Hyperbaric Physiological and Pharmacological Effects of Gases

Function

The effects of HBOT may be broadly divided into physiological and pharmacological mechanisms, although significant overlap exists between these categories. Oxygen functions both as an essential biological element and as a pharmacologic agent capable of modifying disease processes. HBOT uses oxygen as a drug and, therefore, requires the establishment of dosing protocols, definition of its therapeutic index, and recognition of potential adverse effects to ensure safe and effective use.[6][7][8]

Physiological Effects

At sea level, ambient air contains approximately 21% oxygen, producing an alveolar oxygen pressure (PAO2) of about 100 mm Hg. Hemoglobin remains nearly fully saturated under these conditions, with only a small amount of oxygen dissolved in plasma.

The alveolar oxygen pressure rises to approximately 2,280 mm Hg when a patient breathes 100% oxygen at 3 atmospheres absolute (ATA). According to Henry’s law, the increase in partial pressure markedly elevates the amount of oxygen dissolved in plasma, raising total blood oxygen content from 16.2 mL O2/dL to approximately 23 mL O2/dL—a 42% increase largely attributable to dissolved oxygen. The dissolved fraction accounts for approximately 6.8 mL O2/dL of the total.[9][10][11]

Oxygen serves a primary role in the formation of adenosine triphosphate, the molecule responsible for intracellular energy transfer through cellular respiration. The average human extracts and consumes approximately 6 mL of oxygen per deciliter of blood to sustain metabolism. The increase in dissolved oxygen achieved with HBOT can independently meet metabolic demands, supporting cellular respiration even in cases of severe hemorrhagic anemia.

White blood cells require substantial oxygen to perform phagocytosis and bacterial killing. HBOT improves host defense against infections associated with hypoxia, including cerebral abscesses, necrotizing fasciitis, and gas gangrene, by increasing tissue oxygen levels and enhancing leukocyte bactericidal activity.[12]

Another important physiological effect of oxygen is vasoconstriction. Elevated oxygen levels reduce endothelial nitric oxide production, leading to blood vessel constriction. In contrast, carbon dioxide produced during cellular respiration stimulates nitric oxide production and promotes vasodilation. Hyperoxia can cause cerebral vasoconstriction and reduced cerebral blood flow. Despite this reduction in flow, the elevated blood oxygen content results in increased oxygen delivery to brain tissue. Hyperoxia has also been reported to reduce cerebral edema, although the underlying mechanisms remain incompletely understood. These effects may have therapeutic potential in acute brain injury.

However, vasoconstriction also increases systemic vascular resistance. The resulting increase in afterload can be problematic in patients with heart failure and, in severe cases, may precipitate acute pulmonary edema. Ejection fraction alone remains a poor predictor of which patients will experience worsening congestive heart failure during HBOT.[13]

Pharmacological Effects

Oxygen functions as a drug in the treatment of various conditions through multiple pharmacologic mechanisms. Only a subset of these mechanisms is discussed here. One of the most common contemporary applications of HBOT is in the management of wound healing. Problem wounds developing from diabetic complications, pressure ulcers, burns, delayed radiation injury, or skin grafts are prevalent. Impaired healing often arises from a combination of endarteritis, tissue hypoxia, and inadequate collagen synthesis. The increased arterial oxygen tension achieved with HBOT promotes modulation of several growth factors, stimulates angiogenesis and arborization, and enhances immune responses to infection, collectively improving wound healing.

HBOT has been shown to increase the expression of growth factors, including vascular endothelial growth factor, platelet-derived growth factor, and fibroblast growth factor, in part through the modulation of nitric oxide pathways. Vascular endothelial growth factor and platelet-derived growth factor stimulate capillary budding and wound granulation by altering signaling pathways that promote cell proliferation and migration. Fibroblast growth factor contributes similarly to angiogenesis and, additionally, supports neural development, keratinocyte organization, and fibroblast proliferation at wound sites, facilitating granulation and epithelialization. Although clinical effects require several weeks of treatment, HBOT remains effective for promoting healing in diabetic foot ulcers, radiation-induced tissue injury, and chronic ischemic wounds, as well as for improving skin graft or flap survival.

Oxygen exerts antibacterial effects at wound sites. Neutrophils and macrophages consume large amounts of oxygen while killing bacteria and removing necrotic material. These cells utilize oxygen to generate reactive oxygen species (ROS), including hydrogen peroxide, superoxide anions, hydrochloric acid, and hydroxyl radicals. ROS mediate bacterial killing both intracellularly and extracellularly by damaging cell membranes and denaturing proteins.[14]

Carbon monoxide poisoning and DCS constitute classic indications for HBOT. Carbon monoxide poisoning occurs following inhalation of smoke or automobile exhaust. Carbon monoxide binds hemoglobin with an affinity more than 200 times greater than oxygen, severely impairing oxygen delivery and cellular respiration. HBOT accelerates the dissociation of carbon monoxide from hemoglobin in accordance with the law of mass action. The half-life of carboxyhemoglobin is 4 to 6 hours under normobaric conditions while breathing room air, whereas breathing 100% oxygen at 3 ATA reduces the molecule's half-life to 23 minutes.

