Surf Beyond Rds


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Surf Beyond Rds

  1. 1. Surfactant Replacement Therapy: Beyond RDS Steven M. Donn, MD, FAAP Professor of Pediatrics Chief, Neonatal-Perinatal Medicine C.S. Mott Children’s Hospital University of Michigan Health System
  2. 2. Pulmonary Surfactant <ul><li>Multicomponent complex of several phospholipids, neutral lipids, and associated proteins </li></ul><ul><li>Synthesized and secreted by Type II epithelial cells within the lung </li></ul><ul><li>Reduces collapsing force in the alveolus, conferring stability and maintaining alveolar surface free of liquid </li></ul>
  3. 3. Efficacy of Surfactant Therapy <ul><li>Demonstrated for both prophylaxis (within first few minutes of life) and rescue (after 2 hrs. and with signs of respiratory failure) </li></ul><ul><li>>40 trials and 20,000 enrolled infants </li></ul><ul><li>40% reduction in odds of neonatal death </li></ul><ul><li>35-50% reduction in air leak </li></ul>
  4. 4. Other Neonatal Disorders with Surfactant Lack or Dysfunction <ul><li>Term infants with respiratory failure </li></ul><ul><li>Meconium aspiration syndrome </li></ul><ul><li>Pulmonary hemorrhage </li></ul><ul><li>Pneumonia </li></ul><ul><li>Congenital diaphragmatic hernia </li></ul><ul><li>Early bronchopulmonary dysplasia </li></ul>
  5. 5. Other Pediatric Disorders with Surfactant Lack or Dysfunction <ul><li>Bronchiolitis </li></ul><ul><li>ARDS </li></ul><ul><li>Cystic Fibrosis </li></ul><ul><li>Asthma </li></ul><ul><li>Chronic bronchitis </li></ul><ul><li>Otitis media </li></ul>
  6. 6. Surfactant and MAS
  7. 7. Surfactant Inhibitors in MAS <ul><li>Among infants with MAS, concentrations in lung fluid of total protein, albumin, and membrane-derived phospholipid are elevated </li></ul><ul><li>Infants with MAS frequently have hemorrhagic pulmonary edema </li></ul><ul><li>Surfactant therapy may mitigate these findings </li></ul>*Dargaville PA, et al. J Pediatr 2001;138:113-115
  8. 8. Alveolus Dilute Surfactant Dilute Surfactant Lavage
  9. 9. Surfactant and MAS <ul><li>Cochrane Review: </li></ul><ul><ul><li>Mortality: no significant effect </li></ul></ul><ul><ul><li>Pneumothorax/PIE: no significant effect </li></ul></ul><ul><ul><li>Duration of PPV: no significant effect </li></ul></ul><ul><ul><li>Supplemental oxygen at D/C: no sig. effect </li></ul></ul><ul><ul><li>Chronic lung disease: no sig. effect </li></ul></ul><ul><ul><li>Need for ECMO: RR 0.64 (surfactant) </li></ul></ul><ul><ul><li>Hospitalization: mean decrease of 8 days (surfactant) </li></ul></ul>El Shahed, Dargaville, Ohlsson, Soll
  10. 10. But…what about LAVAGE? Lavage: [French, from the Latin lavo, to wash]. The washing out of a hollow cavity or organ by copious injections and rejections of fluid. Portique de lavage
  11. 11. Surfaxin ® Lavage Trial <ul><li>Pilot trial of 22 infants with MAS </li></ul><ul><li>15 treated by lavage, 7 controls (SOC) </li></ul><ul><li>MAS, mechanical vent., OI 8-25 </li></ul><ul><li>Lavage procedure: 8 mL/kg dilute Surfaxin per lung X2, then third lavage with concentrated Surfaxin </li></ul>Wiswell TE. Knight GR, Finer NN, Donn SM, et al. Pediatrics 2002;109:1081 Lucinactant (Surfaxin®) is an investigational product not approved by the US Food and Drug Administration .
  12. 12. *Wiswell TE, et al. Pediatrics 2002;109:1081-1087. Instill Surfaxin ®
  13. 15. Conclusions <ul><li>Trends toward faster weaning from mechanical ventilation (6.3 v. 9.9 days) </li></ul><ul><li>More rapid decline in OI </li></ul><ul><li>Safe </li></ul><ul><li>Well tolerated </li></ul>
  14. 16. … but we can deal with it!
