
with a mean operative mortality of 0.6\%, mean cardiopulmonary bypass
time of 77 minutes and cross-clamp time of 49
minutes.\textsuperscript{29-32} Repair for multiple defects, their
``category 2'', accounted for 4.5\% of operations, with an operative
mortality of 2.6\%, requirement of mechanical circulatory support in
2.6\%, and the need for a permanent pacemaker in 3.4\% of cases. When
compared with isolated perimembranous defects, the rate of mortality was
thrice as high with multiple defects, the rate of reoperation was over 4
times higher with muscular defects, and the rate of heart block was 3
times higher with muscular and multiple septal
defects.\textsuperscript{1,29-32} It is not possible, however, to
interrogate the registry according to outcomes for the different
anatomical subsets.

Opinion is divided on the recommendation of limited apical left
ventriculotomy for closure of apical defects. Although favorable short-
and long-term results have been reported by some investigators, others
have reported left ventricular dysfunction apical aneurysm formation,
and ventricular arrhythmia in long-term survivors undergoing left
ventriculotomy.\textsuperscript{2,41,43,46,47,57-60,61,65}

Recent results of use of devices inserted percutaneously to close
multiple septal defects have allegedly been
encouraging.\textsuperscript{19-28,54,55,66,75,76} In terms of outcomes,
nonetheless, in some of these small series rates of mortality have been
between 14 and 24\%, with rates of failure between 20 and
40\%.\textsuperscript{53,75,76} In a combined series, Holzer and
associates reported the results of a multicentric trial involving 14
tertiary referral centers in the United States of America. They
collected outcomes from 75 treated patients, finding a total of 59
(45\%) adverse events, and 10.7\% major procedure-related complications,
including device embolization, cardiac perforation, stroke. There were
two deaths (2.7\%).\textsuperscript{20-28,60,66-70,75}

\textbf{Discussion}

Although the diagnostic procedures, surgical techniques, and results are
standardized for patients with isolated ventricular septal defects,
diagnosis is less secure, surgical techniques are more varied, and
published incidence of perioperative mortality, ventricular dysfunction,
and complete heart block are higher in those with multiple defects,
including the Swiss-cheese septum,. Major associated cardiac lesions add
to the complexity of repair.\textsuperscript{1-72}

Analysis of the STS Congenital Heart Surgery Database analysis over a
period of 4 years revealed that, when defects are multiple, it takes
longer to close them. When compared with the more common isolated
perimembranous defects, the rate of heart block is three times higher
with multiple defects. The rate of unplanned reoperation is over four
times higher even with isolated muscular septal defects, and almost
twice as high with multiple septal defects. Before discharge from the
hospital, the mortality rate is over twice as high with muscular septal
defects, and over three times as high with multiple septal
defects.\textsuperscript{29-32} As already discussed, however, it did
not prove possible to analyse the outcomes in terms of the outcomes for
the anatomical combinations of multiple defects as suggested in our
reviews. This is something that might be achieved in the future, since
the anatomical differences are striking, and certainly impact on the
optimal therapeutic approach.

The key to closure of multiple defects is accurate identification, edge
detection, and proper cavitary entry. Guidance for closure have been
described by multiple investigators using three dimensional color-coded
echocardiography, echocardiographic en-face reconstruction of the right
ventricular septal surface, contrast enhanced and multidetector computed
tomography, fast gradient magnetic resonance cardiac imaging,
angiocardiography, and perventricular wire placement, or by
cardioscopy.\textsuperscript{1-9,14,22-28,71}

Taken together, these investigations collectively provide comprehensive
assessment of anatomical information to obtain an accurate preoperative
diagnosis, yet it remains difficult to ascertain whether all defects are
recognised, particularly when one large defect is
non-restrictive.\textsuperscript{1-28,59,64,71} Our review revealed
several instances of diagnosis of additional defects intraoperatively,
postoperatively, or at necropsy.\textsuperscript{1,7,13}

The optimal surgical repair involves complete closure of the multiple
defects. Ideally the moderator band and septomarginal trabeculation
should remain intact, without a need for ventriculotomy, without
compromising the size of the ventricular cavities, without producing
ventricular dysfunction, surgical complete heart block, aortic and
tricuspid regurgitation, and without compromising the coronary arterial
flow. That this ideal has yet to be achieved is evident from the
numerous surgical and interventional techniques described, along with
short-term follow-up studies that report an undesirable incidence of
perioperative mortality and morbidity.\textsuperscript{1-72} Residual
defects, and postoperative myocardial dysfunction, are still the
Achille's heel of poor surgical results. They are related mainly to the
uncertainty of location of the defects, and the difficulty in obtaining
complete closure without right and/or left
ventriculotomy.\textsuperscript{1-17,19-27,29-32,41,43,46-53,59,61,65}

