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\begin{document}

\title{Recent advances in understanding NARDS, and the effect of the budesonide
on the prevention of NARDS}



\author[1]{Yiyang Liu}%
\author[1]{Ruilin Wu}%
\author[1]{Xiaoping Lei}%
\author[1]{WENBIN DONG}%
\affil[1]{The Affiliated Hospital of Southwest Medical University}%


\vspace{-1em}



  
  \date{June 18, 2024}


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\selectlanguage{english}
\begin{abstract}
Acute respiratory distress syndrome (ARDS) is an acute respiratory
failure syndrome caused by non-cardiogenic pulmonary edema of various
etiologies.{[}1{]}(\#ref-0001) When the fetus encounters asphyxia,
acidosis, infection, meconium inhalation, et al. during childbirth, the
inflammatory pathway will be activated. The systemic inflammatory
response can remove pathogens, but the excessive inflammatory response
will prompt pulmonary surfactant (PS) inactivation and increase the
permeabilities of alveolar epithelial and endothelial cells, resulting
in the accumulation of edema fluid in the alveoli and eventually leading
to severe hypoxemia, respiratory distress and decreased lung
compliance.{[}1,2{]}(\#ref-0001) Population-based studies in the United
States, Australia, Europe, and New Zealand reported that the incidence
of ARDS in children is 2.0-12.8 per 100000
person-years,{[}3{]}(\#ref-0003) and according to the interim report of
the International Neonatal ARDS Multicenter Study, the mortality of
neonatal ARDS (NARDS) is approximately 20\%.{[}4{]}(\#ref-0004) Due to
the high mortality of NARDS, the researchers try to explore potential
new treatments to limit the incidence and mortality of NARDS. Systemic
inflammatory response plays a significant role in the occurrence and
development of NARDS, budesonide, a non-halogenated corticosteroid, has
a potent local pulmonary anti-inflammatory effect, therefore, it may be
an effective treatment option for NARDS. This article reviews the
evolution of ARDS definition and diagnosis, pathophysiological
mechanisms of NARDS, and gives an outlook on the application of
budesonide in NARDS.%
\end{abstract}%



\sloppy


\textbf{Introduction}

\textbf{The evolution of ARDS definition and diagnosis (Table. 1)}

In an observational study of 272 adult patients receiving
ventilator-assisted ventilation, Ashbaugh et al. found that some
patients did not respond to conventional ventilator-assisted supportive
treatment, and their clinical and pathophysiological changes were
similar to those of infants with neonatal respiratory distress syndrome
(nRDS), such as severe dyspnea, tachypnea (the average respiratory rate
for all patients was 42 breaths per minute), cyanosis that did not
respond to oxygen supplement, loss of lung compliance, and bilateral
white lung changes on chest radiographs. And at autopsy in some
patients, aggregation of alveolar macrophages and hyaline membrane
formation could be seen microscopically in the lungs. From this, they
first proposed the concept of acute respiratory distress syndrome (ARDS)
in 1967.\textsuperscript{5}

The American European Consensus Conference (AECC) on ARDS has made new
recommendations on the definition, pathogenesis, diagnostic criteria,
treatment, and future research directions of ARDS. For example, the
committee proposed that ARDS specifically refers to acute respiratory
distress syndrome, not adult respiratory distress syndrome, so the age
limitation was removed. The AECC defined ARDS as an acute onset of
hypoxemia (arterial partial pressure of oxygen to fraction of inspired
oxygen (PaO\textsubscript{2}/FiO\textsubscript{2}\(\ \leq\ \)200
mmHg), with the pulmonary artery wedge pressure\(\ \leq\ \)18 mm,
with bilateral infiltrates on the frontal chest radiograph. The AEEC
proposed a new definition of acute lung injury (ALI) using similar
criteria but with less severe hypoxemia
(PaO\textsubscript{2}/FiO\textsubscript{2}\(\ \leq\ \)300 mmHg).
The committee emphasized nitric oxide inhalation, tracheal gas
insufflation, perfluorocarbon-associated (partial liquid) ventilation,
prostacyclin inhalation, anti-endotoxin immunotherapy, corticosteroids,
and et al. may be effective in the treatment of ARDS. The committee also
proposed new recommendations on the future research directions of ARDS
such as linking cellular and humoral responses to physiological and
clinical outcome measures, measuring long-term outcomes of ARDS in
multiple ways such as the 2-month survival rate and the quality of life
for survivors, and linking short-term outcomes such as changes in gas
exchange to long-term outcomes such as functional status and
mortality.\textsuperscript{6,7}

