1. Precursor Preference in Surfactant Synthesis of Newborns Sarah Frankel, PhD Human Studies Committee Washington University School of Medicine

2. Inclusion Criteria Controls –Full term infants with “normal lungs” that are viable –Are in the NICU –Require mechanical ventilation for breathing difficulties caused by illness other than lung disease Infants with lung disease –28 weeks or less at birth –Up to 6 weeks old after birth

3. Exclusion Criteria Infants for whom death is imminent –Non-viable infants Those with known infections Infants with congenital anomalies and pulmonary hemorrhage

4. Rationale for Inclusion/Exclusion Criteria Preliminary data indicates that kinetic parameters of surfactant metabolism evolve with infants age To determine impact of age vs. worsening chronic lung disease need to study surfactant metabolism in infants without lung disease

5. Research Procedures 24 hour continuous infusion of non- radioactive stable isotopes [1- 13 C 1 ] acetate and [1,2,3,4 – 13 C 4 ] palmitate.

6. Research Procedures 2.5 ml blood draw done in 5 - 0.5 ml increments over the first 27 hours in addition to routine blood draws needed for treatment of the infant’s illness –Indwelling catheter exists Blood draws will be done through the catheter –Indwelling catheter does not exist 2-3 blood draws occur at clinically indicated times

7. Clinical Procedures Used Tracheal aspirates –Obtained with routine airway suctioning over the next 14 days or as long as infant is intubated Blood samples –Drawn before the infusion begins at selected intervals over the next 2 weeks Amount of blood drawn dependent on treatment for illness

8. Research Risks Rarely: blood stream infection –Isotope infusions are prepared in sterile fashion by pharmacists –Rate of blood stream infection to be monitored by the Data Monitoring Committee for the study

9. Clinical Risks Likely: the need for a blood transfusion –Dependent on the infant’s illness

10. Benefits Develop a better understanding of how surfactant is made and used in premature infants –No direct benefits to the infants

11. Expedited Category 2 Collection of blood samples by finger stick, heel stick, ear stick, or venipuncture as follows: a)from healthy, nonpregnant adults who weigh at least 110 pounds. For these subjects, the amounts drawn may not exceed 550 ml in an 8 week period and collection may not occur more frequently than 2 times per week; or b) from other adults and children considering the age, weight, and health of the subjects, the collection procedure, the amount of blood to be collected, and the frequency with which it will be collected. For these subjects, the amount drawn may not exceed the lesser of 50 ml or 3 ml per kg in an 8 week period and collection may not occur more frequently than 2 times per week.

12. Minimal Risk Collections Expedited Category 2 –Does not include or exclude collections through a catheter –Specifies 2 times per week for collections through finger stick, heel stick, ear stick, or venipuncture Can more collections done if using a catheter? Will the study still qualify as minimal risk?

13. 45 CFR 46 Risk Classifications 46.404 Minimal Risk –“The probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or the performance of routine physical or psychological examinations or tests.” – The study has: 5 blood draws in a 27 hour period Rare risk of bloodstream infections Therefore this study does not fit 46.404.

14. 45 CFR 46 Risk Classifications 46.405: Greater than Minimal and it presents the prospect of direct benefit to the participant –The benefits of this study are stated as: To develop a better understanding of how surfactant is made and used in premature infants. There is no direct benefit to the participant. Therefore this study does not fit 46.405.

15. 45 CFR 46 Risk Classifications 46.406: Greater than minimal with no direct benefit to the minors but it is likely to yield generalizable knowledge about the subject’s disorder or condition. –This study includes control infants in the NICU for illnesses not related to lung disease. The control group does have a “disorder or condition” but the information obtained would not yield generalizable knowledge about the control groups’ disorder or condition. The control group would not necessarily have stable isotopes infused or additional blood draws as part of their routine care. Therefore this study does not fit 46.406.

16. 45 CFR 46 Risk Classifications 46.407: Uses healthy minors and is greater than minimal risk –The study uses: Infants with normal lungs that are considered “healthy” for this study. Infusion of isotopes and 5 blood draws in 27 hours that is considered greater than minimal risk.

17. Conclusions The control group is not really “healthy.” Indirectly, the information obtained could provide information on surfactant that would eventually benefit any infant that has a breathing disorder. But, the committee feels that this is not in the spirit of 46.406. Therefore, the control group does not really fit any category of risk for minors. And, the committee concluded that this study should most appropriately be classified as 46.407.