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\begin{document}

\title{Respiratory Setback Associated with Extubation Failure in Extremely
Preterm Infants}



\author[1]{Dhruv Gupta}%
\author[2]{Rachel Greenberg}%
\author[3]{Girija Natarajan}%
\author[1]{Sanket Jani}%
\author[1]{Amit Sharma}%
\author[2]{Michael Cotten}%
\author[1]{Ronald Thomas}%
\author[3]{Sanjay Chawla}%
\affil[1]{Children's Hospital of Michigan}%
\affil[2]{Duke University}%
\affil[3]{Wayne State University}%


\vspace{-1em}



  
  \date{June 08, 2024}


\begingroup
\let\center\flushleft
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\selectlanguage{english}
\begin{abstract}
Background and Objectives: Extubation failure in preterm infants is
associated with increased risk of mortality and morbidities. There is
limited evidence to suggest if the increased morbidities are due to
inherent differences among infants who fail or succeed; or whether these
are due to a true respiratory setback among those who fail extubation.
The aim of this study was to evaluate the respiratory status of infants
who fail extubation and to assess the time taken for these infants to
achieve pre-extubation respiratory status. Methods: This was a
retrospective study of infants with birth weight [?]1,250 g who were born
between January 2009 and December 2016. Infants were eligible if they
failed first elective extubation. Extubation failure was defined as need
for re-intubation within 5 days of extubation. Ventilator settings,
blood gas parameters, respiratory severity score and ventilation index
were used to assess respiratory status of infants. Results: Of 384
infants, 76\% were successful and 24\% failed extubation. Among those
who failed extubation 91\%, 77\% and 56\% infants remained intubated at
24 hours, 72 hours and 7 days, respectively. Respiratory status was
worse at 24 hours and 72 hours after re-intubation when compared to
pre-extubation levels. The median times for respiratory severity score
and ventilation index to reach pre-extubation levels were 4 days and 7
days respectively. Conclusion: Among preterm infants, failed elective
extubation is associated with a significant setback in the respiratory
status. Infants who fail an extubation attempt may not achieve
pre-extubation respiratory status for many days after reintubation.%
\end{abstract}%



\sloppy


\textbf{Respiratory Setback Associated with Extubation Failure in
Extremely Preterm Infants}

Dhruv Gupta, MD\textsuperscript{a}, Rachel G. Greenberg, MD, MB,
MHS\textsuperscript{b}, Girija Natarajan, MD\textsuperscript{a}, Sanket
Jani, MD\textsuperscript{a}, Amit Sharma, MD\textsuperscript{a}, Michael
Cotten, MD, MHS\textsuperscript{b}, Ronald Thomas,
PhD\textsuperscript{a}, Sanjay Chawla, MD\textsuperscript{a}

\textbf{Affiliations} : \textsuperscript{a} Department of Pediatrics,
Wayne State University, Detroit, Michigan, USA; and
\textsuperscript{b}Department of Pediatrics, Duke University, Durham,
North Carolina, USA

\textbf{Address Correspondence to:} Sanjay Chawla, Department of
Pediatrics, 3901 Beaubien, Detroit, MI, USA, 48201. Email:
schawla@dmc.org. Ph. 313 745 1436, Fax: 313 745 5867

\textbf{Short title:} \textbf{Respiratory Setback with Extubation
Failure}

\textbf{Funding Source:} The project was done with no specific funding
support

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

\textbf{Conflict of Interest:} The authors have no conflicts of interest
relevant to this article to disclose

\textbf{Abbreviations} :

MV: Mechanical Ventilation

BPD: Bronchopulmonary Dysplasia

NICU: Neonatal Intensive Care Unit

NCPAP: Nasal Continuous Positive Airway Pressure

NIPPV: Nasal Intermittent Positive Pressure Ventilation

Pco\textsubscript{2:} Partial pressure of carbon dioxide in arterial or
capillary blood

RSS: Respiratory Severity Score

FiO\textsubscript{2:} Fraction of Inspired Oxygen

ANS: Antenatal Steroids

GA: Gestational Age

PIH: Pregnancy-Induced Hypertension

MAP: Mean Airway Pressure

VI: Ventilation Index

CI: Confidence Interval

\textbf{ABSTRACT ( [?] 250 words)}

\textbf{Background and Objectives:} Extubation failure in preterm
infants is associated with increased risk of mortality and morbidities.
There is limited evidence to suggest if the increased morbidities are
due to inherent differences among infants who fail or succeed; or
whether these are due to a true respiratory setback among those who fail
extubation. The aim of this study was to evaluate the respiratory status
of infants who fail extubation and to assess the time taken for these
infants to achieve pre-extubation respiratory status.