In 2012, the European Society of Intensive Care Medicine convened an
international panel of experts to revise the definition of ARDS. The
Berlin definition proposed that the patients with ARDS were identified
within 72 hours to 7 days. The Berlin definition retained bilateral
infiltrates on the frontal chest radiograph as defining criteria for
ARDS. The Berlin definition removed exclusion criteria for pulmonary
artery wedge pressure\(\ \geq\ \)18 mm, because the patients with
ARDS may also have hydrostatic edema in the form of heart failure or
fluid overload, therefore, in the absence of risk factors, ARDS may also
be diagnosed if the respiratory failure is not entirely explained by
heart failure or fluid overload, and other objective assessment such as
echocardiography was needed to rule out hydrostatic edema. The Berlin
definition classified the severity of ARDS according to the degree of
hypoxemia (mild
(200mmHg\(\ <\ \)PaO\textsubscript{2}/FiO\textsubscript{2}\(\ \leq\ \)300mmHg),
moderate
(100mmHg\(\ <\ \)PaO\textsubscript{2}/FiO\textsubscript{2}\(\ \leq\ \)200mmHg)
and severe
(PaO\textsubscript{2}/FiO\textsubscript{2}\(\ \leq\ \)100mmHg)).
The Berlin definition had a better predictive validity for mortality
than the AECC definition, with an area under the receiver operating
curve of 0.577 (95\% CI, 0.561-0.593) vs 0.536 (95\% CI, 0.520-0.553;
P\(\ <\ \)0.001).\textsuperscript{8}

In 2015, Pediatric Acute Lung Injury Consensus Conference (PALICC)
proposed new recommendations for the definition, epidemiology, and
diagnosis of pediatric ARDS (PARDS). PALICC recommended using the
oxygenation index (OI) (( FiO\textsubscript{2}\(\ \times\ \)Mean
airway pressure\(\ \times\ \)100
)\(\ \div\ \)PaO\textsubscript{2}) to define the everity of
patients receiving invasive mechanical ventilation. If the OI is not
available, we could use the oxygen saturation index (OSI)
((FiO\textsubscript{2}\(\ \times\ \)Mean airway
pressure\(\ \times\ \)100)\(\ \div\ \)SpO\textsubscript{2})
to define the everity of patients receiving invasive mechanical
ventilation. But for the patients receiving noninvasive, full face mask
ventilation, we could use PF ratio
(PaO\textsubscript{2}\(\ \div\ \)FiO\textsubscript{2}) to
diagnose PARDS. PALCC did not emphasize the bilateral infiltrates on
chest imaging, this was different from the AEEC and Berlin
definitions.\textsuperscript{3} PALICC believed that children with
preexisting chronic lung disease or cyanotic congenital heart disease
may also develop ARDS if they fulfilled diagnostic criteria (acute
onset, a known clinical insult, chest imaging supporting new-onset
pulmonary parenchymal disease) and had an acute deterioration in
oxygenation not explained by the underlying cardiac
disease.\textsuperscript{9} The use of PALICC criteria increases the
number of patients diagnosed with PARDS and lowers the overall mortality
rate.\textsuperscript{10}

