Hallman et al, Natural surfactant substitution of RDS 463

J. Perinat. Med.15 (1987) 463

Natural surfactant substitution in respiratory distress syndrome

Mikko Hallman1'2, Kari Teramo2, Olavi Ylikorkala2, and T. Allen Merritt3

department of Pediatrics and departments of Obstetrics and Gynecology, Uni-versity of Helsinki, Finland, and 3 Department of Pediatrics, University of Califor-nia, San Diego, California, U.S.A.

1 Introduction

Despite advances in perinatal care, serious mor-bidity among small preterm infants still necessi-ates pronged, expensive neonatal care. While anincreased number of infants with respiratory dis-tress syndrome (RDS) survive, a considerable pro-portion of them may develop chronic debilitatingdisease, known as bronchopulmonary dysplasia(BPD) [18, 21]. Thus, a prevention of the longterm morbidity among the small preterm infantswith lung immaturity is a great challenge. Sincelack of surfactant is the main cause of RDS,surfactant supplementation could be an effectivemethod to prevent the morbidity associated withimmaturity. Natural surfactant, applied to imma-ture animal lung causes a striking acute improve-ment in respiratory function [1, 11, 12], whereasthe synthetic surfactant preparations have had

modest acute effects, if any. Following the reportof FUJIWARA [4], natural surfactant has beenmainly used in clinical trials. Non-randomizedstudies have demonstrated that surfactant substi-tution acutely improves the oxygenation and de-creases the respiratory support [3, 4, 9, 24]. Onlywell-designed, randomized studies can evaluateobjectively the ri$ks and benefits of surfactantsupplementation.

2 Natural surfactant

Composition: "Natural" surfactant consists of un-ique proteins [14] and lipids [6]. Surfactant is con-sidered to be "natural" when its principal compo-nents are derived from the lung. Extensive investi-gation is required to establish a "new" surfactantto be used in therapy [20]. Table I highlights the

Table I. Natural surfactants used in clinical trials.

Natural surfactant Dose Placebo Retreatment Reference

Lipid extract of bovine lung+ synthetic phospholipids

TA-surfactant: lipid extract of a fractionof bovine lung + synthetic lipidsLipid extract of calf lung lavage

Lipid extract of calf lung lavage

Chromatographie fraction of the lipidextract of porcine or bovine lung

Phospholipid-rich complex from humanamniotic fluid by differential anddensity gradient centrifugation

150mg/kg

55 or 108 mg/kg

100mg or 75 mg90 mg

200 mg

60 mg/kg, orminimum of 60 mg

No

No

AirSaline

No

AirAir

No

No

NoNoYes

YesYes

[4]

[3]

[2][15, 23][19]

[7][17]

1987 by Walter de Gruyter & Co. Berlin · New York

464 Hallman et al, Natural surfactant substitution of RDS

features of the natural surfactants that have beenused in clinical trials. Only the human surfactantfrom amniotic fluid contains the disulfide-linkedoligomer, composed of polypeptide units of 35kDalton glycoprotein. This protein enhances thebiological activity of synthetic phospholipids,saturated phosphatidylcholine and phosphatidyl-glycerol [22] and it is a structural component ofthe tubular myelin [26]. All natural surfactantscontain low molecular weight proteolipid(s). Thesmall molecular weight surfactant proteolipids(5 — 18 kDalton) enhance greatly the surface ad-soprtion of phospholipids, thereby allowing satu-rated phosphatidylcholine to concentrate on inter-phases and eliminate the surface forces. Liposo-mes containing synthetic phospholipids and thesurfactant proteolipid may approach the activityof the natural surfactant in stabilizing the alveoliof surfactant deficient lungs. Besides the bio-chemical composition, the biophysical micellarform is another issue that influences the biologicalactivity. Many surfactants, including that fromhuman amniotic fluid, consist mainly of multi-lamellar structures.Availability: Heterologous surfactant from animallungs may become available for treatment ofRDS. Human surfactant may be harvested fromamniotic fluid and distrivuted from "surfactantbanks" for treatment of RDS (figure 1). Humansurfactant should be the model for the "natural"surfactant produced by available biomedical tech-niques in unlimited quantities.Administration and dosage: According to currentpractice, surfactant is introduced through an en-dotracheal tube as a bolus of 3 to 5 ml using asaline vehicle to small preterm infants (table I). Inpreterm lambs at birth a bolus of 60 mg/kg re-sulted in maximal acute improvement in respirat-ory failure [11]. A similar dose, given in RDS tosmall preterm infants permanently improved therespiratory function only in 50% of the cases,whereas in the others the response was unsatisfac-tory or it vanished resulting in a relapse of respir-atory failure [7]. Exogenous surfactant decreasedconcomitant with the relapse [8]. Altogether 22out of 31 of immature small preterm infants re-ceiving 60 mg human surfactant within ten min-utes of birth required retreatment because of(mostly mild) respiratory failure [17]. Most infantsresponded favorably to retreatment (figure 2),whereas in 8% of the infants the alleviation of therespiratory failure was transient despite retreat-ment. Although the exogenous surfactant disap-