\textbf{Methods:} This was a retrospective study of infants with birth
weight [?]1,250 g who were born between January 2009 and December 2016.
Infants were eligible if they failed first elective extubation.
Extubation failure was defined as need for re-intubation within 5 days
of extubation. Ventilator settings, blood gas parameters, respiratory
severity score and ventilation index were used to assess respiratory
status of infants.

\textbf{Results:} Of 384 infants, 76\% were successful and 24\% failed
extubation. Among those who failed extubation 91\%, 77\% and 56\%
infants remained intubated at 24 hours, 72 hours and 7 days,
respectively. Respiratory status was worse at 24 hours and 72 hours
after re-intubation when compared to pre-extubation levels. The median
times for respiratory severity score and ventilation index to reach
pre-extubation levels were 4 days and 7 days respectively.

\textbf{Conclusion:}

Among preterm infants, failed elective extubation is associated with a
significant setback in the respiratory status. Infants who fail an
extubation attempt may not achieve pre-extubation respiratory status for
many days after reintubation.

\textbf{INTRODUCTION}

Approximately 80\% of extremely preterm (gestational age \textless{}28
weeks) infants receive mechanical ventilation (MV) to maintain
oxygenation and ventilation.\textsuperscript{1} A long cumulative
duration of MV in preterm infants hospitalized in the Neonatal Intensive
Care Unit (NICU) has been associated with higher rates of death and
various neonatal morbidities, including bronchopulmonary dysplasia
(BPD), upper airway injury, neurodevelopmental impairment, and
nosocomial infections.\textsuperscript{1-5} An early extubation may
reduce the risk of some of these complications.\textsuperscript{3, 4,
6}However, about 25\%-40\% of elective extubations in preterm infants
are not successful.\textsuperscript{7-11} Unsuccessful extubations lead
to a substantial proportion of infants receiving multiple courses of MV
before first discharge from NICUs.\textsuperscript{12} Failed extubation
has been independently associated with an increased risk of mortality,
BPD, death or BPD, severe intracranial hemorrhage, longer
hospitalization, and longer duration of supplemental oxygen and
ventilator support.\textsuperscript{7, 11, 13-15} It is not known if the
higher rate of morbidities noted among infants who fail extubation,
compared to infants who are successfully extubated, are just
associations due to inherent differences among infants who fail or
succeed extubation and failure of extubation is just a marker of
immaturity and sickness; or whether failed extubation is independently
associated with a setback in the respiratory status of these infants.
The aim of this study was to evaluate the pre-extubation and post
reintubation respiratory status of infants who failed an extubation
attempt and to assess the time taken for these infants to achieve the
pre-extubation respiratory status after reintubation.

\textbf{METHODS}

\textbf{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, Detroit.

\textbf{Study Population}

All preterm infants with birth weights less than 1,250 g who were
admitted to the NICU at Hutzel Women's Hospital were screened. Infants
were eligible for the study if they received MV via an endotracheal tube
and had an elective extubation. Infants who were never intubated, died
before an extubation attempt was made or had an unplanned extubation
prior to an elective extubation attempt were excluded from the analysis.
Data were collected for only the first elective extubation attempt.
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). The decisions for
initial endotracheal intubation, timing of extubation, post-extubation
support, and need for reintubation were at the discretion of the primary
clinical team.

\textbf{Definitions}

Extubation failure was defined as need for reintubation within 5 days of
the first elective extubation.\textsuperscript{7,8} Respiratory status
was assessed using ventilator set rate, fraction of inspired oxygen
(FiO\textsubscript{2}) received, mean airway pressure and peak
inspiratory pressure given by the ventilator along with the respiratory
severity score (RSS: product of mean airway pressure and
FiO\textsubscript{2}) and ventilation index (VI: 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 1,000). Ventilation index
was used as an objective measure of adequacy of ventilation in response
to the respiratory support provided,\textsuperscript{16} and respiratory
severity score (RSS) was used as an objective marker of oxygenation in
relation to mean airway pressure received by the
patient.\textsuperscript{17} We also analyzed blood gas parameters that
included arterial or capillary blood gas pH and Pco\textsubscript{2},
and compared pre-extubation levels with levels 24 hours and 72 hours
post reintubation.

Among those infants who failed extubation, time to reach pre-extubation
respiratory status (such as RSS and VI) was defined as time to reach
same level of these respiratory parameters or extubation to non-invasive
ventilation, whichever occurred first.

