Surfactant-treated Infants Research Articles

Serious Error

In Reply.— I write in response to your letter regarding an error in Table 5 of my recently published follow-up report of surfactant-treated infants.1 Dr Jain, Vidyasagar, and Raju are correct in noting an error in the citation for the source of their surfactant material. The correct text should have stated that their material was obtained from bovine lung preparations rather than therapeutic abortions. We thank the authors for pointing out this discrepancy.

Does Prophylactic Use of Bovine Surfactant Change Drug Utilization in Very Premature Infants during Neonatal Period?

The efficacy of a bovine surfactant preparation (SF-RI 1) to increase survival without bronchopulmonary dysplasia (BPD) was studied in very premature infants in a multicenter, randomized sequential trial. Thirty-four infants were randomized to surfactant treatment, whereas 35 infants served as controls. As part of the study, pharmacotherapy with antibiotics, sedatives, catecholamines, diuretics, methylxanthines, mucolytics, muscle relaxants, digoxin, and indomethacin was registered during week 1 and weeks 2-4. As to the endpoint of the study a significantly increased survival rate without BPD was observed in surfactant-treated infants (76%) compared to controls (40%). Significant differences concerning drug utilization were found through week 1 with increased use of methylxanthines in surfactant-treated infants, which persisted during weeks 2-4 as well as a reduced incidence of diuretic therapy in surfactant-treated infants during weeks 2-4. These differences may be attributed to the shorter interval of mechanical ventilation in surfactant-treated infants (11 days) compared to controls (27 days), and to the above mentioned increased survival rate without BPD.

A controlled trial of human surfactant replacement therapy for severe respiratory distress syndrome in very low birth weight infants

In a randomized, controlled study, human surfactant derived from amniotic fluid was administered within 12 hours of birth to infants with severe respiratory distress syndrome who were born at 24 to 32 weeks of gestation weighing less than or equal to 1500 gm. A second dose of surfactant was given to patients in the treatment group if they met ventilator requirements indicating relapse or lack of response to the initial dose. No significant improvement was observed in mortality rate (9/28 vs 15/31) or incidence of bronchopulmonary dysplasia (5/28 vs 3/31) when surfactant-treated infants were compared with control subjects, although there was a significant reduction in initial respirator and inspired oxygen requirements and the arterial/alveolar oxygen ratio improved. In addition, there was a significant reduction in pulmonary air leak in treated infants (10/28 vs 20/31; p less than 0.05). Retreatment was associated with an attenuated ventilatory response and with a higher mortality rate (7/14) than that of infants who did not require a second dose (2/14; p = 0.05), indicating a more severe form of disease. Multiple discriminant analysis, including eight independent variables, revealed that increasing birth weight, earlier age at surfactant treatment, and female gender were significantly associated with survival. These data suggest that early surfactant treatment may reduce mortality rates in very low birth weight infants with severe respiratory distress syndrome, as well as reduce ventilator requirements and the incidence of pulmonary air leaks.

Impact of antenatal dexamethasone administration on respiratory distress syndrome in surfactant-treated infants

Neonatal lung disease is primarily responsible for the perinatal morbidity and mortality associated with preterm birth. Recently exogenous surfactant replacement therapy has been used to prevent or treat respiratory distress syndrome. As part of a multicenter, preventive trial between February 1986 and December 1988 using calf-lung surfactant extract, we treated 147 infants with single dose calf-lung surfactant extract. We analyzed this experience to evaluate the possibility that antenatal steroids may be additive (with calf-lung surfactant extract) in reducing both the incidence and severity of respiratory distress syndrome. Although a reduction in the incidence of respiratory distress syndrome was observed among the 33 neonates exposed to antenatal dexamethasone when compared with the 114 infants given calf-lung surfactant extract alone, the difference was not significant (37.7% vs. 24.2% p = 0.15). However, comparison of neonatal subsets previously shown to benefit most from steroid use revealed an additive effect between calf-lung surfactant extract and dexamethasone in reducing both the incidence and severity of respiratory distress syndrome. Of the 99 singleton pregnancies, only 2 of 16 infants treated with calf-lung surfactant extract and dexamethasone developed respiratory distress syndrome, compared with the 33 of 83 calf-lung surfactant extract cases (p < 0.05). A similar reduction was observed in infants between 28 and 32 weeks' gestation (calf-lung surfactant extract, 21 of 79 vs. calf-lung surfactant extract and dexamethasone, 0 of 24; p < 0.05). A reduction in disease severity was observed in male offspring (moderate or severe respiratory distress syndrome only; 22 of 63 vs. 2 of 22; p < 0.05). Potential confounding variables (e.g., gestational age at birth, birth weight, exposure to tocolytics before delivery, fetal pH at birth) were similar in all comparisons. We conclude that an additive effect between dexamethasone and calf-lung surfactant extract is observed in selected cases. It may therefore be appropriate to maximize antenatal steroid use in centers where exogenous surfactant is available.

Daily Sequential Changes in Plasma Atrial Natriuretic Factor Concentrations in Mechanically Ventilated Low-Birth-Weight Infants

Plasma atrial natriuretic factor (ANF) concentrations are elevated in mechanically ventilated infants. To test the hypothesis that changes in pulmonary compliance affect ANF concentration, we measured plasma ANF concentrations sequentially in low-birth-weight, ventilated infants who either received surfactant replacement or placebo on day 1. ANF concentrations were elevated as compared to adult controls on day 1 and increased significantly on days 2 and 3 before declining. Day 5 concentrations were not different from day 1. Several infants had ANF concentrations greater than 1,280 pg/ml on days 2-4. There were no significant differences in ANF concentrations between surfactant-treated and non-treated infants on any day. ANF concentrations increased in parallel with changes in salt and water balance, but no significant relationships were apparent between absolute ANF concentrations and parameters of salt and water balance. The results suggest that ANF secretion is elevated in infants with pulmonary disease. While the temporal relationship between the initial rise in ANF concentration and increase in salt and water excretion suggest that ANF is involved in this diuresis, the role it may play is unclear from the present data.

