DOI: 10.1542/peds.2011-1395; originally published online November 28, 2011; 2011;128;e1588Pediatrics

Neetu Singh, Kristy L. Hawley and Kristin ViswanathanRespiratory Distress Syndrome: Systematic Review and Meta-analysis

Efficacy of Porcine Versus Bovine Surfactants for Preterm Newborns With  

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of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2011 by the American Academy published, and trademarked by the American Academy of Pediatrics, 141 Northwest Pointpublication, it has been published continuously since 1948. PEDIATRICS is owned, PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly

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Efficacy of Porcine Versus Bovine Surfactants forPreterm Newborns With Respiratory DistressSyndrome: Systematic Review and Meta-analysis

abstractOBJECTIVE: To compare the efficacy of a porcine surfactant (poractantalfa) versus bovine surfactants (beractant and calfactant) with re-spect to clinical outcomes among preterm infants with respiratorydistress syndrome.

METHODS: A search of major electronic databases, including Medline(1980–2010) and the Cochrane Central Register of Controlled Trials,for randomized controlled trials that compared poractant alfa versusberactant and/or calfactant among preterm infants with respiratorydistress syndrome who required intubation and surfactant treatmentwas performed. The primary outcome was oxygen requirement at apostmenstrual age of 36 weeks.

RESULTS: Five randomized controlled trials involving 529 infants com-pared poractant alfa versus beractant for rescue treatment. No trialsstudied surfactant prophylaxis, and none compared poractant alfa ver-sus calfactant. The incidences of oxygen dependence at a postmen-strual age of 36 weeks were similar for poractant alfa and beractant.Infants treated with poractant alfa at 100 mg/kg (low dose) or 200mg/kg (high dose) exhibited statistically significant reductions indeaths (relative risk: 0.51 [95% confidence interval: 0.30–0.89]), theneed for redosing (relative risk: 0.71 [95% confidence interval: 0.57–0.88]), oxygen requirements, duration of oxygen treatment, and dura-tion of mechanical ventilation. The test of heterogeneity yielded posi-tive results for the latter 2 outcomes. The difference remainedstatistically significant for deaths and the need for redosing with high-dose poractant alfa but not for low dose poractant alfa.

CONCLUSIONS: There were significant reductions in deaths and theneed for redosing with high-dose poractant alfa but not low-dose po-ractant alfa, compared with beractant. Pediatrics 2011;128:e1588–e1595

AUTHORS: Neetu Singh, MD,a Kristy L. Hawley, MPH,b andKristin Viswanathan, MPHc

aDepartment of Pediatrics, Dartmouth Hitchcock Medical Center,Lebanon, New Hampshire; bSchool of Medicine and HealthSciences, George Washington University, Washington, DC; andcBoard of Health Sciences Policy, Institute of Medicine, NationalAcademy of Sciences, Derwood, Maryland

KEY WORDSpulmonary surfactant, poractant alfa, calfactant, beractant

ABBREVIATIONSRDS—respiratory distress syndromeBPD—bronchopulmonary dysplasiaCLD—chronic lung diseaseRCT—randomized controlled trialRR—relative riskCI—confidence intervalFIO2—fraction of inspired oxygenMAP—mean airway pressurePDA—patent ductus arteriosusROP—retinopathy of prematurityIVH—intraventricular hemorrhage

www.pediatrics.org/cgi/doi/10.1542/peds.2011-1395

doi:10.1542/peds.2011-1395

Accepted for publication Aug 15, 2011

Address correspondence to Neetu Singh, MD, Department ofNeonatology, Dartmouth Hitchcock Medical Center, 1 MedicalCenter Dr, Lebanon, NH 03756. E-mail: neetu.singh@hitchcock.org

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

Copyright © 2011 by the American Academy of Pediatrics

FINANCIAL DISCLOSURE: The authors have indicated they haveno financial relationships relevant to this article to disclose.

