medicina

Review
A General Overview on the Hyperbaric Oxygen Therapy:
Applications, Mechanisms and Translational Opportunities
Miguel A. Ortega 1,2,3, * , Oscar Fraile-Martinez 1,2, * , Cielo García-Montero 1,2 , Enrique Callejón-Peláez 4 ,
Miguel A. Sáez 1,2,5 , Miguel A. Álvarez-Mon 1,2 , Natalio García-Honduvilla 1,2 , Jorge Monserrat 1,2 ,
Melchor Álvarez-Mon 1,2,6 , Julia Bujan 1,2 and María Luisa Canals 7

1 Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of
Alcalá, 28801 Alcala de Henares, Spain; cielo.gmontero@gmail.com (C.G.-M.); msaega1@oc.mde.es (M.A.S.);
maalvarezdemon@icloud.com (M.A.Á.-M.); natalio.garcia@uah.es (N.G.-H.); jorge.monserrat@uah.es (J.M.);
mademons@gmail.com (M.Á.-M.); mjulia.bujan@uah.es (J.B.)
2 Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain
3 Cancer Registry and Pathology Department, Hospital Universitario Principe de Asturias,
28806 Alcala de Henares, Spain
4 Underwater and Hyperbaric Medicine Service, Central University Hospital of Defence—UAH Madrid,
28801 Alcala de Henares, Spain; ecalpel@fn.mde.es
5 Pathological Anatomy Service, Central University Hospital of Defence—UAH Madrid,



28801 Alcala de Henares, Spain

 6 Immune System Diseases—Rheumatology, Oncology Service an Internal Medicine, University Hospital
Citation: Ortega, M.A.; Príncipe de Asturias, (CIBEREHD), 28806 Alcala de Henares, Spain
7 ISM, IMHA Research Chair, Former of IMHA (International Maritime Health Association), 43001 Tarragona,
Fraile-Martinez, O.; García-Montero,
C.; Callejón-Peláez, E.; Sáez, M.A.; Spain; mlcanalsp@gmail.com
* Correspondence: miguel.angel.ortega92@gmail.com (M.A.O.); oscarfra.7@hotmail.com (O.F.-M.);
Álvarez-Mon, M.A.;
Tel.: +34-91-885-40-45 (M.A.O.); Fax: +34-91-885-48-85 (M.A.O.)
García-Honduvilla, N.; Monserrat, J.;
Álvarez-Mon, M.; Bujan, J.; et al. A
Abstract: Hyperbaric oxygen therapy (HBOT) consists of using of pure oxygen at increased pressure
General Overview on the Hyperbaric
(in general, 2–3 atmospheres) leading to augmented oxygen levels in the blood (Hyperoxemia) and
Oxygen Therapy: Applications,
Mechanisms and Translational
tissue (Hyperoxia). The increased pressure and oxygen bioavailability might be related to a plethora
Opportunities. Medicina 2021, 57, 864. of applications, particularly in hypoxic regions, also exerting antimicrobial, immunomodulatory and
https://doi.org/10.3390/ angiogenic properties, among others. In this review, we will discuss in detail the physiological rele-
medicina57090864 vance of oxygen and the therapeutical basis of HBOT, collecting current indications and underlying
mechanisms. Furthermore, potential areas of research will also be examined, including inflammatory
Academic Editors: Costantino and systemic maladies, COVID-19 and cancer. Finally, the adverse effects and contraindications asso-
Balestra and Jacek Kot ciated with this therapy and future directions of research will be considered. Overall, we encourage
further research in this field to extend the possible uses of this procedure. The inclusion of HBOT
Received: 26 July 2021
in future clinical research could be an additional support in the clinical management of multiple
Accepted: 20 August 2021
pathologies.
Published: 24 August 2021

Keywords: hyperbaric oxygen therapy (HBOT); Hyperoxia; wound healing; antimicrobial properties;
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Coronavirus Disease-19 (COVID-19)
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1. Introduction
Hyperbaric oxygen therapy (HBOT) is a therapeutical approach based on exposure to
Copyright: © 2021 by the authors.
pure concentrations of oxygen (O2 ) in an augmented atmospheric pressure. According to
Licensee MDPI, Basel, Switzerland.
the Undersea and Hyperbaric Medical Society (UHMS), this pressure may equal or exceed
This article is an open access article
1.4 atmospheres (atm) [1]. However, all current UHMS-approved indications require that
distributed under the terms and patients breathe near 100% oxygen while enclosed in a chamber pressurized to a minimum
conditions of the Creative Commons of 2 ATA [2].
Attribution (CC BY) license (https:// The first documented use of hyperbaric medical therapy was in 1662 by Henshaw,
creativecommons.org/licenses/by/ a British physician who placed patients in a container with pressurized air. Interestingly,
4.0/). it was conducted before the formulation of the Boyle-Mariotte Law, which described the

Medicina 2021, 57, 864. https://doi.org/10.3390/medicina57090864 https://www.mdpi.com/journal/medicina

Medicina 2021, 57, 864 2 of 25

relationship between the pressure and volume of a gas, and prior to the discovery of O2 by
John Priestly over 100 years later [3]. Afterwards, the pathway of HBOT in medical care was
retarded by the observation of possible O2 -derived adverse effects at 100% concentrations
by Lavoisier and Seguin in 1789. Years later, in 1872 Paul Bert, considered the “father of
the hyperbaric physiology”, described the physiological basis of pressurized air in the
human body, also defining the neurotoxic effects of O2 in the human body, consequently
named the Paul Bert effect [4], followed by the description of the pulmonary toxicity of
O2 by Lorrain Smith [5]. Simultaneously, a growing interest in the use of HBOT in the
treatment of different affections was reported, including treatment for divers who suffered
decompression sickness during World War II [6]. Since then, a plethora of studies were
prompted, with hundreds of facilities based on HBOT being established at the beginning
of the 21st century [7].
Currently, there are 14 approved indications for HBOT, including a wide variety
of complications like air embolism, severe anemia, certain infectious diseases or idio-
pathic sensorial hearing loss. In addition, in the last European Consensus Conference on
Hyperbaric Medicine highlighted the use of HBOT as a primary treatment method for
certain conditions according to their moderate to high degree of evidence (e.g., after carbon
monoxide (CO) poisoning), or as a potential adjuvant to consider in other conditions with a
moderate amount of scientific evidence (e.g., Diabetic foot) [8]. In this work we will review
in detail the basis of O2 as a therapeutical agent and the principles of hyperbaric medicine
regarding most relevant applications concerning HBOT, and potential implications for
different approaches including COVID-19.

2. Physiological Role of Oxygen in the Organism

O2 is a frequently disregarded nutrient because of its particular access inside the
human body, through the lungs instead of the gastrointestinal tract, typical of all other
nutrients [9]. O2 is key for human cells to perform so-called aerobic respiration, which
takes places in the mitochondria. Here, O2 acts as an electron acceptor finally leading to
ATP synthesis in a process known as oxidative phosphorylation. From an evolutionary
perspective, the uptake of O2 was the origin of eukaryotic cells, emerging as a result of
an endosymbiotic relationship between prokaryotic cells (archaea and eubacteria) which
were capable of using this nutrient [10]. This fact represented an adaptative advantage
with regard to those cells unable to utilize it, complex organisms were coevolving with O2 ,
thus becoming an essential nutrient for our cells [11].
In a simple manner, O2 is introduced in our body by two distinguished process: ven-
tilation, in which gases are transported from the environment to the bronchial tree and
diffusion, where an equilibrium in the distribution of O2 between alveoli space and blood
is reached. Given that the partial pressure of O2 (PO2 ) here is low, and rich in carbon
dioxide (CO2 ), gas exchange occurs [12]. Simultaneously, the difference in the pressure
and volume in the chest wall and lungs are essential to permit the oxygen flow, as atmo-
spheric pressure does not vary at all [13]. Once in the bloodstream, O2 is mostly bound
to haemoglobin (Hb) in the erythrocytes, and to a little extent in a dissolved form, being
systemically distributed. Then, oxygen exchange is produced between the microcirculatory
vessels—Not only capillaries, but also arterioles and venules-and the rest of the tissues,
due to the different partial pressure of O2 and the Hb oxygen saturation (SO2 ), which is
also dependant on other variables like temperature, PCO2 and pH, among others [14].
If, however there is a lack of oxygen in the tissue it may appear a condition designed as
hypoxia. This may be due to low O2 content in the blood (Hypoxemia), which may be a
consequence of either a disruption in the blood flow to the lungs (Perfusion), airflow to
the alveoli (Ventilation) or problems in the gas diffusion in the haemato-alveolar barrier.
Furthermore, low blood supply (ischaemia) or difficulties in the O2 delivery, may also be
responsible for tissue hypoxia [15]. Consequently, within cells there are specific sensors
named as Hypoxia-inducible factors (HIF) that under hypoxic conditions will bind to
the hypoxia response element (HRE), thereby regulating a wide variety of cellular pro-
Medicina 2021, 57, 864 3 of 25

