Intensive Care Medicine

, Volume 37, Issue 3, pp 510–517 | Cite as

Pharmacokinetics and clinical predictors of surfactant redosing in respiratory distress syndrome

  • Paola E. CogoEmail author
  • Maddalena Facco
  • Manuela Simonato
  • Daniele De Luca
  • Francesca De Terlizi
  • Umberto Rizzotti
  • Giovanna Verlato
  • Maria Paola Bellagamba
  • Virgilio P. Carnielli
Pediatric Original



Limited data are available on predictors for surfactant retreatment in preterm infants with respiratory distress syndrome (RDS).


To study the pharmacokinetics of exogenous surfactant and the clinical parameters associated with surfactant redosing.


Exogenous surfactant pharmacokinetics was studied in 125 preterm infants (birth weight 997 ± 432 g; gestational age 28.0 ± 2.6 weeks) with moderate to severe RDS requiring mechanical ventilation. Clinical and respiratory parameters were recorded hourly, and surfactant disaturated-phosphatidylcholine (DSPC) half-life, pool size, and endogenous synthesis were calculated by stable isotope tracing of surfactant DSPC isolated from serial tracheal aspirates. Univariate and multiple logistic regression were used to study the effects of clinical and surfactant kinetic variables on the need for redosing.


Fifty-three infants (42.4%) received one dose, 51 (40.8%) two doses, and 21 (16.8%) three doses. Median (interquartile range, IQR) DSPC half-life was 21 (13–39), 11 (7–17), and 10 (7–16) h after the first, second, and third dose, respectively (p = 0.07). Univariate analysis showed a significantly shorter DSPC half-life in infants requiring more surfactant doses. On logistic analysis, risk of redosing was higher with lower birth weight, worse radiological score, shorter DSPC half-life, and surfactant dose of 100 mg/kg, whilst it was lower with elective high-frequency ventilation at time of intubation, instead of conventional ventilation.


When optimizing surfactant replacement therapy and its cost–benefit ratio, pharmacokinetics and clinical variables associated with need of redosing should be taken into account.


Pulmonary surfactant Isotopes Low-birth-weight infants Respiratory distress syndrome 



We thank all the nurses of the two neonatal intensive care units for their valuable contribution to the collection of the tracheal samples. The study was supported by a grant of the University of Padova, Italy on the “surfactant kinetics in humans with severe respiratory failure measured by stable isotopes.” Virgilio P. Carnielli has received a fee for speaking for an educational event sponsored by Dey Laboratories, Napa, CA, USA, and has received research grants from Chiesi Pharmaceuticals, Parma, Italy. All other authors declare no potential conflicts of interest with this work.

Supplementary material

134_2010_2091_MOESM1_ESM.doc (114 kb)
Supplementary material 1 (DOC 114 kb)


