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\begin{document}

\title{Outcomes of Truncus Arteriosus Repair and Predictors with Mortality}



\author[1]{Mohammed Hamzah}%
\author[2]{Hasan F. Othman}%
\author[1]{Kshama Daphtary}%
\author[1]{Rukmini Komarlu}%
\author[1]{Hany Aly}%
\affil[1]{Cleveland Clinic Children's Hospital}%
\affil[2]{Sparrow Health System}%


\vspace{-1em}



  
  \date{May 25, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Abstract: The objective of this study was to identify patient and
hospitalization characteristics associated with in-hospital mortality in
infants with truncus arteriosus. We conducted a retrospective analysis
of a large administrative database, the National Inpatient Sample
dataset of the Healthcare Cost and Utilization Project for the years
2002--2017. We also sought to evaluate the resource utilization in the
subgroup of subjects with truncus arteriosus and 22q11.2 deletion
syndrome. Neonates with truncus arteriosus were identified by ICD-9 and
ICD-10 codes. Hospital and patient factors associated with inpatient
mortality were analyzed. Overall, 3009 neonates met inclusion criteria;
a total of 326 patients died during the hospitalization (10.8\%).
Extracorporeal membrane oxygenation utilization was 7.1 \%. Univariate
and multivariate logistic regression analyses were used to identify risk
factors for in-hospital mortality. Independent risk factors for
mortality were prematurity (aOR = 2.43, 95\% CI: 1.40--4.22, p = 0.002),
diagnosis of stroke (aOR = 26.2, 95\% CI: 10.1--68.1, p \textless{}
0.001), necrotizing enterocolitis (aOR = 3.10, 95\% CI: 1.24--7.74, p =
0.015) and presence of venous thrombosis (aOR = 13.5, 95\% CI:
6.7--27.2, p \textless{} 0.001). Patients who received ECMO support or
had cardiac catheterization procedure during the hospitalization had
increased odds of mortality (aOR = 82.0, 95\% CI: 44.5--151.4, p
\textless{} 0.001, and aOR = 1.65, 95\% CI: 0.98--2.77, p = 0.060,
respectively). 22q11.2 deletion syndrome was associated with an inverse
risk of death despite having more non-cardiac comorbidities; this
patient subpopulation also had a higher length of stay and increased
cost of hospitalization.%
\end{abstract}%



\sloppy


\section*{Title:}

{\label{title}}

Outcomes of Truncus Arteriosus Repair and Predictors with Mortality

\textbf{Authors:}

Mohammed Hamzah, MD\textsuperscript{a}; Hasan F. Othman,
MD\textsuperscript{b}; Kshama Daphtary, MD\textsuperscript{a}; Rukmini
Komarlu, MD\textsuperscript{c}; Hany Aly, MD\textsuperscript{d}

\textbf{Affiliations:}

\textsuperscript{a} Department of Pediatric Critical Care, Cleveland
Clinic Children's, Cleveland, OH

\textsuperscript{b} Department of Pediatrics, Michigan State
University/Sparrow Health System, Lansing, MI

\textsuperscript{c} Department of Pediatric Cardiology, Cleveland Clinic
Children's, Cleveland, OH

\textsuperscript{d} Department of Neonatology, Cleveland Clinic
Children's, Cleveland, OH

\textbf{Address correspondence to:} Mohammed Hamzah, Department of
Pediatric Critical Care, Cleveland Clinic Children's,

9500 Euclid Ave. M14, Cleveland, OH 44195, E-mail: HamzahM@ccf.org, Fax:
(216) 444-3310, Telephone: (216) 444-0732

\textbf{Short title:} Outcomes of truncus arteriosus in children.

\textbf{Funding Source:} No funding was secured for this study.

\textbf{Financial Disclosure:} All authors have no financial
relationships relevant to this article to disclose.

\textbf{Conflict of Interest:} All authors have no conflicts of interest
to disclose.

\textbf{Abbreviations:}

NIS: National Inpatient Sample

HCUP: Healthcare Cost and Utilization Project

AHRQ: Agency for Healthcare Research and Quality

ICD-9: International Classification of Disease, Ninths Revision

ICD-10: International Classification of Disease, Tenths Revision

LOS: length of stay

OR: odds ratio

IQR: Interquartile range.

