The HOT-TOPIC study is a prospective interventional (pilot) study.
The study was performed in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice guidelines. The protocol has been approved by the Medical Ethical Committee (METC 2017_132) and has been published previously. The trial has been registered at the Dutch Trial Registry (NL 6489/NTR 6676).
The complete follow-up period for the study is 60 weeks, with outcomes of Week 16 (ie 8 weeks after finishing hyperbaric oxygen treatment) presented in this article.
All authors had access to the study data and reviewed and approved the final manuscript.
The study has been conducted in the Amsterdam University Medical Center (UMC), location AMC. Patients were recruited at the multidisciplinary tertiary out-patient (fistula)-clinic of the IBD centre. All consecutive eligible patients were counselled for available treatment options by both a gastroenterologist and surgeon simultaneously. Patients who were eligible for the study but did not wish to undergo hyperbaric oxygen therapy were asked to serve as a control group.
All participants provided written informed consent.
Patients of 18 years or older with a confirmed diagnosis of Crohn's disease with one or more actively draining high perianal fistula (a high fistula tract is defined as transversing the upper 2/3 of the external sphincter/puborectal muscle, regardless of the number of internal and external openings) failing standard care (medical and/or surgical, defined as persisting fistula drainage in the preceding >6 months) or intolerance to standard treatment were included. Treatment regimens had to be stable for at least 6 weeks prior to starting hyperbaric oxygen treatment, that is, no starting of antibiotics, no surgical intervention except for seton placement, no addition of immunosuppressants and/or no dose changes in biologicals.
Patients with a stoma, rectovaginal fistulas, anal strictures and/or fluid collections/abscesses requiring surgical drainage were excluded, as well as patients who were unwilling to undergo seton drainage or patients with a seton in situ >12 months. Patients with proctitis were excluded, unless there were no deep ulcers seen at endoscopy. Patients who underwent a prior surgical procedure in the preceding 3 months (except from seton placement) or changes in medical treatment (including dose and interval changes in biologicals, addition of antibiotics or immunosuppressants or switching biologics) in the preceding 6 weeks were also excluded, as well as patients who were unfit to undergo hyperbaric oxygen treatment (as assessed by the hyperbaric physician).
Eligible patients were treated with 40 daily hyperbaric oxygen sessions on working days, that is, for a duration of 8 weeks in total. Sessions consisted of administration of a total of 80 minutes of 100% oxygen at 243–253 kilopascal. This treatment profile was similar to the normal clinical hyperbaric oxygen protocol in the Netherlands and remains well within non-decompression and oxygen toxicity limits. Hyperbaric oxygen treatment was provided in the hyperbaric unit of the Amsterdam UMC as well as in seven hyperbaric chambers across the Netherlands.
Treatment was started directly after enrolment and after investigation of fitness for hyperbaric oxygen treatment by the hyperbaric physician. All patients were treated in a multiplace chamber. If patients received less than 35 hyperbaric oxygen sessions or in case they missed more than two consecutive sessions (excluding weekends) they were replaced in the study or the treatment regimen was started anew.
If patients did not have adequate seton drainage at the start of hyperbaric oxygen therapy, one or more setons were placed in theatre before the start of treatment. Seton removal was planned after 30 sessions (ie at Week 6 after starting hyperbaric oxygen therapy) in order to allow for fistula closure. The medical treatment regimen patients received for their Crohn's disease remained unchanged in principle, but if necessary a change in medication (such as addition of antibiotics) could be made at the discretion of the primary physician.
Patients who were eligible to participate but did not wish to undergo hyperbaric oxygen therapy were asked to serve as a control group. The control group was added to the study in order to keep track of the feasibility of hyperbaric oxygen therapy, and in order to assess baseline characteristics and the disease course of patients who declined hyperbaric oxygen treatment. Patients in the control group continued to receive standard care (medical and/or surgical) as deemed suitable by their primary physician during their visits at the fistula clinic.
The co-primary outcome parameters were improvement in perianal disease activity index (PDAI) and improvement on magnetic resonance imaging (MRI) as measured by the (modified) van Assche index at Week 16 (ie 8 weeks after finishing hyperbaric oxygen treatment). For the PDAI, inactive perianal disease was defined as a score of 4 or less.
Secondary outcome parameters included clinical response and remission at Week 16 as measured by the fistula drainage assessment, with clinical response defined as a reduction of ≥50% in the number of draining fistulas and clinical remission defined as the absence of draining fistulas upon gentle finger compression.
Biochemical changes in C-Reactive Protein and faecal calprotectin levels were assessed at Week 16, as well as the proportion of patients with normal values of C-reactive protein (5 mg/L) and faecal calprotectin values below the cut-off score for remission of IBD (250 μg/g).
For patient-reported outcomes, scores of a visual analogue scale (VAS, that records the respondent's self-rated health on a scale from 0 to 100, with higher scores indicating higher quality of life), the Inflammatory Bowel Disease Questionnaire (IBDQ, range 32–224 with higher scores reflecting better quality of life) and a validated decision regret scale (scale 0–100 with higher scores reflecting higher regret of the decision to undergo hyperbaric oxygen therapy) were assessed at Week 16.[23,24] For the IBDQ, the proportion of patients with a relevant clinical response (increase of ≥27 points) and the proportion of patients in remission (score of ≥168) were also assessed. Patients were also asked to answer "yes" or "no" on the question if they felt their fistula(s) had improved due to hyperbaric oxygen treatment.
Furthermore, changes in use of concomitant medication, re-interventions and adverse events during the study (16 weeks) were reported. At the end of hyperbaric oxygen treatment, in addition to assessment of any unsolicited adverse events, patients were specifically asked about common side-effects of hyperbaric oxygen therapy, that is, complaints of trouble equalising, visual changes and fatigue (solicited events).
Clinical outcomes were assessed by the treating physician of the patients (gastroenterologist and/or surgeon) at the out-patient fistula clinic. The (modified) van Assche scores were assessed in a nonrandom order by an independent abdominal radiologist with 26 years of experience in MRI of fistulising Crohn's disease who was blinded to clinical outcomes. Adverse events during hyperbaric oxygen treatment were assessed by the supervising hyperbaric physician. None of the assessors were blinded to the intervention.
In the control group, the same outcome measures were assessed, except for MRI and biochemical response. Reasons for refusal to undergo hyperbaric oxygen treatment were noted. Assessment of outcome parameters was performed at the same time point as for the hyperbaric oxygen therapy group, at Week 16.
Sample Size and Statistical Analysis
As no spontaneous healing was expected in this therapy-refractory group, the outcome of 20 patients after hyperbaric oxygen therapy was estimated to give an indication of the success of hyperbaric oxygen therapy and should also be enough to determine the feasibility and possible efficacy of the treatment.
The number of patients in the control group was unlimited.
All parameters were tested for a two-tailed significance of P < 0.05 and were assessed using nonparametric tests. The co-primary endpoints PDAI and MRI are (semi-)continuous variables and were analysed with the Wilcoxon signed rank test. Differences in (semi-) continuous variables, such as the patient-reported outcomes and C-reactive protein/faecal calprotectin, were analysed using the Wilcoxon signed rank test.
Aliment Pharmacol Ther. 2021;53(5):587-597. © 2021 Blackwell Publishing