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The Role of Hyperbaric Oxygen Treatment for COVID-19: A Review

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Abstract

The recent coronavirus disease 2019 (COVID-19) pandemic produced high and excessive demands for hospitalizations and equipment with depletion of critical care resources. The results of these extreme therapeutic efforts have been sobering. Further, we are months away from a robust vaccination effort, and current therapies provide limited clinical relief. Therefore, several empirical oxygenation support initiatives have been initiated with intermittent hyperbaric oxygen (HBO) therapy to overcome the unrelenting and progressive hypoxemia during maximum ventilator support in intubated patients, despite high FiO2. Overall, few patients have been successfully treated in different locations across the globe. More recently, less severe patients at the edge of impending hypoxemia were exposed to HBO preventing intubation and obtaining the rapid resolution of symptoms. The few case descriptions indicate large variability in protocols and exposure frequency. This summary illustrates the biological mechanisms of action of increased O2 pressure, hoping to clarify more appropriate protocols and more useful application of HBO in COVID-19 treatment.
Adv Exp Med Biol - Clinical and Experimental Biomedicine
https://doi.org/10.1007/5584_2020_568
#Springer Nature Switzerland AG 2020
The Role of Hyperbaric Oxygen
Treatment for COVID-19: A Review
Matteo Paganini, Gerardo Bosco, Filippo A. G. Perozzo,
Eva Kohlscheen, Regina Sonda, Franco Bassetto,
Giacomo Garetto, Enrico M. Camporesi, and Stephen R. Thom
Abstract
The recent coronavirus disease 2019 (COVID-
19) pandemic produced high and excessive
demands for hospitalizations and equipment
with depletion of critical care resources. The
results of these extreme therapeutic efforts
have been sobering. Further, we are months
away from a robust vaccination effort, and
current therapies provide limited clinical relief.
Therefore, several empirical oxygenation sup-
port initiatives have been initiated with inter-
mittent hyperbaric oxygen (HBO) therapy to
overcome the unrelenting and progressive
hypoxemia during maximum ventilator
support in intubated patients, despite high
FiO2. Overall, few patients have been success-
fully treated in different locations across the
globe. More recently, less severe patients at
the edge of impending hypoxemia were
exposed to HBO preventing intubation and
obtaining the rapid resolution of symptoms.
The few case descriptions indicate large
variability in protocols and exposure fre-
quency. This summary illustrates the
biological mechanisms of action of increased
O
2
pressure, hoping to clarify more appropri-
ate protocols and more useful application of
HBO in COVID-19 treatment.
Keywords
COVID-19 · Hyperbaric oxygen therapy ·
Hypoxemia · Inammation
1 Introduction
Coronavirus disease 2019 (COVID-19) is a health
emergency that is saturating the care and receptive
capacities of many national health systems. While
most of the patients (up to 81% of the total) do not
show any symptom or present with u-like illness,
others can develop severe respiratory compromise
and must be hospitalize due to interstitial pneumo-
nia with consequent hypoxia (Wu and McGoogan
2020). Besides, recent works suggest that most
M. Paganini and G. Bosco (*)
Department of Biomedical Sciences, University of
Padova, Padova, Italy
e-mail: gerardo.bosco@unipd.it
F. A. G. Perozzo, E. Kohlscheen, R. Sonda,
and F. Bassetto
Plastic and Reconstructive Surgery Unit, Padova
University Hospital, Padova, Italy
G. Garetto
ATIP Hyperbaric Medical Center, Padova, Italy
E. M. Camporesi
Teamhealth Anesthesia Attending, Emeritus Professor of
Surgery, USA, Tampa, FL, USA
S. R. Thom
Emergency Medicine, University of Maryland, Baltimore,
MD, USA
severe cases are characterized by a complex pat-
tern of systemic activation consequent to cytokine
storm resulting in immune system impairment and
pro-inammatory imbalance (Mehta et al. 2020).
Given the signicant mortality and morbidity
associated with COVID-19, the benecial poten-
tial of adjunctive therapies cannot be dismissed.
Several treatments, such as antiviral, antimalarial,
or immunosuppressant drugs, are tested, as well
as hyperbaric oxygen (HBO). To date, evidence
of the clinical utility of HBO in COVID-19 is still
limited (De Maio and Hightower 2020; Moon and
Weaver 2020), but the interest is growing, and at
least three trials have been registered online
(ChiCTR 2020; US National Library of Medicine
2020). The objective of this article is to review
and discuss HBO mechanisms of action and data
addressing possible benets, adverse effects, and
potential applications in treating COVID-19
patients.
2 Hyperbaric Oxygen (HBO):
Mechanisms of Action
HBO therapy is based on the laws of gas physics
related to pressure and involves the intermittent
inhalation of 100% oxygen in pressurized
chambers. Most studies have involved oxygen
administration between 1.5 and 3.0 atmosphere
absolute (ATA), a range in which risks of adverse
effects are minimized while obtaining therapeutic
effects.
HBO increases the partial pressure of oxygen
in plasma and tissues (Camporesi and Bosco
2014) and is commonly used in the treatment of
decompression sickness, carbon monoxide intox-
ication, arterial gas embolism, necrotizing soft
tissue infections, chronic skin ulcers, severe mul-
tiple trauma with ischemia, and ischemic diabetic
foot ulcers (Moon 2019; Thom et al. 2011b). The
differences and advantages of HBO therapy from
atmospheric oxygen absorption are the following:
(a) the improvement in diffusion efciency of
oxygen through the alveolar barrier; (b) the higher
physically dissolved oxygen content in the blood,
more than the combined hemoglobin transport
capacity; and (c) the increased diffusion distance
of oxygen. Altogether, these properties meet the
demand of aerobic metabolism in hypoperfused
regions of the body.
