Hyperbaric Oxygen Therapy for the Treatment of Perianal Fistulas in 20 Patients With Crohn's Disease

Corine A. Lansdorp; Krisztina B. Gecse; Christianne J. Buskens; Mark Löwenberg; Jaap Stoker; Willem A. Bemelman; Geert R.A.M. D'Haens; Rob A. van Hulst

Disclosures

Aliment Pharmacol Ther. 2021;53(5):587-597. 

In This Article

Results

Inclusion and Baseline Characteristics

Screening for eligible patients took place between October 2017 and June 2019. In total, 29 eligible patients were counselled. All patients gave informed consent to participate: 21 patients accepted treatment with hyperbaric oxygen (72%) and 8 patients were included in the control group. One patient in the hyperbaric oxygen therapy group withdrew from the study after five hyperbaric oxygen sessions because of inadequate seton drainage and was replaced by another patient. Twenty patients in the hyperbaric oxygen therapy group and eight patients in the control group completed the study and follow-up (16 weeks). A study CONSORT flowchart is available in Appendix S1.

Patient baseline characteristics for the hyperbaric oxygen therapy group are shown in Table 1. The median duration of the current active perianal fistula(s) was 4 years. Luminal disease activity (based on the results of the last endoscopy in case of stable luminal complaints) was present in the ileum (n = 3), right colon (n = 1), left colon and sigmoid (n = 1) and rectum (n = 2). Eighty-five per cent of patients used concomitant medication: most patients used combination therapy consisting of anti-TNF combined with an immunomodulator (n = 9). Other medication regimens included anti-TNF monotherapy (n = 4), anti-TNF therapy combined with chronic antibiotic use (n = 1), vedolizumab (n = 1), ustekinumab (n = 1) and mesalamine (n = 1). A total of 17 of 20 patients (85%) had the last change in medication more than 6 months before the start of hyperbaric oxygen therapy, the remaining three patients had a change in medication less than 6 months before the start of hyperbaric oxygen therapy (but more than 6 weeks as required per study protocol). Including previous treatment, 19 of 20 patients received anti-TNF therapy at some point during the course of their perianal disease. Four patients had a previous surgical closure attempt for their fistula: three mucosal advancement flaps and one bioprosthetic plug. One of these patients also had a temporary diverting ostomy. Five patients had four or more external fistula openings: three patients had four openings, one patient had five openings and another patient seven openings. All patients started with one or more setons in place after examination under anaesthesia (as required per study protocol) to assure adequate drainage before the start of hyperbaric oxygen therapy; the majority of patients (11 of 20) had this procedure performed more than 6 months before the start of hyperbaric oxygen therapy. There were no comorbidities relevant to the perianal disease or hyperbaric treatment.

HBO and Seton Removal

Three patients received less than 40 sessions (37, 38 and 39 sessions); in two cases this was due to personal and unrelated issues and in one case a common cold was the reason for early termination of the treatment. All other patients completed 40 consecutive sessions. In 18 of 20 patients, all setons were removed during hyperbaric oxygen treatment, after a median of 26 sessions (range 20–30). In the remaining two patients, it was deemed there was still too much induration to remove all setons during hyperbaric oxygen treatment: one patient had four setons of which two were removed during hyperbaric oxygen treatment and two were still in situ at follow-up. The other patient had four setons of which three were removed during hyperbaric oxygen treatment and the last seton at follow-up.

Co-primary Outcome Parameters: PDAI and (Modified) van Assche Index

Median PDAI and (modified) van Assche scores are depicted in Table 2. Individual changes in scores can be found in Figure 1.

Figure 1.