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Surfactant replacement therapy hasbecome the standard of care for pre-term infants with surfactant deficiencyand respiratory distress syndrome(RDS). Multiple randomized controlledtrials (RCTs) and meta-analyses ofthose trials established the benefits ofsurfactant in improving survival ratesand reducing the incidence of pneu-mothorax.1–4 The trials also showedbetter efficacy of animal-derived sur-factants, compared with non–protein-containing synthetic surfactants.2 Al-though several animal-derived sur-factants are available, beractant, po-ractant alfa, and calfactant are the 3most-commonly used, animal-derivedsurfactants throughout the world.Less-commonly used, animal-derivedsurfactants include bovine lipid surfac-tant (in Canada), bovactant (in some Euro-pean countries), surfactant-TA (in Japan),Surfacen (in Cuba), and Newfacten (inKorea).

These animal-derived surfactants dif-fer in their composition (amounts ofphospholipids, surfactant-associatedproteins B and C, and plasmalogens),viscosity, and volume of administra-tion, which might affect their clinicalefficacy and ease of administration.Beractant is a minced bovine lung ex-tract that has added lipids (colfoscerilpalmitate, palmitic acid, and tripalmi-tin) to standardize its composition andto make it similar to other naturallung surfactants. It contains smalleramounts of phospholipids, surfactant-associated protein B, and plasmalo-gen, compared with calfactant, whichis a lavage preparation from bovinelung. Poractant alfa is a surfactantthat is derived from minced porcinelungs, subjected to chloroform/metha-nol extraction, and further purifiedthrough liquid-gel chromatography. Asa result, it contains the largestamounts of phospholipids distributedin the smallest volumes, as well as thelargest amount of plasmalogen.5 Many

retrospective studies and RCTs havebeen published to compare the clinicalefficacies of animal-derived surfac-tants; however, controversy remainsregarding the animal-derived surfac-tant with superior clinical efficacy. Be-cause of the small size of most of theRCTs, the 2008 American Academy ofPediatrics recommendation states, “itis unclear whether significant differ-ences in clinical outcomes exist amongthe available animal-derived surfac-tant products.”6 We conducted this sys-tematic review with the objective ofcomparing the efficacy of a porcinesurfactant (poractant alfa) with that ofcommonly used bovine surfactants(beractant and calfactant), with re-spect to clinical outcomes for preterminfants with RDS or at risk of RDS.

METHODS

Eligibility Criteria

We included studies in this review ifthey were RCTs (published as com-plete articles or as abstracts) thatcompared porcine surfactant (porac-tant alfa) versus bovine surfactant (be-ractant and/or calfactant) for preterminfants whowere at risk for RDS or hadclinical and/or radiologic evidence ofRDS. To be included, each study had toreport �1 of the clinical outcomeslisted below. We excluded quasi-randomized studies for this review. Wedid not restrict studies according tolanguage, type of administration strat-egy (prophylaxis or rescue treatment),or dosage of surfactant.

Information Sources

We used broad search strategies toidentify eligible studies. We conducteda systematic literature search in De-cember 2010, using the methods of theCochrane Collaboration for SystematicReviews of Interventions.7 The data-bases searched included Medline(1980 to December 2010) and theCochrane Central Register of Con-

trolled Trials (all years). We used thefollowing key words: “pulmonarysurfactant,” “surfactant treatment,”“poractant alfa,” “calfactant,” and“beractant.” For Medline, we limitedour search to human studies and tostudies involving all infants from birthto 23 months. We applied the Cochranesensitivity-maximizing and Cochranesensitivity- and precision-maximizingstrategies as our special searchstrategies.7

We also searched the abstract ar-chives of the Society of Pediatric Re-search annual meetings (2000–2009),the Food and Drug Administrationdatabase, and the clinicaltrials.govWeb site. Finally, we hand-searchedthe references cited in the studiesidentified through our electronicsearch and in review articles on sur-factant therapy.