Gestational age was estimated based on best obstetric approximation
using early ultrasonography findings, date of last menstrual period, or
modified Ballard score in that order.\textsuperscript{18} Small for
gestational age (SGA) was defined as per the Olsen
definition.\textsuperscript{19} The usual practice at our center through
the study period was to use noninvasive ventilation whenever possible
(NCPAP: nasal continuous positive airway pressure or NIPPV: nasal
intermittent positive pressure ventilation), and to limit endotracheal
intubation and MV to infants who were persistently apneic ([?]3 episodes
in a 24-hour period) and/or failed attempted noninvasive ventilation.
Extubation was usually attempted at ventilator set rates of 16 to 20
breaths per minute, mean airway pressure of less than 8 cm
H\textsubscript{2}O, and FiO\textsubscript{2} below 0.4, with blood gas
pH greater than 7.25 and Pco\textsubscript{2} less than 60 mm Hg.

\textbf{Statistical Analysis}

Pre-extubation RSS, VI, ventilator set rate, mean airway pressure (MAP),
peak inspiratory pressure (PIP), FiO\textsubscript{2} being provided
through the ventilator, blood gas Pco\textsubscript{2}, and blood gas pH
were compared with these parameters at 24 hours and 72 hours after
reintubation. The comparisons were performed using the Wilcoxon signed
rank test. A \emph{P} value of \textless{}.05 was considered
statistically significant. Statistical analysis was conducted using
Stata version 16.1 (College Station, TX).

\textbf{RESULTS}

During the study period, a total of 384 infants met the inclusion
criteria. Of these 384 infants, 290 (76\%) succeeded and 94 (24\%)
failed extubation.

\textbf{Perinatal and Peri-Extubation Characteristics}

The 94 infants that failed extubation had a median gestational age (GA)
of 25.5 (IQR 24-27) weeks, median birth weight of 780 (680-914) grams,
14\% infants were SGA, 52\% were male, 51\% had an APGAR score of [?] 6 at
5 minutes of age, median age at first extubation attempt was 4 (2-12)
days, median post menstrual age at extubation was 27 (26-28) weeks.

\textbf{Time to reach pre-extubation support}

Among those who failed elective extubation, median time to reach
pre-extubation RSS level was 4 days (IQR 2-7) and pre-extubation VI
level was 7 days (IQR 3-14).

Among infants who failed extubation, 86 (91\%), 72 (77\%) and 53 (56\%)
infants remained intubated 24 hours, 72 hours and 7 days after
re-intubation, respectively.

\textbf{Comparison of respiratory and blood gas parameters}

Respiratory parameters including RSS, VI, ventilator set rate, MAP, PIP
and FiO2 at 24 hours and 72 hours were compared to the pre-extubation
levels. All respiratory parameters were noted to be significantly worse
at 24 hours and 72 hours post reintubation, when compared to
pre-extubation levels. The pre-extubation blood gas pH and
pre-extubation PCO\textsubscript{2} were compared to post-reintubation
blood gas pH and PCO\textsubscript{2} at 24 hours, and 48 hours. Blood
gas parameters measured at 24 hours and 72 hours post re-intubation were
noted to be significantly worse when compared to pre-extubation levels
(\textbf{Table 1; Figure 1-3).}

\textbf{DISCUSSION}

The current study noted that 24\% of the extreme preterm infants failed
their first elective extubation. ~These results are comparable to
previous studies of extremely preterm infants, which have demonstrated
extubation failure of approximately 23 to 40\%.
\textsuperscript{7-11.}The time taken to achieve comparable
pre-extubation respiratory support (RSS: 4 days with IQR of 2-7 days;
VI: 7 days with IQR of 3-14 days) is concerning and provides an estimate
of the significant respiratory setback among infants who fail
extubation. All respiratory and blood gas parameters were significantly
worse at both 24 and 72 hours post re-intubation when compared with
pre-extubation levels.

There could be multiple potential reasons for respiratory setback among
these infants after failed extubation. It is possible that some infants
develop atelectasis and loss of functional residual capacity due to lack
of adequate respiratory support post extubation or during the intubation
attempt.\textsuperscript{20} Extubation failure requiring reintubation
is not a benign process and may be associated with multiple
complications. Endotracheal intubation is associated with discomfort to
the patient, and wrong position of endotracheal tube can cause airway
trauma along with hemodynamic instability.\textsuperscript{21-24} There
is also a risk of introduction of infectious micro-organisms every time
a new endotracheal tube is inserted.\textsuperscript{25} Reported rates
of successful intubations for preterm neonates are between 50\% and 73\%
with a long time (51 \selectlanguage{ngerman}± 28 seconds) needed for
intubation.\textsuperscript{26,27} Endotracheal intubations have also
been associated with alterations in brain function as monitored by
electroencephalography.\textsuperscript{28} The current study provides
more insight into the pathophysiology of failed extubation and outcomes
of preterm infants related to respiratory setback.

