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\begin{document}

\title{Management of diuretics in infants with bronchopulmonary dysplasia
discharged on home oxygen.}



\author[1]{Sara Dawson}%
\author[1]{Lynn D'Andrea}%
\author[1]{Joanne  Lagatta}%
\affil[1]{Medical College of Wisconsin Department of Pediatrics}%


\vspace{-1em}



  
  \date{June 10, 2024}


\begingroup
\let\center\flushleft
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\selectlanguage{english}
\begin{abstract}
\textbf{Background:} Infants with Bronchopulmonary Dysplasia (BPD) are
often prescribed diuretics before the neonatal intensive care unit
(NICU) discharge. It is unknown whether outpatient medication weaning
strategies affect duration of home oxygen therapy. \textbf{Methods:}
This was a secondary cohort analysis of infants born \textless{}32 weeks
gestational age with BPD from 2015-2018 discharged from our NICU or
regional NICUs, referred to our pulmonary clinic for home oxygen
management. We compared three groups: those discharged with no
diuretics, diuretics actively weaned (dose decreased) and diuretics
passively weaned (dose not adjusted). \textbf{Results:} Out of 125
infants, 116 were included in the analysis. Forty-five infants were
discharged without diuretics; 52 infants were discharged with diuretics
that were actively weaned; 19 infants were discharged with diuretics
that were passively weaned. Infants who were passively weaned spent the
most time on home oxygen (median 28 weeks, IQR 16-52; p=0.011); there
were no differences in home oxygen duration in infants actively weaned
(median 13 weeks, IQR 10-26) versus not on diuretics (median 22 weeks,
IQR 12-30, p=0.285). Multivariable adjustment for other illness
characteristics associated with duration of home oxygen did not change
this finding. \textbf{Conclusions:} Active weaning of diuretics did not
prolong duration of home oxygen, in the setting of a standardized
clinical guideline for weaning home oxygen in infants with BPD. These
data can serve as baseline information to implement and test
standardized strategies for outpatient medication management.%
\end{abstract}%



\sloppy


\textbf{Title: Management of diuretics in infants with bronchopulmonary
dysplasia discharged on home oxygen.}

Sara K Dawson MD\textsuperscript{1}, Lynn A D'Andrea
MD\textsuperscript{1}, Joanne M Lagatta MD MS\textsuperscript{2}

\textsuperscript{1}Department of Pediatrics, Division of Pulmonary and
Sleep Medicine, Medical College of Wisconsin, and Children's Wisconsin,
Milwaukee, Wisconsin, USA

\textsuperscript{2} Department of Pediatrics, Division of Neonatology,
Medical College of Wisconsin and Children's Wisconsin, Milwaukee,
Wisconsin, USA

\textbf{Address Correspondence:} Sara Dawson, MD, Division of Pediatric
Pulmonary Sleep Medicine, Medical College of Wisconsin, 9000 W.
Wisconsin Ave MS\#B620, Milwaukee WI 53226. Phone: 414-266-6730. Fax:
414-266-6742. Email: sdawson@mcw.edu

\textbf{Funding Source} \textbf{:}K23 HL136525 (JL), the Children's
Research Institute (JL) and the Medical College of Wisconsin Department
of Pediatrics (SD)

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

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

\textbf{Key Words:} Bronchopulmonary dysplasia, diuretics, inhaled
corticosteroids, home oxygen therapy

\textbf{Running title} : medication management of infants on home oxygen

\textbf{Background:}

Infants with Bronchopulmonary Dysplasia (BPD) are often prescribed
diuretics before the neonatal intensive care unit (NICU) discharge. It
is unknown whether outpatient medication weaning strategies affect
duration of home oxygen therapy.

\textbf{Methods:}

This was a secondary cohort analysis of infants born \textless{}32 weeks
gestational age with BPD from 2015-2018 discharged from our NICU or
regional NICUs, referred to our pulmonary clinic for home oxygen
management. We compared three groups: those discharged with no
diuretics, diuretics actively weaned (dose decreased) and diuretics
passively weaned (dose not adjusted).

