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Synthetic Surfactants: The Search Goes on

2005; American Academy of Pediatrics; Volume: 115; Issue: 4 Linguagem: Inglês

10.1542/peds.2005-0202

1098-4275

John Kattwinkel,

Congenital Diaphragmatic Hernia Studies

When Avery and Mead1 first described surfactant deficiency as being responsible for hyaline-membrane disease, it seemed as if the therapeutic implications would be simple: Because we knew that pulmonary surfactant was made up primarily of phosphatidyl choline, perhaps administering a solution or aerosol of this readily available lipid to the surfactant-deficient lung should solve the problem. Unfortunately, this simplistic approach did not work regardless of whether surfactant was delivered to humans2 or animals.3 Improving the spreading characteristics by adding alcohols or altering the physical preparation improved the function somewhat,4,5 but the first dramatic effect on pulmonary function and survival was shown only with modified natural surfactants that had been extracted from lung minces6,7 and airway washes of animal lungs.8 Various head-to-head trials of natural versus synthetic surfactants have consistently favored the natural preparations.9 Accordingly, although 2 synthetic surfactant preparations (Exosurf and Pumactant) were approved for commercial distribution in the United States and Britain, respectively, Exosurf is no longer readily available in the United States, and Pumactant was recently removed from the market in Britain.The search for a synthetic preparation that is equivalent or superior to the animal-derived surfactants has continued, because there has always been concern about the potential antigenic and infectious complications that might be associated with animal-derived preparations. Although in vitro studies have generally been reassuring10,11 and no lasting adverse effects of this nature have been described after delivery of several million doses of these preparations, the theoretical concerns remain.It is generally accepted that the primary reason for the superiority of natural surfactants is the presence of 2 apoproteins, surfactant protein B (SP-B) and surfactant protein C (SP-C), that associate biophysically with the phospholipids and facilitate surfactant spreading, configuration, and recycling.12 Addition of surfactant proteins to phospholipid mixtures will improve their surface-tension–altering qualities in vitro and the inflation characteristics of the lung in vivo. Also, patients or transgenic mice that are missing SP-B and/or SP-C have severe or moderate respiratory disease despite the presence of normal or excessive quantities of phospholipids in the lung. SP-B, in particular, seems to be essential for lamellar body formation as well as for dipalmitoyl phosphatidylcholine configuration at the air-fluid interface at body temperature. Therefore, the search has gone on for an artificial surfactant preparation that contains a functional synthetic apoprotein. The molecular structure of SP-B has been synthesized in the laboratory, but unfortunately the molecule will not configure appropriately, and therefore no successful trials with a synthetic SB-B-containing preparation have been published. An analog of SP-C has been produced and will promote film adsorption in vitro and has been shown to treat surfactant deficiency in animal models.13 Although a trial of this material in adult respiratory distress syndrome was unsuccessful,14 to date there have been no published neonatal trials with this material.Two articles appear in this issue of Pediatrics that report randomized, clinical trials of a new, all-synthetic surfactant preparation that contains a polypeptide that has been described as mimicking SP-B.15,16 This substance, termed lucinactant, contains a mixture of phospholipids plus a polypeptide, termed sinapultide, previously known as KL-4 because of its amino acid arrangement, which involves a repeating sequence of 1 lysine followed by 4 leucine molecules. The first trial15 had 3 arms and randomized infants of 600- to 1250-g birth weights to receive colfosceril (Exosurf), lucinactant (Surfaxin), or beractant (Survanta), in a 2:2:1 assignment weighting, and given as prophylaxis. The infants receiving lucinactant had less respiratory distress syndrome and less bronchopulmonary dysplasia than those receiving colfosceril, but not less than those receiving beractant. The second trial16 had 2 arms, examined infants of the same birth-weight range, and compared lucinactant with poractant (Curosurf), in a 1:1 assignment, and also was given as prophylaxis. No significant differences were found between the 2 groups in the incidence of respiratory distress syndrome, mortality, or bronchopulmonary dysplasia.There are some problems with both studies that indicate that we may not yet have found the “holy grail.” First, the studies were designed as “noninferiority” studies, presumably to satisfy licensing requirements, and therefore were not designed to test some of the scientific questions about the relative roles of the various surfactant components. The first study15 included large numbers for testing the primary hypothesis (ie, that lucinactant is equivalent or superior to colfosceril), but colfosceril is no longer used in the United States and the study was underpowered to examine its efficacy versus beractant. The second study16 was halted halfway through enrollment and thus was underpowered in its attempt to establish equivalency between lucinactant and poractant. Second, both studies were conducted almost exclusively outside of the United States and presumably included only a moderate number of centers that had a history of participating in rigorously controlled clinical trials. We are not given the participation rates and range of outcomes among the 50 and 22 centers, but such wide geographic distribution must have made communication, coordination, and quality control difficult. Third, depending on the unit one chooses to calculate dosing, the preparations varied considerably in respect to the quantity of phospholipids (175, 67.5, 100, and 176 mg/kg) and volume of solution (5.8, 5.0, 4.0, and 2.2 mL/kg) administered. Again, this was likely a reflection of the study having been designed primarily for licensing purposes, for which the concentration of the approved products had to be maintained.There are also several qualities about this new substance that may not be optimum or require more information before we accept it as equivalent to the natural surfactants with which we have now had nearly 2 decades of experience. First, because the KL-4 polypeptide does not lipid-associate as readily as SP-B and SP-C, lucinactant forms a gel in its storage form and must be heated to 44°C and shaken before administration; this complicates the process somewhat, requires special equipment, and may introduce another possibility for error. Finally, we know very little about the fate of lucinactant. Native and exogenous natural surfactants are largely recycled and resecreted many times by the type II pneumocyte before being catabolized.12 We know very little about the fate of the KL-4 polypeptide and the phospholipids in lucinactant. Are they incorporated into native surfactant? What influence does its presence have on the metabolism of surfactant in the host lung?Despite these precautions and concerns, these 2 studies represent a tremendous concerted effort of a large number of clinicians and investigators and may well be the first encouraging sign that our search for a successful synthetic surfactant is headed in the right direction.