Why provide 40 sessions of hyperbaric oxygen therapy to patients with traumatic brain injury?

Traumatic brain injury (TBI), a signature war disease of the 21^st century: The wars in Iraq and Afghanistan ushered in the recognition of TBI as a significant unmet clinical need. TBI can be categorized into two main types. Penetrating TBI involves a projectile that pierces the skull, whereas closed head TBI occurs due to nonpenetrating mechanical impact, blast or external forces affecting the brain through acceleration–deceleration phenomena.

TBI severity is typically based on the patient’s presentation, including loss of consciousness, posttraumatic amnesia and Glasgow Coma Scale score, which are used to determine patient prognosis. Mild TBI, which accounts for 70–90% of cases, usually involves postconcussion symptoms, including headaches, dizziness, neuropsychiatric symptoms, balance difficulties, fatigue, sleep and cognitive impairments. Most mild TBI patients completely recover, whereas 10–25% may experience prolonged chronic symptoms. A total of 10–30% of the cases are moderate to severe TBIs, presenting with alterations in mental status, confusion, agitation, seizures, focal deficits, dysphasia, dysarthria, and vomiting, among others. While moderate TBIs may lead to lingering symptoms or moderate disability, severe TBIs have a higher mortality rate and significant physical, cognitive and psychological deficits.

TBI presents as an acute primary brain injury followed by secondary injury, which may lead to chronic injury. Addressing both primary and secondary cell death processes is paramount in neurocritical care since these cascades of cell death mechanisms are multifaceted and involve factors such as ionic disturbances, neurotransmitter release, mitochondrial dysfunction, neuronal apoptosis, lipid degradation, and inflammatory responses, causing significant perturbations in oxygen-containing blood vessels and impairing the neurovascular unit.

Understanding the complexities of TBI pathophysiology, its primary and secondary injury mechanisms, and the importance of prompt and appropriate care is essential for the treatment of TBI. Here, we highlight the significant perturbations in oxygen-containing blood vessels, which are key disease hallmarks of TBI, necessitating a strategy that delivers oxygen and repairs the neurovasculature, i.e., the neurovascular unit.

Hyperbaric oxygen therapy (HBOT): oxygen delivery and vascularization: HBOT is a treatment approach that involves exposing a person to 100% oxygen at pressures higher than atmospheric pressure (above 1 atmosphere absolute or 1 ATA or 101 atmospheric pressure or 101 kPa). HBOT has been used for more than eight decades to treat various medical conditions, and its mechanisms of action have been extensively studied and explored. Since the 1860s, HBOT has been used to treat decompression sickness (DCS). DCS manifests routinely in scuba divers experiencing a sudden or too rapid decrease in pressure (i.e., decompression). The pathophysiology of DCS involves the formation of bubbles in the bloodstream and tissues due to the inadequate elimination of inert gases, primarily nitrogen, that dissolve in the body’s tissues during exposure to elevated pressures. In its most dangerous form, intravascular bubbles occlude oxygen-containing vessels and cause tissue ischemia and central nervous system injury. For DCS,1 the HBOT regimen targets oxygenation and recompression of bubbles. Similarly, chronic wounds became a signature war disease during World War II, and since then, HBOT has been the treatment of choice for chronic wounds.1 Chronic nonhealing wounds present a healing process that fails to produce anatomic and functional integrity, largely due to microvascular dysfunction, i.e., depletion of oxygen-containing vessels, leading to chronic ischemia or a lack of oxygen in the wounded tissue.

Given that ischemia induces a cascade of secondary cell death mechanisms in brain trauma, TBI subsequently became a candidate target disease for HBOT. Although HBOT was initially tested in TBI animal models in 1966 and in human patients in 1971, the bulk of HBOT clinical trials for TBI did not commence until the 2000s following the return of soldiers from the Middle East wars, with surprising numbers of TBIs due to blast injuries.2

Oxygen compromise, specifically hypoxia and a lack of oxygen-containing vessels or ischemia, are two key etiologies shared by chronic wounds and TBI. In recognition of these disease hallmarks, HBOT is poised to slow these underlying cell death processes by increasing the oxygen supply while accelerating the washout of inert gas to the blood circulation and tissue and the growth of new oxygen-containing blood vessels via angiogenesis.1,3,4 In addition, HBOT has been shown to promote several other neuroprotective and neuroregenerative effects, such as increasing anti-inflammatory and antioxidative stress responses, increasing the secretion of growth factors, improving mitochondrial function, and mobilizing endogenous stem cells.