\textbf{Results:}

Out of 125 infants, 116 were included in the analysis. Forty-five
infants were discharged without diuretics; 52 infants were discharged
with diuretics that were actively weaned; 19 infants were discharged
with diuretics that were passively weaned. Infants who were passively
weaned spent the most time on home oxygen (median 28 weeks, IQR 16-52;
p=0.011); there were no differences in home oxygen duration in infants
actively weaned (median 13 weeks, IQR 10-26) versus not on diuretics
(median 22 weeks, IQR 12-30, p=0.285). Multivariable adjustment for
other illness characteristics associated with duration of home oxygen
did not change this finding.

\textbf{Conclusions:}

Active weaning of diuretics did not prolong duration of home oxygen, in
the setting of a standardized clinical guideline for weaning home oxygen
in infants with BPD. These data can serve as baseline information to
implement and test standardized strategies for outpatient medication
management.

\textbf{Introduction}

Infants with bronchopulmonary dysplasia (BPD) are often discharged with
home oxygen therapy.\textsuperscript{1} Along with home oxygen therapy,
infants are often discharged with diuretic medications. Evidence to
support the use of diuretic therapy in BPD is controversial, with many
questioning the need for this treatment.\textsuperscript{2-4} After NICU
discharge, data show that diuretic usage decrease over the first year of
life. \textsuperscript{4,5} The American Thoracic Society recently
published recommendations for outpatient respiratory management which
suggest against the routine use of diuretics, and recommend
discontinuing them in the outpatient setting.\textsuperscript{6}However,
for infants on home oxygen therapy, it remains unclear how and when to
discontinue diuretics, balancing the recommendations to wean medication
against a potential logistic preference to wean from home oxygen first.

Our outpatient BPD clinic uses a structured guideline to wean from home
oxygen using recorded home oximetry and monthly clinic
visits.\textsuperscript{7} Along with home oxygen weaning guidelines, we
recently introduced guidelines for active weaning of diuretic
medications for all infants who did not otherwise require them for
cardiovascular indications. The objective of this study was to evaluate
whether actively weaning diuretics, instead of an alternative approach
of allowing the infant to passively outgrow their dose, would be
associated with prolonged weaning from oxygen or trigger unexpected
visits. We hypothesized that active weaning of diuretics in premature
infants discharged on home oxygen would not prolong the duration of home
oxygen therapy.

\textbf{Methods}

This was a secondary cohort analysis of infants born \textless{}32 weeks
gestational age with BPD discharged with home oxygen from 2015-2018.
Infants were either discharged from our level IV NICU or regional level
III NICUs and referred to our pulmonary clinic after NICU discharge for
home oxygen management. BPD was defined as respiratory support at 36
weeks post-menstrual age.\textsuperscript{7-9} Infants with
tracheostomies and surgical non-respiratory comorbidities were excluded;
only one member of a multiple gestation was included. For the larger
prospective observational cohort study in our NICU caregivers were
consented. The infants referred to our pulmonary clinic were considered
exempt as a retrospective chart review.

Infants in our BPD clinic are seen 4-6 weeks after discharge from the
NICU. Home oxygen is weaned using a structured algorithm, which has been
previously published. \textsuperscript{7} We also have a standardized
guideline for the management of diuretics. Diuretic medications are
either actively or passively weaned (Figure 1). We start active diuretic
weaning during the first BPD clinic visit if the infant had a
pre-discharge pCO2 less than 60 mmHg, no cardiac abnormalities, gaining
weight appropriately and passes a room air trial in clinic. If the
infant is on a therapeutic dose, we decrease the dose from twice a day
to daily one week before the next clinic visit and discontinue at that
visit if the infant is clinically stable. If the infant is on a
subtherapeutic dose, we decrease the dose to daily at the first visit
and tell the parents to discontinue a week before the next visit.
Passively weaned means we allow the infant to gradually outgrow their
dose. Weaning diuretics and home oxygen occur at the same time.

Our primary exposure variable of interest was diuretic weaning strategy.
To test our primary hypothesis that active weaning of diuretics does not
prolong duration of home oxygen therapy or trigger unexpected visits, we
defined three groups: those discharged from the NICU without diuretics,
those actively weaned from diuretics, and those who were passively
weaned from diuretics without high-risk indications including patent
ductus arteriosus, pulmonary hypertension on echocardiogram after 36
weeks corrected age, or other illness related reason. Infants passively
weaned due to high-risk indications were excluded for this analysis.

