**5. Decades of science: studying HBOT to treat TBI**

A review of the scientific evidence produced in both animal and human HBOT trials over the past twenty years demonstrates conclusively that Hyperbaric Oxygenation of TBI is safe and effective [40]. As early as 1977, Holbach and Wasserman demonstrated that HBOT at 1.5ata puts the most oxygen into the brains

**127**

metabolism.

*Hyperbaric Oxygenation in the Treatment of Traumatic Brain Injury*

of chronic stroke patients [41]. The overriding principle of wound healing, of course, is that the wound must have energy and oxygen to heal. Hypoxia is the most pervasive result of brain insults of all kinds, occasioned by inflammation that leads

Following a Consensus Conference in 2008, at which it was declared that HBOT was safe [42], DoD/Army/VA researchers commenced a series of studies to discern whether HBOT was effective in treating TBI. Those studies over nearly eight years consumed over \$126Million. Other studies in the private sector costing orders of magnitude fewer dollars were also conducted. To date, there have been at least seventeen peer-reviewed studies that have produced data and findings [43].

U.S. and Israelis clinical trials have provided well-structured, controlled studies demonstrating HBOT medicinal properties in mild TBI and persistent postconcussive symptoms [44]. Positive symptom scores for TBI and PTSD symptom scores for the two government-sponsored studies [45], the Army-sponsored study of Miller et al. [46], a civilian-sponsored study of Harch et al. [47], and an Israeli civilian study [48] show statistically significant improvements over baseline after

The studies involved patients with TBI who also suffered from Persistent Post-Concussive Syndrome (PPCS) for at least two years. It was highly unlikely that spontaneous recovery would occur. Five studies provide useful cross-study comparable measures. The U.S. studies used the Immediate Post-Concussion Assessment,

Clinical improvements in the studies were significant and consistent. Looking at dose response profiles shows that lower oxygen levels (100% O2) and lower pressures (2.0 ATA) are probably better for PTST/mTBI and PPCS symptom recovery. Government-sponsored study authors assumed incorrectly that their control groups received inactive treatment. Yet they write; "We recognize that a sham is not inert, and we cannot completely discount the physiological effects of minimal increases in nitrogen or oxygen from pressurized room air. However, we believe it is biologically implausible that air at 1.2 ATA (equivalent to 2 m of seawater pressure) has a beneficial effect on healing the damaged brain remotely after mTBI [49]. (It is worth noting that the comment bears on relationship to the established science about the medicinal effects of low levels of either oxygen or pressure.) [50] Positive improvements from pretreatment (baseline) measures are observed in all the DoD/ VA/Army and civilian studies. The measured responses to both HBO and HBA treatment groups are therapeutic, but a minimal effective dose of O2 at 1ata pressure has not been established in the hyperbaric medical literature. Thus, the use of a sham is

Deng and his team in a metanalysis evaluated nine studies comparing the efficacy between hyperbaric oxygen treatment and controls in traumatic brain injury patients [51]. "Brain metabolism, cognitive function, and outcome were taken into consideration. Results showed that HBO treatment significantly improved the Glasgow outcome scale (GOS) score and reduced overall mortality in patients with severe TBI compared with controls. In patients with mild TBI, HBO showed function alleviating the cognitive disorder after trauma, including memory, executive function, attention, and information processing speed." In patients with TBI, HBO showed significant improvement of Glasgow outcome scale score and reduction of overall mortality while NBO may play a favorable role in improving brain

Cognitive Testing, Rivermead Post-Concussion Questionnaire, and PTSD Checklist–Military (PCL-M) as the primary and secondary endpoint measures. Even though the Army/VA/DoD sponsored studies claim to be "sham-controlled,"

they are really dosing and-pressure-varying trials.

problematic and confounding for study interpretation.

*DOI: http://dx.doi.org/10.5772/intechopen.94401*

to reduced oxygen delivery to all body organs.

HBOT treatments.

#### *Hyperbaric Oxygenation in the Treatment of Traumatic Brain Injury DOI: http://dx.doi.org/10.5772/intechopen.94401*

*Advancement and New Understanding in Brain Injury*

hospital-based and private clinics.

ate withdrawal/detox [37].

sent home after as few as five treatments [39].

