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\begin{document}

\title{LUNG ULTRASOUND SCORE AND DIURETICS IN PRETERM INFANTS BORN BEFORE 32
WEEKS}



\author[1]{Almudena Alonso-Ojembarrena}%
\author[1]{Alfonso María Lechuga Sancho}%
\author[1]{Patricia Morales-Arandojo}%
\author[1]{Silvia Acuñas-Soto}%
\author[1]{Rosa López-de-Francisco}%
\author[1]{Simon Lubian-Lopez}%
\affil[1]{Hospital Universitario Puerta del Mar}%


\vspace{-1em}



  
  \date{June 15, 2024}


\begingroup
\let\center\flushleft
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\selectlanguage{english}
\begin{abstract}
OBJECTIVE To describe if weekly determined lung ultrasound (LU) scores
in preterm infants born before 32 weeks (PTB32W) change with diuretic
therapy. DESIGN This is a secondary analysis of a prospective study
about weekly performed LU in PTB32W: we included infants who received
diuretics, and compared LU scores according to their evolution on
respiratory support (RS) before and after diuretics. RESULTS We included
17 PTB32W. Both groups were similar in terms of median gestational age:
26 weeks (interquartile rank (IQR) 25-28) in the responders group, and
27 weeks (IQR 25-29) in the other; but different in median number of
days on invasive mechanical ventilation: 27 (IQR 11-43) vs. 76 (IQR
35-117) in the non-responders group, p=0.03; and number of infants with
moderate-severe bronchopulmonary dysplasia: 2 (25\%) vs. 8 (89\%),
p=0.005. The responders group showed lower LU scores at one week after
diuretics: median LU score 3 (IQR 0-10) vs. 12 (IQR 12-12) in the
non-responders group, p=0.04; and after three weeks of treatment: median
value 6 (IQR 3-6) in the responders group vs. 12 (10-15) in the
non-responders group, p=0.01. The decrease in RS was achieved since the
beginning of diuretics: 4 out of 8 (50\%) were extubated in the
responders group, and 8 out of 9 (11\%) in the non-responders group,
p=0.048. CONCLUSIONS There is a group of PTB32W whose LU score improves
after diuretics. This change appears later than that observed in the RS.%
\end{abstract}%



\sloppy


\textbf{LUNG ULTRASOUND SCORE AND DIURETICS IN PRETERM INFANTS BORN
BEFORE 32 WEEKS}

Alonso-Ojembarrena, Almudena\textsuperscript{1}, MD.

Lechuga-Sancho, Alfonso Mar\selectlanguage{ngerman}ía \textsuperscript{2,3}, MD, PhD.

Morales-Arandojo, Patricia \textsuperscript{2}, MD.

Acuña-Soto, Silvia \textsuperscript{2}, MD.

López-de-Francisco, Rosa \textsuperscript{2}, MD.

Lubián-López, Simón Pedro\textsuperscript{1,3}, MD, PhD.

\textsuperscript{1} Neonatal Intensive Care Unit, Puerta del Mar
University Hospital, Cádiz. Spain.

\textsuperscript{2} Department of Pediatrics. Puerta del Mar University
Hospital, Cádiz. Spain.

\textsuperscript{3} Department of Maternal and Child Health and
Radiology. School of Medicine. University of Cádiz, Spain.

\textbf{*Corresponding Author}

Full name: Almudena Alonso-Ojembarrena

Department: Neonatal Intensive Care Unit

Hospital: Puerta del Mar University Hospital

Street Name \& Number: Avenida Ana de Viya 11

City, State, Postal code, Country: Cádiz 11010. Spain

Tel: 34956002314

Fax: 34956004801

E-mail: almudena.alonso.sspa@juntadeandalucia.es

ORCID number: 0000-0002-2413-9758

\textbf{KEYWORDS:} bronchopulmonary dysplasia, diuretics,
lung/diagnostic imaging, neonatal intensive care unit, ultrasonography.

\textbf{WORD COUNT:} 2346.

This research received no specific grant from any funding agency in the
public, commercial or not-for-profit sectors

\textbf{Abbreviated article:} Diuretics and lung ultrasound in preterm
infants.

\textbf{LUNG ULTRASOUND SCORE AND DIURETICS IN PRETERM INFANTS}

\textbf{BORN BEFORE 32 WEEKS}

\textbf{ABSTRACT}

\textbf{OBJECTIVE}

To describe if weekly determined lung ultrasound (LU) scores in preterm
infants born before 32 weeks (PTB32W) change with diuretic therapy.