cesses [16]. Occasionally, hypoxia might provide favourable implications for health, for
instance during early developmental stages [17] or in the case of intermittent exposures [18].
Nonetheless, hypoxia mostly induce a pathological stress for cells that is closely related
with the appearance and progress of a broad spectrum of diseases [19]. As a result, oxygen
has been proposed as a potential therapeutic agent for patients undergoing different acute
or chronic conditions [20,21]. As targeting cellular hypoxia is a promising, but still an
emerging approach [22], clinical management of hypoxia is directed to modulate global
hypoxemia and oxygen delivery within the tissues [23]. In this context, HBOT arises as an
extraordinary support in the handling of hypoxia and other hypoxia-related phenomena
by increasing blood and tissue levels of oxygen [24]. Hereunder, we will describe the
principles and mechanisms of action of HBOT, regarding its therapeutical basis and specific
considerations of this therapy.

3. Principles of Hyperbaric Oxygen Therapy. Therapeutical Basis

As above mentioned, HBOT consist of the supply of pure oxygen under augmented
pressure. This procedure is conducted in a monoplace or multiplace chamber if there are
only one or various patients undergoing this procedure, respectively. In the first case, the
chambers are usually compressed with O2 whereas in the second, people breath oxygen
individually through a face mask, hood, or an endotracheal tube [25]. In the case of
critically ill patients, it seems that multiplace chambers allow a better monitoring of the
vital functions in comparison to monoplace chambers, although the use of the latter are
also safe and well tolerated by patients [26,27]. Depending on the protocol, the estimated
duration of session varies from 1.5 to 2 h and may be performed from one to three times
daily, being given among 20 to 60 therapeutical doses depending on the condition [28].
Frequently, this method utilizes between 2 to 3 atms of pressure. Nevertheless, it has
also been obtained promising results in some studies from <2 atms (1.5 atms) for certain
conditions [29,30], although according to all UHMS currently approved indications it is
required a chamber pressurized to a minimum of 2 ATA [2]. Despite some protocols accept
the use of 6 atms (i.e., treatment of gas embolism), little benefits are usually reported from
>3 atms as it may be associated with a plethora of adverse effects [31]. Moreover, it is
not possible to breath pure O2 at higher pressures than 2.8 atm, and in those cases it is
accompanied with other gases like helium, nitrogen or ozone. The alternative, normobaric
oxygen therapy (NBOT), utilizes oxygen at 1 atm of pressure. In comparison with HBOT,
NBOT is cheaper and easier to apply, and it could be found in almost all hospitals, as it does
not require hyperbaric chambers [32]. However, some studies have reported a reduced
efficacy of NBOT in comparison with HBOT [33,34], therefore showing the relevance of
HBOT for certain conditions. Conversely, the use of NBOT could be critical for patients
suffering from some maladies in absence of HBOT facilities.
The therapeutical basis of hyperbaric oxygenation are consequence of three main
factors: (1) By breathing 100% O2 , a positive gradient is created, hence favouring diffusion
for hyperoxigenated lungs to hypoxic tissues; (2) due to the high pressure, O2 concentration
in the blood raises according to Henry’s Law (the amount of dissolved gas within a liquid
is directly proportional to its partial pressure) and (3) it decreases the size of gas bubbles
in the blood following Boyle-Mariotte Law and Henry’s Law [6]. In other words, the
creation of a hyperbaric environment with pure oxygen permits a significant increment of
the oxygen supply to blood (Hyperoxemia) and to the tissues (Hyperoxia) even without
the contribution from Hb [35]. Thus, HBOT provides multiple effects in the organism, and
it could be used to correct tissue hypoxia, chronic hypoxemia and to aid in the clinical
management of different pathological processes including wound healing, necrosis, or
reperfusion injuries [36].
Contrary to hypoxia, the human body has not developed any specific adaptation
to hyperoxia. Interestingly, the exposure to intermittent hyperoxia, share many of the
mediators and cellular mechanisms which are induced by hypoxia. This is called the
hyperoxic-hypoxic paradox [37]. Importantly, it does not have to be considered a negative
Medicina 2021, 57, 864 4 of 25

property. As occurring with intermittent hypoxia, the submitting of short-term hyperoxia

may provide favourable outcomes in the cell. The explanation resides in a crucial concept
in biology, the hormesis, which correlates the type of response obtained with the dose
received [38]. From a molecular perspective, high PO2 in the tissues may have important
implications in the cellular signalling, particularly through increasing the production of
reactive oxygen species (ROS) and reactive nitrogen species (RNS). These changes induce
multiple effects in the organism, including the synthesis of different growth factors, improv-
ing neovascularization or showing immunomodulatory properties, among others, therefore
exerting its clinical efficacy [39,40]. Moreover, HBOT upregulates HIF, by ROS/RNS and
Extracellular Regulated Kinases (ERK1/ERK2) pathway [37,41]. In the same manner, an
excessive production of ROS and RNS due to hyperoxia may lead to the appearance of
oxidative stress, DNA damage, metabolic disturbances, endothelial dysfunction, acute
pulmonary injury and neurotoxicity [42]. As hyperbaric O2 may provide both beneficial
and adverse effects, it is essential to balance the different factors to clinically recommend or
reject HBOT [43]. Due to the physics of HBOT, it is not easy to design adequate studies and
clinical trials to fully endorse its use. Despite this, there are some predictive models that
may be an additional tool to evaluate what patients may benefit the most from receiving
this therapy, considering distinct therapeutical approaches if necessary [44].
In Figure 1 conditions and characteristics of hyperbaric chambers are illustrated,
besides the main effect of pressurized O2 administration. Below, main applications and
translational applications of HBOT will be subsequently discussed, in order to review the
actual importance of this procedure in current clinical practice and potential uses.

Figure 1. Illustration of a monoplace hyperbaric chamber and the effect of hyperbaric O2 . Pressurized O2 (2–3 atm) at
100% concentration is administered normally during 1.5–2 h per session and repeated three times a day. Depending on the
clinical condition sessions vary in number, from 20 to 60. The inhalated air comes from an external elevated PO2 , hence
positive gradient allows higher O2 entry, which per diffusion will be higher also in alveoli, bloodstream and therefore there
will be greater arrival to tissues. This effect of “hyperoxemia” and “hyperoxia” is independent from haemoglobin (Hb),
then will lessen hypoxia in tissues. This will result in a major supply of reactive oxygen species (ROS) and reactive nitrite
species (RNS), with a consequent higher expression of growth factors and promotion of neovascularization and enhanced
immunomodulatory properties.
Medicina 2021, 57, 864 5 of 25

4. Approved Indications for HBOT

Due to the multiple characteristics of HBOT, the possible applications of this proce-
dure are numerous. For instance, HBOT may be used as an urgent treatment for acute
pathologies but also as an additional support for chronic diseases [41]. Currently, there
are 14 approved indications for HBOT are represented in Table 1. Most of these uses,
can be grouped according to three main effects (a) in the wound healing acceleration
and angiogenesis enhancement (b) exerting antimicrobial effects, and (c) as a medical
emergency.