Individual median perianal disease activity index, modified van Assche and original van Assche index scores at baseline and Week 16 in patients treated with hyperbaric oxygen therapy (median scores are indicated by dotted black line)

The median PDAI score decreased from 7.5 (95% CI 6–9) to 4 (95% CI 3–6, P < 0.001) at Week 16, reflecting an improvement in perianal disease. Inactive perianal disease, defined as a PDAI score of 4 or less, was achieved in 13 patients (65%).[20]

The median time between the baseline MRI and the start of hyperbaric oxygen treatment was 28 days. The median modified van Assche and original van Assche scores decreased from 9.2 (95% CI 7.3–11.2) to 7.3 (95% CI 6.9–9.7, P = 0.004) and from 13 (95% CI 12–15) to 12 (95% CI 10–13, P = 0.005), respectively, at Week 16. Items of the MRI indices that were most reactive to change after hyperbaric oxygen treatment were inflammatory items (ie rectal wall involvement and inflammatory mass), as well as the dominant feature of the primary tract and extensions. Three patients had a fibrotic fistula complex at follow-up. Examples of MRI images showing change in these respective items can be found in Figures 2 and 3. Counts and changes in the individual scoring items of the original and modified van Assche score are available in Appendix S1 (Table S1).

Figure 2.

Axial oblique T1-weighted MRI imaging at baseline (A) and Week 16 (B) of a patient with a decreased (modified) van Assche score on the item 'inflammatory mass' after treatment with hyperbaric oxygen therapy

Figure 3.

Axial oblique T2-weighted MRI imaging at baseline and Week 16 of a patient with a decrease modified van Assche score on the item 'dominant feature of primary tract and extensions', being predominantly fibrotic after hyperbaric oxygen therapy

Secondary Outcome Parameters

Fistula Drainage Assessment. Twelve of 20 patients (60%) showed a clinical response as measured by the fistula drainage assessment at Week 16, and 4 of 20 patients (20%) were in clinical remission. In total, 50 external fistula openings were present at baseline, of which 24 were closed at Week 16 (48%).

Biochemical Response. The median C-reactive protein value at baseline was 4.2 mg/mL (95% CI 1.6–8 mg/mL) which decreased to 2.2 mg/mL (95% CI 0.9–4.3 mg/mL) at Week 16, P = 0.003. Eleven patients had normal baseline C-reactive protein values, and 15 patients had normal values at Week 16. For faecal calprotectin, the median value decreased from 399 μg/g (95% CI 52–922 μg/g) to 31 μg/g (95% CI 16–245 μg/g) at Week 16, P = 0.001. Nine patients had values of faecal calprotectin indicating remission at baseline, and 16 patients had these values at Week 16. Figure 4 shows the individual C-reactive protein and faecal calprotectin values of patients at baseline and Week 16.

Figure 4.

Individual C-reactive protein and faecal calprotectin values at baseline and Week 16 in patients treated with hyperbaric oxygen therapy (median scores are indicated by dotted black line)

Patient-reported Outcomes. The median VAS score increased from 67.5 (95% CI 61–78) to 70 (95% CI 60–76, P = 0.26) at Week 16. The median IBDQ score at baseline was 169 (95% CI 141–191) and increased to 183 (95% CI 167–199, P = 0.001). Based on the IBDQ scores, 11 patients were in clinical remission at baseline, and three additional patients achieved clinical remission at Week 16 (14 patients in clinical remission in total). Four patients had a relevant clinical response, indicated by an increase in score of ≥27 points. The median score of the decision regret scale was 15 (IQR 5–25). Fourteen of 20 patients (70%) answered "yes" on the dichotomous question if patients felt their fistula(s) had improved at Week 16. The median VAS, IBDQ and decision regret scale scores can also be found in Table 2.

Adverse Events

Hyperbaric Oxygen Therapy-related Adverse Events. One patient withdrew from the study after five hyperbaric oxygen sessions due to ongoing perianal complaints and abscess formation due to inadequate seton drainage. After multiple surgeries to improve drainage that were unsuccessful she underwent an ostomy and was replaced in the study.