Study Selection

All of the studies retrieved through thesearch strategies described abovewere imported to an electronic biblio-graphic management program (Ref-works [ProQuest, Ann Arbor, MI]), andduplicates were removed. We re-viewed the titles and abstracts (whereavailable) of the remaining articlesand excluded those that were not rele-vant to our topic and those that did notmeet the eligibility criteria. The full-text versions were obtained for the rel-evant articles that could be included inthe systematic review.

Data-Collection Process

Data from included trials were ex-tracted, on standard data collectionforms, independently by 3 reviewers.Data collected included study design,study interventions, number of sub-jects in each arm, prenatal cortico-steroid use, infant and maternaldemographic characteristics, inclu-sion and exclusion criteria, primaryand secondary outcomes, and vari-

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ables used to assess study quality(see below). Discrepancies betweenthe 3 reviewers were resolvedthrough discussion.

Data Items

The primary outcome measure wasthe incidence of oxygen requirementsat a postmenstrual age of 36 weeks,which was labeled either bronchopul-monary dysplasia (BPD) or chroniclung disease (CLD) in the articles. Theincidencewas calculated fromdata forall enrolled infants in each study. Sec-ondary outcomes related to respira-tory care were pulmonary air leaks(including pneumothorax and/or pul-monary interstitial emphysema), pul-monary hemorrhage (defined as thepresence of bright red blood in the en-dotracheal tube, with rapid deteriora-tion of the patient’s clinical status),mean airway pressure (MAP) usedduring mechanical ventilation (de-scribed as the median and interquar-tile range in the first 6 hours), durationof mechanical ventilation, fraction ofinspired oxygen (FIO2) (described asthe median value in the first 6 hours),duration of supplemental oxygen treat-ment, and the need for surfactant re-dosing. Secondary outcomes relatedto complications of prematurity in-cluded the incidences of sepsis (de-fined as positive blood culture re-sults), necrotizing enterocolitis, patentductus arteriosus (PDA) (diagnosed onthe basis of clinical signs, with or with-out echocardiographic findings), reti-nopathy of prematurity (ROP),8 andintraventricular hemorrhage (IVH)(classified according to the system de-scribed by Papile et al9), length of hos-pital stay, and death before hospitaldischarge. We included pneumotho-rax, pulmonary interstitial emphy-sema, and unspecified air leaks underthe term pulmonary air leaks. With re-spect to PDA, we included only data forclinical PDA cases and those treatedmedically (with the assumption that

surgically ligated cases had beentreated medically as well, althoughthis might underestimate the true inci-dence of PDA).

Risk of Bias in Individual Studies

The Cochrane Risk of Bias tool7 wasused to assess the methodologicquality of the included studies. Threeindependent reviewers evaluated thevalidity and design characteristics ofeach study for significant sources ofbias, which included adequacy ofrandom sequence generation, allo-cation concealment, and blinding forinterventions and outcome assess-ment and use of intention-to-treatanalysis. Each item was assessed asyes (low risk of bias), no (high risk ofbias), or unclear (investigators wereunable to determine, on the basis ofavailable data). Discrepancies be-tween the 3 reviewers were resolvedthrough discussion.

Summary Measures and Synthesisof Results

The analysis was performed with Re-view Manager 5.0 (Nordic CochraneCentre, Copenhagen, Denmark), by us-ing a fixed-effect model to obtain rela-tive risks (RRs) and 95% confidenceintervals (CIs) for dichotomous vari-ables and weighted mean differencesand 95% CIs for continuous variables.We assessed data through qualitativeanalysis if noncomparable measure-ment units were used in different stud-ies. We planned to perform analyses bypooling the data for different surfac-tants irrespective of the dosages usedand then performing subgroup analy-ses on the basis of different dosagesfor the porcine and bovine surfactants.Significant heterogeneity was consid-ered to be present if the I2 statistic was�50%, which suggests caution in in-terpretation of the results of themeta-analysis.

