Introduction

For a long time, hyperbaric oxygen therapy (HBOT) has been used in clinical practice to treat decompression sickness, carbon monoxide poisoning, clostridial infections, and enhance wound healing. However, newer applications of this therapy have been shown to successfully treat a wide range of conditions such as compartment syndrome, burns and frostbite, and even sensorineural hearing loss. HBOT works through inhalation of high concentrations of oxygen in a pressurized chamber. Under typical therapeutic conditions, the partial pressure of oxygen dissolved in the plasma may reach levels greater than 20 times that of breathing room air at normal atmospheric pressure. Oxygen-rich plasma can then be transported to the hypoxic or ischemic tissue to promote angiogenesis, reduce edema, and even modulate the immune system response.[1][2][3]

Function

The function of HBOT can roughly be divided into two types of effects, physiologic and pharmacologic, with much overlap. Oxygen can be thought of as both a naturally occurring elements essential for life, and as a drug used to alter disease pathology. Indeed, HBOT uses oxygen as a drug and, therefore, has proper dosing protocols, a therapeutic index, and side effects that need to be understood in order to be used safely and effectively.[4][5][6]

Physiological Effects

Under normal conditions at sea level, ambient air is composed of approximately 21% oxygen resulting in an alveolar oxygen pressure (PAO2) of about 100 mmHg. Under these conditions, plasma hemoglobin is almost entirely saturated, and there is minimal dissolved plasma oxygen. Therefore, assuming a hemoglobin concentration of 12 g/dL, the combined blood oxygen content in whole blood is about 16.2 mL O2/dL. Under hyperbaric conditions breathing 100% oxygen at 3 atmospheres absolute (ATA), the PAO2 value increases to around 2280 mmHg, and according to Henry’s law, the combined oxygen content in whole blood increases to 23.0 mL O2/dL. This 42% increase from baseline is almost entirely from an increase in oxygen dissolved in plasma. The increase in oxygen supply and arterial oxygen tension forms the basis of HBOT.[7][8][9]

Oxygen is primarily used by the body in the formation of adenosine triphosphate, the molecule responsible for intracellular energy transfer through a process called cellular respiration. The average human uses around 6 mL of O2/dL of blood to maintain metabolism; therefore, HBOT offers sufficient plasma oxygen to drive cellular respiration and the potential to overcome massive hemorrhagic anemia.

Another main physiological effect of oxygen relates to vasoconstriction. Increased levels of oxygen cause a decrease in local nitric oxide (NO) production by endothelial cells, thereby leading to vasoconstriction. Conversely, increased levels of carbon dioxide, the byproduct of respiration, promote NO production and vasodilation. This is especially important as it relates to cerebral blood flow as short-term hyperoxia causes cerebral vasoconstriction and reduced blood flow. However, even with reduced blood flow, more oxygen is delivered to the cerebrum as a result of the hyperoxic state. Additionally, hyperoxia has also been shown to decrease cerebral edema, although the mechanisms behind this are still not well understood, and further studies are needed to characterize this proposed phenomenon. Applications of these effects have some promise in acute brain injury.

Pharmacological Effects

As previously stated, oxygen is used as a drug to treat a variety of conditions through a variety of pharmacologic mechanisms. However, only a small portion of these effects will be discussed here. Perhaps the most common use of HBOT today is in wound healing. Problem wounds resulting from diabetic complications, pressure ulcers, burns, delayed radiation injury, or skin grafts are quite prevalent. Poor healing is often a result of a combination of endarteritis, tissue hypoxia, and inadequate collagen synthesis. Increased arterial oxygen tension of HBOT promotes modulation of a number of growth factors, angiogenesis, and arborization, and enhances the immune system response to infection, leading to enhanced healing.

HBOT has been shown to upregulate the production of vascular endothelial growth factor (VEGF), variants of platelet-derived growth factor (PDGF), and fibroblast growth factor (FGF) partially through nitric oxide modulation. VEGF and PDGF are responsible for stimulating capillary budding and wound granulation, and do so by altering signaling pathways leading to cell proliferation and migration. FGF plays a similar role in angiogenesis, but also induces neural development, keratinocyte organization, and fibroblast proliferation at wound sites leading to granulation and epithelialization.

Oxygen also has antibacterial effects at wound sites. As neutrophils and macrophages enter these environments to kill bacteria and remove necrotic material, they consume large amounts of oxygen. Oxygen is then utilized by these cells to create hydrogen peroxide, superoxide anions, hydrochloric acid, and hydroxyl radicals. Through indirect and direct mechanisms, these reactive oxygen species (ROS) can then kill bacteria both intracellularly and extracellularly through membrane disruption and protein denaturation.