In 2017, an international, collaborative, multicenter, and
multidisciplinary project proposed a consensus definition applicable to
neonatal ARDS (NARDS). The Montreux definition applies to infants from
birth until 44-week postmenstrual age (PMA) or until postnatal age
4-week (for neonates born after PMA 40 weeks) without congenital
anomalies (such as pulmonary adenomatous malformation, sequestration, or
diaphragmatic hernia), genetic disorders of the surfactant system, RDS
and transient tachypnoea of the neonate. This definition defined NARDS
as an acute onset (within one week) of hypoxemia from a known or
suspected clinical injury, with diffuse, bilateral, irregular opacities,
infiltrates, or complete opacification of the lungs on the radiographs
and scans. The Montreux definition used the same OI as in the PALICC
definition to define the severity of ARDS and emphasized the special
role of perinatal factors, such as meconium aspiration syndrome,
perinatal asphyxia, necrotizing enterocolitis. And the research on the
associated risk factors, clinical epidemiology, characteristics of the
clinical pathogenesis, treatment, and prognosis of NARDS and tne, and
the applicability of the Montreux definition is
ongoing.\textsuperscript{10}

With the deepening of research, some scholars believe that NARDS can be
superimposed on some more classic neonatal respiratory diseases, such as
neonatal respiratory distress syndrome (NRDS), a neonatal idiopathic
respiratory distress syndrome (NIRDS) that occurs due to insufficient
synthesis and secretion of pulmonary surfactant (PS) because of the
immature lung development. The combination of the two may lead to more
serious clinical symptoms.\textsuperscript{11} NIRDS is caused by
primary PS system insufficiency,\textsuperscript{12} while NARDS is
caused by secondary PS system dysfunction.\textsuperscript{13} The
etiology of NIRDS is single, but NARDS is the result of multi-factor
interaction.\textsuperscript{14} If NIRDS is not treated in time,
dyspnea will progressively worsen, resulting in changes such as hypoxia,
acidosis, atelectasis, and pulmonary vascular exudation. The
inflammatory response is promoted, resulting in impaired PS system
function, further aggravation of pulmonary edema and atelectasis
decreased lung compliance, and worsening lung function. Due to the
multi-factor interaction, respiratory failure will progress to
multi-organ failure and finally causes NIRDS to superimpose NARDS.
Therefore, the treatment of NARDS requires not only PS replacement
therapy but also causal therapy and systemic supportive therapy, while
the NIRDS can be easily solved by PS replacement
therapy.\textsuperscript{15,16} The ''superposition'' theory runs
through the whole process of NARDS etiology, pathology, diagnosis, and
therapy, it can more comprehensively and profoundly recognize and
understand the essence of NARDS, which has a positive effect on the
diagnosis and treatment of NARDS.

Based on the update of the above definitions, clinicians have a new
understanding of the definition and diagnosis of NARDS. However, there
are few large-sample clinical studies on NARDS. Since January 2018, the
Chinese NARDS Collaborative Group and the International NARDS
Collaborative Group have simultaneously launched their own multi-center
cross-sectional surveys to investigate the epidemiology of NARDS and
explore the applicability of the Montreux Criteria for the diagnosis of
NARDS.\textsuperscript{17} A single-center retrospective study using the
''Montreux criteria'' for the diagnosis of NARDS, reported that among
the 204 reported cases of NARDS, 137 cases (67.2\(\ \%\ \))
were mild ARDS, 49 cases (24.0\(\ \%\ \)) were moderate ARDS,
and 18 cases (8.8\(\ \%\)) were severe ARDS, the cure rate of
NARDS was 79.9\(\ \%\), and the death rate of NARDS was
20.1\(\ \%\),\textsuperscript{18} the NARDS mortality
reported by this single-center retrospective study was similar to the
mortality rate reported in an interim report of an international NARDS
multicenter study.\textsuperscript{4} While another single-center
retrospective study of NARDS based on the ''Montreux criteria'' reported
that the children with NARDS accounted for 2.46\(\ \%\ \)of
children admitted to neonatal units during the same period, mild NARDS
accounted for 41.4\(\ \%\), moderate NARDS accounted for
37.3\(\ \%\), severe NARDS accounted for
21.3\(\ \%\), and the mortality rate was
9.6\(\ \%\).\textsuperscript{17} The difference in mortality
between the two single-center studies may be due to differences in
severity and gestational age among the children with NARDS included in
the studies.

