Double-blind clinical trial of calf lung surfactant extract for the prevention of hyaline membrane disease in extremely premature infants

The present study was undertaken to determine if a synthetic peptide, KLLLLKLLLLKLLLLKLLLLK (KL4), in which K = lysine and L = leucine, in an aqueous dispersion of phospholipids (DPPC and POPG), would expand pulmonary alveoli and improve gas exchange in premature human infants with respiratory distress syndrome (RDS). The KL4 peptide was synthesized to resemble the amino acid pattern of surfactant protein B (SP-B). Forty-seven infants with RDS were treated within 4 h of birth with the KL4-peptide/phospholipid mixture, called KL4-Surfactant. The average arterial-to-alveolar oxygen tension ratios (a/A O2) of 39 patients included in efficacy analyses rose from pretreatment values of 0.14 +/- 0.02 (mean +/- SEM) to 0.40 +/- 0.04 (normal value > or = 0.40) by 12 h of age. Mean airway pressures and oxygenation index values fell concomitantly, and expansion of the lungs was observed on radiographs. The median duration of mechanical ventilation was 5.0 d. Of the 39 included infants, 29 required only a single dose. Radiographic data indicate that those patients requiring a second instillation of KL4-Surfactant but not showing a sustained rise in a/A O2 ratios did, in fact, exhibit expansion of alveoli in the lung. There were no RDS-related deaths; the incidence of complications was no higher than found in other comparable published studies. The data demonstrate that the synthetic peptide, KL4, which mimics the hydrophobic and hydrophilic pattern of SP-B, when formulated in an aqueous dispersion with the phospholipids DPPC and POPG, creates a strong and durable surfactant activity as judged by expansion of pulmonary alveoli and improvement of gas exchange in infants with RDS.

The efficacy and safety of KL4-surfactant in preterm infants with respiratory distress syndrome.

Respiratory-distress syndrome (RDS) in the newborn is a major cause of neonatal mortality and morbidity. Although prematurity is the most-important risk factor for RDS, the syndrome does not develop in many premature infants. The main cause of RDS is a deficiency of pulmonary surfactant, which consists of phospholipids and specific proteins. The genes underlying susceptibility to RDS are insufficiently known. The candidate-gene approach was used to study the association between the surfactant protein A (SP-A) gene locus and RDS in the genetically homogeneous Finnish population. In the present study, 88 infants with RDS and 88 control infants that were matched for degree of prematurity, prenatal glucocorticoid therapy, and sex were analyzed for SP-A genotypes. We show that certain SP-A1 alleles (6A 2 and 6A 3 ) and an SP-A1/SP-A2 haplotype (6A 2 /1A 0 ) were associated with RDS. The 6A 2 allele was overrepresented and the 6A 3 allele was underrepresented in infants with RDS. These associations were particularly strong among small premature infants born at gestational age 2 (.22 vs. .71), 6A 3 (.72 vs. .17), 6A 2 /1A 0 (.17 vs. .68), 6A 3 /1A 1 (.39 vs. .10), and 6A 3 /1A 2 (.28 vs. .06) in the two groups, respectively, were strikingly different. According to the results of conditional logistic-regression analysis, diseases associated with premature birth did not explain the association between the odds of a particular homozygous SP-A1 genotype (6A 2 /6A 2 and 6A 3 /6A 3 ) and RDS. In the population evaluated in the present study, SP-B intron 4 variant frequencies were low and had no detectable association with RDS. We conclude that the SP-A gene locus is an important determinant for predisposition to RDS in premature infants.

https://www.cell.com/ajhg/pdf/S0002-9297(07)62987-5.pdf

Association between the surfactant protein A (SP-A) gene locus and respiratory-distress syndrome in the Finnish population.

