Development of an International, Multicenter, Hyperbaric Oxygen Treatment Registry and Research Consortium: Protocol for Outcome Data Collection and Analysis

Introduction

Hyperbaric oxygen (HBO₂) treatment, defined as breathing 100% oxygen at pressures greater than 1.4 atmospheres absolute, is used for 14 indications approved by the Undersea and Hyperbaric Medical Society (UHMS), such as soft tissue radiation injury and enhancement of healing in selected problem wounds (see Table 1) [1]. HBO₂ greatly increases the amount of oxygen dissolved in plasma and is effective at relieving hypoxia. This effect is useful in conditions such as ischemic wounds or compromised flaps or grafts, where inadequate oxygenation is a factor. Laboratory studies also suggest HBO₂ has actions beyond the relief of hypoxia (eg, promoting angiogenesis in irradiated tissue, anti-inflammatory effects, radiosensitization of tumors, hypoxia preconditioning, and fungal growth inhibition) and has potential to treat other currently unapproved conditions, such as inflammatory bowel disease and pyoderma gangrenosum [2-4]. Approximately 1350 hyperbaric chamber facilities exist in the United States, and outpatient facility claims for hyperbaric services to Medicare alone totaled US $178 million in 2015. Although HBO₂ treatment is used for a variety of indications, much of the evidence to support its use is based on small trials, case series, and retrospective studies (see Table 1) [2,5-11].

This inconsistent evidence base has led to a range of opinions about when and how HBO₂ should be used. For example, a common application of HBO₂ is in treating radiation cystitis, which is supported by most insurance policies in the United States [12,13]. The evidence base and practice patterns are strong enough that when a randomized trial of HBO₂ for radiation cystitis was attempted (ie, ClinicalTrials.gov Identifier: NCT00134628), the trial had to be closed due to poor recruitment. It was difficult to find patients who were willing to be randomized to placebo treatment and providers who were willing to refer them. In one review describing the many treatment options for radiation cystitis, the authors concluded “there are currently no adequate treatment options.” They cited HBO₂ response rates between 27% and 92%, and recurrence rates after treatment from 8% to 63% [14]. The lower end of this response rate range suggests HBO₂ should only be tried occasionally for selected patients, while the higher end argues that HBO₂ should be the treatment of choice. The largest prospective study of HBO₂ treatment for radiation cystitis included in that review was based on 40 patients [12]. Since that review, five Nordic university hospitals were able to complete a randomized trial for radiation cystitis, although they excluded from enrollment patients with severe ongoing bleeding (ie, the patients where the impact from HBO₂ treatment would be most meaningful). The trial showed benefit from HBO₂ [15].

This diversity of opinion and practice creates a difficult situation where the published evidence base is small, but advancing to large-scale clinical trials has been difficult. Also, hyperbaric centers worldwide are being asked to provide a stronger level of evidence to support the treatments they deliver. For example, the National Health Service (NHS) England will now support the routine use of HBO₂ treatment only for decompression illness and gas embolism [16]. Conditions reviewed and not recommended for routine hyperbaric therapy because of the perceived lack of reliable outcome data include the UHMS-approved indications of carbon monoxide poisoning, soft tissue radiation damage, and necrotizing soft tissue infections. A new approach is needed to collect outcome data for HBO₂ treatments.

The study of HBO₂ treatment presents unique challenges. Because HBO₂ treatment usually requires daily treatments over the course of 1-2 months in a hyperbaric chamber, single hyperbaric centers typically do not treat large numbers of patients and cannot accrue sufficient numbers to conduct credible studies. Furthermore, because patients are referred for treatment from other specialties, follow-up tends to be conducted by the referring specialist, and outcome data are not available to the hyperbaric program beyond the treatment period. Obtaining meaningful data on HBO₂ outcomes requires pooling of data from multiple centers and establishing an infrastructure of centers motivated to conduct research and initiate long-term follow-up. The HBO₂ Registry Consortium described here will provide this framework for urgently needed evaluative observational studies, with the potential to improve the clinical application of HBO₂ dramatically. In addition, the consortium will provide an efficient platform for conducting trials on a wide range of HBO₂ indications, as well as studies of the molecular underpinnings of the treatment itself. This consortium infrastructure could be used to develop the platform from which multiple studies could be conducted at much lower cost.

Beyond the fundamental question of whether HBO₂ treatment should be recommended for given indications, the HBO₂ community needs data to answer more detailed questions, such as: Are some forms of radiation injury (eg, brain radionecrosis) more or less responsive than others to HBO₂ treatment? Are some patients more likely than others to benefit from HBO₂ for a given indication, and can those patients be identified? Having identified the patients most likely to benefit from treatment, can trials be designed more effectively to test HBO₂ treatment (eg, crossover trials)? A well-designed registry can provide the data required to answer these questions.