With the evolving knowledge of the complex variable anatomy,
individualized surgical techniques have been described to suit the
different anatomical variants. Some approaches, furthermore, are
suitable for several variants. All surgeons acknowledge, nonetheless,
that these defects, when multiple, are difficult to close, particularly
in small infants presenting with congestive cardiac
failure.\textsuperscript{1-17,19-27,29-32,41,43,46-53,59,61,65}

It may be hard to recognize the boundaries of defects because the
moderator band and multiple trabeculations hide apical defects, while
Swiss-cheese defects may remain
misdiagnosed.\textsuperscript{1-72}Visualization and closure of most
muscular defects is usually possible via a right atriotomy. Exposure of
apical defects from the right side, however, has been plagued by poor
visualization, and the uncertainties of identifying the true margins of
the defects when approaching through the coarse trabeculations of right
ventricular apex.\textsuperscript{1-72} These problems are then still
further exacerbated in the setting of the Swiss-cheese septum. It is
because of the limited exposure, and difficulties in exploring
Swiss-cheese defects, that banding of the pulmonary trunk is still being
performed in premature infants with low body weight to protect the
pulmonary vascular bed and to relieve symptoms of congestive heart
failure to delay definitive repair.\textsuperscript{14-17,30-32}

As we have discussed, such banding can also have its place in treatment
of individuals with other combinations of multiple defects. Presently,
banding as an initial palliative procedure is being performed in select
institutions under specific circumstances. These include the proximity
of margins of the defect to the atrioventricular conduction axis, which
predisposes to atrioventricular block in small infants when constraints
exist in terms of space for placing a permanent pacemaker. Other
indications include multiple apical defects, particularly the
Swiss-cheese septum, selected patients with large trabeculations
traversing the defects that could interfere with complete closure,
co-existing perimembranous and muscular inlet defects, an associations
with coarctation in infants aged less than 2 months, association with
lesions such as twisted atrioventricular connections and those selected
individuals deemed generally to be at
high-risk.\textsuperscript{13,14,16,17,30-32,37} The staged approach,
furthermore, is known to promote spontaneous closure of some of the
smaller defects. Against these potential advantages must be weighed the
deleterious effects of biventricular muscular and fibrous hypertrophy
and long-lasting hypoxia leading to arrhythmic events, increased
mortality, and chronic heart
failure.\textsuperscript{22-24,30,32,41,42,48}

Since the pulmonary vascular bed is both pressure and volume overloaded,
there is difficulty in determining the optimal tightness of the band.
Hence the need for frequent reoperations for adjustment. The added
complexity of the second stage includes pericardial adhesions, need for
pulmonary arterioplasty, damage to the potential neoaortic valve and
right ventricular hypertrophy, further contributing to difficult
exposure of septal defects.\textsuperscript{16,17,29-32} To address
these concerns, Corno and associates introduced the telemetrically
adjustable FloWatch pulmonary artery band (FloWatch-PAB®). Use of this
approach not only eliminates the requirement of reoperation to adjust
the band, but also allows for precise and progressive tightening over
days or weeks.\textsuperscript{16,17} The non-circular shape of
FloWatch, furthermore, maintains the pliability of pulmonary arterial
wall and avoids pulmonary arterioplasty.

The approach through the left ventricle still retains its advocates.
Thus, when using this technique, Aaron and Hanna demonstrated that
exposure and repair of apical defects was much
easier.\textsuperscript{11} It is particularly appropriate for those
cases with a solitary defect seemingly having multiple channels when
assessed from the right ventricle. Its use has been advocated by
multiple surgeons producing small series with excellent short- and
long-term results. Recently, a limited apical left ventriculotomy
approach has been introduced.\textsuperscript{2,57,61,65} Debate
continues, nonetheless, with regard to its potential risks. The exposure
gained can also be disappointing at times. Because of all these
considerations, some argue that the risks, in the long-term, are
unacceptable, since they include apical dyskinesia, aneurysm formation,
left ventricular dysfunction, ventricular arrhythmia, and the need for
cardiac transplantation.\textsuperscript{2,30-32,57-61,65,66} The
mechanisms identified that result in left ventricular dysfunction and
aneurysm formation have included damage to epicardial coronary arteries,
the myocardium, and the left ventricular conduction
system.\textsuperscript{11,58,60,61} It is also the case that the
precise anatomic location and orientation of the ventriculotomy has
great impact on the results. Waldhausen and DiBernardo, for example,
demonstrated that a longitudinal left ventriculotomy causes less
disruption to coronary vasculature, less injury to papillary muscles,
better preservation of ventricular function, and smaller areas of
ischemia when compared to transverse lesions.\textsuperscript{2,58}

