Hyperbaric oxygen therapy to prevent central airway stenosis after lung transplantation

https://doi.org/10.1016/j.healun.2021.01.008Get rights and content

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.

Section snippets

Subject selection

The study protocol was approved by the Duke Institutional Review Board (Pro00055849) and posted on www.clintrials.gov (NCT02363959). All subjects provided written informed consent before study procedures. Subjects were eligible for the study if they had developed extensive (Stage 3–4) (refer to Supplementary Table S1 available online at www.jhltonline.org) post-transplant airway necrosis10 after lung transplantation that did not spontaneously resolve after 2 to 3 weeks. Subjects were excluded

Results

A total of 20 subjects (11 males, 9 females) who were transplanted in the previous 4.6 (4–5.6) weeks were enrolled and randomized to either usual care (n = 10) or HBOT (n = 10). Age and sex distributions were comparable between the groups: 54.5 (36–65) vs 59.7 (41–62) years and 50% vs 40% female, respectively. Individual subject characteristics are shown in Table 1. A total of 2 subjects were screened but not randomized owing to transplant-related complications developed before study activities

Discussion

We report a randomized, controlled trial comparing HBOT with usual care in treating established airway necrosis after lung transplantation. Although many clinical factors are known to contribute to ischemic airway complications, such as hypotension, prolonged mechanical ventilation, infection, primary graft dysfunction, and ACR,1,2,6,22, 23, 24 our hypothesis was that HBOT might improve donor bronchial mucosal healing and reduce the incidence of CAS and the need for stenting. However, the study

Disclosure statement

B.D.K. reports funding from the National Institutes of Health/National Heart, Lung, and Blood Institute (K08HL130557). The remaining authors have no conflicts of interest to disclose.

The authors thank the chamber operators, nurses, and physicians at the Duke Center for Hyperbaric Medicine and Environmental Physiology (Durham, NC) for assistance with this study and thank the Duke Lung Transplant clinical coordinators and patient care providers.

The study was funded by Duke Pulmonary Divisional

Authors contributions

All authors approved the draft and overall research plan of the manuscript. All authors are accountable for the submitted work.

Concept and design: S.L.S.

Acquisition, analysis, or interpretation of data: B.D.K., K.M., N.P.H., M.G.H., L.D.S., H.B.S., S.L.S.

Drafting of the manuscript: B.D.K. and K.M.

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These authors have contributed equally to this work.

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