malloy et al., 2005

REGULAR ARTICLES

A randomized trial comparing beractant and poractant treatment inneonatal respiratory distress syndrome

COLLEEN ANN MALLOY, PAMELA NICOSKI & JONATHAN K. MURASKAS

Ronald McDonald Children’s Hospital at Loyola University Medical Center, Division of Neonatology, Department of

Pediatrics, Maywood, IL, USA

AbstractAim: To compare the effects of beractant and poractant in neonatal respiratory distress syndrome (RDS). Methods: Infantswith RDS were randomized to receive beractant or poractant. The primary outcome measure was fraction of inspired oxygen(FiO2) requirement in the first 48 h after surfactant therapy. Results: 58 infants completed the study. The mean gestationalages for the poractant and beractant groups were 29.6+3.6 and 29.3+2.9 wk, with average birthweights of 1394+699 and1408+534 g, respectively. In the first 48 h, infants who received poractant had a lower FiO2 requirement compared to thosewho received beractant (p=0.018). The prevalence of patent ductus arteriosus (PDA) was lower in the group of infants thatreceived poractant (17%) compared to the group that received beractant (45%) (p=0.02).

Conclusions: Infants with RDS treated with poractant had a lower FiO2 requirement during the first 48 h compared toinfants who received beractant. Infants who received poractant also had fewer PDAs than infants who received beractant. Thedifference in FiO2 was not associated with a difference in age of first extubation, total intubation time, or incidence ofbronchopulmonary dysplasia between groups.

Key Words: Beractant, infant, poractant, respiratory distress syndrome, surfactant

Introduction

Twenty-five years after Fujiwara’s initial report of the

effects of exogenous surfactant, we still do not have

sufficient clinical data to define the relative value of

different lung surfactant replacement preparations in

the treatment or prevention of respiratory distress

syndrome (RDS) [1]. The administration of surfactant

improves pulmonary gas exchange, reduces the

occurrence and severity of RDS, and may reduce the

severity of chronic lung disease [2–4]. While treatment

with either natural or synthetic surfactant preparations

reduces the incidence of neonatal mortality and

pneumothorax in infants with RDS, natural surfactants

seem to improve oxygenation and lung function more

rapidly than synthetic surfactants [5–8]. There are only

a few studies comparing different natural surfactants

[3,9–11].

We compared the bovine surfactant preparation

beractant (Survanta1, Ross Laboratories, Columbus,

OH, USA) and the porcine surfactant preparation

poractant (Curosurf1, Dey Incorporated, Napa, CA,

USA). Each surfactant preparation has been carefully

evaluated in clinical trials and is licensed for use in the

United States and Europe [12–17]. While they have

several similar features, they differ in some potentially

important biophysical characteristics. It is unclear to

what extent these differences influence their physio-

logical and clinical properties under in vivo conditions.

Both beractant and poractant improve oxygenation

and ventilation in the neonate, resulting in improved

alveolar–arterial gradients and allowing for reduced

levels of oxygen therapy. Our aim was to elucidate a

difference in the effect of one surfactant preparation

compared to the other upon the oxygen requirement in

neonatal RDS.

Correspondence: Jonathan Muraskas, Department of Pediatrics, Neonatology, Loyola University Medical Center, 2160 South First Avenue, Maywood,

Illinois 60153, USA. E-mail: [email protected]

(Received 19 November 2004; revised 21 December 2004; accepted 27 December 2004)

Acta Pædiatrica, 2005; 94: 779–784

ISSN 0803-5253 print/ISSN 1651-2227 online # 2005 Taylor & Francis Group Ltd

DOI: 10.1080/08035250510028740

FOR PERSONAL USE ONLYTHE DISSEMINATION IS STRICTLY PROHIBITED

Methods

We designed a prospective, randomized study.

