A General Overview on the Hyperbaric Oxygen Therapy: Applications, Mechanisms and Translational Opportunities

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

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This study provides a comprehensive review of hyperbaric oxygen therapy (HBOT), discussing its applications, mechanisms, potential research opportunities, and implications for various medical conditions, including COVID-19.

Overview of Hyperbaric Oxygen Therapy ​

Hyperbaric oxygen therapy (HBOT) involves administering pure oxygen at increased atmospheric pressure, enhancing oxygen levels in blood and tissues. ​ This therapy has various applications, mechanisms, and potential research opportunities, particularly in treating hypoxia-related conditions.

Historical Context of Hyperbaric Oxygen Therapy

The use of hyperbaric oxygen therapy dates back to 1662, with significant developments in understanding its physiological effects occurring over the centuries. ​ Key figures include Paul Bert, who described the physiological basis of pressurized air, and the therapy gained traction during World War II for treating decompression sickness. ​

• First documented use in 1662 by Henshaw.
• Paul Bert defined the physiological basis of hyperbaric effects. ​
• Gained popularity during WWII for treating divers' decompression sickness. ​
• Hundreds of HBOT facilities established in the early 21st century. ​

Current Indications and Applications of HBOT

There are currently 14 approved indications for HBOT, including conditions like air embolism, severe anemia, and certain infectious diseases. ​ The European Consensus Conference on Hyperbaric Medicine recognizes HBOT as a primary treatment for some conditions and a potential adjunct for others. ​

• 14 approved indications for HBOT. ​
• Conditions include air embolism, severe anemia, and infectious diseases.
• Recognized as primary treatment for carbon monoxide poisoning.
• Considered as an adjunct for conditions like diabetic foot.

Mechanisms of Action in Hyperbaric Oxygen Therapy

HBOT operates through three main mechanisms: creating a positive oxygen gradient for diffusion, increasing oxygen concentration in blood due to pressure, and reducing gas bubble size in blood. ​ This results in hyperoxemia and hyperoxia, aiding in the management of various pathological processes. ​

• Positive oxygen gradient enhances diffusion to hypoxic tissues. ​
• Increased oxygen concentration in blood due to pressure (Henry’s Law).
• Reduces gas bubble size in blood (Boyle-Mariotte Law).
• Provides significant oxygen supply independent of hemoglobin. ​

Physiological Relevance of Oxygen in the Body ​

Oxygen is crucial for aerobic respiration, enabling ATP synthesis in mitochondria. ​ Its uptake is essential for complex organisms, and hypoxia can lead to various diseases, making oxygen a potential therapeutic agent for acute and chronic conditions. ​

• Oxygen key for aerobic respiration and ATP synthesis. ​
• Essential for complex organisms due to evolutionary advantages. ​
• Hypoxia can induce pathological stress and various diseases. ​
• Oxygen proposed as a therapeutic agent for multiple conditions. ​

Adverse Effects and Contraindications of HBOT

While HBOT has therapeutic benefits, it can also lead to adverse effects such as oxidative stress and neurotoxicity. Balancing the benefits and risks is essential for clinical recommendations regarding HBOT. ​

• Potential adverse effects include oxidative stress and DNA damage. ​
• Risks of metabolic disturbances and acute pulmonary injury.
• Importance of balancing benefits and risks in clinical use.

Future Directions and Research Opportunities

Further research is encouraged to explore the potential uses of HBOT in various conditions, including inflammatory diseases, COVID-19, and cancer. The inclusion of HBOT in clinical research could enhance the management of multiple pathologies. ​

• Encouragement for further research in HBOT applications.
• Potential areas include inflammatory diseases, COVID-19, and cancer. ​
• HBOT could support clinical management of various pathologies. ​

Approved Indications for HBOT ​

HBOT (Hyperbaric Oxygen Therapy) has 14 approved medical indications, primarily categorized into three main effects: wound healing and angiogenesis, antimicrobial effects, and emergency medical treatments. ​ These indications include conditions such as carbon monoxide poisoning, diabetic foot ulcers, and necrotizing soft tissue infections.

14 approved indications for HBOT include:

• Acute thermal burn injury

• Carbon monoxide poisoning

• Central retinal artery occlusion

• Clostridial myositis and myonecrosis ​

• Compromised grafts and flaps

• Crush injury and compartment syndrome ​

• Decompression sickness ​

• Delayed radiation injury

• Enhancement of healing in selected problem wounds ​

• Idiopathic sudden sensorineural hearing loss

• Intracranial abscess

• Necrotizing soft tissue infections

• Refractory osteomyelitis ​

• Severe anemia

• Air or gas embolism

HBOT's Role in Wound Healing ​

HBOT accelerates wound healing by enhancing oxygen supply, which is crucial for tissue regeneration and angiogenesis. ​ It is particularly effective for diabetic foot ulcers and other chronic wounds, although results can vary among patients. ​

• HBOT speeds up wound healing by providing 100% oxygen. ​

• Effective for microbial-infected wounds, traumatic wounds, and diabetic ulcers. ​

• Diabetic foot ulcers affect 15% of diabetic patients; HBOT improves healing rates. ​

• Increases nitric oxide levels and endothelial progenitor cells. ​

• Enhances angiogenic markers like EGF and VEGF. ​

• Reduces inflammation and lowers amputation rates.

