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Research on Crohn's Disease

J Clin Gastroenterol 1994;19(3): 202-5                                                      
Hyperbaric Oxygen for Perianal Crohn’s Disease 
A.    Lavy, M.D., G. Weisz, M.D., Y. Adir, M.D., Y. Rarnon, M.D.,
Y.    Melamed, M.D., and S. Eidelman, M.D. 


Perianal involvement in Crohn's disease is common (<= 50%),distressing, and frequently refractory to treat­ment. Clinical features include painful induration and stenosis, discharging fistulas, and fissures. The patho­genesis of these lesions is unclear, but local ischemia and secondary anaerobic infection may play a role.

Following three sporadic reports of successful treatment with hyperbaric oxygen (HBO), we undertook a trial of this method in 10 patients with refractory perianal disease. These patients' perianal Crohn's disease had not responded to treatment that included local medications, salicylates, corticosteroids, metronidazole, or 6-mercap-topurine were treated. Treatment was administered in a hyperbaric chamber at a pressure of 2.5atm absolute. Each session lasted 90 min, and each course consisted of 20 daily sessions. Complete healing occurred in 5 patients after one to two courses. In an additional 2, after three courses, 1 patient improved but did not heal, and 2 did not improve. No adverse effects were noted by any of the 10 patients. Follow-up of 18 months did not reveal any recurrence. These preliminary results confirm that HBO therapy is a safe and efficient therapeutic option for perianal Crohn's disease.

Key Words: Crohn's disease-Perianal involvement-Hyperbaric oxygen therapy. 

Received October 5, 1993. Sent for revision December 13, 1993. Accepted April 30, 1994. From the Department of Gastroenterology, Rambam Medi­cal Center, and Israeli Naval Hyperbaric Institute, Haifa, Israel. Address correspondence and reprint requests to Dr. A. Lavy at Department of Gastroenterology, Rambam Medical Center, and Israeli Naval Hyperbaric Institute, Haifa, Israel.

Crohn's disease involves the perianal region in <= 50%of patients (1) and causes painful induration, abscesses, fistulas with discharge, and fissures, which are extremely distressing to the patient and refractory to treatment (2,3). The reason for these lesions is poorly understood (4,5). Their indolent nature is compatible with ischemia and secondary bacterial invasion as possible pathogenetic factors. Wakefield et al. (5) conducted morphological studies that demonstrated occlusive fibrinoid lesions of the arteries supplying areas of the intestine affected by Crohn's disease. Hypoxia can compromise  wound healing (6), whereas improved tissue oxy­genation can restore a favorable cellular milieu in which the wound healing process and host antibacterial mechanisms, particularly against anaerobes, are enhanced (6,7).

Following sporadic case reports of the successful integration of hyperbaric oxygen (HBO) treatment in patients with fistulas due to Crohn's disease (8-10), we undertook a trial of this therapy in 10 consecutive patients, some of whom had not responded to prolonged conventional therapy with salicylates, corticosteroids, metronidazole, and 6-mercaptopurine. Our results are reported here.

METHODS
 
Ten patients with Crohn's disease involving the perianal region were treated with HBO. Perianal disease was selected as the only obvious parameter to follow objectively. In most of the patients, activity of the disease, as demonstrated by the Harvey Bradshaw activity index (11), was relatively low grade except for the perianal disease (Table 1).

Inclusion Criteria
The treatment was offered to all patients with perianal Crohn's disease who were willing to undergo the 90-mm  daily sessions in the hyperbaric chamber. Each had a complete physical examination and routine blood tests, as well as chest x-ray and ear, nose, and throat (ENT) examination before therapy. The nature and severity of the perianal disease were documented before and after each course of therapy.

HBO was administered in a multiplace hyperbaric chamber constructed by Drager, Germany. A course of 20 daily treatments (6 times weekly) was given (100% oxygen for 90 mm  at a pressure of 2.5 atm absolute). The patients were reexamined at the end of the treatment period. A further treatment of 20 sessions was administered if complete resolution had not occurred. The patients were reex­amined, and a decision was made regarding a third course. 

