Resuscitation of very preterm infants with 30% vs. 50% oxygen: a randomized controlled trial
Background Preterm infants are susceptible to the damaging effects of hyperoxia which may lead to bronchopulmonary dysplasia (BPD) and intestinal damage. Hyperoxia also affects intestinal microbiota. The optimal initial FiO2 for the resuscitation of premature infants is unknown.
Objective To determine the effect of different initial oxygen concentrations on BPD, oxidative stress markers, damage to the gastrointestinal mucosa, and the intestinal microbiome.
Methods We conducted an unblinded, randomized controlled clinical trial in premature infants requiring supplemental oxygen in the first minutes of life. Infants started at an FiO2 of either 30% (low) or 50% (moderate), which was adjusted to achieve target oxygen saturations (SpO2) of 88-92% by 10 minutes of life using pulse oximetry. The primary outcome was incidence of BPD. Secondary outcomes included markers of oxidative stress [oxidized glutathione (GSH)/reduced glutathione (GSSG) ratio and malondialdehyde (MDA)], intestinal integrity indicated by fecal alpha-1 antitrypsin (AAT), and intestinal microbiota on fecal examination.
Results Eighty-four infants were recruited. There was no significant difference in rates of BPD between the 30% FiO2 and 50% FiO2 groups (42.8% vs. 40.5%, respectively). Nor were there significant differences in GSH/GSSG ratios, MDA concentrations, fecal AAT levels, or changes in facultative anaerobic and anaerobic microbiota between groups.
Conclusion In premature infants resuscitated using low vs. moderate initial FiO2 levels, we find no significant differences in BPD incidence, markers of oxidative stress, intestinal mucosa integrity, or intestinal microbiota.
2. Northway WH Jr, Rosan RC, Porter DY. Pulmonary disease following respirator therapy of hyaline-membrane disease. Bronchopulmonary dysplasia. N Engl J Med. 1967;276:357–68. DOI: 10.1056/NEJM196702162760701.
3. Campbell K. Retrolental fibroplasia. Med J Aust. 1971;2:282.
4. Tin W, Gupta S. Optimum oxygen therapy in preterm babies. Arch Dis Child Fetal Neonatal Ed. 2007;92:F143–7. DOI: 10.1136/adc.2005.092726.
5. Vento M, Moro M, Escrig R, Arruza L, Villar G, Izquierdo I, et al. Preterm resuscitation with low oxygen causes less oxidative stress, inflammation, and chronic lung disease. Pediatrics. 2009;124:e439–49. DOI:10.1542/peds.2009-0434.
6. Kapadia VS, Chalak LF, Sparks JE, Allen JR, Savani RC, Wyckoff MH. Resuscitation of preterm neonates with limited versus high oxygen strategy. Pediatrics. 2013;132:e1488–96. DOI:10.1542/peds.2013-0978.
7. Forman HJ, Fukuto JM, Miller T, Zhang H, Rinna A, Levy S. The chemistry of cell signaling by reactive oxygen species and nitrogen species and 4-hydroxynonenal. Arch Biochem Biophys. 2008;477:183–95. DOI: 10.1016/j.abb.2008.06.011.
8. Escobar J, Cernada M, Vento M. Oxygen and oxidative stress in the neonatal period. Neoreviews. 2011;12:e613–24. DOI:10.1542/neo.12-11-e613.
9. Perrone S, Tataranno ML, Negro S, Longini M, Marzocchi B, Proietti F, et al. Early identification of the risk for free radical-related diseases in preterm newborns. Early Hum Dev. 2010;86:241–4. DOI: 10.1016/j.earlhumdev.2010.03.008.
10. Friel JK, Friesen RW, Harding SV, Roberts LJ. Evidence of oxidative stress in full-term healthy infants. Pediatr Res. 2004;56:878–82. DOI: 10.1203/01.PDR.0000146032.98120.43.
11. Pitkanen OM, O’Brodovich HM. Significance of ion transport during lung development and in respiratory disease of the newborn. Ann Med. 1998;30:134–42. DOI: 10.3109/07853899808999396.
12. MacNee W. Oxidants/antioxidants and COPD. Chest. 2000;117:303–17. doi: 10.1378/chest.117.5_suppl_1.303s-a.
13. Wang CL, Anderson C, Leone TA, Rich W, Govindaswami B, Finer NN. Resuscitation of preterm neonates by using room air or 100% oxygen. Pediatrics. 2008;121:1083–9. DOI: 10.1542/peds.2007-1460.
