Hyperbaric oxygen therapy in inflammatory bowel disease: a systematic review and meta-analysis

Abstract

Background
Translational data suggest a potential role of hyperbaric oxygen therapy (HBOT) in a subset of patients with inflammatory bowel disease (IBD). We performed a systematic review and meta-analysis for the efficacy and safety of HBOT in IBD.

Methods
We searched Pubmed, Embase and CENTRAL to identify studies reporting the efficacy of HBOT in ulcerative colitis or Crohn’s disease. We pooled the response rates for HBOT in ulcerative colitis and Crohn’s disease separately.

Results
A total 18 studies were included in the systematic review and 16 in the analysis. The overall response rate of HBOT in ulcerative colitis was 83.24% (95% confidence interval: 61.90–93.82), while the response in Crohn’s disease was 81.89 (76.72–86.11). The results of randomized trials for HBOT as adjuvant therapy in ulcerative colitis were conflicting. The complete healing of fistula in fistulizing Crohn’s disease was noted 47.64% (22.05–74.54), while partial healing was noted in 34.29% (17.33–56.50%). Most of the adverse events were minor.

Conclusion
Observational studies suggest benefit of use of HBOT in ulcerative colitis flares and Crohn’s disease. However, adequately powered

Full text

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Original article
DOI: 10.1097/MEG.0000000000002164 1
Hyperbaric oxygen therapy in inflammatory bowel
disease: a systematic review and meta-analysis
Anupam Kumar Singha, Daya Krishna Jhaa, Anuraag Jenaa, Praveen Kumar-Mb, Shaji Sebastianc and
Vishal Sharmaa
Introduction
Inammatory bowel disease (IBD) is a chronic inamma-
tory disease of the gastrointestinal tract, which is recog-
nized to have two distinctive patterns: ulcerative colitis
and Crohn’s disease. The therapy for IBD is often lifelong
with drugs required to maintain remission from disease
activity. The disease is punctuated by periods of exacerba-
tions or ares, which often require intensication of ther-
apy and introduction of newer drugs [1].
In the evolving world of IBD therapeutics, recent years
have witnessed many advances with the use of biologics
and small molecules [1]. While these agents are recognized
to be effective and improve outcomes in patients who
fail conventional treatment, cost pressures are a barrier
particularly in the developing world. In addition, these
therapies are initiated with hesitancy by the patients and
care providers due to concerns for safety and long-term
risks [2]. Furthermore, these drugs may have signicant
primary nonresponse and in a proportion of patients sec-
ondary loss of response [3]. Unfortunately, active IBD
is associated with considerable impact on quality of life
and impairs work productivity [4]. The physicians iden-
tify failure to biological therapy and institution of newer
drugs as signicant challenges in IBD care [5]. Despite the
advances with biologics and small molecules, refractory
disease needing surgery is common in certain clinical set-
tings like nonresponding acute ulcerative colitis and stu-
lizing Crohn’s disease [6]. Therefore, newer therapies are
required to address these challenges.
Hyperbaric oxygen therapy (HBOT) has shown benet
in many conditions including carbon monoxide poison-
ing, decompression sickness, gangrene, gas embolism and
high-altitude pulmonary edema. It involves inhalation of
100% oxygen under high pressure in special chambers [7–
9]. Multiple mechanisms have been proposed to explain
the benets of HBOT including hyperoxygenation, vaso-
constriction, reduced leukocyte adherence and oxidative
killing, promotion of angiogenesis and broblast prolifer-
ation, synergic effects on antibiotics and oxidative effects
on bacteria [7,8]. Animal studies have demonstrated
that HBOT reduces the generation of proinammatory
cytokines and expression of inducible NO-synthase,
thereby attenuating the severity of colitis [10].
In the setting of IBD, HBOT could increase tissue oxy-
genation with resultant reduction in inammation result-
ing in clinical improvement [11,12]. We aimed to perform
a systematic review on the use of HBOT in patients with
IBD and determine its safety and efcacy in IBD.
Methods
This meta-analysis was conducted in accordance with the
Preferred Reporting Items for Systematic Reviews and
Meta-Analyses (PRISMA) guidance [13].
European Journal of Gastroenterology & Hepatology 2021, XXX:00–00
Keywords: colectomy, Crohn’s disease, remission, ulcerative colitis
Departments of aGastroenterology and bPharmacology, Postgraduate Institute
of Medical Education and Research, Chandigarh, India and cIBD Unit, Hull
University Teaching Hospitals NHS Trust, Hull, UK
Correspondence to Dr. Vishal Sharma, Department of Gastroenterology,
Postgraduate Institute of Medical Education and Research, Chandigarh, India
E-mail: sharma.vishal@pgimer.edu.in
Received 30 December 2020 Accepted 3 March 2021
Supplemental Digital Content is available for this article. Direct URL citations
appear in the printed text and are provided in the HTML and PDF versions of this
article on the journal's website, www.eurojgh.com
Background Translational data suggest a potential role of hyperbaric oxygen therapy (HBOT) in a subset of patients with
inflammatory bowel disease (IBD). We performed a systematic review and meta-analysis for the efficacy and safety of HBOT
in IBD.
Methods We searched Pubmed, Embase and CENTRAL to identify studies reporting the efficacy of HBOT in ulcerative colitis
or Crohn’s disease. We pooled the response rates for HBOT in ulcerative colitis and Crohn’s disease separately.
Results A total 18 studies were included in the systematic review and 16 in the analysis. The overall response rate of
HBOT in ulcerative colitis was 83.24% (95% confidence interval: 61.90–93.82), while the response in Crohn’s disease was
81.89 (76.72–86.11). The results of randomized trials for HBOT as adjuvant therapy in ulcerative colitis were conflicting. The
complete healing of fistula in fistulizing Crohn’s disease was noted 47.64% (22.05–74.54), while partial healing was noted in
34.29% (17.33–56.50%). Most of the adverse events were minor.
Conclusion Observational studies suggest benefit of use of HBOT in ulcerative colitis flares and Crohn’s disease. However,
adequately powered randomized trials are needed to draw a definite conclusion. Eur J Gastroenterol Hepatol XXX: 00–00
Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.
LWW