Our primary outcome was duration of home oxygen in weeks after NICU
discharge. Discontinuation of home oxygen was defined as passing a home
overnight pulse oximetry study on room air, determined by manual chart
review. Secondary outcomes included number of failed room air trials in
clinic, overnight pulse oximetry trials, oxygen weaned off-protocol,
need for sleep study, increased home oxygen above baseline and new or
increased diuretics during emergency department, inpatient and clinic
encounters, number of visits to BPD clinic and number of missed clinic
visits. Off-protocol weaning included infants whose parents started room
air trials, advanced room air trials quicker than instructed or took the
infant off supplemental oxygen completely. This includes those who were
ultimately told to continue the process they started and those that were
told to go back to the original plan.

We reviewed charts for NICU illness variables including gestational age
at birth, sex, birth weight, multiple gestation, antenatal steroids,
surfactant, patent ductus arteriosus (PDA) ligation or medical therapy;
number of days requiring ventilation, home oxygen liter flow at
discharge, corrected gestational age at discharge, family history of
asthma, and discharge with diuretics, bronchodilators, or inhaled
corticosteroids. After NICU discharge we reviewed the chart for illness
characteristics that might have affected decision-making regarding
diuretic or oxygen weaning, which included emergency department visits,
readmissions, pediatric intensive care admission, or receipt of systemic
corticosteroids. Because inhaled corticosteroids are also frequently
used in infants with BPD discharged with home oxygen therapy, both
prescribed before and after NICU discharge, we categorized use of
inhaled corticosteroids in three groups: no inhaled corticosteroids,
prescribed at NICU discharge, and started after NICU discharge.

\emph{Statistical analysis}

We compared illness differences between diuretic weaning groups, using
chi squared or Fisher's exact tests for differences in proportions, and
Kruskal-Wallis tests for differences in medians. To compare our primary
outcome of duration of home oxygen therapy, we used Cox survival curves
to describe differences between diuretic weaning groups. Differences in
secondary outcomes were compared by chi-squared or Fisher's exact tests
or Kruskal-Wallis tests. We similarly assessed whether other illness
covariates were associated with differences in duration of home oxygen
weaning. To evaluate the association between diuretics and duration of
home oxygen therapy adjusted for other illness covariates, we used a
series of Cox regression models of time to successful weaning from home
oxygen, with failure set as failure to wean by 1 year after discharge.
Model was run in steps with key covariate of diuretic management
retained at each step: first, an unadjusted comparison of diuretic
management; second, adjusted for potential NICU illness covariates that
were significantly associated in bivariable analysis with either
diuretic weaning plan or duration of home oxygen therapy; third,
adjusting for post-NICU significant covariates. Between the second and
third steps, variables associated at a p\textgreater{}0.2 were dropped
from the model. In the post-NICU-discharge model, emergency and
readmission encounters were retained a priori because it was
hypothesized that they significantly impacted clinical decision-making
about medication management. Variables that were not directly part of
the home oxygen weaning process, such as failed room air trials or
overnight pulse ox studies, were not included in modeling. A p value of
\textless{}0.05 was considered statistically significant for all
analyses. The institutional Review Board of Children's Wisconsin
approved this study.

\textbf{Results}

A total of 125 infants were seen in pulmonary clinic for home oxygen
management after NICU discharge; 71 infants were discharged from our
NICU and 54 infants were referred from local NICUs. Of the 125 infants,
123 had complete 1 year follow up. Diuretics were used at NICU discharge
in 78 (62\%) infants. Common medications included
spironolactone/hydrochlorothiazide (53), chlorothiazide (11) and
hydrochlorothiazide (14).

Active diuretic weaning was used in 52 infants; the median time to
discontinuing diuretics for actively weaned infants was 12 weeks after
NICU discharge (IQR 9-17 weeks). Passive weaning was used in 19 infants,
with 12 who were passively weaned because they failed initial room air
trial and 7 who were passively weaned for other etiologies. Their median
time to discontinuing diuretics was 16 weeks after NICU discharge (IQR
14-21, p=0.025 compared to active weaning). An additional 7 infants were
passively weaned due to secondary medical reasons including pulmonary
hypertension (3), pulmonary vein stenosis (1), PDA (1) and recurrent
hospitalization (2). These 7 infants were dropped from subsequent
comparisons.