The advocates of an apical right ventriculotomy have demonstrated the
safety and effectiveness of this approach for large solitary apical
defects with multiple overlying trabeculations, and for apical and
anterior defects.\textsuperscript{12-15} The technical features include
a limited right ventricular incision that is close to left anterior
interventricular coronary artery without endangering the vessel. As
described by Tsang and associates, a ventriculotomy in this area allows
entry to the space between the papillary muscles and the
septum.\textsuperscript{15}

All surgeons acknowledge that the Swiss-cheese septum is particularly
difficult to close, particularly when encountered in neonates and
premature infants with low body weight presenting with congestive
cardiac failure.\textsuperscript{1-72} The true Swiss-cheese septum
emdodies all the morphologic features of so-called ``non-compaction''.
Repair of the non-compacted septum essentially involves ventricular
septation, either with an oversized patch, or by right ventricular
apical exclusion. Outcomes of such procedures may be complicated by
abnormal ventricular function requiring cardiac transplantation. In many
circumstances, initial placement of an adjustable pulmonary arterial
band remains a safer and desirable
option.\textsuperscript{14,16,17,30-32} The techniques of ``over-sized
pericardial patch'', ``composite patch'', ``double patch sandwiching the
septum'', ``felt sandwich patch'' have all been described, with or
without transection of moderator band/septal trabeculations without left
ventriculotomy.\textsuperscript{1-8,79} The majority of patients
required prolonged diuretics, angiotensin converting enzyme inhibitors,
thereby suggesting impairment of left ventricular function in the
postoperative period. The non-compacted septum can be notoriously
difficult to identify before the initial repair. Once obvious defects
have been closed, additional defects can be unmasked, and may require
additional intervention.\textsuperscript{1-8} If a large patch is used
to cover the entire septum, it is desirable to address multiple points
of fixation to avoid the development of aneurysmal new
septum.\textsuperscript{4,5} Although the use of oversized pericardial
patches yielded good results, residual defects are frequently reported,
along with reduced right ventricular size, and late complications
including cardiac cirrhosis, late opening of the oval fossa, and atrial
tachyarrhythmias.\textsuperscript{68}

It follows that there are wide variations in practice between centers in
the approach to interventions for multiple muscular septal defects. Many
surgeons prefer to repair mid muscular septal defects in the operating
room using traditional techniques.\textsuperscript{7-14,38,72} Recently,
transcatheter device closure and hybrid techniques for closure of
multiple muscular septal defects have reported encouraging early
outcomes. Percutaneous device closure in infants below 5 kg poses a
variety of challenges because of low body weight and poor venous
access.\textsuperscript{22-25,28,52-55} The stiff delivery catheters and
sheath can splint open the tricuspid valve, mitral valve, and/or aortic
valve, leading to arrhythmias, heart block and hemodynamic
decompensation. In these clinical situations, a perventricular hybrid
approach is a feasible ``off pump'' therapeutic option with acceptable
mortality and morbidity.\textsuperscript{23-25,51-55,69}