This study has some limitations. Endotracheal intubation, extubation,
and reintubation were at the discretion of the clinical team. We did not
have data on occurrence of other complications during peri-extubation
period such as sepsis, and NEC. We did not explore the reasons for
extubation failure in this study. Also, there was no sub-group

analysis done based on the timing of reintubation, other than the
predefined criteria of 5 days. All infants were born in a single center,
which reduces generalizability of the study. Strengths of the study were
inclusion of all eligible infants using pre-defined criteria with no
selection bias, and use of objective criteria to compare the respiratory
status of these infants in relation to extubation failure.

\textbf{CONCLUSION}

Preterm infants who failed their first extubation attempt had
significant respiratory setback. Most infants had worse respiratory
status post reintubation for multiple days.

Table 1. Comparison of respiratory and blood gas parameters\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
\begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
Variable\textsuperscript{a}\strut
\end{minipage} & \begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
Pre-extubation (n=94)\strut
\end{minipage} & \begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
24 hrs. post re-intubation (n=86)\strut
\end{minipage} & \begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
72 hrs. post re-intubation (n=72)\strut
\end{minipage} & \begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
P Value\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
VI\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
5.60 (4.43-8.14)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
13.10 (9.36-19.20)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
11.43 (7.82-16.40)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
\textless{}.001\textsuperscript{b}
\textless{}.001\textsuperscript{c}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
RSS\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
1.64 (1.40-1.90)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
2.24 (1.60-3.08)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
1.79 (1.48-2.62)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
\textless{}.001\textsuperscript{b}
\textless{}.001\textsuperscript{c}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
PIP (cm H\textsubscript{2}O)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
14 (14-16)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
16 (14-17)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
16 (14-16)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
\textless{}.001\textsuperscript{b}
\textless{}.001\textsuperscript{c}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Ventilator rate (per minute)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
15 (14-18)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
26 (22-35)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
22 (18-31)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
\textless{}.001\textsuperscript{b}
\textless{}.001\textsuperscript{c}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
MAP (cm H\textsubscript{2}O)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
6.2 (5.6-6.9)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
7.1 (6.2-7.9)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
6.8 (6.0-7.7)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
\textless{}.001\textsuperscript{b}
\textless{}.001\textsuperscript{c}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Fio\textsubscript{2} (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
25 (21-30)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
30 (25-38)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
28 (23-35)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
\textless{}.001\textsuperscript{b} .04\textsuperscript{c}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
pH\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
7.34 (7.29-7.37)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
7.32 (7.26-7.37)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
7.30 (7.25-7.35)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
.04\textsuperscript{b} .007\textsuperscript{c}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Pco\textsubscript{2} (mmHg)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
38 (33-45)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
45 (38-52)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
46 (42-51)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
\textless{}.001\textsuperscript{b}
\textless{}.001\textsuperscript{c}\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\textsuperscript{a} Data are given as Median (Interquartile range)

\textsuperscript{b} Comparison between variables, pre-extubation vs 24
hrs. post re-intubation

\textsuperscript{c} Comparison between variables, pre-extubation vs 72
hrs. post re-intubation

Abbreviations: RSS, respiratory severity score; Fio\textsubscript{2},
fraction of inspired oxygen; MAP, mean airway pressure; PIP, peak
inspiratory pressure; VI, ventilation index; Pco\textsubscript{2,}
Partial pressure of carbon dioxide in arterial or capillary blood; pH,
Arterial or capillary blood gas pH

Figure 1: Changes in RSS Changes in VI\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image2/image2}

\end{center}
\end{figure}

Data are given as Median with Interquartile range

Abbreviations: RSS, respiratory severity score; VI, ventilation index;
*, \emph{P} value \textless{} .05

Figure 2: Changes blood gas pH\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image3/image3}

\end{center}
\end{figure}

Data are given as Median with Interquartile range (mmHg)

Abbreviations: pH, Arterial or capillary blood gas pH; *, \emph{P} value
\textless{} .05

Figure 3: Changes blood gas Pco\textsubscript{2}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image4/image4}

\end{center}
\end{figure}

Data are given as Median with Interquartile range (mmHg)

Abbreviations: Pco\textsubscript{2,} Partial pressure of carbon dioxide
in arterial or capillary blood; *, \emph{P} value \textless{} .05

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{[}2{]} Walsh MC, Morris BH, Wrage LA, Vohr BR, Poole WK, Tyson JE, et
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{[}3{]} Sant'Anna GM, Keszler M. Weaning infants from mechanical
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{[}4{]} Miller JD, Carlo WA. Pulmonary complications of mechanical
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{[}5{]} Jensen EA, DeMauro SB, Kornhauser M, Aghai ZH, Greenspan JS,
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{[}6{]} Berger J, Mehta P, Bucholz E, Dziura J, Bhandari V. Impact of
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{[}7{]} Chawla S, Natarajan G, Shankaran S, Carper B, Brion LP, Keszler
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