\textbf{DESIGN}

This is a secondary analysis of a prospective study about weekly
performed LU in PTB32W: we included infants who received diuretics, and
compared LU scores according to their evolution on respiratory support
(RS) before and after diuretics.

\textbf{RESULTS}

We included 17 PTB32W. Both groups were similar in terms of median
gestational age: 26 weeks (interquartile rank (IQR) 25-28) in the
responders group, and 27 weeks (IQR 25-29) in the other; but different
in median number of days on invasive mechanical ventilation: 27 (IQR
11-43) vs. 76 (IQR 35-117) in the non-responders group, p=0.03; and
number of infants with moderate-severe bronchopulmonary dysplasia: 2
(25\%) vs. 8 (89\%), p=0.005.

The responders group showed lower LU scores at one week after diuretics:
median LU score 3 (IQR 0-10) vs. 12 (IQR 12-12) in the non-responders
group, p=0.04; and after three weeks of treatment: median value 6 (IQR
3-6) in the responders group vs. 12 (10-15) in the non-responders group,
p=0.01. The decrease in RS was achieved since the beginning of
diuretics: 4 out of 8 (50\%) were extubated in the responders group, and
8 out of 9 (11\%) in the non-responders group, p=0.048.

\textbf{CONCLUSIONS}

There is a group of PTB32W whose LU score improves after diuretics. This
change appears later than that observed in the RS.



\textbf{LUNG ULTRASOUND SCORE AND DIURETICS IN PRETERM INFANTS BORN
BEFORE 32 WEEKS}

\textbf{INTRODUCTION}

Lung ultrasound (LU) is proving very useful in Neonatal Intensive Care
Units (NICU): it is diagnostic for respiratory diseases with a higher
accuracy than X-ray \textsuperscript{1--3}, predicts the need for
admission of neonatal patients \textsuperscript{4}, non-invasive
ventilation failure \textsuperscript{5,6}, or even the need for
surfactant in preterm \textsuperscript{7} and very low birth weight
infants \textsuperscript{8}. It also predicts bronchopulmonary dysplasia
(BPD) in very low birth weight infants in the first week of
life\textsuperscript{9,10}. Therefore, it is a harmless, and easy to
learn technique, rendering high intraobserver and interobserver
agreement\textsuperscript{11}. For all these reasons, it is becoming
widely extended in NICUs around the world.

LU score is a semiquantitative value that correlates well with the
oxygenation status of neonatal patients \textsuperscript{7}, and the
severity of respiratory diseases \textsuperscript{12}. It can be used to
monitor progression of lung diseases, and to compare LUs in the same
patient. LU detects pulmonary edema better than
X-ray\textsuperscript{13}, and it is helpful to evaluate lung edema in
neonates, according to the guidelines on Point of Care Ultrasound for
critically ill neonates and children by the European Society of
Paediatric and Neonatal Intensive Care \textsuperscript{14}. LU score is
a real time indicator of extravascular lung water \textsuperscript{15},
and it also correlates with lung inflammation in preterm
neonates\textsuperscript{16}. On the other hand, LU scores remain high
since birth until 36 weeks' postmenstrual age (PMA) in very low birth
weight infants with BPD \textsuperscript{10}.

Diuretics are often prescribed in preterm infants with established BPD,
although there is little evidence to support their long-term efficacy
and safety \textsuperscript{17}. Different studies have demonstrated
that furosemide may improve respiratory function in preterm infants, due
to fluid removal from lung tissue \textsuperscript{18--20}. Anyway, some
studies in BPD patients have failed to show real benefits in these
subgroup of preterm infants \textsuperscript{21,22}, but a more recent
one shows a decrease in BPD or death in preterm infants on
furosemide\textsuperscript{23}. On the other hand, secondary effects due
to their long-term use have been described in terms of decreased bone
mineralization, hearing loss or nephrotoxicity.

Therefore, we conducted a study with the aim to describe if weekly
determined LU scores in preterm infants born before 32 weeks (PTB32W)
change with diuretic therapy.

\textbf{MATERIAL AND METHODS:}

\textbf{Patients}

This is a secondary analysis of a prospective study performed in PTB32W.
From November 2017 to April 2020, every PTB32W admitted to the NICU at
Hospital Puerta del Mar in Cádiz, Spain (inborn or transferred from
another hospital in the first 24 hours of life) was recruited with
parental consent. Infants with chromosomal abnormalities, major
malformations or those who died before 36 weeks' PMA were excluded. The
local Ethics Committee approved the study protocol, with the internal
number LUS-NEO-17-01. We selected the patients that received diuretics
before 36 weeks' PMA, and had more than one LU before and after
beginning of treatment. Diuretics recorded were furosemide,
hydrochlorothiazide and spironolactone. Diuretics were prescribed by the
attending neonatologist, who was not aware of the LU results.