3 Hyperbaric Oxygen (HBO)
and Inflammation
HBO has benecial effects in reducing the inam-
matory state by modulating oxidative stress,
including lipid peroxidation, and increasing anti-
oxidant enzymes (Thom 2011; Bosco et al. 2007).
Accordingly, in animal models, HBO can modu-
late the inammatory response and cytokine level
(Halbach et al. 2019; Pedoto et al. 2003) or reduce
TNF-αproduction and lung neutrophil sequestra-
tion (Yang et al. 2001). Studies in humans have
conrmed this experimental evidence concerning
the benet emanating from HBO during different
inammatory states (Bosco et al. 2018; Marmo
et al. 2017; Li et al. 2011). In the diabetic patient,
whose peripheral arterial vascularization is
compromised, HBO is indicated for its ability to
increase tissue oxygenation and limit ischemic
damage through several mechanisms (Thom
et al. 2011a). In the same vein, HBO can improve
the perfusion of peripheral systems by reducing
the risk of multiple organ failure (MOF) (Bosco
et al. 2014; Rinaldi et al. 2011; Yang et al. 2006).
Oxidative stress and reactive species of oxy-
gen (ROS) and nitrogen have complex effects on
cell signaling mediators such as HIF-1αand
NK-kB. There are competing pathways that inu-
ence levels of these agents in cells, and some
evidence exists for a benecial inuence of
HBO in certain situations (Bosco et al. 2018).
The HIF-1αand NF-kB cross talk regulates
essential inammatory functions in myeloid
cells. HIF-1αincreases macrophage aggregation,
invasion, and motility. Whereas HIF-1αdrives
the expression of pro-inammatory cytokines,
enhanced microbial clearance can limit the over-
all production of inammatory mediators. HIF-1α
enhances intracellular bacterial killing by
macrophages and promotes granule protease pro-
duction and release of nitric oxide (NO) and
TNF-α, which in turn further contribute to anti-
microbial control. HIF-1αin myeloid cells
M. Paganini et al.
increases the transcription of key glycolytic
enzymes, resulting in increased glucose uptake
and glycolytic rate. HBO can increase HIF-1α
via an oxidative stress response mediated in part
by thioredoxin to increase the recruitment of stem
cells. HBO can also increase the activity of iNOS
in leukocytes and eNOS in platelets (Thom et al.
2006,2008,2011a,2012).
4 Coronavirus Disease 2019
(COVID-19) Pathogenesis:
Between Inflammation
and Cytokine Storm
To date, there is no vaccine and no specic
antiviral medicine shown to be effective in
preventing or treating COVID-19. Those
suffering severe illness appear to have higher
initial viral load and prolonged viral shedding
suggestive of a failure to clear the infection due
to an inadequate immune response (Liu et al.
2020b). Based on murine studies and viral shed-
ding and IgG production patterns present in the
past severe acute respiratory syndrome (SARS)
outbreak due to SARS-CoV-1, lung injuries may
arise due to an excessive or aberrant host inam-
matory response.
Severe COVID-19 manifests clinically as
acute lung injury associated with high initial
virus titers, macrophage/neutrophil accumulation
in the lungs, and elevated pro-inammatory
serum cytokines (Conti et al. 2020; Kowalewski
et al. 2020). During infections, pathogens rst
encounter the innate immune system that directs
anti-pathogen effects and induces adaptive
immune responses. One innate inammatory
pathway involves the inammasome, a
multimeric protein complex that is responsible
for the activation of caspase-1. Caspase-1, in
turn, processes members of the IL-1 family of
cytokines into their active forms leading to their
secretion. These cytokines, including IL-1α,
IL-1β, and IL-18, are pro-inammatory and may
induce either protective or damaging host
response. IL-1 and IL-18 participate in the control
of viral replication. IL-18, through its ability to
increase interferon-gamma, seems to have a
strong host pro-survival effect in coronavirus
infections (Liu et al. 2020a).
IL-1αand IL-1βinduce recruitment of
neutrophils, polarize T-cells, and promote den-
dritic cell activation for priming. However,
IL-1βoverproduction is linked to a wide range
of inammatory pathologies, including those
caused by respiratory viruses (Kim et al. 2015).
IL-1βplays a central role in many inammatory
responses because of its auto-catalytic production
and because it can trigger the synthesis of alterna-
tive cytokines and other inammatory agents.
Several coronavirus accessory proteins and the
envelope (E) protein trigger robust activation of
the inammasome NOD-, LRR-, and pyrin
domain-containing protein 3 (NLRP3). The E
protein is involved in virulence and specically
correlates with enhanced pulmonary damage,
edema accumulation, and death. This protein
establishes an ion channel in host cells to induce
NLRP3 inammasome activation resulting in
overproduction of IL-1β. The central issue
concerning possible effects of HBO pertains to
the pathological role of inammasome activation
and, specically, the role of IL-1β(Debuc and
Smadja 2020).
5 Hyperbaric Oxygen Therapy
(HBO) and Coronavirus Disease
2019 (COVID-19)
From the clinical standpoint, prediction of arterial
oxygenation at increased atmospheric pressure in
patients with pulmonary gas exchange
impairment can be extrapolated from published
clinical data and the application of gas laws
(Moon et al. 1987). A few published case series
of HBO-treated COVID-19 patients appear to
follow similar ratios, reporting improved survival
(Guo et al. 2020; UHMS 2020) and success in
preventing mechanical ventilation (Thibodeaux
et al. 2020). Yet it is still unclear whether the
clinical course of those patients, when improved,
was due to HBO itself or only time. In the follow-
ing sections, we will detail possible positive and
negative interactions between HBO and COVID-
19, as depicted in Fig. 1. According to the
The Role of Hyperbaric Oxygen Treatment for COVID-19: A Review
available literature, the increased amount of oxy-
gen in the plasma could mobilize stem cells,
block the inammatory cascade, interfere with
interstitial brosis development in the lungs,
delay the onset of severe interstitial pneumonia,
and reduce the risk of multiple organ failure
(MOF) due to an overall abated COVID-19 viral
load. However, all these possible effects have yet
to be demonstrated and should be weighed on
possible harms deriving from the administration
of HBO.
