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\begin{document}

\title{Comparison of Porcine Versus Bovine Surfactant in preterm respiratory
distress syndrome: Evidence from real world data. A multicenter
collaboration from Karnataka}



\author[1]{Abhishek  Aradhya }%
\author[1]{Sharath Ghalige S}%
\author[2]{Babu Madarkar}%
\author[3]{Pruthvishree HV}%
\author[4]{Praveen Venkatagiri}%
\author[5]{Prashant Urs}%
\author[2]{Daizy Ngangom}%
\author[1]{Sandeep Rangaiah}%
\author[3]{Vimal Kumar}%
\author[4]{Chinnaraja Harini}%
\author[5]{Arpna Bansal}%
\author[1]{Maneesha Halkar P}%
\affil[1]{Ovum Hospitals}%
\affil[2]{Rainbow Children's Hospital and BirthRight by Rainbow Marathahalli}%
\affil[3]{Ovum Woman \& Child Speciality Hospital Banaswadi}%
\affil[4]{Chinmaya Mission Hospital}%
\affil[5]{Apollo Hospitals Bannerghatta}%


\vspace{-1em}



  
  \date{May 18, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
\textbf{BACKGROUND \& OBJECTIVES:} Porcine surfactant (200 mg/kg initial
dose) seems to be superior over bovine surfactants (100 mg/kg) in
respiratory distress syndrome (RDS). There is limited data on choice of
surfactant from the developing world. Logically using higher doses of
porcine surfactant comes with additional burden of cost. We decided to
evaluate the clinical effect of different types of surfactants.
\textbf{METHODS:} A retrospective analysis was conducted from August
2019 to December 2022 in 6 tertiary centres. Neonates 24-34 weeks of
gestation with RDS requiring either porcine (200 mg/kg) or bovine
surfactant (100 mg/kg) were enrolled. The proportion of combined
outcomes of death and or CLD, redosing and other morbidities in either
group were analysed. The subgroup of preterm \textgreater{}28 weeks and
outcomes between different surfactants were analysed. \textbf{RESULTS:}
Out of 1149 eligible babies, 302 (26\%) received surfactant after
stabilisation with CPAP. 158 received porcine and 144 received bovine
surfactant via INSURE technique. There was a higher combined outcome of
death or CLD in porcine compared to the bovine group {[}48 (30\%) vs 20
(13\%), OR:2.7; 95\% CI:1.5-4.8; p=0.001{]} and similar combined
outcomes in \textgreater{}28 weeks sub-group. Redosing {[}27 (17\%) Vs
18 (12\%), OR:1.4; 95\% CI:0.7-2.7; p=0.2{]} was similar. Other
morbidities like air leak, invasive ventilation, CPAP duration were
similar between both the groups and different types of surfactants.
\textbf{CONCLUSION:} Porcine surfactant at 200mg/kg had similar combined
outcomes of death/ CLD and redosing compared to bovine surfactant in
preterm \textgreater{}28 weeks. Considering the cost burden in the
developing world, the efficacy needs evaluation in randomised clinical
trials.%
\end{abstract}%



\sloppy


\textbf{Title: Comparison of Porcine Versus Bovine Surfactant in preterm
respiratory distress syndrome: Evidence from real world data. A
multicenter collaboration from Karnataka}

\textbf{Authors:} Sharath S Ghalige\textsuperscript{1}, Abhishek S
Aradhya\textsuperscript{2}, Babu Madarkar\textsuperscript{3},
Pruthvishree HV\textsuperscript{4}, Praveen
Venkatagiri\textsuperscript{5}, Prashant Urs\textsuperscript{6}, Daizy
Ngangom\textsuperscript{3}, Sandeep Rangaiah\textsuperscript{2}, Vimal
Kumar\textsuperscript{4}, Chinnaraja Harini\textsuperscript{5}, Arpna
Bansal\textsuperscript{6}, Maneesha P Halkar\textsuperscript{1}

\textbf{Affiliations:} 1- Department of Pediatrics, Ovum Woman \& Child
Specialty Hospital, Banashankari; 2- Department of Pediatrics, Ovum
Woman \& Child Specialty Hospital, Hoskote, Bangalore rural; 3-
Department of Pediatrics, Rainbow Children's Hospital, Bangalore; 4-
Department of Pediatrics, Ovum Woman \& Child Specialty Hospital, HRBR
layout; 5-Department of Pediatrics, Chinmaya Mission Hospital,
Bangalore; 6- Department of Pediatrics, Apollo hospital, Bannerghatta
Road, Bangalore.