Methods

Overview

This paper outlines the development of an international, multicenter, prospective registry consortium. A center joins the consortium by signing the consortium agreement. This agreement covers membership, governance, data sharing requirements, use of member data, publications, intellectual property, liability, confidentiality, and insurance. Data are collected using Research Electronic Data Capture (REDCap), a widely available, easily accessible, Health Insurance Portability and Accountability Act (HIPAA)-compliant, web-based data collection system [17]. Each participating center determines its own start date for data collection (ie, reference date) and records baseline data for every patient referred to the treatment center, whether or not treatment is indicated for, or accepted by, the patient after that start date. Patients included in the registry are those patients who have been evaluated for possible treatment of any UHMS-approved condition, or any non-UHMS-approved condition, including those who are part of research studies or trials. The registry gathers data on whether the evaluation determined that treatment was contraindicated, indicated and scheduled, or indicated but declined by the patient.

Each center’s participation is overseen by its own US Institutional Review Board (IRB) or the country-specific equivalent, or a center can opt to rely on the Dartmouth Committee for the Protection of Human Subjects (ie, the Dartmouth IRB). The REDCap-based data collection template is the same at all centers, so all centers collect the same outcome measures. Quarterly, each center performs a deidentified data download from their REDCap database to the coordinating center’s REDCap database at Dartmouth College. These deidentified data from each center are combined into a single REDCap database, which is the multicenter data registry. Optional consent for longer-term follow-up is being pilot tested at one center.

Data Collected

The design approach to the registry is to create a system that can be used at any hyperbaric center. This means the system must be low cost and not require excessive staff effort. Although gathering data from electronic medical record systems is desirable to avoid repeated data entry, this is not practical for this project due to the diversity of medical record systems and the level of effort and funding required to standardize and update outcome measures and procedures among them. To minimize staff effort, data entry needs to be minimal, which means extensive data on comorbid conditions, medications, and medical history cannot be collected. Instead, the registry has to focus on a few key outcome measures whose data any center can collect and enter reliably. For studies using registry data where more information on the individual patients is needed, an interested investigator can obtain IRB or ethics approval to work with more detailed data at the individual centers using procedures outlined in the consortium agreement.

The registry database was initially designed by a consensus of founding members of the HBO₂ research consortium—the Geisel School of Medicine at Dartmouth in Hanover, New Hampshire, and the Dartmouth-Hitchcock Medical Center in Lebanon, New Hampshire—and core data are collected for UHMS-approved and some nonapproved conditions. Data are collected using four main data collection instruments (see Table 2). The Demographics instrument collects demographic information as well as information on insurance and distance traveled. The Pre Treatment Information instrument collects information on the condition being treated, treatments prescribed and administered, and subjective and objective measurements of the patient’s status at treatment start. A quality-of-life measure—the EuroQol, 5-dimension, 5-level (EQ-5D-5L)—is also administered at baseline on all patients [18,19] as part of the Pre Treatment Information instrument. The Pre Surgical Information instrument collects subjective and objective measures of the patient’s status prior to a surgical intervention (eg, tooth extraction) if one is performed. The Treatment and Outcomes instrument repeats information collection of the Pre Treatment Information outcome measures, records the actual treatment given, asks about complications, and repeats the quality-of-life questionnaire.

Both indication-specific outcomes and general outcomes are collected, including HBO₂ treatment complications (eg, changes in refraction, seizures, pneumothorax, confinement anxiety, barotrauma, and placement of pressure-equalization tubes in the ear). Wherever possible, common objective outcome measures are used. The registry uses validated questionnaires that have supporting evidence in the literature (eg, the Common Terminology Criteria for Adverse Events [CTCAE] hematuria grading scale for radiation cystitis and the European Organisation for Research and Treatment of Cancer [EORTC] Quality of Life Questionnaire Head and Neck [QLQ-H&N35] for head and neck symptoms) [20,21] as well as some questionnaires that were custom developed for the registry (see Table 2) [22-24]. Factors that might affect the effectiveness of the therapy are also collected (eg, diabetes, smoking, and other nicotine use). Future plans, including long-term follow-up and linkage to cancer registries and vital status data, depend on future funding. Table 3 lists the parameters measured [25,26].

