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\begin{document}

\title{Association of Patent Ductus Arteriosus with extubation failure among
preterm infants}



\author[1]{Dhruv Gupta}%
\author[2]{Rachel Greenberg}%
\author[3]{Girija Natarajan}%
\author[3]{Sanket Jani}%
\author[3]{Amit Sharma}%
\author[2]{Michael Cotten}%
\author[3]{Ronald Thomas}%
\author[3]{Sanjay Chawla}%
\affil[1]{Maternal Fetal Medicine of Southwest Florida}%
\affil[2]{Duke University Department of Pediatrics}%
\affil[3]{Central Michigan University}%


\vspace{-1em}



  
  \date{May 24, 2024}


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\selectlanguage{english}
\begin{abstract}
\textbf{Backround:} Mechanical ventilation is associated with
mortality/morbidities in preterm infants. Nearly a third of these
infants fail extubation and this may increase morbidities.
\textbf{Objective:} To evaluate the association of symptomatic patent
ductus arteriosus with failure of extubation among preterm infants.
\textbf{Methods:} This was a retrospective study on preterm infants
(birth weight \textless{}1,250 grams and gestational age [?]23weeks) born
between January 2009 and December 2016, who were mechanically ventilated
and extubated within the first 60 days of age. \textbf{Results:} 360
infants were evaluated, of these, 26\% failed and 74\% succeeded the
initial extubation attempt. On adjusted analysis, symptomatic ductus was
associated with an increased risk of extubation failure.
\textbf{Conclusion(s):} Presence of symptomatic patent ductus arteriosus
was associated with extubation failure. Further investigations are
needed to establish whether screening for presence of ductus and
treatment of the same, prior to extubation among these infants, improves
chances of successful extubation and cardiorespiratory outcomes.%
\end{abstract}%



\sloppy


\textbf{INTRODUCTION}

Patent ductus arteriosus (PDA) is a common morbidity in extremely
preterm infants. Failure of ductal closure has been associated with many
severe morbidities, including broncopulmonary dysplasia (BPD),
intraventricular hemorrhage (IVH), necrotizing enterocolitis (NEC) and
mortality {[}1-4{]}, but there is lack of evidence for a
cause-and-effect relationship {[}5{]}. Practices in PDA management are
not consistent among institutions ranging widely from universal
prophylactic treatment to selective treatment on the basis of various
clinical criteria, to no treatment at all {[}6{]}.

The majority of extremely preterm infants receive invasive mechanical
ventilation (IMV) to maintain oxygenation and ventilation {[}7{]} and
prolonged IMV has been associated with an increased risk of mortality
and neonatal morbidities, including upper airway injury, nosocomial
infections and BPD {[}8-10{]}. Failed extubation is also independently
associated with increased risk of mortality, BPD, severe IVH, longer
hospitalization, more days on respiratory support and significant
respiratory setback lasting multiple days after
re-intubation.{[}11-15{]}

There have been reports of an association between presence of PDA and
extubation failure in preterm infants {[}16, 17{]}. Limitations of these
studies include small sample size (9 out of 39 infants {[}16{]} and 22
out of 82 infants {[}17{]}) with extubation failure, lack of use of
Nasal Intermittent Positive Pressure Ventilation (NIPPV) prior to
re-intubation {[}17{]} and lack of data on the timing of diagnosis of
PDA.

The objective of the current study was to evaluate the association
between a hemodynamically significant PDA and failure of first elective
extubation among extremely low birth weight infants.

\textbf{METHODS}

\emph{Study Design:}

This was a retrospective, cohort study that included preterm infants
born at Hutzel Women's Hospital, Detroit, MI, from January 2009 to
December 2016. The study was approved by the Institutional Review Board
at Wayne State University.

\emph{Study Population:}

All infants with a birth weight \textless{}1,250 grams, gestational age
[?]23weeks, and admitted to the Neonatal Intensive care Unit (NICU) at
Hutzel Women's Hospital were screened. Infants were eligible for the
study if they a) received MV with an endotracheal tube, and b) had a
first elective extubation attempt within 60 days of age. The decision
for initial endotracheal intubation, weaning of respiratory support,
extubation, post-extubation respiratory management and need for
reintubation were at the discretion of the clinical team.