\textbf{Corresponding Author:}

\textbf{Dr Abhishek S Aradhya}

Consultant Neonatologist and Pediatrician

Ovum Woman and Child Specialty Hospital,

Hoskote, Bangalore-562114

\textbf{Email:} abhishekaradhyas@gmail.com

\textbf{ORCID ID: 0000-0003-3524-0939}

\textbf{Abbreviations:} RDS-Respiratory distress syndrome, CPAP-
Continuous positive airway pressure, INSURE- Intubate Surfactant
Extubate, OR- Odds ratio, SD- standard deviation, CLD- Chronic lung
disease.

\textbf{Keywords:} Surfactant types, preterm, RDS, Chronic lung disease

\textbf{Funding: None}

\textbf{Ethical clearance: Ethical clearance obtained. (IRB
no.RCHEC-01-2023)}

\textbf{Disclosure of Conflicts of Interest: None}

\textbf{Patient consent for publication: Not required}

\textbf{Word Count: Main text: 2842 words Abstract: 255 words}

\textbf{Acknowledgement:}

\textbf{Data entry:} Dr. Rosamma, Medical Officer, Chinmaya Mission
Hospital, Bangalore

\textbf{Contributors statement:}

\textbf{Sharath Ghalige:} Designed data collection tool, data
collection, assisted in data analysis,

drafted the initial manuscript and approved the final manuscript.

\textbf{Abhishek S Aradhya:} Conceptualized the study, supervised data
collection, data analysis, assisted in drafting initial manuscript and
approved final manuscript

\textbf{Babu Madarkar:} supervised data collection, assisted in data
analysis and approved the final manuscript.

\textbf{Pruthvishree HV:} Designed data collection tool, data collection
and approved final manuscript

\textbf{Dr Praveen Venkatagiri, Prashant Urs:} Supervised data
collection, critical inputs to the manuscript and approved final
manuscript.

\textbf{Daizy Ngangom, Sandeep, Vimal Kumar, Chinnaraja Harini, Arpna
Bansal, Maneesha PH:} Data collection, critical inputs to the
manuscript, approved final manuscript

\textbf{Abstract}

\textbf{BACKGROUND \& OBJECTIVES:} Porcine surfactant (200 mg/kg initial
dose) seems to be superior over bovine surfactants (100 mg/kg) in
respiratory distress syndrome (RDS). There is limited data on choice of
surfactant from the developing world. Logically using higher doses of
porcine surfactant comes with additional burden of cost. We decided to
evaluate the clinical effect of different types of surfactants.

\textbf{METHODS:} A retrospective analysis was conducted from August
2019 to December 2022 in 6 tertiary centres. Neonates 24-34 weeks of
gestation with RDS requiring either porcine (200 mg/kg) or bovine
surfactant (100 mg/kg) were enrolled. The proportion of combined
outcomes of death and or CLD, redosing and other morbidities in either
group were analysed. The subgroup of preterm \textgreater{}28 weeks and
outcomes between different surfactants were analysed.

\textbf{RESULTS:} Out of 1149 eligible babies, 302 (26\%) received
surfactant after stabilisation with CPAP. 158 received porcine and 144
received bovine surfactant via INSURE technique. There was a higher
combined outcome of death or CLD in porcine compared to the bovine group
{[}48 (30\%) vs 20 (13\%), OR:2.7; 95\% CI:1.5-4.8; p=0.001{]} and
similar combined outcomes in \textgreater{}28 weeks sub-group. Redosing
{[}27 (17\%) Vs 18 (12\%), OR:1.4; 95\% CI:0.7-2.7; p=0.2{]} was
similar. Other morbidities like air leak, invasive ventilation, CPAP
duration were similar between both the groups and different types of
surfactants.

\textbf{CONCLUSION:} Porcine surfactant at 200mg/kg had similar combined
outcomes of death/ CLD and redosing compared to bovine surfactant in
preterm \textgreater{}28 weeks. Considering the cost burden in the
developing world, the efficacy needs evaluation in randomised clinical
trials.

