Medical and Rehabilitation Innovations Hyperbaric Oxygen Therapy for Traumatic Brain Injury

Medical and Rehabilitation Innovations Hyperbaric Oxygen Therapy for Traumatic Brain Injury

BACKGROUND Traumatic Brain Injuries (TBI) have become a national interest over the recent years due to a growing prevalence in the US population. This increase is primarily due to military personnel returning from Iraq and Afghanistan with brain/blast injuries, and a greater awareness of concussions stemming from football and other sports, elderly falls, and motor vehicle accidents. Due to the enormous economic burden, estimated to exceed $60 billion per year 1, and long term disability associated with TBI conditions, there is a great need and interest among the medical community to identify effective treatment methods that can reduce mortality while improving clinical and functional outcomes. It is important to understand that the extent of a brain injury from a traumatic event involves both the primary impact to the brain at the moment of injury, as well as the extensive secondary brain injury phase resulting from the reduction of blood flow (ischemia) caused by microvascular injury/occlusions, oxygen supply (hypoxia), neurotransmitter (glutamate) mediated excite-toxicity, mitochondrial dysfunction, inflammatory responses, apoptosis (genetically programmed cell death), and even brain cell electrolyte imbalances in homeostasis (e.g. calcium & glucose). Interestingly, since the 1960s there have been anecdotal reports of Hyperbaric Oxygen Therapy (HBOT) improving outcomes following brain trauma. 2 And in the past decade, many basic science research studies have been published supporting HBOT benefits on brain recovery in rodents. The studies explored where the brain cell s mitochondrial recovery and decrease in apoptosis in hypoxic nerve cells led to improved cognitive recovery and a reduction in hippocampal neuronal cell loss. The proposed mechanisms of HBOT on brain injury include neural stem cell activation and growth, reduced hypoxic-induced myelin damage, elevated cellular ATP levels, and enhanced neuronal tolerance to hypoxia. 3 Treatment Overview Hyperbaric Oxygen Therapy is approved by the Food and Drug Administration (FDA) as a biologically repairing and regenerative treatment modality 4 currently used for medical conditions involving carbon monoxide poisoning, burn injury, crush injury, air embolism, diabetic wound ulcers, necrotizing gas gangrene, radiation necrosis, osteomyelitis, arterial insufficiencies including retinal artery blockages, decompression sickness, severe anemia, intracranial brain abscess, and compromised skin flaps/graphs. HBOT is a medical procedure that provides 100% oxygen therapy in a sealed chamber that is pressurized to a specific multiple of sea level pressure (1 atmosphere absolute or ATA) and treated for a given period of time (e.g. 30, 60, 90 minutes, etc.) depending upon a given medical condition. HBOT is believed to improve oxygen supply to the injured brain, reduce the swelling associated with low oxygen levels, and reduce the volume of brain that will ultimately perish thanks to improved mitochondrial function, decreased neuro-inflammation and free radical-mediated damage. 2,5 2 Paradigm Outcomes, Proprietary