Table 1. Approved indications for HBOT.

Air or gas embolism

Acute thermal burn injury
Carbon monoxide poisoning
Carbon monoxide poisoning complicated by cyanide poisoning
Central retinal artery occlusion
Clostridial myositis and myonecrosis (gas gangrene)
Compromised grafts and Flaps
Crush injury, Compartment Syndrome and other acute traumatic ischemia
Decompression sickness
Delayed radiation injury (soft tissue and bony necrosis)
Enhancement of healing in selected problem wounds
Idiopathic sudden sensorineural hearing loss
Intracranial abscess
Necrotizing soft tissue infections
Refractory osteomyelitis
Severe anaemia

4.1. HBOT and Wound Healing: The Angiogenesis Enhancement

In clinical practice, it has been observed how HBOT can speed wound healing. As
wounds need oxygen to regenerate tissues properly, an exposure of 100% oxygen accelerates
this process. The application in this field is quite extensive, comprising microbial-infected
wounds (e.g., Clostridial myonecrosis and Fournier’s gangrene), traumatic wounds, ther-
mal burns, skin grafts, radiation-induced wounds, diabetic and vascular insufficiency
ulcers [45].
In the field of diabetes, there is a critical complication called “diabetic foot ulcers”,
an open wound at the bottom of the foot that affects 15% of patients. HBOT has been
specially regarded for this injury, being implicated many inflammatory and tissue repairing
parameters. For instance, there was some evidence that HBOT may improve the healing
rate of wounds, by increasing nitric oxide (NO) levels and the number of endothelial pro-
genitor cells, in the non-healing vasculitis, calcific uremic arteriolopathy (CUA), livedoid
vasculopathy (LV), pyoderma gangrenosum (PG) ulcers [46]. Some trials show a prominent
angiogenesis while reducing inflammation: angiogenic markers like epithelial growth
factor (EGF) and VEGF become enhanced, and positively associates to Nrf2 transcription
factor increase [47]. Furthermore, anaerobic infections have a lower occurrence and ampu-
tation rates immensely decrease [48,49]. Different systematic reviews support the adjuvant
use of systemic but not topical HBOT in the wound healing of diabetic foot ulcers [50,51].
However, studies results are quite heterogeneous, and it is still necessary to define which
group of patients may benefit most from this intervention [52]. For instance, patients with
diabetic foot ulcers and peripheral arterial occlusive disease may not improve wound
healing [53]. Another recent study demonstrated that the use of HBOT may be associated
with improved six-year survival in patients with diabetic foots [54]. Further studies and
greater samples are required to identify the most suitable candidates for HBOT.
Additionally, HBOT may be an excellent adjuvant in surgery injuries resolutions, and
it is key as it may provide better outcomes if it is earlier administered. When wounds
do not follow conventional treatments for healing, an extra aid can be found in HBOT.
Medicina 2021, 57, 864 6 of 25

Animal models have described the importance of this procedure in the wound healing
by the acceleration of epithelialization and neovascularization [55,56]. Reported effects
on these events resides in the up-regulation of host factors like tumour necrosis factor-α
(TNF-α), matrix metallopeptidase 9 (MMP-9) and tissue inhibitor of metalloproteinase-1
(TIMP-1) [57]. In a rabbit model of irradiated tissue, NBOT O2 was compared to hyperbaric
demonstrating once again that O2 is required at higher pressures to provoke an angiogenic
effect [56]. More studies in vivo have alleged tension exerted by hyperbaric O2 modulates
proliferation rate of stem cells in small intestinal crypts and raises angiogenesis in chorio-
allantonic membrane in Gallus gallus embryos [58]. In a clinical trial of patients with chronic
non-healing wounds (more than 20 months without healing), HBOT was standardized for
20 sessions (five sessions/week). The results were increased levels of vascular endothelial
growth factor (VEGF) and interleukine-6 (IL-6), and lower levels of endothelin-1. These
facts entail an activation of host wound resolution factors, angiogenesis and vascular
tone [59]. Vasculogenesis gains efficiency thanks to HBOT upregulation of nitric oxide
(NO) and associates to a decrease in lesions area [60].
Multiple lines of research have also been opened to evaluate the enhanced angio-
genesis and healing of tissues following HBOT. For instance, a phase 2A clinical trial
demonstrated the possible benefits from HBOT in combination with steroids for patients
with ulcerative colitis in terms of achieving higher rates of clinical remission, and a reduced
probability of progression to second-line therapy during the hospitalization [61]. However,
there are few studies in this field, and soon an updated meta-analysis and systematic review
of the available evidence will be published [62]. Similar conclusions might be extrapolated
to radiation-induced hemorrhagic cystitis and proctitis [63]. Osteoradionecrosis is also a
frequent and worrisome condition in oncological patients after receiving radiotherapy. Fre-
quently, this condition affects to the jaw and consists of the development aseptic, avascular
necrosis which can lead to infection, tooth loss, and even pathological fracture of the jaw.
Moreover, it often results in an ulceration and necrosis of the mucosa with exposed bone.
HBOT plays a critical role in the treatment of this condition, improving the tissue response
to surgical wounding, and even as prophylactic approach in patients with previous head
and neck irradiation undergoing dental extractions or complete exodontia [64]. The en-
hancing angiogenesis and wound healing make HBOT an adequate adjuvant treatment in a
wide variety of conditions, although future studies should be directed to evaluate the most
effective dose and to identify the most suitable candidates for submitting this procedure.

4.2. HBOT and Infections: The Antimicrobial Activity

The use of HBOT as an antimicrobial adjuvant is particularly useful in healing con-
text now that microbial infections are the most important cause of non-healing wounds:
meta-analysis affirm that prevalence of bacterial biofilms in chronic wounds is 78.2% [65].
HBOT is considered a non-conventional strategy for non-healing wounds consisting in
a modification of biophysical parameters in the wound microenvironment, breaking the
bacterial biofilms [66]. HBOT upregulates HIF that induces the expression of Nitric Oxide
Synthases (NOS) and virus killing peptides (defensins and cathelicidins such as cathelin-
related antimicrobial peptide) with consequent neutrophil and monocyte phagocytosis of
the microbes [67–69]. Increased cathelicidins in mice lungs provide a better response to the
flu virus [70]. Cathelicidin-deficient mice show higher susceptibility to viral damage [71].
The most important applications of the antimicrobial activity of HBOT are under
necrotizing soft tissue infections (NSTIs), including necrotizing fasciitis, Fournier’s gan-
grene and gas gangrene. There is a calamitous soft tissue infection implying a wide variety
of gram-positive, gram-negative, aerobic and anaerobic bacteria. It happens under condi-
tions of trauma or minor lesions that become more complicated, normally, due to systemic
problems like diabetes or vascular disfunctions [45,72]. An early and combined HBOT
therapy plus current practices may be crucial as a lifesaving and cost-efficacy therapy,
particularly in the most critical patients [73]. Clinical practice agrees on the necessity of
HBOT in the event of an anaerobic infection, as anaerobic bacteria are killed by a much
Medicina 2021, 57, 864 7 of 25