14. Escrig R, Arruza L, Izquierdo I, Villar G, Saenz P, Gimeno A, et al. Achievement of targeted saturation values in extremely low gestational age neonates resuscitated with low or high oxygen concentration: a prospective, randomized trial. Pediatrics. 2008;121:875–81. DOI: 10.1542/peds.2007-1984.
15. Braamskamp MJ, Dolman KM, Tabbers MM. Clinical practice. Protein-losing enteropathy in children. Eur J Pediatr. 2010;169:1179–85. doi: 10.1007/s00431-010-1235-2.
16. Lisowska-Myjak B. AAT as a diagnostic tool. Clin Chim Acta. 2005;352:1–13. DOI: 10.1016/j.cccn.2004.03.012.
17. Carrel RW. Alpha 1-antitrypsin: molecular pathology, leukocytes, and tissue damage. J Clin Invest. 1986;78:1427–31. DOI: 10.1172/JCI112731.
18. Mitsuoka T, Kaneuchi C. Ecology of the bifidobacteria. Am J Clin Nutr. 1977;30:1799–810. DOI: 10.1093/ajcn/30.11.1799.
19. Balmer SE, Wharton BA. Diet and faecal flora in the newborn: breast milk and infant formula. Arch Dis Child. 1989;64:1672–77. DOI: 10.1136/adc.64.12.1672.
20. Berg RD. Bacterial translocation from the gastrointestinal tract. Trends Microbiol. 1995;3:149–54. DOI: 10.1016/s0966-842x(00)88906-4.
21. Ehrenkranz RA, Walsh MC, Vohr BR, Jobe AH, Wright LL, Fanaroff AA, et al. Validation of the National Institutes of Health consensus definition of bronchopulmonary dysplasia. Pediatrics. 2005;116:1353–60. DOI:10.1542/peds.2005-0249.
22. O’Donnell CP, Kamlin CO, Davis PG, Morley CJ. Obtaining pulse oximetry data in neonates: a randomised crossover study of sensor application techniques. Arch Dis Child Fetal Neonatal Ed. 2005;90:84–5. DOI: 10.1136/adc.2004.058925.
23. Perlman JM, Wyllie J, Kattwinkel J, Atkins DL, Chameides L, Goldsmith JP, et al. Part 11: neonatal resuscitation: 2010 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations. Circulation. 2010;122:S516–38. DOI: 10.1161/CIRCULATIONAHA.110.971127.
24. Repetto, M. , Semprine, J. , Boveris, A. . Lipid peroxidation: chemical mechanism, biological implications and analytical determination. In: Catala, A. , editor. Lipid peroxidation [Internet]. London: IntechOpen; 2012 [cited 2019 November]. Available from: https://www.intechopen.com/chapters/38477. DOI: 10.5772/45943.
25. Oxford Biomedical Research. Microplate assay for GSH/GSSG (reduced/oxidized glutathione) [Internet]. 2008 [cited 2019 November 13]. Available from: https://www.oxfordbiomed.com/sites/default/files/spec_sheet/GT40.pdf. p. 1–7.
26. Leone TA, Rich W, Finer NN. A survey of delivery room resuscitation practices in the United States. Pediatrics. 2006;117:164–75. DOI: 10.1542/peds.2005-0936
27. Jobe AH, Hillman N, Polglase G, Kramer BW, Kallapur SH, Pillow J. Injury and inflammation from resuscitation of the preterm infant. Neonatology. 2008;94:190–6. DOI: 10.1159/000143721
28. Lundstrom KE, Pryds O, Greisen G. Oxygen at birth and prolonged cerebral vasoconstriction in preterm infants. Arch Dis Child Fetal Neonatal Ed. 1995;73:F81–6. DOI: 10.1136/fn.73.2.f81
29. Rook D, Schierbeek H, van der Eijk AC, Longini M, Buonocore G, Vento M, et al. Resuscitation of very preterm infants with 30% vs. 65% oxygen at birth: study protocol for a randomized controlled trial. Trials. 2012;13:65. DOI: 10.1186/1745-6215-13-65
30. Rabi, Y, Singhal N, Nettel-Aguirre A. Room-air versus oxygen administration for resuscitation of preterm infants: the ROAR study. Pediatrics. 2011;128:e374–81. DOI: 10.1542/peds.2010-3130
31. Rook D, Schierbeek H, Vento M, Vlaardingerbroek H, Eijk AC, Longini M, et al. Less stress: oxidative stress and gluthatione kinetics in preterm infants. Rotterdam: Erasmus University Rotterdam; 2013. p. 62–73.