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2 European Journal of Gastroenterology & Hepatology xxx 2021 • Volume XXX • Number XXX
Search strategy
Electronic search was conducted using PubMed, Embase
and CENTRAL from inception to 25 January 2021.
Keyword used for the search included Hyperbaric oxy-
gen, hyperbaric oxygenation, hyperbaric oxygen thera-
pies, HBOT, combined with ‘AND’ colitis, enterocolitis,
proctitis, enteritis, IBD, ulcerative colitis, Crohn disease
or Crohn’s disease (detailed search strategy as described
in Supplementary Table 1, Supplemental digital content
1, http://links.lww.com/EJGH/A684). References of eli-
gible studies were searched for any additional articles.
Eligible titles were combined, and after removal of dupli-
cate publications, the rest of the titles and abstracts
were screened by the two reviewers (D.K.J. and A.K.S.).
Relevant articles were selected for full-text screening.
Any discrepancy was resolved after discussion with a
third reviewer (V.S.).
Study inclusion
We included all the studies that reported about the use of
HBOT for IBD as a treatment modality. We did not restrict
our search for the type of publication or the language of
publication. We included randomized controlled trials,
observational studies and case series, which reported on
the use of HBOT in IBD. We excluded those studies where
clinically relevant data were not available or if the number
of participants was less than ve.
Data extraction and outcomes
Two reviewers (D.K.J. and A.K.S.) extracted the data
from the included studies. Extracted data included details
of study (author, country and period of study), baseline
characteristics (age, gender, extent and severity of the dis-
ease), HBOT (number of sessions, pressure, duration of
therapy), control group, duration of follow up, denition
and fraction of patients having response (clinical, endo-
scopic and imaging, if available), patients requiring colec-
tomy or second-line treatment, adverse events of HBOT.
The data were extracted separately for ulcerative colitis
and Crohn’s disease.
Data analysis
We calculated the pooled response to HBOT therapy
for the ulcerative colitis as well as Crohn’s disease. The
denition of clinical response was as used in the individ-
ual studies. For ulcerative colitis, we also calculated the
pooled rates of use of HBOT as a second-line treatment
and estimated the colectomy rates during the index hos-
pitalization and during the follow up. For Crohn’s disease
patients, rates of overall clinical response as well as partial
and complete stula healing rates were calculated. Adverse
effects of HBOT therapy were discussed descriptively for
ulcerative colitis and Crohn’s disease separately.
The statistical analysis was conducted using R version
4.0.2 and meta package was used in addition to the base
Fig. 1. PRISMA flowchart depicting the process of study selection for the systematic review.