• Systematic reviews support systemic HBOT for diabetic foot ulcers, but results are heterogeneous. ​

Antimicrobial Activity of HBOT ​

HBOT serves as an effective antimicrobial treatment, particularly for chronic wounds with bacterial biofilms. ​ It modifies the wound microenvironment, enhancing the immune response and reducing infection rates.

• HBOT is effective against anaerobic infections, such as necrotizing soft tissue infections. ​
• It breaks down bacterial biofilms, with a prevalence of 78.2% in chronic wounds.
• Upregulates HIF, NOS, and antimicrobial peptides, enhancing phagocytosis. ​
• Recommended for Clostridium perfringens infections, with specific treatment protocols.
• Reduces tissue damage and infection spread through anti-inflammatory effects.
• Clinical trials show improved survival rates in sepsis models with early HBOT. ​

HBOT Applications in Medical Emergencies ​

HBOT is crucial in treating various medical emergencies, including decompression sickness, air embolism, and acute ischemia. ​ Its rapid therapeutic effects can be life-saving in critical situations. ​

• Effective for conditions like decompression sickness and air embolism.
• Provides rapid tissue oxygenation and promotes gas reabsorption. ​
• Recommended for central retinal artery occlusion (CRAO) to improve vision recovery. ​
• Beneficial for crush injuries and acute ischemia, enhancing angiogenesis. ​
• Reduces neurological sequelae in carbon monoxide and cyanide poisoning.
• Can improve outcomes in severe anemia and sudden sensorineural hearing loss. ​

HBOT's Immunomodulatory Properties ​

HBOT has significant immunomodulatory effects, influencing inflammatory responses and potentially aiding in autoimmune diseases. ​ It alters immune cell ratios and reduces lymphocyte proliferation.

• Alters CD4+:CD8+ ratio and reduces lymphocyte proliferation. ​
• Activates neutrophils, promoting migration to hyperoxic regions.
• Potential role in managing autoimmune diseases, showing promising results. ​
• Reduces inflammatory cytokines in conditions like DSS-induced colitis. ​
• Improves quality of life in fibromyalgia and exercise-induced inflammation.

Potential Role of HBOT in COVID-19 ​

HBOT has been proposed as an adjunctive treatment for severe COVID-19 cases, potentially improving oxygenation and reducing inflammation. ​ Early studies show promising results, but further research is needed. ​

• Proposed for severe COVID-19 patients to improve oxygen diffusion. ​
• May alleviate "silent" hypoxemia, which can lead to rapid deterioration. ​
• Increases production of nitric oxide and reduces inflammatory cytokines.
• Preliminary studies show rapid alleviation of hypoxemia in patients. ​
• Not yet an accepted indication, but may be beneficial for post-viral sequelae.

HBOT's Applications in Cancer Treatment ​

While not an approved indication, HBOT shows potential in cancer management by targeting tumor hypoxia and enhancing the effectiveness of radiotherapy and chemotherapy. ​

• HBOT may inhibit tumor growth and improve therapy success. ​
• Effective in various cancers, including breast, prostate, and head and neck cancers.
• Can act as a radiotherapy and chemotherapy adjuvant. ​
• Studies show mixed results; further research is needed to establish efficacy. ​
• Potential for combined therapies to enhance treatment outcomes.

Other Emerging Applications of HBOT ​

Research is exploring additional applications of HBOT, including its effects on erectile dysfunction, brain injuries, and aging. ​ These areas show promise but require further investigation.

• Potential benefits for erectile dysfunction through penile angiogenesis. ​
• May prevent neuronal death in stroke and traumatic brain injury. ​
• Research indicates HBOT could mitigate aging effects on the immune system and skin. ​
• Encouraging results in improving cognitive functions in aging models.

Adverse Effects and Contraindications of HBOT ​

Despite its benefits, HBOT can cause adverse effects, including barotrauma and claustrophobia, and has specific contraindications that must be considered. ​

• Common complications include claustrophobia and barotrauma. ​
• Barotrauma can affect the middle ear and sinuses. ​
• Untreated pneumothorax is an absolute contraindication.
• Relative contraindications include certain respiratory conditions and pregnancy. ​
• Careful screening and monitoring are essential to minimize risks.

Hyperbaric Oxygen Therapy (HBOT) Overview

HBOT is a therapeutic method that enhances oxygen levels in blood and tissues, providing benefits for various medical conditions. ​ Its applications range from treating infections and wounds to managing medical emergencies like gas poisoning. ​

Mechanisms and Effects of HBOT

HBOT operates through physical, physiological, and cellular mechanisms, leading to increased oxygenation and modulation of immune responses. ​

• Increases blood and tissue oxygen levels independently of hemoglobin.
• Enhances angiogenesis and modulates cytokine production.
• Directly affects infectious agents and immune cells.

Applications of HBOT in Medical Conditions

HBOT has shown efficacy in a wide range of pathologies, including infections, inflammatory diseases, and wound healing. ​

• Effective in managing medical emergencies such as air embolism and gas poisoning. ​
• Reported benefits in treating COVID-19, particularly in controlled clinical trials.
• Used as an adjunctive treatment in malignancies and delayed radiation injuries. ​

Challenges and Future Directions for HBOT

Despite its benefits, there are challenges in optimizing HBOT applications and understanding potential adverse effects. ​

• Need for strategies to address tumor hypoxia, as HBOT may not fully eliminate it. ​
• Importance of developing predictive models to assess risks and benefits for patients.
• Currently, only 14 approved indications exist for HBOT, indicating room for further research.