HYPERBARIC OXYGEN (HBO) AS ADJUNCT THERAPY IN REFRACTORY OR FISTULIZING CROHN'S DISEASE
The clinical course of Crohn's disease is unpredictable with frequent relapses and many complications. Active or fistulizing disease refractory to various therapeutic agents are major problems in clinical practice , result in patient's poor quality of life and may lead to serious adverse drug reactions or complications requiring surgical intervention.
Current theory of Crohn's disease pathogenesis implicates genetic susceptibility triggered by environmental factors (microbial agents, toxins).This combination leads to inappropriate inflammatory response in which activated immune and non-immune cells release various inflammatory mediators and toxic molecules (cytokines, cell adhesion molecules, NO, ROMs) resulting in perpetuation of inflammation and tissue injury. According to vascular hypothesis endothelial dysfunction plays a central role in initiating and perpetuating inflammation. Vascular injury is a prominent feature of Crohn’s disease caused by various mechanisms leading to tissue ischemia and damage(necrosis).1, 2, 3
Hyperbaric oxygen therapy (HBOT) is thought to restore tissue hypoxia , downregulate inflammation and promote tissue repair.4, 5 Uncontrolled clinical studies have utilized Hyperbaric oxygen therapy (HBOT) as adjunctive modality in severe perianal Crohn’s disease with encouraging results.6
Evaluate HBO efficacy and safety as adjunctive therapy in patients with treatment resistant active or fistulizing Crohn's disease through a multicenter controlled unblind prospective study.
MATERIALS AND METHODS :
Adult patients with refractory or fistulizing Crohn’s disease will be enrolled in an international controlled unblind trial in which Hyperbaric oxygen will be applied as adjuvant therapy to conventional treatment .
Patient Selection :
Patients will be eligible for the study if their Crohn’s disease status (active or fistulizing) is refractory to the conventional treatment (mesalamine , corticosteroids , mercaptopurine or azathioprine ) with or without surgical intervention.
Crohn's disease activity assessment is based in various indexes which evaluate and score various indices ( symptoms , signs , complications , laboratory parameteres and general well being ). In our protocol we estimate the disease activity using the widely accepted and commonly used Crohn's Disease Activity Index (CDAI). The CDAI incorporates 8 Crohn’s disease–related variables : number of liquid or very soft stools , abdominal pain and cramping , general well-being , extraintestinal manifestations, complications , abdominal mass , use of antidiarrheal medications , hematocrit , and body weight. These items yield a composite score ranging from 0 to 600 , with higher scores indicating greater disease activity. Scores of <150 indicate remission, and scores of >450 indicate severe illness.7
In our study we consider disease as "refractory" two dinstinct groups of patients , those who remain symptomatic with a CDAI score-indicating activity despite adequate doses of steroids (steroid refractory) and those who flare when the steroid dose is being decreased (steroid dependent) irrespectively of concomitant use of other conventional therapeutic agents (aminosalycilates, azathioprine , mercaptopurine , metrnidazole etc.).
Patients with fistulizing disease are also included in the study. These patients usually have active disease . Of particular interest are patients with external perianal fistulas who represent a common and difficult problem in clinical practice often resistant to medical and surgical therapy. [ The severity of fistulizing disease is assesed using the Perianal Disease Activity Index ( PDAI ) which incorporates five elements: the presence or absence of discharge , pain or restriction of activities of daily living , restriction of sexual activity , the type of perianal disease , and the degree of induration , yielding a composite score ranging from 0 to 20 , with higher scores indicating more severe disease.8]
Inclusion Criteria: Patients between 18 to 65 years old , with Crohn’s disease for at least 6 months based on previous medical data , having Crohn’s Disease Activity Index (CDAI) scores between 220 and 400 or persistent fistulizing disease (regardless of surgical intervention) will be eligible for the study. All patients will give written informed consent for both the treatment ( conventional & HBOT) and endoscopic procedures.
