A Primer on Using HBOT in Patients With COVID-19

The SARS-Cov-2 (COVID-19) pandemic hit an unprepared world with unprecedented force. Initial medical interventions addressed the severe hypoxia and inflammatory response, but for many critically ill patients, that was not enough. Critical care physicians were turning up ventilators to settings that were previously unheard of and still not achieving adequate oxygenation. Members of the hyperbaric community began chatting about the potential use of hyperbaric oxygen therapy (HBOT) in the treatment of these hypoxic patients. Some brave clinicians took the plunge and started treating these folks in the hope of getting them through their hypoxia and past the greatest risk of intubation and possible death.

The Undersea and Hyperbaric Medical Society (UHMS) put together a research group to address whether or not hyperbaric oxygen therapy could play a significant role in the treatment of hospitalized patients who were hypoxemic and hypoxic. The paper is published open access and has a detailed and elegant explanation of why hyperbaric oxygen could be of potential benefit.¹ The following is the “CliffsNotes” version of that paper.

Q:

Why would hyperbaric oxygen therapy be considered in the treatment of COVID-19 patients?

A:

We have learned a lot about the pathophysiology of the COVID-19 infection since the beginning of the pandemic. The vast majority of people who get infected will have relatively mild symptoms. Those who develop pulmonary symptoms can have severe respiratory compromise. An excessive inflammatory response and the unbridled release of inflammatory cytokines contribute to the development of interstitial fluid and pulmonary fibrosis.

Oxygen normally diffuses out of the alveoli into the adjacent capillary network and then attaches onto the red blood cells for transport to remote tissues. When interstitial fluid increases, a barrier to the diffusion of oxygen is created. The distance that oxygen has to travel from the alveoli to the capillary bed increases, and less oxygen makes it to the plasma, and subsequently to the red blood cells. In these patients, they have enough red blood cells, but the red blood cells are not carrying their usual oxygen load, resulting in hypoxemia. When these oxygen-deprived red blood cells go to remote tissues, they do not have enough oxygen to offload to those tissues, resulting in tissue hypoxia.

Q:

How would hyperbaric oxygen help in this scenario?

A:

Under hyperbaric conditions, near 100% oxygen is inhaled under pressure. Gas exchange in the lungs occurs in the fluids that surround the alveoli and the adjacent capillary bed. The capillaries carry plasma and red blood cells. Normally, the red blood cells’ four sites for oxygen transport are fully occupied and cannot carry more oxygen. Under hyperbaric conditions, the plasma becomes saturated with oxygen, and it is the plasma that becomes the conduit for oxygen transport to remote tissues. When the blood gets to the target tissues, oxygen is offloaded to provide a fuel source for various metabolic activities within the cells. A steep oxygen gradient facilitates this release of oxygen from the red blood cell into the adjacent tissues. In the hyperbaric environment, oxygen is transferred from the capillaries into the adjacent tissues under the principle of diffusion; that is, the higher the difference in concentration of a gas between two areas, the further the gas diffuses to achieve equilibrium.

If the oxygen at hand cannot meet the metabolic needs of the tissues, an “oxygen debt” continues to accumulate. COVID-19 patients are both hypoxemic and have tissue hypoxia. Over a period of time, respiratory and multiorgan failure ensues. Hyperbaric oxygen has been used to treat hypoxia in patients with severe blood loss that cannot be addressed by transfusion. The ability of oxygen to be transported to tissues in high concentrations in the plasma is thought to be the reason HBOT is effective in keeping anemia patients alive long enough for their own bone marrow to produce red blood cells. In COVID-19 patients, we are waiting for the cytokine storm to abate.

Q:

How does hyperbaric oxygen blunt the inflammatory response?