\emph{Definitions:}

Gestational age was estimated based on best obstetric estimate using
early ultrasound, last menstrual period or Ballard examination {[}20{]}
in that order. Acute chorioamnionitis was based on placental pathology.
The primary outcome was successful extubation, defined as survival for
minimum of five days on either no or non-invasive respiratory support.
Extubation failure was defined as need for re-intubation within 5 days
of extubation. Hemodynamically significant PDA was defined by
Echocardiogram findings suggestive of a moderate to large PDA in an
infant with low diastolic blood pressure, wide pulse pressure,
hypotension, renal insufficiency, or signs of pulmonary edema
(tachypnea, increased respiratory support and oxygen requirements),
either before or within five days of elective extubation.
Echocardiograms in our center were generally ordered for symptomatic
patients as assessed by the primary clinical team.

Ventilation index (VI) was used as an objective measure of adequacy of
ventilation in response to the respiratory support provided. VI was
calculated as the product of the set rate, partial pressure of carbon
dioxide in arterial or capillary blood (pCO\textsubscript{2}) and the
difference between peak inspiratory and positive end expiratory pressure
divided by 1000{[}18{]}. We calculated the highest respiratory severity
score (RSS) in the first 6 hours of age, as an objective marker of
oxygenation in relation to mean airway pressure received by the patient.
RSS was calculated as the product of the mean airway pressure (MAP) and
fraction of inspired oxygen (FiO\textsubscript{2}) {[}19{]}.

\emph{Statistical Analysis:}

Perinatal and peri-extubation characteristics were compared between
those who failed the first extubation attempt and those who were
successful. Categorical variables between the two groups were compared
using chi-squared or Fisher's exact tests, and continuous variables were
analyzed using Wilcoxon rank sum tests. Logistic regression analysis was
performed to determine associations between perinatal and
peri-extubation characteristics, including PDA, with success of
extubation. Variables in the logistic regression analysis were selected
based on a backward selection method (all covariates were initially
included, and then nonsignificant covariates were removed if the P value
was \textgreater{}0.2). Statistical analysis was conducted using Stata
version 16.1 (StataCorp, College Station, TX).

\textbf{RESULTS}

During the study period, a total of 702 infants with birth weight
\textless{} 1,250 grams and gestational age [?]22 weeks were admitted to
the NICU. Infants who died prior to an extubation attempt or had an
unplanned extubation prior to their first elective extubation attempt
were excluded from the analysis. One infant with missing outcome of
successful extubation was excluded and twelve patients were excluded
from the analysis as they were part of another study on extubation
readiness---Automated Prediction of Extubation Readiness
(clinicaltrials.gov NCT01909947). After excluding the infants as listed
above, a total of 360 infants were included in the study who received MV
via an endotracheal tube and had an elective extubation attempt within
the first 60 days of age. Among them, 268 (74\%) were successful and 92
(26\%) failed extubation.

\textbf{Factors associated with successful extubation}

Infants who failed extubation had a higher incidence of hemodynamically
significant PDA at extubatio. These infants were also noted to have a
lower gestational age, lower birth weight, higher RSS in first 6 hours
of age, and higher incidence of histological chorioamnionitis. These
infants also had a lower post-menstrual age, lower weight at extubation,
higher receipt of nasal CPAP or non-invasive positive pressure
ventilation (NIPPV) as post extubation respiratory support, lower
pre-extubation pH, and higher pre-extubation Fio\textsubscript{2}
\textbf{(Table 1)} .

On logistic regression analysis successful extubation was significantly
associated with absence of hemodynamically significant PDA (Odds Ratio
0.32, 95\% Confidence Interval 0.17-0.61) after adjusting for
gestational age, age at extubation, sex, pH at extubation,
Fio\textsubscript{2} at extubation and highest RSS in first 6 hours of
age.

\textbf{DISCUSSION:}

In the current study, we noted a significant association between the
presence of a hemodynamically significant PDA and extubation failure,
which is in concurrence with previous studies {[}16, 17{]} that have
reported a similar association.

We speculate that PDA may contribute to extubation failure due to
pulmonary edema, leading to increased work of breathing. The PDA may
become more hemodynamically significant after reduction of mean airway
pressure applied to the lungs after extubation.