LITERATURE SUMMARY A review of the medical literature on HBOT in traumatic brain injuries on human subjects through 2015 reveals some interesting findings. Due to the assertions over the years that HBOT may be beneficial in treating traumatic brain injuries, Bennett et al. led the Cochrane Collaboration initiative in 2012 and reviewed the 962 literature citations, including 45 papers published and available over a 36 year period up to 2010. The reviewers identified only seven trials with a total of 571 participants available for evaluation and analysis due to poor methodological quality of many of the cited trials and publications. After their diligent review and analysis of the available acceptable published information, the authors concluded that there is some limited evidence that HBOT creates some improvement in Glasgow Coma Scale (GCS) ratings and reduces the chance of mortality. They added that there is little evidence that more survivors have a good outcome and therefore, the routine adjunctive use of HBOT in traumatic brain injured patients cannot be justified by the review. 2 The reviewers further commented that with the findings of some improved survival and GCS with the use of HBOT in acute traumatic head injuries, there needs to be a larger randomized trial of high methodological rigor in order to better define the true extent of the benefit from HBOT in TBI. In addition, the reviewers emphasized the need for trials to specify and carefully define the severity of TBI patients, as well as appropriate ranges of oxygen doses per treatment sessions and appropriate outcome measures. Since 2010, there have been a number of clinical trials and interventional studies focused on both safety of HBOT in treating TBI, as well as the effectiveness of HBOT. Three clinical trials focused on the safety of HBOT while the other 10 articles addressed the HBOT effectiveness on specific clinical outcomes. Among these clinical studies, two trials involved severe TBI cases that were prospective randomized clinical trials, while eight trials were specific to mild TBI. The following three studies all demonstrated and concluded that HBOT was clinically safe to utilize in patients with TBI conditions: 1. Gossett, W.A. et al. The Safe Treatment, Monitoring and Management of Severe Traumatic Brain Injury Patients in a Monoplace Chamber. Undersea & Hyperbaric Medicine, vol. 37, no 1. 2010 2. Wolf, E.G. et al. Hyperbaric Side Effects in a Traumatic Brain Injury Randomized Clinical Trial. Undersea & Hyperbaric Medicine, vol. 39, no. 6 2012 3. Churchill, S. et al. A Prospective Trial of Hyperbaric Oxygen for Chronic Sequelae after Brain Injury. Undersea & Hyperbaric Medicine, vol. 40, no. 2 2013 The following two prospective randomized clinical trials with severe TBI cases clearly demonstrated effectiveness of HBOT in improving oxidative cerebral metabolism in pericontusional brain tissue. These trials demonstrated reduced intracranial hypertension, decreased therapeutic intensity of treatment of intracranial hypertension, reduced mortality and improved favorable outcomes as measured by the Glasgow Outcome Scale (GOS) at 6 months post injury. The severe TBI patients in these studies were randomized within 24 hours post-injury to HBOT versus standard care as control while patients were in an acute trauma 3 Paradigm Outcomes, Proprietary

facility intensive care unit (ICU) setting. The study participants assigned to HBOT protocol received the given treatment once every 24 hours for three consecutive days. These studies demonstrated no significant oxygen toxicity associated with the HBOT. 1. Rockswold, S.B. et al. A Prospective, Randomized Phase II Clinical Trial to Evaluate the Effect of Combined Hyperbaric and Normobaric Hyperoxia on Cerebral Metabolism, Intracranial Pressure, Oxygen Toxicity, and Clinical Outcome in Severe Traumatic Brain. Journal of Neurosurgery, vol. 118 2013 2. Rockswold, S.B. et al. A Prospective, Randomized Clinical Trial to Compare the Effect of Hyperbaric to Normobaric Hyperoxia on Cerebral Metabolism, Intracranial Pressure, Oxygen Toxicity in Severe Traumatic Brain. Journal of Neurosurgery, vol. 112 2010 The following six clinical trials involved mild TBI patients, and the studies were randomized and double blinded in addition to having a sham control group. The researchers of these clinical studies concluded that HBOT was not effective in treating mild TBI with persistent postconcussive symptoms (PPCS) and/or post-traumatic stress disorder (PTSD). 1. Miller, R.S. et al. Effects of Hyperbaric Oxygen on Symptoms and Quality of Life among Service Members with Persistent Postconcussion Symptoms: A Randomized Clinical Trial. JAMA Internal Medicine, vol. 175, no. 1 2015 2. Walker, W.C. et al. Randomized Sham-controlled, Feasibility Trail of Hyperbaric Oxygen for Service Members with Postconcussion Syndrome: Cognitive and Psychomotor Outcomes 1 Week Postintervention. Neurorehabilitation and Neural Repair, vol. 28, no. 5 2014 3. Cifu, D. et al. Hyperbaric Oxygen for Blast-Related Post Concussion Syndrome: Three- Month Outcomes. Annals of Neurology, vol. 75 2014 4. Cifu, D. et al. Effects of Hyperbaric Oxygen on Eye Tracking Abnormalities in Males after Mild Traumatic Brain Injury. Journal of Rehabilitation Research and Development, vol. 51, no. 7 2014 5. Cifu, D. et al. The Effect of Hyperbaric Oxygen on Persistent Post Concussion Symptoms. Journal of Head Trauma Rehabilitation, vol. 29, no. 1 2013 6. Wolf, G. et al. The Effect of Hyperbaric Oxygen on Symptoms after Mild Traumatic Brain Injury. Journal of Neurotrauma, vol. 29 2012 The following two articles one from an Israeli study and one a US clinical study on mild TBI patients implied that the HBOT was effective in treating mild TBI related post-concussive syndrome, as well as PTSD. The critics of these two articles assert the studies did not have the clinical trial methodological rigor or appropriate control groups, thus raising some concern about the validity of the findings. 1. Boussi-Gross, R. et al. Hyperbaric Oxygen Therapy Can Improve Post Concussion Syndrome Years after Mild Traumatic Brain Injury Randomized Prospective Trial. PLOS ONE, vol. 8, no. 11 2013 2. Harch, P.G. et al. A Phase I Study of Low Pressure Hyperbaric Oxygen Therapy for Blast Induced Post-concussion Syndrome and Post-Traumatic Stress Disorder. Journal of Neurotrauma, vol. 29 2012 4 Paradigm Outcomes, Proprietary

