Pharmacology: BLES (bovine lipid extract surfactant) restores surfactant activity in neonates with respiratory distress syndrome (NRDS), thereby improving gaseous exchange by decreasing alveolar surface tension and promoting lung compliance in the infant with NRDS.
BLES is an extract of natural bovine surfactant which contains numerous phospholipids, with dipalmitoylphosphatidylcholine (DPPC) being the most abundant. It also includes hydrophobic surfactant-associated proteins SP-B and SP-C, which facilitate their dispersion. When administered intratracheally, BLES is rapidly adsorbed, forming an active phospholipid monolayer at the air-fluid interface.
The metabolic fate of BLES has not been investigated.
BLES can have an immediate effect on lung compliance, usually within 5 to 30 minutes after treatment with a single dose. Clinical experience with BLES has shown that BLES significantly improved gas exchange and lung compliance by the 4-hour time-point. Fraction of inspired oxygen (FiO2) and ventilatory requirements were significantly decreased, and there was a reduction in the severity of NRDS and its associated complications.
Clinical Trials: Study demographics and trial design: The efficacy of BLES (bovine lipid extract surfactant) is supported by the results of a Phase III pivotal trial, Study No. 92-001, comparing the safety and efficacy of BLES with Exosurf Neonatal (colfosceril palmitate; Glaxo Wellcome) in the rescue treatment of neonates with respiratory distress syndrome. Exosurf was chosen as the comparator because it was the only approved exogenous surfactant therapy available in Canada at that time.
This 10 centre double-blinded randomized controlled trial involved 1133 infants. Infants were stratified into weight groups of <750 grams (n=180), 750-1250 grams (n=455) and >1250 grams (n=499). Infants could receive up to four doses of surfactant, as required, within the first five days of life. (See Table 2.)
Click on icon to see table/diagram/image
Infants with NRDS were enrolled in three birth weight arms and randomized to receive BLES or Exosurf. There were no statistically significant differences between treatment groups for demographic variables or pre-dose complications, except a significantly greater incidence of prolonged rupture of the membranes (PROM) in BLES -treated infants weighing 750-1250 g compared with those receiving Exosurf (26% and 18%, respectively; p=0.0450). Because both treatment groups had a similar severity of hyaline membrane disease prior to treatment, as measured by ventilation parameters, age of intubation and age of first treatment, this increased incidence of PROM was considered not likely to have affected the study outcomes.
Study results: Efficacy parameters were evaluated by birth weight group. Table 3 provides results for intact cardiopulmonary survival and ventilatory requirements. (See Table 3.)
Click on icon to see table/diagram/image
BLES was as effective as the comparator Exosurf for intact cardiopulmonary survival at 36 weeks gestational age. BLES was as effective or more effective than Exosurf for secondary endpoints. Of infants treated in the 750-1250 g arm: significantly more infants treated with BLES were alive at discharge (p=0.0435); infants treated with BLES had fewer air leaks (p<0.0001); infants treated with BLES had a decreased incidence of high oxygen requirements (p=0.0234); and there were no significant differences in the incidences of IVH (intraventricular haemorrhage) or severe IVH/PVL (periventricular leukomalacia).
Other Studies: A published study by Lam et al. (2005) compared the efficacy of BLES and Survanta in a randomized clinical trial in premature infants with birth weights between 500 and 1,800 g who developed RDS requiring mechanical ventilation with oxygen requirements of more than 3% within the first 6 hours of life. Sixty infants were recruited, with 29 in the BLES and 31 in the Survanta group. The trial was not blinded due to the different administration methods recommended for each product, particularly the number of aliquots and rotations. The primary outcome was the oxygen index within 12 hr of treatment. Neonatal complications were analysed as secondary outcomes.
Both groups had significant and sustained improvements in their oxygenation index after treatment, with the BLES group associated with a significantly lower oxygenation index throughout the 12-hr period compared with infants who received Survanta. There was no difference in secondary outcomes, including mortality, ventilator days and occurrence of chronic lung disease. The authors attributed the difference in speed of response to the higher concentration of surfactant-associated proteins in BLES.
In open-label trials, over 5000 infants have received BLES.
