Inflammatory Mediators in Tracheal Aspirates of Preterm Infants Participating in a Randomized Trial of Permissive Hypercapnia

Sarah Gentner; Mandy Laube; Ulrike Uhlig; Yang Yang; Hans W Fuchs; Jens Dreyhaupt; Helmut D Hummler; Stefan Uhlig; Ulrich H Thome

doi:10.3389/fped.2017.00246

Inflammatory Mediators in Tracheal Aspirates of Preterm Infants Participating in a Randomized Trial of Permissive Hypercapnia

Front Pediatr. 2017 Nov 21:5:246. doi: 10.3389/fped.2017.00246. eCollection 2017.

Authors

Sarah Gentner¹, Mandy Laube², Ulrike Uhlig³, Yang Yang³, Hans W Fuchs⁴, Jens Dreyhaupt⁵, Helmut D Hummler⁶, Stefan Uhlig³, Ulrich H Thome²

Affiliations

¹ Division of Vascular Surgery, University of Ulm, Ulm, Germany.
² Center for Pediatric Research Leipzig, Hospital for Children and Adolescents, Division of Neonatology, University of Leipzig, Leipzig, Germany.
³ Institute of Pharmacology and Toxicology, RWTH Aachen University, Aachen, Germany.
⁴ Center for Pediatrics, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
⁵ Institute of Epidemiology and Medical Biometry, University of Ulm, Ulm, Germany.
⁶ Division of Neonatology and Pediatric Critical Care, Department of Pediatrics, University of Ulm, Ulm, Germany.

Abstract

Background: Ventilator-induced lung injury is considered to be a main factor in the pathogenesis of bronchopulmonary dysplasia (BPD). Optimizing ventilator strategies may reduce respiratory morbidities in preterm infants. Permissive hypercapnia has been suggested to attenuate lung injury. We aimed to determine if a higher PCO₂ target range results in less lung injury compared to the control target range and possibly reduces pro-inflammatory cytokines and acid sphingomyelinase (ASM) in tracheal aspirates (TA), which has not been addressed before.

Methods: During a multicenter trial of permissive hypercapnia in extremely low birthweight infants (PHELBI), preterm infants (birthweight 400-1,000 g, gestational age 23 0/7-28 6/7 weeks) requiring mechanical ventilation within 24 h of birth were randomly assigned to a high PCO₂ target or a control group. The high target group aimed at PCO₂ values of 55-65, 60-70, and 65-75 mmHg and the control group at PCO₂ values of 40-50, 45-55 and 50-60 mmHg on postnatal days 1-3, 4-6, and 7-14, respectively. TA was analyzed for pro-inflammatory cytokines from postnatal day 2-21. BPD was determined at a postmenstrual age of 36 weeks ± 2 days.

Main findings: Levels of inflammatory cytokines and ASM were similar in both groups: interleukin (IL)-6 (p = 0.14), IL-8 (p = 0.43), IL-10 (p = 0.24), IL-1β (p = 0.11), macrophage inflammatory protein 1α (p = 0.44), albumin (p = 0.41), neuropeptide Y (p = 0.52), leukotriene B₄ (p = 0.11), transforming growth factor-β₁ (p = 0.68), nitrite (p = 0.15), and ASM (p = 0.94). Furthermore, most inflammatory mediators were strongly affected by the age of the infants and increased from postnatal day 2 to 21. BPD or death was observed in 14 out of 62 infants, who were distributed evenly between both groups.

Conclusion: The results suggest that high PCO₂ target levels did not result in lower pulmonary inflammatory activity and thus reflect clinical results. This indicates that high PCO₂ target ranges are not effective in reducing ventilator-induced lung injury in preterm infants, as compared to control targets.

Trial registration: ISRCTN56143743.

Keywords: bronchopulmonary dysplasia; permissive hypercapnia; preterm infants; pulmonary inflammation; tracheal aspirates.