\textbf{Study background and rationale}

Respiratory Distress Syndrome (RDS) is a common cause of morbidity and
mortality in preterm neonates, especially those \textless{}34 weeks of
gestation. Though the cases of classical severe Hyaline Membrane Disease
(HMD) are seen very less recently with the increasing usage of Antenatal
Corticosteroid, a sizable number of preterm neonates do require
Surfactant Replacement Therapy despite receiving best of the Delivery
room practices including Continuous Positive Airway Pressure (CPAP).

Animal-derived Natural Surfactant preparations are the ones now
recommended as standard of care practice for Surfactant replacement
therapy in RDS\textsuperscript{1}. Among these, bovine origin surfactant
or Beractant (Survanta), Bovine Lung Extract Surfactant -- BLES
(Neosurf) and Porcine origin surfactant -- Poractant \selectlanguage{greek}α \selectlanguage{english}(Curosurf) are
available for commercial use in India. There have been a few comparative
studies evaluating natural surfactants. Results differ based on
comprehensive newborn unit policies used for overall management of RDS.
An important study among these, Ramanathan et al. compared the efficacy
and safety of poractant alfa and beractant in preterm infants with RDS
(3 groups: 100 mg/kg of poractant alfa, 200 mg/kg of poractant alfa, and
100 mg/kg of beractant). Mortality, redosing of surfactant, and oxygen
supplements were significantly reduced in the 200 mg/kg of poractant
alfa group than in the 100 mg/kg of poractant alfa or beractant
groups\textsuperscript{2}. However, it has also been reported that the
timing of administration of the surfactant, such as prophylactic versus
rescue and early (within 2 hours after birth) versus delayed (later than
2 hours after birth) treatment, is more important than the composition
of the surfactant\textsuperscript{3}. A recent meta-analysis in 2019,
showed that poractant-\selectlanguage{greek}α \selectlanguage{english}(at 200 mg/kg dose) is associated with better
short term respiratory outcomes including lesser combined outcome of
BPD/mortality when compared to bovine surfactants at their licensed dose
(100 mg/kg) in preterm neonates with RDS\textsuperscript{4}. The pooled
analysis also showed an unusually high rate of redosing with bovine
surfactant (45\% vs 21\%) compared to porcine, which is hardly seen in
clinical practice. Most of these studies are a decade older, where the
practice of antenatal steroids, delivery room CPAP, timing of
surfactant, surfactant need (rescue/prophylactic) etc. were still
evolving. Higher doses of Poractant- \selectlanguage{greek}α \selectlanguage{english}will also incur higher cost. In
contrast to meta-analysis, systematic review of studies of real-world
evidence shows similar outcomes in both types of animal derived
surfactant.\textsuperscript{5} Also, there is limited evidence from the
Indian subcontinent comparing the animal-derived natural surfactants in
their standard prescribed doses in real world scenarios. Hence, the
current study was planned to evaluate the effect of surfactant
preparations in preterm RDS on various morbidities.

\textbf{Material and methods}

This retrospective study was conducted involving 6 tertiary care NICU of
South India over a period from August 2019 to December 2022. Both inborn
and outborn preterm neonates born between 24- 34 weeks of gestation
having RDS and requiring rescue surfactant were enrolled. Exclusion
criteria included babies with antenatally or postnatally suspected or
diagnosed structural lung disease, major congenital malformations and
where death or discharge (against medical advice) or referred to other
NICU occurred within 24 hours of life. The Institutional ethics
committee approved the study at all centres.

Of the 6 tertiary centres that participated, one was a trust hospital,
while the other 5 were private sector hospitals. All the centres catered
to both inborn and outborn neonates. All the centres started delivery
room CPAP with settings of 5 PEEP and 30\% FiO2 using a T piece
resuscitator in spontaneously breathing infants. Surfactant was
administered predominantly using INSURE technique when the baby
continued to have respiratory distress on settings of [?] 6 cm PEEP and
FiO2 \textgreater{}30\%.\textsuperscript{1} All units either used
porcine surfactant (Curosurf, Chiesi, USA Inc) at 200 mg/kg or bovine
(Neosurf, Cipla/Survanta, Abbott) at 100 mg/kg. The choice of surfactant
was individual clinician based, however there was inclination towards
usage of porcine for extreme preterm owing to smaller volume of the
dose. Redosing was considered when the baby continued to have
respiratory distress needing [?] 6 cm PEEP and FiO2 \textgreater{}30\%,
after 12 hours of first dose. Nasal mask was used as a nasal interface
in 5 centres and Ram's cannula was used in one centre. All centres had
nurse:patient ratio of 1:2. Overall the protocols of managing RDS were
similar across centres.