Many of the standardizations and field tests of HBOT originated from the US Navy, owing in part to the primary applications of HBOT for treating DCS in Navy scuba divers and submariners. The advent of hyperbaric schedules or tables allows safety and efficacy optimization of HBOT, specifying the pressure profile over time and the breathing gas to be used during quantified periods for medical treatment. From one of the earliest hyperbaric schedules of 4 hours used for DCS to the present 40–60 hours, protocols for brain injuries have been proposed, and newer schedules are much safer and more effective than older schedules are.5 There also appears to be a consensus of using a single exposure to HBOT for DCS, whereas multiple daily sessions are indicated for chronic wounds.2,4 The choice of treatment between single HBOT for DCS and multiple sessions of HBOT for TBI may be justified by the disease-specific targeted pathophysiology. Whereas DCS requires recompression of bubbles to restore oxygenation and perfusion, TBI, on the other hand, necessitates fostering the complex process of angiogenesis to achieve perfusion. Indeed, in the three most recent systematic reviews of hyperbaric schedules for TBI, 40 HBOT sessions of 1.5 ATA are deemed safe and show efficacy for TBI patients, i.e., both clinical- and imaging-based improvements persisted after the 40^th HBOT. This regimen meets the Center for Evidence-Based Medicine Level 1 criteria and supports the American Society of Plastic Surgeons Class A Recommendation for HBOT treatment of mild TBI persistent postconcussion syndrome. A recent randomized trial involving military personnel with mild TBI with ongoing symptoms and persistent postconcussive symptoms utilized the 40-session HBOT regimen.2,6 Finally, recent studies have demonstrated that increasing the number of HBOT sessions to 60 may be more beneficial for chronic TBI, considering the inherent progression and prolonged secondary cell death.6,7,8

Equally compelling is the physiological evidence supporting the need for at least 40 HBOT sessions when contemplating growing new blood vessels for TBI. Vascular plasticity after TBI recapitulates developmental plasticity. Vasculogenesis in human embryos (i.e., neural tube embryogenesis) requires 7–8 weeks. In adults, the onset of neovascularization occurs at 32 days but is not detectable in the first 14 days. Moreover, the maturation of newly formed blood vessels requires an extended period of 4–6 weeks for the continued presence of the therapeutic agent. Taken together, these findings suggest that the optimal timeframe for the growth of new blood vessels requires at least 6 weeks of daily treatment, i.e., 6 weeks × 7 days equates to 42 HBOT sessions.9

However, the caveat is that these newly grown vessels may not be fully functional. The plasticity of the vascular network is intimately linked with neuronal developmental and adult plasticity.10 Normal brain vasculature expansion in the postnatal brain occurs from postnatal days 8 to 12, which equates to 36–40 weeks gestation in humans. Injured brain vasculature expansion initiates at 3 weeks after injury in adult mice, which is equivalent to 1.5 years in humans.9 Accordingly, new blood vessel growth may be achieved after approximately 40 HBOT sessions, but recognizing a functional vascular network may require a much longer maturation period, suggesting that more HBOT sessions (e.g., 60 dives) are needed in parallel with newer hyperbaric schedules.8 In Tal’s study,11 angiogenesis was reported in humans via brain MRI perfusion studies of chronic TBI patients treated with 60 HBOT sessions.

In summary, historical accounts and clinical evidence indicate that 40 or more HBOT sessions are safe and effective. Scientific evidence indicates that growing blood vessels require at least 42 days or more of continued vasculature-targeted therapy.

Finally, the U.S. Food and Drug Administration guidelines state that the HBOT chamber is a medical device that is cleared for use in specific disorders but is not currently approved for treating chronic TBI. However, the optimal number of treatments for TBI appears to be in the range of 40–80 HBOT daily 1-hour sessions.12 Improved brain tissue oxygen levels combined with enhanced neurovascular unit remodeling can positively impact the recovery of brain function and neurological outcomes in TBI patients.

We acknowledge the assistance of Dr. Napasiri Putthanbut and Dr. Jea-Young Lee from Morsani College of Medicine, University of South Florida, in the preparation of this manuscript.