Close
New

Medscape is available in 5 Language Editions – Choose your Edition here.

 

Hyperbaric Oxygen Therapy

  • Author: Emi Latham, MD, FACEP, FAAEM; Chief Editor: Ryland P Byrd, Jr, MD  more...
 
Updated: Jul 22, 2016
 

Overview

Overview

Hyperbaric oxygen therapy (HBOT) is breathing 100% oxygen while under increased atmospheric pressure. HBOT is a treatment that can be traced back to the 1600s. The first well-known chamber was built and run by a British clergyman named Henshaw. He built a structure called the domicilium that was used to treat a multitude of diseases.[1] The chamber was pressurized with air or unpressurized using bellows. The idea of treating patients under increased pressure was continued by the French surgeon Fontaine, who built a pressurized, mobile operating room in 1879.[2] Dr. Orville Cunningham, a professor of anesthesia, ran what was known as the "Steel Ball Hospital." The structure, erected in 1928, was 6 stories high and 64 feet in diameter. The hospital could reach 3 atmospheres of pressure.[2] The hospital was closed in 1930 because of the lack of scientific evidence indicating that such treatment alleviated disease. It was deconstructed during World War II for scrap.

The military continued work with hyperbaric oxygen. The work of Paul Bert, who demonstrated the toxic effects of oxygen (producing grand mal seizures), as well as the work of J. Lorrain-Smith, who demonstrated pulmonary oxygen toxicity, were used with Navy divers. Exposure times to oxygen at different depths of water (and, hence, different levels of pressure) were quantified and tested based on time to convulsions.[2]

The United States may have an inadequate number of HBOT treatment facilities. Of the 361 chambers identified nationwide, only 43 were equipped to handle high-acuity patients. HBOT is instrumental in treating decompression sickness, arterial gas embolisms, and acute carbon monoxide poisoning.[3]

Oxygen chambers

When a patient is given 100% oxygen under pressure, hemoglobin is saturated, but the blood can be hyperoxygenated by dissolving oxygen within the plasma. The patient can be administered systemic oxygen via two basic chambers: Type A, multiplace; and Type B, monoplace. Both types can be used for routine wound care, treatment of most dive injuries, and treatment of patients who are ventilated or in critical care.

Multiplace chamber

Multiplace chambers treat multiple patients at the same time, generally with a nurse or another inside observer who monitors the patients and assists with equipment manipulation or emergencies (see images below). Patients in a multiplace chamber breathe 100% oxygen via a mask or close-fitting plastic hood. Multiplace chambers can usually be pressurized to the equivalent of about six atmospheres of pressure.

If a different mixture of gas (nitrogen or helium mixture) is desired, the mixture can be given, via the mask, to only the patient, not the employee. All equipment used with patients, such as ventilators and intravenous lines, is put into the chamber with the patient. Since the employee is breathing air during the treatment (not using a mask), his or her nitrogen intake must be monitored, as this presents a risk for problems similar to those sometimes developed by scuba divers (eg, decompression sickness [DCS]).

Rectangular hyperbaric chamber. Rectangular hyperbaric chamber.
Interior of rectangular chamber. Interior of rectangular chamber.
Cylindrical multiplace chamber. Cylindrical multiplace chamber.

Monoplace chamber

A monoplace chamber compresses one person at a time, usually in a reclining position (see image below). The gas used to pressurize the vessel is usually 100% oxygen. Some chambers have masks available to provide an alternate breathing gas (such as air). Employees tend to the patient from outside of the chamber and equipment remains outside the chamber. Only certain intravenous lines and ventilation ducts penetrate through the hull. Newer Duoplace chambers can hold two people. Their operation is similar to that of a monoplace chamber.

Monoplace chamber. Monoplace chamber.

Other chambers

Two other types of chambers are worth mentioning, although they are not considered HBOT.

Topical oxygen, or Topox, is administered through a small chamber that is placed over an extremity and pressurized with oxygen. The patient does not breathe the oxygen, nor is the remainder of the body pressurized. Therefore, the patient cannot benefit from most of the positive effects of HBOT, which are systemic or occur at a level deeper than topical oxygen can penetrate (see Hyperbaric Physics and Physiology section below). Topox is based on the concept that oxygen diffuses through tissue at a depth of 30-50 microns.[4] This method does not treat DCS, arterial gas emboli (AGE), or carbon monoxide (CO) poisoning.

Another problem with Topox is the design of the unit. A pressure differential must be created between the machine and open atmosphere to compress the machine. In order to keep the extremity from being pushed out of the pressurized machine, the cuff of the box must fit very tightly around the extremity, thereby creating a tourniquetlike effect. Topox is not covered by insurance, nor is it endorsed by the journal Diabetes Care for the treatment of foot ulcers.[5]

The other type of chamber is the portable "mild" hyperbaric chamber. These soft vessels can be pressurized to 1.5-1.7 atmospheres absolute (ATA). They are only approved by the FDA for the treatment of altitude illness. The number of these chambers has increased, as they are being used more commonly in off-label indications.