The data were identified from the unit specific registers/database. Case
records of NICU admissions across the hospitals in the collaboration
were retrieved. Data retrieved included demographic, antenatal,
perinatal parameters related to RDS and neonatal morbidities and
mortality. A standardised data collection proforma was used across all
units. Data was entered into a common database with coding of the
centres. Chronic lung disease (CLD) was defined as need for supplemental
oxygen at 36 weeks i.e., moderate to severe CLD as per the NICHD
criteria\textsuperscript{6}.

The primary outcome measure studied was combined outcome of Mortality or
Chronic Lung Disease (CLD). The secondary outcome measures which were
studied are proportion of babies requiring redosing of surfactant, Air
leaks, invasive ventilation, ROP requiring LASER, PDA requiring
treatment, Intraventricular hemorrhage (IVH) (\textgreater{}Grade 3 or
4), Necrotizing enterocolitis (NEC) (\textgreater{}Stage 2B) and
duration of hospital stay.

\textbf{Statistical analysis}

The collected data was coded and entered to the Statistical Package for
Social Science (IBM- SPSS v.25, SPSS Inc) for analysis. The variables
listed were analysed and compared between the groups. The quantitative
data were presented as mean and standard deviation when their
distribution is parametric and as median and range when their
distribution is nonparametric. Qualitative variables were presented as
number, percentages, or proportions. The confidence interval was set to
95\% and the margin of error accepted was set to 5\%. P-value was
considered significant if P [?] 0.05. Appropriate statistical tests were
used to compare the variables. The confidence interval was set to 95\%
and P-value considered significant if P [?] 0.05. Subgroup analysis was
done for gestation \textgreater{}28 weeks and between surfactant types
(Curosurf, Survanta, Neosurf)

\textbf{Results}

Out of 1149 infants, between 24-34 weeks of gestation, 302 (26\%) babies
received surfactant after stabilisation with CPAP (rescue surfactant).
158 babies received porcine and 144 received bovine surfactant via
INSURE technique. The mean gestation (standard deviation) of the
enrolled babies were 29 (2) weeks. The mean birth weight (standard
deviation) of the babies was 1270 grams (437). The demographic
characteristics are summarised in table 1. At baseline, the porcine
group had babies with lower gestation and birth weight and higher
proportion of babies with completion of antenatal steroid course, lower
APGARs, CLD, screen positive early onset sepsis, PDA requiring
treatment; and longer length of stay compared to babies receiving any
bovine surfactant. The combined outcome of death or CLD was
statistically significant in porcine compared to the bovine group {[}48
(30\%) vs 20 (13\%), OR:2.7; 95\% CI:1.5-4.8; p=0.001{]}. Redosing {[}27
(17\%) Vs 18 (12\%), OR:1.4; 95\% CI:0.7-2.7; p=0.2{]} was similar in
both the groups. Other important morbidities like duration of CPAP,
invasive ventilation, air leak, severe IVH, ROP requiring LASER, NEC
were similar.

Subgroup analysis of babies \textgreater{}28 weeks showed a similar rate
of combined outcome of CLD/death {[}16 (14\%) Vs 14 (10\%), OR1.4; 95\%
CI:0.6-3; p=0.4. There was a higher proportion of screen positive early
onset sepsis and longer length of stay. Other morbidities like redosing,
air leak, need for invasive ventilation and CPAP duration were similar
between both the groups. The subgroup analysis is summarised in table 2.

On comparison of three different surfactant preparations, the CLD or
combined outcome with CLD and mortality was higher in the porcine group
compared to the other two bovine preparations. However, the porcine
group had lower gestational age and weight. Other morbidities like
redosing, air leak, need for invasive ventilation and CPAP duration was
similar. The comparison is summarised in table 3.