\textbf{Pathophysiology and pathogenesis of ARDS (Figure 1)}

ARDS is not merely a disease, but an involute clinical syndrome with a
heterogeneous clinical phenotype.\textsuperscript{19} Sine the concept
of ARDS was first introduced by Ashbaugh et al. in
1967,\textsuperscript{5} numerous valuable insights into the mechanism
responsible for the pathophysiology and pathogenesis of ARDS have been
presented. ARDS is caused by pulmonary and nonpulmonary factors such as
asphyxia, sepsis, and meconium aspiration.\textsuperscript{2} Regardless
of the risk factors, dysregulated inflammation and increased lung
endothelial and epithelial permeabilities, leading to diffuse alveolar
injury, are critical in the development of ARDS.\textsuperscript{1} The
pathophysiological changes in ARDS can be divided into three consecutive
phases, including the inflammatory phase, proliferative phase, and
fibrotic phase.\textsuperscript{20,21}

Initially, microbial products and cell injury-associated endogenous
molecules will activate a variety of signal transduction pathways such
as nuclear factor kappaB (NF-\selectlanguage{greek}κ\selectlanguage{english}B), mitogen-activated protein kinase
(MAPK), nucleotide-binding oligomerization domains, leucine-rich
repeats, and pyrin domain-containing signal transduction pathway 3
(NLRP3), toll-like receptors (TLRs), adrenergic receptors, and JAK/STAT
signaling pathways.\textsuperscript{22-24} During these processes, cells
including polymorphonuclear neutrophils (PMNs), macrophages, vascular
endothelial cells (VEC), and alveolar epithelial cells are involved. The
PMNs, VEC, macrophages, and platelets can be activated to produce
pro-inflammatory factors such as TNF-\selectlanguage{greek}α, \selectlanguage{english}IL-1, IL-9, IL-8, IL-6, IL-10,
interferons (IFNs), chemokines, reactive oxygen species, and leukocyte
proteases, and all of these products will aggravate the lung
injury.\textsuperscript{25} The pro-inflammatory factors will lead to
disruption of the endothelial basement membrane, the epithelial basement
membrane, and the cell connections between alveolar endothelial and
epithelial, therefore the lung microvascular barrier will be destroyed,
resulting in interstitial and alveolar edema of
pulmonary.\textsuperscript{26} Meanwhile the inflammatory response will
lead to the degradation of PS and the damage of type II alveolar cells,
which will reduce the synthesis of PS, thus the secondary PS deficiency
occurred and eventually led to the formation of hyaline membranes and
alveolar collapse, causing refractory hypoxia.\textsuperscript{2}

As the disease recovers, lung tissue enters a proliferative phase, the
character of this phase is the recovery of type II alveolar epithelial
cells, which is critical for survival, later the type II alveolar
epithelial cells will differentiate into type I alveolar cells,
establishing the functional epithelial layer. The regeneration of the
functional epithelial layer allows the exudative fluid to be cleared
into the interstitium, and alveolar architecture and function will be
reestablished.\textsuperscript{20}

The third stage is the fibrotic phase, including the failure to remove
the alveolar collagen formed early in the injury process, coupled with
the development of cystic changes, most children with severe ARDS will
have significant fibrosis later in life, resulting in lung tissue
permanent structural change.\textsuperscript{21}

\textbf{The use of budesonide in ARDS}

In the complex pathophysiological mechanism of ARDS, the widely
activated host immune response and inflammatory response play key roles
in the occurrence and development of ARDS.\textsuperscript{27}Budesonide
has a wide range of anti-inflammatory and anti-host immune response
effects, which can effectively reduce airway inflammation and promote
airway remodeling. \textsuperscript{28,29} Therefore, budesonide may be
a potentially effective treatment for ARDS.