Next

Hyperbaric Physics and Physiology

Physics of hyperbaric medicine

The physics behind hyperbaric oxygen therapy (HBOT) lies within the ideal gas laws.

The application of Boyle law (p1 v1 = p2 v2) is seen in many aspects of HBOT. This can be useful with embolic phenomena such as decompression sickness (DCS) or arterial gas emboli (AGE). As the pressure is increased, the volume of the concerning bubble decreases. This also becomes important with chamber decompression; if a patient holds her breath, the volume of the gas trapped in the lungs overexpands and may cause a pneumothorax.

Charles law ([p1 v1]/T1 = [p2 v2]/T2) explains the temperature increase when the vessel is pressurized and the decrease in temperature with depressurization. This is important to remember when treating children or patients who are very sick or are intubated.

Henry law states that the amount of gas dissolved in a liquid is equal to the partial pressure of the gas exerted on the surface of the liquid. By increasing the atmospheric pressure in the chamber, more oxygen can be dissolved into the plasma than would be seen at surface pressure.

The clinician must be able to calculate how much oxygen a patient is receiving. In order to standardize this amount, atmospheres absolute (ATA) are used. This can be calculated from the percentage of oxygen in the gas mixture (usually 100% in HBOT; 21% if using air) and multiplied by the pressure. The pressure is expressed in feet of seawater (fsw), which is the pressure experienced if one were descending to that depth while in seawater. Depth and pressure can be measured in many ways; some common conversions are 1 atmosphere (atm) = 33 feet of seawater (fsw) = 10 meters of sea water (msw) = 14.7 pounds per square inch (psi) = 1.01 bar.

Hyperbaric physiology

Table 1 below summarizes the physiologic mechanisms of HBOT. Each of these is discussed in the context of the indications for HBOT later in this article.

Table 1. Physiologic Mechanisms of Hyperbaric Oxygen Therapy (Open Table in a new window)

Mechanism References Clinical Application
Hyperoxygenationa Boerema I[6]



Bassett BE[7]



Bird AD[8]



DCS/AGE



CO poisoning



Central retinal artery occlusion



Crush injury/compartment syndrome



Compromised grafts and flaps



Severe blood loss anemia



Decrease gas bubble size Boyle law Air or gas embolism
Vasoconstrictionb Nylander G[9]



Sukoff MH[10]



Crush injury/compartment syndrome



Thermal burns



Angiogenesis Knighton DR[11] Problem wounds



Compromised grafts and flaps



Delayed radiation injury



Fibroblast proliferation/collagen synthesis Hunt TK[12] Problem wounds



Delayed radiation injury



Leukocyte oxidative killingc Mader JT[13]



Park MK[14]



Mandell GL[15]



Necrotizing soft tissue infections



Refractory osteomyelitis



Problem wounds



Reduces intravascular leukocyte adherence Zamboni WA[16]



Thom SR[17, 18]



Crush injury/compartment syndrome
Reduces lipid peroxidation Thom SR[19] CO poisoning



Crush injury/compartment syndrome



Toxin inhibition Van Unnik A[20] Clostridial myonecrosis
Antibiotic synergy Mirhij NJ[21]



Keck PE[22]



Mendel V[23]



Muhvich KH[24]



Necrotizing soft tissue infections



Refractory osteomyelitis



aMost oxygen carried in the blood is bound to hemoglobin, which is 97% saturated at standard pressure. Some oxygen, however, is carried in solution, and this portion is increased under hyperbaric conditions due to Henry's law. Tissues at rest extract 5-6 mL of oxygen per deciliter of blood, assuming normal perfusion. Administering 100% oxygen at normobaric pressure increases the amount of oxygen dissolved in the blood to 1.5 mL/dL; at 3 atmospheres, the dissolved-oxygen content is approximately 6 mL/dL, which is more than enough to meet resting cellular requirements without any contribution from hemoglobin. Because the oxygen is in solution, it can reach areas where red blood cells may not be able to pass and can also provide tissue oxygenation in the setting of impaired hemoglobin concentration or function.



bHyperoxia in normal tissues causes vasoconstriction, but this is compensated by increased plasma oxygen content and microvascular blood flow. This vasoconstrictive effect does, however, reduce posttraumatic tissue edema, which contributes to the treatment of crush injuries, compartment syndromes, and burns.



cHBOT increases the generation of oxygen free radicals, which oxidize proteins and membrane lipids, damage DNA, and inhibit bacterial metabolic functions. HBO is particularly effective against anaerobes and facilitates the oxygen-dependent peroxidase system by which leukocytes kill bacteria.