\textbf{Discussion}

In our study there was a higher combined outcome of death or CLD in
porcine compared to bovine groups {[}48 (30\%) vs 20 (13\%), OR:2.7;
95\% CI:1.5-4.8; p=0.001{]}. This finding is unlike Cochrane review
which found lesser mortality (in-hospital) in porcine group. Cochrane
Meta-analysis done by Singh et.al. demonstrated a significant increase
in death or oxygen requirement at 36 weeks' postmenstrual age (typical
RR 1.30, 95\% CI 1.04 to 1.64; typical RD 0.11, 95\% CI 0.02 to 0.20;
NNTH 9, 95\% CI 5 to 50; 3 studies and 448 infants; moderate quality
evidence) in bovine group compared to porcine
group.\textsuperscript{7}Systematic review by Tridente et.al. shows a
trend favouring porcine groups as well\textsuperscript{4}. In this
review, 12 trials reported data on the composite BPD/mortality outcome,
analysing poractant-\selectlanguage{greek}α \selectlanguage{english}given at a dose of 200 mg/kg and another study
evaluating poractant-\selectlanguage{greek}α \selectlanguage{english}at a dose of 100mg/kg which showed significantly.
The concept CLD has evolved over a period of time with changing
definitions based on the pathophysiological understanding of the
condition. Even after the widely used NICHD workshop definition which is
used in our study, modifications are ongoing. \textsuperscript{6,18-25}
This finding is unlike Cochrane review which found lesser mortality
(in-hospital) in porcine groups. Cochrane Meta-analysis done by Singh
et.al. demonstrated a significant increase in death or oxygen
requirement at 36 weeks' postmenstrual age (typical RR 1.30, 95\% CI
1.04 to 1.64; typical RD 0.11, 95\% CI 0.02 to 0.20; NNTH 9, 95\% CI 5
to 50; 3 studies and 448 infants; moderate quality evidence) in bovine
group compared to porcine group.\textsuperscript{6} Systematic review by
Tridente et.al. shows a trend favouring porcine groups as
well\textsuperscript{4}. In this review, 12 trials reported data on the
composite BPD/mortality outcome, analysing poractant-\selectlanguage{greek}α \selectlanguage{english}given at a dose
of 200 mg/kg and another study evaluating poractant-\selectlanguage{greek}α \selectlanguage{english}at a dose of
100mg/kg which showed significantly lower incidence in neonates treated
with 200 mg/kg poractant-\selectlanguage{greek}α \selectlanguage{english}(p \textless{} 0.001), and pooling together
neonates treated with both doses (p \textless{} 0.001) compared to
bovine surfactant.\textsuperscript{4} The review by Luna et.al. which
compares RWE and RCTs showed that the composite endpoint of BPD or death
occurred with similar incidence in the beractant and poractant alfa
groups in the two studies with RWE that reported this
outcome.\textsuperscript{5,9-12}

Moderate-Severe BPD, were more common among babies which received
Porcine surfactant. This was unlike Cochrane review where no difference
was found and in contrast to Tridente et.al.
meta-analyses.\textsuperscript{6,4} This could be due to the babies
which received Porcine surfactant being smaller babies with average GA
of 28 weeks compared with those who received bovine surfactant with
average GA of 30 weeks (p\textless{}0.001), which inherently increases
the chances of having BPD of any severity. This observation can also be
seen to be coherent with the subgroup analysis of
infants\textgreater{}28 weeks, which does not show a statistically
significant difference in case of Moderate-Severe BPD. A real-world
study by Paul S et.al. that compared the incidence of BPD with beractant
and poractant alfa found no significant difference between
treatments.\textsuperscript{11}