\textbf{Lung ultrasound}

We performed beside LU at birth, at three days, and weekly thereafter
until 36 weeks' PMA, and we calculated LU score as previously described
in neonatal patients \textsuperscript{7} by adding the score (0-3)
obtained in three areas of the thorax defined by the anterior axillary
line, the posterior axillary line and the mammary line (upper anterior,
lower anterior and lateral), with a total range of 0 to 18.

We used a portable ultrasound machine (Sonoscape Medical Corp.,
Shenzhen, China) with a high-frequency linear 8-15 MHz probe, holding
the probe perpendicular to the ribs. All LU were performed by the same
neonatologist, and were recorded anonymously.

\textbf{Groups}

We divided the patients in two groups according to their response to
diuretics in terms of decreasing respiratory support (RS). We registered
RS at the time of each LU, and we categorized it as: invasive mechanical
ventilation (IMV), nasal intermittent positive pressure ventilation
(NIV), nasal continuous positive airway pressure (nCPAP), high flow
nasal cannula (HFNC) and none. As the diuretics' effect in pulmonary
function tests have been described to occur as late as four weeks
afterwards \textsuperscript{21}, we compared the highest RS two weeks
before LU, with the lowest RS four weeks after LU.

- Responders: the lowest RS four weeks after diuretics is, at least, one
level lower than the higher RS two weeks before diuretics. -
Non-responders: the lowest RS four weeks after diuretics is the same or
worse than the highest RS two weeks before diuretics.

As the time at which infants required diuretics was different, we
centered the date of LU in the day when diuretics were started. We
created these groups of dates: ''32 days or more before diuretics''
(B1), ''31-24 days before diuretics'' (B2), ''23-16 days before
diuretics'' (B3), '' 15-8 days before diuretics'' (B4), ''7-4 days
before diuretics'' (B5), ''3 days before to 1 day after diuretics''
(T0), ''2 to 5 days after diuretics'' (A1), ''6 to 9 days after
diuretics'' (A2), ''10 to 17 days after diuretics'' (A3), ''18 to 25
days after diuretics'' (A4), ''26 to 33 days after diuretics'' (A5),
''34 or more days after diuretics'' (A6).

BPD was defined according to Walsh et al.
definition\textsuperscript{24}: mild BPD (oxygen requirement for the
first 28 days but in room air at 36 weeks' PMA), moderate BPD (oxygen
requirement for the first 28 days and oxygen \textless{}30\% at 36
weeks' PMA. A room-air challenge was performed in these infants and only
those that failed the reduction (oxygen saturation 80-87\% for 5
minutes, or \textless{}80\% for 1 minute) were diagnosed as moderate
BPD), and severe BPD (oxygen requirement for the first 28 days and
oxygen \textgreater{}30\% or continuous positive airway pressure or
mechanical ventilation at 36 weeks' PMA).

\textbf{Statistical analysis}

We calculated median and interquartile range (IQR), or absolute numbers
and percentages to describe the variables measured. To compare variables
between groups, we used Student's T-test or Wilcoxon rank sum test
depending on the distribution of the variables, with Bonferroni
correction for multiple comparisons. We compared clinical variables, LU
scores and RS at the different moments analysed between the two groups.

Differences were considered statistically significant if
p\textless{}0.05. We used STATA v.14.2 (StataCorp. 2015. \emph{Stata
Statistical Software} : Release 14. College Station, TX, USA: StataCorp
LP.).

\textbf{RESULTS}

We selected 17 PTB32W patients out of the 106 infants included in the
original study (16\%), that had serial LU until 36 weeks' PMA and
received diuretics: 8 were included in the responders group, and 9 in
the non-responders group (see figure 1). We performed a total of 108 LU,
with a median number of LU per patients of 6 (IQR 5-8). The assistant
neonatologists started diuretic therapy at a median age of 32 days (IQR
28-39) in our sample. The responders group had a median gestational age
(GA) at birth of 26 weeks (IQR 25-28), and the non-responders were born
at a median GA of 27 weeks (25-29) (p=0.78). The median birth weight in
the responders group was 819g (575-1060 g), and it was 760g (602-920g)
in the other group (p=0.65). The rest of clinical variables in each
group are shown in table 1. Both groups were different in terms of: days
of invasive mechanical ventilation (median days in responders group was
27 days (IQR 11-43 days), and it was 76 days (IQR 35-117 days) in the
other group, p=0.03), RS at the beginning of diuretic treatment (4
patients (50\%) in the responders group were on invasive mechanical
ventilation, while 8 patients (89\%) in the non-responders group were
intubated, p=0.048), and BPD (2 patients (25\%) in the responders group
developed moderate-severe BPD, while 8 patients (89\%) in the
non-responders group were diagnosed as moderate-severe BPD, p=0.005).

