An overview of pulmonary surfactant in the neonate: Genetics, metabolism, and the role of surfactant in health and disease

Background. Available therapeutic surfactants are either animal-derived or non–protein-containing synthetic products. Animal-derived surfactants contain variable amounts of surfactant apoproteins, whereas the older-generation synthetic products contain only phospholipids and lack surfactant proteins (SPs). Both decrease morbidity and mortality rates associated with respiratory distress syndrome (RDS) among preterm infants, compared with placebo. However, excess mortality rates have been observed with non–protein-containing synthetic surfactants, compared with the animal-derived products. Evidence suggests that synthetic surfactants consisting solely of phospholipids can be improved with the addition of peptides that are functional analogs of SPs. Lucinactant is a new synthetic peptide-containing surfactant that contains sinapultide, a novel, 21-amino acid peptide (leucine and lysine repeating units, KL4 peptide) designed to mimic human SP-B. It is completely devoid of animal-derived components. Objective. We hypothesized that the outcomes for premature infants treated with lucinactant and poractant alfa would be similar. Therefore, we compared lucinactant (Surfaxin; Discovery Laboratories, Doylestown, PA) with porcine-derived, poractant alfa (Curosurf; Chiesi Farmaceutici, Parma, Italy) in a trial to test for noninferiority. Methods. A total of 252 infants born between 24 and 28 weeks of completed gestation, with birth weights between 600 and 1250 g, were assigned randomly in a multicenter, multinational, noninferiority, randomized, controlled study to receive either lucinactant (n = 124) or poractant alfa (n = 128) within 30 minutes of life. The primary outcome was the incidence of being alive without bronchopulmonary dysplasia (BPD) through 28 days of age. Key secondary outcomes included death at day 28 and 36 weeks postmenstrual age (PMA), air leaks, neuroimaging abnormalities, and other complications related to either prematurity or RDS. An independent, international, data and safety monitoring committee monitored the trial. Results. The treatment difference between lucinactant and poractant alfa for survival without BPD through 28 days was 4.75% (95% confidence interval [CI]: −7.3% to 16.8%) in favor of lucinactant, with the lower boundary of the 95% CI for the difference, ie, −7.3%, being greater than the prespecified noninferiority margin of −14.5%. At 28 days, 45 of 119 infants given lucinactant were alive without BPD (37.8%; 95% CI: 29.1–46.5%), compared with 41 of 124 given poractant alfa (33.1%; 95% CI: 24.8–41.3%); at 36 weeks PMA, the rates were 64.7% and 66.9%, respectively. The corresponding mortality rate through day 28 for the lucinactant group was lower than that for the poractant alfa group (11.8% [95% CI: 6.0–17.6%] vs 16.1% [95% CI: 9.7–22.6%]), as was the rate at 36 weeks PMA (16% and 18.5%, respectively). There were no differences in major dosing complications. In addition, no significant differences were observed in the incidences of common complications of prematurity, including intraventricular hemorrhage (grades 3 and 4) and cystic periventricular leukomalacia (lucinactant: 14.3%; poractant alfa: 16.9%). Conclusions. Lucinactant and poractant alfa were similar in terms of efficacy and safety when used for the prevention and treatment of RDS among preterm infants. The ability to enhance the performance of a synthetic surfactant with the addition of a peptide that mimics the action of SP-B, such as sinapultide, brings potential advantages to exogenous surfactant therapy.

A multicenter, randomized, controlled trial of lucinactant versus poractant alfa among very premature infants at high risk for respiratory distress syndrome.