6 Hyperbaric Oxygen Therapy
(HBO) and Viral Diseases
With data showing the anti-inammatory poten-
tial of HBO, questions have been raised of
whether HBO may serve as an adjunct antiviral
treatment in patients with viral pneumonia. How-
ever, interactions between HBO and viral
infections are still poorly understood. Several
studies have shown that oxidative stress can
play a role in the progression of the HIV disease
(Baugh 2000). It has also been suggested that
oxidative stress can contribute to increased viral
replication, transcription, or reactivation of latent
infection (Peterhans 1997; Pace and Leaf 1995).
Nevertheless, previous studies regarding HBO
and viral replication reported uncertain effects
(Hosokawa et al. 2014; Peng et al. 2012; Savva-
Bordalo et al. 2012; Wong et al. 2008;
Gabrilovich et al. 1990).
There is consensus in the literature that a viral
infection per se does not trigger oxidative stress,
while it is the host defense armamentarium that
induces ROS to counter viral effects. Viruses use
phospholipids and proteins taken from the host
membranes to make their capsid (envelop), and
ROS avidly react with phospholipids, modifying
their structure, thus function. The rationale in
using HBO in viral infections could thus be
linked to the increased production of ROS.
Since a higher viral load is associated with a
more severe manifestation of COVID-19, it
could be reasonable to test HBO to hamper viral
replication and possibly to reduce the viral load,
rstly on cultured cells and then on patients
Fig. 1 Possible effects of hyperbaric oxygen (HBO) therapy in coronavirus disease 19 (COVID-19) patients
M. Paganini et al.
presenting with a moderate but potentially
evolving disease.
7 Hyperbaric Oxygen Therapy
(HBO), Cytokine Storm,
and Stem Cells
Recently, intermittent hyperoxia or different oxy-
gen partial pressures demonstrated to have an
impact on stem cell proliferation, cytokine
expression, and neuroprotection (MacLaughlin
et al. 2019; Schulze et al. 2017; Milovanova
et al. 2009). Also, Gardin et al. (2020) have
suggested that the exposure of mesenchymal
stem cells to HBO in in vitro simulated inam-
matory conditions with pro-osteogenic factors
increases the differentiation toward the osteo-
genic phenotype. In severe COVID-19, release
of IL-1 beta and IL-6 seems to sustain a
pro-inammatory state, predisposing to pulmo-
nary brosis (Conti et al. 2020; Kowalewski
et al. 2020). Specically, IL-6 and IL-8 have
been associated with faster progression of pulmo-
nary brosis, while IL-10, TGF-beta, IL-4, and
IL-13 have not shown statistically signicant
associations (Papiris et al. 2018). In such an envi-
ronment, HBO could attenuate the production of
pro-inammatory cytokines, as already described
in response to post-surgery inammation (Bosco
et al. 2007) and in modulation of immune
responses (Thom 2011). More specically, a sin-
gle preoperative HBO session the day before
pancreatic surgery demonstrated to alter the
inammatory response, decreasing the pro-
inammatory IL-6 and increasing the anti-inam-
matory IL-10 (Bosco et al. 2014). Also, a course
of HBO treatments determined a signicant
reduction in TNF-αand IL-6 plasma levels in
patients with avascular femoral necrosis (Bosco
et al. 2018). Therefore, HBO could be used in
COVID-19 to reduce cytokine levels and to
enhance mobilization of stem cells from the
bone marrow, especially mesenchymal stem
cells, to the most damaged sites (Debuc and
Smadja 2020).
8 Hyperbaric Oxygen Therapy
(HBO) and Other Possible
Effects in Coronavirus Disease
19 (COVID-19)
Nitrogen oxide has multiple and fundamental
capacities, including vasodilation, reduced platelet
activation, and decreased leukocyte adhesion to
the endothelium and consequent diapedesis
(Bosco et al. 2010;Thom2009). Breathing oxygen
underwater (12-m depths) a condition like HBO
therapy showed to improve the antioxidant activ-
ity of lymphocytes and to preserve calcium
homeostasis, suggesting a protective role in the
physiological functions of lymphocytic cells
(Morabito et al. 2011). Overall, these effects of
HBO could counteract several modications
recently demonstrated in COVID-19 patients,
such as disturbances of aggregation (Ciceri et al.
2020;Xuetal.2020a) and coagulation (Lodigiani
et al. 2020), and immune system impairment
(Giamarellos-Bourboulis et al. 2020). For exam-
ple, daily treatments with HBO could reduce plate-
let activation and aggregation in the lungs, thus
hampering the development of pulmonary micro-
circulation dysfunction and catastrophic inamma-
tion already reported in autoptic and pathologic
studies (Luo et al. 2020;Xuetal.2020b).
9 Possible Adverse Effects
of Hyperbaric Oxygen Therapy
(HBO)
Conventional HBO therapy has several
drawbacks. From the logistical standpoint, dedi-
cated large-scale equipment and complex struc-
ture are needed to administer HBO. Given the
high infectivity of SARS-CoV-2, disinfection
measures should be further strengthened, and the
attending personnel should follow medical pro-
tection guidelines of the European Committee for
Hyperbaric Medicine (ECHM) and the European
Underwater and Baromedical Society (EUBS)
(ECHM- EUBS 2020; UHMS 2020).