After comparing LU scores in the different moments analysed (see image 2
and table 2), we found differences after the start of diuretics between
the two groups, at A2 and A4. Although there was not a statistical
significant difference in the other intervals of time after diuretics,
the values obtained at A5 and A6 are markedly different between the
groups: at A5, median LU score was 6 (IQR 3-8) in the responders group,
and 12 (IQR 7-14) in the non-responders group, p=0.08; at A6, median LU
score was 5 (IQR 4-6) in the responders group, and 12 (IQR 5-13) in the
non-responders group, p=0.25.

However, in terms of RS, both groups had differences from the very first
day they were began on diuretics. In the following time intervals
analysed, these differences remained significant (see table 3).

\textbf{DISCUSSION}

We found that LU scores do not change in the same way in all PTB32W
after diuretics.

As we have demonstrated previously \textsuperscript{10}, BPD patients
have higher LU scores than non-BPD patients, and maintain them high
until 36 weeks' PMA, while non-BPD patients experience a decrease in LU
scores since the very first week of life, and maintain them close to
zero.

In this study, we show that there is a specific group of patients whose
LU scores improve with diuretic therapy, while the other group maintain
them high. Diuretics were started on day 30 to 35 in both groups, and
the number of BPD patients in both groups was similar, so the expected
LU score evolution in all of them would have been to remain high until
36 weeks' PMA, according to our previous study.

In the responders group, the RS was reduced since the very first
interval of time studied, when we compared it to the other group. On
parallel, LU score also improved in the responders group, although a few
days later: probably the small sample size made that not all intervals
reached statistical significance when comparing LU score after
diuretics.

This can be explained because BPD is a multifactorial disease, not just
influenced by an increase in lung extravascular water. LU is a very
sensitive method to detect an excess of lung extravascular
water\textsuperscript{15}, and that makes LU very useful to study the
lung water content in neonates at birth \textsuperscript{25}, to predict
the need of admission and respiratory support \textsuperscript{4}, and
non-invasive ventilation failure \textsuperscript{5,6}. But the lung
with BPD also includes an inflammatory damage, with a decrease of
alveolar type cells in the alveoli and of elastin fibres in the
extravascular matrix, while there is an increase of collagen fibres that
grow under-regulated, and a decrease in pulmonary
microvasculature\textsuperscript{26}. Although LU score correlates with
the degree of lung inflammation in preterm infants with hyaline membrane
disease\textsuperscript{16}, it is very usual to have infants with
evolving BPD, or recovering from BPD, whose LU scores remain the same
thorough their initial admission in NICU \textsuperscript{10}. This
condition can explain why LU improves later than clinical condition in
preterm infants on diuretics.

Our findings should be interpreted with caution: although GA, birth
weight, CRIB, CRIB-II and SNAPPE-II indexes were similar in both groups,
half of the responders group were extubated at diuretics initiation,
while just one patient in the non-responders group. As this is a
retrospective analysis, diuretics were prescribed according to the
assistant neonatologist's criteria, thus it could be that the responders
group was composed by a subgroup of PTB32W with a milder form of BPD
than the non-responders group: in fact, we had less moderate-severe BPD
patients in the responders group (25\% versus 89\% in the non-responders
group, p=0.005), and they received shorter courses of diuretics (12 days
(IQR 4-14) versus 59 days (IQR 45-65), p=0.035).

As we described earlier \textsuperscript{10}, LU score decreases later
in the most immature patients that don't develop moderate-severe BPD:
patients born before 28 weeks of GA have higher values of LU score
physiologically, even though they have healthy lungs, and LU score in
them cannot predict BPD as early as the first week of life. It could
well be that our responders' group are those more immature infants
without moderate-severe BPD, that would have improved their LU scores
anyway, without needing diuretics.

For all these reasons, the main limitation of our study is its
retrospective and not-blinded design, because we cannot assure that the
changes described in LU score in the responders group are due to
diuretic treatment.

Further research on this topic is warranted, as maybe LUS score
progression after treatment (diuretics, corticosteroids\ldots{}) could
be a suitable biomarker of DBP development in PTB32W.

\textbf{CONCLUSSION}

There is a group of PTB32W whose LU score improves after diuretics. This
change appears later than that observed in the RS, but soon enough to be
a suitable tool to monitor BPD progression in PTB32W on diuretics.

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