CI: confidence interval

ECMO: ExtraCorporeal Membrane Oxygenation

AKI: Acute Kidney Injury

\textbf{Keywords:} truncus arteriosus; outcomes; ECMO; 22q11.2 deletion
syndrome

\textbf{Contributor's Statement Page:}

Dr. Hamzah conceptualized and designed the study, drafted and revised
the manuscript.

Dr. Othman carried out the analyses and reviewed and revised the
manuscript.

Dr. Daphtary contributed to the initial draft of the manuscript and
revised the manuscript.

Dr. Komarlu contributed to the initial draft of the manuscript and
revised the manuscript.

Dr. Aly designed the study, critically reviewed the manuscript for
important intellectual content.

All authors approved the final manuscript as submitted and agree to be
accountable for all aspects of the work.

\section*{Abstract:}

{\label{abstract}}

The objective of this study was to identify patient and hospitalization
characteristics associated with in-hospital mortality in infants with
truncus arteriosus. We conducted~a retrospective analysis of a large
administrative database, the National Inpatient Sample dataset of the
Healthcare Cost and Utilization Project for the years 2002--2017. We
also sought to evaluate the resource utilization in the subgroup of
subjects with truncus arteriosus and 22q11.2 deletion syndrome. Neonates
with truncus arteriosus were identified by ICD-9 and ICD-10 codes.
Hospital and patient factors associated with inpatient mortality were
analyzed. Overall, 3009 neonates met inclusion criteria; a total of 326
patients died during the hospitalization (10.8\%). Extracorporeal
membrane oxygenation utilization was 7.1 \%. Univariate and multivariate
logistic regression analyses were used to identify risk factors for
in-hospital mortality. Independent risk factors for mortality were
prematurity (aOR = 2.43, 95\% CI: 1.40--4.22, p = 0.002), diagnosis of
stroke (aOR = 26.2, 95\% CI: 10.1--68.1, p \textless{} 0.001),
necrotizing enterocolitis (aOR = 3.10, 95\% CI: 1.24--7.74, p = 0.015)
and presence of venous thrombosis (aOR = 13.5, 95\% CI: 6.7--27.2, p
\textless{} 0.001). Patients who received ECMO support or had cardiac
catheterization procedure during the hospitalization had increased odds
of mortality (aOR = 82.0, 95\% CI: 44.5--151.4, p \textless{} 0.001, and
aOR = 1.65, 95\% CI: 0.98--2.77, p = 0.060, respectively). 22q11.2
deletion syndrome was associated with an inverse risk of death despite
having more non-cardiac comorbidities; this patient subpopulation also
had higher length of stay and increased cost of hospitalization.

\textbf{Introduction:}

Truncus arteriosus is an infrequent cyanotic congenital heart disease
that occurs at a rate of 0.56--1.3 per 10,000 live births (1). Surgical
mortality in patients with truncus arteriosus is high relative to other
congenital heart disease and is reported to be between 6.9--11\% (2, 3).
Few studies had evaluated outcomes and risk factors for mortality in
truncus arteriosus; these studies were limited by either small sample
size or single center studies (4--6). The main objective of this study
was to identify patient and hospitalization characteristics associated
with mortality in infants with truncus arteriosus who had surgical
repair. We evaluated 3,009 infants who underwent truncus arteriosus
surgical repair. This is the largest cohort of patients with repaired
truncus arteriosus . We hypothesized that using data from a large
multicenter national database with both a large number of patients and a
wide range of practice variations would allow us to evaluate the
surgical outcomes better and to identify the factors associated with
mortality in infants who had truncus arteriosus repair. We also sought
to evaluate the resource utilization in the subgroup of subjects with
truncus arteriosus and 22q11.2 deletion syndrome. Syndrome of 22q11.2
deletion occurs in 25\% of patients with truncus arteriosus. We
hypothesize that having 22q11.2 deletion syndrome would influence the
resource utilization in the postoperative period, as these subjects
would have a prolonged and more complicated postoperative course given
the presence of immunodeficiency and multiple non-cardiac anomalies that
are associated with 22q11.2 deletion syndrome (7).



