Acta Pcediatrica, 2005; 94: 779-784 Taylor & Francisraylort-funclj Croup

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 ofPediatrics, 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(FiOa) 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 FiOj 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 theeffects of exogenous surfactant, we still do not havesufficient clinical data to define the relative value ofdifferent lung surfactant replacement preparations inthe treatment or prevention of respiratory distresssyndrome (RDS) [1]. The administration of surfactantimproves pulmonary gas exchange, reduces theoccurrence and severity of RDS, and may reduce theseverity of chronic lung disease [2-4]. While treatmentwith either natural or synthetic surfactant preparationsreduces the incidence of neonatal mortality andpneumothorax in infants with RDS, natural surfactantsseem to improve oxygenation and lung function morerapidly than synthetic surfactants [5-8]. There are onlya few studies comparing different natural surfactants[3,9-11].

We compared the bovine surfactant preparationberactant (Survanta ", Ross Laboratories, Columbus,OH, USA) and the porcine surfactant preparationporactant (Curosurf", Dey Incorporated, Napa, CA,USA). Each surfactant preparation has been carefullyevaluated in clinical trials and is licensed for use in theUnited States and Europe [12-17]. While they haveseveral similar features, they differ in some potentiallyimportant biophysical characteristics. It is unclear towhat extent these differences influence their physio-logical and clinical properties under in vivo conditions.Both beractant and poractant improve oxygenationand ventilation in the neonate, resulting in improvedalveolar-arterial gradients and allowing for reducedlevels of oxygen therapy. Our aim was to elucidate adifference in the effect of one surfactant preparationcompared to the other upon the oxygen requirement inneonatal RDS.

Correspondence: Jonathan Muraskas, Department of Pediatrics, Neonatology, Loyola LTniversity Medical Center, 2160 South First Avenue, Maywood,Illinois 60153, USA. E-mail: e-malloytonorthwestern.edu

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

ISSN 0803-5253 printyiSSN 1651-2227 online i 2005 Taylor & Francis Group I.idDOl: 10.1080/08035250510028740

780 C. A. Mallov ei al.

Methods

We designed a prospective, randomized study.Approval by the Loyola University Medical CenterInstitutional Review Board was obtained prior toinitiation of tlie investigation. Infants eligible for thestudy were those less than 37 wk gestational age withclinical signs and symptoms of RDS who requiredintubation and surfactant therapy per clinical judg-ment independent of the study. Per unit policy,surfactant was routinely administered to infants^ 28 wk gestational age and to ventilated infants with afraction of inspired oxygen CFiO2) 5=0.30. Onceinfants were identified as requiring intubation andsurfactant treatment, they were eligible for studyenrollment. Informed parental consent was obtainedfor all study infants. Infants with cyanotic heart disease,persistent pulmonary hypertension of the newborn, orabdominal wall pathology were excluded.

Using sealed envelopes, infants were randomizedto receive either beractant or poractant accordingto birthweight stratification blocks. Infants were ran-domized into the following categories: ^ 750 g,751 -1000 g, 1001 -1500 g, and > 1500 g. Infants ran-domized to beractant treatment received 100 mg/kg(4.0 ml/kg) instilled into the endotracheal tube asrecommended by the product package insert.Retreatment with beractant was performed 6 h afterthe last dose if the infant required ventilator supportand FiOs ^0.30 to maintain the PaO3 5^50 mmHg(6.7 kPa). All infants randomized to poractant treat-ment received 200 mg/kg (2.5 ml/kg) instilled into theendotracheal tube as recommended by the productpackage insert. Retreatment with 100 mg/kg (1.25ml/kg) per dose was performed at 12 h and 24 h afterthe first treatment if the infant required ventilatorsupport and an FiOj 5^0.30 to maintain the PaO25=50 mmHg (6.7 kPa).Up to three additional doses ofberactant and two additional doses of poractant weregiven as needed. Thus, the maximum cumulative dosefor both beractant and poractant was 400 mg/kg. Aftersurfactant administration, the infant was reconnectedto the ventilator; no airway suctioning was allowedduring the first 6 h after surfactant instillation.

Written instructions were provided to the caregiversregarding oxygen weaning for pulse oximetry satur-ations according to gestational age. Goal pulse oximetrysaturations were consistent with unit policy: infants^28 wk, 85-92%; infants 28-34 wk, 90-95%; infants5= 34 wk, 93-98%. Ventilator weaning was mandatoryfor PaCOa ^45 mmHg (6 kPa) and pH >7.28. Theprimary outcome was to compare the FiOn require-ments in the beractant and poractant groups for 48 hafter the first surfactant treatment.