Two-Year Follow-up of Infants Enrolled in a Randomized Trial of Surfactant Replacement Therapy for Prevention of Neonatal Respiratory Distress Syndrome

A randomized clinical trial of the use of bovine surfactant for the prevention of neonatal respiratory distress syndrome was completed at our Institution in 1984 (Pediatrics 1985;76:145-153). All infants entering the trial were enrolled in our follow-up clinic and seen at regular intervals for assessment of growth and development, neurologic and sensory status, and incidence of respiratory disease and allergic conditions. Infants have now been followed-up for at least 2 years. Of those infants for whom follow-up is complete, two of 32 (6.3%) surfactant-treated infants died, five (15.6%) had major neuro-developmental handicaps, and five had minor neurodevelopmental handicaps. In the control group, eight of 33 (24%) infants died, whereas only two (6.1%) survived with major neurodevelopmental handicaps, and four (12.1%) were left with minor handicaps. Except for an increased neonatal death rate in the control group, other differences were not statistically significant. The groups were also comparable in terms of the incidence of late respiratory or allergic disease as assessed by history. Treatment with bovine surfactant at birth of premature infants at high risk for respiratory distress syndrome appears to be safe and of short-term benefit, although no decrease in neurodevelopmental handicap at 2 years' follow-up can be demonstrated.

Neurodevelopmental and Respiratory Outcome in Early Childhood After Human Surfactant Treatment

We assessed postnatal growth, neurodevelopmental outcome, and occurrence of respiratory illnesses in 46 infants of very low birth weight who were enrolled in a randomized, controlled, bicenter clinical trial of human surfactant treatment for respiratory distress syndrome. No long-term adverse effects of human surfactant treatment were detected between control and human surfactant-treated infants with respect to growth, neurologic, or developmental outcome. Infants with chronic lung disease, regardless of treatment group, had poorer growth and were more likely to have neurodevelopmental abnormalities at 12 to 24 months of age.

Pulmonary Surfactant Replacement in Respiratory Distress Syndrome

Exogenous surfactant therapy in infants with HMD leads to dramatic improvement in oxygenation and disease course. Both prophylactic and rescue treatments have shown a significant reduction in morbidity and mortality from the disease. There are several questions yet to be answered regarding the most effective surfactant, the appropriate time of treatment, and the appropriate dose, as well as the number of treatments required. Based on the available data, surfactant TA has shown promising and consistent results. Another important question to be answered is the role of surfactant in milder cases of HMD and its impact on the cost of hospitalization. Hopefully, future studies will be able to provide answers to these questions.

Randomized Controlled Trial of Exogenous Surfactant for the Treatment of Hyaline Membrane Disease

We conducted a prospective, randomized, unblinded, controlled trial of exogenous bovine surfactant (surfactant TA) in premature infants requiring ventilator support for the treatment of severe hyaline membrane disease. Forty-one low birth weight infants with severe hyaline membrane disease were randomly assigned to saline or surfactant therapy and treated within eight hours of birth. Significant improvements in oxygenation (increased arterial/alveolar PO2) and respiratory support (decreased mean airway pressure) were seen in the group receiving surfactant within four hours after treatment. These improvements were maintained in the surfactant-treated infants, who also had fewer pneumothoraces and fewer number of days in environments of fractional inspiratory oxygen greater than 0.4 mm Hg. No problems were associated with administration of surfactant, and no acute side effects were detected. We conclude that exogenous surfactant, administered early in the course of severe hyaline membrane disease, is an effective therapy that can diminish the amount of respiratory support required during the first 48 hours of life.

Double-Blind, Randomized Trial of a Calf Lung Surfactant Extract Administered at Birth to Very Premature Infants for Prevention of Respiratory Distress Syndrome

Organic solvent extraction of surfactant obtained by lavage of calf lungs yields a highly surface-active material. A double blind, randomized clinical trial to determine the effect of this material on respiratory distress syndrome in premature infants was initiated in the Neonatal Intensive Care Unit at the University of Rochester in December 1983. Infants 25 to 29 weeks gestational age were eligible for entry into the trial. At the time of this interim analysis 32 patients had been randomly selected and entered into the trial, 16 surfactant-treated patients and 16 in a control group who received only saline. At birth, intrapulmonary instillation of the calf lung surfactant extract dispersed in saline or saline alone occurred in the delivery room immediately after intubation and prior to ventilation; infants were then ventilated and treated as usual. At 6, 12, 24, 48, and 72 hours after birth, the severity of respiratory distress was categorized as either minimal, intermediate, or severe based on oxygen and mean airway pressure requirements. Differences observed at six hours after birth were of marginal significance, but at 12 and 24 hours the surfactant-treated group had significantly (P less than .01) less severe respiratory distress compared with the control group. Differences between treated and control infants were not statistically significant at 48 and 72 hours after birth. In four surfactant-treated infants the severity of respiratory distress worsened between 24 and 48 hours after birth, suggesting that one dose of surfactant at birth may not be sufficient for some infants.