Illness characteristics of infants in diuretic weaning groups are
displayed in Table 1. Compared to infants discharged without diuretics,
infants discharged with actively-weaned diuretics were born at an
earlier gestational age; received more surfactant, and days on
mechanical ventilation; were discharged at a later corrected gestational
age and with higher liter flow of home oxygen. After discharge, they
were at higher risk for readmissions. There were fewer illness
differences between infants actively versus passively weaned from
diuretics. Notably, there were no significant differences between the
three groups in family history of asthma or discharge with inhaled
corticosteroids; after NICU discharge.

Figure 2 shows the primary outcome of duration of home oxygen. Actively
weaning diuretics was not associated with longer duration of home oxygen
compared to infants who were never discharged on diuretics. Passively
weaned infants spent the most time on home oxygen. Table 2 shows
differences in secondary outcomes related to home oxygen weaning.
Compared to infants discharged without diuretics, infants with
actively-weaned diuretics had more failed overnight pulse oximetry
studies, but without differences in sleep studies done, number of clinic
visits, missed appointments, or off protocol weaning attempts. Passive
weaning of diuretics was more likely to be recommended for infants who
failed room air trials in clinic. Seventy eight percent of infants on
diuretics had their diuretics discontinued prior to the discontinuation
of home oxygen (75\% of those who were actively weaned; 25\% of those
who were passively weaned).

Table 3 shows associations between duration of home oxygen therapy and
other illness characteristics in addition to diuretic weaning strategy.
Longer duration of home oxygen was associated with lower birth weight,
PDA ligation, more days of mechanical ventilation and higher liter flow
of home oxygen at NICU discharge. After NICU discharge, longer duration
of home oxygen was associated with use of inhaled and systemic
corticosteroids, respiratory readmissions, and emergency department
visits. Off protocol weaning of home oxygen therapy was also associated
with longer duration of home oxygen. In multivariable regression
analysis, passively-weaned diuretics were associated with longer
duration of home oxygen therapy, adjusted for NICU and post-discharge
illness characteristics. Other significant associations with home oxygen
duration included post-discharge inhaled corticosteroids and infants who
had their home oxygen weaned off-protocol (Table 4).

\textbf{Discussion}

This study examines the association between diuretic weaning strategy
and duration of home oxygen in the year following discharge from the
NICU in infants with BPD in the setting of guidelines for management of
home oxygen. We found that actively weaning diuretics was not associated
with longer duration of home oxygen, but passively weaning diuretics was
associated with longer duration of home oxygen. We also found that
infants started on inhaled corticosteroids after NICU discharge and
whose parents weaned home oxygen off-protocol experienced a longer
duration of home oxygen.

Infants with BPD discharged with home oxygen therapy are often also
discharged with diuretics. It has been shown that diuretics in infants
with BPD may improve pulmonary mechanics such as improved pulmonary
compliance, lung function and
oxygenation.\textsuperscript{2,4,10-13}However, diuretics do not
decrease oxygen dependence in the inpatient setting, and evidence is
limited regarding the impact of long term
treatment.\textsuperscript{3,14-16} The American Thoracic Society (ATS)
guidelines for outpatient management of diuretics suggest that infants
with post-prematurity respiratory disease who were discharged home with
diuretic therapy should have diuretics discontinued in a careful manner;
the guidelines also recommend avoiding routine use of
diuretics.\textsuperscript{4,6,16} Partially due to the wide variation
in both home oxygen and use of respiratory medication use between
centers, there are few recommendations regarding how and when to wean
diuretics specifically in conjunction with home oxygen
therapy.\textsuperscript{5,16} Bhandari et al. described an active
medication taper in infants with stable BPD, though few infants in that
study were also receiving home oxygen therapy. \textsuperscript{17} Palm
et al. found that most infants with home oxygen therapy have diuretics
discontinued prior to home oxygen discontinuation, though this study did
not address the specific method of diuretic weaning.\textsuperscript{18}
Using our guidelines, we were able to effectively start many infants'
weaning process for supplemental oxygen and diuretics in the same visit.

