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by the Undersea & Hyperbaric Medical Society
Introduction
As SARS-CoV-2 infection accelerated in early 2020, many patients deteriorated rapidly and became ventilator-dependent. The death rate from serious infection was frightening, especially in patients with other chronic diseases. Clinicians and medical researchers began developing strategies to treat and prevent this new worldwide public health threat. They looked to novel interventions because no highly effective therapies existed, and care was mostly supportive. Some recommended hyperbaric oxygen (HBO2) therapy because of its demonstrated success in providing oxygen and reducing end-organ damage in patients with severe carbon monoxide poisoning or anemia. A publication from China reported dramatic results in five critically ill patients treated with HBO2 [1]. A second case series published by Thibodeaux, et al. [2]. showed that patients who received hyperbaric oxygen at a critical junction when intubation seemed imminent avoided intubation. Gorenstein and colleagues have now reported in a publication in pre-print form a series of 20 patients treated with hyperbaric oxygen and compared to propensity matched controls. They conclude that HBO2 is safe and possibly effective. [3] Additional anecdotal reports appeared to show an impressive improvement in sick patients even in the setting of progressive respiratory failure despite delivery of prolonged high FiO2s (fraction of inspired oxygen). One of our committee members based on her personal experiences in treating a small group of patients has suggested utility in using transcutaneous oxygen in monitoring patients’ responses to hyperbaric oxygen, including the continued use of this technology after a hyperbaric treatment and return of the patient to the ICU [4]. Two prior publications had reported experiences in applying transcutaneous oxygen measurements as a monitoring tool to be applied to critically ill patients [5,6].
With these reported successes interest in the possible role of hyperbaric oxygen in COVID-19 treatment increased. The Undersea and Hyperbaric Medical Society (UHMS) was called upon to render an opinion, and a UHMS Policy Statement was developed and released at:
https://www.uhms.org/images/Position-Statements/UHMS_Position_Statement_Hyperbaric_Oxygen_for_COVID19_Patients_v13_Final_copy_edited.pdf
The Society initially supported treatment only when patients were enrolled in clinical trials approved by an Institutional Review Board (IRB). Subsequent to that initial position statement the UHMS has conducted a webinar reporting likely mechanisms and early clinical experiences. Two prominent hyperbaric experts authored an editorial discussing the major issues of applying hyperbaric oxygen to the treatment of COVID-19 patients [7]. An even more recent paper by Paganini et al. discusses the biological mechanisms of action of hyperbaric oxygen and identifies potential logistic difficulties and toxicities of treatment [8].
The incidence of COVID-19 has increased dramatically, and this unfortunate abundance of patients has led to a significant understanding of what treatments are effective and which are not. Much of this evolution in treatment has been in the utilization of a known technology in a novel application. The UHMS has, therefore, reconsidered its position on the compassionate use of hyperbaric oxygen for COVID patients based on the strong mechanistic evidence and from the impressive results in the patients reported to date.
We encourage the enrollment of patients in formal, IRB-approved clinical 2 trials and would prefer that they be randomized and controlled. Given the dire and widespread implications of the spreading pandemic and the absence of highly effective therapies, we recognize and support single-armed studies and the compassionate application of hyperbaric oxygen when an IRB-approved protocol cannot be reasonably obtained. We encourage those treating COVID patients to utilize the most recent literature and science to guide clinical decision-making. The following sections will provide guidance for study design and can also serve to guide patient management and clinical assessment standards for all patients receiving hyperbaric oxygen therapy for COVID-19 infections. Regardless of protocol, patient presentation, progress and outcome information should be meticulously documented. The UHMS encourages the involvement of hospital medical staff, administration, and legal counsel in the development and implementation of all innovative therapies.
The UHMS tasked its Research Committee to develop recommendations to the hyperbaric community for study designs simple enough to be used widely by the majority of interested facilities, with a consistent approach so that combined data may be collated for future meta-analyses. This document outlines the committee’s efforts. The research committee has been augmented by several additional individuals with special experience, skills, and interests related to COVID-19 who were willing to invest their efforts to develop clinical trial model designs and to provide guidance to those planning to develop their own research protocols. Eight institutional trials are now listed on clinicaltrials.gov ; many are international in their scope and are actively recruiting patients.
The report’s authors realize that the ideal scientific design for such clinical trials is a randomized controlled trial (RCT). We recommend that design if possible and recognize that ultimate acceptance of HBO2 therapy in this setting should be supported by reproducible RCTs. In this time of urgent need, however, we feel additional single-arm Phase I/II trials are more likely to be proposed and conducted. With this in mind, we propose a model that defines our preferred protocol for hyperbaric treatment, including oxygen dosage and treatment frequency. In our suggested model, those receiving hyperbaric oxygen can serve as the study arm; the control arm could be composed of case-controls or propensityscore matched controls who receive “standard treatment.” We do not discuss randomization techniques. We believe that given the frequency of cases, investigators will likely be able to identify a well-matched historical control group at their institution. Local investigators are obviously limited by both human and financial resources and may not be able to adhere to every aspect of our recommendations. In selecting our suggested diagnostic studies we highlighted those studies/tests we feel are of high value and cost-effective. Individual investigators will need to obtain and follow diagnostics that are available at their institutions.
The Committee considered how to address the issue of hyperbaric-induced oxygen toxicity. Most clinical measures of oxygen toxicity are non-specific (e.g., cough, chest tightness) and are likely already present in patients with COVID-19. Also, patients with COVID-19 are already receiving high levels of normobaric oxygen, which can also produce oxygen toxicity. The cases that have been treated to date with HBO2 have not shown evidence of acute oxygen toxicity and have not shown acute worsening due to hyperbaric oxygen treatment. The presentations of Drs. Thibodeaux, Lee and Gorenstein at the webinar sponsored by the UHMS on July 20, 2020 were consistent in this observation. The Committee feels that if there is an adverse effect due to oxygen toxicity this might be seen in worse outcomes for the 3 hyperbaric group, but there were no specific measures identified that could be used to distinguish oxygen HBO2 toxicity from lung damage due to standard care or the underlying disease.
The overriding concern and reality are that this patient population needs effective supplemental oxygen, and anecdotal experience demonstrates that HBO2 therapy accomplishes this exceptionally well.
This discussion will offer the following sections:
- Proposed rationale and mechanisms of action for HBO2 therapy
- Recommended study design
- Recommended diagnostics and outcome parameters
Continued on page 3: https://www.uhms.org/images/MiscDocs/Rational_and_study_design_for_treating_COVID_patients_with_HBO2.pdf
