ORIGINAL PAPER

Comparison of three treatment regimens of natural surfactantpreparations in neonatal respiratory distress syndrome

Received: 21 May 2002 / Accepted: 26 November 2002 / Published online: 23 April 2003� Springer-Verlag 2003

Abstract The aim of the study was to compare thetreatment regimen of three natural surfactants of differentextraction and formulation (Alveofact [Surfactant A =SA], Poractant [Surfactant B = SB] and Beractant[Surfactant C = SC]) in neonatal respiratory distresssyndrome (RDS). Premature infants of £ 32 weeks’gestation with birth weight of £ 2,000 g and withestablished RDS requiring artificial ventilation with aFiO2 ‡0.3 were randomly assigned to receive at least twodoses of SA, SB or SC (100 mg/kg per dose). Infants whoremained dependent on artificial ventilation with a FiO2‡0.3 received up to two additional doses. There were nodifferences among the groups regarding the necessity formore than two doses. The SA and the SB groups spentfewer days on a ventilator (p-value SA/SB 0.7, SA/SC0.05, SB/SC 0.043) compared with the SC group, neededfewer days of oxygen administration (p-value SA/SB 0.14,SA/SC 0.05, SB/SC 0.04) and spent fewer days in hospital(p-value SA/SB 0.65, SA/SC 0.04, SB/SC 0.027). Therewere no statistically significant differences in the incidenceof mortality, chronic lung disease, air leaks, necrotisingenterocolitis, retinopathy of prematurity and intraven-tricular haemorrhage among the three groups. Conclu-sion: The Alveofact and Poractant groups spent fewerdays on the ventilator, needed fewer days of oxygenadministration and spent fewer days in hospital com-pared with the Beractant group but no differences wereobserved among the three groups with regards to mor-tality and morbidity.

Keywords Surfactant Æ Respiratory distresssyndrome Æ Alveofact Æ Poractant Æ Beractant

Abbreviations RDS respiratory distress syndrome Æ SAsurfactant A (Alveofact) Æ SB surfactant B(Poractant) Æ SC surfactant C (Beractant) Æ OIoxygenation index Æ VEI ventilatory efficiencyindex Æ CLD chronic lung disease Æ PDA patent ductusarteriosus Æ NEC necrotising enterocolitis Æ ROPretinopathy of prematurity Æ IVH intraventricularhaemorrhage

Introduction

It is widely accepted that treatment with natural orsynthetic surfactant preparations substantially reducesmortality as well as morbidity in infants with respiratorydistress syndrome (RDS). A wide variety of surfactantpreparations have been developed and tested. These in-clude synthetic surfactants and surfactants derived fromanimal resources [11]. Pre-clinical trials have demon-strated differences both in the in vitro and in vivo surf-actants that are commercially available [6, 8, 12, 14].

Meta-analysis of 11 randomised controlled clinicaltrials comparing administration of synthetic surfactantswith administration of natural surfactant extracts inpremature infants at risk of having RDS showed greaterearly improvement in the requirement for ventilatorsupport, fewer air leaks and fewer deaths associated withnatural surfactant preparations [9]. Recently, Clark et al.[4] compared retrospectively the outcomes of a largeseries of neonates treated with two different naturalsurfactants (Infusurf and Survanta) and found nodifference regarding mortality.

The present study was designed prospectively tocompare the outcome of infants with RDS treated withthree natural surfactants of different extraction andformulation: Alveofact (bovine), Poractant (porcine)

Eur J Pediatr (2003) 162: 476–480DOI 10.1007/s00431-002-1144-0

Georgios Baroutis Æ Joseph Kaleyias

Theodora Liarou Æ Eugenia Papathoma

Zoe Hatzistamatiou Æ Christos Costalos

G. Baroutis Æ J. Kaleyias (&) Æ T. Liarou Æ E. PapathomaZ. Hatzistamatiou Æ C. CostalosDepartment of Neonatal Medicine,General District Hospital ‘‘Alexandra’’,Athens, Greece

J. Kaleyias31 Atho Street, 26226Patra, GreeceE-mail: kalevias@hotmail.comTel.: +30-610-311981Fax: +30-610-220511

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and Beractant (bovine + synthetic DPPC, tripalmitinand palmitic acid).