**5. Decades of science: studying HBOT to treat TBI**

Those chambers are primarily used for Wound Healing. For a variety of reasons, those chambers are not put to use on off-label uses of HBOT. Nevertheless, the bulk of science on animal and human patients with TBI has been collected in both

Dr. Paul Harch prepared voluminous evidence on HBOT for wound healing in his arguments for recognition of DFW in 2002 [29]. More specific to TBI, Dr. Philip James, in "Head Injuries – the Curse of Life in the Fast Lane," [30] traces the development of HBOT-for-TBI research as far back as 1972 [31]. The study found that tissue oxygen levels that fight hypoxia rise with the increase in either the oxygen concentration or pressure: hyperbaric oxygenation. James writes that "*this one study* answers all the questions and objections raised about using hyperbaric oxygen treatment for patients with head injury." [32] Oddo in 2011 identified hypoxia as a culprit. Brain hypoxia is associated with poor short-term outcome after severe traumatic brain injury independently of elevated ICP, low CPP, and injury severity. Reduced brain oxygen (Pbto [2]) may be an important therapeutic target after severe traumatic brain injury [33]. Dr. Daphne Denham, the nation's premier expert on HBOT treatment of acute concussion, reported that 98% of her patients in her Fargo ND clinic [348 out of 350] treated within ten days of suffering a concussion, completely resolved their symptoms in five treatments or less [average of 2.4 treatments] [34]. The only difference in her patients and the thousands of concussed athletes in North Dakota who linger with symptoms for weeks and months using standard of care medicine [AKA "the tincture of time"] was HBOT. [NOTE: Maroon and Bost in 2011 write that nonpharmaceutical alternatives, dietary supplements and hyperbaric oxygen "may be a better first-line choice for the treatment of PCS, which has generally been underreported by both athletes and the military." [35] Of note for the CMS population is the work of Dr. Anne McKee on the connections between concussion and Chronic Traumatic Encephalopathy (CTE) [36]. "CTE is a progressive neurodegeneration clinically associated with memory disturbances, behavioral and personality change, Parkinsonism, and speech and gait abnormalities.... traumatic injury may interact additively with [Alzheimer's Disease] to produce a mixed pathology with greater clinical impact or synergistically by promoting pathological cascades that result in either AD or CTE."

Of no small importance is groundbreaking research from Washington State University. Researchers found that HBOT can halve the pain and symptoms of opi-

And in current investigations of the use of HBOT to arrest and reverse the effects of COVID-19, preliminary evidence from China [38] (five cases) strongly suggests that based on the immutable science of HBOT and recent clinical application to deteriorating severely hypoxemic COVID-19 pneumonia patients, HBOT has significant potential to impact the COVID-19 pandemic. Fifty-eight patients as of this writing have been positively affected. Further, clinicians in at least five independent studies in the US using HBOT are raising the PO2 levels in patients in ICUs to the point where they avoid being put on ventilators and, in many cases, are being

A review of the scientific evidence produced in both animal and human HBOT

Wasserman demonstrated that HBOT at 1.5ata puts the most oxygen into the brains

trials over the past twenty years demonstrates conclusively that Hyperbaric Oxygenation of TBI is safe and effective [40]. As early as 1977, Holbach and

**126**

of chronic stroke patients [41]. The overriding principle of wound healing, of course, is that the wound must have energy and oxygen to heal. Hypoxia is the most pervasive result of brain insults of all kinds, occasioned by inflammation that leads to reduced oxygen delivery to all body organs.

Following a Consensus Conference in 2008, at which it was declared that HBOT was safe [42], DoD/Army/VA researchers commenced a series of studies to discern whether HBOT was effective in treating TBI. Those studies over nearly eight years consumed over \$126Million. Other studies in the private sector costing orders of magnitude fewer dollars were also conducted. To date, there have been at least seventeen peer-reviewed studies that have produced data and findings [43].

U.S. and Israelis clinical trials have provided well-structured, controlled studies demonstrating HBOT medicinal properties in mild TBI and persistent postconcussive symptoms [44]. Positive symptom scores for TBI and PTSD symptom scores for the two government-sponsored studies [45], the Army-sponsored study of Miller et al. [46], a civilian-sponsored study of Harch et al. [47], and an Israeli civilian study [48] show statistically significant improvements over baseline after HBOT treatments.

