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Table 1. FDA-Cleared Indications for Hyperbaric Oxygen Therapy
- Air or Gas Embolism
- Carbon Monoxide Poisoning and Smoke Inhalation, Carbon Monoxide Complicated by Cyanide Poisoning
- Clostridial Myonecrosis (Gas Gangrene)
- Crush Injury, Compartment Syndrome, and Other Acute Traumatic Ischemias
- Decompression Sickness
- Enhancement of Healing in Selected Problem Wounds
- Exceptional Blood Loss (Anemia)
- Intracranial Abscess
- Necrotizing Soft Tissue Infections (Subcutaneous Tissue, Muscle, Fascia)
- Osteomyelitis (Refractory)
- Radiation Tissue Damage (Osteoradionecrosis)
- Skin Grafts and Flaps (Compromised)
- Thermal Burns
The confusion over this mis-definition and Table 1 is that no physician has been able to connect the dots …until now. In 1999, HBOT was redefined scientifically as "…a medical treatment that uses high pressure oxygen as a drug by fully enclosing a person or animal in a pressure vessel and then adjusting the dose of the drug to treat pathophysiologic processes of the diseases."11 HBOT had been shown in multiple animal species to have profound effects on acute and chronic disease pathophysiology.9 It was felt that the intermittent exposure to increased pressure of oxygen acted to ameliorate acute disease pathophysiology and the repetitive application in chronic conditions to have trophic effects, i.e., grow new tissue.
This definition, however, was inadequate. It still did not explain the 300+ years of pressurized air,6,7 the Russian experience with very low doses of hyperbaric therapy,12 nor the confusing HBOT cerebral palsy study of 2001 where 1.3 atmospheres absolute of air (9.9 feet of seawater pressure, the depth of a swimming pool) improved children with cerebral palsy (CP).13 All of these examples feature elevated pressures with minimal elevations in oxygen. The FDA inadvertently clarified the matter in their 2012 response to this author's Investigational New Drug Exemption (IND) application: "…we consider your intervention to be a combination therapy, the constituents of which are hyperbaric treatment and hyperoxic treatment. Each of these constituents has the potential to contribute independently to the overall therapeutic effect…" This suggested for the first time in the modern history of hyperbaric medicine the possible contribution of hydrostatic pressure to the clinical effects of HBOT.
Figure 4. After 80 HBOTs, SPECT brain blood flow imaging transverse slices and four-view three-dimensional surface reconstruction of 58-year-old male with Alzheimer's disease. Clear area in top-of-head view in right lower quadrant is artifact due to edge cutoff of camera field of view.
A quick investigation revealed 70 years of published research demonstrating the responsiveness of living organisms to the slightest elevations in atmospheric pressure that began within as little as one minute of pressurization.14 Somehow, this treasure trove of literature escaped the purview of the entire modern clinical hyperbaric medicine field. Pressures from 1.0015 to 1.26 ATA delivered to human and animal cells for 15 minutes or longer have caused the elaboration of a wide variety of bioactive proteins and stimulated cell proliferation.15 In other words, hydrostatic pressure effects were an essential component of hyperbaric therapy, and they are elicited by very small increases in pressure.
Acknowledging this wide range of hyperbaric and hyperoxic bioactivity, the controversial applications to CP,13 autism,16 mild traumatic brain injury/persistent post-concussion syndrome (PPCS),17 PPCS with post-traumatic stress disorder,18 and other diagnoses become understandable as multi-dosing hyperbaric therapy studies have demonstrated effectiveness of some doses of hyperbaric therapy, ineffectiveness of others, and toxicity of others.15,19 In particular, all of these studies have demonstrated the benefit of hyperbaric therapy in the low pressure/low hyperoxic range. This low-dosing range was reinforced by the recent publication of a two-year-old drowned girl who experienced dramatic neurological recovery and global regrowth of brain tissue after three months of normobaric oxygen and hyperbaric oxygen therapy.20
The question remained, however, how do repetitive administrations of intermittent increases in pressure and oxygen reverse pathophysiology and stimulate tissue growth? Tissue growth requires replication of DNA. In 1997, Siddiqui et al argued that the oxygen component of HBOT was a DNA signaling agent.21 Multiple publications confirmed this concept in the next 11 years,22-30 culminating in the demonstration that a single HBOT at the pressure used for diabetic foot wounds and radiation wounds up- or down-regulated the expression of 8,10131 of the known 19-20,00032 protein-coding genes in the human genome. The largest clusters of upregulated genes were the anti-inflammatory genes and those that coded for growth and repair hormone, and the largest clusters of downregulated genes were the pro-inflammatory genes and apoptotic genes. Further work showed the differential gene effects of pressure and oxygen,33 whereby different and similar clusters of neuronal genes are affected by different pressures and different amounts of hyperoxia.34 In essence, during hyperbaric therapy physicians are playing a symphony with patients' gene expression, the music of which is determined by the various pressures and amounts of hyperoxia to which the patient is exposed.