\section*{Methods}

{\label{methods}}

The study was conducted using de-identified patient data from the
National Inpatient Sample (NIS) database, a part of the Healthcare Cost
and Utilization Project (HCUP), which is compiled by the agency for
Health care Research and Quality (AHRQ). The NIS database randomly
samples 20 percent of the discharges from participating hospitals in 47
US states and the District of Columbia. It contains data from more than
seven million hospital stays each year (8). Data from the years
2000--2017 were used for the purposes of this study. The study was
exempt from an institutional board review as the use of data from
approved unidentified public data sets is not considered human subject
research.

The study population was identified using the International
Classification of Disease, Ninth and Tenth Revisions, Clinical
Modification (ICD-9\&10-CM). Patients were included in the study if they
meet the following criteria. In essence, the patient was less than one
year of age, had a diagnosis of truncus arteriosus (ICD codes: 745.0 \&
Q20.0), and had truncus arteriosus repair procedure (ICD-9-PCS: 35.83,
35.92 and corresponding ICD-10 procedure codes) during the index of
hospitalization. Patient data queried included demographics and patient
clinical characteristics. Patient demographic data collected included:
age, sex, race, primary payer, location of the hospital, type of
hospital, hospital bed size, the region of the hospital, type of
admission (elective or non-elective) and admission day of the week
(weekend or weekday). Primary outcomes were identified before the
analysis; these included death before hospital discharge, length of stay
(LOS), and hospital cost of charge. We compiled a list of common
procedures, comorbidities, and complications and evaluated their
prevalence in those who died during the hospitalization. For the
analysis of outcomes in patients with 22q11.2 deletion syndrome,
patients were stratified into two groups: those with and without 22q11.2
deletion syndrome using ICD code 279.11, 758.32, D82.1, and Q93.81. Data
were described using median (interquartile range) for continuous
variables as deemed appropriate. Categorical variables were described as
frequency (percentage). Survivors and Non-survivors were compared with
regards to demographic, clinical characteristics, and outcomes using
Mann-Whitney U test for continuous characteristics and Chi-square or
Fisher's exact tests for categorical characteristics. Frequency of
truncus arteriosus repair, in-hospital mortality, and LOS were evaluated
over the years of the study. Trends were assessed for significance using
Jonckheere--Terpstra test. P \textless{} 0.05 was considered
significant. In an effort to minimize bias and to adjust for measurable
confounders, a univariate analysis was initially performed to identify
potential predictors of in-hospital mortality, thereafter, variables
with statistical significance (p \textless{} 0.15) were incorporated in
a multivariable analysis using a logistic regression model.~We used the
SPSS software, version 25 (SPSS Inc., Chicago, IL) for all statistical
analyses.

Results:

Overall, there were 3009 infants with truncus arteriosus that met the
inclusion criteria. The majority of these patients (2026, 67.4\%) had
their surgical repair at [?] 28 days of age. There was no predominance of
either sex (male 51.2\% vs. female 48.8\%). The majority of the patients
were of the White race (51.6\%), followed by the Hispanic race (23.3\%).
Primary payer insurance was equally divided between Private insurance
and Medicaid (46.6\% and 46.3\%, respectively). The majority of the
patients were admitted to large bed-size hospitals (59.9\%). Patients
discharged from the hospital were equally spread throughout the year
with no seasonal variation. The majority of the hospitalizations were
non-elective admissions (78.8\%). In-hospital mortality was 326
(10.8\%). Mortality was stable with a non-significant decrease over the
years of the study (Std. J-T statistics -1.063, p = 0.288, Figure 1).
Characteristics of survivors versus non-survivors are presented in table
1. Mortality rates were higher in neonates (12.9\% vs. 6.4\%, p
\textless{} 0.001). Patients with Black, Native American or Hispanic
race had significantly higher mortality than White race (16.5\%, 15.6\%,
13.5\% vs. 7.9\%, p \textless{} 0.001, respectively) and mortality in
patients with Medicaid insurance was significantly higher than those
with private insurance (14.4\% vs. 8.0\%, p \textless{} 0.001).
Mortality rates during elective admissions was 7.4\% versus 10.6\% for
non-elective admissions (p = 0.020).