Materials and methods

Premature infants of £ 32 weeks’ gestation with birth weight£ 2,000 g, born in the same perinatal centre, were enrolled in thetrial if they had RDS that had been established within the first 24 hof life and required mechanical ventilation with a FiO2 >0.3. In-formed written parental consent was required. Exclusion criteriawere major congenital or chromosomal abnormalities or anomaliesinterfering with lung development or function (such as cyanoticcongenital heart disease, diaphragmatic hernias, pulmonary hypo-plasia and hydrops fetalis), congenital sepsis, with blood culturepositive for pathogen within first 24 h of life, or pneumonia andsevere asphyxia.

Infants were randomly assigned using sealed envelopes to re-ceive at least two doses (100 mg of surfactant/kg) of Alveofact(Surfactant A = SA), Poractant (Surfactant B = SB) or Beractant(Surfactant C = SC). The initial dose of surfactant was adminis-tered as soon as possible after intubation and stabilisation butwithin 4 h of birth, while the second dose was given 12 h later.Third and fourth doses were administered depending on the in-fant’s clinical situation. The method of surfactant administrationfor the SA and the SB was by rapid bolus infusion directly into thedistal endotracheal tube, after disconnecting the baby frommechanical ventilation. On the other hand, SC was given slowly bypump via a side port adaptor to the endotracheal tube as recom-mended on the package insert.

Only conventional ventilation was used. The ventilator strategiesto initiate ventilation and to wean patients from the ventilator werestandardised. The typical start settings for mechanical ventilationwere: PIP 18–25 cmH2O, PEEP 4–6 cmH2O, gas flow rate 6–8 l/min, ventilator rate 60/min, inspiratory/expiratory ratio 1:2, inspi-ratory time 0.33 s and expiratory time 0.67 s. The assessment ofRDS severity was based on the oxygenation index (OI = [meanairway pressure {cmH2O}·FiO2·100]/postductal PaO2 [mmHg])[1]. The dynamic compliance of the lungs was estimated with theVentilatory Efficiency Index (VEI = 3,800: [{inspiratory pressure )end expiratory pressure} · respiratory rate · PaCO2]). The weaningstarted when the infant required FiO2<0.4, was able to maintainsatisfactory blood gases at a low rate ( £ 20 breaths/min), neededlow inspiratory pressure ( £ 15 cmH2O) and was clinically andmetabolically stable.

The three groups were compared with respect to the followingNICU-related morbidities: chronic lung disease (CLD) (oxygendependency beyond 36 weeks’ PCA) [15], patent ductus arteriosus(PDA) (echocardiograms and Doppler measurements to assess

shunting if clinical signs of PDA were detected), air leaks(pneumothorax or pulmonary intestinal emphysema) [16], reti-nopathy of prematurity (ROP) [5], necrotising enterocolitis (NEC)(confirmed) [2] and intraventricular haemorrhage (IVH) (‡II) [13].Discharge criteria were weight around 2 kg, feeding well on breastor bottle, not oxygen dependent and thermo regulating well.

Quantitative variables were compared using the Mann-WhitneyU test. For qualitative variables, the Fisher’s exact test was used.Statistical analysis was performed using the SPSS package (SPSSInc., Cary, NC, USA).

Results

Population characteristics

There were no differences among the SA, SB and SCgroups regarding birth weight and gestational age(Table 1). In addition, the three groups were similarregarding sex ratio, in vitro fertilisation, prenatal steroidsadministration, rupture of membrane and mode ofdelivery.

Respiratory distress syndrome status

The severity of the RDS estimated by the FiO2, the OIand the mean airway pressure before the administrationof the first dose of surfactant was similar among thethree groups (Table 2).

There were no significant differences among groups inthe VEI 6 h before weaning and the rate of adminis-tration of third and fourth doses of surfactant.

The SA and SB groups spent fewer days on a venti-lator and needed fewer days of oxygen administrationcompared with the SC group.

Correlation of the outcome with the surfactantpreparation

The mortality rates before discharge were 25.9% inAlvofact, 18.5% in Curosurf and 23% in the Survantagroup (p=not significant; Table 3).

