Ethical Considerations for Approved & Off-Label Use of Hyperbaric Medicine

Guidelines exist for the ethical off-label use of HBOT. An institutional review board- approved protocol is not required for case- by-case decisions to use HBOT off-label. It is possible to utilize HBOT unethically for approved indications. The most crucial issue is that of the patient’s informed consent.

What exactly is “off-label” use of hyperbaric oxygen therapy (HBOT)? A medical condition is considered off-label for HBOT if it is not one of the conditions for which the use of the chamber is “cleared” by the U.S. Food & Drug Administration (FDA). There are two broad categories of hyperbaric chambers cleared by the FDA for human use in the United States: acrylic chambers that generally hold one person (monoplace chambers) and steel chambers that hold more than one person (multiplace chambers). Because hyperbaric chambers are medical devices, they must be cleared for use by the FDA. For many years, the FDA has deferred to the Undersea & Hyperbaric Medical Society (UHMS) to establish the list of indications for which hyperbaric chambers could be utilized, and both types of chambers are cleared for the same indications.¹ Recently, the UHMS added idiopathic sudden sensorineural hearing loss to its list of approved indications, but the FDA does not recognize this indication. The use of HBOT for any indication that is not on the FDA’s approved list is considered to be off-label use of a medical device. There are also portable, inflatable “hyperbaric” chambers that can only be pressurized to the equivalent of about 10 feet of sea water pressure. They were designed for the treatment of acute mountain sickness, and that is the only indication for which the FDA has cleared them. However, they are heavily marketed for home use and are often found in health spas to treat patients for off-label hyperbaric indications. The amount of pressure to which an individual is exposed inside an inflatable device does not meet the accepted definition of “hyperbaric” therapy. This will be explained shortly, as will the ethical implications that all wound care providers should consider when administering HBOT to their patients. It should not have to be stated, but these implications must be considered in addition to the legal aspects of HBOT delivery. 

THE FDA & MEDICINE 

While the FDA does not regulate the practice of medicine, it does regulate claims made about the use of medical devices. When individuals advertise the use of HBOT for off-label indications, they are considered by the FDA to be making false claims. The FDA warns consumers not to be misled by claims regarding the use of HBOT for unproven indications and provides its MedWatch website as an outlet for problems to be reported.² Instances of false claims are subject to FDA censure, which, theoretically, can include seizure of hyperbaric equipment. However, recent court cases have acknowledged that these restrictions may limit the First Amendment right to free speech, which may explain why the FDA has taken no action on the thousands of Internet advertisements for the off-label use of HBOT, including those on social media. To get any new indications added to the FDA’s list, it will be necessary to present the FDA with compelling data from prospective clinical trials that are rare in the field of hyperbaric medicine. That is unfortunate, since there are off-label indications for which the rationale for HBOT is solid, the evidence of benefit is compelling, and the success of alternative treatments is disappointing (eg, central retinal artery occlusion [CRO]). Since prospective trials for these conditions are unlikely, they will probably never be added to the FDA’s list. Therefore, it is likely that most hyperbaric practitioners will use HBOT off-label at some point, if only for conditions that have wide acceptance, such as CRO. But as payers restrict coverage for long-accepted indications, and as interest in the use of HBOT for conditions such as traumatic brain injury (TBI) expands, off-label use of HBOT for less accepted indications is likely to increase. Hyperbaric practitioners need guidance to help them navigate these complicated situations. (Readers are also referred to an important article published 17 years ago that remains the definitive work on the subject and is available free of charge from the UHMS Rubicon Foundation.³)

The off-label use of HBOT is not unethical per se, assuming that appropriate informed consent is obtained and that other ethical considerations are addressed (as will be discussed in this article).  The off-label use of HBOT does not necessitate having a research protocol reviewed by an institutional review board (IRB). Case-by-case decisions to utilize HBOT for an off-label indication are considered the practice of medicine. However, repeated use of HBOT for an unproven indication, with the intention to apply the information acquired to the care of other patients, is considered research. To perform research in an ethical manner, a protocol must be approved by an IRB and patients must be informed that they are subjects in a research study, participation in which they have the right to consent or decline. Physicians and hospitals can charge for providing off-label HBOT, if the charges are reasonable. Patients can also pay to participate in ethically conducted clinical research. 

ETHICAL ISSUES WITH OFF-LABEL USE OF HBOT

1. Desperate patients and family members who are vulnerable: Most of the conditions for which HBOT is sought for off-label use have few effective treatments. These situations often involve young children and are, without exception, heart-wrenching for the patients and families involved. There is a heavy burden on physicians to ensure that desperate individuals are protected from financial or emotional exploitation.⁴ 

2. Financial burden: Patients or their family members may pay thousands of dollars for the off-label use of HBOT when the potential benefit is unknown. This may negatively impact their financial future while reducing available resources for traditional therapies, or even basic necessities such as food and rent.

