Colfosceril Palmitate

Summary

Synopsis

Colfosceril palmitate (dipalmitoylphosphatidylcholine) is the primary surface-active agent of natural lung surfactant and the major constituent of exogenous surface replacement preparations. Exogenous surfactants derived from either natural (i.e. animal and human) or synthetic sources are indicated for the prophylaxis and treatment of neonatal respiratory distress syndrome. One of the synthetic surfactants, Exosurf® Neonatal™ is the focus of this review. This preparation is composed of colfosceril palmitate plus cetyl alcohol and tyloxapol, which facilitate rapid spreading and adsorption of the surface-active agent at the air-alveolar interface. For review purposes, this preparation is referred to only as colfosceril palmitate.

Comparative trials with air placebo have shown that colfosceril palmitate improves clinical outcome in infants weighing greater than 700g at birth by reducing mortality and increasing the number of infants who survive without bronchopulmonary dysplasia. It also reduces the number of deaths from respiratory distress syndrome and decreases the incidence of air leak events such as pulmonary interstitial emphysema and pneumothorax.

Although colfosceril palmitate itself is very well tolerated and does not increase the incidence of most complications of prematurity or of respiratory distress syndrome, its use is associated with a higher incidence of apnoea of prematurity and pulmonary haemorrhage compared with air placebo, possibly because of earlier extubation of surfactant-treated infants following an improved clinical course and decreased pulmonary vascular resistance secondary to improved ventilation, respectively.

Colfosceril palmitate thus has an established efficacy in the prophylaxis and treatment of premature infants with respiratory distress syndrome. Ongoing trials may identify whether prophylactic or rescue administration of the surfactant preparation is the preferred approach and whether different dosage regimens or different administration techniques impart greater therapeutic efficacy. Importantly, it also remains to be determined whether any of the available surfactant preparations, including Exosurf® Neonatal™, will provide distinct therapeutic advantages over the others.

Neonatal Respiratory Distress Syndrome

Neonatal respiratory distress syndrome is a condition caused by pulmonary immaturity, affecting approximately 10% of infants born at less than 37 weeks’ gestation. It is characterised by tachypnoea, expiratory grunting, cyanosis and intercostal retractions. Risk factors for the development of respiratory distress syndrome include premature birth, male sex, delivery by caesarean section, second-born twins and maternal diabetes mellitus.

The primary pathogenic feature of this disease is a deficiency of endogenous lung surfactant caused by pulmonary immaturity. Surfactant is necessary to lower surface tension forces at the air-alveolar interface, thereby preventing the alveoli from collapsing during expiration. In the absence of adequate surfactant, the infant requires increasingly higher inspiratory pressures to re-expand the alveoli and achieve adequate gas exchange. As the infant tires, progressive pulmonary failure develops.

Treatment of respiratory distress syndrome consists of supplemental oxygen and mechanical ventilation to facilitate gas exchange, and replacement therapy with exogenous surfactant.

Surfactant Replacement Therapy

Natural human surfactant is composed of phospholipids (85%), neutral lipids (10%), and apoproteins (5%). The phospholipids are the primary surface-active ingredients, while the apoproteins facilitate adsorption and respreading of the surfactant within the lungs. Colfosceril palmitate is the most abundant and active phospholipid found in natural surfactant and is the major constituent of exogenous surfactant preparations.

Since the first successful clinical outcome was reported in infants with respiratory distress syndrome treated with a bovine surfactant extract enriched with phospholipids, exogenous surfactant replacement therapy has been widely investigated. Exogenous surfactant preparations have included those derived from human amniotic fluid, those isolated from calf or pig lungs with or without the addition of phospholipids and those that are entirely synthetic. One of the synthetic surfactants (Exosurf® Neonatal™) has undergone extensive investigation and is the primary focus of this review; hereafter, it is referred to as colfosceril palmitate.

Therapeutic Efficacy

Large-scale double-blind randomised studies have compared the efficacy of colfosceril palmitate with that of air placebo in premature infants with respiratory distress syndrome. As prophylaxis or as ‘rescue’ therapy, colfosceril palmitate improved clinical outcome in infants weighing more than 700g at birth by reducing the mortality rate and increasing the incidence of survival without bronchopulmonary dysplasia. Although preliminary data documented early benefit (i.e. improved ventilatory and oxygen requirements) in extremely low birthweight premature infants (those weighing 500 to 749g at birth) and revealed an emerging trend in some measures of clinical outcome, further trials are needed to determine whether colfosceril palmitate provides any significant survival advantage to infants in this weight category.

Preliminary findings in infants weighing more than 1250g at birth with established respiratory distress syndrome have indicated that a larger cumulative ‘rescue’ dose of colfosceril palmitate provides additional early benefit over the current standard dose (i.e. 15 vs 10 mg/kg), although no survival advantages were documented. Moreover, compared with 1 prophylactic dose administered at birth, 2 additional doses of colfosceril palmitate administered 12 hours apart reduced mortality by an additional 39% at 28 days and 44% at 1 year in infants weighing 700 to 1100g at birth.

Clinical Tolerability

Colfosceril palmitate is well tolerated and does not cause any adverse effects per se. Infants treated with this drug had a lower incidence of pulmonary air leak events, and there were no significant differences observed between colfosceril palmitate and air placebo in the number of infants with intra ventricular haemorrhage, peri ventricular echodensities, patent ductus arteriosus, necrotising enterocolitis, arterial hypotension, sepsis, meningitis and nosocomial or congenital pneumonia. However, colfosceril palmitate was associated with an increased incidence of both apnoea of prematurity and pulmonary haemorrhage. There may be an increased opportunity for apnoea to develop in surfactant-treated infants because of earlier extubation subsequent to clinical improvement, and the incidence of pulmonary haemorrhage may be increased because of improved lung compliance leading to decreased pulmonary vascular resistance.

Early indications are that colfosceril palmitate is not associated with any long term sequalae. At 1-year follow-up, functional handicaps and overall growth and development were equivalent in infants treated with colfosceril palmitate or air placebo.

Dosage and Administration

The recommended dose of colfosceril palmitate is 5 ml/kg. For prophylactic treatment of infants at risk of developing respiratory distress syndrome, colfosceril palmitate is given as a single dose as soon as possible after birth, with repeat doses administered 12 and 24 hours later to infants who remain on mechanical ventilation. In infants with established respiratory distress syndrome, rescue administration of colfosceril palmitate is initiated with a 5 ml/kg dose, with a repeat dose administered 12 hours later to infants remaining on mechanical ventilation. Colfosceril palmitate is administered intratracheally, without interrupting mechanical ventilation.