It is not known if proactively evaluating for PDA prior to extubation
and its treatment would be associated with an improved likelihood of
successful extubation. The data from the current study are hypothesis
generating and may serve as a basis for future prospective observational
and randomized controlled trials to evaluate the role of treatment for
PDA prior to extubation to improve the cardiorespiratory outcomes of
these infants.

There is no consensus on the definition of extubation success for
premature infants. We defined extubation success as need for re
intubation within five days of extubation as a significant proportion
(25\%) of infants might fail extubation beyond 48-72 hours of
extubation. {[}13{]}

Current study had some limitations. As this was an observational study,
we cannot establish a cause-and-effect relationship between presence of
PDA and extubation failure. Endotracheal intubation, extubation and
reintubation, were at the discretion of the primary clinical team.
Strengths of the current study include inclusion of all eligible infants
using well defined criteria with no selection bias. All infants were
born in a single center that reduced the variability in clinical
practice.

\textbf{CONCLUSION}

Among a recent cohort of extremely low birth weight infants, presence of
hemodynamically significant PDA was significantly associated with
failure of first elective extubation. Further investigations are needed
to establish whether proactive screening for presence of PDA and
treatment of the same prior to extubation, improves the chances of
successful extubation and neonatal outcomes.

\textbf{References:}

1. Schena F, Francescato G, Cappelleri A, et al. Association between
hemodynamically significant patent ductus arteriosus and
bronchopulmonary dysplasia. \emph{J Pediatr} . 2015;166(6):1488--1492

2. Noori S, McCoy M, Friedlich P, et al. Failure of ductus arteriosus
closure is associated with increased mortality\textbackslash{} in
preterm infants. \emph{Pediatrics} . 2009;123(1). Available at: www.
pediatrics. org/ cgi/ content/ full/ 123/ 1/ e138

3. Dollberg S, Lusky A, Reichman B. Patent ductus arteriosus,
indomethacin and necrotizing enterocolitis in very low birth weight
infants: a populationbased study. \emph{J Pediatr GastroenterolNutr} .
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4. Marshall DD, Kotelchuck M, Young TE, Bose CL, Kruyer L, O'Shea TM;
North Carolina Neonatologists Association.Risk factors for chronic lung
disease in the surfactant era: a North Carolina population-based study
of very low birth weight infants. \emph{Pediatrics} .
1999;104(6):1345--1350

5. Benitz WE. Treatment of persistent patent ductus arteriosus in
preterm infants: time to accept the null hypothesis? \emph{J Perinatol}
. 2010;30(4):241--252

6. Slaughter JL, Reagan PB, Bapat RV, Newman TB, Klebanoff MA.
Nonsteroidal anti-inflammatory administration and patent ductus
arteriosus ligation, a survey of practice preferences at US children's
hospitals. Eur J Ped

7. Stoll BJ, Hansen NI, Bell EF, Walsh MC, Carlo WA, Shankaran S, et al.
Trends in Care Practices, Morbidity, and Mortality of Extremely Preterm
Neonates, 1993-2012. JAMA. 2015;314:1039-51.

8. Walsh MC, Morris BH, Wrage LA, Vohr BR, Poole WK, Tyson JE, et al.
Extremely low birthweight neonates with protracted ventilation:
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pediatrics. 2005;146:798-804.

9. Sant'Anna GM et al. Clin Perinatol 2012

10. Miller JD, Carlo WA. \emph{Pulmonary complications of mechanical
ventilation in neonates. Clin Perinatol
2008;35:273--81.doi:10.1016/j.clp.2007.11.004}

\emph{11.} Gupta D, Greenberg RG, Sharma A, Natarajan G, Cotten M,
Thomas R, Chawla S. A predictive model for~extubation~readiness in
extremely preterm infants. J Perinatol.~2019 Dec;39(12):1663-1669. doi:
10.1038/s41372-019-0475-x. Epub 2019 Aug 27

\emph{12.} Berger J, Mehta P, Bucholz E, et al. \emph{Impact of early
extubation and reintubation on the incidence of bronchopulmonary
dysplasia in neonates. Am J Perinatol
2014;31:1063--72.doi:10.1055/s-0034-1371702}

\emph{13.} Chawla S, Natarajan G, Shankaran S, Carper B, Brion LP,
Keszler M, et al. Markers of Successful Extubation in Extremely Preterm
Infants, and Morbidity After Failed Extubation. J Pediatr.
2017;189:113-9 e2.