The Role of Hyperbaric Oxygen Treatment for COVID-19: A Review
The main side effects of HBO are limited to
the pulmonary and neurological areas. Pulmonary
toxicity usually manifests with tracheobronchial
irritation. Oxygen toxicity has been previously
reported (Heyboer et al. 2017; Clark et al. 1999;
Thorsen et al. 1998; Clark and Lambertsen 1971),
but current protocols below 3 ATA minimize this
risk. Randomized studies in animal models report
damages to the complex phospholipidic system of
the lung surfactant, with a consequent increase in
alveolar surface tension causing atelectasis and
hyperoxic toxicity (Webb et al. 1966). Changes
in protein and phospholipid complexes in the
surfactant after prolonged periods of oxygen
exposure have also been reported (Prokofev
et al. 1995; Bergren and Beckman 1975). Treat-
ment protocols aimed at limiting O
2
exposure at
high ATA have shown that the effect on the
surfactant of such exposures is of no clinical
relevance (Fife and Piantadosi 1991). Further, it
is now consolidated that HBO does not compro-
mise lung function in patients without chronic
lung disease (Hadanny et al. 2019), but specic
effects on COVID-19 patients are unknown.
Clinical signs of neurological toxicity include
visual impairment, tinnitus, nausea, facial
spasms, dizziness, and disorientation. In the
worst-case scenario, seizures and loss of con-
sciousness may develop, which can be rapidly
treated with removal of the oxygen mask and
restoration of atmospheric pressure. More recent
hyperbaric therapy protocols have allowed
overcoming or minimizing these issues, mainly
through air respiration pauses, reduction of each
session duration (< 2 h), and the use of pressures
below the threshold of neural toxicity (US Navy
2008). Other effects, such as those reported on the
crystalline lens, are usually reversible over time
(Anderson and Farmer 1978). Additionally,
adverse effects of HBO seem of smaller concern
in case of COVID-19 in the face of rather limited
number of patients in whom such therapy could
be considered and applied.
10 Conclusions
HBO therapy demonstrates multiple benecial
effects and rare, but preventable, adverse
consequences. Since the pathophysiology of
COVID-19 has not yet been claried, several
questions about the potential clinical utility of
HBO in treating this infection remain unan-
swered. We believe that the literature ndings
summarized in this article provide the
practitioners with the necessary evidence to con-
sider HBO as adjunctive treatment for COVID-
19. Further, patients should be treated carefully,
in hospital-based facilities that can manage the
patient transport issues and can provide adequate
infection control strategies to ensure safety of
healthcare personnel. Through careful monitoring
of the patient during the HBO treatment, major
side effects could be early detected and avoided.
Nevertheless, HBO therapy should be considered
carefully, after weighing harms and potential
benets, and it should be tailored to the patient
and beforehand veried through a rigorous scien-
tic process.
Acknowledgments We would like to thank Prof.
Nazareno Paolocci for his precious iconographic
contribution.
Conicts of Interest All authors declare no conicts of
interest in relation to this article.
Ethical Approval This review article does not contain
any studies with human participants or animals directly
performed by any of the authors.
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The Role of Hyperbaric Oxygen Treatment for COVID-19: A Review
... [13] The beneficial effects of hyperbaric oxygenation are facilitating the diffusion of oxygen to damaged or insufficiently vascularized tissues, stimulating their healing; improving the immune system by activating lymphocytes to fight viral infection; rapid reduction of inflammation and edema through vasoconstriction caused by hyperoxia. [14] If treatment is safely administered, complications such as eardrum damage, transient diplopia, pneumothorax (caused by barotrauma) are rare. The only absolute contraindication to HOT is pneumothorax. ...
... Studies in patients with COVID-19 treated with hyperbaric oxygen therapy have shown improved survival and successful prevention of mechanical ventilation. [14] Conclusions Given the occupational exposure and the lack of protective equipment or the use of non-compliant equipment (inadequate protective masks, lack of disinfectants, etc.), medical workers have an increased risk of illness. The healthcare professionals are the most exposed to SARS-CoV-2 infection during the pandemic, so assessing the rate of disease and the characteristics associated with occupational exposure is essential for effective organizational management to improve the protective measures needed for this vulnerable group. ...
Article
Full-text available
The infection with the new coronavirus SARS-CoV-2 was declared a global health emergency in early 2020 and, two months later, became recognized as a pandemic, affecting the world’s population regardless of age, ethnicity, geographical area. COVID-19 generally presents with altered general condition (fever, chills, marked fatigue, muscle aches, headache), respiratory manifestations from cough to dyspnea, acute respiratory distress, and multiorgan damage in critical forms. Manifestations can occur between 2 days and two weeks after exposure, the disease evolving from mildly symptomatic to moderate, severe, and even fatal forms. Our reported clinical case of COVID-19 is that of a 59-year-old nurse with diabetes and hypertension as risk factors. Accidental occupational exposure to SARS-CoV-2 infection occurred due to non-compliance with the existing dressing-undressing protective equipment protocols in facilities with treatment beds. We diagnosed a moderate-severe COVID-19, displaying bilateral lung damage and mild desaturation, complicated by bacterial superinfection with Klebsiella spp. The patient underwent antiviral, antibiotic, anticoagulant, cortisone treatment during hospitalization. In the first two months after discharge, we recommended seven hyperbaric therapy sessions to relieve respiratory symptoms and enhance regression of fibrotic lung lesions.
... 6 Moreover, hyperbaric hyperoxia has been associated with reduction of the inflammatory response. 7 Hypoxaemia correction and hyperoxia generation could trigger an anti-inflammatory effect that, in turn, could lead to a clinical improvement in patients with hypoxaemic severe pneumonia associated with COVID-19. 5 8 In case studies, HBO 2 therapy has proved to be effective and safe in patients with COVID-19 pneumonia. ...
... 11 Case series have reported that patients with COVID-19 treated with HBO 2 showed improved survival and could avoid mechanical ventilation. 7 Our findings support case series suggesting the beneficial effect of HBO 2 in the correction of hypoxaemia. In case series, as suggested by Paganini et al 7 , it is not possible to determine if improved outcomes were the effect of the treatment or time. ...
