Top Ten Things You Need to Know About HBOT #8: HBOT Mechanism: More Than Correction of Hypoxia

Hyperbaric oxygen therapy (HBOT) is an accepted therapeutic modality for use in several medical conditions including problem wounds. HBOT enhances oxygen supply to hypoxic tissues and increases wound healing and tissue remodeling capacity. Currently, HBOT therapy is applied in a wide range of clinical conditions.
 
In the third in a series of articles, these authors continue counting down the top ten things you need to know about HBOT. 

8

Did you know that HBO therapy is much more than a correction of hypoxia?

Yes, HBOT involves oxygen, but we mustn't reduce its mechanism to the mere correction of hypoxia. Let’s take a look into the role of oxygen within wound healing and the molecular processes that HBOT aids.
 
At sea level or 1 atmosphere absolute (ATA), blood oxygen concentration is 0.3 mL/dL (0.3% vol). Tissue at rest draws 5–6 milliliters of oxygen per deciliter of blood assuming normal perfusion. Administering 100% oxygen at normobaric pressure increases the amount of oxygen dissolved in the blood to 1.5 mL/dL (fivefold). However, at 3 ATA the dissolved oxygen content is approximately 6 mL/dL, much more than the resting cellular requirement.¹ Due to the low solubility of oxygen in the blood, the amount of dissolved oxygen in arterial blood attainable during normobaric exposures to 100% oxygen (about 2% vol) can provide only one-third of resting tissue oxygenation requirements. Through HBOT, in which patients are exposed to oxygen at a pressure of 3 ATA, there is enough oxygen dissolved in the plasma to meet the average requirement of resting tissues using oxygen alone without contribution from oxygen bound to hemoglobin.²
 
The rate at which wounds heal is highly oxygen dependent. All wounds have a hypoxic center of variable size. The hypoxic nature of wounds has been demonstrated and the hypoxia, when increased, correlates with impaired wound healing and increased rates of wound infection.^3,4 The state of wound oxygenation is a key determinant of healing outcomes. From a diagnostic standpoint, measurements of wound oxygenation are commonly used to guide treatment planning such as the decision to proceed with amputation or determining failure to heal.⁵
 
Additionally, peri-wound hypoxia alters local responses to infection and vice versa. Significant amplification of tissue hypoxia often occurs in inflammation, infection, or ischemia due to damage to the vasculature, a high metabolic activity of pathogens and host cells, or a reduction in metabolic substrates.
 
At the same time, neutrophils that are operating in hypoxic areas are subject to functional modulation by hypoxia. Neutrophils play a vital role in protecting us against invading pathogens and hypoxia compromises their defense ability.⁶
 
Furthermore, migration and functions of polymorphonuclear leukocytes in hypoxic tissues are impaired and microorganisms can easily replicate in them. Once an infection develops in these tissues, cure depends greatly on the oxygenation of the infected region.⁷ Periwound hypoxia also alters local tissue reparative processes. When the average PO₂ is less than 30mm hg in nondiabetics, less than 40 mmHg in diabetics and less than 50mm Hg in patients with diabetes and renal failure⁸, wound healing becomes impaired. Poor wound healing has also been linked to the failure of collagen formation and angiogenesis. Fibroblasts need oxygen to proliferate and perform their function. HBOT can play a valuable role in the therapeutic approach to all aforementioned issues.
 
So, how can HBOT help? While HBOT has a great role in correcting the hypoxia in the wound/periwound environment, its role is not limited to the correction of hypoxia but also has a great role in wound infections, stem cell mobilization, and engraftment, producing an anti-inflammatory environment and many others.
 
Let’s start by talking about the bactericidal effects of HBOT. When oxygen value is less than 30 mmHg, polymorphonuclear killing is inhibited due to loss of oxidative burst, and leukocyte killing capacity is decreased by 50%.⁹ In the same vein, both animal and human studies have shown that rich oxygen tissue states inhibit anaerobic infections and increase the oxidative burst ability of human leukocytes, which aid in the killing of bacteria.¹⁰ HBOT helps with increased leukocyte bacterial killing via direct toxicity to anaerobic organisms, suppression of exotoxin production, and synergism with certain antibiotics.
 