Carbon monoxide poisoning and decompression sickness (DCS) are probably the most classic conditions treated with HBOT. Carbon monoxide poisoning occurs after smoke or automobile fume inhalation. It is particularly deadly because carbon monoxide binds hemoglobin with an affinity greater than 200 times that of oxygen, thus impairing cellular respiration. HBOT can decrease this burden by reducing the half-life of carbon monoxide dissociation from hemoglobin through the law of mass action. Under normobaric conditions breathing room air, the half-life of carboxyhemoglobin is 4-6 hours, but breathing 100% oxygen at 3 ATA reduces the half-life to 23 minutes.

DCS occurs when gases in the bloodstream become less soluble following rapid ascent from diving. These gases form bubbles and result in symptoms ranging from severe musculoskeletal pain to paralysis, and in the most severe cases, an air gas embolism can result in death. When HBOT is administered, compression of the bubbles occurs, and their volume is reduced according to Boyle’s law. Under 3 ATA, bubble volume can be reduced by one-third. With a reduction in size, bubbles can be better eliminated, circulation is improved, and local hypoxia is reversed. Oxygen is also paramount in displacing nitrogen in the bubbles through diffusion, essentially dissolving the bubbles away.

Issues of Concern

Oxygen toxicity most commonly affects the lungs, central nervous system (CNS), and eyes. Pulmonary oxygen toxicity, formerly known as the Lorrain Smith effect, usually manifests as coughing progressing to chest pain, burning pain on inhalation, and dyspnea. Symptoms often resolve after cessation of the dive, and long-term complications are considered to be inconsequential, though special consideration should be given to current smokers or those with respiratory conditions.

CNS toxicity, formerly known as the Paul Bert effect, is a more severe complication and can result in the seizure. Luckily this is relatively uncommon with an incidence of between 0.2 to 3 in 10,000. Initial symptoms are nonspecific and may include vision changes, tinnitus, anxiety, or nausea, but can quickly progress to a tonic-clonic seizure. To date, no serious sequelae or increased risk of subsequent seizures have been found. Factors thought to lower the seizure threshold include the history of epilepsy, hypoglycemia, hyperthyroidism, current fever, and select drugs such as penicillin and disulfiram.

Ocular toxicity has been shown to affect both the retina and lens. The retinopathy is thought to be due to abnormal angiogenesis and fibroblast production, while myopia occurs due to a transient increase in the refractive power of the lens. Both of these conditions will usually reverse within days to weeks following cessation of HBOT, though there is a risk of premature cataract development.

Apart from oxygen toxicity, the most common side effects of concern are barotrauma from the pressures used, and confinement anxiety while in the chamber. Barotrauma of the tympanic membrane is most common with a reported incidence as high as 2%, though barotrauma of the sinuses can also occur. The potential for tympanic membrane barotrauma is usually ameliorated by auto-inflating the middle ear through the Valsalva maneuver or placement of tympanostomy tubes. Anyone with a significant history of middle or inner ear pathology should be carefully screened. Claustrophobia can also be overcome with the familiarity of the chamber and the use of anxiolytics during therapy.

Clinical Significance

There are currently many FDA-approved clinical applications of HBOT with quality evidence of its effectiveness. Most recently, the treatment of acute sensorineural hearing loss with HBOT was recognized in 2011. A number of other approved indications such as severe anemia, crush injuries, necrotizing soft tissue infections, and osteomyelitis have been mentioned above; however, not all health care providers are aware of the effectiveness of HBOT and often refer patients after the critical window of opportunity has passed. [10]

Therefore, it is essential to educate the medical community that HBOT reaches beyond DCS in divers and carbon monoxide poisoning. Surgeons can use HBOT preoperatively and postoperatively to improve surgical outcomes. Internists can better treat diabetic foot ulcers or refractory anemia, while otolaryngologists can treat hearing loss with HBOT. The list of approved and experimental conditions continues to grow, and it is essential for providers to not only familiarize themselves with HBOT but to educate their patients about its potential and offer it as supplementary therapy when appropriate.

Enhancing Healthcare Team Outcomes

Just like any form of medical treatment, HBOT has potential side effects, complications, and contraindications. Side effects can be divided into two categories, those related to oxygen and those related to the hyperbaric conditions and the chamber itself. Breathing 100% oxygen at greater than 2 ATA for prolonged periods of time can result in oxygen toxicity. This phenomenon is still not completely understood, but it is thought to be due to natural byproducts of cellular respiration called reactive oxygen species (ROS). ROS can damage cell structures like cellular membranes and cause oxidative stress.