\textbf{Pharmacology of budesonide}

Budesonide, a non-halogenated corticosteroid, has potent glucocorticoid
activity and weak mineralocorticoid activity.\textsuperscript{30} Its
corticosteroid activity is mediated through glucocorticoid receptors
(GRs) presenting in the cytoplasm of most
cells.\textsuperscript{31}Budesonide is lipid-soluble and it can diffuse
freely across cell membranes, it will produce both genomic and
non-genomic effects when binding to GRs in the
cytoplasm.\textsuperscript{32} The genomic effects of budesonide are
described below: 1) when budesonide bind to GRs, then the GRs
conformational change occurs, which results in dissociation of anchoring
chaperone proteins and exposure of nuclear localization signals, which
allow the rapid translocation of the active GR-ligand complex into the
nucleus.\textsuperscript{33} GRs dimerize in the nucleus and bind
directly to glucocorticoid response elements (GREs) in the promoters of
the target genes to enhance the expression of genes,\textsuperscript{34}
which encode mitogen-activated protein kinase phosphatase-1
(MKP-1)\textsuperscript{35}, annexin-1 (Anx-1)\textsuperscript{36} and
glucocorticoid-induced leucine zipper (GILZ)\textsuperscript{37}, all of
them will interfere inflammation-activated MAPKs to exert
anti-inflammatory effects.\textsuperscript{35} 2) GRs will interact with
other transcription factors, such as nuclear factor kappa-B (NF-\selectlanguage{greek}κ\selectlanguage{english}B) and
activator protein-1 (AP-1)\textsuperscript{38-41}, to suppress their
ability to activate gene expression. NF-\selectlanguage{greek}κ\selectlanguage{english}B is activated by many
pro-inflammatory stimuli and it is important for the expression of many
inflammatory mediators, therefore the inhibition of NF-\selectlanguage{greek}κ\selectlanguage{english}B is a powerful
anti-inflammatory mechanism.\textsuperscript{42}Trans-inhibition of AP1
may also help suppress the expression of anti-inflammatory genes, but
the mechanism appears to be different.\textsuperscript{43} An animal
research revealed that the combination of GRs and AP-1 will inhibit
12-O-tetradecanoylphorbol-13-acetate (TPA)-responsive element (TRE),
thereby exerting anti-inflammatory effects,\textsuperscript{44} because
activation of AP-1 and its subsequent binding to TRE is important in
mediating the proinflammatory effects of many cytokines, growth factors,
and proteases.\textsuperscript{45} Meanwhile GRs will also interact with
the signal transducer and activator of transcription (STAT),
CCAAT/enhancerbinding protein (C/EBP) to exert an anti-inflammatory
effect.\textsuperscript{46} The non-genomic effects of budesonide
typically manifest within seconds to minutes. The budesonide will embed
into membranes, which alters cation transport across the plasma membrane
and promotes mitochondrial proton leak,\textsuperscript{47} which is an
important part of cellular metabolism, involved in tissue thermogenesis
and anti-reactive oxygen species. \textsuperscript{48}

What's more, budesonide has been shown to induce pulmonary epithelial
cells to differentiate into type II alveolar cells and produce PS, and
type II alveolar cells can further differentiate into type I alveolar
cells, alveolar-capillary membranes will be established and the
effective gas exchange will be carried out.\textsuperscript{49} And
budesonide enhances the expression of surfactant protein (SP),
especially surfactant protein B (SP-B), and epithelial sodium channel
(ENaC), to promote lung maturation,\textsuperscript{50,51} Increased
synthesis of endogenous SP-B will decrease alveolar surface tension,
resulting in increased alveolar area, therefore the lung function will
be improved.