3. Risk of side effects: HBOT is an exceptionally safe treatment, but is not without adverse effects. Otic barotrauma occurs in 0.5%-10.0% of patients and 1:10,000-1:50,000 experience treatment-related oxygen toxicity seizures. A relative contraindication to HBOT is chronic obstructive pulmonary disease (COPD) or emphysema; air trapping, which can predispose someone to pulmonary overpressurization; pneumothorax; arterial gas embolism; and death. Yet, HBOT is not infrequently touted as a “treatment” for COPD and emphysema at facilities offering the off-label use, raising concern that patients receiving treatment at these centers do not undergo adequate informed consent regarding the risks and that the practitioners providing it are not trained to do so.

4. The difficulty of providing adequate informed consent: All medical decisions involve evaluating the risk of treatment versus the possible benefit of therapy. The use of HBOT (regardless of whether it is on- or off-label) is ethical only when the potential benefit is greater than the risk for that specific patient. For most of the approved HBOT indications, the likelihood of benefit can be estimated from published data, and thus the risk-to-benefit ratio can be determined. However, when the likelihood of benefit is unknown (or perhaps even nonexistent), any risk of complication or side effect is unacceptable. This is particularly true when family members undergo HBOT acting as attendants to their children. In one particularly tragic case, the grandmother of a small child died along with the child in a hyperbaric chamber fire.⁵ While both deaths could have been prevented by proper equipment maintenance, the grandmother could only experience negative consequences from her exposure to HBOT since no therapeutic benefit was ever intended. At the 2012 UHMS annual scientific meeting, when the legal implications of this chamber fire were discussed, hyperbaric technicians from more than one hospital facility publicly admitted that they routinely allowed the parents of small children to undergo hyperbaric exposures with their children in order to attend to them during HBOT.  They justified this practice stating that they “did not have sufficient staff” to provide pediatric HBOT otherwise. Defense attorneys agree that exposing non-patients to HBOT is inappropriate because, in the absence of any possible therapeutic benefit or doctor-patient relationship, the individual is exposed to only the risk of adverse events, which is entirely unjustifiable.

5. Knowledge of alternative treatments: HBOT is aggressively marketed for some conditions that may have less costly and more accessible therapeutic treatment options (eg, anxiety disorders, depression). 

6. Misleading information about what constitutes “hyperbaric oxygen therapy”: Many proponents of HBOT for off-label use in neurological conditions favor what they call “low-pressure oxygen.” HBOT is defined by the UHMS as the administration of oxygen at pressures ≥ 1.4 atmospheres absolute (ATA), which is equivalent to about 13 feet of sea water pressure. Inflatable chambers can only achieve atmospheric pressures of 1.3 ATA (about 10 feet), which is equivalent to breathing 27% oxygen at sea level. (For the mathematical calculations, visit this author’s article entitled “Explaining The Math for Hyperbaric Oxygen.”⁶) A patient can receive the same amount of oxygen without the inflatable chamber simply by breathing a little extra oxygen at sea level through a mask. Proponents of low-pressure oxygen therapy insist that the additional 0.3 ATA of atmospheric pressure achieved by entering the chamber is somehow beneficial in its own right, a theory that has no scientific evidence. Regrettably, confusion as to what constitutes HBOT has led to misleading research regarding HBOT.⁷ In a randomized controlled trial widely cited by advocates of HBOT for treatment of autism, 62 young children diagnosed as being on the autism disorder spectrum were treated with 24% oxygen administered at 1.3 ATA in a traditional, hard-sided hyperbaric chamber. Their results were compared to a sham group treated with 21% oxygen (room air) in a chamber pressurized to only 1.03 ATA. The authors of that study found that the “HBOT group” [sic] significantly improved in overall functioning, language, social skills, eye contact, and cognitive behavior compared to the control group. The partial pressure of oxygen received by the “HBOT group” was 237 mmHg PO₂, equivalent to 31% O₂ at sea level. This partial-pressure oxygen could also have been easily achieved at ground level while breathing oxygen from a mask. In other words, the children who were touted as receiving “hyperbaric oxygen therapy” could have been treated just as easily without going into a chamber. A similar problem occurred with a study evaluating neurologically impaired adults and children treated at 1.3 ATA with 24% oxygen.⁸ Clearly a cheaper, safer and, therefore, more ethical therapy would have been to use sea-level oxygen breathing in both studies. In fact, oxygen breathing at sea level could provide a higher partial pressure of oxygen with less risk of side effects and at a much lower cost than “low-pressure hyperbaric oxygen.” (Note: This is what should be suggested to those individuals who seek HBOT treatment for autistic children.)  