In our study, the need for redosing of surfactant in RDS was not
different between porcine and bovine surfactant in their standard
initial dose (p=0.2). Subgroup analysis of infants of \textgreater{}28
weeks as well as individual surfactants did not show any
difference(p=0.1). This is in contradiction with the meta-analyses by
Tridente et.al.\textsuperscript{4} where redosing was needed more often
in the bovine group than in the porcine group with a statistically
highly significant difference (p=0.001). The said study also concludes
that the effect on the need for redosing is greater at higher
gestational ages unlike what we found in our study. This could be likely
attributed to the usage of studies well from 3 decades back when the
supportive care for preterm babies who might have RDS was not
standardised compared to the present day. Lanciotti L et.al. noted that
if poractant alfa is used, need for re-dosing can be minimised by using
a larger initial dose of 200 mg/ kg. For other surfactants, such data
are not available.\textsuperscript{8} As per The Cochrane review by
Singh et.al. , significant increase in the incidence of 'receiving
\textgreater{} 1 dose of surfactant' was noted in infants treated with
modified bovine minced lung surfactant extract compared with porcine
minced lung surfactant extract. Clinical equivalence was noted with no
significant differences in comparative trials between bovine lung lavage
surfactant and modified bovine minced lung
surfactants.\textsuperscript{7}

In our study there was no difference in the duration of CPAP needed as
well as Invasive ventilation needed (p=0.06 and p=0.6 respectively).
Length of hospital stay was more in babies which received porcine
surfactant (p\textless{}0.001). This may be due to the fact that porcine
group babies compared to bovine groups were of a lower gestational age
(28 weeks vs 30 weeks) and lower birth weight (1113 grams vs 1443
grams).

In our study we did not find any statistically significant difference
for any pulmonary air leaks like Pneumothorax(p=1). This is in line with
Cochrane review\textsuperscript{7} but contrasts Tridente et.al.
study\textsuperscript{4} which concludes less chances of Air leak among
porcine surfactant use. This could be due to understanding that the
occurrence of air leaks may be more attributable to the lung tissue,
sepsis, ventilatory strategies than the surfactant.

The occurrence ROP requiring LASER was similar in both bovine and
porcine groups in our study(p=0.6). As per Cochrane review as well, no
significant difference was found between surfactant preparations and
occurrence of ROP needing LASER.\textsuperscript{7}

PDA requiring treatment was noted to be more in porcine group (24\%)
compared to bovine group (12\%) which was statistically significant
(p=0.006). However, Cochrane reported no effect of surfactant
preparation on risk of PDA requiring treatment with cyclooxygenase
inhibitor or surgery.\textsuperscript{7} In a study by Mussavi et.al. it
was noted that in neonates over 32 weeks there was a significant
difference between groups for the incidence rate of PDA (P = 0.011) but
not below 32 weeks.\textsuperscript{15} The smaller the gestation, the
more chances of having a PDA needing treatment due to inherent
prematurity related factors probably explains the occurrence in our
study.

The study did not find a statistically significant difference between
bovine and porcine groups with respect to IVH (of any grade) and more
importantly IVH of Grade 3 or more. The Cochrane review also did not
show demonstrable significant difference among the surfactant
preparations on the risk of IVH (of any grades) as well as severe IVH of
Grade 3 or more.\textsuperscript{7}

The incidence of NEC in our study was no different than among bovine and
porcine groups (p=0.6). Even the Cochrane review does not show any
difference between the surfactant preparations with respect to
occurrence of NEC of any stage.\textsuperscript{7} In a study by
Najafian et.al. they found that intraventricular haemorrhage (IVH) and
necrotizing enterocolitis (NEC) are more frequent in the Curosurf group
in comparison with Survanta in 29-32 weeks neonates. It was also
realised that lower birth weight and lower gestation were associated
with more complication in both groups.\textsuperscript{16}

We chose retrospective data from December 2022 backwards to August 2019
as it was after an Update by European Consensus Guidelines on management
of RDS\textsuperscript{1} had been published and widely being discussed
and adopted in our Neonatal units. A sub-group analysis of neonates
\textgreater{} 28 weeks was chosen because these were babies who were
candidates for less RDS, less CLD (or BPD) and other morbidities
compared to those [?] 28 weeks. Also, there was an inclination towards
porcine surfactant by some clinicians in [?] 28 weeks based on European
consensus guidelines. Alongside subgroup analysis was done with all the
3 commercially available surfactants in India.