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www.eurojgh.com 3
Hyperbaric oxygen therapy in IBD Singh et al.
Table 1. The included studies with details on patient selection, hyperbaric oxygen therapy protocol and outcomes
Author,
country, year
Study
design
Patients
characteristics
Dosage and
duration of HBOT Additional treatment Outcomes assessed Response with HBOT
Follow-up
period
Ulcerative colitis
Karkumov
M, 1991,
Bulgariaa
Nonrandomized, case-control
study, consecutive patients
of active ulcerative colitis
n=34 (cases)
(control data not
given)
2.4 ATA for 120min per
session for 12 sessions
•Symptoms resolution •Clinical improvement:
34/34
NA
•Laboratory parameters: normalization of ESR
•Endoscopic improvement: healing of ulcer
Zhang P,
2001,
Chinaa
Randomised controlled
trial, singe center;
HBOT therapy group,
n=42
2 ATM for 60min once a day Oral sulphasalazine 1gm TDS •Clinical cure rate In-hospital outcome 1year
•Recurrence rates at 1year •Clinical response: 40/42
Age: 35.4years for 20days Additional outcome
Ulcerative colitis patients M:F=20:22 •Effect on cellular and humoral
immunity (using lymphocyte transformation
rate and change in immunoglobulins levels)
Control group, n=40
Age: 34years
M:F=18:22
Grigoreva
GA 2011,
Russiaa
Nonrandomized, case-
control study
n=277, previously
exposed to
immunomodulators
Induction: 1.7 Oral 5-ASA, steroids and
immunomodulators
•Symptoms resolution Clinical improvement:
238/277
Upto
20yearsATA for 40 min per ses-
sion; consecutive for 12
sessions
•Endoscopic resolution of activity
(Control data not
given) Maintenance: 1.7 ATA for
40min per session; once
yearly
Total number of session: 12–32
Pagoldh M,
2013,
Sweden
Open-labelled, randomised
trial, single-center study;
HBOT group, n=10 2.4 ATM for 90 min/session, 5
days/week, for 6 consec-
utive weeks (a total of 30
HBOT sessions)
Intravenous GCS treatment
(prednisolone equivalence 67mg),
oral mesalazine (1 200mg twice
daily on days 1–5 and thereafter
2 400mg twice daily), rectal
suppository prednisolone
(20mg once daily) and enema
prednisolone (37.5mg once
daily)
•Assessment of clinical outcome with
change in Mayo score, laboratory tests
and fecal weight.
In-hospital outcome 6months
Age: 29.5years •Clinical response: 2/10 Colectomy
rates reg-
istered for
4years
M:F=7:3 •Colectomy: 2/10
E2: 2 6 months outcome
•Clinical response: Reduction of ≥3 in the
Mayo score compared with baseline
•Colectomy: 5/10
Severe attack (Mayo score
>10) of extensive or left-
sided UC and negative
fecal cultures for infective
causes (including Clostrid-
ium difcile toxin)
E3:8
Control group, n=8
Age: 34.8years •PMSS,
M:F=4:4 •HRQoL using SF 36 and IBDQ
E2: 1
E3:7 Additional outcome
•Avoidance of colectomy
•HBOT safety evaluation
Bekheit M,
2016,
Egypt
Case series, consecutive
patients with refractory
UC
N-32 2.8 ATA for 60min per
session
Oral 5-ASA (3.2–4.8g/d) with 4g
(5-ASA) enema/day
•Clinical improvement at the end of HBOT
therapy – change in stool frequency and
presence of blood
In-hospital outcome At
1–3weeks
after com-
pletion of
HBOT
M/F-16/16 •Clinical improvement:
32/32Median Age: 34.5year
(range 19–50)
No of sessions: 5/week for
8 weeks (4 pts received
at 2.5 ATA were excluded
from analysis)
For severe cases
Oral methylprednisolone 40–50mg/d
and tapered over 4–6 weeks, plus
Azathioprine 2–2.5mg/kg/day
•Endoscopic improvement at 1–3 weeks
after completion of therapy – Mayo Clinic
Grading Scale
For more severe disease
Intravenous steroids (60mg
prednisolone equivalent per day)
•Histological improvement at 1–3weeks
after completion of therapy – Geboes
Scores and CD44 positivity, to estimate
the number of stem cells in the mucosa
Dulai PS,
2018,
USA
Sham controlled muticentric
randomizer trial;
HBOT group, n=10 2.4 atmospheres for 90min
for 5–10days;
Intravenous steroids were administered
at a dose equivalent to 60mg intrave-
nous methylprednisolone every 24h.
•Clinical remission at day 5: partial Mayo
score ≤2 with no subscore >1
In-hospital outcome 12months
Age: 47 (40–57) •Clinical remission at day
5: 5/10
Hospitalized UC moder-
ate–severe ares (Mayo
score≥6 and endoscopic
subscore≥2)
M:F=4:6 Monoplace hyperbaric
chambers
•Clinical response at day
5: 8/10E2: 2 •Clinical response: reduction in partial
Mayo score≥2, rectal bleeding
subscore of 0–1)
•Second-line treatment
(Iniximab): 1/10
E3: 8
Control group, n=8 12-month outcome
Age: 31 (22–43) Second-line therapy (colectomy or biologic
therapy) during the hospitalization or
during 12-month follow up
•Iniximab: 2/10
M:F=5:3 Colectomy: 4/10
(Continued)