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peared from the airways with a half life of 30(range 20 — 36) hours there was no relapse ofrespiratory failure since the amount of endoge-nous surfactant in the airways increased [8]. Theoccasional therapeutic failure can be due to sur-factant inhibitors or exceptionally rapid disap-pearance of exogenous surfactant from the air-ways. Furthermore, exogenous surfactant doesnot distribute evenly in peripheral airways insevere lung injury [13].According to animal studies prophylactic surfac-tant at birth is more efficacious than surfactantgiven in respiratory failure [12]. The superiorityof "prophylactic" to "rescue" surfactant has notyet been demonstrated in a concurrent clinicaltrial.

J. Perinat. Med. 15(1987)

Halhnan et al, Natural surfactant substitution of RDS 465

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3 Surfactant substitution in management of res- '·§piratory failure 3Randomized clinical trials: Table II lists the present 3randomized clinical trials thus far. Many others αare underway. The infants, who were given bovine t3surfactant before the first breath had a lower <§incidence of RDS than the controls who were ^given air [2]. It is unclear, whether bovine surfac- °tant actually prevented RDS, since the degree of ;§biochemical lung maturity was not studied. &

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J. Perinat. Med. 15(1987)

466 Hallman et al, Natural surfactant substitution of RDS

PDA shunting [2, 7, 17]. Indomethacin prior tosurfactant did not improve the remission of therespiratory failure [5]. Indeed, the ductus ar-teriosus may constrict shortly after exogenous sur-factant administration. The left to right shuntthrough PDA needs to be closely surveyed andpromptly treated, since the limited reserve of theleft ventricle could result in severe cardiac failure,pulmonary edema, and proteinacecous inhibitors"leaking" into the airspaces.Some patients have demonstrated a transient de-crease in the blood pressure following surfactantinstillation. This phenomenon may be due to acutevasodilatation, possibly as a result of an oxygen-induced increase in prostacyclin and a decrease inplatelet-derived tromboxane (unpublished re-sults). The risk can be eliminated by infusingblood volume expanders before surfactant.Present evidence suggests that exogenous surfac-tant does not inhibit the endogenous secretion.Instead, it could provide substates for a rate limit-ing step in endogenous surfactant synthesis, andstimulate the secretion of endogenous surfactant[8].Surfactant could conceivably be antigenic whenadministered intratracheally, thus raising concernsabout the potential for sensitization or imrnuno-logic injury on infants so treated. STRAYER et al.demonstrated a transient increase in surfactant-anti-surfactant immunocomplex formation inRDS regardless whether they had received exogen-ous human surfactant. This observation suggeststhat in RDS surfactant gains access to the systemiccirculation; however, there was no evidence ofimmunocomplex-related disease detectable byclinical or by serologic means [25]. No antibodiesagainst exogenous animal surfactant were de-tected in six survivors with RDS [19]. This issue isstill unsettled because of lack of adequate studies.

Antibody formation against surfactant proteinsmust be rigorously excluded prior to suggestingthe safety of heterologous surfactant.A drug may contain microbes or toxins. All natu-ral surfactants used in clinical trials are reportedlyfree from bacteria, fungi or even viruses. Today,our human surfactant undergoes heat treatment toeliminate HI virus. No toxic reactions, includingpyrogen reactions, have thus far been reportedalthough continuous surveillance is required.

Does surfactant improve the outcome of small pre-term infants? Randomized trials in small preterminfants have demonstrated that surfactant substi-tution decreases the occurrence of acute complica-tions, pulmonary interstitial emphysema andPneumothorax (table II). There has been no de-tectable (i.e. more than 50%) decrease in theincidence of intraventricular hemorrhage or PDA,whereas the incidence of death and BPD decreasedfollowing human surfactant (table II). Thus far,there are neither published cost benefit analysesnor follow up data.

Possible indications of exogenous surfactant: RDSis a spectrum of diseases involving infants withvarious degrees of "immaturity" and other abnor-malities [6]. In adult respiratory distress syndromeserious surfactant defects are virtually always pre-sent, too [10]. Exogenous surfactant has a favor-able response in respiratory failure in animals,regardless of the etiology [16]. Therefore, the indi-cations of surfactant therapy can be wider thanexpected merely on the basis of the trials publishedat present. It is hoped that the more general avail-ability of surfactant for therapeutic purposes doesnot result in injudicious practise but instead stimu-lates research on a wide variety of issues thateventually maximize the benefits and minimize theside effects of this potent therapy.

