the effect of hyperbaric oxygen therapy on immune response and oxidative stress

Hyperbaric oxygen therapy

HBO consists of breathing 100% oxygen under higher than normal atmospheric
pressure:
usually 1.5-2.8 atmosphere absolute (ATA). This increases plasma and tissue
oxygen levels,
and decreases hypoxia. HBOT is commonly used in the treatment of decompression
sickness, carbon monoxide intoxication, arterial gas embolism, necrotizing soft
tissue infections, chronic skin ulcers, severe multiple trauma with ischemia
and ischemic diabetic foot ulcers.

HBOT and immunologic response

Several reports have been published in regards to the immunologic effects of
HBO on specific patient populations (for instance patients with Crohns Disease)
and animals. For example it has been shown to alter signaling pathways such as
Hypoxia Induced Factor (HIF) and heme-oxygenase (HO), both involved in tissue
response to hypoxia and wound repair. Furthermore, the production of
pro-inflammatory cytokines and chemokines (IL-1, IL-6, TNF-alfa) is suppressed
by HBO. [1] Also, in general, oxidative stress is recognized to play a role in
stem cell mobilization and promoted wound healing. [2].
However, to our knowledge, there are no reports in regards to the immunologic
effects of HBO in healthy individuals. We have performed a search of literature
but found no such articles. In our study we will investigate the effect of HBO
on the immunologic parameters and oxidative stress factors:

HBOT and surgery

Previous data by Yang and colleagues on animals demonstrated that HBO inhibits
TNF- * production during intestinal ischemia-reperfusion [3] with a beneficial
effect, mediated by decreased production of both TNF-* and IL-1*, on
indomethacin-induced enteropathy [4]. Preconditioning with HBO might be useful
as an adjunct for various types of surgery. For instance, a better outcome in
left ventricular function was demonstrated after on-pump coronary artery bypass
surgery after pretreatment with three HBO sessions [5]. The positive role of
HBO in human surgery has further been demonstrated in other cardiovascular [6,
7], orthopedic surgery [8], and after liver transplantation, as reported by
Franchello et al. which documented a reduction of ischemic areas and an
increase of intrahepatic arterial vascularisation by collateral vessels after
20 HBO sessions in a patient affected by Hepatic Artery Thrombosis (HAT) after
liver transplantation [9] Bosco et al performed a prospective randomized,
double blind study in which they evaluated the post-operative biological and
clinical effects of single hyperbaric-treatment the day before surgery for
pancreatic ductal adenocarcinoma [10]. This study showed that HBOT
significantly decreased the serum IL-6 level which was associated with biliary
fistula. It also showed significantly less pulmonary infections in patients in
the HBO group. However, IL-8 and IL-12 were not affected by HBO exposure. A
recent meta-analysis of our group showed that post-operative HBO had a positive
effect on colorectal anastomoses in rats [11]. This study effect was most
prominent on colorectal anastomoses in rats without a malignancy and in
ischemic anastomoses. To investigate the full potential of HBO to prevent
anastomotic leakage in human patients undergoing colorectal surgery, a pilot
study should be performed in due time. However, all earlier studies have been
conducted on animals or specific patient populations. To understand the
underlying mechanisms of HBOT, we first need to determine the immunologic
effects of HBO in healthy volunteers.

Study
We initiated the present pilot study to evaluate effects of HBOT on the immune
response and oxidative stress in healthy young, male volunteers. These findings
will help guide further re-search and sample size assumptions.

To explore the effects of HBOT on immunologic parameters and oxidative stress.

Pilot of a prospective cohort study.

A total of 15 healthy volunteers will undergo the HBOT sessions. The volunteers
will receive a total of three HBOT sessions with 24-hour intervals. Hyperbaric
treatment will consist of three treatments breathing 100% air at a pressure of
2.4 atmosphere absolute. The total duration of one treatment is 110 minutes
(total of 80 minutes of breathing 100% oxygen with 5-minute breaks on normal
air, total session time: 110 minutes)

Laboratory findings will be obtained before and after the 3 HBOT sessions
according to schedule below. In total, six 10.5 ml blood samples will be drawn
from the volunteers, adding up to 63 ml in total. Patients will be seen by the
hyperbaric physician before the start of hyperbaric treatment. During
hyperbaric sessions patients will be under supervision of the hyperbaric
physician and a separate appointment will be scheduled at the end of treatment,
at which side-effects of treatment will be evaluated. Inclusion, treatment and
assessment of outcomes will be done in an outpatient clinic-setting.

Blood sample schedule.
- Directly before session one * T0
- Directly after session one * T1
- Directly before session two * T2
- Directly after session two * T3
- Directly after session three * T4
- 24 hours after session three * T5

The volunteers will receive a total of three HBOT sessions. Hyperbaric
treatment in the intervention group will consist of three treatments breathing
100% air at a pressure of 2.4 atmosphere absolute. The total duration of one
treatment is 110 minutes (total of 80 minutes of breathing 100% oxygen with
5-minute breaks on normal air, total session time: 110 minutes)

The risk of this study is considered negligible. 63ml blood sampling is a
relatively small amount and harmless in healthy volunteers. Hyperbaric oxygen
therapy is routinely used in the treatment of for instance different wound
healing problems. Risks associated with HBO include ear and/or sinus complaints
(squeeze/perforations), myopia, acute oxygen toxicity (seizures) and
decompression illness.
* Ear and/or sinus complaints include middle ear and sinus squeeze, due to an
inability to or late equalizing. This presents as acute pain and if not dealt
with, may result nose or ear bleeding and in case of middle ear squeeze result
in perforation of the ear drum. The overall risk to develop ear and sinus
complaints is reported to be 2-3%.1,2
* Visual changes due to myopia have been reported in up to 60 to 70% of
patients, but these changes are reversible and mostly mild. No lasting effects
are seen in patients receiving less than 50 treatment sessions (as is the case
in this protocol).2,3
* Acute oxygen toxicity results in seizures when the central nervous system is
exposed to a toxic level of oxygen. These symptoms resolve quickly en without
residue once the exposure to high level of oxygen is diminished. The clinical
HBO protocol takes this into account by limiting oxygen breathing to sections
20 minutes before a 5-minute break breathing room air. The risk to develop
acute oxygen poisoning is reported to be 0.02 to 0.3% in a clinical setting.4,5
* Given that patients breathe 100% oxygen, there is no risk of decompression
illness.


[1] D. T. Fitzpatrick, B. A. Franck, K. T. Mason, et al. Risk factors for
symptomatic otic and sinus barotrauma in a multiplace hyperbaric chamber.
Undersea Hyperb Med, vol. 26, nr. 4, pp. 243-7, 1999.
[2] E. M. Camporesi. Side effects of hyperbaric oxygen therapy. Undersea Hyperb
Med, vol. 41, nr. 3, pp. 253-7, 2014.
[3] Churchill S, Deru K, Wilson G, Cable R, Bell JE, Weaver LK. Rates of visual
acuity change in patients receiving hyperbaric oxygen in monoplace and
multiplace chambers. Undersea Hyperb Med 2016;43:217-23.
[4] S. Yildiz, S. Aktas, M. Cimsit, et al. Seizure incidence in 80,000 patient
treatments with hyperbaric oxygen. Aviat Space Environ Med, vol. 75, nr. 11,
pp. 992-4, 2004.
[5] S. Hadanny, O. Meir, Y. Bechor, et al. Seizures during hyperbaric oxygen
therapy: retrospective analysis of 62,614 treatment sessions. Undersea Hyperb
Med, vol. 43, nr. 1, pp. 21-8, 2016.