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4 European Journal of Gastroenterology & Hepatology xxx 2021 • Volume XXX • Number XXX
Dulai PS,
2020,
USA
Open label, muticentric
study;
N=20 2.4 atmospheres for
90min for 3days;
Responders at day 3
randomised to additional
2days of HBOT or not
(both monoplace and
multiplace)
Methylprednisolone at least
40mg/day
•Clinical response at Day 3: reduction in the
modied partial Mayo score (SFS+RBS)
of 2 with atleast 1 point drop in RBS
In-hospital outcome 3 months
•Clinical response at day
3: 11/20
Mean age: 37±15
years
UC patients hospitalized
for acute ares (Mayo
score 6 or more)
•Second-line treatment
(iniximab/colectomy):
3/20
M:F=10:10
E3: 17
75% biologic failure 3-month outcome
•Need for second-line therapy Colectomy
rates (3 months)
•Rehospitalization: 2/20
Colectomy: 6/20
•Rehospitalization (3months)
Additional outcome
Comparison of Day 3 and Day 5 therapy
Crohn’s disease
Lavy, 1994,
Israel
Case series, multicentre
study,:
n=10 2.5 ATA for 90min, 6days/
week in multiplace cham-
ber;
ASA/sulfasalazine-9 •Clinical response: healing of stula Clinical response: 8/10 18 months
M:F=6:4 Steroids-1 (3 after one session, 2
after two session, and
3 after three sessions)
pL1=1 No medications-1
pL2=6
Refractory perianal CD pL3=3 No. of sessions: 20-60
sessions (based on clinical
response)
Weisz G,
1997,
Israel
Case series, multicentre
study;
n=7 2.5 ATA for 90min in a multi-
place hyperbaric chamber;
5-ASA or sulfasalazine •Change in proinammatory cytokine (IL-1,
IL-6 and TNF-α) in perianal CD patients
Clinical response: 7/7 NA
M:F=3:4 (complete healing- 5/7
and partial healing -2/7)Perianal CD with low grade
of disease activity
Mean age
45.5±13years •Clinical response: stula healing
No. of sessions: 20-40
sessions (depending on
clinical response)
Colombel
JF, 1995,
France
Case series, single-center
study;
n=10 2.5 ATA for 120min; two
session/day
All had previous surgery •Clinical healing Clinical response: 6/10 3 months- 1
yearMean age: 30years •Cardiff classication (complete healing-3 and
partial healing-3)Severe perianal Crohn’s
disease
M:F=2:8 ±TPN (3 patients) ±AZA/Sulpha (6
patients) ±5-ASA (5 patients) ±Met-
ronidazole (6 patients) ± local surgery
(4 patients)
pL1=1 Total 40 sessions over 4weeks
in multiplace chamberpL2=7
pL3=2
Grigoreva
GA 2011,
Russiaa
Nonrandomized, case-con-
trol study
n=242, previously
exposed to immuno-
modulators (control
data not given)
Induction: 1.7 Oral 5-ASA, steroids and
immunomodulators
•Symptoms resolution Clinical improvement:
208/242
Upto
20yearsATA for 40 min per session; •Endoscopic resolution of activity
Consecutive for 12 sessions
Maintenance:
1.7 ATA for 40min per ses-
sion; once yearly
Total number of session:
12–32
Iezzi LE,
2011,
Brazil
Case series, single-center
study;
n=14 2.4 ATA for 2h daily in
monoplace chamber;
NA •Clinical response: closure of enterocutane-
ous stulas, complete healing of
Pyoderma Gangrenosum and perineal
Crohn’s disease
Clinical response: 11/14
(complete or partial
response)
No long-
term
follow-up
PCD, n=8
pharmacotherapy refractory
CD associated with ECF,
PCD or PG
ECF, n=3
ECF+PG, n=1
ECF+PCD, n=1 No of sessions: 10–50
ECF+PG+PCD, n=1
Agrawal
G, 2015,
Australia
Case series, single-center
study; severely active CD
and intractable stulae
n=9 2.0– 2.4 ATM (2–2.4 bar)
for 90min for 18–30
daily sessions (mean: 21.8
sessions) in a monoplace
or multiplace chamber
Iniximab 5mg/kg (three to eight
infusions; mean: 4.4 infusions)
•Clinical response: Change in clinical symp-
toms, complete stula healing with dry,
nonoozing skin
Clinical response: 9/9 Mean 18
months(complete stula
healing- 9)
All biologic failure AND
Anti-MAP therapy: •Endoscopic response: ndings of healed
mucosaRifabutin, clarithromycin and clo-
fazimine±ethambutol±Ciprooxa-
cin/ Metronidazole
•Imaging response: MRI improvement
(Pre and post-treatment) (Continued)
Table 1. (Continued)
Author,
country, year
Study
design
Patients
characteristics
Dosage and
duration of HBOT Additional treatment Outcomes assessed Response with HBOT
Follow-up
period