Table 1 Population characteristics. SA Alveofact, SB Poractant, SC Beractant

SA (n=27) SB (n=27) SC (n=26) p-value* SA/SB p-value* SA/SC p-value* SB/SC

Birth weight (g)Mean ± SD 1,195±390 1,233±380 1,180±410Median 1,120 1,280 1,135 0.79 0.83 0.67(25th, 75th percentile) (890–1,530) (920–1,550) (856–1,540)

Gestational age (weeks)Mean ± SD 29±1.2 28.7±0.5 29.2±1Median 29 29 29 0.59 0.95 0.57(25th, 75th percentile) (27–30) (28–30) (28–30)Sex ratio (male/female) 15/12 16/11 10/16 1 0.275 0.17In vitro fertilization 5/27 5/27 3/26 1 0.7 0.7Prenatal steroids ‡24h 9/27 7/27 8/26 0.5 0.9 0.9Rupture of membranes‡24h

5/27 6/27 4/26 0.8 0.9 0.8

Caesarean section 15/27 19/27 15/26 0.39 1 0.33

*Fisher’s Exact Test

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There were no significant differences in the incidenceof CLD, PDA, air leaks, NEC, IVH and ROP amongthe three groups.

The SA and SB groups spent fewer days in thehospital compared with the SC group (p-values: SA/SB0.65, SA/SC 0.04, SB/SC 0.027). The length of stay atthe hospital for infants with no CLD was similar for allthree groups (Table 4).

Discussion

There are many clinical comparisons between syntheticand natural surfactants and they all conclude that treat-

ment with natural surfactant resulted in a greater reduc-tion in the severity of RDS [9, 10, 19, 20], but at the time ofthe study design there were very few studies comparingnatural surfactants [3, 4, 17]. Bloom et al. [3] comparedtwo natural surfactants (Infasurf and Survanta) andconcluded that infants treated with Infasurf had amodestbenefit in the acute phase of RDS, but there were nosignificant differences in the incidence of air leaks, com-plications associating with dosing, complications of pre-maturity, mortality or survival without chronic lungdisease. Recently, Clark et al. [4] compared the samesurfactants (Infasurf/Survanta) and concluded that themost important variables associated with neonatal death,IVH or NEC were birth weight and gestational age, while

Table 2 Status of respiratory distress syndrome (RDS)

SA(n=27)

SB(n=27)

SC(n=26)

p-value*SA/SB p-value*SA/SC p-value*SB/SC

FiO2Mean ± SD 0.65±0.15 0.68±0.1 0.58±0.13Median 0.55 0.59 0.54 0.9 0.65 0.7(25th, 75th percentile) (0.45–0.70) (0.47–0.72) (0.44–0.67)

PaO2/PAO2

Mean ± SD 0.32±0.35 0.32±0.33 0.34±0.22Median 0.18 0.33 0.28 0.17 0.21 0.92(25th, 75th percentile) (0.11–0.44) (0.16–0.43) (0.14–0.48)

Mean airway pressure before the first doseMean ± SD 8.3±2.4 8±1.5 8.5±2Median 9 8.5 8 0.52 0.19 0.59(25th, 75th percentile) (7.5–10) (7–10) (7–9)

Ventilatory Efficiency Index<6 h before weaningMean ± SD 1.6±0.6 0.9±0.3 1.5±0.4Median 0.8 0.75 0.7 0.56 0.213 0.92(25th, 75th percentile) (0.58–1.41) (0.46–0.9) (0.5–2)Infants received >2doses of surfactant

5/27 4/27 6/26 0.71 0.465 0.27

Intubation daysMean ± SD 6.6±2.1 5.7±1.5 11.5±2.3Median 4 4 5 0.7 0.05 0.043(25th, 75th percentile) (4–9) (2–11) (3–11)Range 1–31 1–28 2–45

Oxygen daysMean ± SD 8.7±3.2 9.9±4.1 16±5.7Median 8 7 10 0.44 0.05 0.04(25th, 75th percentile) (5–14) (4–15) (5–20)Range 1–95 1–107 1–150