\textbf{The advantages of budesonide}

Noah H Hillman et al. reported that intratracheal administration of
budesonide with PS improved lung physiology and decreased the level of
pro-inflammatory cytokine responses in the lung, liver, and brain, the
findings were consistent with those of another animal
study.\textsuperscript{52,53} It has been reported that intratracheal
administration of budesonide with PS on the day of birth limited
hyperoxia-associated disruption of lung function and structure in
preterm rabbits.\textsuperscript{54} In an observational study of 2
premature infants diagnosed with ARDS and receiving ventilator-assisted
ventilation, Burak Deliloglu et al found that intratracheal
administration of budesonide with PS can effectively improve pulmonary
ventilation function and oxygenation index.\textsuperscript{27} In a
case-control study, T. Brett Kothe et al found that compared with the
use of PS alone, the intratracheal administration of budesonide with PS
can shorten the duration of mechanical ventilation. \textsuperscript{55}

Budesonide can be rapidly taken up by the lung and can remain in the
airways and lung parenchyma for a long time,\textsuperscript{56} because
most of the budesonide will be esterified
intracellularly.\textsuperscript{44,57,58} Budesonide ester has been
shown to have no pharmacological activity, but it can be hydrolyzed by
intracellular lipases to release free, pharmacologically active
budesonide.\textsuperscript{57,58} Therefore the anti-inflammatory
effect of the budesonide can be prolonged. But fluticasone propionate
and beclomethasone dipropionate do not produce fatty acid esters, this
is why budesonide has a longer pharmacological action in airway tissue
than other corticosteroids. \textsuperscript{59} Meanwhile in a standard
in vitro experiment, it is reported that compared with cortisol,
budesonide has higher receptor affinity and local anti-inflammatory
ability, the affinity of budesonide for the glucocorticoid receptor is
200-fold higher than cortisol, and the topical anti-inflammatory potency
of budesonide is 1000-fold higher than cortisol.\textsuperscript{30}

\textbf{The side effects of budesonide}

Studies have shown that the combination of budesonide and surfactant
improves gas exchange, matures the lung, and reduces lung inflammation
in animal models of respiratory distress syndrome
(RDS).\textsuperscript{50,51,60-63} However, the budesonide was detected
in the plasma of premature infants and premature sheep that were given
budesonide mixed with surfactant. Such systemic exposure may cause
associated systemic side effects, therefore, close monitoring of the
systemic effects of budesonide, including in the brain, is
critical.\textsuperscript{50,60,62,64} Therefore although administration
of budesonide through the airway limits systemic exposure, the risk of
systemic corticosteroid-related adverse effects including metabolic
derangements, such as the development of the adrenal crisis,
dyslipidemia, insulin resistance, glucose intolerance, caused by
budesonide cannot be ignored.\textsuperscript{65,66} Meanwhile it is
shown that steroid use in the early postpartum period affects
neurodevelopment, thus it is critical to understand the role of
budesonide in neurodevelopment.\textsuperscript{67} The inhaled
budesonide has one of the longest safety records of the current
commercially available ICS.\textsuperscript{65} The study by Yeh et al.
demonstrated that plasma levels of budesonide are low, but they did not
explore its other systemic effects.\textsuperscript{62} A review
revealed that inhaled budesonide therapy only in very rare cases appears
to be associated with an increased risk of adrenal
crisis.\textsuperscript{65} And in the developmental follow-up of an
observational study of infants exposed to intratracheal budesonide for
the reduction of BPD, the infants who received budesonide had similar
fine and gross motor skills at 4--6 months corrected age (CA), similar
muscle tone on physician exams at 6 months CA, similar scores at 18--22
months CA on the Bayley III, these findings are similar to those of Yeh
and Bassler et al. Their studies confirmed that budesonide exposure did
not affect nervous system development.\textsuperscript{62,68,69} First
of all, budesonide will be absorbed through the airways and it will
rapidly dissolve into cellular lipids in the airways, there it will be
rapidly and reversibly esterified by oleic and palmitic acids, and the
budesonide esters have a low affinity for GR, thus no pharmacological
effect will be exerted.\textsuperscript{70,71} secondly, the systemic
half-life of budesonide is much shorter than that of fluticasone
propionate, the budesonide can be metabolized by members of the
cytochrome P450 (CYP) 3A family of enzymes into a variety of inactive
products in lung and liver microsomes, and finally cleaved to
16\selectlanguage{greek}α-\selectlanguage{english}hydroxyprednisolone, thus the systemic exposure to budesonide can be
minimized.\textsuperscript{72}