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www.eurojgh.com 5
Hyperbaric oxygen therapy in IBD Singh et al.
Keihanian
S, 2015,
USAb
Retrospective case series,
single-center study;
perianal and/or EC stula
with CD
n=7 2.4 ATA for 90 minutes, 5
days per week;
Biologics-5 • Response denition not given (divided as
complete, partial or response)
Clinical response: 5/7 NA
M:F - 3:4 Tacrolimus-2 (Complete response - 3/7,
partial response - 2/7,
and no response - 2/7
Mean age: 35years Tofacitinib-1
ECF=4 (1 with PG and
1 with PF)
No of sessions: >20sessions No medical treatment-1
PF=1
Vulvar stula-1
Periostomal wound=1
Feitosa MR,
2016,
Brazil
Case series, single-center
study; pharmacotherapy
refractory CD associated
with ECF, PCD or PG
n=29(27)c2.4 ATA for 2h; Local surgical debridement if needed • Clinical response: Closure of
enterocutaneous stulas, complete
healing of Pyoderma Gangrenosum and
perineal Crohn’s disease
Clinical response: 22/29 No long
term
follow up
M:F-15:14 Median number of
sessions: 20 (range, 10-86)
PG: 3/3
PCD, n=15 ECF(±PG±PCD: 10/11
ECF, n=8 PCD: 10/15
PG, n=3 2nd line therapy: 7/29
(major surgery, intestinal
diversion with proc-
tectomy or abdominal
perineal)
ECF+PCD=1
ECF+PG, n=1
PCD+ECF+PG, n=1
Lansdorp
CA, 2020,
Nether-
land
Case series, Crohn’s
disease patients with
high perianal stula(s)
failing conventional treat-
ment for over 6 months
n=20 243-253 kilopascal for
80min;
Anti-TNF with an immunomodulators:
9 patients
Primary outcome (at week 16) Decrease in median PDAI
score from 7.5 (95% CI
6–9) to 4 (95% CI 3–6
Decrease in modied
van Assche score from
9.2 (95% CI 7.3–11.2)
to 7.3 (95% CI 6.9–9.7)
16 Weeks
(Follow
up of 60
weeks for
the study
to be
com-
pleted)
M:F-13:7
Median age: 34 (24–49)
years
•Improvement in perianal disease activity
index (PDAI) at week 16
Total 40 sessions over
8-week duration
(5 session/week)
Anti-TNF
Monotherapy: 4 patients
Biological failure: 15 •Improvement in modied vanAssche index
(on MRI) week 16
Anti-TNF therapy with chronic
antibiotic: 1 patient
Clinical response: 12/20
Secondary outcome (at week 16) Clinical remission: 4/20
Vedolizumab: 1 patient
Ustekinumab: 1 patient •Clinical response: reduction of ≥50% in
the number of draining stulasMesalamine: 1 patient
•Clinical remission: absence of draining
stulas upon gentle nger compression
Piotrow-
icz G,
Polandb
Observational study, multi-
centre
n=7 2.5 ATA for 90 minutes
for 30 sessions
Biological therapy and immunomodu-
latory therapy: 3 patients
•CDAI scale Clinical response: 5/7 6 weeks
M:F=4:3 • Biomarkers: fecal calprotectin, blood CRP Imaging response
(MRI+endoscopy): 5/7Two groups
Group 1: 3 patient,
(biological therapy
and immunomodula-
tory therapy)
Only immunomodulatory therapy: 4
patients
•Endoscopy and MRI of the pelvis with
contrast
Group 2: 4 patients
(only immunomodula-
tory therapy)
CD, Crohn’s disease; HBOT, hyperbaric oxygen therapy; UC, ulcerative colitis.
aNon-English.
bPublished as abstract.
cWe excluded two patients with pyoderma gangrenosum only.
Table 1. (Continued)
Author,
country, year
Study
design
Patients
characteristics
Dosage and
duration of HBOT Additional treatment Outcomes assessed Response with HBOT
Follow-up
period

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6 European Journal of Gastroenterology & Hepatology xxx 2021 • Volume XXX • Number XXX
package. The outcomes were extracted as binary values.
The summary proportion was calculated by inverse var-
iance method with random effect approach. The pro-
portions were logit transformed for the computation of
summary. The summary odds ratio was calculated by
inverse variance method with random effect approach.
The heterogeneity was estimated by I2 and using P-value
of heterogeneity (P<0.10).
Risk of bias analysis
Two of the investigators (A.J. and D.K.J.) independently
assessed the methodological quality and risk of bias of
every study. For randomized controlled trial, risk of bias
assessment was done using Cochrane revised risk of bias
tool RoB 2.0 [14]. We used the Joanna Briggs Institute
Critical appraisal checklist for observation studies and
case series [15]. Joanna Briggs Appraisal checklist includes
questions about inclusion, standard and similar methods
of diagnosing the condition and consecutiveness & com-
pleteness of participant data and outcomes.
Results
Study selection
A total of 263 titles were identied and two additional
articles were identied from cross references and citations.
Among the 265 titles, there were 75 duplicates. Therefore,
a total of 190 articles were screened for title and abstract
and 21 studies underwent full-text screening (Fig. 1,
PRISMA ow chart). After full-text assessment, three stud-
ies were excluded (reasons for exclusion in Supplementary
Table 2, Supplemental digital content 1, http://links.lww.
com/EJGH/A684) [16–18]. For quantitative synthesis, the
data from 16 studies were used (six for ulcerative colitis,
nine for Crohn’s disease and one for both ulcerative colitis
and Crohn’s disease), while two studies reporting about
use of HBOT in pouchitis were used for the systematic
review only [19–36]. Table1 provides the details of the
studies included in the meta-analysis including location,
type of study, characteristics of subjects, HBOT treatment
protocol, outcome assessed, denition of clinical response
and response rate and adverse events [19–34].
Ulcerative colitis
Seven observational studies including 425 participants
reported clinical response for ulcerative colitis. The pooled
response rate of HBOT in ulcerative colitis was 83.24%
[95% condence interval (CI): 61.90–93.82; I2 83%]
(Fig.2). Three randomized studies with 118 participants
were available for analysis. However, considering the dif-
ferent populations of the trials, treatment protocols, co-in-
terventions and treatment end-points, we did not combine
the three trials for pooled estimates in comparison to the
control group (Table2).
The pooled rates for second-line usage of therapy in
ulcerative colitis patients initially treated with HBOT was
15.36% (95% CI: 7.05–30.27; I2 0%) during hospitali-
zation and 42.75% (95% CI: 18.09–71.64; I2 69%) for
overall estimate (Supplementary Figure 1, Supplemental
digital content 1, http://links.lww.com/EJGH/A684). The
pooled rates of colectomy in ulcerative colitis patients ini-
tially treated with HBOT was 29.70% (95% CI: 12.50–
55.55; I2 60%) (Supplementary Figure 2, Supplemental
digital content 1, http://links.lww.com/EJGH/A684).
Crohn’s disease
There were 10 studies with 353 participants included in
estimating the pooled clinical response for Crohn’s dis-
ease. The pooled response rate of HBOT in Crohn’s disease
was 81.89% (95% CI: 76.72–86.11; I2 4%) (Fig.3). The
pooled prevalence of partial stula healing with the usage
of HBOT in Crohn’s disease patients was 34.29% (95%
CI: 17.33–56.50; I2 46%) and for the total stula healing
in Crohn’s disease patients was 47.64% (95% CI: 22.05–
74.54; I2 65%) (Supplementary Figure 3, Supplemental
digital content 1, http://links.lww.com/EJGH/A684).
Pouchitis
Two studies reported about the use of HBOT in the set-
ting of medically refractory or complicated pouchitis and
found improvement in modied Pouchitis Disease Activity
Index and improvement in seven of nine patients with s-
tula was noted in one of the studies (Supplementary Table
3, Supplemental digital content 1, http://links.lww.com/
EJGH/A684) [35–36].
Adverse effects
Adverse effects were reported in nine studies with 146
participants (Table 3). Most of the adverse effects were
nonsevere, reversible after completion of HBOT and did
not require interruption of therapy. Among the four ulcer-
ative colitis studies, only one study noted adverse effects
Fig. 2. Pooled clinical response rates of hyperbaric oxygen therapy in ulcerative colitis.