higher amount of pressurized O2 [74,75]. For instance, the use of HBOT in the anaerobic
Clostridium perfringens bacteria is specially recommended [76]. This bacterium produces
more than 20 recognized toxins. However, two toxins, alpha and theta are the main media-
tors of the infection caused by this agent. Clostridium perfringens growth is restricted at O2
tensions up to 70 mm Hg, and alpha-toxin production is halted at tensions of 250 mm Hg,
also achieving bacteriostasis and other antimicrobial effects. Thus, recommended treatment
is O2 at 3 ATA for 90 min three times in the first 24 h and twice a day for the next 2 to 5 days,
always in combination with proper antibiotic use [77]. The anti-inflammatory potential of
HBOT also aids to lessen tissue damage and infection expansion [72], also explained by
a decrease in neutrophil activation, eviting rolling and accumulation of white blood cells
(WBCs), hence limiting the production of ROS by neutrophils and avoiding reperfusion
injury [45]. Moreover, this is observed in In vitro studies, having been demonstrated the
biofilm shrinkage ability with the significant decreases in cellular load of anaerobic bacteria
and fungi after HBOT [75]. A sepsis mouse model showed a significant increase in survival
rate, >50%, with early HBOT compared to a control group that did not receive the treatment
and was associated with lower expression of TNF-α, IL-6 and IL-10 [78]. Translation to
clinical experience reports that the improvements in oxygenation follow the neovascular-
ization, which avoid undesired events like amputation [28]. This is the case, for example,
of Fournier’s gangrene, where bacteremia and sepsis are top factors of fatality, which can
be avoided by adjuvant HBOT, providing much higher survival rates in clinical trials [79].
Sometimes unwanted events are underestimated until it is late and polymicrobial infection
has bursted into surgical bone and joint lesions [80]. For that reason, molecular assessments
of bacterial identification like mass spectrometry, are every time more accomplished to
consider if HBOT is worthy for patients’ better recovering.
On the other hand, the use of HBOT might provide a central therapeutical option
in the intracranial abscess (ICA). ICA presentation includes cerebral abscess, subdural
empyema, and epidural empyema, and it is caused by an encapsulated infection in which
the proper inflammatory response may damage the surrounding brain parenchyma [81].
The etiological agent might be bacteria, fungi, or a parasite, and it might appear as a
consequence of a dissemination of previous infections like sinusitis, otitis, mastoiditis,
dental infection; hematogenous seeding or cranial trauma [82]. Due to the high morbidity
and mortality, along with the urgency of a non-invasive and effective method, HBOT has
been proposed as a well-accepted adjunctive therapy for ICA, being regarded as a safe
and tolerated method [83]. The main mechanisms by which HBOT represent an additional
tool in the management of ICA resides on the impairment of the acidotic and hypoxic
environment in ICAs due to the proper infection and the use of antibiotics [84]. Similarly,
osteomyelitis is a chronic infection in the bone marrow frequently caused by bacteria or
mycobacteria. It is a difficult condition to treat, as many antimicrobials do not penetrate
in the bone properly. When this condition does not respond to the treatment or reemerge
after receiving the therapy it is designed refractory osteomyelitis [85]. HBOT is a potential
indication of refractory osteomyelitis as it provides synergist antibiotic activity, while
enhancing angiogenesis, leukocyte oxidative killing and osteogenesis process [86]. A recent
systematic review [87] reported that adjuvant HBOT provided almost a 75% of therapeutic
success in patients with chronic refractory osteomyelitis, hence showing the importance
of this treatment in bacterial infections. Malignant otitis externa, another infection, a
necrotizing infection of the soft tissue of the external auditory canal which may rapidly
cause skull base osteomyelitis may also benefit from the use of HBOT, although further
studies are needed to conclude its effects [88].
Finally, some authors have also proposed a potential clinical use of HBOT as a medical
emergency treatment of mucormycosis, a fungal infection [89]. Despite there still being
few studies supporting its use, a compelling evidence show its potential use in a similar
manner than necrotizing fasciitis, although further research is needed in this area.
Medicina 2021, 57, 864 8 of 25

4.3. HBOT in Medical Emergencies

Apart from the previously discussed applications, there has been further conditions
in which HBOT may be considered. Some of them are designed as medical emergencies, in
which the use of HBOT is an urgent indication for these patients. These are the cases of some
infections above mentioned, decompression sickness, air or gas embolism, acute arterial
insufficiencies such as central retinal arterial occlusion (CRAO), crush injury, compartment
syndrome and acute traumatic ischemia, along with CO/Cyanide poisoning [89]. In this
context, the central role of HBOT is derived from the rapid and effective response of the
tissues under certain conditions that may be severe and even life-threatening [90].
A. Decompression sickness is a condition occurring due to the formation of bubbles
caused by a reduction in ambient pressure that introduced dissolved gases within the body
accidents. In turn, these bubbles drive to mechanical disruption of tissues, blood flow
occlusion, endothelial dysfunction, platelet activation and capillary leakage. [91]. However,
the term decompression sickness has been abandoned by the ECHM to be replaced by
“Decompression illness” (DCI) [92], so in this article we will refer this malady as DCI.
Clinical manifestations are at least one of more of the following: generalized fatigue or rash,
joint pain, hypesthesia and in serious cases motor weakness, ataxia, pulmonary edema,
shock and death [71]. DCI can occur in aviators, divers, astronauts, compressed air workers
and, in some cases, it may appear due to iatrogenic causes [93]. HBOT/recompression
therapy tables (US Navy Treatment Table 6 or helium/oxygen (Heliox Comex Cx30 or
equivalent) are recommended for the initial treatment of DCI (Type 1 recommendation,
Level C evidence). US Navy Treatment Table 5 can be used as the first recompression
schedule for selected mild cases [94]. Therapies at higher pressure could be administered
in exceptional cases, but it entails higher difficulties and risks. To maximize its efficacy,
different adjunctive therapies are used in combination with HBOT including fluid adminis-
tration, non-steroidal anti-inflammatory drugs and prophylactic agents to prevent venous
thromboembolism events, particularly in paralyzed patients [93,95]. Overall, because of
the high pressure, HBOT provide the opposite effects of the pathological mechanisms of
DCIs, therefore exerting its therapeutical efficacy.
B. Air embolism. Apart from DCI, bubble formation of large arterial air embolism
during operations are unusual occurrences but also ruinous and life-threatening. For
bubble gas formation in veins from lung biopsy, arterial catheterization, cardiopulmonary
bypass, HBOT is strictly necessary as there are no better alternatives in time. It provides
tissue oxygenation by promoting gas reabsorption, and hence reduces ischemic injuries [96].
In this context, retrograde cerebral air embolism is a worrisome condition that may appear
in major procedures (neurosurgery and cardiovascular operations, endoscopy), or during
minor interventions (peripheral or central venous access), being particularly lethal when
presented with encephalopathy [97]. The therapeutic basis of air embolism is similar to
DCS, with HBOT as first-line therapy [98]. Some reports have emphasized the importance
of an early HBOT, in the first 6 h since diagnosis, for this complication to obtain better
outcomes, less sequelae or death rate [99]. However, there is some evidence of late benefits
from its use, up to 60 h after the onset [100]. Even when there is no gas seen in on image
test, patients may benefit from the use of HBOT [101]. On the other hand, recent data
indicates that less cases appears to be treated by HBOT probably by the lack of belief of
some physicians in HBOT, particularly in UK [102]. However, available evidence supports
the use of this therapy to prevent and improve the outcome of such a dangerous condition.
C. CRAO is an ophthalmological complication caused by a permanent occlusion of
the central retinal artery, mostly due to a embolus at its narrowest part that is typically
associated with a sudden, massive loss of vision in the affected eye [103]. Prognosis for
visual recovery is poor, as the retinal tissue is not tolerant to hypoxia, and it presents the
highest oxygen consumption rate in the body at 13 mL/100 g per min [104]. As a result,
HBOT is a robust indication for patients with CRAO and many studies have reported en-
couraging results from its use, minimum at eight sessions, with some advantages presented
in comparison to other lines of treatment such as being a non-invasive method with low
Medicina 2021, 57, 864 9 of 25

