Pilot case study of the therapeutic potential of hyperbaric oxygen therapy on chronic brain injury

Abstract

Background

Recently, the effect of hyperbaric oxygen (HBO₂) therapy was explored in the treatment of chronic TBI. It has been speculated that idling neurons in the penumbra zone remain viable several years after injury and might be reactivated by enhanced oxygenation. We studied the therapeutic potential of HBO₂ therapy in a 54-year-old man who had sustained traumatic brain injuries one year before testing that resulted in permanent neurological symptoms.

Methods

Two treatment series separated by a one-year inter-session interval were administered. Treatment series consisted of 20 and 60 daily one-hour exposures to 100% oxygen at 2 ATA. Electrophysiological (event-related potentials), metabolic and behavioral (sensorimotor and neuropsychological) measurements were obtained to evaluate the effects of hyperbaric oxygen therapy on neurocognitive functioning.

Results

Following the initial treatment, the patient showed improvements in sensorimotor functions, as well as enhanced P300 amplitude in the damaged hemisphere. Although most of these gains were no longer observed one year after treatment, these were reinstated with an additional series of 60 exposures. Neuropsychological improvements were also observed after the completion of the second series of treatments.

Conclusion

The present single-case study provides preliminary evidence of neuropsychological and electrophysiological improvements after series of 20 and 60 treatments, although the first dosage appeared to be insufficient to produce permanent benefits. Longitudinal studies using different treatment parameters should be conducted if we are to systematically investigate long-term improvements resulting from HBO₂ therapy.

Introduction

Despite increasingly rapid intervention, medical experts are still struggling when attempting to reduce the adverse impact of a reduction of cerebral blood flow in the affected area following brain injury (TBI) and cerebrovascular (stroke) accidents. Treatment alternatives offered to TBI and stroke patients are primarily concerned with emerging complications in an attempt to preserve the patients' well-being and overall quality of life [1]. Improvements after brain injury resulting from a combination of spontaneous recovery and rehabilitation efforts are well-documented [2]. In fact, intensive functional therapy and rehabilitation programs are considered essential to minimize cognitive and physical sequelae associated with acquired brain injury in order to maximize the patient's quality of life. However, these programs are often only partially successful such that alternative approaches dedicated to the metabolic recovery of vulnerable cerebral tissues and others that attempt to limit the negative impact of ischemic insults need to be further explored in order to improve the functional outcome of a patient's acquired brain injury.

One of the goals in treating cerebral ischemia is to increase cerebral perfusion pressure and blood O₂ content with the use of supplemental O₂ [3]. For this reason, hyperbaric oxygen (HBO₂) therapy has recently been considered to offer new possibilities of recovery for patients with brain injury. However, a conservative approach is mandated due to our insufficient understanding of the underlying effects of high-concentration oxygen therapy on metabolic processes and much uncertainty remains about its potential risks and relatively unexplored long and short-term side effects [4]. So far, the application of HBO₂ has only been approved for medical conditions for which extensive clinical trials have been carried out to document its effectiveness and low risk. Some of these conditions are gas embolism, carbon monoxide poisoning, myonecrosis, crush injury and other acute traumatic ischemic events, as well as decompression sickness, thermal burns and exceptional blood loss [4]. Therefore, further investigations are required before this treatment alternative can be more widely used in the treatment of brain-injured patients.

HBO₂ therapy entails the inhalation of high concentrations of O₂ (94–100%) at pressure higher than sea level. Its effects result from the combined action of hyperoxia and hyperbaria, the pressurized pure O₂ being dissolved in all bodily fluids, especially in the plasma and cerebrospinal fluid [5], [6]. At two atmospheres absolute (ATA) for instance, the plasma O₂ tension rises above 1110 mm Hg, whereas it merely reaches 98 mm Hg in normal environmental conditions at sea level. Thus, in the hyperbaric condition there is a ten-fold increase in the amount of O₂ that reaches hypoxic brain tissues. This therapy is well tolerated and considered safe when used according to standard protocols with oxygen pressures not exceeding 3 ATA and treatment sessions limited to a maximum of 120 min [7].

Most studies based on case reports, clinical trials and animal work suggest that patients with neurological conditions such as brain injury and cerebrovascular disease may derive some benefits from HBO₂ therapy, especially in the acute stage, since hypoxia and ischemia are frequently involved in the pathophysiology. Although the efficacy of HBO₂ therapy still remains speculative, its appeal lies in its potential for preserving ischemic tissue by providing enough O₂ for the maintenance of a normal neuronal metabolism [8], [9]. It has been assumed that HBO₂ may enhance “idling neurons” function by increasing oxygenation in the cerebral ischemic penumbra where the neurons are thought to be still viable although metabolically “lethargic” and electrically nonresponsive [10], [11]. These cells may have sufficient oxygen to maintain ion pump mechanisms but not enough to generate action potentials and be fully functional [12]. The interruption of metabolic and electrical function that characterizes this intermediate zone is thought to be reversible when additional oxygen is made available to these cells [13]. Most researchers believe that physiological recovery of cortical functions is limited to a short period ranging from 30 min to a few hours after injury, depending on the duration of the ischemic event and the magnitude of cerebral perfusion within the cerebral blood flow range that defines the penumbra [13], [14], [15]. In fact, HBO₂ research has shown that the time elapsed between the brain insult and treatment is critical for restricting the damage induced by cerebral infarction. According to these studies, the optimal therapeutic window in which to initiate therapy should be within 6 h from the accident [8], [16], [17]. On the other hand, some investigators suggest that neurons in the ischemic penumbra remain viable for a longer period of time, lasting from 4 months up to several years after brain insult, and that the idling neurons could still be reactivated by exposure to HBO₂ [18], [19], [20], [21], [22]. However, there is a paucity of studies that have investigated the effect of HBO₂ therapy in the postacute stage (6 months or more after the insult), at which time brain-injured patients usually experience permanent neurological symptoms.

An important limitation to the study of HBO₂ is that major methodological issues are at the core of most studies reported in the literature. In fact, researchers often have to rely on anecdotal studies that have generally supported the efficacy of HBO₂ in the treatment of TBI. In this context, our group conducted the first double-blind analysis of children suffering from cerebral palsy who were submitted to a series of HBO₂ treatments [23], [24] and found that exposure to HBO₂ treatments was no more beneficial than a “placebo treatment”. With regard to TBI, a recent meta-analysis has only identified two fair-quality randomized controlled trials of patients with severe brain injury [25]. However, these two studies investigated the effects of this treatment alternative in the acute phase following the injury, which cannot validate the efficacy of HBO₂ offered to patients in the chronic phase following TBI [26]. Therefore, the present case study is intended to provide the first objective examination of the therapeutic value of repeated exposure to HBO₂ after clinical stabilization has taken place in a chronic severe brain-injured patient. This pilot study systematically assessed neurological/neurocognitive changes resulting from series of HBO₂ treatments using event-related potentials, neurobehavioral and metabolic measures.