Objective. Infants with meconium aspiration syndrome (MAS) have marked surfactant dysfunction. Airways and alveoli of affected neonates contain meconium, inflammatory cells, inflammatory mediators, edema fluid, protein, and other debris. The objective of this study was to compare treatment with bronchoalveolar lavage using dilute Surfaxin with standard therapy in a population of newborn infants with MAS. Methods. Inclusion criteria were 1) gestational age ≥35 weeks, 2) enrollment within 72 hours of birth, 3) diagnosis of MAS, 4) need for mechanical ventilation, and 5) an oxygenation index ≥8 and ≤25. Subjects were randomized to either lavage with Surfaxin or standard care (2:1 proportion). In lavaged infants, a volume of 8 mL/kg dilute Surfaxin (2.5 mg/mL) was instilled into each lung over approximately 20 seconds followed by suctioning after 5 ventilator breaths. The procedure was repeated twice. The third and final lavage was with a more concentrated solution (10 mg/mL) of Surfaxin. Results. Twenty-two infants were enrolled (15 Surfaxin and 7 control). Demographic characteristics were similar. There were trends (not significant) for Surfaxin-lavaged infants to be weaned from mechanical ventilation earlier (mean of 6.3 vs 9.9 days, respectively), as well as to have a more rapid decline in their oxygenation indexes compared with control infants, the latter difference persisting for the 96-hour-long study period. The therapy was safe and generally well tolerated by the infants. Conclusions. Dilute Surfaxin lavage seems to be a safe and potentially effective therapy in the treatment of MAS. Data from this investigation support future prospective, controlled clinical trials of bronchoalveolar lavage with Surfaxin in neonates with MAS.

A multicenter, randomized, controlled trial comparing Surfaxin (Lucinactant) lavage with standard care for treatment of meconium aspiration syndrome.

Background and Objective. Evidence sug- gests that synthetic surfactants consisting solely of phos- pholipids can be improved through the addition of pep- tides, such as sinapultide, that mimic the action of hu- man surfactant protein-B (SP-B). A synthetic surfactant containing a mimic of SP-B may also reduce the potential risks associated with the use of animal-derived products. Our objective was to compare the efficacy and safety of a novel synthetic surfactant containing a functional SP-B mimic (lucinactant; Discovery Laboratories, Doylestown, PA) with those of a non-protein-containing synthetic surfactant (colfosceril palmitate; GlaxoSmithKline, Brentford, United Kingdom) and a bovine-derived sur- factant (beractant; Abbott Laboratories, Abbott Park, IL) in the prevention of neonatal respiratory distress syn- drome (RDS) and RDS-related death. Methods. We assigned randomly (double-masked) 1294 very preterm infants, weighing 600 to 1250 g and of <32 weeks gestational age, to receive colfosceril palmi- tate (n 509), lucinactant (n 527), or beractant (n 258) within 20 to 30 minutes after birth. Primary outcome measures were the rates of RDS at 24 hours and the rates of death related to RDS during the first 14 days after birth. All-cause mortality rates, bronchopulmonary dys- plasia (BPD) rates, and rates of other complications of prematurity were prespecified secondary outcomes. Pri- mary outcomes, air leaks, and causes of death were as- signed by an independent, masked, adjudication com- mittee with prespecified definitions. The study was monitored by an independent data safety monitoring board. Results. Lucinactant reduced significantly the inci- dence of RDS at 24 hours, compared with colfosceril (39.1% vs 47.2%; odds ratio (OR): 0.68; 95% confidence interval (CI): 0.52-0.89). There was no significant differ- ence in comparison with beractant (33.3%). However, lucinactant reduced significantly RDS-related mortality rates by 14 days of life, compared with both colfosceril (4.7% vs 9.4%; OR: 0.43; 95% CI: 0.25-0.73) and beractant (10.5%; OR: 0.35; 95% CI: 0.18-0.66). In addition, BPD at 36 weeks postmenstrual age was significantly less com- mon with lucinactant than with colfosceril (40.2% vs 45.0%; OR: 0.75; 95% CI: 0.56-0.99), and the all-cause mortality rate at 36 weeks postmenstrual age was lower with lucinactant than with beractant (21% vs 26%; OR: 0.67; 95% CI: 0.45-1.00). Conclusions. Lucinactant is a more effective surfac- tant preparation than colfosceril palmitate for the pre- vention of RDS. In addition, lucinactant reduces the in- cidence of BPD, compared with colfosceril palmitate, and decreases RDS-related mortality rates, compared with beractant. Therefore, we conclude that lucinactant, the first of a new class of surfactants containing a functional protein analog of SP-B, is an effective therapeutic option for preterm infants at risk for RDS. Pediatrics 2005;115: 1018-1029; lucinactant, colfosceril palmitate, beractant, surfactant, respiratory distress syndrome.