\textbf{The dose of budesonide}

Yeh et al. proposed the dose of budesonide combined with intratracheal
administration of PS to treat severe RDS based on the application of
budesonide in childhood asthma, namely intratracheal instillation of a
mixture of 0.25 mg/kg of budesonide and 100.00 mg/kg of PS, budesonide
at this dose can exert effective anti-inflammatory effect without
inhibiting adrenal function and increasing adverse
effects.\textsuperscript{73} Studies have shown that using different
doses of budesonide, such as 0.25 mg/kg, 0.5 mg/kg, and 1 mg/kg
budesonide, there is no significant difference in the anti-inflammatory
effect.\textsuperscript{60} And a dose-escalation trial of budesonide in
surfactant for prevention of bronchopulmonary dysplasia reported that
even lower doses of budesonide can provide effective anti-inflammatory
treatment with lower systematic risk.\textsuperscript{74} But an animal
research reported that lower doses of budesonide were not as effective
as budesonide 0.25 mg/kg at decreasing lung inflammation. Meanwhile, the
research found that in the group using 0.25 mg/kg budesonide, the amount
of budesonide esters formed in the lungs accounted for about 40\% of the
total budesonide, whereas in the group using 0.1 mg/kg (14\%) and 0.04
mg/kg (19\%) budesonide, there were fewer budesonide esters formed,
therefore the prolonged anti-inflammatory effects found by Yeh et al.
may not occur at lower doses.\textsuperscript{75} However, most of the
studies were animal studies, and they only analyzed the short-term
efficacy of different doses of budesonide, and the long-term effects of
budesonide at different doses were not considered, so more clinical
randomized controlled trials were needed to explore the short-term
efficacy and long-term effects of different doses of budesonide.

\textbf{The way of administration of budesonide}

Budesonide aerosols, a budesonide inhalation suspension, developed to
meet the drug delivery needs of infants and young children with
persistent asthma, are the first inhaled corticosteroid approved for
nebulizer administration.\textsuperscript{76} Numerous
placebo-controlled trials demonstrated the tolerability and efficacy of
budesonide inhalation suspension.\textsuperscript{77-79} Meanwhile
previous studies have shown that surfactants can assist in the delivery
of drugs in the lungs, such as
antibiotics,\textsuperscript{80,81}immunosuppressive
drugs,\textsuperscript{82}antioxidants\textsuperscript{83,84}, and other
anti-inflammatory molecules,\textsuperscript{85-87} therefore there are
also studies using budesonide suspension combined with surfactant
administered intratracheally.\textsuperscript{62} A randomized
controlled clinical trial reported that the intratracheal administration
of budesonide with PS reduces the incidence of BPD, need for repeated
doses of surfactant, duration of assisted ventilation, and
hospitalization.\textsuperscript{88} It is also reported that budesonide
inhalation could decrease the RDS grades, Downes scores, serum IL-8
levels, and the duration of hospitalization of infants with
RDS.\textsuperscript{89} A meta-analysis suggested that early combined
utilization of budesonide and PS by airway could shorten the duration of
assisted ventilation, duration of invasive ventilation, and hospital
stays of preterm infants with RDS. And its subgroup analysis based on
the mode of budesonide administration (inhalation or intratracheal
instillation) showed that reductions in mortality, duration of assisted
ventilation, and hospital stay were primarily in the budesonide
intratracheal instillation subgroup rather than the budesonide
inhalation subgroup.\textsuperscript{90} And an observational study
reported that intratracheal instillation of the budesonide could
significantly improve lung function, and reduce the duration of assisted
ventilation and PS reuse.\textsuperscript{91} First of all,
intratracheal administration of budesonide with PS can ensure high
initial pulmonary bioavailability, secondly, administering inhaled
glucocorticoids to preterm infants is technically challenging and the
effects are limited.\textsuperscript{92} Meanwhile some scholars
revealed that inhaled budesonide would increase the death rate of
extremely preterm infants.\textsuperscript{69} However the death rate or
adverse physical or neurological outcomes of the extremely preterm
infants using intratracheal administration of budesonide with PS were
not increased.\textsuperscript{62,73,93} Therefore intratracheal
administration of budesonide with PS may be a better way of
administration, but more well-designed randomized controlled trials with
larger sample sizes and longer follow-up from all over the world ought
to be conducted in the future.