Article
Full-text available
Background Hyperbaric oxygen (HBO 2 ) therapy has been proposed to treat hypoxaemia and reduce inflammation in COVID-19. Our objective was to analyse safety and efficacy of HBO 2 in treatment of hypoxaemia in patients with COVID-19 and evaluate time to hypoxaemia correction. Methods This was a multicentre, open-label randomised controlled trial conducted in Buenos Aires, Argentina, between July and November 2020. Patients with COVID-19 and severe hypoxaemia (SpO 2 ≤90% despite oxygen supplementation) were assigned to receive either HBO 2 treatment or the standard treatment for respiratory symptoms for 7 days. HBO 2 treatment was planned for ≥5 sessions (1 /day) for 90 min at 1.45 atmosphere absolute (ATA). Outcomes were time to normalise oxygen requirement to SpO 2 ≥93%, need for mechanical respiratory assistance, development of acute respiratory distress syndrome and mortality within 30 days. A sample size of 80 patients was estimated, with a planned interim analysis after determining outcomes on 50% of patients. Results The trial was stopped after the interim analysis. 40 patients were randomised, 20 in each group, age was 55.2±9.2 years. At admission, frequent symptoms were dyspnoea, fever and odynophagia; SpO 2 was 85.1%±4.3% for the whole group. Patients in the treatment group received an average of 6.2±1.2 HBO 2 sessions. Time to correct hypoxaemia was shorter in treatment group versus control group; median 3 days (IQR 1.0–4.5) versus median 9 days (IQR 5.5–12.5), respectively (p<0.010). OR for recovery from hypoxaemia in the HBO 2 group at day 3 compared with the control group was 23.2 (95% CI 1.6 to 329.6; p=0.001) Treatment had no statistically significant effect on acute respiratory distress syndrome, mechanical ventilation or death within 30 days after admission. Conclusion Our findings support the safety and efficacy of HBO 2 in the treatment of COVID-19 and severe hypoxaemia. Trial registration number NCT04477954 .
... 6 Moreover, hyperbaric hyperoxia has been associated with reduction of the inflammatory response. 7 Hypoxaemia correction and hyperoxia generation could trigger an anti-inflammatory effect that, in turn, could lead to a clinical improvement in patients with hypoxaemic severe pneumonia associated with COVID-19. 5 8 In case studies, HBO 2 therapy has proved to be effective and safe in patients with COVID-19 pneumonia. ...
... 11 Case series have reported that patients with COVID-19 treated with HBO 2 showed improved survival and could avoid mechanical ventilation. 7 Our findings support case series suggesting the beneficial effect of HBO 2 in the correction of hypoxaemia. In case series, as suggested by Paganini et al 7 , it is not possible to determine if improved outcomes were the effect of the treatment or time. ...
... An animal experiment showed that the effect of reducing the viral load is related to the drug dosage, and it was proven that some drugs, such as massetini, can reduce the viral load by more than 99% [42]. Hyperbaric oxygen therapy can reduce the viral load, so changes in the viral load are often used to observe the effect of treatment [43]. ...
Article
Full-text available
COVID-19 has been prevalent for the last two years. The transmission capacity of SARS-CoV-2 differs under the influence of different epidemic prevention policies, making it difficult to measure the infectivity of the virus itself. In order to evaluate the infectivity of SARS-CoV-2 in patients with different diseases, we constructed a viral kinetic model by adding the effects of T cells and antibodies. To analyze and compare the delay time of T cell action in patients with different symptoms, we constructed a delay differential equation model. Through the first model, we found that the basic reproduction number of severe patients is greater than that of mild patients, and accordingly, we constructed classification criteria for severe and mild patients. Through the second model, we found that the delay time of T cell action in severe patients is much longer than that in mild patients, and accordingly, we present suggestions for the prevention, diagnosis, and treatment of different patients.
... This allows five to ten times more oxygen to enter the blood plasma and to reach tissues suffering from low oxygen supply (following, e.g., brain injury, stroke, or vascular dysfunction). Therefore, it is not surprising that HBOT has been used for over 50 years for wounds (nonhealing diabetic foot ulcers), air embolisms or decompression sickness, burned tissue repair, carbon monoxide intoxication, peripheral arterial occlusive disease, smoke inhalation, radiation injury, and promoting recovery from serious illness [3][4][5][6][7][8][9][10]. Nevertheless, today, there are only 13 FDA-approved HBOTs [11]; however, in parallel, there are a growing number of "off-label" uses, which have not been cleared by the FDA, such as treatment for stroke patients or patients suffering from Alzheimer's disease (AD) [12,13], and even treatment of COVID-19 patients, which have shown very promising results [14][15][16][17][18][19]. Further clinical trials that are currently in progress, and additional basic scientific studies aimed at understanding HBOT's mechanisms of action, will most probably expand the use of HBOT to other areas. ...
Article
Full-text available
Hyperbaric oxygen treatment (HBOT)—the medical use of oxygen at environmental pressure greater than one atmosphere absolute—is a very effective therapy for several approved clinical situations, such as carbon monoxide intoxication, incurable diabetes or radiation-injury wounds, and smoke inhalation. In recent years, it has also been used to improve cognition, neuro-wellness, and quality of life following brain trauma and stroke. This opens new avenues for the elderly, including the treatment of neurological and neurodegenerative diseases and improvement of cognition and brain metabolism in cases of mild cognitive impairment. Alongside its integration into clinics, basic research studies have elucidated HBOT’s mechanisms of action and its effects on cellular processes, transcription factors, mitochondrial function, oxidative stress, and inflammation. Therefore, HBOT is becoming a major player in 21st century research and clinical treatments. The following review will discuss the basic mechanisms of HBOT, and its effects on cellular processes, cognition, and brain disorders.