Additionally, evidence is growing that HBOT alters the levels of proinflammatory mediators and may blunt the inflammatory cascade. More studies are needed to further elucidate this complex interaction.

As HBOT is known to decrease heart rate while maintaining stroke volume, it has the potential to decrease cardiac output. At the same time, through systemic vasoconstriction, HBOT increases afterload. This combined effect can exacerbate congestive heart failure in patients with severe disease. However, clinically significant worsening of congestive heart failure is rare.

Previous
Next

Contraindications

As with most medical treatments, absolute and relative contraindications exist with the use of hyperbaric oxygen therapy (HBOT).[2]

Table 2. Absolute Contraindications to Hyperbaric Oxygen Therapy (Open Table in a new window)

Absolute Contraindications Reason Contraindicated Necessary Conditions Prior to HBOT
Untreated pneumothorax Gas emboli



Tension pneumothorax



Pneumomediastinum



Thoracostomy
Bleomycin Interstitial pneumonitis No treatment for extended time from use of medication
Cisplatin Impaired wound healing No treatment for extended time from use of medication
Disulfiram Blocks superoxide dismutase, which is protective against oxygen toxicity Discontinue medication
Doxorubicin Cardiotoxicity Discontinue medication
Sulfamylon Impaired wound healing Discontinue and remove medication

 

Table 3. Relative Contraindications to Hyperbaric Oxygen Therapy (Open Table in a new window)

Relative Contraindications Reason Contraindicated Necessary Conditions Prior to HBOT
Asthma Air trapping upon ascent leading to pneumothorax Must be well controlled with medications
Claustrophobia Anxiety Treatment with benzodiazepines
Congenital spherocytosis Severe hemolysis None; HBOT for emergencies only
Chronic obstructive pulmonary disease (COPD) Loss of hypoxic drive to breathe Observation in chamber
Eustachian tube dysfunction Barotrauma to tympanic membrane Training, PE tubes
High fever Higher risk of seizures Provide antipyretic
Pacemakers or epidural pain pump Malfunction or deformation of device under pressure Ensure company has pressure-tested device and learn to what depth
Pregnancy Unknown effect on fetus (Previous studies from Russia suggest HBOT is safe.) None, but HBOT may be used in emergencies
Seizures May have lower seizure threshold Should be stable on medications; may be treated with benzodiazepines
Upper respiratory infection (URI) Barotrauma Resolution of symptoms or decongestants
Previous
Next

Decompression Sickness and Air Embolism

Decompression sickness

Decompression sickness (DCS) refers to symptoms caused by blocked blood supply, damage from direct mechanical effects, or later biochemical actions from suspected bubbles evolving from inert gas dissolved in blood or tissues when atmospheric pressure decreases too rapidly.[25, 26] DCS can occur after scuba diving, ascent with flying, or hypobaric or hyperbaric exposure.

DCS can be broken down into the following 3 types:

  • Type I involves musculoskeletal, skin, and lymphatic tissue, and often has accompanying fatigue.
  • Type II includes neurologic systems (either CNS or peripheral), cardiorespiratory, audiovestibular, and shock. [26]
  • Type III DCS describes a syndrome that presents with severe symptoms of DCS as well as AGE. Some of these cases can be refractory to recompression.

The bubbles causing DCS also can injure vessel endothelium, which leads to platelet aggregation, denatured lipoproteins, and activation of leukocytes, causing capillary leaks and proinflammatory events.[27, 28]

Hyperbaric oxygen therapy (HBOT) is used to diminish the size of the bubbles, not simply through pressure, but also by using an oxygen gradient. According to Boyle's law, the volume of the bubble becomes smaller as pressure increases. With a change in 1.8 ATA, this is only about 30%. The bubble causing DCS is thought to be composed of nitrogen. When a tissue compartment is at equilibrium and then ascends to a decreased atmospheric pressure, nitrogen seeps out of blood, tissue, or both, causing a bubble. During HBOT, the patient breathes 100% oxygen, creating oxygen-rich, nitrogen-poor blood. This creates a gradient of nitrogen between the blood and the bubble, causing nitrogen to efflux from the bubble into the bloodstream, which, in effect, makes the bubble smaller.[26]

The treatment of choice is recompression. Although treatment as soon as possible has the greatest success, recompression is still the definitive treatment, and no exclusionary time from symptom onset has been established.[26, 27] DCS Type I can be treated using the US Navy Treatment Table 5: 60 fsw for two 20-min periods, with a slow decompression to 30 fsw for another 20 minutes. For DCS types I, II, and III, the US Navy Treatment Table 6 is a recommended treatment protocol. Patients are placed at 60 fsw (2.8 ATA) for at least three 20-min intervals and then are slowly decompressed to 30 fsw. They remain there for at least another 2.5 hours. The time a patient is kept at 60 or 30 fsw can be extended depending on the patient's symptom response to therapy.[29]