Food and Drug Administration Approval The Food and Drug Administration has approved HBOT for specific indications. These include air/gas embolism, arterial insufficiency related conditions, such as central retinal artery occlusion, carbon monoxide poisoning, gas gangrene, crush injury, compartment syndromes, compromised skin flaps/graphs, decompression sickness, delayed radiation injuries to both soft tissues and bony necrosis, significant anemia, intracranial abscess, necrotizing soft tissue infections, and osteomyelitis. However, since the FDA has accepted the safety of HBOT for a range of medical conditions, the agency does not necessarily prevent physicians and healthcare providers from using HBOT for treating other non-approved conditions. PARADIGM POSITION There is currently sufficient evidence-based medicine data to support the safety of HBOT in TBI patients. In addition, there is literature evidence from recent prospective randomized clinical trials supporting the benefit and effectiveness of HBOT in managing severe TBI patients acutely within 24 hours post brain injury in the trauma hospital s ICU setting. Due to the demonstration of statistically significant improvements in cerebral metabolism, intracranial pressures, mortality rates, and favorable clinical outcomes with HBOT in severe TBI patients, acute care trauma facilities with institutional expertise and resources in the management of severe TBI and critical care hyperbaric medicine would be allowed to use HBOT. However, there is not sufficient evidence-based clinical benefit to support using HBOT in mild TBI, persistent post-concussive syndrome (PPCS), and post-traumatic stress disorder (PTSD). Summary Help: There is evidence for both safety and effectiveness of HBOT for acute management of severe TBI in the ICU setting. Hope: There is hope for HBOT being a therapeutic modality in addressing mild TBI, persistent post-concussive syndrome, and post-traumatic stress disorder. Hype: Claims about HBOT being a regenerative brain therapy are merely hype. 5 Paradigm Outcomes, Proprietary

ENDNOTES References 1. Finkelstein, E.A. et al. The Incidence and Economic Burden of Injuries in the United States. New York: Oxford University Press, 2006 2. Bennett, M.H. et al. Hyperbaric Oxygen Therapy for the Adjunctive Treatment of Traumatic Brain Injury (Review). Cochrane Database of Systematic Reviews, vol. 12. 2012 3. Cifu, D. et al. Effects of hyperbaric oxygen on eye tracking abnormalities in males after mild Traumatic Brain injury. Journal of Rehabilitation Research & Development, 2014 51(7): 1047-1055 4. Stollar, K. Hyperbaric Oxygen Therapy in the treatment of Traumatic Brain injury. EP Magazine. August 2011: 34-38 5. Rockswold, S.B. et al. A Prospective, Randomized Phase II Clinical Trial to Evaluate the Effects of Combined Hyperbaric and Normobaric Hyperoxia on Cerebral metabolism, Intracranial Pressure, Oxygen Toxicity, and Clinical Outcome in Severe Traumatic Brain. Journal of Neurosurgery, vol. 118. 2013 Acknowledgments Special thanks to the Paradigm Outcomes Medical Affairs Group, for contributing to this paper, as well as the facilitators Michael Choo, MD, and Steven Moskowitz, MD. 2015 Paradigm Management Services, LLC ( Paradigm ). No part of this publication may be reproduced, transmitted, transcribed, shared, disseminated, summarized, stored in a retrieval system, adapted, or translated into any language in any form by any means without the written permission of Paradigm. Trademarks, service marks, products names, company names or logos of Paradigm are protected by trademark and other laws of the United States, as well as international conventions and the laws of other countries. 6 Paradigm Outcomes, Proprietary