Recommendations were suggested in 2011 by the American Heart Association
for device closure of multiple muscular septal defects. Infants weighing
more than 5 kg, and children and adolescents with hemodynamically
significant shunts were placed in Class IIA. In Class IIB were placed
neonates, and infants weighing less than 5 kg with hemodynamically
significant lesions and associated cardiac defects requiring
cardiopulmonary bypass, albeit for initial hybrid perventricular closure
off bypass, followed by surgical repair of the remaining defects.
Neonates, infants and children with hemodynamically significant inlet
multiple septal defects with inadequate space between the defect and the
atrioventricular or arterial valves were not recommended for
closure.\textsuperscript{28} When considering these recommendations, it
is those multiple defects located in the mid, apical, inferior, or
anterior parts of the apical septum that are most amenable to closure in
transcatheter fashion.\textsuperscript{19-28,52-55} In recent years,
with the introduction of the Amplatzer muscular and perimembranous
occluders, the hybrid perventricular technique has been used for
selected individuals with perimembranous and outlet defects to avoid
surgical intervention, or to simplify operative
repair.\textsuperscript{67,73-78} In the multicentric trial on device
closure carried out in the United States of America, almost
three-quarters of individuals had only a single device inserted. In
nearly one-fifth, however, it was necessary to use two devices, while
three devices were needed in just over
one-twentieth.\textsuperscript{28} Other investigators have also
reported successful closure with multiple
devices.\textsuperscript{28,52-55} The exclusion criteria of device
closure include weight less than 3 kg, distances of less than 4 mm
between the defects and valvar leaflets, pulmonary vascular resistance
greater than 7 indexed Wood units, sepsis, more than trivial aortic or
tricuspid regurgitation, obvious aortic valve prolapse, diameters
greater than 10mm, preoperative arrhythmias, and contraindications to
antiplatelet agents.\textsuperscript{19-28} Patients with multiple
ventricular septal defects with associated defects or undergoing hybrid
procedures, represent a set of very particular clinical situations. A
collaborative approach using transcatheter/hybrid device closure
followed by surgical repair is emerging when preoperative evaluation is
suggestive of relatively inaccessible location of the septal defect
which may necessitate an incision in the systemic ventricle and those
with complex associated lesions.\textsuperscript{28-32,45,61,78} The
advantages of percutaneous closure include avoidance of transection of
trabeculations, avoidance of ventricular incisions and immediate
confirmation of adequate closure. As already discussed, however,
multiple adverse events have been reported in four series of
intraoperative closure.\textsuperscript{28,60,67-70}

Pooling the available data for interventional closure of multiple
defects reveals an incidence of such adverse events of between 2.8\% and
45\%. The reported complications are many and varied. They include
arrhythmias, cardiac arrest, device embolization, residual shunting,
cardiac perforation, and even procedure-related
death.\textsuperscript{19-28,60,66-70} When compared with surgery, in
which complete heart block appears early postoperatively, complete heart
block is unpredictable after device closure, and is a late problem.
Direct compression, inflammatory reaction, and formation of scarring in
the conduction tissues have all been variously incriminated as the
causative mechanism of complete heart
block.\textsuperscript{19-28,66-70,73,80}

\textbf{Study Limitations}

The nature of the data currently available in the published literature
carries its own inherent limitations. Patients with multiple defects and
the Swiss-cheese septum undergoing different types of surgical
procedures, and transcatheter/hybrid closure are small in number, with
incomplete follow-up. This makes it difficult to draw long-term
conclusions at this stage. The numbers of patients reported with the
different anatomical sub-sets, including the Swiss-cheese variety, were
not large enough for analysis to be convincing, although the results are
consistent with the clinical practice. Thus far, furthermore, patients
have not been randomized between surgical, and interventional or hybrid
closure, thus meaning that comparisons between the groups may be biased.
Experienced hands, with highly specialized backup, must be available for
safety. Whereas the long-term safety and efficacy of surgery are well
documented, the long-term results of device closure are unknown. Future
prospectively designed multicentric studies with larger sample sizes
will be needed to substantiate our inferences made on the basis of from
the published literature.

\textbf{Conclusions}

Based on the published literature, we conclude that color-Doppler flow
mapping should allow precise delineation of the number, size, and
location of multiple defects in infants and children, and facilitate
planning of optimal strategy for intervention. The closure of
Swiss-cheese defects still presents a technical challenge, and carries
increased mortality. Use of an adjustable pulmonary arterial band is a
desirable option in premature infants with low body weight, and body
surface area less than 0.4m\textsuperscript{2}, as it allows possible
spontaneous closure of some smaller defects. Following its use, other
defects can safely be closed on a bigger heart. Although oversized and
Sandwich patch techniques are recommended for reconstituting the
Swiss-cheese septum, biologic glue appears useful. Its downside is the
need for extensive division or transection of right ventricular
trabeculations for optimal visualization, with the potential long-term
risk of myocardial and septal dysfunction.

Apical left or right ventriculotomies reliably provide access to apical
defects, simplifying placement of patches, preserving ventricular volume
compliance, and avoiding complications related to transection of
trabeculations. With the current development of device closure, left
ventriculotomy may be replaced in highly specialized centers by
transcatheter or hybrid procedures. Perventricular device closure is
here to stay. This means that surgeons should firmly embrace and study
this new technology. For most teams, nonetheless, interventional or
hybrid procedures are not recommended in premature infants, nor for
those with low body weight or with the true Swiss-cheese septum.