32. Buonocore G, Perrone S. Biomarkers of oxidative stress in the fetus and newborn. Haematol Rep. 2006;2:103–7.
33. Tangsilsat D, Atamasirikul K, Treepongkaruna S, Bed SN, Sumritsopak R, Kunakorn M. Fecal alpha1-antitrypsin in healthy and intestinal-disorder Thai children. J Med Assoc Thai. 2007;90:1317–22.
34. Oswari H, Prayitno L, Dwipoerwantoro PG, Firmansyah A, Makrides M, Lawley B, et al. Comparison of stool microbiota compositions, stool alpha1-antitrypsin and calprotectin concentrations, and diarrhoeal morbidity of Indonesian infants fed breast milk or probiotic/prebiotic-supplemented formula. J Paediatr Child Health. 2013;49:1032-9. DOI: 10.1111/jpc.12307.
35. Darani HY, Rahimian G, Nafisi M, Amini SA, Najafi A, Sarafpoor M. Unsuitability of fecal alpha 1-antitrypsin as a marker for differentiation of microbial and non-microbial diarrhea. Kuwait Med J. 2005; 37:91–3.
36. Penders J, Thijs C, Vink C, Stelma FF, Snijders B, Kummeling I, et al. Factors influencing the composition of the intestinal microbiota in early infancy. Pediatrics. 2006;118:511–21. DOI: 10.1542/peds.2005-2824.
37. Favier CF, Vaughan EE, De Vos WM, Akkermans AD. Molecular monitoring of succession of bacterial communities in human neonates. Appl Environ Microbiol. 2002;68:219–26. DOI: 10.1128/AEM.68.1.219-226.2002.
38. Millar MR, Linton CJ, Cade A, Glancy D, Hall M, Jalal H. Application of 16S rRNA gene PCR to study bowel flora of preterm infants with and without necrotizing enterocolitis. J Clin Microbiol. 1996;34:2506–10. DOI: 10.1128/jcm.34.10.2506-2510.1996.
39. Harris MC, D’Angio CT, Gallagher PR, Kaufman D, Evans J, Kilpatrick L. Cytokine elaboration in critically ill infants with bacterial sepsis, necrotizing entercolitis, or sepsis syndrome: correlation with clinical parameters of inflammation and mortality. J Pediatr. 2005;147:462–8. DOI: 10.1016/j.jpeds.2005.04.037
40. Harding D. Impact of common genetic variation on neonatal disease and outcome. Arch Dis Child Fetal Neonatal Ed. 2007;92:408–13. DOI: 10.1136/adc.2006.108670.
41. Gewolb IH, Schwalbe RS, Taciak VL, Harrison TS, Panigrahi P. Stool microflora in extremely low birthweight infants. Arch Dis Child Fetal Neonatal Ed. 1999;80:167–73. DOI: 10.1136/fn.80.3.f167
42. Rook GA, Brunet LR. Microbes, immunoregulation, and the gut. Gut. 2005;54:317–20. DOI: 10.1136/gut.2004.053785.
43. Huurre A, Kalliomäki M, Rautava S, Rinne M, Salminen S, Isolauri E. Mode of delivery-effects on gut microbiota and humoral immunity. Neonatology. 2008;93:236–40. DOI: 10.1159/000111102.
44. Matamoros S, Gras-Leguen C, Le Vacon F, Potel G, de La Cochetiere M-F. Development of intestinal microbiota in infants and its impact on health. Trends Microbiol. 2013;21:167–73. DOI: 10.1016/j.tim.2012.12.001.
45. Arboleya S, Binetti A, Salazar N, Fernandez N, Solis G, Hernandez-Barranco A, et al. Establishment and development of intestinal microbiota in preterm neonates. FEMS Microbiol Ecol. 2012;79:763–72. DOI: 10.1111/j.1574-6941.2011.01261.x
46. Division of Infectious Diseases, Department of Clinical Pathology Cipto Mangunkusumo General Hospital. Bacterial and antibiotics susceptibility profile at cipto mangunkusumo general hospital. Jakarta: Rumah Sakit Cipto Mangunkusumo (RSCM); 2015. p. 98–100.
47. Albenberg L, Esipova TV, Judge CP, Bittinger K, Chen J, Laughlin A, et al. Correlation between intraluminal oxygen gradient and radial partitioning of intestinal microbiota. Gastroenterology. 2014;147:1055–63. DOI: 10.1053/j.gastro.2014.07.020.
Copyright (c) 2022 Risma Karina Kaban
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
Authors who publish with this journal agree to the following terms:
Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution License that allows others to share the work with an acknowledgement of the work's authorship and initial publication in this journal.
Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgement of its initial publication in this journal.
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.