Copyright © 2021 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
www.eurojgh.com 7
Hyperbaric oxygen therapy in IBD Singh et al.
Table 2. The response rates in various randomised trials for use of hyperbaric oxygen therapy in ulcerative colitis as compared to controls
Author, country,
year Study design
Patients
characteristics
HBOT
regimen
Additional
treatment Outcomes assessed Response
Follow-up
period Comments
Zhang P, 2001,
ChinaaRandomised controlled trial,
single-center;
HBOT group 2 ATM for 60 min
once a day for
20 days
Oral sulphasalazine •Clinical cure rate HBOT group 1 year •Severity and extent of ulcer-
ative colitis patient was not
given
•Recurrence rates at 1 year In-hospital outcome
N = 42 •Clinical response: 40/42
Age: 35.4 years
Ulcerative colitis patients Additional outcome Control group •Outcome measures not
standardizedIn-hospital outcome
•HBOT regimen different from
other studies
•Clinical response: 30/40
M:F = 20:22 •Effect on cellular and humoral
immunity (using lymphocyte
transformation rate and
change in immunoglobulins
levels)
Control group N
= 40
Age: 34 years
M:F = 18:22
Pagoldh M,
2013,
Sweden
Open-labelled, randomised
trial, single-center study;
HBOT group 2.4 ATM for 90
min/session, 5
days/week, for
6 consecutive
weeks (a total
of 30 HBOT
sessions)
Intravenous steroids
(tapering doses),
•Assessment of clinical out-
come with change in Mayo
score, laboratory tests and
fecal weight.
HBOT group 6 months •Number of patients included
(n = 18) were less than
the calculated number of
patients (n = 24)/number of
patients necessary to detect
a possible difference (n = 96)
N = 10 In-hospital outcome Colectomy
rates
registered
for 4 years
Age: 29.5 years •Clinical response: 2/10
Oral mesalazine,
•Clinical response: reduction
of ≥3 in the Mayo score
compared with baseline
•Colectomy: 2/10
Inclusion 6 months outcome
•Severe attack (Mayo
score >10) of extensive
or left-sided UC, and
M:F = 7:3 Rectal suppository
prednisolone,
•Colectomy: 5/10
E2: 2 Control group
E3:8 •Patients’ Medical Safety
Score (PMSS)Control group Enema prednisolone In-hospital outcome •Denition of severe disease
based on Mayo score (Mayo
score >10)
•HRQoL using SF 36 and
IBDQ
•Clinical response: 5/8
•Negative fecal cultures for
infective causes
N = 8
Additional outcome •Colectomy: 0/8
Age: 34.8 years •Avoidance of colectomy 6 months outcome
•>17 years of age •Excludes the patients on
systemic anti-inammatory
drugs
Exclusion M:F = 4:4 •HBOT safety evaluation •Colectomy: 2/8
•On systemic anti-inamma-
tory drugs (steroids,
IMMs, or anti-TNF)
E2: 1
E3:7 •HBOT regimen was as used
in other clinical situations
Dulai PS, 2018,
USA
Sham-controlled
muticentric randomised
Trial;
HBOT group
N = 10
2.4 atmospheres
for 90 min for
5–10 days;
Intravenous •Clinical remission at day 5:
partial Mayo score ≤2 with
no subscore > 1
HBOT group 12 months •Study was terminated early
due to poor recruitment
(recruited 18 patients of 70
planned)
steroids In-hospital outcome
Age: 47 (40–57) • Clinical remission at day 5: 5/10
Hospitalized UC moder-
ate–severe ares
(Mayo score ≥ 6 and
endoscopic
subscore ≥ 2)
•Clinical response: reduction
in partial Mayo score ≥ 2,
rectal bleeding subscore
of 0–1)
•Clinical response at day 5: 8/10 •Included patients with
moderate to severe disease
(Mayo score ≥ 6, endoscopic
subscore ≥ 2)
M:F = 4:6 Monoplace •Second-line treatment (inixi-
mab): 1/10E2: 2 Hyperbaric
chambersE3: 8 12-month outcome
Control group Second-line therapy (colec-
tomy or biologic therapy)
during the hospitalization or
during 12 month follow up
•Iniximab: 2/10
•Colectomy: 4/10 •Includes patients developing
are on systemic anti-in-
ammatory drugs: steroids,
anti-TNF
N = 8 Control group
In-hospital outcome
Age: 31 (22–43) •Clinical remission at day 5: 0/8
•Initial HBOT sessions planned
for 10 days and later
changed to 5 days due to
patients unwillingness to
return to complete 10 daily
sessions
M:F = 5:3 •Clinical response at day 5: 3/8
•Second-line treatment: 5/8 (anti-
TNF-2, Colectomy-3)
12-month outcome
•Iniximab: 2/8
•Colectomy: 5/8
CD, Crohn’s disease; HBOT, hyperbaric oxygen therapy; UC, ulcerative colitis.