  15. 17. Bronchopulmonary Dysplasia <ul><li>Affects 30-40% of infants <1500g </li></ul><ul><li>May result in severe respiratory compromise and growth and development </li></ul><ul><li>Some evidence for surfactant inadequacy during recovery phase of RDS </li></ul>
  16. 18. Carl Bose and Matthew Laughon University of North Carolina, Chapel Hill, NC Fernando R. Moya New Hanover Regional Medical Center, Wilmington, NC Judy L. Aschner Vanderbilt University Medical Center, Nashville, TN Steven M. Donn University of Michigan Health System, Ann Arbor, MI Robert Segal, Carlos Guardia, and Genzhou Liu Discovery Laboratories, Inc., Warrington, PA for the Surfaxin ® BPD Study Group Late Treatment with a Synthetic Surfactant for the Prevention of Bronchopulmonary Dysplasia * Lucinactant (Surfaxin®) is an investigational product not approved by the US FDA.
  17. 19. Disclosure <ul><li>This study was funded by Discovery Laboratories. </li></ul><ul><li>Personnel employed by Discovery were directly responsible for: </li></ul><ul><ul><li>Protocol development </li></ul></ul><ul><ul><li>Data management </li></ul></ul><ul><ul><li>Statistical analysis </li></ul></ul><ul><li>Authors not employed by Discovery were compensated for their efforts and were responsible for: </li></ul><ul><ul><li>Advice regarding protocol development </li></ul></ul><ul><ul><li>Interpretation of results and preparation of presentation </li></ul></ul>
  18. 20. Background <ul><li>Bronchopulmonary dysplasia (BPD) is the most frequent serious complication of preterm birth. </li></ul><ul><li>Preterm infants requiring prolonged ventilation have surfactant dysfunction, presumably as a result of </li></ul><ul><ul><ul><li>lung inflammation </li></ul></ul></ul><ul><ul><ul><li>protein leak into air spaces </li></ul></ul></ul><ul><li>Short-term improvement in lung function has been reported after surfactant administration in chronically ventilated infants. </li></ul>
  19. 21. Risk for BPD Relative to Oxygen Therapy From Laughon et al. PAS abstract # 7935.9, 2007
  20. 22. Objective <ul><li>The purpose of this study was to estimate the effect of the administration of lucinactant after the first two days of life to extremely preterm infants at risk for developing BPD. </li></ul><ul><li>We hypothesized that this treatment would reduce the incidence of death or BPD. </li></ul>
  21. 23. Methods <ul><li>Masked, multi-center, randomized, controlled trial </li></ul><ul><li>Inclusion Criteria </li></ul><ul><ul><li>Birth weight 600-900 grams </li></ul></ul><ul><ul><li>3-10 days of age </li></ul></ul><ul><ul><li>Mechanical ventilation and FiO 2 ≥ 0.3 </li></ul></ul><ul><ul><li>Early surfactant therapy, if indicated </li></ul></ul>
  22. 24. <ul><li>Exclusion Criteria </li></ul><ul><ul><li>Severe lung disease (FiO 2 > 0.8 and mean P aw > 12 cm H 2 O) </li></ul></ul><ul><ul><li>Prolonged rupture of membranes </li></ul></ul><ul><ul><li>Culture proven sepsis </li></ul></ul><ul><ul><li>Severe IVH </li></ul></ul><ul><ul><li>Major congenital anomalies </li></ul></ul><ul><ul><li>Prior treatment with iNO or steroids </li></ul></ul>Methods
  23. 25. Derivation of Patient Population
  24. 26. Methods <ul><li>Stratified by center </li></ul><ul><li>Randomized to three groups: </li></ul><ul><ul><ul><li>Lucinactant 175 mg TPL/kg BW (S-175) </li></ul></ul></ul><ul><ul><ul><li>(standard dose) </li></ul></ul></ul><ul><ul><ul><li>Lucinactant 90 mg TPL/kg BW (S-90) </li></ul></ul></ul><ul><ul><ul><li>Placebo (sham air) </li></ul></ul></ul><ul><li>Up to 5 doses at 48 hour intervals </li></ul><ul><li>No treatment after 18 days of age </li></ul>
  25. 27. Surfactant Preparation Lucinactant* <ul><li>Phospholipids (30 mg/mL) </li></ul><ul><ul><li>- Dipalmitoylphosphatidylcholine </li></ul></ul><ul><ul><li>(22.5 mg/mL) </li></ul></ul><ul><ul><li>- Palmitoyl-oleoyl phosphatidylglycerol </li></ul></ul><ul><ul><li>(7.5 mg/mL) </li></ul></ul><ul><li>KL 4 peptide– 21 AA synthetic peptide </li></ul>