Approval by the Loyola University Medical Center

Institutional Review Board was obtained prior to

initiation of the investigation. Infants eligible for the

study were those less than 37 wk gestational age with

clinical signs and symptoms of RDS who required

intubation and surfactant therapy per clinical judg-

ment independent of the study. Per unit policy,

surfactant was routinely administered to infants

428 wk gestational age and to ventilated infants with a

fraction of inspired oxygen (FiO2) 50.30. Once

infants were identified as requiring intubation and

surfactant treatment, they were eligible for study

enrollment. Informed parental consent was obtained

for all study infants. Infants with cyanotic heart disease,

persistent pulmonary hypertension of the newborn, or

abdominal wall pathology were excluded.

Using sealed envelopes, infants were randomized

to receive either beractant or poractant according

to birthweight stratification blocks. Infants were ran-

domized into the following categories: 4750 g,

751–1000 g, 1001–1500 g, and41500 g. Infants ran-

domized to beractant treatment received 100 mg/kg

(4.0 ml/kg) instilled into the endotracheal tube as

recommended by the product package insert.

Retreatment with beractant was performed 6 h after

the last dose if the infant required ventilator support

and FiO2 50.30 to maintain the PaO2 550 mmHg

(6.7 kPa). All infants randomized to poractant treat-

ment received 200 mg/kg (2.5 ml/kg) instilled into the

endotracheal tube as recommended by the product

package insert. Retreatment with 100 mg/kg (1.25

ml/kg) per dose was performed at 12 h and 24 h after

the first treatment if the infant required ventilator

support and an FiO2 50.30 to maintain the PaO2

550 mmHg (6.7 kPa). Up to three additional doses of

beractant and two additional doses of poractant were

given as needed. Thus, the maximum cumulative dose

for both beractant and poractant was 400 mg/kg. After

surfactant administration, the infant was reconnected

to the ventilator; no airway suctioning was allowed

during the first 6 h after surfactant instillation.

Written instructions were provided to the caregivers

regarding oxygen weaning for pulse oximetry satur-

ations according to gestational age.Goal pulse oximetry

saturations were consistent with unit policy: infants

428 wk, 85–92%; infants 28–34 wk, 90–95%; infants

534 wk, 93–98%. Ventilator weaning was mandatory

for PaCO2 445 mmHg (6 kPa) and pH 57.28. The

primary outcome was to compare the FiO2 require-

ments in the beractant and poractant groups for 48 h

after the first surfactant treatment.

All infants were compared with respect to the

following complications diagnosed within 40 wk

corrected gestational age: pneumothorax, patent

ductus arteriosus (PDA), intraventricular hemorrhage

(IVH), periventricular leukomalacia (PVL), pulmo-

nary hemorrhage, sepsis, bronchopulmonary dysplasia

(BPD), retinopathy of prematurity (ROP) requiring

laser photocoagulation, and death. BPDwas defined as

a need for oxygen at 36 wk postmenstrual age and

528 d of age. Sepsis was defined as a positive blood

culture in a sick infant, with early onset sepsis occur-

ring within the first 72 h of age, and late onset sepsis

thereafter. Pulmonary hemorrhage was diagnosed

based on the presence of frank blood in the endo-

tracheal tube associated with a rapid deterioration in

clinical condition. All ROP examinations and assess-

ments of need for laser photocoagulation were made by

the same pediatric ophthalmologist who wasmasked to

surfactant type received. Cranial ultrasound evalu-

ations performed on all infants at days 7 and 28 of age

were used to classify intraventricular hemorrhages by

the Papile method and to diagnose PVL [20]. Echo-

cardiograms and chest radiographs were performed

according to clinical indication. Pediatric cardiologists

and radiologists who interpreted imaging studies were

masked regarding type of surfactant received. PDA

diagnosis required an echocardiogram with Doppler

verification and cardiology recommendation of indo-

methacin therapy based on significance of flow. No

infant received prophylactic prostaglandin inhibitor

therapy.

The groups were also compared with regard to

intubation time, duration of nasal CPAP (cycled and

continuous positive airway pressure) ventilation,

duration of supplemental oxygen, and length of

hospital stay. FiO2, O2 saturation, peak inspiratory

pressure, mean airway pressure, positive end-expira-

tory pressure, and ventilator rate were recorded every

20 min after surfactant therapy for 2 h, then every

30 min for the following 6 h, every hour for the next

6 h, and then every 2 h until 48 h. Demographic data

including gender, gestational age, Apgar scores,

birthweight, admission data, andmaternal history were

collected for all infants.

