CURRENT LITERATURE AND CLINICAL ISSUES

Abstracts from the literature

Early versus delayed neonatal administration of a synthetic surfactant: the judgment of OSIRIS The OSIRIS Collaborative Group. Lancet 1992;340: 1363-9.

Objectives: (1) To compare the effectiveness of early administration of synthetic surfactant with delayed selec- tive administration and (2) to compare the effectiveness of two doses with up to four doses of surfactant. Design: Two randomized, nonblinded, controlled trials running contemporaneously for 21 months. Setting: A total of 229 hospitals (teaching and nonteaching) in 21 countries on 5 continents (105 hospitals in the United Kingdom.) Patients: Infants <2 hours old who underwent intubation and were at high risk of respiratory distress syndrome (RDS) were enrolled in the comparison of immediate ver- sus delayed selective treatment with surfactant. They were also randomly assigned to a comparison of two versus four doses; the latter study also included infants who were >2 hours old, if they had clinical RDS with an arterial/alveo- lar oxygen ratio less than 0.22 and had an endotraeheal tube in place. A total of 6774 infants were enrolled and 6757 (99.7%) were analyzed; 2690 were analyzed in the early versus delayed and the dosage comparisons, and 4067 were analyzed in the dosage comparison only. Intervention: In the first study, two doses of synthetic sur- factant (Exosurf), 5 ml/kg, were given 12 hours apart, starting immediately after enrollment in one group (early) versus starting after 2 hours of age if RDS was present, with an arterial/alveolar 02 ratio less than 0.22 in the other group (delayed). In the second study, two doses only of the same synthetic surfactant were given 12 hours apart versus two initial doses with the option of two further doses up to 24 hours after the initial doses. Main outcome measure: Primary outcomes were death or oxygen dependence at 28 days, death before discharge from the hospital, and the need for oxygen at the equivalent of term. Secondary outcomes included air leaks, patent ductus arteriosus, apnea, necrotizing enterocolitis, and retinopathy of prematurity. Results: In the first study, 96% of the early-allocation group received surfactant (median age of 118 minutes), whereas, in the delayed group, only 73% received surfactant (medi- an age, 182 minutes). The relative risk of oxygen depen- dence or death at the expected date of delivery was reduced

by 16% (relative risk -- 0.84; 95% confidence interval = 0.75 to 0.93), an absolute reduction of 6%. Early administration resulted in an increased likelihood of extubation by 1 month of age, nondependence on oxygen, and discharge from the hospital by 3 months of age, and 32% fewer cases of pneu- mothorax. Differences in mortality rates or in the risk of death or oxygen dependence at 28 days of age did not reach significance. There was no difference in apnea, necrotizing

entercolitis, treated patent duetus arteriosus, or treated retinopathy of prematurity. In the second study, babies re- cruited to participate in the dosing comparison tended to be larger (1413 vs 112l gm), more mature, and about 160 minutes older than those who participated in the early ver- sus the late comparison. Of those who could receive up to four doses, 45.4% received a third dose and 31% received a fourth dose; extra usage was associated with more reports of dosing intolerance (6.7% vs 4.2%; absolute risk differ- ence = +2.5%; 95% confidence interval = + 1.4% to +3.6%). Death or O2 dependence or both were similar at 28 days and at due date in both groups; even in babies with an arterial/ alveolar 02 ratio <0.22 at 24 hours, additional doses had no beneficial effect (total mortality rate, 26.7% vs 27.0%; sup- plemental oxygen at due date, 12.2% and 11.7%).

Conclusions: Earlier administration of surfactant appears to reduce death by 3% and long-term oxygen dependence by 3%; however, it entails the additional use of surfactant in about 25% of babies. The option of additional third and fourth doses provides no clinical benefit.

Comment: Exogenous surfactants have been demonstrated to reduce the mortality and morbidity rates of infants at high risk for, or who already have, RDS. This extremely large controlled trial (the largest ever conducted in neona- tal medicine) addressed the timing and duration of treat- ment. Blinding of caretakers and investigators was a prac- tical impossibility; however, this was balanced by the use of primary outcome measures that are objective and tempo- rally well separated from the interventions, and by the con- firmation of the actual timing of administration.

