Crohn ’ s disease and hyperbaric oxygen therapy

PURPOSE: Evaluate the application of Hyperbaric Oxygen Therapy (HBO) in patients with Crohn’s disease (CD) refractory to pharmacologic therapy, who developed abdominal, anorectal or skin complications. METHODS: Fourteen selected patients with refractory CD and treated at the School of Medicine of Ribeirao Preto, University of Sao Paulo (FMRP-USP) and at the Center of Hyperbaric Medicine, São Paulo Hospital (CEMEHI) were submitted to HBO. RESULTS: Of the 14 patients evaluated, 11 had a satisfactory response. CONCLUSION: HBO has shown benefits in patients with CD refractory to pharmacologic therapy.


Introduction
Crohn's disease (CD) is an idiopathic, chronic, transmural, inflammatory disorder that can affect the whole gastrointestinal tract 1 .Studies demonstrate a dysfunctional relationship between genetic, immunological and environmental factors resulting in an imbalance between proinflammatory and anti-inflammatory mediators [2][3][4] .Its incidence has increased in recent decades, especially in developed countries; and this has stimulated the interest in novel pharmacological and surgical therapies.
The "Biological therapy" is the most advanced weapon against the disease and it targets the TNF-alpha.TNF is a naturally occurring cytokine involved in inflammatory and immune responses.Several studies have demonstrated the benefits of these medications as they provide a longer-lasting remission, corticosteroids independence and prevention of complications such as fistulas and stenosis [5][6][7][8] .
With the advent of new drugs for CD there has been a remarkable clinical improvement as these medications seek to control the inflammatory cascade [9][10][11][12][13] .However, even with the anti-TNF therapy associated or not to other immunosuppressive drugs, there are still challenging cases refractory to medical and surgical treatment and tissue destruction is the ultimate result 14,15 .
Poor healing of the mucosa, fistulae persistence, infectious processes and progressive stenosis are some of the complications that can cause nutritional depletion and immunosuppression of the patients.These factors lead to prolonged hospitalization, systemic infections and significant increase in morbidity and mortality [16][17][18][19] .
Drug optimization tends to be ineffective and surgical intervention may be necessary 20 .There is a higher risk of complication in patients with CD and it is known that correct healing in the areas of resection is impaired by bacterial colonization 21 .
Several authors advocate the use of Hyperbaric Oxygen Therapy (HBO) as an adjuvant option in patients with refractory disease and the results are favorable [22][23][24] .Is consists in expose the patient in a chamber with 100% oxygen with higher pressure (2ATA).HBO promotes increments in plasmatic partial pressures of O 2, thus enhancing tissue levels of oxygenation.It´s know that HBO promotes healing in chronic wounds 24 .
The purpose of this study is to report the experience of the authors with the utilization of HBO as adjuvant therapy in selected cases.

Methods
Fourteen patients prospectively selected were followed at the Division of Coloproctology in FMRP-USP and in the CEMEHI with chronic abdominal wounds (enteric-cutaneous fistula), perineal disease (fistulas or chronic perineal wounds) or pyoderma gangrenosum were considered refractory to pharmacological therapy.
The number of sessions ranged from 10-50 according to patient's evolution.We used a Sechrist monoplace chamber pressurized to 2.4 ATA.The sessions lasted 2 hours and were performed daily.

Results
Of the 14 patients studied, 6 had abdominal injuries due to enteric-cutaneous fistula, 10 had perineal disease and 2 presented with pyoderma gangrenosum.Eleven patients (78,5%) had a satisfactory improvement, healing and good local control of inflammation.Three patients (21,5%) maintained injuries and required surgical approaches (Table 1).In the present study 11 of the 14 patients had a complete or partial improvement of their cicatrization.The following images show these benefits (Figures 1, 2 and 3).

Discussion
Even with all pharmacological advances in the treatment of CD, many patients still present a relapsing course.Some cases are impressively aggressive and mutilating.This situation usually requires surgical intervention and other measures to improve wound healing 20 .
Utilization of HBO in patients with CD has increased in recent years.HBO promotes increments in plasmatic partial pressures of O 2, thus enhancing tissue levels of oxygenation.Tissue hyperoxia increases the healing processes as it leads to vasoconstriction and decreased edema and also stimulates angiogenesis and proliferation of fibroblasts and collagen.There are also some reports of increased bacteriostatic and bactericidal effects [17][18][19][20][21][22][23] .
HBO acts directly in the inflammatory cascade and the effect of such therapy can be explained by reduced activity of nitric oxide synthase and inhibition of inflammatory cytokines.It is effective in suppressing the activity of COX-2 and the stimuli for the THF-alpha production.Vascular endothelial growth factor (VGEF) is significantly increased with HBO 25 .

Conclusions
The understanding of the pathophysiology of CD has increased in recent years as our genetic and molecular knowledge progresses, resulting in more effective therapies.Nevertheless, the response is not uniform among patients and progression to complications such as extensive perineal disease may be inevitable.HBO was initially indicated only for complex perineal disease.Our report, as many other in the literature, expands the traditional HBO applications and shows its efficacy in controlling both systemic and local inflammatory activity.The benefits become evident as the healing process advances.

FIGURE 1 -
FIGURE 1 -LGM, 29 years -abdominal (before and after) and perineal (before and after) disease.Before and after 20 sessions of HBO.

TABLE 1 -
Patients and results.