Hyperbaric oxygen therapy for traumatic brain injury

Hyperbaric oxygen therapy (HBOT) is a treatment by which high oxygen concentrations are administered to a patient at a pressure greater than atmospheric pressure at sea level (i.e. one atmosphere absolute, ATA). The increased partial pressure of oxygen (pO2) within the blood and subsequent improved mitochondrial metabolism/tissue oxygenation constitutes the net effect of HBOT.

Given that the dissolved oxygen content in the plasma increases linearly after hemoglobin is 100% saturated, plasma bound oxygen can be used more readily than that bound to hemoglobin which enables tissue oxygen delivery even in the absence of red blood cells. Thus, HBOT induces a much larger oxygen-carrying capacity in the blood that dramatically increases the driving force of oxygen diffusion to tissues.

Although HBOT-induced cerebral vasoconstriction appears to be undesirable within the context of ischemic conditions this may not be necessarily deleterious due to increased oxygen availability to injured tissues. HBOT may also counter vasodilation of the capillaries within hypoxic tissues, thereby minimizing the collection of extravascular fluids (edema) which ultimately reduces brain vasogenic edema and the ensuing decrease in intracranial pressure (ICP).

Emerging evidence has shown the neuroprotective effects of HBOT in a range of multiple injuries and/or disorders. The most common clinical applications include decompression sickness, carbon monoxide poisoning, minimization of radiation therapy-induced tissue damage and enhancing skin grafts.

There are numerous “unapproved” uses of HBOT that focus on more complex neurological disorders, including autism, multiple sclerosis, and stroke, which have shown promising results in experimental settings, but clinical efficacy is still elusive. Recent efforts have applied HBOT to traumatic brain injury.

Over the past several decades, the neuroprotective mechanisms of HBOT have been investigated in a variety of animal models of TBI. The initial work in dogs has shown the HBOT was able to increase tissue oxygen delivery as well as to protect penumbra tissue from secondary ischemia. Based on the dog model, a similar freeze-induced brain injury was conducted in rats to evaluate local cerebral glucose utilization using the autoradiographic 2-deoxyglucose technique. Compared to animals that underwent NBOT, a four-day HBOT course (2 ATA for 90 minutes daily) significantly reversed the depressed glucose utilization within gray matter ipsilateral to the lesion.

Interestingly, HBOT tended to decrease glucose utilization in sham-operated animals. However, it was still uncertain whether the favorable outcomes were directly attributable to improved glucose metabolism associated with HBOT. HBO-improvements in tissue oxygenation and mitochondrial metabolic function were further investigated in a rat model of fluid percussion injury (FPI). HBOT (1 hr 1.5 ATA with 3 hrs 100% normobaric oxygen) treatments significantly improved, 1) brain tissue pO2 (more than 6 fold) near the site of injury; 2) ex vivo brain tissue oxygen consumption (vO2, more than 1 fold); and 3) recovery of synaptosomal mitochondrial metabolic activity.

Given that the prognosis of TBI clearly depends on the processes of cell death and survival that occur within the traumatized tissues, neuroprotective therapies need to mitigate and improve survival and function within the remaining viable perilesional brain tissue. The neuroprotective effects of HBOT against secondary brain damage in the penumbra region have been extensively investigated.

Using a model of dynamic cortical deformation (DCD) to produce focal cerebral contusion in rats, HBOT (2 sessions at 2.8 ATA for 45 min/each) were administered at 3 hrs after TBI and compared to the effects of NBOT. There were significantly smaller lesion volumes and decreased numbers of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL, a biomarker for apoptosis) positive cells after HBOT. Normobaric oxygen therapy (100%) also improved tissue measures but not to the extent found after HBOT.

The anti-apoptotic modulator, B-cell lymphoma (Bcl-2), was increased after HBOT and correlated to reduced tissue apoptosis. Similar changes were found for B-cell lymphoma-extra large (Bcl-xl) expression, while the pro-inflammatory protein, B-cell lymphoma-associated X protein (Bax), was observed primarily in astrocytes instead of neurons. The ratio between pro-apoptotic Bax and antiapoptotic Bcl-2/Bcl-xl proteins has been shown to act as a “rheostat” that sets the threshold [44] of susceptibility to apoptosis by competitively modulating the opening of the mitochondrial permeability transition pore (mPTP).

Enhanced Bcl-2 expression inhibits the mPTP that subsequently preserves mitochondrial homeostasis and therefore the integrity of the electron transport chain. Palzur et al thus hypothesized that HBOT-induced increases in Bcl-2 expression and the resultant increase in intracellular oxygen bio-availability may contribute both to preserve mitochondrial integrity and to reduce the activation of the mitochondrial-mediated apoptotic pathway following TBI.

In the same animal model, HBOT (2.8 ATA for 45 min at 3 and 24 hrs post-injury) substantially facilitated the recovery of mPTP expression. Subsequently, TBI-induced injury to tissue morphology was reversed with enhanced neuronal survival and preserved axonal architecture within perilesional tissues [6]. Similar findings of improved mitochondrial redox after HBOT in the FPI model of TBI have also been reported.

The preservation of mitochondrial integrity by HBOT hindered the activation of mitochondria-associated apoptotic pathways by significantly lowering caspase 3 and 9, but not caspase 8 expressions (critical for non-mitochondrial apoptotic pathway) in injured brain tissues. These results underscore the importance of HBOT-induced reductions in delayed cell death within the tissue penumbra after TBI. Such, mechanisms echo the neuroprotection of HBO seen in brain ischemia and subarachnoid hemorrhage.

Acute inflammation also plays an important role in secondary brain damage after TBI. An influx of inflammatory cells induced by TBI provides the primary source of matrix metalloproteinases (MMPs) activity. MMPs in the injured brain further play a deleterious role and promote cell death, including apoptosis.

The effects of HBOT on inflammatory infiltration and the expression of (MMPs) have been explored in a rat model of DCD. Both HBOT (2.8 ATA for 45 min at 3 hrs after injury and twice a day thereafter for 3 consecutive days) and NBOT significantly decreased myeloperoxidase-positive neutrophils within the traumatic penumbra, but HBOT had a more pronounced effect. HBOT also significantly reduced the elevation of MMP-9 expression associated with neutrophilic infiltration.

Thus, HBOT substantially decreases the harmful effects of inflammation by reducing MMP-9 over-expression that then results in a reduction of delayed cell death in penumbral tissues surrounding the site of injury. Interestingly, reduced MMP-9 has also been proposed to be the underlying mechanism associated with HBO pretreatment induced neuroprotection against TBI at high altitude in a rat model.

However, what is still unresolved is whether the decreased numbers of apoptotic cells following HBOT is a direct anti-apoptotic effect or secondary consequence due to HBOT anti-inflammatory effects. Further studies are warranted to disclose the complex mechanisms underlying the neuroprotective effects of HBOT after TBI.

Translational investigation of HBOT in a variety of models of TBI has demonstrated neuroprotective effects in the absence of increased oxygen toxicity when a pressure less than 3 ATA is administered. All human studies have involved patients with severe TBI and are likely to be more effective in patients with mild or moderate TBI. Recent clinical trials favor HBOT as a safe and promising therapeutic strategy for patients with TBI graves. Although both NBOT (normobaric oxygen) and HBOT at 1.5 ATA can be neuroprotective, HBOT exerts more robust and lasting effects on the absence of pulmonary or cerebral oxygen toxicity.

Lei Huang and Andre Obenaus. (2011). Hyperbaric oxygen therapy for traumatic brain injury. Medical Gas Research.

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