Summing up the current understanding of this 355-year-old therapy, HBOT appears to be an epigenetic therapy in the broad sense of the original definition of Waddington: "…the branch of biology which studies all molecular pathways modulating the expression of a genotype into a particular phenotype."35 The combination of hyperoxia and increased pressure are acting at the epigenetic level to differentially and temporarily alter gene expression and suppression of over 40% of all of our protein-coding genes. The net effects are permanent tropism and tissue repair and temporary and permanent inhibition of inflammation and apoptosis.9,31,36-38 By mechanisms involving oxygen-sensitive gated membrane ion channels39 and pressure-induced strain on cell and mitochondrial membranes,14,40 hyperbaric pressure and hyperoxia are two organically, and naturally, manipulating, ubiquitous natural-occurring agents that effect salutary changes in disease at the epigenetic level. Essentially, this is the oldest, most pervasive and panoramic gene therapy finally known to mankind.
Viewed as a gene therapy, this discussion comes full circle to the constrained list of clinical applications in the United States and begs the question of what other diagnoses may be responsive to oxygen and pressure epigenetics. Controlled trials exist for many diagnoses, including idiopathic sudden sensorineural hearing loss,41 acute severe traumatic brain injury,42 acute myocardial ischemia,43 CP,13 autism,16 prevention of post-coronary artery bypass cognitive decline,44 multiple sclerosis,45 avascular necrosis,46 fibromyalgia,47 complex regional pain syndrome,48 and vascular dementia.49 This last study is most exciting because it confirms in a controlled trial the author's previously mentioned 31-year experience treating diagnoses of cognitive decline, premature aging, and dementia. The possibilities and impact of treatment of these diagnoses of aging are inestimable. Considered in combination with all the other potentially treatable diagnoses based on the mechanism of oxygen and pressure epigenetics, the 132 conditions listed in the 1987 critique of HBOT, "A Therapy in Search of a Disease,"50 may in fact be a limited list.
In conclusion, hyperbaric therapy is the use of increased pressure and hyperoxia to treat diseases through temporary gene expression and suppression. After 355 years, we finally understand hyperbaric therapy as the most long-standing, panoramic, and effective gene therapy known to man; yet the therapy is in its infancy of dose exploration and disease application.
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Paul G. Harch, MD, is a clinical professor of medicine, section of emergency medicine, at Louisiana State University School of Medicine (New Orleans), a graduate of The Johns Hopkins University School of Medicine, and a magna cum laude/Phi Beta Kappa graduate of the University of California, Irvine. Dr. Harch is the director of the University Medical Center Hyperbaric Medicine Department and separately maintains an active private practice and research program where he has adapted the concepts of conventional hyperbaric oxygen therapy to wounds in the central nervous system.
Beginning with brain-injured divers and boxers in 1989, he applied his protocol to the first HBOT-treated cerebral palsy and autistic children in this country and multiple other cerebral disorders, including most recently a subacute drowned child (Medical Gas Research. March 2017). He has successfully treated US servicemen with TBI and PTSD, publishing the latest findings in Medical Gas Research, October 2017. His studies in brain-injured veterans have continued with a randomized trial funded by a Louisiana-generated congressional appropriation. The early case experience was confirmed in an animal model of chronic traumatic brain injury that was published in Brain Research in October 2007.
He has presented his research seven times to the US Congress and been nominated for the NIH Director's Pioneer Award. In April 2007, he published The Oxygen Revolution with co-author Virginia McCullough. This groundbreaking book, which has been released in its third updated edition in May 2016, explains HBOT as an epigenetic gene therapy and its projected revolutionary effects on medicine and neurology.