\textbf{Limitations}

As far as limitations of our study, apart from being a retrospective
study from across 6 centres, an important limitation of our study is
that we have not collected the data on pulmonary haemorrhage and its
association with the type of surfactant used. Study by Tridente et.al.
favours use of porcine surfactant which had noted lesser lung
haemorrhage whereas the cochrane review showed no
difference.\textsuperscript{4,7} We felt lung haemorrhage having
multiple etiologies in very small newborns including hemodynamically
significant PDA, sepsis, DIC has more confounding factors and
attributing it to type of surfactant type may not be easy in a
retrospective design. Possibility of approximation of dose of surfactant
due to more common whole-vial based dosing in place of exact
weight-based dosing remains inherent limitation of retrospective
study.\textsuperscript{13}

Cost benefit analysis comparing the surfactant preparations has not been
attempted owing to the varied hospital policies of billing. This
precludes our assumption that bovine surfactant use may reduce the cost
compared to porcine surfactants. Magni et.al. have noted that here were
no significant differences in neonatal intensive care unit (NICU) length
of stay or NICU total costs between infants treated with beractant
(Survanta\selectlanguage{ngerman}®), calfactant (Infasurf®) or poractant alfa (Curosurf®) in a
study data from developed countries and funded by Chiesi Farmaceutici
S.p.A.\textsuperscript{14}

More data from a larger sample size, randomised controlled studies, from
India may be needed to address the issues of type of surfactant usage in
RDS with different morbidities and mortality.

\textbf{Conclusion}

Porcine surfactant at 200mg/kg had similar combined outcomes of death/
CLD and redosing compared to bovine surfactant in preterm
\textgreater{}28 weeks. Considering the cost burden in the developing
world, with no added advantage of using higher doses of porcine
surfactant over bovine surfactant, there is an urgent need to evaluate
the efficacy in randomised clinical trials.