adverse effects [104–107]. However, and despite these benefits, HBOT is rarely offered for
patients with CRAO [108], probably due to the lack of facilities in the hospital services.
D. Another approved indication for HBOT is crush injury and acute ischemia occurred
as result of a trauma. Presentations of these damage vary from mild contusions to limb
threatening damage, involving multiple tissues, from skin to muscles and bones. A severe
consequence of trauma is the skeletal muscle-compartment syndrome (SMCS), a condition
affecting both muscle and nerves [1]. Subsequently to trauma, the affected tissue will suffer
from hypoxia, edema and ischemia. Here, the efficacy of angiogenesis has been also proved
to be boosted by HBOT in animal models for ischemic limbs when combined with bone
marrow derived mononuclear cells transplantation [109]. Some translational studies of
multicenter randomized trials did not show a significant complete progress of healing [110],
but in contrast, other trials showed the advantage of HBOT as adjunct for ischemic limbs
when reconstructive surgery was not possible [111]. Evaluating skin peripheral circulation
as well, the outcomes showed significant improvements in revascularization [112], therefore
demonstrating the important role of HBOT in this condition.
E. CO poisoning is a problem that happens when household devices which use gas or
coal produce CO due to an uncomplete combustion. Inhalation of this gas can be lethal
and cause long-term problems particularly cognitive and brain deficits, presented up to a
40% of the patients and approximately one in three people develop cardiac dysfunction,
like arrhythmia, left ventricular systolic dysfunction, and myocardial infarction [113]. To
address these problems, HBOT has been applied [114] being associated to neurological
sequelae reduction [115] and when applied in the first 24 h can reduce the risk of cognitive
sequelae months later more efficiently [116]. In general, NBOT is immediately used after
CO poisoning until HBOT is available [117]. Evidence indicates that HBOT should be
considered for all cases of serious acute CO poisoning, loss of consciousness, ischemic
cardiac changes, neurological deficits, significant metabolic acidosis, or COHb greater than
25% [113]. Another kind of poisoning in which HBOT has its application is cyanide toxicity.
This issue appears with uncomplete combustion, this time, of materials like plastics, vinyl,
acrylics, nylon, etc. HBOT is the primary treatment, but it exceeds when is combined with
the antidote hydroxycobalamin, ameliorating mitochondrial oxidative phosphorylation
function [118,119]. Potential uses of HBOT in a wide range of urgent conditions at least
might be considered as an important tool in medical emergencies.
F. Severe anemias and idiopathic sudden sensorineural hearing loss. Despite not being
considered a medical emergency, the use of HBOT is also indicated for these conditions [89].
In the first case, as Hb levels critically drops, O2 delivery to the tissues may be impaired. In
this line, the use of 100%, hyperbaric O2 might solve this issue, simultaneously exerting a
wide range of favorable effects in the hematological profile [120]. This could be especially
important in patients who cannot be transfused for religion, immunologic reasons, or
blood availability problems. Idiopathic sudden sensorineural hearing loss or acute acoustic
trauma (AAT) are also important conditions in which HBOT could be a valuable tool. In
fact, a recent systematic review and meta-analysis conducted by Rhee et al. [121] showed
that the addition of HBOT to standard medical therapy is a valuable treatment option
particularly for patients with severe to profound hearing loss and in those patients which
received, at least 1200 min of HBOT. Apart from the regulation of ROS and inflammatory
response, previous research has demonstrated the protective role of HBOT in the hair cell
stereocilia, probably through hormetic mechanisms [122].
G. Finally HBOT can significantly improve symptoms and quality of life of patients
affected by femoral head necrosis (ECHM recommendation type II level of evidence
B) [123] as well as the previously mentioned NSTI, gas gangrene and urgent HBO alpha
toxin neutralized
Medicina 2021, 57, 864 10 of 25

5. Translational and Potential Applications of HBOT

Besides approved indications, further lines of research have demonstrated the po-
tential applications and translation of HBOT in the field of inflammatory and systemic
conditions, cancer, COVID-19 and other conditions are summarized.

5.1. HBOT and Inflammation: Immunomodulatory Properties

HBOT might also be applicated in the regulation of inflammatory responses and its
derived complications. Among the most important immunomodulatory effects, HBOT
drives an alteration in CD4+:CD8+ ratio, a reduced proliferation of lymphocytes, and an
activation of neutrophils with migration to hyperoxic regions [124]. Thus, HBOT might be
used in a wide variety of conditions presenting an altered immune system as part of its
pathogenesis. In this sense, it has been proposed the role of HBOT in the management of
autoimmune diseases (ADs). A study conducted by Xu et al. [125] observed the overall
effect of HBOT in general immune populations and particular Th1 and B lymphocytes
subsets, proving its promising role in certain ADs. Furthermore, long-term exposure
to HBOT was proven to supress the development of autoimmune symptoms, including
proteinuria, facial erythema and lymphadenopathy [126]. In the same manner, the use of
HBOT in early and middle stage of disease mice also show a significant increase in survival
with a decrease in inflammatory cells, anti-dsDNA antibody titers, and amelioration of
immune-complex deposition in comparison to later stage of disease [127] The use of HBOT
has also proven its efficacy on rheumatoid arthritis, particularly due to the polarization of
Th17 cells to T reg, with a significative reduction of cell hypoxia [128].
Similarly, these results could be extrapolated to other inflammatory conditions. For
instance, HBOT provides an anti-inflammatory response in DSS-induced colitis. Through
direct effects on HIF, HBOT induces antioxidant expression and the downregulation of
proinflammatory cytokines like IL-6, therefore reducing colonic inflammation [129]. In vitro
studies with lymphocytes from type 1 diabetes mellitus have proved effects of HBOT on
inducible NOS expression, observing lower activity with a consequent decreased levels of
NFkB [130]. Additionally, HBOT comprises another potential approach regarding muscu-
loskeletal dysfunctions. Fibromyalgia represents an incapacitant disorder characterized
by a widespread muscle and joint pain, frequently accompanied by systemic symptoms
including cognitive dysfunction, mood disorders, fatigue, and insomnia [131]. HBOT
exerts direct effects on brain activity, chronic pain and immune dysregulation, therefore im-
proving quality of life of affected patients [132]. Interestingly, Woo et al. [133] also observed
that HBOT could be considered an interesting alternative to attenuate exercise-induced
inflammation and muscle damage.
Overall, previous research has indicated the favourable effects of HBOT in the immune
system and also on the whole body.

5.2. Role of HBOT in the COVID-19 Pandemic

COVID-19 pandemic has challenged healthcare systems worldwide, overloading
them with a huge burden in economy and our normalcy [134,135]. The urge of conducting
massive vaccination programs besides finding better therapies for clinical management,
have been the focus these months. In this context, HBOT has been proposed as an adjuvant
for clinical practice in severe patients, and also for recovery after SARS-CoV-2 infection.
Results from clinical trials have already demonstrated the potential uses of this treatment
to redirect O2 diffusion avoided by hypoxemia, and its ability to eliminate inflammatory
cytokines.
Nevertheless, not only hyperbaric O2 may be worthy for severe patients, but also for
treating the named “silent” hypoxemia in those patients that do not have a bad clinical
course yet [136]. This silent hypoxemia is not characterized by typical respiratory distress
in critically ill patients, but it may be dangerous if it is not sooner detected as a prompt
deterioration can occur without noticing [137]. In fact, previous studies have demonstrated
the association between hypoxemia with fatal outcomes in patients with COVID-19 [138].
Medicina 2021, 57, 864 11 of 25