We found that infants started on inhaled corticosteroids after NICU
discharge had a longer duration of home oxygen therapy, similar to
recent findings by White and colleagues among patients in a trial of
recorded home oximetry.\textsuperscript{4} As with diuretics, the
prescribing pattern of inhaled corticosteroids varies between
institutions.\textsuperscript{18} Infants in our center are variably
discharged home from the NICU on inhaled corticosteroids; in clinic we
follow a guideline to prescribe inhaled corticosteroids only if the
infant has recurrent coughing and wheezing, following the recent
published ATS recommendations.\textsuperscript{6} It is unlikely that
the longer duration of home oxygen therapy was related to inhaled
corticosteroids themselves but rather to intercurrent illness; we also
noted that respiratory rehospitalizations, emergency department visits,
and systemic corticosteroid bursts were associated with longer duration
of home oxygen therapy. Nonetheless, our data provide reassurance that
starting routine inhaled corticosteroids in infants with BPD discharged
with home oxygen therapy does not appear beneficial in decreasing the
length of home oxygen.

We found that infants whose parents did not follow the home oxygen
weaning protocol ultimately had a longer duration of home oxygen.
Off-protocol weaning issues included some parents taking infants off
supplemental oxygen before being instructed to do so, or delays in
implementing the home oxygen weaning process. Since half of infants with
off-protocol weaning had either failed an overnight pulse oximetry study
or had ED visits or admissions, it may be that these infants had a
longer duration of home oxygen due to the severity of their illness,
rather than the weaning process itself. Other infants and their families
experienced delays in clinic appointments or ordering of home oximetry
testing to discontinue oxygen, which contributed to the longer duration
of home oxygen. For these infants and their families, implementing
additional educational and clinical interventions to reduce the family
impact of home oxygen therapy may have the potential to shorten the
length of oxygen. This cohort was followed before our newer strategy of
offering telehealth visits which helps families who have difficulty
getting back and forth. It will be interesting in future studies how the
utilization of remote health strategies effects the length of home
oxygen.

Strengths of this study were the high degree of follow up and use of
pre-specified clinical guidelines. This biggest limitation was that it
was a single-center study. We were not able to control the exact time of
appointments which may affect the exact duration of home oxygen and
medications. We did evaluate other proxy measures of home oxygen weaning
to try to mitigate this weakness. Some factors associated with prolonged
home oxygen weaning are hard to evaluate as ``independent'' risk
factors, such as use of systemic corticosteroids, respiratory
readmissions, and emergency department encounters, since these are all
likely single events related to acute illness.

In the setting of a standardized clinical guideline for weaning home
oxygen in infants with BPD, actively weaning diuretics was not
associated with longer duration of home oxygen. We did find that
beginning inhaled corticosteroids after NICU discharge and off-protocol
weaning were associated with a longer duration of home oxygen. These
data can serve as a baseline information to implement and test
standardized strategies for diuretic weaning. These results also
highlight the need for future studies regarding the use of inhaled
corticosteroids in infants with BPD, telehealth visits, more remote
health strategies for weaning home oxygen and parental education
interventions effects on the duration of home oxygen.



\textbf{References}

1. Lagatta JM, Clark RH, Brousseau DC, Hoffmann RG, Spitzer AR. Varying
patterns of home oxygen use in infants at 23-43 weeks' gestation
discharged from United States neonatal intensive care units. \emph{J
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2. Bhandari A, Panitch H. An update on the post-NICU discharge
management of bronchopulmonary dysplasia. \emph{Semin
Perinatol.}2018;42(7):471-477.

3. Stewart A, Brion LP, Ambrosio-Perez I. Diuretics acting on the distal
renal tubule for preterm infants with (or developing) chronic lung
disease. \emph{Cochrane Database Syst Rev.} 2011(9):CD001817.

4. White H, Berenson A, Mannan J, Feldman HA, Rhein L, Group RHOS.
Utilization trends of respiratory medication in premature infants
discharged on home oxygen therapy. \emph{Pediatr
Pulmonol.}2020;55(6):1359-1365.

5. Ryan RM, Keller RL, Poindexter BB, et al. Respiratory Medications in
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Pediatr.} 2019;208:148-155 e143.