  1. 1.
    Engle WA (2008) Surfactant-replacement therapy for respiratory distress in the preterm and term neonate. Pediatrics 121:419–432CrossRefPubMedGoogle Scholar
  2. 2.
    Robertson B, Halliday HL (1998) Principles of surfactant replacement. Biochim Biophys Acta 1408:346–361PubMedGoogle Scholar
  3. 3.
    Dijk PH, Heikamp A, Oetomo SB (1998) Surfactant nebulization versus instillation during high frequency ventilation in surfactant-deficient rabbits. Pediatr Res 44:699–704CrossRefPubMedGoogle Scholar
  4. 4.
    Cogo PE, Facco M, Simonato M, Verlato G, Rondina C, Baritussio A, Toffolo GM, Carnielli VP (2009) Dosing of porcine surfactant: effect on kinetics and gas exchange in respiratory distress syndrome. Pediatrics 124:e950–e957CrossRefPubMedGoogle Scholar
  5. 5.
    Bjorklund LJ, Ingimarsson J, Curstedt T, John J, Robertson B, Werner O, Vilstrup CT (1997) Manual ventilation with a few large breaths at birth compromises the therapeutic effect of subsequent surfactant replacement in immature lambs. Pediatr Res 42:348–355CrossRefPubMedGoogle Scholar
  6. 6.
    Corbet A, Gerdes J, Long W, Avila E, Puri A, Rosenberg A, Edwards K, Cook L (1995) Double-blind, randomized trial of one versus three prophylactic doses of synthetic surfactant in 826 neonates weighing 700 to 1100 grams: effects on mortality rate. American exosurf neonatal study groups i and iia. J Pediatr 126:969–978CrossRefPubMedGoogle Scholar
  7. 7.
    Liechty EA, Donovan E, Purohit D et al (1991) Reduction of neonatal mortality after multiple doses of bovine surfactant in low birth weight neonates with respiratory distress syndrome. Pediatrics 88:19–28PubMedGoogle Scholar
  8. 8.
    Hoekstra RE, Jackson JC, Myers TF et al (1991) Improved neonatal survival following multiple doses of bovine surfactant in very premature neonates at risk for respiratory distress syndrome. Pediatrics 88:10–18PubMedGoogle Scholar
  9. 9.
    Dunn MS, Shennan AT, Possmayer F (1990) Single-versus multiple-dose surfactant replacement therapy in neonates of 30–36 weeks’ gestation with respiratory distress syndrome. Pediatrics 86:564–571PubMedGoogle Scholar
  10. 10.
    Speer CP, Robertson B, Curstedt T et al (1992) Randomized european multicenter trial of surfactant replacement therapy for severe neonatal respiratory distress syndrome: single versus multiple doses of curosurf. Pediatrics 89:13–20PubMedGoogle Scholar
  11. 11.
    Kattwinkel J, Bloom BT, Delmore P, Glick C, Brown D, Lopez S, Willett L, Egan EA, Conaway M, Patrie J (2000) High-versus low-threshold surfactant retreatment for neonatal respiratory distress syndrome. Pediatrics 106:282–288CrossRefPubMedGoogle Scholar
  12. 12.
    Soll RF (2000) Multiple versus single dose natural surfactant extract for severe neonatal respiratory distress syndrome. Cochrane Database Syst Rev CD000141Google Scholar
  13. 13.
    Soll R, Ozek E (2009) Multiple versus single doses of exogenous surfactant for the prevention or treatment of neonatal respiratory distress syndrome. Cochrane Database Syst Rev CD000141Google Scholar
  14. 14.
    Sweet D, Bevilacqua G, Carnielli V, Greisen G, Plavka R, Didrik Saugstad O, Simeoni U, Speer CP, Valls ISA, Halliday H, Working Group on Prematurity of the World Association of Perinatal M, European Association of Perinatal M (2007) European consensus guidelines on the management of neonatal respiratory distress syndrome. J Perinat Med 35:175–186CrossRefPubMedGoogle Scholar
  15. 15.
    Cogo PE, Simonato M, Toffolo GM, Stefanutti G, Chierici M, Cobelli C, Ori C, Carnielli VP (2008) Dexamethasone therapy in preterm infants developing bronchopulmonary dysplasia: effect on pulmonary surfactant disaturated-phosphatidylcholine kinetics. Pediatr Res 63:433–437CrossRefPubMedGoogle Scholar
  16. 16.
    Cogo PE, Toffolo GM, Gucciardi A, Benetazzo A, Cobelli C, Carnielli VP (2005) Surfactant disaturated phosphatidylcholine kinetics in infants with bronchopulmonary dysplasia measured with stable isotopes and a two-compartment model. J Appl Physiol 99:323–329CrossRefPubMedGoogle Scholar
  17. 17.
    Torresin M, Zimmermann LJ, Cogo PE, Cavicchioli P, Badon T, Giordano G, Zacchello F, Sauer PJ, Carnielli VP (2000) Exogenous surfactant kinetics in infant respiratory distress syndrome: a novel method with stable isotopes. Am J Respir Crit Care Med 161:1584–1589PubMedGoogle Scholar
  18. 18.
    Thome U, Topfer A, Schaller P, Pohlandt F (1998) Comparison of lung volume measurements by antero-posterior chest X-ray and the sf6 washout technique in mechanically ventilated infants. Pediatr Pulmonol 26:265–272CrossRefPubMedGoogle Scholar
  19. 19.