\textbf{References}

\begin{enumerate}
\tightlist
\item
  Sweet DG, Carnielli V, Greisen G, Hallman M, Ozek E, Te Pas A et al.
  European Consensus Guidelines on the Management of Respiratory
  Distress Syndrome - 2019 Update. Neonatology. 2019;115(4):432-450.
\item
  Ramanathan R, Rasmussen MR, Gerstmann DR, Finer N, Sekar K; North
  American Study Group. A randomized multicenter masked comparison trial
  of poractant alfa (Curosurf) versus beractant (Survanta) in the
  treatment of respiratory distress syndrome in preterm infants. Am J
  Perinatol 2004;21:109-19
\item
  Lopez E, Gascoin G, Flamant C, Merhi M, Tourneux P, Baud O, et al.
  Exogenous surfactant therapy in 2013: what is next? Who, when and how
  should we treat newborn infants in the future? BMC Pediatr 2013;13:165
\item
  Tridente A, De Martino L, De Luca D. Porcine vs bovine surfactant
  therapy for preterm neonates with RDS: systematic review with
  biological plausibility and pragmatic meta-analysis of respiratory
  outcomes. Respir Res 2019;20:28
\item
  Sánchez Luna M, Bacher P, Unnebrink K, Martinez-Tristani M, Ramos
  Navarro C. Beractant and poractant alfa in premature neonates with
  respiratory distress syndrome: a systematic review of real-world
  evidence studies and randomized controlled trials. J Perinatol. 2020
  Aug;40(8):1121-1134.
\item
  Jobe AH, Bancalari E. Bronchopulmonary dysplasia. Am. J. Respir. Crit.
  Care Med. 2001; 163, 1723--1729
\item
  Singh N, Halliday HL, Stevens TP, Suresh G, Soll R, Rojas-Reyes MX.
  Comparison of animal-derived surfactants for the prevention and
  treatment of respiratory distress syndrome in preterm infants.
  Cochrane Database Syst Rev. 2015;12: CD010249
\item
  Lanciotti L, Correani A, Pasqualini M, Antognoli L, Dell'Orto VG,
  Giorgetti C, et al. respiratory distress syndrome in preterm infants
  of less than 32 weeks: what difference does giving 100 or 200 mg/kg of
  exogenous surfactant make? Pediatr Pulmonol. 2022 May 16; 57(9):
  2067--73.
\item
  Trembath A, Hornik CP, Clark R, Smith PB, Daniels J, Laughon M, et al.
  Comparative effectiveness of surfactant preparations in premature
  infants. J Pediatr. 2013;163:955--60. E951.
\item
  Ramanathan R, Bhatia JJ, Sekar K, Ernst FR. Mortality in preterm
  infants with respiratory distress syndrome treated with poractant
  alfa, calfactant or beractant: a retrospective study. J Perinatol.
  2013;33:119--25.
\item
  Paul S, Rao S, Kohan R, McMichael J, French N, Zhang G, et al.
  Poractant alfa versus beractant for respiratory distress syndrome in
  preterm infants: a retrospective cohort study. J Paediatr Child
  Health. 2013;49:839--44.
\item
  Naseh A, Yekta BG. INSURE method (INtubation-SURfactant- Extubation)
  in early and late premature neonates with respiratory distress:
  factors affecting the outcome and survival rate. Turk J Pediatr.
  2014;56:232--7.
\item
  Goss KCW, Gale C, Malone R, Longford N, Ratcliffe K, Modi N. Effect of
  surfactant dose on outcomes in preterm infants with respiratory
  distress syndrome: the OPTI-SURF study protocol. BMJ Open
  2020;10:e038959.
\item
  Magni T, Ragni C, Pelizzi N, Sharma S, Perez-Kempner L, Turkstra E et
  al. Health Economic Studies of Surfactant Replacement Therapy in
  Neonates with Respiratory Distress Syndrome: A Systematic Literature
  Review. Pharmacoecon Open. 2023 May;7(3):359-371.
\item
  Mussavi M, Mirnia K, Asadollahi K. Comparison of the efficacy of three
  natural surfactants (Curosurf, Survanta, and Alveofact) in the
  treatment of respiratory distress syndrome among neonates: a
  randomized controlled trial. Iran J Pediatr. 2016;26: e5743.
\item
  Najafian B, Karimi-Sari H, Khosravi MH, Nikjoo N, Amin S, Shohrati M.
  Comparison of efficacy and safety of two available natural surfactants
  in Iran, Curosurf and Survanta in treatment of neonatal respiratory
  distress syndrome: a randomized clinical trial. Contemp Clin Trials
  Commun. 2016; 3:55--9.
\item
  Sherman RE, Anderson SA, Dal Pan GJ, Gray GW, Gross T, Hunter NL, et
  al. Real-world evidence---what is it and what can it tell us? N Engl J
  Med. 2016; 375:2293--7.
\item
  Thébaud B, Goss KN, Laughon M, Whitsett JA, Abman SH, Steinhorn
  RH\emph{et al.} Bronchopulmonary dysplasia. \emph{Nat Rev Dis
  Primers}2019; 5, 78
\item
  Northway WH Jr, Rosan RC, Porter DY. Pulmonary disease following
  respirator therapy of hyaline-membrane disease. Bronchopulmonary
  dysplasia. N Engl J Med. 1967 Feb 16;276(7):357-68.
\item
  Shennan AT, Dunn MS, Ohlsson A, Lennox K, Hoskins EM. Abnormal
  pulmonary outcomes in premature infants: prediction from oxygen
  requirement in the neonatal period. Pediatrics. 1988 Oct;82(4):527-32.
\item
  Walsh MC, Yao Q, Gettner P, Hale E, Collins M, Hensman A et al. Impact
  of a physiologic definition on bronchopulmonary dysplasia rates.
  Pediatrics 2004; 114, 1305--1311
\item
  Higgins RD, Jobe AH, Koso-Thomas M, Bancalari E, Viscardi RM, Hartert
  TV et al. Bronchopulmonary dysplasia: executive summary of a workshop.
  J. Pediatr. 2018; 197, 300--308
\item
  Isayama T, Lee SK, Yang J, Lee D, Daspal S, Dunn M et al. Revisiting
  the definition of bronchopulmonary dysplasia: effect of changing
  panoply of respiratory support for preterm neonates. JAMA Pediatr.
  2017; 171, 271--279.
\item
  Svedenkrans J, Stoecklin B, Jones JG, Doherty DA, Pillow JJ.
  Physiology and Predictors of Impaired Gas Exchange in Infants with
  Bronchopulmonary Dysplasia. Am J Respir Crit Care Med. 2019 Aug
  15;200(4):471-480.
\item
  Jensen EA, Dysart K, Gantz MG, McDonald S, Bamat NA, Keszler M et al.
  The diagnosis of bronchopulmonary dysplasia in very preterm infants:
  an evidence- based approach. Am. J. Respir. Crit. Care Med. 2019; 200,
  751--759.
\end{enumerate}

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