OBJECTIVE. Our aim was to quantify contemporary infant mortality risks and to evaluate the change by plurality, gestation, and race during the most recent decade. PATIENTS AND METHODS. The study population included live births of 20 to 43 weeks9 gestation from the 1989–1991 and 1999–2001 US Birth Cohort Linked Birth/Infant Death Data Sets, including 11317895 and 11181095 live births and 89823 and 67129 infant deaths, respectively. Adjusted odds ratios and 95% confidence intervals were calculated to evaluate the change in risk by plurality and gestation and to compare the change with that for singletons. RESULTS. Overall, the infant mortality risk decreased significantly for singletons, twins, and triplets but nonsignificantly for quadruplets and quintuplets. Compared with singletons, significantly greater reductions were experienced by twins overall and at CONCLUSIONS. The improvements in survival were greater for multiples versus singletons and for white versus black infants. Within each plurality, at each gestation the racial disparity in mortality has widened.

The Changing Risk of Infant Mortality by Gestation, Plurality, and Race: 1989–1991 Versus 1999–2001

A deficiency in alveolar surfactant due to immaturity of alveolar type II epithelial cells causes respiratory distress syndrome (RDS). In contrast to animals, the fetal maturation of surfactant in human lungs takes place before term, exceptionally large quantities of surfactant accumulating in the amniotic fluid. The antenatal development of surfactant secretion is very variable but corresponds closely to the risk of RDS. The variation in SP-A and SP-B genes, race, sex and perinatal complications influence susceptibility to RDS. Surfactant therapy has improved the prognosis of RDS remarkably. Abnormalities in alveolar or airway surfactant characterize many lung and airway diseases. In the acute respiratory distress syndrome, deficiencies in surfactant components (phospholipids, SP-B, SP-A) are evident, and may be caused by pro-inflammatory cytokines (IL-1, TNF) that decrease surfactant components. The resultant atelectasis localizes the disease, possibly allowing healing (regeneration, increase in surfactant). In the immature fetus, cytokines accelerate the differentiation of surfactant, preventing RDS. After birth, however, persistent inflammation is associated with low SP-A and chronic lung disease. A future challenge is to understand how to inhibit or redirect the inflammatory response from tissue destruction and poor growth towards normal lung development and regeneration.

Surfactant in respiratory distress syndrome and lung injury.

We review and analyze the various exogenous surfactant agents used in randomized, controlled clinical trials in infants with or at risk for respiratory distress syndrome (RDS). Analysis of all published trials utilizing natural, or modified natural, surfactant extracts or syntheticsurfactants inpremature infants at risk for RDS treated at birth (prophylactic treatment) shows an improvement in the need for supplemental oxygen and ventilatory support over the course of RDS and a reduction in many morbidities of prematurity, especially pneumothorax, but little or no impact on the incidence of intraventricular hemorrhage. Treatment of established RDS alter onset of mechanical ventilation is also reviewed, showing similar improvements over the course of RDS and lessening of morbidities, including pneumothorax. Overviews of study results account for the effect of treatment, the number of infants included, and the power of the outcomes; studies of similar design are compared using meta-analysis that which clearly documents the impact of surfactant therapy (both prophylactic and postventilatory treatment) on neonatal mortality. Comparisons between outcomes of studies comparing prophylactic to later treatment found no clear advantage of preventative treatment, except among infants less than 26 to 28 weeks’ gestation. Variations in response to surfactant treatment due to high permeability lung edema, decreased pulmonary perfusion, lung hypoplasia, and obstructive lung disease are reviewed, and the effects of dose and multidose therapy clearly document that doses between 100 to 200 mg/kg of modified natural surfactants are optimal, although there is no specific advantage of more than two doses of synthetic surfactant. Complications of surfactant therapy include transient hipoxia and hypercarbia during administration, an increased occurrence of pulmonary hemorrhage, and concerns regarding imrnunogenicity of surfactant proteins contained in natural o r modified surfactants. Long-term follow-up studies have been uniformly encouraging among infants treated with exogenous surfactants.

Roger F. Soll

Papers

Overview of Exogenous Surfactant Replacement Therapy