    Plavka R, Kopecky P, Sebron V, Svihovec P, Zlatohlavkova B, Janus V (1999) A prospective randomized comparison of conventional mechanical ventilation and very early high frequency oscillatory ventilation in extremely premature newborns with respiratory distress syndrome. Intensive Care Med 25:68–75CrossRefPubMedGoogle Scholar
  20. 20.
    Pandit PB, Dunn MS, Kelly EN, Perlman M (1995) Surfactant replacement in neonates with early chronic lung disease. Pediatrics 95:851–854PubMedGoogle Scholar
  21. 21.
    Laughon M, Bose C, Moya F, Aschner J, Donn SM, Morabito C, Cummings JJ, Segal R, Guardia C, Liu G (2009) A pilot randomized, controlled trial of later treatment with a peptide-containing, synthetic surfactant for the prevention of bronchopulmonary dysplasia. Pediatrics 123:89–96CrossRefPubMedGoogle Scholar
  22. 22.
    Sandri F, Plavka R, Simeoni U (2008) The curpap study: an international randomized controlled trial to evaluate the efficacy of combining prophylactic surfactant and early nasal continuous positive airway pressure in very preterm infants. Neonatology 94:60–62CrossRefPubMedGoogle Scholar
  23. 23.
    Morley CJ, Davis PG, Doyle LW, Brion LP, Hascoet JM, Carlin JB (2008) Nasal cpap or intubation at birth for very preterm infants. N Engl J Med 358:700–708CrossRefPubMedGoogle Scholar
  24. 24.
    Walti H, Paris-Llado J, Breart G, Couchard M (1995) Porcine surfactant replacement therapy in newborns of 25–31 weeks’ gestation: a randomized, multicentre trial of prophylaxis versus rescue with multiple low doses. The French collaborative multicentre study group. Acta Paediatr 84:913–921CrossRefPubMedGoogle Scholar
  25. 25.
    Moriette G, Paris-Llado J, Walti H, Escande B, Magny JF, Cambonie G, Thiriez G, Cantagrel S, Lacaze-Masmonteil T, Storme L, Blanc T, Liet JM, Andre C, Salanave B, Breart G (2001) Prospective randomized multicenter comparison of high-frequency oscillatory ventilation and conventional ventilation in preterm infants of less than 30 weeks with respiratory distress syndrome. Pediatrics 107:363–372CrossRefPubMedGoogle Scholar
  26. 26.
    Rimensberger PC, Beghetti M, Hanquinet S, Berner M (2000) First intention high-frequency oscillation with early lung volume optimization improves pulmonary outcome in very low birth weight infants with respiratory distress syndrome. Pediatrics 105:1202–1208CrossRefPubMedGoogle Scholar
  27. 27.
    Bollen CW, Uiterwaal CS, van Vught AJ (2007) Meta-regression analysis of high-frequency ventilation vs conventional ventilation in infant respiratory distress syndrome. Intensive Care Med 33:680–688CrossRefPubMedGoogle Scholar
  28. 28.
    De Jaegere A, van Veenendaal MB, Michiels A, van Kaam AH (2006) Lung recruitment using oxygenation during open lung high-frequency ventilation in preterm infants. Am J Respir Crit Care Med 174:639–645CrossRefPubMedGoogle Scholar
  29. 29.
    Cools F, Askie LM, Offringa M et al (2010) Elective high-frequency oscillatory versus conventional ventilation in preterm infants: a systematic review and meta-analysis of individual patients’ data. Lancet 375:2082–2091CrossRefPubMedGoogle Scholar
  30. 30.
    Cogo PE, Zimmermann LJ, Meneghini L, Mainini N, Bordignon L, Suma V, Buffo M, Carnielli VP (2003) Pulmonary surfactant disaturated-phosphatidylcholine (DSPC) turnover and pool size in newborn infants with congenital diaphragmatic hernia (CDH). Pediatr Res 54:653–658CrossRefPubMedGoogle Scholar
  31. 31.
    Cogo PE, Ori C, Simonato M, Verlato G, Isak I, Hamvas A, Carnielli VP (2009) Metabolic precursors of surfactant disaturated-phosphatidylcholine in preterms with respiratory distress. J Lipid Res 50:2324–2331CrossRefPubMedGoogle Scholar
  32. 32.
    Verlato G, Cogo PE, Balzani M, Gucciardi A, Burattini I, De Benedictis F, Martiri G, Carnielli VP (2008) Surfactant status in preterm neonates recovering from respiratory distress syndrome. Pediatrics 122:102–108CrossRefPubMedGoogle Scholar

Copyright information

© Copyright jointly held by Springer and ESICM 2010

Authors and Affiliations

  • Paola E. Cogo
    • 1
    Email author
  • Maddalena Facco
    • 1
  • Manuela Simonato
    • 1
  • Daniele De Luca
    • 2
  • Francesca De Terlizi
    • 3
  • Umberto Rizzotti
    • 4
  • Giovanna Verlato
    • 1
  • Maria Paola Bellagamba
    • 2
  • Virgilio P. Carnielli
    • 2
  1. 1.Department of PaediatricsUniversity of PadovaPadovaItaly
  2. 2.Division of Neonatology, Institute of Clinical SciencesPolytechnic University of Marche and Azienda Ospedaliera Universitaria Ospedali Riuniti AnconaAnconaItaly
  3. 3.Igea Scientific DepartmentModenaItaly
  4. 4.Preformulation and DevelopmentVelferd srlPeschiera del GardaItaly

Personalised recommendations