Table 2 shows the outcomes of infants with repaired truncus arteriosus.
Non-survivors had prolonged median length of stay (non-survivors 29 days
{[}IQR 12--61{]} vs. survivors 24 days {[}IQR 14--40{]}, p = 0.009),
this was associated with twofold increase in the cost of hospitalization
in the non-survivors (non-survivors \$522,615 {[}\$253,366--\$842,009{]}
vs. survivors \$285,114 {[}\$170,681--\$526,175{]}, p \textless{}
0.001). Of note, 47.4\% of the non-survivors were receiving
ExtraCorporeal Membrane Oxygenation (ECMO) life support during the
hospitalization versus 2.2\% of survivors (OR = 39.4, p \textless{}
0.001). Prematurity (gestational age \textless{} 37 weeks) and low birth
weight (weight \textless{} 2500g) were associated with increased odds
risk of mortality (OR = 1.95, 95\% CI: 1.40--2.72, p \textless{} 0.001,
and OR = 1.39, 95\% CI: 0.95--2.03, p = 0.087, respectively).
Chromosomal anomalies other than 22q11.2 deletion syndrome were present
at a similar frequency in both survivors and non-survivors (survivors
4.7\% vs. non-survivors 4.9\%, p = 0.782). Surprisingly, 22q11.2
deletion syndrome was present less frequently in non-survivors
(non-survivors 20.9\% versus survivors 28.0\%, p = 0.007). Overall,
22q11.2 deletion syndrome was present in 27.2\% of the patients. In
table 3, we compiled a list of in-hospital complications and evaluated
the association of these complications with in-hospital mortality (table
2). Stroke, acute kidney injury (AKI), pleural effusion, venous
thrombosis, intraventricular hemorrhage, and necrotizing enterocolitis
were all associated with increased odds risk of mortality (OR = 12.8,
4.37, 1.69, 4.85, 1.73 and 4.89, respectively). Pulmonary hypertension
was not associated with an increased odds risk of mortality.

A univariate analysis followed by a multivariable regression analysis
was performed to further analyze the dynamics between mortality
predictors (tables 3 and 4). The following factors were found to be
associated with increased mortality in the multivariate analysis:
prematurity (aOR = 2.43, 95\% CI: 1.40--4.22, p = 0.002), diagnosis of
stroke (aOR = 26.2, 95\% CI: 10.1--68.1, p \textless{} 0.001),
necrotizing enterocolitis (aOR = 3.10, 95\% CI: 1.24--7.74,~p = 0.015)
and presence of venous thrombosis (aOR = 13.5, 95\% CI: 6.7--27.2, p
\textless{} 0.001). Private insurance and 22q11.2 deletion syndrome were
associated with lower odds of mortality (aOR = 0.34, 95\% CI:
0.20--0.55, p \textless{} 0.001, and aOR = 0.54, 95\% CI: 0.34--0.87, p
= 0.011, respectively). In the multivariate analyses: AKI and pleural
effusion were not associated with increased mortality. Patients who
received ECMO support or had cardiac catheterization procedure during
the hospitalization had increased odds of mortality (aOR = 82.0, 95\%
CI: 44.5--151.4, p \textless{} 0.001, and aOR = 1.65, 95\% CI:
0.98--2.77, p = 0.060, respectively). Successful cardiopulmonary
resuscitation during the hospitalization was not associated with a
significant increase in mortality (aOR = 1.29, 95\% CI: 0.54--3.11, P =
0.570).

\emph{Outcomes of the subgroup with 22q11.2 deletion syndrome (Table
5):}

22q11.2 deletion syndrome was present in 820 (27.2\%) patients with
truncus arteriosus who had a surgical repair. Patients with 22q11.2
deletion syndrome had significantly prolonged median length of stay (32
days {[}IQR: 19--53{]} compared to 22 days {[}IQR: 12--37{]}, p
\textless{} 0.001) and this was associated with significant increase in
median cost of hospitalization (\$382,621 {[}IQR \$231,360--\$657,527{]}
versus \$273,713 {[}IQR \$163,272--\$522,615{]}, p \textless{} 0.001).
Lower mortality rates were observed in the 22q11.2 deletion syndrome
group (8.3\% versus 11.7\%, p = 0.007). The two groups (22q11.2 deletion
and no-22q11.2 deletion) had similar baseline characteristics and
comorbidities. Low birth weight, prematurity (gestational age
\textless{}37 weeks) were present in similar frequency in both groups.
Similarly, ECMO, cardiopulmonary resuscitation, mechanical ventilation,
and cardiac catheterization procedures were utilized at a similar rate
in both groups.