In the 20 patients who completed hyperbaric oxygen treatment, there were 10 unsolicited events in eight patients of trouble equalising middle ear pressure during hyperbaric oxygen therapy. Subsequent otoscopy showed signs of mild-to-moderate barotrauma in five of these eight patients, with no perforation of the eardrums. Three patients required tympanostomy tubes to complete the course of treatment.

One other patient complained of abdominal pain during hyperbaric oxygen therapy, with no residual complaints outside of the hyperbaric chamber and no relation to pressure differences. An extensive evaluation including laboratory tests showed no abnormalities, and no relation to luminal Crohn's disease was found. One patient had gastrointestinal complaints (vomiting, diarrhoea) for 1 day during hyperbaric oxygen therapy, with complete resolution of complaints the next day.

Solicited events during hyperbaric oxygen therapy were fatigue (5 patients) and visual changes (2 patients), which were all reversed after the treatment.

Re-interventions and Medical Changes Related to Fistulas. There were no surgical (re-)interventions during hyperbaric oxygen therapy and/or the study (16 weeks), including no drainage of abscess, seton placement or deviating colostomy. One patient had an increase in perianal complaints during the first week of hyperbaric oxygen therapy for which an MRI was performed (no signs of abscess formation was seen) and antibiotics were started. Because of ongoing complaints, the patient had an inspection under anaesthesia in theatre, but no abnormalities were found and no surgical intervention took place.

Apart from antibiotic treatment in this patient, two other medical changes took place. In one patient, the infliximab dose was increased and in another patient the thiopurine agent was stopped (request of the patient).

Control Group

The control group consisted of eight patients, five female and three male patients. The median age was 35 (IQR 24–41), and none of the patients were active smokers. The median disease duration was 6 years (IQR 1–24), and the median disease duration of the current fistula was 2 years (IQR 1–7). Five patients had one internal opening and three patients had two internal openings at enrolment. The median PDAI at baseline for the control group was 8.5 (IQR 5.3–10.8), and the median IBDQ 145 (IQR 90.5–183.5).

The main reasons for refusal of hyperbaric oxygen treatment were interference of the treatment with patients' personal lives such as their jobs and families (three patients), patients having too little complaints for the amount of time that should be invested to undergo the treatment (three patients) and hyperbaric oxygen therapy being too experimental/not proven effective (two patients).

Three patients in the control group had a ligation of the intersphincteric fistula tract that was performed during the follow-up period (16 weeks). Another patient was scheduled for a ligation of the intersphincteric fistula tract, but during surgery it was decided to perform a fistulotomy. In the remaining four patients, all setons were left in situ during follow-up. One of them was treated with a course of antibiotics because of perianal complaints. No other medical changes took place.

The median PDAI score for all patients in the control group decreased from 8.5 at baseline (95% CI 5–12) to 6 (95% CI 1–11, P = 0.04) at Week 16. The median VAS score increased from 60.5 (IQR 25–80) to 63 (95% CI 35–80) and the median IBDQ score increased from 145 (95% CI 78–198) to 154 (95% CI 86–214), both of which were not statistically significant (P = 0.60 and 0.12 respectively).

In the patients who did not receive a surgical re-intervention (n = 4), the PDAI decreased from 6.5 at baseline (IQR 5.25 - 10) to 6 (IQR 3.5 - 10) at Week 16. There were no patients with clinical response or remission as assessed by the fistula drainage assessment. None of the patients had a relevant clinical response based on their IBDQ score (ie an increase in score).

In the patients who underwent a surgical intervention (n = 4), the median PDAI decreased from 10 at baseline (IQR 6.25–11.5) to 5.5 (IQR 1.75–7) at Week 16, with two patients achieving inactive perianal disease (PDAI score ≤4). As assessed by the fistula drainage assessment, one patient was a clinical responder, and three patients were in clinical remission at Week 16. One patient had a relevant clinical response (increase in IBDQ score of ≥27) at Week 16.

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