The studies involved patients with TBI who also suffered from Persistent Post-Concussive Syndrome (PPCS) for at least two years. It was highly unlikely that spontaneous recovery would occur. Five studies provide useful cross-study comparable measures. The U.S. studies used the Immediate Post-Concussion Assessment, Cognitive Testing, Rivermead Post-Concussion Questionnaire, and PTSD Checklist–Military (PCL-M) as the primary and secondary endpoint measures. Even though the Army/VA/DoD sponsored studies claim to be "sham-controlled," they are really dosing and-pressure-varying trials.

Clinical improvements in the studies were significant and consistent. Looking at dose response profiles shows that lower oxygen levels (100% O2) and lower pressures (2.0 ATA) are probably better for PTST/mTBI and PPCS symptom recovery.

Government-sponsored study authors assumed incorrectly that their control groups received inactive treatment. Yet they write; "We recognize that a sham is not inert, and we cannot completely discount the physiological effects of minimal increases in nitrogen or oxygen from pressurized room air. However, we believe it is biologically implausible that air at 1.2 ATA (equivalent to 2 m of seawater pressure) has a beneficial effect on healing the damaged brain remotely after mTBI [49]. (It is worth noting that the comment bears on relationship to the established science about the medicinal effects of low levels of either oxygen or pressure.) [50] Positive improvements from pretreatment (baseline) measures are observed in all the DoD/ VA/Army and civilian studies. The measured responses to both HBO and HBA treatment groups are therapeutic, but a minimal effective dose of O2 at 1ata pressure has not been established in the hyperbaric medical literature. Thus, the use of a sham is problematic and confounding for study interpretation.

Deng and his team in a metanalysis evaluated nine studies comparing the efficacy between hyperbaric oxygen treatment and controls in traumatic brain injury patients [51]. "Brain metabolism, cognitive function, and outcome were taken into consideration. Results showed that HBO treatment significantly improved the Glasgow outcome scale (GOS) score and reduced overall mortality in patients with severe TBI compared with controls. In patients with mild TBI, HBO showed function alleviating the cognitive disorder after trauma, including memory, executive function, attention, and information processing speed." In patients with TBI, HBO showed significant improvement of Glasgow outcome scale score and reduction of overall mortality while NBO may play a favorable role in improving brain metabolism.


**5. Discussion**

The results of the research presented in this article indicate that the application of Markov chains to forecast the bus occupancy level in public transport is entirely justified because it represents, to a reasonable degree, the features of the urban public transport system. Compared to the works mentioned in the literature review, which mostly refer to the problem of passenger flow forecasting in the transport network, the authors' research was strictly focused on forecasting the bus comfort level related to the vehicle occupancy, which can be directly used by travelers to optimize their trips and to change their travel patterns to more environmentally friendly ones. The obtained results can be useful not only for fleet management in the public transport system but also for the development of passenger information systems and trip planning.

Nevertheless, this approach requires further research based on a larger data set sample from an automatic counting system over a longer time horizon. It would also be desirable to determine the influence of other factors on the forecasting effectiveness (season of the year, weather, and specificity of the analysed communication line). The calculated forecast errors are the most significant for interchanging stops, due to the high variability of passenger flows in these places. Therefore, it seems justified to carry out studies with the use of heterogeneous Markov chains, where the transition matrix would be variable depending on the time, type of bus stop or communication line. Such an analysis could be very useful for the practical application and further verification of the proposed approach.


**Author details**

Wan Azlina Wan Ab Karim Ghani1 and Azil Bahari Alias2

1 Department of Chemical and Environmental Engineering, the Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia

2 Faculty of Chemical Engineering, University Technology MARA, 40450 Shah Alam, Selan‐ gor, Malaysia


**2.12 Other diets**

Based on the knowledge about the effects of different macronutrients on circulating glucose levels many other popular diets have been introduced. These diets have not been studied using controlled trials so the outcomes are not authenticated. These diets include the Paleo diet, Atkins diet/keto diet, Nutrisystems etc. They are all focused on weight loss. It is important to account for the different macro and micronutrients on maintaining normal metabolism in the body. Therefore, a carbohydrate free or a fat free diet or vegan diet can be very deleterious to health, unless there is a balance in the nutrient intake.