Of significance, the study finds that patients with 22q11.2 deletion
syndrome had a higher incidence of non-cardiac anomalies. More airway
anomalies were present in the 22q11.2 deletion group (10.9\% vs. 5.9\%,
OR = 1.94, 95\% CI: 1.47--2.58, p \textless{} 0.001), chromosomal
anomalies other than 22q11.2 deletion were present at higher frequency
(7.3\% vs. 3.7\%, p \textless{} 0.001). In association with these
comorbidities, we observed that tracheostomy and G-tube placement were
performed more frequently in the 22q11.2 deletion group (5.4\% vs.
2.7\%, OR = 2.05, 95\% CI: 1.37--3.05, p \textless{} 0.001, and 12.9\%
vs. 4.5\%, OR = 3.13, 95\% CI: 2.35--4.18, p = 0.001, respectively).
Kidney anomalies, acute kidney injury, venous thrombosis, necrotizing
enterocolitis, and pulmonary hypertension were present in similar
frequency in both groups (Table 5).

\section*{Discussion:}

{\label{discussion}}

Using a large multicenter national database, we reported the outcomes of
3,009 infants with truncus arteriosus who underwent surgical repair. The
study provides descriptive but relevant information with regards to
demographics, national trends, in-hospital complications, and outcomes
in infants with truncus arteriosus. The overall mortality in truncus
arteriosus is 10.8\%. A recent report from the society of thoracic
surgeons congenital heart surgery database showed a similar mortality
rate of 9.6\% in truncus arteriosus repair, which is the second-highest
rate of mortality after Norwood procedure (9). Aiming to identify
predictors of mortality in this disease, a multivariate regression
analysis was used, and we also analyzed the outcomes in subjects with
22q11.2 deletion syndrome. The main findings in this study were as
follows: (1) Patient characteristics that were associated with mortality
were a non-White race, prematurity, and Medicaid insurance. (2) 22q11.2
deletion syndrome was associated with an inverse risk of death despite
having more non-cardiac comorbidities. (3) 22q11.2 deletion syndrome
patients had a longer length of hospital stay and higher cost of
hospitalization.

To address the first finding of insurance disparities, Erickson and
colleagues showed in their study that infants with congenital heart
disease and private insurance are cared for at hospitals with lower
surgical mortality and that non-White children with Medicaid insurance
were less likely to use a hospital with lower mortality rate (10). In
addition, prematurity carries a major risk factor for increased
mortality in infants with congenital heart disease, and preterm birth
rates vary by race and ethnicity. Socioeconomic and ethnic-racial
disparities are a major risk for prematurity (11). Studies have shown
that non-Hispanic Black women are 2.5 times more likely to have preterm
birth versus White women (12). The dynamics and interplay between these
three risk factors (preterm birth, non-White race, and government
insurance) are challenging, and the coexistence of these factors is not
uncommon. The second main finding in this study was the presence of an
inverse risk of death associated with 22q11.2 deletion syndrome. The
baseline characteristics for these patients are similar to subjects
without -22q11.2 deletion syndrome. Many researchers have examined the
operative mortality in truncus arteriosus and some have found that
22q11.2 deletion syndrome does not necessarily increase surgical risk
(13--15), while others reveal that 22q11.2 deletion is an independent
risk factor for late mortality (16, 17). However , the results of our
study are in agreement with the results of a study by Michielon and
colleagues, which found that 22q11.2 deletion syndrome was an inverse
risk for death in patients with truncus arteriosus (18). It could also
be that the complex cardiac pathology and challenging nature of the
repair with its prolonged postoperative course could have much more of
an impact than the impact of the diagnosis of 22q11.2 deletion on
truncus arteriosus. , One could also hypothesize that the cardiac
morphology and anatomy in these patients is different from patients
without 22q11.2 deletion syndrome. A study by McElhinney reviewed
details of cardiac features in truncus patients with 22q11.2 deletion
and showed that patients with 22q11.2 deletion had a higher frequency of
right-sided aortic arch and abnormal aortic arch branching. Most
importantly, interrupted aortic arch, which could impact operative
mortality, occurred at a similar frequency in those with and without
22q11.2 deletion syndrome. In McElhinney's study, there was a
statistically insignificant trend for a lower incidence of
moderate-severe truncal valve insufficiency in patients with 22q11.2
deletion (11\% vs. 33\%) which could impact surgical mortality,
suggesting that factors other than chromosome 22q11.2 deletion are the
main determinants of the functional and morphological characteristics of
the truncal valve (19). Previous studies have shown the association with
poor surgical outcomes in subjects with truncal valve regurgitation,
interrupted aortic arch and coronary artery anomalies (20). One of the
limitations of our study is the inability to review patient charts and
cardiac imaging to evaluate for the presence of postoperative truncal
valve regurgitation or the details of coronary anatomy in these
patients. Future studies that also evaluate the cardiac anatomy in
22q11.2 deletion syndrome will likely be able to evaluate our finding of
an inverse death risk that is associated with 22q11.2 syndrome in
truncus arteriosus.