In the same manner, physicians observed that patients exhibit hypoxemia without dyspnea,
being crucial to find care solutions to anticipate a problem with more patients at important
risk [139]. Some cases of people with mild or even without symptoms, that contracted
multi-organ failure and then died, have emphasized the importance of self-monitoring of
pulse oximetry, which typically presents reduced readings in these patients [140]. Collected
data from patients that did not present problems of breathing at admission, agreed with the
suggestion of utilizing pulse oximetry to predict the outcome of hypoxemia/hypocapnia
syndrome that defines asymptomatic hypoxia [141]. Steps forward in the understanding of
our complex respiratory system have also launched reviews about the higher oxygenation
rate in prone position, concerning variables like gravity, lung structure and the higher
expression of nitric oxide (NO) in dorsal lung vessels than in ventral ones [142]. It has
been demonstrated that HBOT increases the production of NO and ROS/RNS, inhibiting
SARS-CoV-2 replication in previous In vitro models [41].
Moreover, all these facts have shed a light on finding better treatments to prevent
fast hypoxia, fatality or even the need for mechanical ventilation [143,144] being HBOT a
suggested adjuvant for its promising outcomes from previous animal models and clinical
cases of sepsis and inflammatory diseases [145]. Preliminary comparisons of HBOT ap-
plications in COVID-19 to other maladies, like livedoid vasculopathy, have exposed the
possible mechanisms that may occur: anti-inflammatory actions (decreased ICAM-1, proin-
flammatory cytokines and neutrophil rolling), anticoagulant actions (boosted fibrinolysis
and increased plasminogen activator) and tissue healing actions (increased fibroblasts and
stem cells) [146].
First studies in a severe patient affirmed that, compared to normobaric oxygen supply,
the better empiric outcome agreed with the theoretic expectance of the potential uses of
HBOT in COVID-19 [147]. Although it is still being evaluated scientifically, positive results
are arising for COVID-19 treatment, finding an attenuation of the innate immune system,
and increasing hypoxia tolerance [148]. In every report, this therapy has been rated as a
potential support in the relieving of cytokine storm [149]. Now that mechanical ventilation
may be long lasting and, preferably, avoided, in a controlled trial, safety and efficacy of
HBOT for COVID-19 patients was successfully evaluated [150]. Another preliminary study
showed rapid alleviation of hypoxemia from the beginning of the treatment in patients
with COVID-19 pneumonia [151].
Anatomically, pathologic examinations of lung with early-phase COVID-19 have
shown edema, proteinaceous exudate, inflammatory cellular infiltration, and interstitial
thickening that entails a disproportional gas exchange. This is due to CO2 diffuses through
tissues much faster than O2 , about 20 times, what leads to hypocapnia [152]. Alveolar
structure is altered in the COVID-19 patient, there is also hyaline membrane formation,
there is thickness in alveolar membrane and the space for the diffusion of oxygen generates
a lot of exudate and inflammation. Hence, diffusion from the alveolus through the haemato-
alveolar membrane does not occur correctly, the concentration of oxygen in the blood
and in the tissues begins to fall and the exchange of the dioxide also becomes difficult.
Due to possible viral interactions with Hb [153] and a hypoxemia-induced shift in the
oxyhemoglobin dissociation curve to the left, there is O2 saturation but low arterial blood
pressure [154].
Clinical evidence from few studies about COVID-19 patients undergoing HBOT, notes
that this therapy may make possible to contribute to reverse hypoxemia and ameliorating
the pulmonary capillary circulation diffusion despite the thickness in alveolar membrane in
disease. According to Henry’s Law, HBOT allows to increase pressure of O2 in the alveoli
above ambient pressure. In this way, there will be a large increase of O2 diffusion into the
pulmonary capillary circulation, more than 10 times, for its arrival in the plasma and reach
the tissues independently of Hb. There will be a gain of O2 supply to the tissues mediated
by the increase in pressure. Experimentally, hematological, biochemical and inflammatory
parameters were significantly improved after HBOT. In first trials the observation of
lymphocyte count was increased, whereas lactate and fibrinogen were decreased [147,151].
Medicina 2021, 57, 864 12 of 25

However, during this procedure patients may suffer from desaturation reflexes. Despite
the etiology of this reflex is unclear, it might be probably caused by a vasoconstriction
affecting the pulmonary arteries, due to the oxidative stress as well as direct damage in
type II pneumocytes and thrombus associated with COVID-19 [124].
Notwithstanding the ongoing clinical trials and the efforts of standardize better pro-
tocols for safety, COVID-19 is not yet an accepted indication for HBOT, but this may be
recommended for post-viral sequelae [155]. In order to guarantee its beneficial effects, there
is still a need of more controlled trials to measure different inflammatory and hematologi-
cal parameters that demonstrate that exudate and inflammation are reduced besides the
improvements in alveolar circulation diffusion. This would confirm the potential of this
adjuvant, also for considering the financial investment in hyperbaric chambers in hospitals.

5.3. HBOT and Cancer

Cancer is a complex entity which encompasses a broad spectrum of unique patholo-
gies that share the following hallmarks: Immune system evasion, tumor-promoting in-
flammation, genome instability, enabling replicative immortality, activating invasion and
metastasis sustaining proliferative signaling, evading growth suppressors, resisting cell
death, inducing angiogenesis, and metabolic reprogramming [156]. Tumor-hypoxia plays a
central role in many of these carcinogenic features, promoting an aggressive phenotype
besides limit the effectiveness of radiotherapy, chemotherapy, and immunotherapy thereby
worsening prognosis in the oncological patients [157]. Thus, targeting tumoral hypoxia
and its downstream effectors have been proposed as a potential therapeutical approach
in cancer management [158–160]. In this line, accumulating evidence supports the role of
HBOT in the inhibition of tumor growth and therapy success, by three main mechanisms:
(1) By limiting cancer-associated hypoxia, (2) through the generation of ROS and RNS
and (3) restoring immune function [161]. Actual investigations show the promising role
of HBOT in a wide variety of malignancies, including breast cancer, prostate cancer, head
and neck cancer, colorectal cancer, leukemia, brain tumors, cervical cancer and bladder
cancer [162]. Main applications derived from HBOT in oncology may be (a) As part of the
treatment (b) as a radiotherapy adjuvant and (c) as a chemotherapy adjuvant [163].
The use of HBOT as part of the cancer therapy is not currently an approved indication,
although some promising results have arisen recently. In this context, Thews & Vaupel [164]
compared the efficacy of NBOT (1 atm) versus HBOT (2 atm) oxygenation reporting broader
reductions of hypoxia under hyperbaric conditions. However, even at high pressure
oxygenation, tumor hypoxia was not completely removed, hence showing that HBOT
alone efficacy is limited. Importantly, as previously described HBOT was associated
with increased angiogenesis, these effects are not significative in tumour cells, so its use
could be important in the cancer management [165]. Conversely, a study conducted by
Pande et al. [166] revealed that notwithstanding HBOT-treated mice initially induced a
decrease in tumor progression, a tumorigenic effect was observed post-therapy, probably
due to impaired DNA repair, mutagenicity and chromosomic aneuploidies together with
an altered blood supply and nutrients. On the other hand, some authors suggest that
the lack of therapeutical efficacy of HBOT might be due to the difficulty on creating a
hyperoxic environment in the tumor and that, by combining HBOT with other methods
it could act a as a potential cure in certain types of cancer. In this line, Lu et al. [167]
proposed a combined use in prostate cancer patients of HBOT with ultrasound guided
transrectal prostate puncture, in order to create a hyperoxic environment within the tumor,
which may lead to DNA damage and a detention in the G2/M cycle, hence establishing
the basis for future research. Similarly, tumor hypoxia is associated with the metabolic
reprogramming of tumour cells, also known as the aerobic glycolysis or “Warburg effect”.
This consists of a glycolytic switch of cancer cells, which refrain from performing oxidative
phosphorylation [168]. In this sense, Poff et al. [169] described the combined effects
of HBOT in combination with ketogenic diet in a murine model, preventing tumoral
metastasis while expanding overall survival. Furthermore, HBOT alone or combined with
Medicina 2021, 57, 864 13 of 25

