Clinical trials of surfactant replacement therapy for the prevention and treatment of the respiratory distress syndrome (RDS) in premature newborns are currently underway in many neonatal units in the United States, Europe, and Japan. As of March 1988, none of the surfactant preparations used in these trials has been approved for general use in the United States by the Food and Drug Administration. All of the clinical trials of surfactant replacement therapy are currently being performed under careful research protocols. This article will discuss the different surfactant preparations under investigation, the strategies for the administration of surfactants, and the relative efficacy of surfactants demonstrated in different clinical trials.
RDS AND SURFACTANT DEFICIENCY
Avery and Mead1 demonstrated in 1959 that the respiratory distress syndrome (RDS), also known as hyaline membrane disease, of premature newborns is due to a deficiency of pulmonary surfacranr. This deficiency leads to alveolar collapse because of unopposed surface tension forces. Alveolar collapse and the work of breathing required to re-expand alveoli leads to the clinical syndrome of RDS characterized by tachypnea, retractions, grunting, flaring of the alae nasi, and a requirement for supplementary oxygen. Intubation and assisted ventilation are frequently needed to maintain the PaO, and PaCO2 within the normal ranges. Roentgenographic findings include poor thoracic expansion, diffuse homogeneous ground-glass densities, and air bronchograms. The barotrauma and oxygen toxicity associated with the treatment of RDS frequently leads to air leak phenomena (pneumothorax and pulmonary interstitial emphysema) and chronic lung disease (bronchopulmonary dysplasia).
DEVELOPMENT OF SURFACTANT REPLACEMENT THERAPY
Following the discovery that RDS is due to a deficiency of pulmonary surfactant, it seemed only natural that replacement therapy with surfactant might be an effective means of treating RDS. During the 1960s a clinical trial of surfactant replacement therapy was conducted in Singapore by an American research team. ¿ Pure dipalmitoyl phosphatidylcholine (DPPC), the major fipid in pulmonary surfactant, was administered as an aerosol to premature newhorns with RDS. The aerosolized DPPC had no salutary effect on the severity of RDS, which led the inves' tigators to question the hypothesis that RDS was due to a deficiency of pulmonary surfactant.
Surfactant Preparations for Clinical Trials
Continued research in the 1970s and 1980s revealed that pulmonary surfactant is really a complex mixture of multiple phospholipids and proteins. The proteins are present in relatively small amounts 1% to 2'Ki), but they play an important biophysical role in the spreading of surfactant at the alveolar air-liquid interface.' As new information accumulated regarding the composition and biophysical properties of pulmonary surfactant, clinical trials of surfactant replacement therapy were again initiated in Europe, Japan, and the United States. These clinical trials were preceded by extensive animal studies which demonstrated the efficacy and safety of several new surfactant preparations.
The Table summarizes the major surfactant preparations which are currently be ing used in clinical trials. There are three major categories: human, bovine/ porcine extracts, and synthetic surfactants.
Human surfactant is prepared from arnniotic fluid obtained at the time oí cesarean section. This material is ideal because it does not contain the foreign animal protein found in the bovine and porcine products. The preparation of large quantities of human surfactant for widespread use, however, is a major problem.
In 1980, Dr. Fujiwara4 first described the clinical efficacv of a surfactant derived from minced bovine lungs. This material has undergone extensive clinical testing and is currently known as Surtaetant-TA. Several other groups are using organic solvent extraction techniques to prepare surfactants derived from the mincing or lavaging of bovine and porcine lungs. The material that is currently used at the University of Rochester is known is calí lung surfactant extract (CLSE). The protein content of the bovine surfactant extracts consists of two low molecular weight hydrophobic proteins known as SP-B and SP-C.
Two different synthetic surfactants are now under investigation. A mixture of DPPC and the phnspholipid phosphatidylglycerol (PG) in a molar ratio of 7:3 has been used extensively in European trials."1 This surfactant (known as ALEC, artificial lung expanding compound) has the advantage ot being free of protein, but it seems to have a delayed onset of action.
A second synthetic surfactant known as Exosurf is currently being used in clinical trials in the United States. Exosurf is formulated by adding two detergentlike substances or emulsifying agents (tyloxapol and hexadecanol) to surfactant phospholipids.
Intense research is now underway to develop a surfactant consisting of phospholipids and human surfactant proteins produced by the new techniques of biotechnology. The genes for the human surfactant proteins have been identified, and recombinant DNA techniques can be used to produce these proteins. The identification ot the best surfactant preparation for clinical use will depend upon continued biophysical and biological laboratory testing as well as the careful analyses of controlled clinical trials.
Figure 1. Decline in the FiO7 requirement for a premature infant with severe RDS following a dose of post-ventilatory CLSE.
STRATEGIES FOR SURFACTANT ADMINISTRATION
The early unsuccessful trial ot surfactant replacement using pure OPPC in Singapore used an aerosol method of delivery. The successful clinical trials reported during the 1980s have all used a method of direct trachéal instillation of surfactant in a saline suspension via the endotracheal tube as a bolus or in repeated small aliquots.
Two different strategies for the endotracheal instillation of surfactant have been used in recent trials: preventilatory and post-ventilatory. The pre-ventilatory or prophylactic administration of surfactant is carried out in the delivery room immediately atter birth. The infant is intubated before the first breath, and the surfactant is instilled as a bolus into the endotracheal tube. The surfactant is therefore delivered to lungs which are still filled with lung fluid. As the lung fluid recedes with aeration of the lungs, the surfactant should theoretically be distributed to the alveoli in a homogeneous fashion.