14. Epstein SK, Ciubotaru RL, Wong JB. Effect of failed extubation on
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15. Baisch SD, Wheeler WB, Kurachek SC, Cornfield DN. Extubation failure
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care medicine 2005;6:312-8.

16. Hermeto F, Martins BM, Ramos JR, Bhering CA, Sant'Anna GM. Incidence
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17. Hiremath GM, Mukhopadhyay K, Narang A. Clinical risk factors
associated with extubation failure in ventilated neonates. Indian
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18. Bohn DJ, James I, Filler RM, Ein SH, Wesson DE, Shandling B, et al.
The relationship between PaCO2 and ventilation parameters in predicting
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1984;19:666-71.

19. Ballard RA, Truog WE, Cnaan A, Martin RJ, Ballard PL, Merrill JD, et
al. Inhaled nitric oxide in preterm infants undergoing mechanical
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20. Ballard JL, Khoury JC, Wedig K, Wang L, Eilers-Walsman BL, Lipp R.
New Ballard Score, expanded to include extremely premature infants. J
Pediatr. 1991;119:417-23.

Table 1: Clinical characteristics of patients with and without
successful extubation\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\textbf{Variable\textsuperscript{a}} & \textbf{Successful (n=268)} &
\textbf{Failure (n=92)} & \textbf{p-value}\tabularnewline
Hemodynamically significant PDA: peri-extubation & 67 (25\%) & 46 (50\%)
& \textless{}0.001\tabularnewline
GA (wks) & 27 (25-28) & 26 (24-27) & \textless{}0.001\tabularnewline
Birth Weight (gms) & 920 (770-1090) & 795 (690-914) &
\textless{}0.001\tabularnewline
Highest RSS in first 6 hours & 3.60 (2.50-4.95) & 3.80 (2.58-6.15) &
0.045\tabularnewline
Gender: Male & 129 (48\%) & 47 (51\%) & 0.63\tabularnewline
Histologic chorioamnionitis & 124/253 (49\%) & 53/84 (63\%) &
0.03\tabularnewline
Complete ANS Course & 168/266 (63\%) & 59/91 (65\%) &
0.77\tabularnewline
Vaginal delivery & 84 (31\%) & 28 (30\%) & 0.87\tabularnewline
Age at extubation (days) & 3 (2-10) & 4 (2-10) & 0.21\tabularnewline
PMA at extubation (wks) & 28 (27-29) & 27 (26-28) &
\textless{}0.001\tabularnewline
Weight at extubation (gms) & 960 (800-1090) & 815 (695-980) &
\textless{}0.001\tabularnewline
Post extubation respiratory support (NIPPV/NCPAP vs
others\textsuperscript{b}) & 186 (69\%) & 73 (80\%) &
0.047\tabularnewline
Caffeine use prior to extubation & 222 (83\%) & 83 (90\%) &
0.09\tabularnewline
Pre-extubation VI & 5.88 (4.34-7.74) & 5.56 (4.43-8.00) &
0.83\tabularnewline
Pre-extubation Fio\textsubscript{2} & 23 (21-28) & 25 (21-30) &
0.001\tabularnewline
Pre-extubation pH & 7.36 (7.30-7.41) & 7.34 (7.29-7.37) &
0.004\tabularnewline
\bottomrule
\end{longtable}

PDA, patent ductus arteriosus, GA gestational age, RSS respiratory
severity score, ANS antenatal steroids, PMA post menstrual age, NCPAP
nasal continuous positive airway pressure, NIPPV nasal intermittent
positive pressure ventilation, VI ventilation index, Fio2 fraction of
inspired oxygen.

\textsuperscript{a} Data are given as median (interquartile range) or
n/N (\%)

\textsuperscript{b} Others include high-flow nasal cannula, nasal
cannula, and room air

\selectlanguage{english}
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