RESULTS

Studies Analyzed

Our Medline and Cochrane CentralRegister of Controlled Trials searchesretrieved 758 articles (after removal ofduplicates). After a review of the titlesand abstracts, we excluded 615 arti-cles that were not relevant to our re-search question, 44 articles that werereviews on surfactants, and 92 articlesthat did not meet study design or in-clusion criteria or did not report�1of the aforementioned outcomes. Weobtained full-text versions for the re-maining 7 studies for completereview.10–16

After review of the full-text versions, 2studies were excluded; 1 of the arti-cles12 discussed the effects of surfac-tant on PDA as a follow-up article afterpublication of the original article,11

and the other study13 did not use truerandomization (interventions were al-located on the basis of whether the pa-tient’s admission code was an odd oreven number) and had poor allocationconcealment. Additional searches ofthe Society of Pediatric Research ab-stract archives, the US Food and DrugAdministration database, and the clini-caltrials.gov Web site and handsearches of the references from stud-ies and review articles identifiedthrough the searches described abovedid not yield any other study eligiblefor inclusion.

Five eligible studies were included inthe final analysis. Tables 1, 2, and 3summarize the characteristics andquality assessments of these stud-ies.10,11,14–16 Three of the studies wereconducted in the United States,11,14,15 1each was conducted in Germany16 andGreece.10 A total of 529 infants wereenrolled in these 5 studies. Most of thestudies were small RCTs except for 1study,15 which contributed 55% of thepooled sample size for the meta-analysis. The studies were comparable

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with respect to the birth weights, ges-tational ages, and genders of the sub-jects included except for the study byFujii et al,11 which included extremelypremature infants. Wide variation inprenatal corticosteroid use was notedamong the different studies (rates var-ied from 28% to 98%). These studiesperformedwell in quality assessmentsfor randomization and allocation con-cealment but suffered from perfor-

mance bias resulting from lack ofblinding for interventions and out-come assessments.

Surfactant was administered for treat-ment of established RDS and not for pro-phylaxis in all included studies. The stud-ies compared poractant alfa withberactant; no studies compared porac-tant alfa with calfactant. The dose of be-ractant was 100 mg/kg for both the ini-

tial and repeat administrations in all ofthe studies. The initial dose of beractantwascomparedagainst ahigh initial dose(200 mg/kg) of poractant alfa in 4 stud-ies11,14–16 and against a low initial dose(100mg/kg) of poractant alfa in 2 stud-ies.10,15 One of the studies15 had 2 armsfor poractant alfa treatment, one witha 200 mg/kg dose and the other with a100 mg/kg dose. Subsequent doses ofporactant alfa were all at 100 mg/kg.

TABLE 1 Characteristics of Included RCTs

N Intervention(Poractant), n

Control(Beractant), n

Gestational Age,Mean� SD, wk

Birth Weight,Mean� SD, g

Male, % Prenatal SteroidUse, %

Speer et al16 73 33 40 28.8� 2.22 1088� 239 45.2 39.7Baroutis10 53 27 26 28.9� 0.81 1207� 392 49 28.3Ramanathan et al15 293 195 98 28.7� 1.73 1161� 265 59 80.9Malloy et al14 58 29 29 29.4� 3.24 1401� 616 46.6 74.1Fujii et al11 52 25 27 27.2� 2.44 917� 254 61.5 98

TABLE 2 Details of Included RCTs

Inclusion Criteria Surfactant Primary Outcome Studied

Speer et al,16 multicenter(Germany)

BW of 700–1500 g with RDS;ventilated with FIO2 of�0.4;surfactant within 1–24 h of life

Poractant, 200 mg/kg, or beractant, 100mg/kg (repeat dose up to maximum of400 mg/kg)

Effects of 2 treatment regimens on gasexchange, ventilator requirements,and 28-d outcomes for infants withRDS

Baroutis,10 1 perinatalcenter (Greece)

BW of�2000 g and GA of�32 wkwith RDS; ventilated with FIO2 of�0.3; surfactant within 4 h of life