TABLE 1. Patients with Crohn's disease treated with hyperbaric oxygen 

No

Age, Sex

Crohn’s index before/after therapy

Duration of disease(duration of perianal disease)

G.I. involvement

Perianal involvement

Concomitant medication

20 treatment assessment

40 treatment assessment

60 treatment assessment

1

58, F

154/148

3 yr
(2 yr)

Colon

Fistual on buttock, Perianal infiltration

Sulfasalazine

Complete healing

 

 

2

30, M

83/92

4 yr
(6 mo)

Terminal ileum Rectum

Perianal infiltration

Mesalazine

Complete healing

 

 

3

36, F

268/245

14 yr
(8 yr)

Colon

2 perianal fistulas to skin, 1 to vagina Severe anal narrowing and infiltration (digital examination impossible)

Sulfasalazine

Closure of 2 fistulas Improved anal diameter

Improved inflammation, less narrowing, resolution of abdominal pain and bloating

Further improvement Resolution of stenosis

4

51, F

154/138

24 yr
(6 mo)

Colon

Perianal fistula and infiltration

Mesalazine

Closure of fistula infiltration remains

Complete healing

 

5

34, F

150/150

14 yr
(4 mo)

Colon

Perianal fistula and infiltration

Sulfasalazine

Closure of fistula infiltration remains

Complete healing

 

6

30, M

308/312

13 yr
(12 yr)

Diffuse small and large bowel

Severe disease with a fistula and 8 cm circular infiltration

Mesalazine

Improved fistula Infiltration reduced

3 cm infiltration, new fistula

 

7

59, M

92/90

40 yr
(10 yr)

Diffuse small and large bowel

Perianal fistula

Prednisone
Sulfasalazine
Imodium

Complete healing

 

 

8

64, M

62/66

11 yr
(1 yr)

Large bowel

2 fistulas and infiltration

Sulfasalazine

Closure of fistulas

less infiltration

Complete healing

9

40, M

374/360

12 yr
(8 yr)

Small bowel

20 cm infiltration, 6 fistulas, 1 fistula to groin

Mesalazine

Closure of 3 fistulas and 1 to groin

No further improvement

No further improvement

10

34, M

34/34

18 mo
(same)

No intestinal involvement

8 fistulas, severe infiltration

None

Closure of 4 fistulas

Improved inflammation

Healing


*Cases 4 and 10 are discussed in greater detail under "Representative Cases" subsection of "Results." See ref. 11.

Cost
The estimated cost of treatment is $100 per hour. This was covered in full by the patients' medical insurance.

RESULTS
The results are summarized in Table 1. Improve­ment occurred in 8 of 10 patients. In 3 patients, complete healing of perianal lesions occurred after a single course; in 2, after two courses. In 3 patients, three courses were required. Two patients did not improve. None of the patients reported side effects.

REPRESENTATIVE CASES  
Case 4
A 51-year-old woman developed perianal disease after a 24-year history of Crohn's colitis with an active fistula and circumferential perianal infiltration. She had been treated with Mesalazine only.

The fistula closed after 20 treatments, but there was residual scarring and inflammation. She was given a further 20 treatment sessions, with complete resolution of the perianal disease that has been maintained for 18 months of follow up on maintenance mesalazine only. 

Case 10

A 34-year-old man developed severe perianal disease without any bowel involvement. Examination revealed severe inflammatory induration and 8 fistulas. Treatment for 1 year with salicylates, steroids, and metronidazole was ineffective. After one course of HBO treatment, 4 fistulas closed, and after two additional courses his disease healed. 

DISCUSSION
 
HBO, the inhalation of 100% oxygen at a pres­sure >1 atm (12), is now an established mode of therapy for a variety of medical conditions (12-14). These conditions include chronic wounds in dia­betes and the complications of trauma and radionecrosis (15),including radiation damage to the gas­trointestinal tract (16). The therapeutic effect of HBO is due to the physiological effect of hyperoxia. Although the inhalation of high concentrations of oxygen has a limited impact on total hemoglobin oxygen content, it produces an increase in the amount of dissolved oxygen in the plasma that is directly proportional to the rise in the ambient pressure. When 100% oxygen is breathed at an absolute pressure of 3 atm, the plasma oxygen content increases from 0.32 to 6.8 vol% (17). This considerable increase in the amount of oxygen that can be delivered and made available to the tissues under conditions of high pressure is probably of great importance in cases where improved tissue oxygenation is required. Hypoxia can appear in normally perfused tissue that is the site of an inflammatory reaction. HBO at an absolute pressure of 2 atm has been shown to improve tissue oxygenation in this situation (18).


