Hyperbaric oxygen therapy to prevent central airway stenosis after lung transplantation

Abstract

Background: Central airway stenosis (CAS) is a severe airway complication after lung transplantation associated with bronchial ischemia and necrosis. We sought to determine whether hyperbaric oxygen therapy (HBOT), an established treatment for tissue ischemia, attenuates post-transplant bronchial injury.

Methods: We performed a randomized, controlled trial comparing usual care with HBOT (2 atm absolute for 2 hours × 20 sessions) in subjects with extensive airway necrosis 4 weeks after transplantation. Endobronchial biopsies were collected at 4, 7, and 10 weeks after transplantation for a quantitative polymerase chain reaction. Coprimary outcomes were incidence of airway stenting and acute cellular rejection (ACR) at 1 year.

Results: The trial was stopped after enrolling 20 subjects (n = 10 per group) after a pre-planned interim analysis showed no difference between usual care and HBOT groups in stenting (both 40%), ACR (70% and 40%, respectively), or CAS (40% and 60%, respectively). Time to first stent placement (median [interquartile range]) was significantly shorter in the HBOT group (150 [73-150] vs 186 [167-206] days, p < 0.05). HIF gene expression was significantly increased in donor tissues at 4, 7, and 10 weeks after transplantation but was not altered by HBOT. Subjects who developed CAS or required stenting had significantly higher HMOX1 and VEGFA expression at 4 weeks (both p < 0.05). Subjects who developed ACR had significant FLT1, TIE2, and KDR expression at 4 weeks (all p < 0.05).

Conclusions: Incidence of CAS is high after severe, established airway necrosis after transplantation. HBOT does not reduce CAS severity or stenting. Elevated HMOX1 and VEGFA expressions appear to associate with airway complications.

Keywords: cell hypoxia/genetics; gene expression; hyperbaric oxygenation; lung transplantation; post-operative complications.

Published by Elsevier Inc.

Figures

Figure 1:. Clinical outcomes.

(A) Plaque scores (mean ± SD) over time for Usual care (open boxes) and HBOT (grey boxes) groups. (B) Time to first balloon airway dilation (median and IQR). (C) Time to first stent placement (median and IQR). *P

Figure 2:. Donor/native tissue gene expression ratios.

Bronchial mucosal gene expression shown as donor/native ratio (relative to 18S mRNA) at 4, 7, and 10 weeks post-transplant. *P

Figure 3:. Gene expression of subjects by group assignment (Usual Care vs. HBOT).

Bronchial mucosal gene expression shown as donor/native ratio (relative to 18S mRNA) in Usual Care (open boxes) and HBOT (grey boxes) groups for FLT1, HMOX1, KDR, TIE2, VEGFA, and TGFB1 at 4, 7, and 10 weeks post-transplant. Error bars are median with IQR.

Figure 4:. Gene expression of subjects by Central Airway Stenosis status.

Bronchial mucosal gene expression shown as donor/native ratio (relative to 18S mRNA) in subjects without central airway stenosis (open circles) and with central airway stenosis (green circles) for FLT1, HMOX1, KDR, TIE2, VEGFA, and TGFB1 at 4, 7, and 10 weeks post-transplant. Error bars are median with IQR. *P<0.05 for group differences within each time point by 2-way ANOVA with the Benjamin-Hochberg post-hoc test.

Figure 5:. Gene expression of subjects by Airway Stent status.

Bronchial mucosal gene expression shown as donor/native ratio (relative to 18S mRNA) in subjects without airway stents (open circles) and with airway stents (blue circles) for FLT1, HMOX1, KDR, TIE2, VEGFA, and TGFB1 at 4, 7, and 10 weeks post-transplant. Error bars are median with IQR. *P<0.05 for group differences within each time point by 2-way ANOVA with the Benjamin-Hochberg post-hoc test.

Figure 6:. Gene expression of subjects by Acute Cellular Rejection status.

Bronchial mucosal gene expression shown as donor/native ratio (relative to 18S mRNA) in subjects without ACR (open circles) and with ACR (red circles) for FLT1, HMOX1, KDR, TIE2, VEGFA, and TGFB1 at 4, 7, and 10 weeks post-transplant. Error bars are median with IQR. *P<0.05 for group differences within each time point by 2-way ANOVA with the Benjamin-Hochberg post-hoc test.