Statistics

The primary outcome was FiO2 requirement in the

first 48 h after the first surfactant dose. With an

expectation of a lower FiO2 requirement with

poractant, we based our sample size determination

on the level of oxygen required at 24 h by the 73 infants

in the Speer study who received beractant or poractant

[9]. It was determined that 23 infants per group were

necessary to detect a 10% difference in FiO2 be-

tween surfactant groups, with an a of 0.05 and a

power of 0.80 [21].

A mixed analysis of variance (ANOVA) was used

to test the difference in FiO2 measurements over time

for the two groups. Other differences between the

780 C. A. Malloy et al.


beractant and poractant groups were tested with

Student’s t-test for independent samples, the Mann-

Whitney U-test, and the z-test for independent

proportions. Significance levels were determined as

p50.05.

Results

Between June 2002 and May 2003, 236 infants

537 wk were admitted with a diagnosis of RDS. Of

the 119 of these infants who were intubated and

received surfactant therapy, 60 infants were enrolled in

our study. Two patients were removed from the study

when they were found to have congenital heart disease.

All study infants were inborn. There were no signifi-

cant differences between surfactant groups with

regards to infant age, birthweight, gender, Apgar

scores, prenatal steroid administration, and maternal

age (Table I).

The FiO2 requirement before surfactant adminis-

tration was not different between the groups, with the

poractant and beractant groups having mean FiO2

requirements of 0.49 and 0.47, respectively. The

mixed ANOVA showed that the FiO2 requirements

were different for the two groups over time. Infants

who received poractant had a lower FiO2 requirement

in the first 48 h compared to those who received

beractant (p=0.018) (Figure 1). There were no

differences between groups with regard to age of first

extubation, reintubation rate, total intubation time, or

development of BPD (Table II).

Three deaths occurred, all of which were in the

beractant group. In two instances, the families with-

drew support secondary to significant intraventricular

hemorrhages; one infant died on day 8 and the other on

day 12. The third infant died on day 120 with multiple

organ failure after a protracted hospital course. Infor-

mation was included as available. For example, data

were included from all three patients regarding FiO2

requirement in the first 48 h and the presence of aPDA.

Conversely, data regarding day of first extubation was

available only for the infant who died at 3 mo of age.

Table I. Infant demographics.

Poractant

(n=29)

Beractant

(n=29)

Mean gestational age (wk) 29.6+3.6 29.3+2.9

23–25 wk gestational age 6 (21%) 3 (10%)




Mean birthweight (g) 1394+699 1408+534

Female gender 15 (52%) 16 (55%)

4750 g 4 (14%) 3 (10%)

751–1000 g 5 (17%) 5 (17%)

1001–1500 g 11 (38%) 10 (34%)

41500 g 9 (31%) 11 (38%)

Apgar 1 min 57 10 (34%) 13 (45%)

Apgar 5 min 57 4 (14%) 5 (17%)

Apgar 10 min 57 2 (7%) 2 (7%)

Maternal steroids received 20 (69%) 23 (79%)

Mean maternal age 31.3+6.7 31.4+5.3

Figure 1. Difference in FiO2 over time (p=0.018).

Table II. Pulmonary outcomes.

Poractant

(n=29)

Beractant

(n=29) p-value

Extubation within 1st 3 d 16 (55%) 12 (41%) 0.43

1st extubation day: median

(range)

2 (0–50) 5 (1—71)a 0.42

1st extubation: median

gestational age, wk (range)

30.4 (25.4–36.3) 31.3 (27.1–35.0)a 0.73

Reintubation for respiratory

distress within 14 d of

extubation

9 (31%) 9 (33%)a 0.82

Median days of intubation (range) 5 (0.5–49) 7 (1–117)a 0.82

Average days of nasal CPAP 7 5b 0.44

Average days of nasal cannula

oxygen administration

19 17b 0.79

Dexamethasone administered 6 (21%) 4 (14%) 0.57

BPD 10 (34%) 10 (37%)a 0.84

a Calculations done with n-2 secondary to two deaths (on days 8 and 12).b Calculations done with n-3 secondary to three deaths (on days 8, 12, and 120).