The perianal lesion of Crohn's disease is in many ways a "chronic non healing wound" because of its indolent nature, its refractoriness to treatment, and the possible role of local ischemia in its pathogenesis (2,3,5).The chronic non healing wound is an established indication for HBO therapy (12-14). The best results have been reported for diabetic wounds, in which microangiopathy, ischemia, and hypoxia are important pathophysiological factors. When a high partial pressure of oxygen is breathed, there is correction of the surrounding hypoxia at sites supported by diseased vessels. The intermittent correction of wound hypoxia by HBO therapy elevates oxygen tensions in ischemic or infected wound tissue (19). Enhanced tissue oxygenation has a vasoconstrictive effect believed to reduce tissue edema (20) and restore fibroblast proliferation, collagen synthesis (21), and capillary angiogenesis (22). Thus, oxygen may be the wound's most essential nutrient (14).

Because of its location, the perianal lesion may be prone to bacterial contamination. Oxygen also has an antimicrobial effect, particularly on anaerobes (7). It plays a crucial role in the cellular response to infection. Neutrophils require molecular oxygen as a substrate for microbial killing by phag­ocytes, a process that depends on the formation of free radicals. The oxidative burst observed in neu­trophils after the phagocytosis of bacteria involves a 10- to 15-fold increase in oxygen consumption (23,24). This oxidative antimicrobial system virtually ceases to function under conditions of hypoxia. A tissue P02 >= 30 mm Hg is considered necessary for normal oxidative function (25).Partial pressure of oxygen in diseased or injured tissue is often < 30 mm Hg (19). Improved oxygenation leads to restoration of white blood cell function and renewal of adequate antimicrobial action.

HBO is administered in a hyperbaric chamber in which 100% oxygen is breathed at pressures greater than atmospheric. The multi-place chamber used in this study is compressed with air, and ox­ygen is delivered to patients at the ambient pressure via a mask. In such a chamber, <= 20 patients may be treated simultaneously and are always accom­panied by a trained attendant during treatment. In­strumentation and all the requirements for critical care support are on hand inside the chamber.

Our present series confirms the encouraging re­sults reported in previous isolated case reports. In all our patients with mild or moderate disease and in some with severe disease, healing was complete after a single course of hyperbaric treatment and has been maintained for <= 18 months following treatment. In some of the severe cases, there was also remarkable improvement although several courses were required. Because systemic activity of Crohn's disease was relatively low grade in all patients reported here, possible effects of HBO on other manifestations of Crohn's disease could not be estimated from this study (see activity indexes, Table 1).

HBO is a safe form of therapy (26-28). No side effects were noted in this group of patients. Therefore, it should be considered in patients suffering from perianal Crohn's disease who have failed to respond to conventional therapy. Definitive proof of the efficacy of this mode of therapy requires a well controlled double blind study that we think is well worth doing.