Alveofact, 100 mg/kg, poractant, 100 mg/kg,or beractant, 100 mg/kg

Comparison of clinical outcomes with 3surfactant regimens

Ramanathan et al,15

multicenter (UnitedStates)

BW of 750–1750 g and GA of�35 wkwith RDS; intubated andventilated with FIO2 of�0.3;surfactant within 6 h of life

Poractant, 100 mg/kg, poractant, 200 mg/kg, or beractant, 100 mg/kg

Evaluation of effectiveness of 100 mg/kg dose of poractant by comparingonset of clinical response with thosefor 200 mg/kg poractant and 100mg/kg beractant

Malloy et al,14 1 perinatalcenter (United States)

GA of�37 wk with RDS Poractant, 200 mg/kg, or beractant, 100mg/kg (repeat dose up to maximum of400 mg/kg)

FIO2 requirement in first 48 h after firstdose of surfactant

Fujii et al,11 2 perinatalcenters (UnitedStates)

GA of 240⁄7 to 296⁄7 wk; surfactant andventilation soon after birth (�6h); randomization immediatelybefore delivery

Poractant, 200 mg/kg, or beractant, 100mg/kg

Short-term treatment efficacy of 2commonly used surfactants

BW indicates birth weight; GA, gestational age.

TABLE 3 Quality Assessment of Included Trials

Speer et al16 Baroutis10 Ramanathan et al15 Malloy et al14 Fujii et al11

Adequate method ofrandomization

Yes Yes Yes, random number Yes Yes, computer-generated(block)

Concealment ofallocation

Yes, opaque sealedenvelopes

Yes, opaque sealedenvelopes

Yes, sealed envelopes Yes, sealed envelopes Yes, sealed opaqueenvelopes

Blinding ofintervention

No No No No No

Blinding of outcomeassessors

No No Yes Yes Unclear

Complete follow-upmonitoring

Yes Yes Yes Yes Yes

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Results of Meta-analyses

Oxygen Requirements at aPostmenstrual Age of 36 Weeks

Each study reported the incidence ofoxygen requirements at a postmen-strual age of 36 weeks (either as BPDor as CLD) for all enrolled infants. Themeta-analysis did not show a signifi-cant difference between the infantstreated with poractant alfa and thosetreated with beractant (RR: 0.98 [95%CI: 0.75–1.29]; P � .89; I2 � 0%). Theresult remained insignificant evenwhen the analysis was restricted tostudies that used a 200 mg/kg dose ofporactant alfa or a 100 mg/kg dose ofporactant alfa in comparison with be-ractant (Table 4).

Respiratory Support

The effects of the type of surfactant onMAP and FIO2 were assessed qualita-tively because of differences in the useof reporting metrics among the stud-ies. Two studies showed significant dif-ferences in MAP values, favoring po-ractant alfa,11,16 whereas 1 study didnot find any difference between the 2groups with respect to this outcome.15

The difference in the effects of surfac-tants on MAP was observed for thefirst 24 hours by Speer et al16 and for

72 hours by Fujii et al,11 favoring porac-tant alfa, whereas no difference wasobserved in the first 6 hours by Ra-manathan et al.15

Four studies reported the effects of thetype of surfactant administration onFIO2. Three studies showed statisticallysignificant decreases in FIO2 require-ments with poractant alfa, comparedwith beractant,14–16 whereas 1 studydid not find any difference between the2 groups with respect to this out-come.11 Faster weaning of oxygen afterporactant alfa administration wasshown for 6 hours by Ramanathan etal,15 for 24 hours by Speer et al,16 for 48hours by Malloy et al,14 and from 12hours to 72 hours (MAP� FIO2) by Fujiiet al.11

Although most studies reported dura-tions of ventilation and oxygen treat-ment, only 2 studies reported themean values of these outcomes,10,15

which could be analyzed with ReviewManager. Our analysis showed statis-tically significant differences in theseoutcomes, favoring poractant alfa(P � .0001). In the subgroup analysis,this difference remained significantonly with low-dose poractant alfatreatment (Table 4). The test of heter-ogeneity yielded significant results for

both ventilation and oxygen treatment(I2� 75%).