A Multicenter, Randomized, Masked, Comparison Trial of Lucinactant, Colfosceril Palmitate, and Beractant for the Prevention of Respiratory Distress Syndrome Among Very Preterm Infants

Biochemical and pharmacological differences between preparations of exogenous natural surfactant used to treat Respiratory Distress Syndrome: role of the different components in an efficient pulmonary surfactant.

Reactive oxygen species (ROS) may play an important role in the chronic pulmonary morbidity of preterm infants. We therefore studied the magnitude and mechanisms of oxidative inactivation of a natural lung surfactant (NLS) and of two surfactants used for treatment of respiratory distress syndrome, beractant and KL4 surfactant (KL4). Incubation with Fenton reagents, 2-4 mM peroxynitrite (ONOO-) or 0.5 mM hypochlorous acid (OCl-), resulted in an increased minimum surface tension (MST) of all surfactants; the order of effect on MST was beractant > KL4 > NLS. After incubation with Fenton reagents, NLS contained a higher concentration of conjugated dienes (p < 0.01) but lower concentration of malondialdehyde (p < 0.001) than beractant. Protein carbonyl concentrations after treatment with Fenton reagents were higher in NLS and KL4 than in beractant (p < 0. 05). Surface area cycling for 24 h with 2 mM ONOO- or 0.5 mM OCl- caused both beractant and KL4 to increase the proportion of light subtypes from 8-10% to 26-29%; with Fenton reagents, there was disappearance of the light subtype and formation of ultraheavy subtype 74-91% with poor MST. Natural and therapeutic surfactants differ markedly in their sensitivity to ROS, which may be important for surfactants in therapeutic use because oxidative inactivation may limit their effect. Oxidation of natural surfactant may result in reduced function and contribute to chronic lung disease.

Oxidative inactivation of surfactants.

Surfactant is not a homogeneous material and can be separated into subtypes. Subtype conversion is clinically important because it is thought to occur naturally and because surface activity varies depending on the subtype. Fibrinogen, a naturally occurring serum protein, is known to affect this conversion. In this study we studied two surfactants, beractant and KL4, to examine their subtype characteristics. Surface area cycling, an in vitro method, was used in conjunction with sucrose gradient ultracentrifugation to separate subtypes in both surfactants. Activity, expressed as minimum surface tension of these subtypes, was measured using a pulsating bubble surfactometer. The effect of fibrinogen on subtype conversion and subsequent change in activity was elucidated. Our results indicate that following surface area cycling, beractant and KL4 have different subtypes and different responses to fibrinogen. Cycling of beractant resulted in two bands, representing a heavy and a light subtype. In the presence of fibrinogen, cycling resulted in two separate heavy subtypes. Cycling of KL4 surfactant also yielded light and heavy subtypes. However, in the presence of fibrinogen, cycling of KL4 resulted in ultraheavy subtypes. These ultraheavy subtypes retained minimum surface tension comparable to that of native KL4 surfactant. We conclude that these two surfactant preparations have different subtype conversions when subjected to surface area cycling and in the presence of fibrinogen. These conversions result in different activities toward lowering surface tension. We speculate that endogenous fibrinogen will also affect these two surfactants differently in vivo and thus affect their clinical effectiveness.

Characterization of surfactant subtypes of beractant and a synthetic peptide containing surfactant KL4 following surface area cycling and addition of fibrinogen.