Copyright © 2021 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
8 European Journal of Gastroenterology & Hepatology xxx 2021 • Volume XXX • Number XXX
where two patients developed HBOT-related events (intol-
erance and inability to normalize the middle ear pressure)
while other three studies found no adverse event. None of
the patients developed severe adverse events after HBOT.
Among the Crohn’s disease, ve studies reported the
adverse events. Two studies noted no HBOT-related adverse
events. Among the three studies with adverse events, intol-
erance to the HBOT was the most common adverse effect
(n=8). Other nonsevere side effects were anxiety, inabil-
ity to normalize the middle ear pressure, abdominal pain,
vomiting, fatigue and visual change. Severe adverse events
noted were middle ear barotrauma in six patients (one
developed bilateral eardrum perforation).
Risk of bias
The risk of bias was assessed using the RoB 2.0 for the
three randomized controlled studies. One study had low
overall risk of bias, one had high risk of bias and one trial
had some concerns (Supplementary Table 4, Supplemental
digital content 1, http://links.lww.com/EJGH/A684).
Risk of bias for the included observational cohort stud-
ies was done using the Joanna Briggs checklist, which
suggests against using a score for quality assessment
(Supplementary Table 5, Supplemental digital content
1, http://links.lww.com/EJGH/A684 and Supplementary
Table 6, Supplemental digital content 1, http://links.lww.
com/EJGH/A684).
Discussion
The results of the present meta-analysis showed a pooled
clinical response rate of 83.24% when HBOT was used
as an adjunct to standard therapy in active ulcerative
colitis. Although pooled estimate suggests a high degree
of benet, the differences in available randomized stud-
ies with different population, co-intervention, treat-
ment protocols and end points, preclude combining the
data and to draw a denite conclusion on the benet of
adjunctive HBOT. Colectomy rates were 30% for ulcera-
tive colitis after initial treatment with HBOT along with
medical therapy. In Crohn’s disease, the pooled response
rate was 81.89% when HBOT was used as an adjunctive
therapy. In stulizing Crohn’s disease, the pooled healing
rates for complete response were 47% and for partial
healing was 34%.
In the setting of active ulcerative colitis, the sum-
mary estimate from the observational studies suggested a
good initial response with the use of HBOT. We found
a cumulative response rate of 83% in ulcerative colitis
ares. Although the cumulative response with HBOT was
excellent, these results should be read with caution in the
absence of placebo-controlled trial/pooled estimate. Of
the three published randomized trials, two studies showed
no benet of using adjunctive HBOT while one study
showed short-term benet in achieving clinical remission
without using second-line therapy. The study by Dulai
et al., which showed benet with the use of HBOT, was
deemed to be methodologically sound with least risk of
bias. The use of HBOT is further supported by a recent
study on cost-effective analysis, which showed that use of
HBOT during acute are reduced the risk of subsequent
hospitalization, in-patient rescue medical therapy and
in-patient emergency colectomy. The initial increase in
cost of HBOT was found cost-effective during a 5-year
Fig. 3. Pooled clinical response rates of hyperbaric oxygen therapy in Crohn disease.
Table 3. Adverse events reported in various studies reporting the use
of hyperbaric oxygen therapy in ulcerative colitis and Crohn’s disease
Study Adverse effects
Ulcerative colitis
Pagoldh M, 2013, Sweden Intolerance due to claustrophobia-1
Inability to normalize middle ear pressure-1
Zhang P, 2001, China NA
Dulai P, 2018, USA None
Karkumov M, 1991, Bulgaria NA
Grigoreva GA 2011, Russia NA
Bekheit M, 2016, Egypt None
Dulai PS, 2020, USA None
Crohn’s disease
Lavy, 1994, Israel None
Weisz G, 1997, Israel NA
Colombel JF, 1995, France Intolerance-7
Bilateral eardrum perforation-1
Grigoreva GA 2011, Russia NA
Iezzi LE, 2011, Brazil NA
Agrawal G, 2015, Australia NA
Keihanian S, 2015, USA* Ear congestion and sinus pressure-1
Anxiety and intolerance-1
Feitosa MR, 2016, Brazil None
Piotrowicz G, Poland NA
Lansdrop, 2020, Netherland Inability to equalize middle ear pressure-3
Mild to moderate barotrauma to middle ear-5
Abdominal pain-1
Vomiting and Diarrhea-1
Fatigue-5
Visual change-2