All infants were compared with respect to thefollowing complications diagnosed within 40 wkcorrected gestational age: pneumothorax, patent

ductus arteriosus (PDA), intraventricular hemorrhage(IVH), periventricular leukomalacia (PVL), pulmo-nary hemorrhage, sepsis, bronchopulmonary dysplasia(BPD), retinopathy of prematurity (ROP) requiringlaser photocoagulation, and death. BPD was defined asa need for oxygen at 36 wk postmenstrual age and^28 d of age. Sepsis was defined as a positive bloodculture in a sick infant, with early onset sepsis occur-ring within the first 72 h of age, and late onset sepsisthereafter. Pulmonary hemorrhage was diagnosedbased on the presence of frank blood in the endo-tracheal tube associated with a rapid deterioration inclinical condition. All ROP examinations and assess-ments of need for laser photocoagulation were made bythe same pediatric ophthalmologist who was masked tosurfactant type received. Cranial ultrasound evalu-ations performed on all infants at days 7 and 28 of agewere used to classify intraventricular hemorrhages bythe Papile method and to diagnose PVL [20], Echo-cardiograms and chest radiographs were performedaccording to clinical indication. Pediatric cardiologistsand radiologists who interpreted imaging studies weremasked regarding type of surfactant received. PDAdiagnosis required an echocardiogram with Dopplerverification and cardiology recommendation of indo-methacin therapy based on significance of fiow. Noinfant received prophylactic prostaglandin inhibitortherapy.

The groups were also compared with regard cointubation time, duration of nasal CPAP (cycled andcontinuous positive airway pressure) ventilation,duration of supplemental oxygen, and length ofhospital stay. FiO2, O2 saturation, peak inspirators^pressure, mean airway pressure, positive end-expira-tory pressure, and ventilator rate were recorded every20 min after surfactant therapy for 2 h, then every30 min for the following 6 h, every hour for the next6 h, and then every 2 h until 48 h. Demographic dataincluding gender, gestational age, Apgar scores,birthweight, admission data, and maternal history werecollected for all infants.

Statistics

The primary outcome was FiOa requirement in thefirst 48 h after the first surfactant dose. With anexpectation of a lower FiOi requirement withporactant, we based our sample size determinationon the level of oxygen required at 24 h by the 73 infantsin the Speer study who received beractant or poractant[9]. It was determined that 23 infants per group werenecessary to detect a 10% difference in FiO2 be-tween surfactant groups, with an 'if. of 0.05 and apower of 0.80 [21].

A mixed analysis of variance (ANOVA) was usedto test the difference in FiO2 measurements over timefor the two groups. Other differences between the

Beractant and poractant in respiratory distress syndrome 781

Table I. Infant demographics. FiO2

Poractant Beractant

Mean gestational age (wk) 29.6 ± 3.6 29.3 + 2.923-25 wk gestational age 6 (21%) 3 (10%)26-28 wk gestational age 7 (24%) 9 (31%)29-31 wk gestational age 9 (31%) 11 (38%)32-36 wk gestational age 7 (24%) 6 (21%)Mean birthweight (g) 1394±699 1408±534Female gender 15 (52%) 16 (55%)^750 g 4(14%) 3(10%)751-1000 g 5(17%) 5(17%)1001-1500 g 11 (38%) 10 (34%)>I500g 9(31%) 11(38%)Apgar 1 min <7 10 (34%) 13 (45%)Apgar 5 min <7 4 (14%) 5 (17%)Apgar 10 min < 7 2 (7%) 2 (7%)Maternal steroids received 20 (69%) 23 (79%)Mean maternal age 31.3 + 6.7 3L4 + 5.3

beractant and poractant groups were tested withStudent's r-test for independent samples, the Mann-Whitney U-test) and the z-test for independentproportions. Significance levels were determined asp<0.05.

Results

Between June 2002 and May 2003, 236 infants< 37 wk were admitted with a diagnosis of RDS. Ofthe 119 of these infants who were intubated andreceived surfactant therapy, 60 infants were enrolled inour study. Two patients were removed from the studywhen they were found to have congenital heart disease.All study infants were inborn. There were no signifi-cant differences between surfactant groups withregards to infant age, birthweight, gender, Apgarscores, prenatal steroid administration, and maternalage (Table I).