Beractant and poractant in respiratory distress syndrome 781


Concerning secondary outcomes, the incidences of

pneumothorax, pulmonary hemorrhage, IVH grades

3–4, sepsis, laser photocoagulation for ROP, and

death were not significantly different between groups

(Table III). The incidence of PDA requiring treatment

with indomethacin was lower in the group of infants

that received poractant (17%) compared to the group

that received beractant (45%) (p=0.02).

The number of surfactant doses required by each

group was significantly different. Compared to the

beractant group, infants in the poractant group

received less surfactant product in terms of number

of doses and milliliters per kilogram (Table IV).

Beractant has 25 mg, and poractant has 76 mg of

phospholipid per milliliter of surfactant [18,19]. Given

the difference in preparations, although infants in

the poractant group received fewer doses and less

volume of surfactant, they received more milligrams

per kilogram of surfactant and of phospholipid.

Discussion

During the first 48 h after surfactant administration,

poractant was associated with a lower FiO2 require-

ment compared to beractant. This disparity was not

associated with a difference in time to extubation,

reintubation rate, intubation time, or development of

BPD. In a study comparing alveofact, poractant, and

beractant, premature infants with RDS who received

alveofact or poractant had fewer ventilator days,

needed fewer days of oxygen administration, and had

shorter hospitalizations compared to those who

received beractant [10]. In 1995, Speer et al.

prospectively studied 75 infants with RDS who

received poractant or beractant and had arterial blood

gases determined at regular intervals [9]. Although

both groups had rapid improvements in oxygenation

and ventilator requirements, infants treated with

poractant had a higher arterial/alveolar oxygen tension

ratio and required lower mean airway and peak

inspiratory pressures at several time points within 24 h

of randomization (p50.05–0.001). A recent multi-

center study randomized 293 infants with RDS to

receive poractant or beractant in a randomized,

masked fashion [11]. The authors found that the mean

FiO2 between 0 and 6 h after the surfactant dose was

significantly lower for the poractant group than the

beractant group. Our findings are consistent with a

lower oxygen requirement in infants who received

poractant compared to beractant.

In addition, the presence of a PDA requiring indo-

methacin treatment was significantly lower in infants

who received poractant compared to beractant. While

this finding has not been reported before in the English

literature, it is a secondary outcome in a small study

and should be interpreted with caution. The use of

exogenous surfactant has been associated with an

earlier appearance of a clinically significant PDA, as

accelerated pulmonary improvement is accompanied

by a fall in pulmonary vascular resistance [22]. A

randomized trial comparing ductal patency in infants

with RDS who received either beractant or placebo

(air) found the need for indomethacin therapy to be

similar between groups [23]. The authors found that

exogenous surfactant therapy was not associated with

an increased risk for delayed closure of the ductus

arteriosus or a greater incidence of indomethacin

usage. In a prospective, masked, controlled study of

amniotic fluid-derived surfactant and time of PDA

closure, the authors concluded that the maturity of the

ductus arteriosus, reflected by its tendency to close

spontaneously, parallels lung maturity and thus would

not be affected by surfactant therapy [24]. The asso-

ciation of poractant therapy with fewer PDAs requires

validation by other studies.

The differences in clinical effectmay be related to the

biophysical characteristics of poractant and beractant.

Both are derived from minced animal lungs and

undergo washing and extraction with organic solvents.

The washing procedure removes water-soluble

components including the surfactant-associated

apoproteins SP-A and SP-D, leaving only the hydro-

phobic surfactant proteins B (SP-B) and C (SP-C).

Poractant is further filtered by a liquid-gel chromato-

graphy treatment that removes neutral lipids such

Table III. Adverse outcomes.