DCS occurs when gases in the bloodstream become less soluble after rapid ascent from a dive. Gas bubbles form and produce symptoms ranging from severe musculoskeletal pain to paralysis. In the most severe cases, shunting of bubbles can result in an air gas embolism, leading to stroke or death.

HBOT treats DCS through multiple mechanisms. According to Boyle’s law, increased pressure compresses gas bubbles, reducing their volume by approximately 1/3 at 3 ATA. Smaller bubbles are more readily eliminated, circulation improves, and local hypoxia is reversed. Breathing 100% oxygen also accelerates the diffusion of nitrogen from the bubbles, promoting dissolution.

HBOT exerts anti-inflammatory effects beyond edema control. These effects include a reduction in inflammatory cytokine production, decreased neutrophil adhesion to the vascular endothelium, and downregulation of specific signaling pathways.[15] Such actions may help ameliorate ischemia-reperfusion injury, traumatic brain injury, crush injury, compartment syndrome, and thermal injuries.

Issues of Concern

Adverse effects of hyperbaric oxygen exposure primarily affect the lungs, central nervous system, and eyes. Pulmonary oxygen toxicity, historically termed the "Lorrain Smith effect," typically presents with coughing that progresses to chest discomfort, burning pain during inspiration, and dyspnea. Symptoms generally resolve after cessation of exposure, and long-term complications are considered minimal, although special consideration is warranted for current smokers or individuals with preexisting respiratory conditions. Central nervous system toxicity, formerly known as the "Paul Bert effect," is a more severe complication and can result in seizures. The incidence remains low, estimated at 0.2 to 3 per 10,000 exposures. Initial symptoms are nonspecific and may include visual disturbances, tinnitus, anxiety, or nausea, but progression to a tonic-clonic seizure can occur rapidly. No serious sequelae or increased risk of subsequent seizures have been documented. Factors that may lower the seizure threshold include a history of epilepsy, hypoglycemia, hyperthyroidism, fever, and certain medications, including penicillin or disulfiram.

Ocular toxicity involves both the retina and lens. Retinal changes are thought to result from abnormal angiogenesis and fibroblast proliferation, while hyperoxic exposure may also induce transient myopia due to increased lens refractive power. Both effects typically resolve within days to weeks after discontinuation of HBOT, although prolonged exposure may increase the risk of premature cataract formation.[16]

In addition to oxygen toxicity, the most common adverse effects of HBOT include barotrauma related to pressure changes and confinement anxiety within the chamber. Tympanic membrane barotrauma is the most common pressure-related complication, with a reported incidence of up to 2%. Barotrauma of the paranasal sinuses may also occur. Risk reduction is typically achieved through auto-inflation of the middle ear via swallowing, yawning, jaw movement, or performance of the Valsalva, Toynbee, or Frenzel maneuvers. Persistent or anticipated barotrauma, such as in intubated patients or individuals with a tracheostomy, may require placement of tympanostomy slits or tubes.[17] Patients with a history of significant middle or inner ear disease require careful screening before treatment.

Pulmonary barotrauma can result from air trapping. Trapped oxygen or air expands during decompression, potentially causing alveolar rupture, pneumothorax, and arterial gas embolism if gas enters the pulmonary venous system.[18] This complication is rare and occurs primarily in patients with underlying lung disease. Routine screening has low diagnostic yield, and chest radiography has poor sensitivity in identifying risk factors. Computed tomography is recommended for screening individuals at higher risk. Patients with chronic obstructive pulmonary disease, asthma, or emphysema should undergo slow decompression protocols to reduce the likelihood of barotrauma.[19]

Claustrophobia may arise during chamber therapy. Management typically involves patient familiarization with the chamber environment and administration of anxiolytic medications when indicated

Clinical Significance

The Food and Drug Administration has approved many clinical applications of HBOT, with substantial evidence supporting its effectiveness. Treatment of acute sensorineural hearing loss with HBOT was recognized in 2011. Several other approved indications, including severe anemia, crush injuries, necrotizing soft tissue infections, and osteomyelitis, have been described above. Considerable evidence also supports the use of HBOT in mitigating the effects of radiation therapy for cancer.[20][21] Despite this evidence, awareness among healthcare providers remains limited, and patients are often referred after the critical window of opportunity has passed.[22]

Education of the medical community regarding HBOT applications beyond DCS in divers and carbon monoxide poisoning is essential. Surgeons may utilize HBOT preoperatively and postoperatively to improve surgical outcomes. Internists may employ HBOT to manage diabetic foot ulcers or refractory anemia, while otolaryngologists may use HBOT to treat hearing loss. The list of approved and experimental indications continues to expand, underscoring the importance of provider familiarity and patient education regarding HBOT as a supplementary therapeutic option.

Enhancing Healthcare Team Outcomes

Like any medical treatment, HBOT carries potential side effects, complications, and contraindications. Side effects can be divided into 2 categories: those related to oxygen and those related to hyperbaric conditions or the chamber environment. Breathing 100% oxygen at pressures exceeding 2 ATA for prolonged periods can produce oxygen toxicity. This phenomenon remains incompletely understood but is thought to arise from the release of ROS, natural byproducts of cellular respiration. ROS can damage cellular structures, including membranes, and induce oxidative stress.