 REFERENCES 
1.       Cohen Z, MeLeod RS. Perianal Crohn's disease. Gastroenterol Clin North Am 1987;16:175-89.
2. Bernstein LH, Frank MS, Brandt U, Boley SI. Healing of perineal Crohn's disease with              metronidazole. Gastroenrer­ology 1980;79:357-65.
3.       Brandt U, Bernstein LH, Boley SI, Frank MS. Metroni­dazole therapy for perineal Crohn's disease: a follow-up study. Gastroenrerology 1982;83:383-7.
4.             Gorbach SL. Intestinal microflora in inflammatory bowel disease-implications for etiology. In: Kiraner lB, Shorter RG, eda. Inflammatory bowel disease. New York: Lea & Febiger,1988:51-64.
5.       Wakefield AJ, Sawycrr AM, Dhillon Ap, et at. Patho­genesis of Crohn's disease: multifocal gastrointestinal in­farction. Lancet 1989;2:1057-62.
6.       Davis IC, Hunt TK, eds. Problem wounds: the role of oxygen. New York: Elsevier, 1988.
7.       Mader IT. Phagocytic killing and hyperbaric oxygen: an­tibacterial mechanisms. HBO Rev 1981;2:37-49.
8.       Grim PS, Gottlieb U, Boodie A, Batson E. Hyperbaric oxygen therapy. JAMA 1990;263:2216-20.
9.       Brady CE, Cooley BI, Davis IC. Healing of severe perineal and cutaneous Crohn's disease with hyperbaric oxy­gen. Gastroenterology 1989;97:756-60.
10. Nelson Lw Jr, Bright DL, Villar LF. Closure of refractory perineal Crohn's lesion. Integration of hyperbaric oxygen into case management. Dig Dis Sci1990;35:1561-5.
11.     Best WR, Becktcl JM, Singleton JW, Kern F. Develop­ment of a Crohn's disease activity index. Gastroenterology 1976;70:439-44.
12.Mader JT, ed. hyperbaric oxygen  therapy:  a committee report. UHMS Publication Number 30 CR(HBO), 1989. Bethesda. Maryland: Undersea and Hyperbaric  Medical Society.
13.     Kindwall E. Hyperbaric oxygen. BMJ 1993;307:515-16.
14.     Grim PS, Gottlieb LI, Boddie A. Batson E. Hyperbaric oxygen therapy. JAMA  1990;263:2216-20.
15.     Nakada T, Kubota Y, Sasagawa 1, Ct al. Therapeutic experience of hyperbaric oxygenation in radiation colitis. Dis Colon Rectum1993;36:962-5.
16.          Charneau I, Bonacour 6, Person B, Burtin P, Ronceray I, Boyer I. Severe hemorrhagic radiation proctitis advancing to gradual cessation with hyperbaric oxygen. DigDis Sci 1991;36:371-5.
17.          Bassett BE, Bennett PB. Introduction to the physical and physiological bases of hyperbaric therapy. In: Davis IC, Hunt TK. eds. Hyperbaric Oxygen  therapy. Bethesda, Mar­yland: Undersea Medical Society, 1977:11-24.
18.     Carnochan FMT, Abbot NC, Beck IS, Ct al. Can hyper­baric oxygen correct hypoxia induced by inflammation:preliminary findings. In: Schmutz 1, Bakker DI, eds. Proceedings of the joint meeting: Second Swiss symposium on hyperbaric medicine and second European conference on hyperbaric medicine. Basel: Foundation for Hyperbaric Medicine. 1990:47-54.
19.     Shcffield P1. Tissue oxygen measurements. In: Davis IC. Hunt TK, eds. Problem wounds the role of oxygen. New York: : Elsevier, 1988:17-51.
20.     Nylander G, Lewis D, Nordstrom H, Larsson I. Reduction of postischemic edema with hyperbaric oxygen. Plast Re­constr Surg 1985;76:596-601.
21.     Hunt TK, Pai MP. The effect of varying ambient oxygen tensions on wound metabolism and collagen synthesis.  Surg Gynecol Obstet 1972;135:561-7
22.     Knighton DR, Silver IA, Hunt TK. Regulation of wound-      healing angiogenesis  effect of oxygen gradients and inspired oxygen concentration. Surgery 1981;90:262-70.
23.     Badwey JA, Karnovsky ML. Active oxygen species and  the functions of phagocytic leukocytes. Annu Rev Diochem           1980;49:695-726.
24.     Forman HJ, Thomas MJ. Oxidant production and bactericidal activity of phagocytes. Annu Rev Phvsiol 1986;48: 669-80.
25. Hohn DC, MacKay RD, Halliday B, Hunt TK. The effect of O2 tension on the microbicidal function of leukocytes            in wounds and in vitro. Surg Forum 1976;27:18-20.
26.     Shupak A, Greenberg E, Hardoff R, Gordon C, Melamed Y, Meyer WS. Hyperbaric oxygenation for necrotizing otitis media. Arch Otolaryngol 1989;115:1470-5.
27.     Gozal D, Ziser A, Shupak A, Melamed Y. Accidental car­bon  monoxide  poisoning.  Clin Pediatr1985;24:132-5.
28.     Melamed Y, Bursztein S. Hyperbaric medieme. In: Reis ND, Dolev E, eds. Manual of disaster medicine. New York: Springer-Verlag, 1989:148-50


For those interested in receiving HBOT that may have difficulty with financing the treatments, we have people that can give advice on fund-raising. The previous case studies are only a glimpse of the hundreds of people which have received HBOT at the Richmond Hyperbaric Center for a variety of conditions with favorable outcomes. Please contact us for more information on a particular condition which may benefit from hyperbaric oxygen therapy.

The Richmond Hyperbaric Health Center has engaged in scientific research projects including a pilot study on the treatment of RSD/CRPS. We would like to pursue future research studies as well and are open to any inquiries about the use of  HBOT  for researching various conditions.

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