Poractant

(n=29)

Beractant

(n=29) p-value

Pneumothorax 2 (7%) 1 (3%) 0.53

Pulmonary hemorrhage 1 (3%) 2 (7%) 0.53

IVH grade 3 or 4 4 (14%)a 6 (21%) 0.93

PVL 2 (7%)a 0 (0%) 0.51

PDA requiring

treatment with

indomethacin

5 (17%) 13 (45%) 0.02

Need for PDA ligation 1 (3%) 2 (7%) 0.53

Early-onset sepsis 1 (3%) 0 (0%) 0.53

Late-onset sepsis 3 (10%) 1 (4%)b 0.33

Laser photocoagulation

for ROP

5 (17%) 1 (4%)b 0.11

Death 0 (0%) 3 (10%) 0.08

a Calculations done with n-1, excluding infant with documented

in utero grade 3 IVH and PVL.b Calculations done with n-2 secondary to two deaths (days 8 and

12).

Table IV. Surfactant received.

Poractant Beractant p-value

Mean no. of surfactant doses 1.2 1.7 0.004

Mean ml/kg of surfactant

administered per infant

2.8 6.9 50.0001

Mean mg/kg of surfactant

administered per infant

224 172 0.002



as triacylglycerol, cholesterol, and cholesteryl esters.

It contains almost exclusively polar lipids, with

phosphatidycholine constituting 60% of the total

phospholipids [25]. In contrast, beractant retains its

neutral lipids and is enriched with synthetic dipalmi-

toyl phosphatidylcholine, triacylglycerol, and palmitic

acid to standardize lipid composition and reduce film

compressibility [26].

Poractant and beractant also differ in their respective

amounts of SP-B. Animal studies support the impor-

tance of higher concentrations of SP-B and SP-C in

surfactant preparations [27]. Rider et al. studied

preterm rabbits and found that the addition of SP-B

to surfactant lipids restored surfactant function,

improved static and dynamic lung mechanism, and

also reduced protein leak into airspaces [28]. This

effect was not reproduced with SP-A and was partially

reproduced by SP-C. In a similar experiment, the

mechanical properties of the lungs improved in a dose-

related manner as increased concentrations of SP-B

were added to surfactant [29]. Surfactant analyses

have shown poractant to have 2–3.7 mg of SP-B per

mmol phospholipid, compared to beractant, which

has 0–1.3 mg/mmol phospholipid [27]. Infants who

received poractant in our study received significantly

more phospholipid, and likewise more SP-B, than

those who received beractant. The amounts of SP-C in

the preparations do not differ significantly, with 5–11.6

and 1–20 mg per mmol phospholipid in poractant and

beractant, respectively [27].

The differences in the preparations are associated

with a difference in dosing and timing. In our study,

infants who received poractant required fewer doses

and less volume of surfactant, although they received

more milligrams per kilogram of surfactant compared

to infants who received beractant. All the infants

who received poractant received an initial dose of

200 mg/kg, and they required fewer retreatment doses

compared to the beractant group, whose initial dose

was 100 mg/kg. It is possible that this difference in

dosing contributed to the disparity in effects. However,

Ramanathan et al. found that FiO2 values for infants

who received initial poractant doses of either 100 or

200 mg/kg were significantly lower than those of

infants in the beractant group in the first 6 h after

treatment [11]. Our data support the concept that a

higher initial surfactant dose benefits infants with RDS

and reduces the need for retreatment [16].

In summary, preterm infants with RDS treated with

poractant had a lower FiO2 requirement during the

first 48 h compared with infants who received

beractant. Infants who received poractant also had

fewer hemodynamically significant PDAs than infants

who received beractant. The difference in FiO2 did not

result in a difference in age of first extubation, total

intubation time, or incidence of BPD. We continue to

seek the optimal combination of medication and

ventilator therapy to treat our premature infants with

RDS.

Acknowledgements

The authors thank Dr. James Sinacore for his knowledge andassistance with statistical analysis. The study was supportedin part by a research grant from Dey Pharmaceuticals, Napa,California. It was designed, conducted, and analyzed inde-pendently of the company.

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