Exclusion Criteria: Patients will be excluded from the study if they have undergone treatment with cyclosporine , methotrexate , or experimental agents ( eg. anti-TNF) within 3 months at least before inclusion. Patients will be also excluded if they have severe disease (CDAI >400) , symptomatic stenosis or strictures and contraindications to HBOT: recent (<2 years) spontaneous pneumothorax , ear-drum or ossicle chain surgery , untreated or insufficiently treated epilepsy , congenital spherocytosis , thyroid hormone replacement therapy , severe glaucoma.
Study Design :
All patients enrolled in the trial will have baseline data recordings ( week 0 ) :
After obtaining baseline data patients will be randomised in two groups : In Group A patients will receive the HBO as adjuvant therapy for 40 - 60 sessions (for 6 to 8 weeks) . In Group B patients will be serve as control group continuing the conventional treatment .
Patients will have close follow up during the study period (6 - 8 weeeks) and for 24 months (at 4 months intervals ) after the end of the study. All steps of baseline evaluation (week 0) will be repeated at the end of the study (weeek 6 or 8). Steps 1 , 2 , 3 ,4 , 7and 8 will be repeated at weeks 2 , 4 and/or 6.
Patients using oral corticosteroids will be allowed to taper the dosage if they are responding to treatment. Increasing corticosteroid dosage above the baseline dose is not accepted during the study. If initiation of corticosteroids or an increase in dose is required, an efficacy evaluation will be completed to document the lack of efficacy and no further study treatment will be given. Patients receiving concomitant treatment with azathioprine, 6-mercaptopurine , sulfasalazine , mesalamine and antibiotics ( metronidazole , ciprofloxacin) will be requested to maintain a stable dosage throughout the 6 or 8-week study period . Surgical intervention during the study is allowed and will not be considered as lack of HBOT efficacy.
Patients will be treated in a monoplace or multiplace hyperbaric chamber 5 days a week , pressurized at 2,5 absolute atmospheres breathing 100 % oxygen in session periods of two hours , with 15 minutes of compression and decompression each. Air interval periods of 5 minutes will follow 30 minutes of oxygen treatment . Treatment period is planned to include 40 - 60 sessions within 6-8 weeks . During HBOT sessions patients can receive simultaneously concomitant therapy . HBOT can be applied in the immediate post-surgery treatment if it is necessary. Every hyperbaric participating centre must be physically or functionally linked to a hospital facility or medical institution and must follow the guidelines of the European Committee for Hyperbaric Medicine (ECHM) regarding personnel, safety and procedures.
In order to evaluate tissue HBO efficacy , transcutaneous oxymetry will be used (TcPO2) to assess tissue hyperoxia during the session's period . In case of severe clinical conditions patient will be monitored for vital clinical signs . Patient will be under close observation during the session from medical and nursing stuff with completion of a flow chart and recording of any adverse reaction or complication.
All patients will be evaluated and have a regular follow up from a gastroenterology team according the aforementioned study design (weeks 0 , 2 ,4 , 6 , 8 & for 24 months post - HBOT ). The participation of a hospital gastroenterology team should be preferable for the study.
Evaluation Criteria :
Successful response to Hyperbaric Oxygen therapy for active refractory disease includes:
Failure includes : patients not improving CDAI score due to a&b conditions of successful response , patients who will need to change medication regimens (defined above) for treatment strategy (worsening disease) , patients who discontinued because of HBOT adverse reactions .
Successful response to Hyperbaric Oxygen therapy for fistulizing disease includes:
Failure includes the steady or worsening state of baseline fistula condition during the study pariod.
Changes in scores on the CDAI , PDAI , CDEIS will be evaluated according to the study design.
After informed consent, patients will be randomised using a fixed scale of random numbers ordered in two groups . The scale will be provided by the main coordinator.
Statistical analyses :
Statistical methods will be determined .
Working forms with indexes will be sent to participating centers after the final study acceptance .
Study protocol NOT finalised !!!