Lastly, this study reported prolonged hospitalization and increased cost
of hospitalization in patients with truncus arteriosus. This is similar
to the study done by Ghimire et al, who showed that the diagnosis of
22q11.1 deletion is associated with longer hospital stay and higher
hospitalization cost (21). The 22q11.2 group had far more non-cardiac
comorbidities and had higher rates of postoperative complications.
Feeding issues were more common in 22q11.2 deletion syndrome, a higher
percentage of these patients had a gastrostomy tube during the index
hospitalization. Airway anomalies were present more frequently in
22q11.2 deletion and this was associated with a higher frequency of
tracheostomy procedure. Immunological dysfunction is not uncommon in
infants with 22q11.2 deletion (22), and it was not surprising to find
higher rates of septicemia and fungal infection in the 22q11.2 deletion
group. Therefore, it was not unexpected to have a prolonged
postoperative hospitalization in patients with 22q11.2 deletion,
modifications in the perioperative care of this subpopulation to address
these complications are warranted to further shorten the postoperative
course and decrease the cost of hospitalization.

Limitations: There are several limitations to this study, the study
relied on the ICD-9 \& ICD-10 codes for the diagnosis of truncus
arteriosus and 22q11.2 deletion syndrome, it didn't describe how the
chromosomal deletion diagnosis was reached. The study span is over a
span of two decades; the field of molecular genetic testing and genomic
profiling has evolved dramatically; this could have affected the
accuracy of the genetic screening method over the years of the study.
The database does not provide details of cardiac anatomy, mainly
coronary artery anomalies, postoperative truncal valve insufficiency,
and aortic arch obstruction. The database lacks information on cardiac
bypass and surgical procedure techniques, which have evolved over the
course of these two decades and therefore is subject to an era effect.
These factors would impact the surgical outcomes in truncus arteriosus.
The current study benefited from the large sample size, some limitations
are inherent to all retrospective studies using administrative
databases. Incorrect or missing data may exist. We rely mainly on ICD
diagnostic and procedure codes to gather information, and we were not
able to refer to specific patient hospital charts to determine the cause
of death. The lack of validation of the data collected by chart review
is a source of potential bias for errors. However, in a large study such
as ours, the patients' volume likely offset these inaccuracies. Another
limitation of our study is the restriction to the hospitalization
period, and this prevented us from evaluating long-term outcomes.

\section*{Conclusion:}

{\label{conclusion}}

Truncus arteriosus is infrequent congenital heart disease with mortality
comparable to that following Norwood procedure. Mortality rates have
trended down over time although continue to remain high. 22q11.2
deletion was not associated with increased mortality compared to
subjects without this deletion. However, this subject population had a
higher incidence of non-cardiac anomalies, higher need for tracheostomy
and G-tube placement, protracted length of stay with an increased cost
of hospitalization. Prematurity, non-White race, and use of Medicaid
insurance were factors associated with higher mortality. These findings
will help direct prenatal counseling and management postnatally.

\section*{References:}

{\label{references}}

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\end{enumerate}

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