Redosing

The incidence of redosing was lower inthe group receiving poractant alfa,compared with the group receiving be-ractant, with the difference being sta-tistically significant (RR: 0.71 [95% CI:0.57–0.88]; P� .002; I2� 0%). In sub-group analysis, the difference re-mained significant with poractant alfaat an initial dose of 200mg/kg (RR: 0.64[95% CI: 0.53–0.83]; P� .0008) but notwith poractant alfa at an initial dose of100 mg/kg, in comparison with berac-tant (I2� 0%).

Mortality Rates

In the meta-analysis, a statistically sig-nificant decrease in mortality rateswas found, favoring poractant alfa incomparison with beractant (RR: 0.51[95% CI: 0.30–0.89]; P� .02; I2� 0%).In the subgroup analysis, this differ-encewas evenmore pronouncedwhenthe 200 mg/kg dose of poractant alfawas compared with beractant (RR:0.29 [95% CI: 0.12–0.66]; P� .004) butwas not statistically significant whenthe 100 mg/kg dose of poractant alfawas compared with beractant (RR:

TABLE 4 Pooled Estimates for Poractant Versus Beractant

Outcome Poractant at 100 mg/kg or 200 mg/kgvs Beractant at 100 mg/kg

Poractant at 200 mg/kg vsBeractant at 100 mg/kg

Poractant at 100 mg/kg vsBeractant at 100 mg/kg

RR (95% CI)BPD 0.98 (0.75 to 1.29) 0.99 (0.74 to 1.33) 0.96 (0.66 to 1.41)Pulmonary hemorrhage 1.06 (0.46 to 2.44) 0.76 (0.32 to 1.81) 1.23 (0.39 to 3.88)Pulmonary air leak 0.67 (0.35 to 1.35) 0.52 (0.22 to 1.22) 1.00 (0.41 to 2.41)Redosing 0.71 (0.57 to 0.88)a 0.64 (0.53 to 0.83)a 0.81 (0.59 to 1.11)Death 0.51 (0.30 to 0.89)a 0.29 (0.12 to 0.66)a 0.89 (0.46 to 1.74)Sepsis 1.69 (0.88 to 3.24)b 1.69 (0.88 to 3.24)b

Necrotizing enterocolitis 1.05 (0.50 to 2.18) 1.03 (0.43 to 2.48) 1.00 (0.36 to 2.76)PDA 0.84 (0.68 to 1.05)b 0.86 (0.68 to 1.08)b 0.84 (0.61 to 1.15)Severe ROP 1.16 (0.57 to 2.36)b 1.16 (0.57 to 2.36)b

Severe IVH 0.89 (0.49 to 1.61) 0.69 (0.36 to 1.31) 1.15 (0.58 to 2.31)Weighted mean difference (95% CI)

Duration of oxygen treatment �5.02 (�7.44 to�2.68)b,c �2.0 (�8.42 to 4.42) �4.98 (�7.44 to�2.52)b,c

Duration of ventilation �5.57 (�6.60 to�4.55)b,c �2.0 (�7.19 to 3.19) �5.61 (�6.64 to�4.57)b,c

Length of hospital stay �26.32 (�36.57 to�16.07)b,c �9.90 (�29.96 to 9.16) �33 (�45.16 to�20.84)c

a P� .05.b Significant test of heterogeneity.c P� .0001.

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0.89 [95% CI: 0.46–1.74]; P � .74; I2 �0%) (Table 4).

Secondary Outcomes

The length of hospital stay was signifi-cantly shorter for infants treated withporactant alfa, compared with thosetreated with beractant (weightedmean difference:�26.3 [95% CI:�36.5to�16.07]; P� .00001) (Table 4). Only2 studies reported this outcome,10,11

and significant heterogeneity was ob-served between the study groups (I2�75%).