Several studies suggest that HBOT may help with wound healing by mobilizing stem cells to the site of injury. Stem cells are pluripotent, which means they can give rise to many different types of cells, making them an attractive target for wound healing modalities. They are identified by their cell surface marker, CD34.
 
Both in murine and human subjects, exposure to HBOT has shown to at least double the number of pluripotent stem cells circulating via the bloodstream.¹¹ This is done by identifying CD 34+ cells and quantification of these via flow cytometry after application of HBOT, as per their respective protocols.¹² In addition to this, HBOT has been shown to increase stem cell engraftment—for example, in the setting of umbilical cord blood. Umbilical cord blood transplantation is an option for stem cell transplantation that could help those patients who have a hematologic malignancy and are unable to find a match. Studies suggest that the use of HBOT before umbilical cord blood transplantation can decrease chronic graft versus host disease, promote significant early B cell recovery, and promote overall increased survival rates.¹³
 
HBOT has been shown to promote angiogenesis in tissues both by increasing growth factor signaling and by changing the oxygenation tissue gradient. The last mechanism is particularly important to those tissues that have been previously irradiated. HBOT has been known to increase growth factors such as vascular endothelial growth factor (VEGF), which is vital for angiogenesis. Increasing oxygen content and delivery to surrounding tissues will noticeably increase the overall tissue gradient between these tissues and the central hypoxic area that we discussed earlier. This increased oxygen gradient triggers angiogenesis.¹⁴ Additionally, in chronic hypoxic wounds we see chronically decreased levels of hypoxic inducible factor (HIF). These low HIF levels may change when “shocked” by the temporarily increased oxygen levels to which the wound is exposed, such as in the setting of HBOT. HBOT has the potential to reset HIF sensing on a molecular level.¹⁵
 
HBOT is associated with a reduction of inflammatory cytokines as well as a notable decrease of neutrophil recruitment to sites of injury.¹⁶ It is most recently associated with the impairment of neutrophil β2 integrin adhesion in particular. β2 integrins are adhesion molecules that are leukocyte specific and are essential for neutrophil trafficking.¹⁷ By inhibiting β2 integrin adhesion molecules, we downregulate the inflammatory process occurring at the site of the wound or damaged tissue, allowing the chronic wound to progress from that stage onto one of proliferation. This inhibition will also prevent adherence of leukocytes to ischemic tissue, which will in turn prevent vasoconstriction and reperfusion injury.¹⁸
 
Lastly, let us not forget the emergent uses of HBOT, which are described in greater detail in an upcoming installment of this series. HBOT is a staple in the treatment of pathological conditions in which gas bubbles are present in the body, such as arterial gas embolism and decompression sickness.¹⁹ When HBOT is administered at 3 ATA, according to Boyle’s law, there will be a reduction of bubble volume of up to one-third. This will lead to the improvement of gas bubble-related conditions by creating a situation in which these can be better eliminated, circulation can be improved, and ultimately local hypoxia can be reversed. Oxygen also then displaces nitrogen in the bubbles and essentially dissolves these bubbles away.²⁰
 
Denise Nemeth is a first-year medical student at the University of the Incarnate Word School of Osteopathic Medicine in San Antonio, TX. Formerly a general and vascular surgery PA in a rural community, Ms. Nemeth aspires to become a general surgeon. She is certified wound specialist with the American Board of Wound Management. Her interests include rural health, wound healing, colorectal surgery, and minimally invasive surgery.
 
Jayesh B. Shah is Immediate Past president of the American College of Hyperbaric Medicine and serves as medical director for two wound centers based in San Antonio, TX. In addition, he is president of South Texas Wound Associates, San Antonio. He is also the past president of both the American Association of Physicians of Indian Origin and the Bexar County Medical Society and Current of Board of Trustees of Texas Medical Association.              

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