ROTTERDAM--Two recent studies have provided reassuring news about the safety and efficacy of repeated surfactant administration in preterm infants. In one study of neonates with respiratory distress syndrome (RDS), treatment with exogenous surfactant was shown to be well tolerated and to stimulate synthesis of endogenous surfactant.[1] The second study demonstrated that surfactant administration improves gas exchange in neonates with respiratory failure as well as group B streptococcal infections.[2]

The first study focused on whether multiple doses of exogenous surfactant disturb the metabolism of endogenous surfactant. In an interview with PULMONARY REVIEWS, Luc J. I. Zimmermann, MD, PhD, one of the study's authors, said, "This is the first clinical trial to focus on this important aspect of surfactant treatment in premature infants." He added, "It now appears that two or even three surfactant doses have few negative effects and may actually stimulate endogenous metabolism."

To study this issue, he and his colleagues designed a prospective clinical study that included 27 preterm infants, all of whom were intubated and mechanically ventilated for respiratory distress. Surfactant (100 mg/kg) was administered endotracheally if an infant's mean airway pressure exceeded 7.5 cm H2O or required fraction of inspired oxygen (FIO2) was above 0.40. If signs of respiratory failure were still present six hours later, a second dose was given; a third dose was administered within 20 hours of the second if these signs failed to resolve. In accordance with these criteria, four neonates were given one dose of surfactant, 15 required two doses, and three received three doses. Surfactant was never given to five of the neonates because the criteria for respiratory failure were never met.

All the infants were also given a 24-hour infusion of glucose labeled with carbon 13 (a stable isotope). Measurement of 13C-incorporation into palmitic acid in endogenous surfactant phosphatidylcholine (PC) isolated from serial tracheal aspirates was used to assess surfactant production.

Not only did surfactant administration not lower endogenous production, but also the absolute synthesis rate (ASR) of surfactant PC rose linearly as administration of exogenous surfactant increased. For each dose of surfactant given, the ASR of surfactant PC rose by a mean 1.3 mg/kg/d.

Dr. Zimmermann, Deputy Chief of Neonatology at Sophia Children's Hospital, in Rotterdam, Netherlands, said that these results are reassuring. He and his colleagues found no evidence of a negative feedback mechanism (whereby exogenous surfactant would suppress endogenous production); in fact, they found quite the opposite.

Furthermore, the researchers discovered that the ASR of surfactant PC increased if prenatal corticosteroids had been given or if the infant had a patent ductus arteriosus. However, the ASR decreased linearly with advancing gestational age. Their analysis also revealed that the combination of prenatal corticosteroid and postnatal surfactant administration may have additive effects on metabolism of endogenous surfactant.

The second study sought to determine the safety of exogenous surfactant administration to neonates with group B streptococcal pneumonia. Lead author Egbert Herting, MD, PhD, told PULMONARY REVIEWS that that this type of pneumonia and RDS can cause similar clinical pictures of severe respiratory failure. Differentiating between the two diseases can be difficult.

"When we started with surfactant therapy about 15 years ago, we soon realized that some infants who were primarily considered to suffer from RDS actually had group B streptococcal infection," said Dr. Herting, a neonatologist at Georg August University in Göttingen, Germany. "We therefore asked ourselves: 'Does surfactant work under such conditions, and is it safe to give surfactant to neonates infected with group B streptococci?'"

To address these questions, Herting et al studied 118 neonates with respiratory failure, all of whom had clinical and/or laboratory signs of acute inflammatory disease and group B streptococcal infection confirmed by culture results. Subjects were recruited in one of two ways: retrospectively from a database of infants treated with surfactant at 28 neonatology units participating in European multicenter trials during 1987-1993, or prospectively from the same units during the next five years.

Using the same database, the researchers selected a nonrandomized control group of 236 infants who had also received surfactant but who did not have evidence of infection. The two groups were similar in terms of clinical characteristics except that the infected infants had a slightly higher mean birth weight, rectal temperature on admission, and age (in minutes) at intubation.

Among the infants with group B streptococcal infection, the median birth weight was 1,468 g and median gestational age was 30 weeks. The mean initial surfactant dose (administered a median of six hours after birth) was 142 mg/kg. Most of these infants were given multiple doses of surfactant.

Within one hour of surfactant treatment, the median FIO2 needed by the infected infants was reduced from 0.84 to 0.50. However, 25% of these infants still required more than 80% oxygen an hour after surfactant instillation. The infants without infection experienced an even greater decline in FIO2. Mean airway pressure in the infected infants also improved after surfactant treatment, but the rate of improvement was slower than that seen in the infants without infection.

The mortality and complication rates for the infants with group B streptococcal infection were high. Overall, 30% of these neonates died, 16% developed pneumothorax, and 43% suffered an intracranial hemorrhage. In comparison, the infants without infection had a 19% mortality rate, a 13% incidence of pneumothorax, and a 35% incidence of intracranial hemorrhage.

Prognosis was especially poor in the infants with group B streptococcal septicemia (mortality rate, 49%). By comparison, among those who had evidence of streptococcal infection in skin swabs or tracheal/gastric aspirate fluid, the mortality rates were 19% and 14%, respectively.

Dr. Herting and his colleagues concluded that high and repeated doses of exogenous surfactant enhance gas exchange in most infants with respiratory failure associated with group B streptococcal infection. However, given the high mortality and morbidity associated with this condition, Herting et al recommend that researchers look for better preventive strategies, such as an effective vaccine that could be given to pregnant women.

Another intriguing avenue of current research, now under investigation in animal models, is the use of surfactant as a carrier for antibiotics or specific immunoglobulins against the polysaccharide capsule of group B streptococci.

--Stanley Nelson

References
1. Bunt JEH, Carnielli VP, Janssen DJ, et al. Treatment with exogenous surfactant stimulates endogenous surfactant synthesis in premature infants with respiratory distress syndrome. Crit Care Med. 2000; 28:3383-3388.

2. Herting E, Gefeller O, Land M, et al. Surfactant treatment of neonates with respiratory failure and group B streptococcal infection. Pediatrics. 2000; 106:957-964.