A second strategy for delivering surfactant is postventilatory or "rescue" therapy. In this case the surfactant is administered in the neonatal intensive care unit following the development of the respiratory distress syndrome. This post-ventilatory administration is usually done by injecting aliquots of surfactant into the endotracheal tube over a period of five to ten minutes. Figure 1 shows the decline in the FiO2 requirement for a premature infant with severe RDS following a dose of post-ventilatory CLSE.
CLINICAL TRIALS OF SURFACTANT REPLACEMENT
It is very difficult to compare the different reported trials of surfactant replacement therapy"1'31 because of the variety of surfactant preparations and administra - t ion strategics which have been utilized. Most of the clinical trials have reported on both short term physiological variables (such as oxygen and ventilatory requirements during the first three days of life) and long term outcome variables such as survival and the incidence of chronic lung disease.
Figure 2. Means and standard errors of measurement for physiologic variables used io compare the groups are shown for placebo-treated control infants (x) and calf lung surfactant extracttreated infants (o) for the first 48 hours of life. Lines are linear regressions by least squares method. Abbreviations used are MAP mean airway pressure [mrnHg); IMV intermittent mandatory ventilation (per minute). VEI ventilatory efficiency index (ml_/mm Hg/ kg/mm).6 (Reprinted with permission from Kowng MS. Egan EA, Notier RH. et al Double-blind clinical trial of calf lung surfactant extract for the prevention of hyaline membrane disease in extremely premature infants. Pedtatfics 1985; 76.)
Almost all of the clinical trials have demonstrated a reduction in the severity ot RDS as defined by indices of oxygénation and ventilación. These variables include decreased FiO2 requirement, improvement in the alveolar-arterial ratio, and an ability to lower the mean airway pressure by reducing ventilatory settings. Figure 2 shows the response of these physiological variables to a pre- vent ila tory dose of calf lung surfactant extract compared to a placebo control in a group of very premature infants of 24 to 28 weeks gestation.6 Many of the reported clinical trials have also demon' strated a decreased incidence of pneumothoraces.
Improved neonatal survival has been demonstrated in a few studies following both pre- ventilatory doses and single post-ventilatory doses of surfactant. Improved survival has been more consistently found in several trials which utilized multiple doses of pre- and post-ventilatory surfactant.
The incidence of chronic lung disease (bronchopulmonary dysplasia or BPD) is a major outcome variable of all surfactant trials. BPD is currently defined as an oxygen requirement greater than room air at 28 days of age associated with chronic changes on chest x-ray. The trials which utilized only a single surfactant dose (pre- or post-ventilatory) were unable to demonstrate a reduction in the incidence of BPD. One trial7 which utilized multiple doses of pre- and post-ventilatory surfactant was able to demonstrate a reduction in the incidence of BPD. It is anticipated that an optimization of surfactant replacement therapy will be achieved in the near future by the administration of frequent doses to maintain minimal oxygen and ventilatory requirements. It is hoped that this will result in a significant reduction in the incidence of chronic lung disease.
COMPLICATIONS OF SURFACTANT THERAPY
The bovine surfactants with a protein content of 1% to 2% have been used in controlled clinical trials since the early 1980s. To date, no immunologie or allergic phenomena have been identified in any infants.
The original study reported by Dr. Fujiwara4 in 1980 showed a very high incidence of patent ductus arteriosus (PDA) in infants treated with surfactant. Only one11 out of many trials5"11 conducted since then has shown an increased incidence of PDA.
Different surfactant preparations administered by a variety of approaches have shown the potential to reduce the incidence and severity of the respiratory distress syndrome. Improved neonatal survival and a reduction in the incidence of major neonatal complications have been reported. Future clinical research will be directed toward the optimization of surfactant replacement therapy, including the use of new surfactant preparations and strategies for administration.
1. Avery ME, Meadj: Suree properties in relation to atelectasisand hyaline membrane disease. An) Pit Child 1959; 97:517.
2. Chu J. Clements JA. Oxton PlC, eta1: Neonatal pulmonary ischernia: Clinical and physiologic studies. fWiassirv 1967; 40:709.
3 Namer RH, Shapiro DL: Lung surfacranra for replacement therapy: Biochemical, hiophysical and clinical aspects. CBs Pesinaeol 1987; 14:433.
4 FujistanT, MacnH, Chida 5, etal: Artificial surfacranr therapy in hyalinensembrane disease. Lanai 1980: i;55.
5. Ten Centre Study Group: Ten centre trial of artificial surtant (artificial lung expanding compound) in very premature babies. Br Mcd) 1987; 294:99!.
6. Kwong MS. Egan PA, Norter RH. er al [k,uble'blind clinical trial of calf lung surfacrant extract for the prevention of hyaliase membrane disease its extremely premature infants. Ibdiant 1985: 76:585.
7. Metritr TA, Hallnian M, Bloom BT. eta1: Prophylactic treatment of very prensanire infants with human surfacranr. N Engl I Mcd 1986; 315:785.
8. Shapiro DL. NcsrterRH, Morin PC Ill. era!: Double-blind. randomized trial of a calf lung surflacranr extsact ad.riinisrrred at birch to very premature infants flat prevention of respiratory distress syndrome. fIdiuffica 1985; 76:593.
9. Enhoessing 0, Slsennan A, Rsssmayer F. et ala Prevention of neonatal respiratory distress syndrome by tracheal insrrllarion of surfacrant: A randomized clinical trial. Pedaanws 1985: 76:145.
10. Girlin iD SoIl PT. l'.arad RB, et al: Randomized controlled trial of exogenous suafactanr foe the treatment of hyaline membrane disease, fldiaxs*a 987; 79:91.
11. Raju TN, Vidyasagar D, Rhar R. et al: Double-blind corsnolled trial of single'dose treatment with lxwine sutfacraut in severe hyaline men branc' disease. Lancei 1987; 1:651.
Surfactant Preparations for Clinical Trials