The Potential for HBO2 Therapy as an Intervention for Hypoxia Related to COVID-19 Infection

The Question

The SARS-Cov-2 (COVID-19) pandemic has been one of the most trying and enduring public health crises experienced in over a century, both in the United States and around the world. It still remains a major worldwide public crisis, even with the advance of vaccine administration and adjunctive therapeutics.^[1] This is unfortunately still the case, despite the administration of efficacious vaccines, along with both a more virulent delta variant and a national and world population sub-cohort hesitant to or even unable to receive vaccination. As we know that supplemental oxygen is the remedy for providing oxygen to support tissue vitality and organ function in those infected with SARS-Cov-2, it has even become a scarce resource around the world as we try to sustain life for those infected with the virus.^[2]

Rationale

The hypoxemia behind COVID infection is not the only mechanism by which tissue viability and organ function are affected. In fact, the interactions are more complex, involving multiple mechanisms and pathways that ultimately lead to the clinical effects expressed by the SARS-Cov-2 virus. These mechanisms include: 1) replication and release of virus via invasion at the ACE-2 receptor: 2) early phase immune response by monocytes, macrophages, dendritic cells and sensitized T-lymphocytes that act to remove infected cells; 3) systematic overproduction and loss of regulation of proinflammatory and inflammatory cytokines/chemokines (NLRP-3, IL-1B, IL-6, IL-2, IP-10, GM-CSF, IFN-G, TNFa, and M1P1a; and 4) extrapulmonary involvement leading to activation of procoagulant response and multiorgan failure.^[3]

However, as mentioned previously, the hallmark of serious life-threatening COVID infection is profound hypoxemia and secondary tissue hypoxia due to pneumonia, often bilateral and leading to acute respiratory distress syndrome (ARDS). Studies examining intracranial Doppler performed in mechanically ventilated COVID-19 patients revealed a ventilation-perfusion (V/Q) mismatch with resultant failure to oxygenate blood returning to the heart, leading to a clinical scenario where low oxygen levels experienced by the patient are unresponsive to supplemental oxygen administration.

The specific pathways where hyperbaric oxygen therapy is known or has been demonstrated to counteract the above mechanisms and pathways include: 1) proven success in restoring or exceeding normoxic status of oxyhemoglobin and tissue oxygenation for the direct amelioration of severe hypoxemia and tissue hypoxia; 2) anti-inflammatory effects on proinflammatory and inflammatory cytokines (including TNFa, IL-1B, IL-6, IL-10, NLRP-3); 3) restoration of anaerobic metabolism in chronically hypoxic tissues and promotion of lactate clearance; and 4) additional anti-inflammatory effects on mesenchymal and possible hematopoietic stem cells.

Pilot Study

In March – April of 2020, Gorenstein et al. published preliminary data on a pilot study looking at the potential safety and efficacy of hyperbaric oxygen therapy in treating patients infected with COVID-19 who were in acute respiratory distress. After treating a total of 20 COVID-19 infected patients with hyperbaric oxygen (ages 30-79, oxygen requirement of 2-15 L/minute, hospital day 0-14 days) and comparing to 60 propensity-matched controls, there was a statistically significant (roughly ~66%, p=0.046) reduction in need for mechanical ventilation and not statistically significant >50% reduction in inpatient mortality (p=0.14). ^[4] While preliminary and requiring additional subjects to prove its efficacy in treatment, this was an early study that prompted additional studies to follow, including the largest current US prospective controlled trial for evaluation of HBO₂ in acute hypoxemia secondary to COVID-19 infection.

Additional Data

While there are several national and international studies to date that suggest the benefit of hyperbaric oxygen therapy with treatment of hypoxemia secondary to COVID-19 infection, there is not enough sufficiently powered clinical data to definitively support hyperbaric oxygen therapy as a primary treatment for hypoxemia secondary to COVID-19 infection. The goal behind the largest prospective randomized control trial (ClinicalTrials.gov Number: NCT04619719) in the United States to evaluate this is further discussed below. The results and outcomes of this study will likely hold more definitive answers as to whether hyperbaric oxygen therapy is a useful clinical adjunct for the treatment of moderate to severe hypoxemia experienced by the COVID-19 infected patient.

Current Study Under Way

Currently, the largest US multi-center prospective randomized controlled trial is underway (ClinicalTrials.gov Number: NCT04619719) and actively enrolling subjects at four major medical centers in the United States. The study goal is to evaluate the effectiveness of hyperbaric oxygen therapy for treating patients with moderate to severe respiratory distress due to COVID-19. The four centers include Legacy Emanuel Medical Center (Portland, OR), New York University (NYU) – Winthrop Hospital (New York, NY), Yale Greenwich Hospital (Greenwich, CT), and Bozeman Health (Bozeman, MT). Legacy Emanuel Medical Center, located in Portland, OR is the leading research/primary sponsor institution, and their Legacy Research Institute is coordinating this multi-center trial. The primary endpoint for the study will be 60-day mortality with secondary outcome measures of time to mechanical ventilation and secondary symptoms at 60-day follow-up periods.

Future Direction

While it remains to be definitively proven with a large prospective randomized control trial that hyperbaric oxygen therapy is a viable therapy for the treatment of COVID patients, there are many sources of evidence that point to its potential utility as an adjunctive therapy for the treatment of COVID patients. Our attempts at reversing the acute hypoxemic failure secondary to this respiratory virus will be definitively evaluated in this study. While our ultimate goal is to evaluate whether or not we can improve outcomes in both morbidity and mortality, our hope is to further elucidate the clinical potential that hyperbaric oxygen therapy may hold for COVID-19 and any potential future treatment of severe hypoxia-inducing respiratory viruses that may compromise oxygenation or tissue function in the human body.

Legacy Emanuel Hyperbaric Department; Portland, Oregon

^[1] Feldmeier et al. Physiologic and biochemical rationale for treating COVID-19 patients with hyperbaric oxygen. UHM 2021 VOL.48 NO. 1, 1-12.

^[2] https://www.nytimes.com/2021/05/04/world/oxygen-shortage-covid.html

^[3] Bohn MK, Hall A, Sepiashvili L. et al, Pathophysiology of COVID-19: mechanisms underlying disease severity and progression. Physiology (Bethesda). 2020;35(5):288-301. Dog:10.1152/physiol.00019.2020.

⁴ Gorenstein et al. Hyperbaric oxygen therapy for COVID-19 patients with respiratory distress: treated cases versus propensity-matched controls. UHM 2020, Vol 47, No. 3, 405-413.