7. Risk of injury from hazardous conditions: The safety record of HBOT in the U.S. has been achieved through stringent regulations. Strict fire safety codes were created by the National Fire Protection Association (NFPA) following fatal fires in oxygen-enriched environments in the 1960s.⁹ Since 2000, these well-established safety requirements have been mandatory for nearly all locations, including shopping malls and business occupancies.¹⁰ As discussed previously, when an inflatable chamber is pressurized to 1.3 ATA (with air), the oxygen partial pressure is equivalent to 27% at sea level. The NFPA considers 27% oxygen to be an “oxygen-enriched atmosphere” that poses an increased risk of fire. The risk of fire is further increased when the chamber is either compressed with oxygen or when an oxygen concentrator is placed inside the chamber and the patient is allowed to breathe oxygen from a mask and expire the oxygen into the chamber, thus raising the oxygen percentage inside the chamber above that of compressed air. FDA labeling requirements prohibit the use of oxygen-enriched air in any of the inflatable chambers cleared for marketing through the Premarket Notification 510(k) clearance program.¹¹ The conditions of every fatal chamber experience since 1980 involved > 28% oxygen. Most chamber fires have been caused by electronics that were brought inside the chamber by the occupant, such as when a mobile phone ignited a fire that killed one hyperbaric patient in China.⁹ It is, therefore, particularly distressing to see advertisements for the off-label use of HBOT featuring children inside of inflatable chambers using laptop computers or other prohibited electronic devices. These photographs make it clear that the operators are not familiar with NFPA standards and do not follow appropriate safety protocols, raising concern for the welfare of their patients.

5 COMPONENTS OF INFORMED CONSENT FOR OFF-LABEL HBOT

The informed consent process between physician and patient provides an opportunity for the patient to understand the potential risks and benefits of any treatment. While informed consent does not have to be written, since the physician needs to document the details of the consent process, it makes sense for consent to take the form of a written document. There are five elements that must be addressed when HBOT is used for an unproven indication:³

1. Are there alternative medical treatments for the condition, and is the patient aware of them?

2. What level and type of scientific data is there to support the use of HBOT for the condition?

a) Patients must be clearly informed that HBOT has not been proven to be beneficial for the condition, and thus it is not certain that they will receive any benefit from the treatment. 

b) There must be evidence (or a good rationale) that HBOT will be of some benefit. For example, there is no credible rationale for providing HBOT as a treatment for wrinkles or aging; however, there may be a rationale for using it immediately after a facelift to reduce postoperative edema.

3. Are the risks of HBOT for this patient acceptable?

a) Using the previous example, a patient may wish to undergo HBOT after a facelift, but if he/she lives with COPD or emphysema, the known risk of undergoing HBOT may outweigh any theoretical potential benefit.

b) Patients or family members must be informed of all possible risks. One physician who is well known for his use of off-label HBOT stated that he did not inform mothers of the risk of hyperoxic seizure because the risk “was very low and he did not want to worry them.” This attitude is paternalistic and robs the patient or family of their autonomous decision-making. 

4. Do the patients understand that they are responsible for the cost?

a) Patients should be provided with a detailed (preferably written) explanation of their financial obligations regarding the treatment that clearly states that insurance will not cover the cost of treatment and that they are responsible for the cost.

b) Patients sometimes try to convince the hyperbaric physician to find a diagnosis for which insurance would cover HBOT. Falsifying a diagnosis in order to bill insurance for hyperbaric treatments is unethical and will result in the physician and/or hospital submitting fraudulent claims. It is not unethical to request that a payer cover an off-label indication. For example, hyperbaric treatment of chemotherapy-induced hemorrhagic cystitis can result in dramatic cost savings for the payer, not to mention relief of pain and suffering in the patient.

5. Has the physician disclosed any financial issues that might affect the physician-patient relationship?

a) If the physician has a financial interest in the facility or is remunerated in some way, which might influence (or appear to influence) the decision to recommend treatment, the patient should be informed.

b) If possible, it is helpful to have an independent physician perform an examination prior to starting HBOT, as well as after some specific number of treatments, in order to help determine in an unbiased way whether benefit has been observed.