As for the stability of budesonide/PS suspension, a study exploring the
biophysical and chemical stability of budesonide combined with PS and
the intrapulmonary distribution of the drug after intratracheal
administration found that when the PS/budesonide concentration ratio was
50:1 or even as high as 160:1, the surface tension-lowering activity of
PS was hardly affected, and the PS/budesonide mixtures with different
concentration ratios were analyzed by high-performance liquid
chromatography (HPLC) at 0, 1, 4, 8, 12, and 24 hours, and no new
compounds were found, this indicated that PS/budesonide has certain
chemical stability.\textsuperscript{92}The intratracheal administration
of budesonide with PS can ensure high initial pulmonary bioavailability,
and also utilize the good diffusion properties of PS to promote the
pulmonary distribution of budesonide. Research using Nano/PET digital
scans technology to explore the distribution of budesonide in the lungs
of rats found that PS promoted the distribution of budesonide in the
peripheral lung. This is consistent with the findings of Riccardo Zecchi
et al. In the study, they used mass spectrometry imaging to analyze the
distribution of PS/budesonide in lamb lungs, and they demonstrated that
compared with the PS/saline group, the PS/budesonide group had a more
uniform distribution of budesonide in the lung and more distribution in
the peripheral lung.\textsuperscript{94}

\par\null

\textbf{CONCLUSIONS}

At present, the treatment for NARDS is mainly PS replacement therapy and
ad adjunctive supportive therapy. Budesonide is a powerful local
anti-inflammatory drug, and a large number of animal and clinical trials
have demonstrated that the utilization of budesonide could reduce the
incidence of BPD, duration of assisted ventilation, and hospitalization.
Therefore, it is reasonable to suppose that budesonide may be an
effective drug for the treatment of NARDS. This review summarizes the
current state of research on the effects of budesonide in ARDS in terms
of clinical aspects and related mechanisms; our findings may provide new
insights for clinical application. However, questions remain regarding
the possible mechanisms of budesonide in the treatment of NARDS. Further
clinical and experimental data are still needed to demonstrate the
safety and efficacy of budesonide in the treatment of NARDS.

\textbf{ACKNOWLEDGMENTS}

The authors would like to express their gratitude to the reviewers and
editors of \emph{Pediatric Pulmonology} . This article was supported by
the National Natural Science Foundation of China (81571480); Luzhou
Municipal People's Government-Southwest Medical University Science and
Technology Strategic Cooperation Project (2020LZXNYDJ03) and the Major
Science and Technology Project of Sichuan Provincial Science and
Technology Department (22ZDYF147).

\textbf{CONFLICTS OF INTEREST}

The authors declare no conflicts of interest.

\textbf{DATA AVAILABILITY STATEMENT}

Data sharing is not applicable---no new data is generated.

\textbf{DRCID}

Liu Yiyang\emph{https://orcid.org/0000-0001-7190-2501}

Lei Xiaoping\emph{https://orcid.org/0000-0003-3818-7117}

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