Governance

The HBO₂ Registry Consortium includes member institutions fulfilling the requirements as shown in Textbox 1. A steering committee is responsible for the governance of the registry. The Geisel School of Medicine at Dartmouth and the Dartmouth-Hitchcock Medical Center are the founding members of the consortium and each have representatives on the steering committee. The steering committee also includes a representative from each participating center. By a majority vote, with affirmative votes from the founding members, the steering committee has the authority to set the strategic direction for the registry, admit or remove members, set membership fees, establish policies, and relocate the registry. Member-initiated research protocols are approved by a majority vote of the steering committee. The committee also votes on any changes to the REDCap data collection instruments. The steering committee meets annually at the UHMS annual meeting, where changes and modifications to the registry are discussed and voted upon. Template IRB application materials are freely shared between participating centers.

Statistical Analysis

Descriptive analyses will be conducted to describe the baseline characteristics and outcomes of patients with each indication, overall and by center, including the numbers, proportions, and confidence intervals for the following: patients with each indication for treatment; those evaluated who were not treated or who were partially treated and the reasons why; baseline characteristics, including referral information and baseline outcome measures; treatments given; occurrence of each type of side effect; and outcome measures at the end of treatment with change scores and relative change scores, as appropriate. For measures with numerical scores, we will assess absolute and relative changes; for other measures, we will report outcomes in terms of the proportions with symptom resolution, improvement, no change, or deterioration. Factors associated with key outcomes will be explored using multifactorial analyses where sample size is sufficient for models to be stable. All results will be presented and discussed in terms of estimates and 95% confidence intervals to avoid focusing on P values alone.

Results

Data collection started within the registry at the Dartmouth-Hitchcock Medical Center as a pilot project in 2012. During this time, the consortium agreement was developed and processes were established to enroll other centers. In 2019, four additional centers began entering patient data. Currently, the registry has 919 individual patient entries from four centers, with the majority from the Dartmouth-Hitchcock Medical Center (n=621). Over time, the registry is gradually collecting sufficient data to robustly explore changes before and after HBO₂ treatment. Figure 1, for example, shows the results for the Head and Neck Questionnaire before and after HBO₂ treatment. Figure 2 shows changes in patient-reported symptoms of xerostomia (ie, dry mouth) after receiving HBO₂ treatment. These responses are important because whether HBO₂ treatment has an effect on xerostomia has been a longstanding question in the HBO₂ field [27]. Figure 3 shows changes in the hematuria score for those patients undergoing treatment with HBO₂ for radiation cystitis. Figure 4 shows the experience to date for patients treated for idiopathic sudden sensorineural hearing loss. These preliminary results show that the registry is useful for tracking trends in outcomes and patient-reported symptoms after HBO₂ treatment. As further patient experiences are collected, these data will also be used in retrospective analyses to determine the characteristics of those patients who responded well and of those who did not.

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Discussion

Principal Findings

An HBO₂ treatment outcomes registry is feasible and can provide consistently recorded outcomes from HBO₂ treatments at multiple centers. Initial analyses of some of the outcome data are already showing significant changes after HBO₂ treatment.

Strengths of the Registry

A key strength of the registry is its use of REDCap [17], a free, secure, web-based, data collection system used to build and manage online surveys and databases in more than 3964 centers worldwide. The HBO₂ REDCap database has been pilot tested and revised at the coordinating center for 6 years, and core variables have been collected on UHMS-approved indications for HBO₂ treatment, as well as some non-UHMS-approved indications. The database includes 1996 variables, many of which are disease specific and are programmed to appear only for particular indications or situations (ie, during data entry, a staff member will only be entering data on a small subset of the variables available). Data entry takes an average of 15 minutes per case, distributed over several clinical visits. The template for the database can be exported to Excel, emailed to another center, and easily uploaded to create an identical registry that is ready for data entry. REDCap provides the ability to perform a deidentified data export from each participating center. This is sent to a central, pooled REDCap database at the Geisel School of Medicine at Dartmouth. Because of the simplicity of the software and the relatively low burden of data entry, the registry is relatively inexpensive for new centers to install and maintain. Because only deidentified data are pooled, the risk to participants is minimal.

Limitations of the Registry

At present, the registry is following individuals who receive HBO₂ treatment, and a registry of similar patients with similar conditions who are not receiving HBO₂ treatment does not exist. Therefore, there is no way to compare outcomes from HBO₂ treatment directly with outcomes from similar patients who did not receive the treatment. As the registry grows, an additional limitation will be funding, which will be needed to maintain a system of data-quality oversight, analysis, longer-term follow-up, and other registry-related activities.

Conclusions

An outcome-focused registry for HBO₂ treatment is needed urgently to provide both patients and providers with the information they need to decide whether and how to use HBO₂ treatment. To be successful, this registry must be practical, easy to use, and easily expandable. The registry described here meets these requirements. The data entry requirements are not excessive and should be within the capabilities of existing staff at any given hyperbaric center. Also, by using REDCap, the registry can be expanded to include detailed information on particular indications and long-term follow-up on selected patients without significantly increasing the basic data entry requirements.