The serum components of C-reactive protein, lysophosphatidylcholine, fibrinogen, and fibrinogen proteolytic products have been shown to reduce surface tension-lowering abilities of lung surfactant. The inhibitory effects of these serum components were compared among four different surfactants: natural lung surfactant, a phospholipid mixture that had no surfactant proteins, KL4 surfactant which has a synthetic surfactant protein B(SP-B)-like peptide, and beractant (BER) which has both SP-B and SP-C. The pulsating bubble surfactometer was used to measure the surface tension of these surfactants after the addition of inhibitors. Inhibition of BER and KL4 surfactant was observed with some serum components within 1 min of pulsation, but was reversed after 3 min of pulsation for KL4 surfactant and to a lesser extent with BER. The surface tension of phospholipid mixture alone was significantly increased and did not improve with further pulsations. Natural lung surfactant was least inhibited and was affected only at very high fibrinogen concentrations (5 mg/mL). At identical concentrations of these inhibitors, KL4 surfactant was inhibited less compared with BER. We conclude that the response of a lung surfactant to inhibitory agents may depend on the presence or absence of surfactant-related protein(s) in the surfactant and the concentration of exogenous surfactant used. KL4 surfactant, which has a synthetic peptide in lieu of SP-B, resists inhibition to these serum components more than BER at similar phospholipid concentrations.

/pdf/comparative-effects-of-some-serum-components-and-proteolytic-4zf5b4zn34.pdf

Comparative effects of some serum components and proteolytic products of fibrinogen on surface tension-lowering abilities of beractant and a synthetic peptide containing surfactant KL4.

Studies were conducted to assess the efficacy and safety of a synthetic peptide-containing surfactant in the treatment of respiratory distress syndrome (RDS) in preterm (approximately 80% of normal gestation) infant rhesus monkeys. Surfactant was prepared consisting of the phospholipids dipalmitoylphosphatidyl choline and palmitoyl-oleoyl phosphatidyl glycerol and a synthetic peptide modeled after surfactant protein B (SP-B), "KL4-Surfactant" contained a peptide having the sequence KLLLLKLLLLKLLLLKLLLLK, where "K" is lysine and "L" is leucine. The peptide was selected because it mimics the repeating stretches of hydrophobic residues with intermittent basic hydrophilic residues seen in SP-B. KL4-Surfactant was shown to have biophysical activity assessed as the ability to lower surface tension at an air-liquid interface in a pulsating bubble surfactometer. Thirty premature rhesus monkeys were treated shortly after birth with one dose of KL4-Surfactant. The arterial to alveolar oxygen partial pressure ratio (a/A) was found to rise from a pretreatment level of 0.11 +/- 0.01 (mean +/- SEM), indicative of severe RDS, to 0.40 +/- 0.02 at 12-13 h post-treatment. The improvement in oxygenation persisted throughout the study period, with a mean a/A at 22-23 h of 0.45 +/- 0.07. Chest radiographs and gross and microscopic examination of the lungs all confirmed the reversal of the atelectasis seen before treatment. Animals treated with a dose of 200 mg/kg showed a faster, more consistent, and greater response than did a group treated with an average dose of 127 mg/kg. There was no evidence of toxicity after treatment with the higher dose as demonstrated by physiologic, hematologic, biochemical, and pathologic data. The importance of the peptide in the synthetic surfactant was apparent from the results obtained with a control group of nine premature monkeys treated with a non-peptide-containing surfactant; the a/A of this group was 0.15 +/- 0.03 at nine hours of age as compared with a value of 0.38 +/- 0.02 for 30 comparable animals receiving KL4-Surfactant.

/pdf/efficacy-of-synthetic-peptide-containing-surfactant-in-the-4wm8jljiur.pdf

Efficacy of synthetic peptide-containing surfactant in the treatment of respiratory distress syndrome in preterm infant rhesus monkeys.

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Oxidative inactivation of surfactants.

Characterization of surfactant subtypes of beractant and a synthetic peptide containing surfactant KL4 following surface area cycling and addition of fibrinogen.

Comparative effects of some serum components and proteolytic products of fibrinogen on surface tension-lowering abilities of beractant and a synthetic peptide containing surfactant KL4.

Efficacy of synthetic peptide-containing surfactant in the treatment of respiratory distress syndrome in preterm infant rhesus monkeys.