*Mann-Whitney U test

Table 3 Mortality andmorbidity incidence

*Fisher’s Exact Test

SA (n=27) SB (n=27) SC (n=26) p-value*SA/SB

p-value*SA/SC

p-value*SB/SC

Death before discharge 7/27 5/27 6/26 0.74 1 0.74Chronic lung disease 3/27 4/27 4/26 0.64 0.69 0.69Patent ductus arteriosus 5/27 4/27 5/26 1 1 0.72Air leaks 2/27 3/27 4/26 1 0.41 0.69Retinopathy of prematurity 4/27 5/27 3/26 1 1 1Necrotizing enterocolitis 2/27 3/27 2/26 1 1 1Intraventricularhemorrhage (‡II grade)

5/27 6/27 4/26 1 0.5 0.72

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the type of surfactant did not significantly influence theoutcome. Speer et al. [17] compared Beractant and Por-actant and they concluded that Beractant treatment re-sulted in a more rapid improvement in oxygenation thanPoractant and reduced ventilatory requirements up to24 h after the start of treatment. In addition, they found atrend towards reduced incidence of serious pulmonaryand non-pulmonary complications in the Beractantgroup.

We found that the Alveofact and the Poractantgroups spent fewer days on mechanical ventilation andneeded fewer oxygen administration days. The Beractantgroup spent more days in hospital, but this difference didnot exist when infants with CLD were excluded from theanalysis. There were no statistical differences amongthese three groups with regards to the major NICU re-lated morbidities. Obviously, the numbers of infants aretoo small to show definite results. As previously noted,Clark et al. [4] studied a large series of neonates andconcluded that previously reported differences did notexist.

Differences in the composition of Beractant andAlveofact or Poractant may account for different clinicalefficacy observed. Beractant contains phospholipidsfrom lung cells as well as lung surfactant. It has higherlevels of non-phosphatidylcholine phospholipids suchas sphingomyelins and phosphatidylethanolamines andthese phospholipids limit the lowest surface tensionattainable in bovine surfactant preparations [7]. There isa step in the Beractant process that removes cholesterol,but it also removes the surfactant apoprotein B, theapoprotein most critical for full biophysical activity [12,20]. Another reason, which is possibly responsible fordifferences observed in clinical activity, is the method ofsurfactant administration. We administered Beractant

by pump via a side port in the endotracheal tube adaptorby pump according to the manufacturer’s recommen-dation. As other researchers have shown, there is anuneven distribution of surfactant when it is given as aslow infusion, leading to a poor clinical response [20].Obviously, a serious bias regarding the methods wasthat the study was not blinded with regard to theadministration of surfactant. The study was blindedwith regards to Poractant and Alveofact but blindingwas not possible in the case of Beractant due to thedifferent method of administration.

In conclusion, in the present study we have observed:

1. Reduced intubation and oxygen days for infants whoreceived Poractant and Alveofact compared withBeractant

2. Fewer days spent in hospital for babies treated withPoractant and Alveofact compared with Beractant

3. No statistical differences among the three studiedsurfactants with regards to mortality and the majorNICU-related morbidities

However, the numbers of patients in the presentstudy were small in each group and more trials areneeded before any firm conclusions can be drawnregarding the choice of the most efficacious naturalsurfactant.

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Table 4 Length of stay athospital and body weight atdischarge

*Mann-Whitney U test

SA SB SC p-value*SA/SB

p-value*SA/SC

p-value*SB/SC

Hospital daysNumber assessed 20 22 20Mean ± SD 62±20 48±15 81±28Median 49 47 55 0.65 0.04 0.027Range 30–149 28–135 23–165

Hospital days (no CLD)Number assessed 19 21 17Mean ± SD 57±16 45 ±17 63±24Median 58 46 54 0.19 0.75 0.28Range 30–80 28–82 23–126

Body weight at discharge (g)Number assessed 20 22 20Mean ± SD 2,130±60 2,100±97 2,120±60Median 2,130 2,090 2,100 0.12 0.42 0.43Range 2,030–2,250 2,000–2,280 2,010–2,200

Corrected postmenstrualage at discharge (weeks)Number assessed 20 22 22Mean ± SD 36.9±1.7 36.4±1.5 38±3.6Median 37 36 37 0.25 0.27 0.036Range 35–42 34–40 36–46

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