Early use of surfactant resulted in its administration to 25 additional babies for every 100 babies treated later, to achieve an absolute reduction in the mortality rate of 3% and a decrease in oxygen dependence of 3%. This small but clinically significant reduction was achieved even though only 25% of the "early" group received surfactant before 90

1 5 9

1 6 0 Abstracts f rom the literature The Journal of Pediatrics July 1993

minutes and there was an average of only 1 hour's differ- ence before initiation of therapy in the two groups. Com- parison of this study with the four reported controlled trials of "prophylactic" surfactant given in the delivery room is difficult because this study included infants with a wider range of gestational ages and birth weights in whom signs

of RDS were actually developing, rather than including only infants who were purely "at risk"; this may account for the higher mortality rate in this trial. Metaanalysis of the four trials of very early prophylaxis (total N = 9 51) showed no significant reduction in mortality rate or incidence of chronic lung disease. 1 Whether delivery room administra- tion is preferable to early administration cannot be an- swered with certainty, but it seems that the size of any dif- ference would be very small.

For the time being, relatively early use of Exosurf (and probably other surfactants) is justified by the reduction in the mortality rate. Long-term outcomes and economic analysis may modify the final recommendations. However, they will not change the conclusion that there is no basis for using more than two doses of Exosurf. No conclusions can yet be drawn regarding preferences for specific surfactant products, the size of individual doses, or routes of adminis- tration. The size of this trial indicates the number of patients needed for an answer to these questions. Subse- quent correspondence regarding this study addressed these and other issues and will be of interest to readers, z, 3

John Watts, MD McMaster University Health Sciences Centre

Hamilton, Ontario L8N 3Z5, Canada 9/34/47840

REFERENCES

1. Soil RF. Prophylaxtic surfactant vs treatment with surfactant. In: Chalmers ID, ed, Oxford database of perinatal trials. Ver- sion 1.2, Disk Issue 8. Autumn 1992, record 5675.

2. Gore SM. OSIRIS trial [Letter]. Lancet 1993;341:172. 3. Robertson B, Speer CP. OSIRIS trial [Letter]. Lancet 1993;

341:172-3.

Reversal of developmental delays in iron-defi- cient anaemic infants treated with iron ldjradinata P, Pollitt E. Lancet 1993;341:1-4.

Objective: To determine the effect of iron supplementation on the scores of 12- to 18-month-old infants with mild ane- mia on the Bayley Mental and Motor development scales. Design: Randomized, placebo-controlled, double-blind trial. Setting: University-based "Under Five" clinic in Indonesia. Patients: Infants aged 12 to 18 months who were born at >2500 gm, who had no chronic illness or known blood dis- order, and who were of appropriate weight and height for age. Infants with a hemoglobin level less than 8 gm/dl and

between 10.5 and 12 gm/dl were excluded. Of 141 infants identified, 15 were not studied because of parental refusal to participate. Infants were stratified into three iron-status classes: 50 with iron-deficiency anemia (hemoglobin level <10.5 gm/dl, transferrin saturation <10%, ferritin <12 tsg/L); 29 with nonanemic iron deficiency (hemoglobin level > 12 gm/dl, transferrin saturation < 10%, ferritin level < l 2 ~zg/L); and 47 with iron sufficiency (hemoglobin level > 12 gm/dl, transferrin saturation > 10%, ferritin level > 12 #g/ L). Baseline evaluation included parental occupation and educational attainment, and the Home Observation Mea- surement of the Environment (HOME) inventory. Intervention: Iron treatment consisted of 3 mg/kg per day elemental iron (as ferrous sulfate) for 4 months. Treatment and placebo syrups were administered by parents, and compliance was checked at weekly home visits by a nurse. Main outcome measure: The Bayley Mental and Motor development scales were administered 1 day before and im- mediately after the end of the intervention period by expe- rienced psychologists unaware of study group assignment. Analyses of changes in hemoglobin levels and of differences between iron-status groups were also undertaken. Results: Before treatment, the group with anemia had sig- nificantly lower developmental scores than either of the groups without anemia. There was significant improvement in mental and motor development scores after treatment versus placebo in the anemic group. No significant change in scores occurred in the nonanemic iron-deficient group or in the iron-sufficient group. Posttreatment scores in the group with anemia rose to the level of the groups without anemia. All analyses included mother's educational achieve- ment (highest grade completed) as a covariate. Iron status and hemoglobin level improved significantly in treated but not in placebo groups. Conclusions: Iron therapy improves the developmental scores of 12- to 18-month-old infants with mild (hemoglo- bin level, 8 to 10.5 gm/dl) iron-deficiency anemia to the level of those of iron-sufficient infants.

Commentary: Previous trials of iron supplementation have had varied results with regard to the effect on developmen- tal status. This carefully conducted trial demonstrates a significant effect on developmental scales for infants with mild to moderate iron-deficiency anemia. The authors spe- cifically assessed several variables relevant to studies of de- velopment: bias caused by systematic differences between the home environments of children with and those without iron deficiency; confounding because of maternal educa- tion; and differences in growth between children with and those without anemia. All these issues were also addressed by randomization. This study has implications not only for therapeutic intervention but also for causal inferences rel-