Copyright © 2021 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
www.eurojgh.com 9
Hyperbaric oxygen therapy in IBD Singh et al.
horizon with increased quality-adjusted life year (QALYs)
[37]. However, limitations exist on the use of HBOT as it
requires daily therapy in specialized centers and consider-
ing the availability and patient’s acceptability may impair
the use of this important adjunctive therapy. These limita-
tions were highlighted in two of the three published rand-
omized trials, where both trials were stopped prematurely
due to slow recruitment of patients [22,24]. Further the
continuous use of HBOT sessions over for maintenance of
response/remission remains unexplored.
Fistulizing Crohn’s disease is a difcult to treat clinical
condition with only a few known effective therapies like
anti-TNF and thiopurines with response rates from 30 to
68% [34,38]. Most of the cases still remain intractable
and require surgical therapies including additional seton
placement, proctectomy and permanent stoma [39,40].
Perianal stulas in Crohn’s disease are prone for co-exist-
ing infection and on-going ischemia further increases the
persistent colonization of anaerobic organism [41]. HBOT
has been recognized as a potential therapeutic option for
stulizing Crohn’s disease and increases the stula healing
by improving the oxygenation of hypoxic tissues and cre-
ating an unfavorable environment for anaerobic survival
[41]. HBOT also decreases the active inammation by sup-
pressing the proinammatory cytokines, i.e. TNG-α, IL-1
and IL-6 and improves wound healing through enhanc-
ing host antibacterial response, growth factor synthesis
and stimulating angiogenesis [38–42]. The data from the
present meta-analysis suggest 83% response rates for s-
tulizing Crohn’s disease. This lays ground for randomized
trials in the setting of difcult to treat IBD like stulizing
Crohn’s disease.
The use of HBOT is further extended in the setting
of medical refractory or pouchitis. Two of the recently
published studies found clinical as well as endoscopic
improvement in patients with pouchitis with or without
stula [35,36]. Refractory pouchitis often impairs the
quality of life and adjunctive HBOT can be considered in
these patients based on the available data. Further pro-
spective data will be required to strengthen the recommen-
dation of HBOT in pouchitis.
Most important issue with the use of HBOT is the
acceptability of this potential adjunctive therapy. It
requires daily treatment sessions, which affect the daily
life activities of the patients. Furthermore, the aspect of
intolerance to therapy due to high pressure and claustro-
phobia leads to early discontinuation of therapy in some
patients [22]. Rare serious adverse events of eardrum
perforation and difcult equalizing middle ear pressure
have been reported. Reported intolerance rates as well as
serious adverse events are low in IBD when comparing
HBOT for other indications; however, this comparison is
difcult to make in the presence of variations in treatment
protocol across the studies and short-term use of HBOT
in the majority of IBD patients and retrospective nature
of some studies. Risk of myopia, vision change and baro-
trauma (including ear perforations and pneumothorax)
will remain a concern in the absence of well-dened treat-
ment protocol. Further trials are required to identify the
adequate pressure and number of sessions of HBOT with
its long-term safety and impact on disease.
The limitations of the present analysis include hetero-
geneity in patient selection, differences in HBOT protocol,
relatively small numbers in randomized studies, variations
in pretreatment severity of the disease. These limit the gen-
eralizability of the ndings. Despite these limitations, this
meta-analysis gives updated evidence on the current status
of use of HBOT in IBD and suggestions for future direc-
tion of research in this eld.
In conclusion, good response rates were reported with
the use of HBOT in active ulcerative colitis in observa-
tional studies. Also, good stula healing rates in Crohn’s
disease were noted in the available case series.
Acknowledgements
Author Contributions: Conception – V.S. and S.S.;
L.iterature Search: V.S. and A.K.S.; Screening and Selection
– A.K.S., D.K.J. and V.S.; Data analysis – P.K.-M.; Risk of
Bias – D.K.J., A.J., A.K.S. and V.S.; Initial Draft – A.K.S.,
P.K.-M. and V.S.; Revisions and Intellectual inputs – V.S.
and S.S.; Approval – all authors.
Conflicts of interest
There are no conicts of interest.
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