low glucose and ketone supplementation also exert multiple benefits against late-stage
metastatic cancers, by increasing the production of ROS and oxidative stress [170]. Despite
the encouraging results, further research is required to establish the efficacy of HBOT in
the different types of cancer, also searching for the most adequate use of this therapy in a
global context.
Radiotherapy (RT) is a central component in cancer management, with approximately
50% of patients receiving this therapy contributing up to a 40% of curative success for
cancer [171]. Through ionizing radiation, it creates a ROS and RNS overproduction, leading
to double strand breaks, chromosomal aberrations and rearrangements with subsequent
cell death or dysfunction, thus exerting its anti-tumoral effects. The effect of HBOT on
human glioblastoma (GBM) was investigated, in laboratory, on patient-derived cells and on
microglia cell biology (CHME-5). The results obtained from the combination of HBO and
RT clearly showed a radiosensitising effect of HBO on GBM cells grown [172]. Hypofrac-
tionated stereotactic radiotherapy (HSRT) after HBO (HBO-RT) appears to be effective for
the treatment of recurrent high-grade glioma (rHGG), as pointed out on a cohort of 9 adult
rHGG patients. It could represent an alternative, with low toxicity, to systemic therapies
for patients who cannot or refuse to undergo such treatments [173]. However, although
non-tumour cells are less sensitive, radiation could also affect them, altering multiple
cellular signaling pathways or inducing apoptosis, hence explaining its multiple adverse
effects [174] One of the most severe consequences resulted from irradiation is the appear-
ance of post-radiation injuries, a process starting during radiotherapy that involves the
dysregulation of multiple bioactive compounds, particularly fibrogenic cytokines like TGF-
β [175]. Similarly, almost all tissues with delayed irradiation injury present a histological
feature named as obliterative endarteritis, finally leading to a tissue damage characterized
by hypoxia, hypovascularity and hypocellularity [176]. In this line, HBOT has consistently
demonstrated its therapeutical effectivity against radiation-induced injury also approved
by the UHMS [177] and the ECHM [8]. Last 2016 Cochrane review [178] evidenced that the
use of HBOT in head, neck, anus and rectum injured tissues were associated with improved
outcomes and, at some extent with osteoradionecrosis following tooth extraction in an
irradiated field. According to ECHM recommendation the use of HBOT is recommended in
the treatment of radiation proctitis (Type 1 recommendation, Level A evidence), mandibu-
lar osteoradionecrosis and haemorrhagic radiation cystitis (Type 1 recommendation, Level
B evidence) and suggested in the treatment of osteoradionecrosis of other bone than the
mandible, for preventing loss of osseointegrated implants in irradiated bone and in the
treatment of soft-tissue radionecrosis (other than cystitis and proctitis), in particular in
the head and neck area (Type 2 recommendation, Level C evidence). Furthermore, it
would be reasonable to use HBOT for treating or preventing radio-induced lesions of the
larynx, in the treatment of radio-induced lesions of the central nervous system (Type 3
recommendation, Level C evidence) [8]
Finally, the combined use of HBOT plus chemotherapy have reported certain benefits.
In this line, a recent study conducted by Brewer et al. [179] demonstrated the effectiveness
of using HBOT to prevent chemotherapy-induced neuropathy In vivo. This fact appears to
be due to the various implications of HBOT in the neuronal activity and signaling [180–182]
Kawasoe et al. also observed [183] that an integrative strategy of carboplatin plus HBOT
significantly reduced mortality in C3H mice with inoculated osteosarcoma cells Similar
results were obtained with HBOT and chemotherapy in lung cancer cultures and animal
models [184]. In particular, the combination of paclitaxel and carboplatin plus HBOT and
hyperthermia show promising results for treating patients with non-small cell lung cancer
and multiple metastasis [185]. Despite these results, the use of HBOT and chemotherapy
may also represent a contraindication for the patients. For instance, the combination of
HBOT with doxorubicin, bleomycin, or cisplatin may exert synergic cardiotoxicity, pul-
monary toxicity or impaired wound healing, respectively [186]. This is an important issue
to address in the oncologic patient. In these cases, it is important to separate chemotherapy
from the use of necessary HBOT, to avoid undesired effects. In addition, further strategies
Medicina 2021, 57, 864 14 of 25

could be considered targeting tumour hypoxia and functioning as therapeutic adjuvants

like physical activity [187]. Overall, the benefits of HBOT in cancer management is a
potential field to keep on exploring.

5.4. Other Applications

In the same manner, other novel lines of research are exploring potential uses of
HBOT in a plethora of conditions. For instance, some studies related to microvascular
or macrovascular insufficiencies causing erectile dysfunction (ED) have hypothesized
the effects of HBOT in patients with this problem. Empirical data suggests that it can
induce penile angiogenesis and improve erectile function in men suffering from ED. This is
due to vasodilatation relies on proper blood vessels in corpora cavernosa. Then, being a
major concentration of oxygen in tissues, there is an increased angiogenesis by VEGF and
endothelial cells differentiation [188]. This application has not provided significant data on
rehabilitation after prostatectomy [189] but it has obtained good symptoms resolution for
other clinical manifestations like ED in diabetes mellitus [190] or in recovery after urethral
reconstruction [191]
Equally, the use of HBOT for ischemic stroke and brain injury is an interesting point of
study. For instance, different studies have demonstrated the importance of this procedure as
a prophylactic approach for sequestration of inflammation inherent in stroke and traumatic
brain injury, preventing neuronal death [192]. Other uses such as brain preconditioning
before stem cells transplantation have also been explored [193]. However, the efficacy and
safety of HBOT in these conditions remains to be fully elucidated, although some basic
and clinical research have shown encouraging results [194].
Finally, the use of HBOT could be potentially extended to novel fields like aging.
Hachmo et al. [195] reported the effect of hyperbaric oxygen in the prevention of telomere
shortening and immunosenescence by the clearance of senescent immune cells. In this
line, other studies have reported the same results in the aging skin, through the accelera-
tion of epidermal basal cells proliferation [196], in the endothelial cells, where it induces
antioxidants expression [197] and also in the brain, where HBOT appears to improve the
cerebral blood flow [198], restoring cognitive parameters, hippocampal functions and even
improved insulin resistance in both normal-weigh and obese aging rats [199].
As summarized in Figure 2, the main consequences of HBOT and its related hyperox-
emia and hyperoxia in the human body could be related with the angiogenesis enhance-
ment, antimicrobial properties and immunomodulatory effects. Approved indications for
this therapy could also be grouped according to its emergency.
Medicina 2021, 57, 864 15 of 25

Figure 2. Summary of top properties of HBOT and its clinical applications. Firstly, it can provide an angiogenesis
enhancement, observed by the prime production of NO which subsequently brings an upregulation of Nrf2 and growth
factors like epidermal growth factor (EGF), vascular endothelial growth factor (VEGF) and endothelin-1. TNF-α, matrix
metallopeptidase 9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) will be boosted too. Secondly, the
antimicrobial activity is visible due to bacterial killing by O2 , removing biofilm and lessening white blood cells (WBCs)
rolling and neutrophils recruitment, hence promoting a downregulation of proinflammatory cytokines (TNF-α, IL-6 and
IL-10). The immunomodulation properties are observed by a downregulation of transcriptional factor NFkB, involving a
proinflammatory response switch off (IL-6) and a polarization from Th17 lymphocytes to Treg. Summarized applications
include: indications for which HBOT is approved (mostly wound healing and infections), primary emergencies (like CO/CN
poisoning or air embolism), and translational research (comprising COVID-19, cancer, inflammatory conditions or aging
among others).