Long-term studies comparing BLES to placebo (sham air) treatment demonstrated no significant differences in development of neurodevelopmental handicaps and allergic manifestations.
Detailed Pharmacology: Twenty adult sheep were given a non-uniform pattern of lung injury by repetitive saline lavage followed by HCl instillation, until arterial PO2 fell below 90 Torr. After the final lavage, the sheep were mechanically ventilated for 60 min before treatment with either BLES (bovine lipid extract surfactant) or Survanta (beractant, Abbott) which had been radiolabelled. Ten animals received 10 mL of surfactant by nebulizer, with 5 mL aliquots added as needed over a three-hour treatment period. Ten animals received instilled surfactant at a dose of 100 mg phospholipid/kg body weight, applied in three aliquots over several inspiratory breaths, while being turned.
The sheep given instilled BLES, aerosolized Survanta and instilled Survanta had significantly increased PaO2 values and decreased A-aPO2 values by 180 min compared with their respective pretreatment values (p<0.01). Those given aerosolized BLES had no statistically significant changes in either PaO2 or A-aPO2 values over this treatment period. Animals given instilled BLES had significantly higher PaO2 and lower A-aPO2 values than did the other three groups at each time point after treatment (p<0.01). Aerosolized BLES values at 180 min were significantly inferior to the other treatment groups (p<0.05).
PaCO2 values following instillation of BLES were significantly lower than the pretreatment values from 60 min after treatment (p<0.05) through to 180 min (p<0.01). PaCO2 values for aerosolized Survanta were significantly lower than the pretreatment values (p<0.01), whereas PaCO2 values were significantly higher following instilled Survanta, and did not change significantly over time for the aerosolized BLES. Animals given instilled BLES or aerosolized Survanta had significantly lower PaCO2 values than did the animals given either instilled Survanta or aerosolized BLES at any time point after treatment (p<0.05).
Three hours after treatment, the proportion of the recovered surfactant present in the airways relative to lung tissue was greater for animals treated with BLES than those treated with Survanta (p<0.05).
Total phospholipid recovery was significantly higher in lavage isolated from the instilled groups compared with the aerosolized groups. The total quantity of protein present in the alveolar lavage was similar for all four treatment groups. The mean small aggregate/large aggregate (SA/LA) of animals given instilled BLES was significantly lower than that of animals receiving instilled Survanta (p<0.05). Animals treated with aerosolized BLES had a significantly higher SA/LA than did aerosolized Survanta animals (p<0.05).
In conclusion, instilled BLES resulted in the greatest improvement in lung function. Viscosity measurements of each preparation using an Ostwald viscometer, showed Survanta to have a viscosity eight times that of BLES. It also was noted that BLES contains significantly more surfactant-associated proteins than does Survanta. These factors may have influenced the distribution of each surfactant, as it was observed that there was acute deterioration in ventilator parameters after instillation of Survanta.
Toxicology: Acute Toxicity: No acute toxicity studies have been conducted with BLES (bovine lipid extract surfactant).
Long-Term Toxicity: In a 17-day intratracheal toxicity study, four groups of male and female western cross lambs were administered BLES or vehicle control by intratracheal instillation every other day for a total of 5 doses. Another four males and four females received no treatment.
Dyspnea was commonly observed during dosing with both the vehicle control and BLES. Two animals given BLES died during the second dosing (Study Day 3) from apparent volume overload (drowning). Further doses of BLES were administered in aliquots spread over several hours. No other consistent adverse pharmacologic, toxicologic or behavioural clinical signs were noted from treatment with BLES or vehicle control.
A localized 2 cm mass (abscess) was observed near the trachea of one lamb in the BLES group; no definitive relationship to treatment was established.
In summary, intratracheal administration of 270 mg/kg BLES in a volume of 10 mL/kg once every other day for a total of 5 doses beginning 24-48 hr after birth produced no distinct or definitive signs of systemic toxicity.
Carcinogenesis, Mutagenesis, and Impairment of Fertility: No studies have been performed to investigate the carcinogenesis, mutagenesis or impairment to fertility of BLES.
Immunogenicity: Animal studies for assessing immunogenicity have not been performed.