Two studies reported the incidence ofsevere ROP (either stage II–IV or re-quiring photocoagulation therapy),11,14

whereas 1 study reported all cases ofROP with no mention of staging. 10 Inour review, we included only data fromthe 2 studies that reported cases ofsevere ROP.11,14 All studies reporteddata on severe IVH (grade III or IV),whereas 1 study also reported on allcases of IVH in addition to severe IVH.16

In this review, we included only data onsevere IVH. There was no difference inthe incidence of sepsis, necrotizing en-terocolitis, PDA, severe ROP, and se-vere IVH between the 2 types of surfac-tants (Table 4). The test ofheterogeneity yielded significant re-sults for sepsis, severe ROP, and PDA.

Immediate adverse effects (reflux anddesaturation) were described only bySpeer et al16; therefore, no comparisoncould be performed. However, therates of pulmonary air leaks and pul-monary hemorrhage were reported inmost of the studies, with no differencebetween the 2 types of surfactants.

To test the effects of prenatal cortico-steroid exposure, a sensitivity analysiswas performed with the exclusion ofstudies that reported �50% prenatalcorticosteroid exposure. The differ-ences remained significant for deathsand redosing, favoring poractant alfa(100 mg/kg or 200 mg/kg), comparedwith beractant, when the 2 studies10,16

with low rates of prenatal corticoste-roid exposure were excluded.

DISCUSSION

We intended to compare the clinical ef-ficacy of a porcine surfactant (porac-tant alfa) with the commonly used bo-vine surfactants (beractant andcalfactant) among preterm infantswith RDS. However, we were able tocompare poractant alfa only againstberactant, because we did not identifyany trials that included a comparisonof poractant alfa against calfactant.

In this meta-analysis, the incidences ofoxygen requirements at a postmen-strual age of 36 weeks (BPD/CLD) were31.5% in the poractant alfa group and29.9% in the beractant group, with thedifference not being statistically signif-icant. Themost significant result notedin our meta-analysis was the effect ofporactant alfa on the rates of deathbefore hospital discharge, with a RRreduction of 49%, compared with be-ractant. Poractant alfa also was notedto decrease significantly the need forredosing, to reduce FIO2 requirementsfor up to 6 to 48 hours of life, and todecrease durations of oxygen treat-ment and mechanical ventilation. It isimportant to mention that the ob-served difference in the effects of sur-factants on FIO2 could be attributable todifferent ventilation strategies used inthe individual studies, with the ex-change of higher MAP values for lowerFIO2 values. Only Fujii et al11 reportedthis exchange, and they observed nodifference in FIO2 values between po-ractant and beractant.

In the subgroup analysis, significantreductions in mortality rates (70% RRreduction) and the need for redosing(36% RR reduction) were observedwith poractant alfa at 200 mg/kg butnot with poractant alfa at 100 mg/kg,compared with beractant. The differ-ences in mortality rates and the needfor redosing favoring poractant alfa

remained significant even when thestudies with low levels of prenatal cor-ticosteroid exposure were excludedfrom the analysis. Significant differ-ences were noted for duration of ven-tilation, duration of oxygen treatment,and length of stay with poractant alfaat 100 mg/kg but not with poractantalfa at 200 mg/kg, compared with be-ractant; however, these findings mustbe interpreted with caution because ofthe presence of significant heteroge-neity. The heterogeneity might be at-tributable to considerable variationsin the results for these outcomesamong the studies, with 1 study report-ing significant differences10 and othersshowing no effect.11,15