6. Adverse Effects and Contraindications

Notwithstanding the multiple benefits and applications of HBOT, there are important
adverse effects that may appear during this procedure. As a result of the hyperoxia and the
hyperbaric environment, there are some issues when using this therapy. The two most com-
mon complications during HBOT are claustrophobia and barotrauma. Both occur during
monoplace or multiplace chamber compression [200]. In the case of barotrauma, it could be
defined as an injury caused by an inability to equalize pressure from an air-containing space
and the surrounding environment. Ear barotrauma is the most frequent condition affecting
the middle ear, although sinus/paranasal, dental or pulmonary barotrauma could also be
reported [201]. Despite the incidence of this complication being extremely rare [202], its
seriousness should be taken into account, considering clinical history of patients at risk of
suffering from these complications while implementing different strategies to prevent this
complication, such as anti-epileptic therapy, prolonged air brakes or controlling treatment
pressure [203]. The last event is associated with the appearance of the Paul Bert effect
because of the formation of seizures that may bring transient but negative consequences
for cognitive functioning and behavioural patterns [204]. These effects are primarily due
to the toxic properties of oxygen at high concentrations. However, to date, no threshold
has been described to precisely assess the pathological levels of oxygen, which could be an
important issue for critical patients [205]. Pulmonary toxicity is not associated with the use
of repeated hyperbaric oxygen following current protocols [206]. Ocular manifestations
Medicina 2021, 57, 864 16 of 25

from HBOT may also be described, particularly hyperbaric myopia, transitory in most cases.
Other ophthalmological complications less frequent observed are cataracts, keratoconus or
retinopathy of prematurity, in the case of pregnant women exposed to HBOT [207,208]. All
these adverse effects may be ameliorated prominently by an adequate screening, through
the use of certain devices and the adjustment of the treatment protocols [200,201]
On the other hand, there are certain conditions in which HBOT might be absolutely
contraindicated or relatively contraindicated. The first case is exclusively represented
by untreated pneumothorax, as it could be a life-threatening procedure [209]. The rest
of contraindications are relative, its indication will depend on the real necessity of this
therapy. Aside from the chemotherapheutic agents previously described other treatments
like sulfamylon (Mafenide), could also share the same action than cisplatin impeding
wound healing effects derived from HBOT, and it should also be interrupted before this
therapy [45]. If patient has a pacemaker or any type of implantable devices, it is neces-
sary to verify its safety with increased pressure or with pure concentrations of oxygen.
Hereditary spherocytosis may also be a contraindication, as hyperbaric oxygen could cause
severe haemolysis [43]. Pregnancy is another potential contraindication for this therapy in
exception of CO poisoning [210]. Although rare in non-diabetic individuals, patients may
also suffer from hypoglycaemia during this procedure, and it is important to evaluate their
blood glucose levels before HBOT, as it could aggravate their hypoglycaemic profile [211].
Similarly, patients with underlying respiratory pathologies like chronic obstructive pul-
monary disease (COPD), asthma and even upper respiratory infections might be also
possible contraindications from receiving HBOT, as it could increase the risk of hypercap-
nia, pulmonary barotrauma and sinus or middle ear barotrauma, respectively [209]. An
additional effect derived from HBOT is the increment of blood pressure [212]. Hyperbaric
oxygen may also induce pulmonary oedema and cardiovascular difficulties in patients
with heart failure or in patients with reduced cardiac ejection fractions [213]. Finally, the
history of epilepsy, hypoglycaemia, hyperthyroidism, current fever, and certain drugs such
as penicillin and disulfiram are also thought to lower the seizure threshold during this
therapy [214]. Diabetic patients may be warned from regulating its doses of HBOT in order
to prevent the hypoglycaemic effect of this therapy.
To summarize, despite the multiple applications of HBOT it is equally important to
consider its potential adverse effects and underlying conditions in which this therapy is
not going to exert its efficacy, also representing a potential risk for these patients.

7. Conclusions and Future Directions

HBOT is an effective method to increase blood and tissue oxygen levels, indepen-
dently from Hb transportation. Its therapeutical basis could be understood from three
different perspectives: Physical (Hyperbaric 100% oxygen), physiological (Hyperoxia and
hyperoxemia) and cellular/molecular effects. All these effects provide HBOT its efficacy in
the management of hypoxia derived conditions and hypoxemia, respectively, also exerting
direct effects in infectious agents and immune cells, modulating a wide variety of cellular
signaling pathways, cytokine production and tissue processes such as angiogenesis. Herein,
the use of HBOT might be extended to a broad spectrum of pathologies, from infections
and inflammatory/systemic maladies to wound healing and vascular complications, also
reporting its efficacy in the management of medical emergencies like air embolism or
gas poisoning. Although respiratory infections and diseases have been mentioned as
contraindications for HBOT, the case of SARS-CoV-2 is an exception. Nowadays, the
potential use of HBOT in the COVID-19 has been specially regarded, exposing results in
numerous controlled clinical trials. Moreover, the use of this procedure in different types of
malignancies represents an important support in the delayed radiation injury. In the same
manner, the use of HBOT as a therapeutical agent have shown promising results in trials
as an adjunctive substance with other approved treatments like chemotherapy and even,
recent research have also reported significative improvements in nanomedicine approaches
when combined with HBOT [215].
Medicina 2021, 57, 864 17 of 25

Despite its benefits, there are still certain challenges which need to be overcome to im-
prove the current and potential applications of HBOT. In this line, a worrisome issue would
be to develop sophisticated strategies to address tissue hypoxia, as for certain conditions
like tumoral cells, the HBOT induced hyperoxia does not completely eliminate tumour
hypoxia. An adequate combination of HBOT with another procedure might be interesting
to targeting this problem [167]. On the other hand, it is equally important to determine
and quantify potential adverse effects derived from HBOT, as well as potential contraindi-
cations from receiving this therapy. Future research should be destinated on developing
accurate systems to determine potential benefits and risks for patients before submitting
HBOT. In this line, the development of predictive models as previously mentioned or novel
strategies could be interesting approaches in these fields.
Currently, there are only 14 approved indications for this therapeutical approach. We
encourage further studies to extend the possible uses of this procedure, always considering
individual benefits and risks from receiving this therapy. The inclusion of HBOT in future
clinical research could be an additional support in the clinical management of multiple
pathologies.

Author Contributions: Conceptualization, M.A.O., O.F.-M., C.G.-M., M.Á.-M., J.B., M.L.C.; Method-
ology, M.A.O., O.F.-M., C.G.-M.; Formal Analysis, M.A.O., O.F.-M., C.G.-M.; Investigation, M.A.O.,
O.F.-M., C.G.-M., E.C.-P., M.A.S., M.A.Á.-M., N.G.-H., J.M., M.Á.-M., J.B., M.L.C.; Data Curation,
M.A.O., O.F.-M., C.G.-M.; Writing-Original Draft Preparation, M.A.O., O.F.-M., C.G.-M., E.C.-P.,
M.A.S., M.A.Á.-M., N.G.-H., J.M., M.Á.-M., J.B., M.L.C.; Writing-Review & Editing, M.A.O., O.F.-M.,
C.G.-M., E.C.-P., M.A.S., M.A.Á.-M., N.G.-H., J.M., M.Á.-M., J.B., M.L.C.; Supervision, M.Á.-M., J.B.,
M.L.C.; Project Administration, M.Á.-M., J.B.; Funding Acquisition, M.Á.-M., J.B. All authors have
read and agreed to the published version of the manuscript.
Funding: The study was supported by the Comunidad de Madrid (B2017/BMD-3804 MITIC-CM),
Univer-sidad de Alcalá (32/2013, 22/2014, 26/2015) and Halekulani S.L.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: The data used to support the findings of the present study are available
from the corresponding author upon request.
Acknowledgments: Oscar Fraile-Martinez had a predoctoral fellowship from the University of
Alcalá during the course of this work.
Conflicts of Interest: The authors declare no conflict of interest.

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