' Beractant

• Poractant

0 4 8 12 16 20 24 28 .-2 .V. 40 44 48

Time after surfactant (h)

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

The FiO2 requirement before surfactant adminis-tration was not different between the groups, with theporactant and beractant groups having mean FiO2requirements of 0.49 and 0.47, respectively. Themixed ANOVA showed that the FiO^ requirementswere different for the two groups over time. Infantswho received poractant had a lower FiO2 requirementin the first 48 h compared to those who receivedberactant (p^ 0.018) (Figure 1). There were nodifferences between groups with regard to age of firstextubation, reintubation rate, total intubation time, ordevelopment of BPD (Table II).

Three deaths occurred, all of which were in theberactant group. In two instances, the families with-drew support secondary to significant intraventricularhemorrhages; one infant died on day 8 and the other onday 12. The third infant died on day 120 with multipleorgan failure after a protracted hospital course. Infor-mation was included as available. For example, datawere included from all three patients regarding FiO2requirement in the first 48 h and the presence of a PDA.Conversely, data regarding day of first extubation wasavailable only for the infant who died at 3 mo of age.

Table II. Pulmonary outcomes.

Poractant Beractantin = 29) /•-value

Extubation within lsi 3 d1 st extubation day: median

(range)1st extubation: median

gestational age, wk (range)Reintubation for respiratory

distress within 14 d ofextubation

Median days of intubation (range)Average days of nasal CPAPAverage days of nasal cannula

oxygen administrationDexamethasone administeredBPD

16 (55%)2 (0-50)

30.4 (25.4-36.3)

9(31%)

5 (0.5-49)7

6(21%)10 (34%)

12(41%)5(1-71)"

31.3 (27.1-35.0)'

9 (33%)'

7(1-117)^gb

17"

4 (14%)10 r37%1"

0.43

0.73

0.S2

0.820.440.79

|, 0.370.84

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

782 C. A. Malloy et al.

Table III. Adverse outcomes. Table IV. Surfactant received.

PneumothoraxPulmonary hemorrhageIVH grade 3 or 4PVLPDA requiring

treatment withindomethacin

Need for PDA ligationEarly-onset sepsisLate-onset sepsisLaser photocoagulation

for ROPDeath

Poractant(» = 29)

2 (7%)1 (3%)4 (14%)"2 (7%)"5 (17%)

1 (3%)1 (3%)3 (10%)5 (17%)

0 (0%)

Beractant(« = 29)

1 (3%)2 (7%)6(21%)0 (0%)

13(45%)

2 (7%)0 (0%)I (4%)^1 (4%)"

3 (10%)

p-valuc

0.530.530.930.510.02

0.530.530.330.11

0.08

Poractant Beractant /vvalue

"Calculations done with n-1, excluding infant with documentedin tmro grade 3 IVH and PVL.** Calculations done with n-2 secondary to two deaths (days 8 and12).

Concerning secondary outcomes, the incidences ofpneumothorax, pulmonary hemorrhage, IVH grades3-4, sepsis, laser photocoagulation for ROP, anddeath were not significantly different between groups(Table III). The incidence of PDA requiring treatmentwith indomethacin was lower in the group of infantsthat received poractant (17%) compared to the groupthat received beractant (45%) (p = 0.02).

The number of surfactant doses required by eachgroup was significantly different. Compared to theberactant group, infants in the poractant groupreceived less surfactant product in terms of numberof doses and milliliters per kilogram Crable IV).Beractant has 25 mg, and poractant has 76 mg ofphospholipid per milliliter of surfactant [ 18,19]. Giventhe difference in preparations, although infants inthe poractam group received fewer doses and lessvolume of surfactant, they received more milligramsper 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 notassociated with a difference in time to extubation,reintubation rate, intubation time, or development ofBPD. In a study comparing alveofact, poractam, andberactant, premature infants with RDS who receivedalveofact or poractant had fewer ventilator days,needed fewer days of oxygen administration, and hadshorter hospitalizations compared to those whoreceived beractant [10]. In 1995, Speer et al.prospectively studied 75 infants with RDS whoreceived poractant or beractant and had arterial bloodgases determined at regular intervals [9]. Althoughboth groups had rapid improvements in oxygenation

Mean no. of surfactant doses 1.2 1.7 0.004Mean ml/kg of surfactant 2.8 6.9 <0.0001

administered per infantMean mg/kg of surfactant 224 172 0.002

administered per infant

and ventilator requirements, infants treated withporactant had a higher arterial/alveolar oxygen tensionratio and required lower mean airway and peakinspiratory pressures at several time points within 24 hof randomization (p<0.05-0.001). A recent multi-center study randomized 293 infants with RDS toreceive poractant or beractant in a randomized,masked fashion f 11 ]. The authors found that the meanFiO2 between 0 and 6 h after the surfactant dose wassignificantly lower for the poractam group than theberactant group. Our findings are consistent with alower oxygen requirement in infants who receivedporactant compared to beractant.