  26. 28. Results <ul><li>136 infants enrolled from 12/2004 to 6/2006 </li></ul><ul><li>34 centers </li></ul><ul><ul><li>19 in the United States </li></ul></ul><ul><ul><li>5 in Chile </li></ul></ul><ul><ul><li>7 in Poland </li></ul></ul><ul><ul><li>3 in Hungary </li></ul></ul>
  27. 29. Patient Characteristics by Group Characteristic S-90 S-175 Placebo Number 47 45 44 GA (wks; median) 25 26 26 BW (g; mean) 734 773 753 Gender (% male) 64* 53 39 Race (% white) 64 80 70 FiO 2 at entry (median) 0.35 0.35 0.36 * p =0.016 vs. placebo
  28. 30. Supplemental Oxygen Requirement First Dose
  29. 31. Peri-dosing Events DOSE 1 S-90 S-175 Placebo Dose interruption (%) 13 20 0 Desaturation* (%) 60 51 9 Bradycardia** (%) 21 13 0 * Desaturation = SaO 2 < 75% for more than 30 seconds **Bradycardia = HR < 100 bpm for more than 30 seconds
  30. 32. Outcomes of Interest S-90 S-175 Placebo BPD (%) 49 47 50 (O 2 at 36 wks PMA) Death (%) 30 11 16 Death or BPD (%) 79 58 66
  31. 33. 4.9 4.3 1.7 1.8 0.8 0.5 0.3 0.3 1.9 1.5 0.7 0.7 0.1 1.0 10 S-90 vs. Placebo Unadjusted Adjusted* Odds Ratio Unadjusted Adjusted* S-175 vs. Placebo Odds Ratios for Death or BPD * adjusted for gestational age, birth weight, and gender
  32. 34. Number of Doses by Group S-90 S-175 Placebo 1 dose (%) 100 100 100 2 doses (%) 87 89 89 3 doses (%) 72 73 77 4 doses (%) 60 60 66 5 doses (%) 55 44 66
  33. 35. Secondary Outcomes <ul><li>No differences between either lucinactant treated group and placebo group in the incidences of: </li></ul><ul><ul><ul><ul><li>Air leak </li></ul></ul></ul></ul><ul><ul><ul><ul><li>IVH </li></ul></ul></ul></ul><ul><ul><ul><ul><li>PVL </li></ul></ul></ul></ul><ul><ul><ul><ul><li>NEC </li></ul></ul></ul></ul><ul><ul><ul><ul><li>ROP </li></ul></ul></ul></ul>
  34. 36. Conclusions <ul><li>Treatment of infants at risk for BPD beginning after the first two days of life with a synthetic, peptide-containing surfactant : </li></ul><ul><ul><li>Appears to reduce supplemental oxygen requirement for up to 48 hours after dosing </li></ul></ul><ul><ul><li>May reduce death or BPD among infants receiving 175 mg/kg TPL per dose </li></ul></ul><ul><li>These results justify a larger RCT to test efficacy. </li></ul>
  35. 37. Other Surfactant Ideas <ul><li>Mix surfactant with non-ionic polymers (PEG, dextran) to reduce inactivation </li></ul><ul><li>Mix surfactant with perfluorochemicals </li></ul><ul><li>Use phospholipid analogues that improve reduction of surface tension and are more resistant to degradation </li></ul><ul><li>SP-A and SP-D analogues </li></ul><ul><li>Add to exogenous surfactants: 1) anti- inflammatory agents; 2) anti-proteases, and/or 3) anti-oxidants </li></ul>
  36. 38. <ul><li>Polymyxin B sulfate is produced by the growth of Bacillus polymyxa </li></ul><ul><li>It is a cyclic decapeptide </li></ul><ul><li>Polymyxin B cross-links lipid vesicles in a manner similar to SP-B, although it is structurally unrelated to SP-B </li></ul><ul><li>It exhibits in vitro surface activity similar to SP-B </li></ul><ul><li>This suggests an avenue for identification of other SP-B analogues </li></ul>
  37. 39. Other Potential Uses of Surfactant <ul><li>Surfactant could be a delivery vehicle for various medications: </li></ul><ul><ul><li>Antimicrobials </li></ul></ul><ul><ul><li>Chemotherapy </li></ul></ul><ul><ul><li>Vasodilators </li></ul></ul><ul><ul><li>Bronchodilators </li></ul></ul>
  38. 40. <ul><li>Bolus into lungs via an ETT </li></ul><ul><li>Bolus into the nasopharynx </li></ul><ul><li>Slow infusion </li></ul><ul><li>Aerosolized </li></ul><ul><li>Lavage </li></ul>Optimal Method of Administration May Differ for Each Application
  39. 41. Got Surfactant!