... 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 applications in COVID-19 to other maladies, like livedoid vasculopathy, have exposed the possible mechanisms that may occur: anti-inflammatory actions (decreased ICAM-1, proinflammatory cytokines and neutrophil rolling), anticoagulant actions (boosted fibrinolysis and increased plasminogen activator) and tissue healing actions (increased fibroblasts and stem cells) [146]. ...
Article
Full-text available
Hyperbaric oxygen therapy (HBOT) consists of using of pure oxygen at increased pressure (in general, 2–3 atmospheres) leading to augmented oxygen levels in the blood (Hyperoxemia) and tissue (Hyperoxia). The increased pressure and oxygen bioavailability might be related to a plethora of applications, particularly in hypoxic regions, also exerting antimicrobial, immunomodulatory and angiogenic properties, among others. In this review, we will discuss in detail the physiological relevance 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 and systemic maladies, COVID-19 and cancer. Finally, the adverse effects and contraindications associated 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 in future clinical research could be an additional support in the clinical management of multiple pathologies.
Article
Severe complications of COVID‑19 are pneumonia and the development of acute respiratory distress syndrome, which is accompanied by hypoxia. Tissue hypoxia increases against the background of inflammatory reactions and hypercoagulation. Hyperbaric oxygenation can effectively reduce systemic hypoxia, improve blood circulation, has a beneficial effect on reducing the severity of the inflammatory condition by modulating oxidative stress, including lipid peroxidation, and increasing antioxidant enzymes. A review of clinical studies conducted in different countries shows the overall effectiveness of systemic maintenance therapy with the inclusion of hyperbaric oxygenation, which reduces the use of artificial ventilation and reduces the mortality rate of severely ill patients with COVID‑19. The article presents the results of our own research on the rehabilitation of 10 patients who had a severe form of COVID‑19. The inclusion in the rehabilitation of COVID‑19 patients of daily sessions of hyperbaric oxygenation in ‘soft’ modes (1,4–1,6 ATA) in combination with respiratory and physical gymnastics showed a positive effect and safety. In patients, shortness of breath decreased, blood saturation indicators improved, cognitive functions decreased, the severity of anxiety and depression decreased, and exercise tolerance increased.
Article
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Objective: In this study, we investigated the efficacy and safety of remdesivir and tocilizumab combination therapy against dexamethasone for the management of severe COVID-19 patients. Methods: This was a multicenter study. Cases were randomly chosen and divided into two groups using an odd–even ratio of 1:1 applied to the hospital registration number. Group A received remdesivir [5 mg/kg (<40 kg) or 200 mg (>40 kg) on day 1 and then 2.5 mg/kg (<40 kg) or 100 mg (>40 kg) daily] + tocilizumab [8 mg/kg up to 800 mg highest 12 h apart], and group B was the control and received dexamethasone 6 mg/day. In addition, a broad-spectrum antibiotic and other essential treatments were received by all patients. To evaluate the mortality risk, the sequential organ failure assessment (SOFA) score was calculated on day-1. Treatment outcomes were measured as time to clinical improvement; mortality rate; duration of ICU stay; total period of hospitalization; the rate of ( Supplementary Material ) oxygen use; time to clinical failure; National Early Warning Score-2 (NEWS), and the percentage of lung recovery on CT of chest on discharge. Clinical trial registration ID: NCT04678739 . Results: Remdesivir-Tocilizumab group had a lower mortality rate (25.49%) than the control (30.77%). The time to clinical improvement (Group A-9.41; B-14.21 days), NEWS-2 on discharge (Group A-0.89; B-1.2), duration of ICU stay (Group A-7.68; B-10.58), and duration of hospitalization (Group A-9.91; B-14.68) were less in the treatment group. Group A had a better percentage of lung recovery on chest CT than the control (Group A-22.13; B-11.74). All these differences were statistically significant ( p = <0.05) in a t -test. However, no significant survival benefit was found among the study groups in Kaplan–Meier survival analysis, p = 0.739. Conclusion: The remdesivir–tocilizumab combination had preferable outcomes compared to the dexamethasone therapy for the treatment of severe COVID-19 concerning mortality rate and clinical and pulmonary improvement, although it did not demonstrate a significant survival benefit. Clinical Trial Registration: https://clinicaltrials.gov , NCT04678739.
Article
Searching for drug and non-drug modalities for the rehabilitation of patients with the post-COVID syndrome is an urgent public health challenge during the COVID-19 pandemic. Hyperbaric oxygenation is a promising method as a part of complex rehabilitation after COVID-19 due to its antihypoxic, anti-inflammatory, antioxidant and anticoagulant effects. Objective: To study the effect of hyperbaric oxygenation as a part of comprehensive outpatient rehabilitation on clinical and functional parameters in COVID-19 convalescents. Material and methods: The effect of hyperbaric oxygenation on clinical and functional parameters of 45 COVID-19 convalescents was studied: 22 males and 23 females aged 40-60 years. Patients were divided into three groups of 15 subjects each, depending on the CT stage of COVID-associated pneumonia (CT-0, CT-1, and CT-2-3). Results: Patients in group 3 (CT-2-3) were on average in the older age group, had a higher body weight and a higher percentage of fat mass according to bioimpedance measurements, compared to the other groups. Most clinical-functional and laboratory parameters in this group were within normal or subnormal ranges. In addition, high cholesterol levels (total cholesterol 6.5±1.2 mmol/L) and subnormal levels of C-reactive protein (9.3 mg/L) were noted in group 3 patients. After comprehensive rehabilitation, an increase in the distance walked in the 6-minute walking test with a significant trend in the CT-0 (467.9±37.7→531.5±44.3 m; p<0.01) and CT-1 (533.9±74.3→570.1±57.8 m; p<0.05) groups was observed. A significant decrease in norepinephrine level in the group of COVID-19 convalescents with CT-2-3 (Δ 13%), and a decrease in glutathione peroxidase in all three groups (6465.0±1637.3→5101.0±1353.3, 6587.8±1919.3→5418.1±1289.7, 7699.5±1747.9→6620.1±1702.1 units/L in groups 1, 2 and 3, respectively; p<0.05) were recorded. Conclusion: The use of hyperbaric oxygenation in comprehensive outpatient rehabilitation of COVID-19 convalescents was associated with benefits, given the improvement of functional parameters, laboratory signs of limiting low-grade inflammation, sympathoadrenal activity, and oxidative stress.
