Editorial: Review of Hyperbaric Therapy & Hyperbaric Oxygen Therapy in the Treatment of Neurological Disorders According to Dose of Pressure and Hyperoxia

Paul Gregory Harch ^1,2* George Mychaskiw, II ³ John Zhang ⁴ Dominic D'Agostino ⁵ Keith Van Meter ² Enrico M Camporesi ⁵

• ¹ School of Medicine, Louisiana State University, New Orleans, United States
• ² LSU Health Sciences Center New Orleans, Louisiana State University, New Orleans, Louisiana, United States
• ³ Ochsner LSU Health, Shreveport, Louisiana, United States
• ⁴ School of Medicine, Loma Linda University, Loma Linda, California, United States
• ⁵ Morsani College of Medicine, USF Health, Tampa, Florida, United States

Disorders According to Dose of Pressure and HyperoxiaHarch PG, Mychaskiw G, Zhang JH, D'Agostino DP, Van Meter K, Camporesi EM Hyperbaric therapy (HT) and hyperbaric oxygen therapy (HBOT) have confused the scientific, medical, and lay communities for 362 years. Therapeutic effectiveness has been attributed to increased barometric pressure for the first 300 years and increased pressure of oxygen in the modern era. A fortuitous observation by the U.S. Food and Drug Administration in 2011 elucidated the contribution of both barometric pressure and hyperoxia and their bioactivity on a continuum of pressure and hyperoxia. Simultaneous research identified epigenetic activity as a primary mechanism of both pressure and hyperoxia. Given these developments and the druglike effects of HT and HBOT this Research Topic attracted 13 articles that addressed dosing of pressure and hyperoxia in HT and HBOT for neurological conditions:Acute and Chronic Pediatric Ischemic/Hypoxic Neurologic Injury:Mielecki, et al and Sanchez, et al reviewed the animal and human literature on HBOT in perinatal asphyxia and hypoxic-ischemic encephalopathy, concluding that HBOT has been safe and more effective than hypothermia in ameliorating or eliminating the sequelae of acute global hypoxic/ischemic insult and subsequent HIE with as little as one rescue treatment administered shortly after birth. Doses in animals were generally at 2.0 ATA and above, while doses in humans tended to be under 2.0 ATA. Marois, et al, compared the effectiveness of typical therapies for the common chronic form of pediatric ischemic/hypoxic and hemorrhagic brain injury, cerebral palsy, and demonstrated that HBOT is four times as effective as the average of all of the other therapies. Using a precise analytic tool he found that increased barometric pressure (1.3-1.75 ATA) was the dominant contributor to HBOT's effect compared to hyperoxia. In light of the science of HBOT in acute HIE and chronic neurological wounding, the numbers of children affected, the devastating consequences, and the impact on quality of life these articles reinforce previous conclusions that "The time has come"…"for HBOT to be standard of care" for these conditions (1). Slade et al and Jingami, et al reported the first cases of temporally-demonstrated HBOT benefit in chronic stroke thalamic pain syndrome and subacute delayed post-hypoxic leukoencephalopathy (DPHL) secondary to opioid overdose. Post stroke pain disorders reduce the quality of life, affect mood, sleep, and social function. In Slade et al the authors treated a 55 year-old man who suffered a right thalamic lacunar infarction and developed thalamic pain syndrome. With extensive HBOT over 11 months (100 treatments) the patient's symptoms resolved and his quality of life improved. Jingami et al reported acute high dose HBOT (2.8 ATA oxygen) for suspected carbon monoxide poisoning in a 47 year-old man who was discovered to have an opioid overdose. Two months later they re-intervened with a similar dose of HBOT used by Slade et al (2.0 ATA oxygen) when DPHL evolved. With 62 HBOTs over 140 days the patient experienced resolution of neurological symptoms from his ishemic/hypoxic injury. While HBOT can improve cerebral blood flow and metabolism in chronic brain injury this patient's clinical improvement with HBOT raises interesting questions since the improvement occurred despite worsened fronto-parietal ioamphetamine SPECT imaging and evolving cortical atrophy. Costa, el al discusses the use of hyperbaric oxygen therapy (HBOT) as a complementary treatment for neuroblastoma, a common pediatric cancer. The authors note that HBOT reverses tumor hypoxia, a major cause of resistance to traditional treatments like chemotherapy and radiotherapy, and has other beneficial effects on cancer. Its greatest effect, however, may be modification of the tumor microenvironment (TME) and enhancing the immune response against neuroblastoma cells. Costa, et al reviewed a controlled study of an HBOT-enhanced IV tumor specific radioactive compound in children with recurrent neuroblastoma Stage IV that demonstrated a nearly 3-fold survival in the HBOT group. They recommended future research with HBOT, immunotherapy, and ketone metabolic therapy (KMT) to exploit cancer cells' unique metabolic vulnerabilities. Wang, et al also argued HBOT's potential to enhance cancer immunotherapy by its modification of the TME. HBO enhances radiotherapy and photodynamic therapy by increasing reactive oxygen species production and restructuring the extracellular matrix to promote immune cell infiltration. They reviewed HBOT's effects on cancer-specific immune targeting by noting HBOT's ability to improve T cell access to the tumor site that boosts the effectiveness of immune checkpoint inhibitors like PD-1/PD-L1 antibodies. Their review of HBOT animal cancer studies showed effectiveness of HBOT at higher doses in combination with chemotherapy and immunotherapy while HBOT alone had mixed effects on tumor growth. Two The authors duplicated the increased pressure benefit with a 0.3 atmosphere daily hyperbaric air treatment (and supplemental glutathione amino acid precursors) that generated a sustained improvement in dementia. MacLaughlin et al used the same 0.3 atmosphere increase in air to produce an increase in circulating stem progenitor cells in human subjects. Both papers convincingly suggest that use of low-dose hyperbaric air as a placebo control in randomized, controlled hyperbaric studies is a treatment in itself, not a control The third article, Simmonet, et al, addressed a longstanding debate about the greater contribution of pressure vs. oxygen in treatment of divers with spinal decompression illness. The authors' experience suggested that a higher oxygen pressure in the initial treatment was more efficacious than a deeper pressure with less oxygen. This is a provocative finding that does not explain the longstanding U.S. Navy treatment algorithm of conversion of a failing shallow oxygen table to a deeper pressure table. Simmonet, et al's findings await replication. Andrews, et al reported a systematic review of HBOT in PTSD. Statistically significant symptomatic improvements were achieved over a wide range of pressures from 1.3 to 2.0 ATA with a linear dose-response relationship between improvement and cumulative oxygen dose. This was accompanied by severe reversible exacerbation of emotional symptoms at the highest oxygen doses in 30-39% of subjects, a potential oxygen toxicity effect. The most surprising findings were imaging abnormalities in PTSD-affected brain regions which suggested that PTSD should no longer be considered a strictly psychiatric disease. Zaghloul, et al and Harch, et al studied oxygen toxicity across a spectrum of doses from normobaric to hyperbaric oxygen. Zaghloul, et al demonstrated a protective effect of Galantamine administration to mouse pups living in a normobaric hyperoxic environment. Medullary, forebrain, and hippocampal hyperoxia-induced neuronal loss, behavioral/ learning/memory deficits, hyaloid artery hyperplasia, retinal cell disruption, and neovascularization were all reduced by daily galantamine administration. These data are highly suggestive of a neuroprotective and ocular protective role for galantamine in oxygen-dependent neonates. In contrast Harch, et al reported a 20-year experience of acute and chronic central nervous system oxygen toxicity observed during hyperbaric hyperoxic treatment of chronic neurological conditions. Chronic oxygen toxicity was documented at significantly lower pressures from often extended numbers of treatments that was measured by a quantitative parameter of cumulative oxygen dose. Multiple clinical observations of hyperoxia were observed before patients attained the parabolic threshold that is documented in the published literature. One case with functional neuroradiology evidence reinforced the significance of these data. The above collection of articles has served the purpose of this Research Topic by demonstrating a wide range of bioactivity of hyperbaric pressure and oxygen on disease physiology, pathology, and neurological diseases. The afforded perspective will hopefully stimulate additional research into hyperbaric oxygen and pressure dosing effects and clinical applications of HBA and HBOT to neurological conditions. It is apparent that the hyperbaric medicine field after 362 years is in its infancy of neurological dosing.