UNETHICAL USE OF APPROVED INDICATIONS

HBOT can be used unethically for approved indications. When physicians, hospital staff, or management company personnel misrepresent medical information in order to provide HBOT to a Medicare beneficiary, they have submitted a false claim and have committed Medicare fraud. Fraudulently billed HBOT services have been the target of government investigation since 2000, when the U.S. Department of Health & Human Services’ Office of Inspector General released a report on the use and appropriateness of HBOT.^12,13 Sadly, unethical standards in the delivery of hyperbaric medicine for approved indications may have done more harm to the field than unsubstantiated claims over off-label indications. The increasingly draconian measures the U.S. healthcare system is employing to limit the overuse and improper use of HBOT could create a scenario in which the approved indications are no longer covered by payers and the primary use of HBOT is for off-label indications paid out of pocket by patients.  

CONCLUSION

Off-label HBOT can be provided in an ethical manner if there is a scientific rationale for the condition, if the patient is informed of any alternative treatments and the risks of HBOT, if the cost of therapy is understood by the patient, and if the clinician discloses any financial incentives that might affect patient decision-making. Case-by-case medical decisions to use HBOT for off-label indications do not require IRB approval, but if data are being collected with the intention of using that information to direct the care of future patients, the activity should be considered research and IRB approval should be sought. The promotion of the off-label use of HBOT can be considered a breach of FDA regulations, but this issue is under FDA review. The desperation of many patients and family members, and the many conditions for which there are few currently accepted satisfactory treatments (eg, autism), combined with the ease of dissemination of information on the Internet, has produced an enormous market for off-label HBOT use. Some studies purporting to involve “hyperbaric oxygen therapy” utilize oxygen pressures that could be achieved or exceeded with an oxygen mask at sea level, without the need for a hyperbaric chamber. This is certainly true of treatments performed using inflatable chambers. Cutbacks on insurance coverage for approved indications could drive even the most conservative hospitals and clinicians to offer HBOT for off-label indications, particularly if military-funded TBI studies are successful and the FDA loosens restrictions on the marketing of the off-label use of medical devices. 

Caroline E. Fife is chief medical officer at Intellicure Inc.; executive director of the U.S. Wound Registry; medical director of St. Luke’s Wound Clinic, The Woodlands, TX; and co-chair of the Alliance of Wound Care Stakeholders. 

References

1. Indications for Hyperbaric Oxygen Therapy. UHMS. Accessed online: www.uhms.org/resources/hbo-indications.html

2. Hyperbaric Oxygen Therapy: Don’t Be Misled. FDA. 2018. Accessed online: www.fda.gov/forconsumers/consumerupdates/ucm364687.htm

3. Chan EC, Brody B. Ethical dilemmas in hyperbaric medicine. Undersea Hyperb Med. 2001;28(3):123-30. Also available online at https://archive.rubicon-
foundation.org

4. Paris JJ, Schreiber MD, Reardon FE. Hyperbaric oxygen therapy for a neurologically devastated child: whose decision is it? J Perinatol. 2003;23(3):250-3.

5. Clary M. Doctor Loses License Over Oxygen Chamber Fire That Killed 2. SunSentinel. 2016. Accessed online: www.sun-sentinel.com/local/broward/fl-ap-hyperbaric-chamber-fire-20160411-story.html

6. Fife CE. Explaining The Math for Hyperbaric Oxygen. CarolineFifeMD.com. 2018. Accessed online: https://carolinefifemd.com/2018/02/06/explaining-the-math-for-hyperbaric-oxygen

7. Rossignol DA, Rossignol LW, Smith S, et al. Hyperbaric treatment for children with autism: a multicenter, randomized, double-blind, controlled trial. BMC Pediatr. 2009;9:21.

8. Heuser G, Heuser SA, Rodelander D, Aguilera O, Uszler M. Treatment of neurologically impaired adults and children with “mild” hyperbaric oxygen (1.3ATA and 24% oxygen). In: Joiner J.T., editor. The Proceedings of the 2nd International Symposium on Hyperbaric Oxygenation for Cerebral Palsy and the Brain-Injured Child; Flagstaff: Best Publishing Co; 2002;109-16.

9. Sheffield PJ, Desautels DA. Hyperbaric and hypobaric chamber fires: a 73-year analysis. Undersea Hyperb Med. 1997;24(3):153-64.

10. NFPA 101: Life Safety Code. Quincy, MA. NFPA. 2018. 

11. 510(k) Clearances. FDA. 2018. Accessed online: www.fda.gov/medicaldevices/productsandmedicalprocedures/deviceapprovalsandclearances/510kclearances

12. Le PNJ. Lessons to learn from federal convictions of HBOT fraud. TWC. 2015;9(2):27-31.

13. Brown JG. Hyperbaric Oxygen Therapy. Its Use and Its Appropriateness. OIG. 2000. Accessed online: https://oig.hhs.gov/oei/reports/oei-06-99-00090.pd