Article
The state of the hemostasis system was studied in 9 patients of the middle age group (44 ± 9.94 years) who received thermal trauma on an area of more than 32% (49.4 ± 18.3) of the body surface, accompanied by the development of burn shock. The standard therapy for burn injury was supplemented with HBO sessions. Treatment with hyperbaric oxygen was carried out in pressure chambers BLKS-307, BLKS-307/1. The state of the coagulation, anticoagulant and fibrinolytic links of the hemostasis system, as well as the viscoelastic properties of the blood, were assessed immediately before the HBO session and immediately after it. The total number of comparison pairs was 45. Under the influence of HBO therapy, there was an increase in the activity of antithrombin III (ATIII), protein C (PrS) and a decrease in the viscoelastic properties of blood (p <0.05). Positive deviations in the values of ATIII, Pr C, von Willebrand factor, APTT, prothrombin and thrombin time, fibrinogen, factor XIII, XIIa-dependent fibrinolysis, D-dimers and thromboelastography parameters were revealed. The maximum frequency of their occurrence was recorded for ATIII (95%), the minimum - for the D-dimer (62%). After HBO procedures, undesirable deviations of the hemostatic system parameters were also noted. They were chaotic, were compensated by an increase in the activity of physiological anticoagulants and were not accompanied by complications of a thrombogenic nature. Thus, conducting HBO therapy sessions in the acute period of burn disease increases the activity of physiological anticoagulants and stabilizes the viscoelastic properties of blood. There is a high frequency of occurrence of positive effects of hyperoxia on the components of the hemostasis system. The identification of its undesirable effects indicates the need to monitor the state of the hemostasis system during HBO procedures.
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Full-text available
SARS-CoV-2 viruses are positive single-stranded RNA viruses, whose infection can be asymptomatic or lead to the coronavirus disease 2019 (Covid-19). Covid-19 is a respiratory infection with a significant impact on the hematopoietic system and hemostasis leading to several cardiovascular complications. Hematologic consequences of this new infection allowed medical community to start new treatment approaches concerning infection going from targeted anti-inflammatory drugs to anticoagulation or stem cell therapies. A better understanding of Covid-19 pathophysiology, in particular hematological disorders, will help to choose appropriate treatment strategies.
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Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has presently become a rapidly spreading and devastating global pandemic. Veno-venous extracorporeal membrane oxygenation (V-V ECMO) may serve as life-saving rescue therapy for refractory respiratory failure in the setting of acute respiratory compromise such as that induced by SARS-CoV-2. While still little is known on the true efficacy of ECMO in this setting, the natural resemblance of seasonal influenza's characteristics with respect to acute onset, initial symptoms, and some complications prompt to ECMO implantation in most severe, pulmonary decompensated patients. The present review summarizes the evidence on ECMO management of severe ARDS in light of recent COVID-19 pandemic, at the same time focusing on differences and similarities between SARS-CoV-2 and ECMO in terms of hematological and inflammatory interplay when these two settings merge.
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Full-text available
Since December 2019, a novel coronavirus has spread throughout China and across the world, causing a continuous increase in confirmed cases within a short period of time. Some studies reported cases of thrombocytopenia, but hardly any studies mentioned how the virus causes thrombocytopenia. We propose several mechanisms by which coronavirus disease 2019 causes thrombocytopenia to better understand this disease and provide more clinical treatment options.
Article
Objectives: To determine whether hyperbaric oxygen (HBO2) therapy be effective to improve hypoxemia for severe COVID-19 pneumonia patients. Methods: Two male patients ages 57 and 64 years old were treated. Each met at least one of the following criteria: shortness of breath; respiratory rate (RR) ≥30 breaths/minute; finger pulse oxygen saturation (SpO2) ≤93% at rest; and oxygen index (P/F ratio: PaO2/FiO2 ≤300 mmHg). Each case excluded any combination with pneumothorax, pulmonary bullae or other absolute contraindications to HBO2. Patients were treated with 1.5 atmospheres absolute HBO2 with an oxygen concentration of more than 95% for 60 minutes per treatment, once a day for one week. Patients' self-reported symptoms, daily mean SpO2 (SO2), arterial blood gas analysis, D-dimer, lymphocyte, cholinesterase (che) and chest CT were conducted and measured. Results: For both patients, dyspnea and shortness of breath were immediately alleviated after the first HBO2 treatment and remarkably relieved after seven days of HBO2 therapy. The RR also decreased daily. Neither patient became critically ill. The decreasing trend of SO2 and P/F ratio was immediately reversed and increased day by day. The lymphocyte count and ratio corresponding to immune function gradually recovered. D-dimer corresponding to peripheral circulation disorders and serum cholinesterase, reflecting liver function had improved. Follow-up chest CT showed that the pulmonary inflammation had clearly subsided. Conclusion: Our preliminary uncontrolled case reports suggest that HBO2 therapy may promptly improve the progressive hypoxemia of patients with COVID-2019 pneumonia. However, the limited sample size and study design preclude a definitive statement about the potential effectiveness of HBO2 therapy to COVID-2019 pneumonia. It requires evaluation in randomized clinical trials in future.