Summary

Natural surfactants consist of unique proteins and lipids.Their effectiveness in improving subnormal lung func-tion in surfactant deficiency should be established priorto any clinical trials. Rigorous tests are required todocument batch to batch variability in surface activityand to exclude toxic contaminants. Up to this daterandomized clinical trials in small preterm infants have

demonstrated a striking improvement in lung function,and a decrease in incidence of acute complications(pneumothorax, interstitial emphysema). Administra-tion of human surfactant at birth or in severe RDSdecreased deaths and incidence of bronchopulmonarydysplasia. Although homologous surfactant may not bemore advantageous than the heterologous one in terms

J. Perinat. Med. 15 (1987)

Hallman et al, Natural surfactant substitution of RDS 467

of its acute beneficial effects on lung function, the safetyand efficacy of animal surfactant in improving the out-come remains to be established. Human surfactant mayserve as a model for unlimited natural surfactant pro-duced by gene technology. The pharmacodynamic as-pects of surfactant substitution, the indications of ex-

ogenous surfactant, and the management of the patientsundergoing surfactant substitution remain to be studied.Exogenous surfactant offers a potential to treat or pre-vent severe respiratory failure in infants, children andadults.

Keywords: Amniotic fluid, hyaline membrane disease, surfactant.

Zusammenfassung

Gabe von natürlichem Surfactant beim Atemnotsyndrom(RDS)Der natürliche Surfactant besteht aus ganz bestimmtenProteinen und Lipiden. Deren Effizienz zur Verbesse-rung einer normalen Lungenfunktion bei Surfactant-mangel sollte vor der klinsichen Erprobung bewiesenwerden. Es sind strenge Kontrollen notwendig, umSchwankungen hinsichtlich der Oberflächenaktivität beiverschiedenen Produktionsserien zu dokumentieren undtoxische Kontaminationen ausschließen zu können. Beirandomisierten klinischen Studien mit kleinen Frühge-borenen zeigte sich eine deutliche Verbesserung der Lun-genfunktion und eine geringere Inzidenz akuter Kompli-kationen (Pneumothorax, interstitielles Emphysem).Nach Gabe von Surfactant vom Menschen bei Geburtoder bei schwerem RDS war die Inzidenz von Todesfal-

len und bronchopulmonalen Dysplasien geringer. Ob-wohl der homologe Surfactant gegenüber dem heterolo-gen im Hinblick auf die akute Verbesserung der Lungen-funktion möglicherweise keine Vorteile bietet, muß dieSicherheit und Effizienz des Surfactants vom Tier zurVerbesserung des neonatalen Zustandes erst noch bewie-sen werden. Der Surfactant vom Menschen könnte alsVorlage für die unbegrenzte, gentechnologische Produk-tion eines natürlichen Surfactants dienen. Pharmakody-namische Aspekte der Surfactantsubstitution, Indikatio-nen für eine exogene Surfactantzufuhr sowie das Mana-gement bei Patienten mit Surfactantsubstitution müssenweiter untersucht werden. Der exogene Surfactant stelltein wirksames Mittel dar zur Behandlung und Präven-tion schwerer respiratorischer Störungen bei Neugebore-nen, Kindern und Erwachsenen.

Schlüsselwörter: Fruchtwasser, hyalines Membransyndrom, Surfactant.

Resume

Substitution de surfactant naturel dans le syndrome dedetresse respiratoireLes surfactants naturels consistent en proteines et enlipides uniques. Leur efficacite ä entrainer une fonctionpulmonaire subnormale en cas de deficit en surfactantdevrait etre etablie avant tout essai clinique. Des testsrigoureux sont necessaires pour documentor la variabi-lite lot par lot, dans Tactivite de surface et excluredes contaminants toxiques. Jusqu'ä cette date des essaiscliniques randomines chez de petits enfants prematuresont demontre une amelioration nette de la fonctionpulmonaire et une diminution de Fincidence des compli-cations aigues (pneumothorax, emphyseme interstitiel).Uadministration de surfactant humain ä la naissance oulors de SDR graves diminue les morts et l'incidence des

dysplasies bronchopulmonaires. Bien que le surfactanthomologue ne soit peut etre pas plus avantageux que lesurfactant heterologue en tenne d'effets aigus benefiquessur la fonction pulmonaire, la securite et Fefficacitedu surfactant animal dans amelioration de 1'evolutionrestent a etablir. le surfactant humain peut servir demodele pour le surfactant naturel illimite produit pargenie genetique. Les aspects pharmacodynamiques de lasubstitution de surfactant, les indications du surfactantexogene et la prise en charge des patients necessitant unesubstitution de surfactant restent ä etudier. Le surfactantexogene offre un potentiel de traitement ou de preven-tion des detresses respiratoires graves chez les nouveaux-nes, les enfants et les adultes.

Mots-cles: Liquide amniotique, surfactant, syndrome de detresse respiratoire.

Acknowledgements: Supported by grants from the National Institutes of Health (HL-35036 to T. A.M, M:H.),the Finnish Academy, and the Sigrid Juselius Foundation (M. H.).

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468 Hallman et al, Natural surfactant substitution of RDS

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Mikko Hallman, M. D.Childrens Hospital, University of HelsinkiStenb ckinkatu 1100290 Helsinki, Finland

J. Perinat. Med. 15 (1987)