A:

When cells are infected with COVID-19, there is upregulation of proinflammatory cytokines, namely interleukin (IL) 6, 8, and 10; granulocyte-colony stimulating factor (G-CSF); and tumor necrosis factor-alpha (TNF-alpha), amongst others. The production of these cytokines and chemokines causes a massive influx of neutrophils and monocytes into the affected tissue, the lung. Leaking endothelium develops, resulting in edema, which provides a physical barrier to oxygen diffusion into the blood. These inflammatory agents also become systemic and may form the basis for the myocardial and neurological injury that is seen in COVID-19 patients.

Hyperbaric oxygen has been shown to blunt the inflammatory response significantly in a wide range of tissues and disease processes. The role of hyperbaric oxygen as a modulatory of the inflammatory response forms the basis of our treatment of compromised tissue flaps, crush injuries, and burns. Recent work done on the effect of hyperbaric oxygen on avascular necrosis of the hip, as well as in ulcerative colitis and Crohn’s patients, has shown that hyperbaric oxygen reduces expression of TNF-alpha, IL-6 and IL-10.^2–4

Q:

What are the studies that have been done that use hyperbaric oxygen to treat COVID-19 patients?

A:

A number of studies that have been published in the literature show that hyperbaric oxygen therapy in patients that are hypoxemic but not yet to the point of intubation show both a reduction in the need for intubation and reduced mortality.^5,6 Other anecdotal reports, both in the United States and internationally, consistently find a reduction in hypoxia with a reduction in the need for intubation. Intubation was a prognostic marker for a poor outcome in patients with COVID-19. It appears that hyperbaric oxygen therapy in these patients is very safe, with minimal complications. Uniformly, the greatest challenge is transporting COVID patients to the hyperbaric oxygen suite since they have such high oxygen requirements. Another complicating factor in the United States is that very few hospital-based programs treat inpatients. Even fewer have 24/7 coverage and the ability to treat critical care patients. Therefore, the number of centers that can treat COVID-19 patients may be limited.

Although we have gotten better at treating the COVID-19 patient that ends up in the hospital, there is no definitive therapeutic intervention that “cures” the illness. We have made progress in assessing the beneficial aspects of systemic steroids in suppressing the inflammatory response and in proning to enhance oxygenation. Hyperbaric oxygen provides these patients with another therapeutic option in the armamentarium by addressing the severe hypoxemia and tissue hypoxia, attenuating the overexuberant inflammatory response and impacting the oxygen debt that accrues.¹  

Helen B. Gelly is emeritus medical director of Hyperbaric Physicians of Georgia and chief executive officer of HyperbaRXs, Marietta, GA.

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References

1. Feldmeier J, Kirby JP, Buckey JC, et al. Physiologic and biochemical rationale for treating COVID-19 patients with hyperbaric oxygen. Undersea Hyperb Med. 2021; 48(1):1–12.

2. Chandrinou A, Korompeli A, Grammatopoulou E, et al. Avascular necrosis of the femoral head: Evaluation of hyperbaric oxygen therapy and quality of life. Undersea Hyperb Med. Fourth-Quarter 2020;47(4):561-569.

3. Dulai PS, Raffals LE, Hudesman D. A phase 2B randomised trial of hyperbaric oxygen therapy for ulcerative colitis patients hospitalised for moderate to severe flares. Aliment Pharmacol Ther. 2020 Sep;52(6):955-963.
 
4. Lansdorp CA, Gecse KB, Buskens CJ. Hyperbaric oxygen therapy for the treatment of perianal fistulas in 20 patients with Crohn's disease. Aliment Pharmacol Ther. 2021 Mar;53(5):587-597.

5. Thibodeaux K, Speyrer M, Raza A, et al. Hyperbaric oxygen therapy in preventing mechanical ventilation in COVID-19 patients: a retrospective case series. J Wound Care. 2020; 29(Sup5a):S4–S8.

6. Gorenstein SA, Castellano ML, Slone ES, et al. Hyperbaric oxygen therapy for COVID-19 patients with respiratory distress: treated cases versus propensity-matched controls. Undersea Hyperb Med. 2020; 47(3):405–413.