Article
Recently the internet has been abuzz with new ideas to treat COVID-19, including hyperbaric oxygen (HBO2) therapy, undoubtedly driven by the fact that until recently there have been few therapeutic options for this highly contagious and often lethal infection. A series of five patients from Wuhan, China, has been reported to the UHMS and their features summarized [1]. Some groups have subsequently promoted HBO2 for COVID-19 infections, largely based upon two possible rationales. The first is treatment of hypoxemia, which is the major indication for endotracheal intubation in this condition. The second proposed rationale for hyperbaric oxygen is its potential anti-inflammatory effect.
Article
Objective A pandemic afflicts the entire world. The highly contagious SARS-CoV-2 virus originated in Wuhan, China in late 2019 and rapidly spread across the entire globe. According to the World Health Organization (WHO), the novel Coronavirus (COVID-19)has infected more than two million people worldwide, causing over 160,000 deaths. Patients with COVID-19 disease present with a wide array of symptoms, ranging from mild flu-like complaints to life threatening pulmonary and cardiac complications. Older people and patients with underlying disease have an increased risk of developing severe acute respiratory syndrome (SARS) requiring mechanical ventilation. Once intubated, mortality increases exponentially. A number of pharmacologic regimens, including hydroxychloroquine-azithromycin, antiviral therapy (eg, remdesevir), and anti-IL-6 agents (e.g., toclizumab), have been highlighted by investigators over the course of the pandemic, based on the therapy's potential to interrupt the viral life-cycle of SARS-CoV-2 or preventing cytokine storm. At present, there have been no conclusive series of reproducible randomised clinical trials demonstrating the efficacy of any one drug or therapy for COVID-19. Cases COVID-19 positive patients (n=5) at a single institution received hyperbaric oxygen therapy (HBOT) between 13 and 20 April 2020. All the patients had tachypnoea and low oxygen saturation despite receiving high FiO 2 . HBOT was added to prevent the need for mechanical ventilation. A standard dive profile of 2.0ATA for 90 minutes was employed. Patients received between one and six treatments in one of two dedicated monoplace hyperbaric chambers. Results All the patients recovered without the need for mechanical ventilation. Following HBOT, oxygen saturation increased, tachypnoea resolved and inflammatory markers fell. At the time of writing, three of the five patients have been discharged from the hospital and two remain in stable condition. Conclusion This small sample of patients exhibited dramatic improvement with HBOT. Most importantly, HBOT potentially prevented the need for mechanical ventilation. Larger studies are likely to define the role of HBOT in the treatment of this novel disease.
Article
Proper management of COVID-19 mandates better understanding of disease pathogenesis. The sudden clinical deterioration 7–8 days after initial symptom onset suggests that severe respiratory failure (SRF) in COVID-19 is driven by a unique pattern of immune dysfunction. We studied immune responses of 54 COVID-19 patients, 28 of whom had SRF. All patients with SRF displayed either macrophage activation syndrome (MAS) or very low human leukocyte antigen D related (HLA-DR) expression accompanied by profound depletion of CD4 lymphocytes, CD19 lymphocytes, and natural killer (NK) cells. Tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) production by circulating monocytes was sustained, a pattern distinct from bacterial sepsis or influenza. SARS-CoV-2 patient plasma inhibited HLA-DR expression, and this was partially restored by the IL-6 blocker Tocilizumab; off-label Tocilizumab treatment of patients was accompanied by increase in circulating lymphocytes. Thus, the unique pattern of immune dysregulation in severe COVID-19 is characterized by IL-6-mediated low HLA-DR expression and lymphopenia, associated with sustained cytokine production and hyper-inflammation.
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Background. Few data are available on the rate and characteristics of thromboembolic complications in hospitalized patients with COVID-19. Methods. We studied consecutive symptomatic patients with laboratory-proven COVID-19 admitted to an university hospital in Milan, Italy (13.02.2020-10.04.2020). The primary outcome was any thromboembolic complication, including venous thromboembolism (VTE), ischemic stroke, and acute coronary syndrome (ACS)/myocardial infarction (MI). Secondary outcome was overt disseminated intravascular coagulation (DIC). Results. We included 388 patients (median age 66 years, 68% men, 16% requiring intensive care [ICU]). Thromboprophylaxis was used in 100% of ICU patients and 75% of those on the general ward. Thromboembolic events occurred in 28 (7.7% of closed cases; 95%CI 5.4%-11.0%), corresponding to a cumulative rate of 21% (27.6% ICU, 6.6% general ward). Half of the thromboembolic events were diagnosed within 24 hours of hospital admission. Forty-four patients underwent VTE imaging tests and VTE was confirmed in 16 (36%). Computed tomography pulmonary angiography (CTPA) was performed in 30 patients, corresponding to 7.7% of total, and pulmonary embolism was confirmed in 10 (33% of CTPA). The rate of ischemic stroke and ACS/MI was 2.5% and 1.1%, respectively. Overt DIC was present in 8 (2.2%) patients. Conclusions. The high number of arterial and, in particular, venous thromboembolic events diagnosed within 24 hours of admission and the high rate of positive VTE imaging tests among the few COVID-19 patients tested suggest that there is an urgent need to improve specific VTE diagnostic strategies and investigate the efficacy and safety of thromboprophylaxis in ambulatory COVID-19 patients.
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We suggest the use of MicroCLOTS (microvascular COVID-19 lung vessels obstructive thromboinflammatory syndrome) as a new name for severe pulmonary coronavirus disease 2019 (COVID-19). We hypothesise that, in predisposed individuals, alveolar viral damage is followed by an inflammatory reaction and by microvascular pulmonary thrombosis. This progressive endothelial thromboinflammatory syndrome may also involve the microvascular bed of the brain and other vital organs, leading to multiple organ failure and death. Future steps in the understanding of the disease and in the identification of treatments may benefit from this definition and hypothesised sequence of events.