6. Cristea AI, Ren CL, Amin R, et al. Outpatient Respiratory Management
of Infants, Children, and Adolescents with Post-Prematurity Respiratory
Disease: An Official American Thoracic Society Clinical Practice
Guideline. \emph{Am J Respir Crit Care Med.} 2021;204(12):e115-e133.

7. Dawson SK, D'Andrea LA, Lau R, Lagatta JM. Using a home oxygen
weaning protocol and pCO2 to evaluate outcomes for infants with
bronchopulmonary dysplasia discharged on home oxygen. \emph{Pediatr
Pulmonol.} 2020;55(12):3293-3303.

8. Jobe AH, Bancalari E. Bronchopulmonary dysplasia. \emph{Am J Respir
Crit Care Med.} 2001;163(7):1723-1729.

9. Jensen EA, Dysart K, Gantz MG, et al. The Diagnosis of
Bronchopulmonary Dysplasia in Very Preterm Infants. An Evidence-based
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10. Kao LC, Durand DJ, Phillips BL, Nickerson BG. Oral theophylline and
diuretics improve pulmonary mechanics in infants with bronchopulmonary
dysplasia. \emph{J Pediatr.} 1987;111(3):439-444.

11. Kao LC, Warburton D, Cheng MH, Cedeno C, Platzker AC, Keens TG.
Effect of oral diuretics on pulmonary mechanics in infants with chronic
bronchopulmonary dysplasia: results of a double-blind crossover
sequential trial. \emph{Pediatrics.} 1984;74(1):37-44.

12. Baraldi E, Filippone M. Chronic lung disease after premature
birth.\emph{N Engl J Med.} 2007;357(19):1946-1955.

13. Allen J, Zwerdling R, Ehrenkranz R, et al. Statement on the care of
the child with chronic lung disease of infancy and childhood. \emph{Am J
Respir Crit Care Med.} 2003;168(3):356-396.

14. Kao LC, Durand DJ, McCrea RC, Birch M, Powers RJ, Nickerson BG.
Randomized trial of long-term diuretic therapy for infants with
oxygen-dependent bronchopulmonary dysplasia. \emph{J Pediatr.}1994;124(5
Pt 1):772-781.

15. Walsh MC, Szefler S, Davis J, et al. Summary proceedings from the
bronchopulmonary dysplasia group. \emph{Pediatrics.} 2006;117(3 Pt
2):S52-56.

16. Slaughter JL, Stenger MR, Reagan PB. Variation in the use of
diuretic therapy for infants with bronchopulmonary
dysplasia.\emph{Pediatrics.} 2013;131(4):716-723.

17. Bhandari A, Chow U, Hagadorn JI. Variability in duration of
outpatient diuretic therapy in bronchopulmonary dysplasia: a clinical
experience. \emph{Am J Perinatol.} 2010;27(7):529-535.

18. Slaughter JL, Stenger MR, Reagan PB, Jadcherla SR. Utilization of
inhaled corticosteroids for infants with bronchopulmonary
dysplasia.\emph{PLoS One.} 2014;9(9):e106838.

\textbf{Figure 1: Diuretic weaning algorithm}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

Figure 1: Algorithm for weaning diuretics. At the first BPD clinic visit
if the infant had a pre-discharge pCO2 less than 60 mmHg, no cardiac
abnormalities, gaining weight appropriately and passes room air trial in
clinic. If the infant is on a therapeutic dose, we tell the parents to
decrease the dose to daily one week before the next clinic visit and
discontinue at that visit if the infant is clinically stable. If the
infant is on a subtherapeutic dose, we decrease the dose to daily at the
first visit and tell the parents to discontinue a week before the next
visit. Passively weaned means we allow the infant to gradually outgrow
their dose.



\textbf{Figure 2: Actively Weaning Diuretics does not Increase duration
of home oxygen}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image2/image2}

\end{center}
\end{figure}

Figure 2: This figure shows the Cox survival curves to describe the
differences between diuretics weaning groups. The y axis shows the
percentage of infants discontinuing home oxygen; the x axis shows the
number of weeks after NICU discharge on home oxygen.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure1/Figure1}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-2/Figure-2}

\end{center}
\end{figure}

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