In addition, the presence of a PDA requiring indo-methacin treatment was significantly lower in infantswho received poractant compared to beractant. Whilethis finding has not been reported before in the Englishliterature, it is a secondary outcome in a small studyand should be interpreted with caution. The use ofexogenous surfactant has been associated with anearlier appearance of a clinically significant PDA, asaccelerated pulmonary improvement is accompaniedby a fall in pulmonary vascular resistance [22]. Arandomized trial comparing ductal patency in infantswith RDS who received either beractant or placebo(air) found the need for indomethacin therapy to besimilar between groups [23]. The authors found thatexogenous surfactant therapy was not associated withan increased risk for delayed closure of the ductusarteriosus or a greater incidence of indomethacinusage. In a prospective, masked, controlled study ofamniotic fluid-derived surfactant and time of PDAclosure, the authors concluded that the maturity of theductus arteriosus, refiected by its tendency to closespontaneously, parallels lung maturity and thus wouldnot be affected by surfactant therapy [24]. The asso-ciation of poractant therapy with fewer PDAs requiresvalidation by other studies.

The differences in clinical effect may be related to thebiophysical characteristics of poractant and beractant.Both are derived from minced animal lungs andundergo washing and extraction with organic solvents.The washing procedure removes water-solublecomponents including the surfactant-associatedapoproteins 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

Beractant and poractant in respiratory distress syndrome 783

as triacylglycerol, cholesterol, and cholesteryl esters.It contains almost exclusively polar lipids, withphosphatidycholine constituting 60% of the totalphospholipids [25]. In contrast, beractant retains itsneutral lipids and is enriched with synthetic dipalmi-toyl phosphatidylcholine, triacylglycerol, and palmiticacid to standardize lipid composition and reduce filmcompressibility [26].

Poractant and beractant also differ in their respectiveamounts of SP-B. Animal studies support the impor-tance of higher concentrations of SP-B and SP-C insurfactant preparations [27]. Rider et al. studiedpreterm rabbits and found that the addition of SP-Bto surfactant lipids restored surfactant function,improved static and dynamic lung mechanism, andalso reduced protein leak into airspaces [28]. Thiseffect was not reproduced with SP-A and was partiallyreproduced by SP-C. In a similar experiment, themechanical properties of the lungs improved in a dose-related manner as increased concentrations of SP-Bwere added to surfactant [29]. Surfactant analyseshave shown poractant to have 2-3.7 ^g of SP-B perl-imol phospholipid, compared to beractant, whichhas 0-1.3 ig/f.imol phospholipid [27]. Infants whoreceived poractant in our study received significantlymore phospholipid, and likewise more SP-B, thanthose who received beractant. The amounts of SP-C inthe preparations do not differ significantly, with 5-11.6and 1-20 ^g per jimol phospholipid in poractant andberactant, respectively [27].

The differences in the preparations are associatedwitli a difference in dosing and timing. In our study,infants who received poractant required fewer dosesand less volume of surfactant, although they receivedmore milligrams per kilogram of surfactant comparedto infants who received beractant. All the infantswho received poractant received an initial dose of200 mg/kg, and they required fewer retreatment dosescompared to the beractant group, whose initial dosewas 100 mg/kg. It is possible that this difference indosing contributed to the disparity in effects. However,Ramanathan et al. found that FiO2 values for infantswho received initial poractant doses of either 100 or200 mg/kg were significantly lower than those ofinfants in the beractant group in the first 6 h aftertreatment [11]. Our data support the concept that ahigher initial surfactant dose benefits infants with RDSand reduces the need for retreatment [16].

In summary, preterm infants with RDS treated withporactant had a lower FiOi requirement during thefirst 48 h compared with infants who receivedberactant. Infants who received poractant also hadfewer hemodynamically significant PDAs than infantswho received beractant. The difference in FiOo did notresult in a difference in age of first extubation, totalintubation time, or incidence of BPD. We continue toseek the optimal combination of medication and

ventilator therapy to treat our premature infants withRDS.

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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