\textbf{Author's contribution}\selectlanguage{english}
\begin{longtable}[]{@{}lllllllll@{}}
\toprule
\textbf{Author's name} & \textbf{Concept/ design} & \textbf{Data
analysis/ interpretation} & \textbf{Drafting article} & \textbf{Critical
revision} & \textbf{Approval of article} & \textbf{Statistics} &
\textbf{Funding} & \textbf{Data Collection}\tabularnewline
\midrule
\endhead
Ujjwal Kumar Chowdhury & ? & ? & ? & ? & ? & - & - & ?\tabularnewline
Robert H. Anderson & ? & ? & ? & ? & ? & - & - & ?\tabularnewline
Diane E. Spicer & ? & ? & ? & ? & ? & - & - & ?\tabularnewline
Lakshmi Kumari Sankhyan & ? & ? & ? & ? & ? & - & - & ?\tabularnewline
Niwin George & ? & ? & ? & ? & ? & - & - & ?\tabularnewline
Niraj Nirmal Pandey & ? & ? & ? & ? & ? & - & - & ?\tabularnewline
Arvind Balaji & ? & ? & ? & ? & ? & - & - & ?\tabularnewline
Shikha Goja & - & ? & ? & ? & ? & - & - & ?\tabularnewline
Vishwas Malik & - & ? & ? & ? & ? & - & - & ?\tabularnewline
\bottomrule
\end{longtable}



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\end{enumerate}



\textbf{Figure Legends}

Figure 1: Schematic diagram of the location of defects in the apical
muscular septum.

Figures 2A, 2B: Panel A: Transthoracic echocardiographic image with
color flow showing multiple defects (red arrows) in the apical muscular
septum (asterisk) which demonstrate a left to right shunt from left
ventricle (LV) to right ventricle (RV). Panel B: Left ventricular
angiogram in left anterior oblique view with cranial angulation
demonstrating multiple oblique defects (asterisks) representing a
Swiss-cheese septum.

Figures 3A-3F: Volume rendered (A) and oblique coronal (B) image showing
the ventricular septum en-face and revealing the presence of multiple
defects (various colored arrows). Short axis images at the mid
ventricular level (C and D), at the ventricular apex (E) and four
chamber image (F) profile the various defects (corresponding colored
arrows).

Figures 4A-4F: Volume rendered (A) and oblique coronal (B) image showing
the ventricular septum en-face and demonstrating the presence of
multiple defects (various colored arrows). Oblique axial images at
various levels (C to F) profile the respective defects (corresponding
colored arrows).

Figures 5A-5F: Surgical photograph showing step-by-step passage of a
thick No.3 black braided SUTUPAK silk (Ethicon, Johnson and Johnson Pvt.
Ltds., USA) ligature (L) through the additional muscular ventricular
septal defect (VSD) in a child with multiple discrete muscular septal
defects. 5A: shows the small aorta (AO), distended right ventricle (RV),
and tense hypertensive pulmonary artery (PA); 5B, 5C: a right angle
forcep (F) is passed through the additional ventricular septal defect,
and kissed against a DeBakey forcep which is inserted through the larger
VSD. The tip of silk ligature is grasped and looped through the
additional septal defect. Traction on the silk ligature facilitated
exposure of the margins of septal defect; 5D, 5E: two ventricular septal
defects are closed separately using Dacron knitted polyester patches
(BAARD® SAUVAGE® Filamentous, BARD peripheral vascular Inc, Temple, AZ,
USA) and 5-0 interrupted pledgeted mattress sutures; 5F: shows the
separately closed ventricular septal defect.

Figures 6A, 6B: Schematic drawing of Kitagawa's technique of insertion
of an oversized patch on the left ventricular side of the defect.

Figures 7A, 7B: Mace's technique of surgical closure of the Swiss-cheese
septum using a single large patch on the right ventricular side with
intermediate fixation to prevent septal bulging.

Figure 8: Ootaki's technique of sandwiching the apical defects between
the two polyester felt patches.

Figure 9: Kitagawa's technique of closure of multiple apical defects,
sandwiching the septum with the anterior wall of the ventricle.

Figures 10A-10C: Surgical closure of apical defects through an apical
right ventriculotomy.

Figure 11: Surgical approach to apical defects through a modified apical
left ventriculotomy.

Figure 12: Wu's two-patch and right ventricular apex exclusion technique
of repair of the Swiss-cheese septum.\selectlanguage{english}
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