The results of our systematic reviewand meta-analysis are in agreementwith the findings of other reviews onthis subject. Five reviews that com-pared animal-derived surfactants5,17–20

were identified during our search;however, none was a systematic re-view. A meta-analysis by Fox and Sothi-nathan17 showed a reduced need forredosing, better short-term oxygen-ation, and reduced risk of death withporactant alfa, compared with berac-tant; however, only 3 RCTs10,15,16 wereincluded in the meta-analysis. A reviewof 4 studies10,14–16 by Ramanathan20 re-ported a similar survival advantage,reduced need for redosing, and costbenefit in favor of poractant alfa, com-pared with beractant. Moya and Mat-urana19 also reviewed those 4 studiescomparing poractant alfa and berac-tant10,14–16 and commented on de-creased oxygen requirements favoringporactant, compared with beractant.However, that review did not include ameta-analysis of data for any out-comes. Halliday21 performed a meta-analysis of 6 comparisons between po-ractant alfa and beractant10,14–16,22 (2arms of the study by Ramanathan etal15 were considered separate com-parisons) and showed significant re-

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ductions in mortality rates and theneed for redosing with poractant alfa,similar to our meta-analysis. That re-view did not address surfactant effectson other outcomes.

Although some of the results of ourmeta-analysis were statistically andclinically significant, they should be in-terpreted cautiously because of thefollowing limitations. Only 7 of the 92relevant articles on surfactant identi-fied in the search were considered suf-ficiently rigorous to be included in themeta-analysis, because of a narrow,specific, research question for thissystematic review. Studies included inthe meta-analysis were of compara-tively small size except for 1 study,15

which contributed the most to theweighted average of the summarytreatment effect. All of the studieswere at risk of performance bias re-sulting from lack of blinding for boththe interventions and the outcome as-sessments. Another limitation of thisreview is that all of the studies usedsurfactant for treatment rather thanfor prophylaxis for RDS; therefore, ourresults do not necessarily apply to pro-phylactic use of surfactant. The in-cluded studies analyzed clinical out-comes only until hospital dischargeand did not examine long-term out-comes such as neurodevelopmental

outcomes. Finally, this systematic re-view did not intend to include uncom-monly used bovine surfactants (eg, bo-vactant, surfactant-TA, and bovine lipidsurfactant) in the comparison withporcine surfactant.

Despite these limitations, this meta-analysis differs from other reviews inthat it includes the largest number ofRCTs comparing poractant alfa and be-ractant, with a fairly large cumulativesample size. The superior outcomesnoted in this meta-analysis with porac-tant alfa, compared with beractant,particularly with respect to reductionsin mortality rates, the need for redos-ing, and initial respiratory support,might be attributable to differences inthe biochemical and biophysical prop-erties of poractant alfa itself or to theinitial higher dose (200 mg/kg) used.The higher dose of poractant alfa, withgreater contents of phospholipids andsurfactant-associated proteins B andC, might have resulted in greater im-provements in lung function and hencebetter outcomes. Because the lowdose of poractant alfa (100 mg/kg) didnot have the same effects on mortalityand redosing rates as did the highdose of poractant alfa, it seems thatthe greater concentrations of phos-pholipids and surfactant proteins in agiven volume might be responsible for

the observed superior effects whenhigh-dose poractant alfa is comparedwith beractant at the dosage volumesrecommended by the manufacturers.

CONCLUSIONS

Our systematic review and meta-analysis provide evidence that high-dose poractant alfamay result in supe-rior short-term clinical outcomes,compared with beractant, when usedfor the treatment of preterm infantswith established RDS. Cost analysescomparing poractant alfa versus be-ractant23 and poractant alfa versuscalfactant24 showed significant costsavings with poractant alfa even whenit was used at a dose twice the dose ofberactant.

No conclusions can be drawn regard-ing the effects of these 2 surfactantswhen they are used prophylactically.Future research should focus on un-derstanding what specific biochemicaland biophysical aspects of one surfac-tant confer superiority over othersand should address the issue of out-come advantages with dose-equivalentconcentrations of poractant alfa andberactant with a large sample of pre-mature infants at greatest risk.

ACKNOWLEDGMENTWe thank Dr GauthamSuresh for his help-ful editorial review and comments.

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Neetu Singh, Kristy L. Hawley and Kristin ViswanathanRespiratory Distress Syndrome: Systematic Review and Meta-analysis

Efficacy of Porcine Versus Bovine Surfactants for Preterm Newborns With  

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