Air embolism

Air embolism refers to bubbles in the arterial or venous circulation. Venous bubbles can result from compressed gas diving (such as scuba)[30] but are often filtered through the pulmonary capillary bed. If a large volume of bubbles is noted, they may overwhelm the pulmonary filter and enter the arterial circulation.[31] Arterial gas emboli (AGE) can also result from pulmonary barotrauma[26] or accidental intravenous air injection or some surgical procedures.[32, 33, 34, 35, 36] Symptoms usually occur within seconds to minutes of the event and can include loss of consciousness, confusion, neurological deficits, cardiac arrhythmias, or cardiac arrest.

The treatment of choice is recompression therapy. Gas embolism used to be treated with US Navy Treatment Table 6A, which required a pressure of 6 ATA. The rationale was that the larger volume of gas warranted increased pressure to force bubble redistribution or elimination. No conclusive evidence demonstrates that this offers superior treatment to the US Navy Treatment Table 6 for most cases. However, if complete relief is not achieved after initial recompression, deeper recompression may be needed.[26]

Previous
Next

Carbon Monoxide Poisoning

Carbon monoxide (CO) poisoning, whether intentional or accidental, occurs when one inhales the colorless and odorless carbon monoxide gas. Despite improved awareness and sensory alarms, multiple deaths occur each year.

CO binds to hemoglobin with 200 times the affinity of oxygen. CO also shifts the oxygen dissociation curve to the left (the Haldane effect), which decreases oxygen release to tissues. CO can also bind cytochrome oxidase aa3/C and myoglobin. Reperfusion injury can occur when free radicals and lipid peroxidation are produced.

The treatment of CO poisoning with hyperbaric oxygen therapy (HBOT) is based upon the theory that oxygen competitively displaces CO from hemoglobin. While breathing room air, this process takes about 300 minutes. While on a 100% oxygen nonrebreather mask, this time is reduced to about 90 minutes. With HBOT, the time is shortened to 32 minutes. HBOT (but not normobaric oxygen) restores cytochrome oxidase aa3/C[37] and helps to prevent lipid peroxidation.[38] HBOT is also used to help prevent the delayed neurologic sequelae (DNS). Treatment instituted sooner is more effective.[39] Multiple papers describe controversial methods and conclusions about the use of HBOT for CO poisoning.[40, 38, 41, 42, 43]

Patients with CO poisoning can present with myriad symptoms that they may not initially attribute to CO poisoning, as CO is considered the “great imitator” of other illnesses.[19, 44, 45] Presentation can include flulike symptoms such as headache, visual changes, dizziness, and nausea. More serious manifestations include loss of consciousness, seizures, chest pain, ECG changes, tachycardia, and mild to severe acidosis.

Candidates for HBOT are those who present with morbidity and mortality risks that include pregnancy and cardiovascular dysfunction and those who manifest signs of serious intoxication, such as unconsciousness (no matter how long a period), neurologic signs, or severe acidosis. CO-hemoglobin (Hgb) level usually does not correlate well with symptoms or outcome;[46, 38, 47] many patients with CO-Hgb levels of 25-30% are treated.

Pregnant females often have a CO level that is 10-15% lower than the fetus. Fetal Hgb not only has a higher affinity for CO but also has a left-shifted oxygen dissociation curve compared with adult hemoglobin. Exposure to CO causes an even farther leftward shift, in both adult and fetal hemoglobin, and decreased oxygen release from maternal blood to fetal blood and from fetal blood to fetal tissues. Pregnant patients with CO-Hgb levels greater than 10% should be treated with HBOT.[2]

HBOT is administered at 2.5-3 ATA for periods of 60-100 minutes. Depending on patient presentation and response, 1-5 treatments are recommended.[4]

Previous
Next

Enhancement of Healing in Selected Problem Wounds

Normal wound healing proceeds through stages of hemostasis, removal of infectious agents, resolution of the inflammatory response, reestablishment of a connective tissue matrix, angiogenesis, and resurfacing. Problem (or chronic) wounds are those which do not proceed completely through this process because of any number of local and systemic host factors. For this reason, chronic wounds are often categorized as diabetic wounds, venous stasis ulcers, arterial ulcers, or pressure ulcers.

Wounds that fail to heal are typically hypoxic.[48] Multiple components of the wound healing process are affected by oxygen concentration or gradients, which explains why hyperbaric oxygen therapy (HBOT) may be an effective therapy to treat chronic wounds. Angiogenesis occurs in response to high oxygen concentration.[11] This is likely a multifactorial effect of HBOT. First, fibroblast proliferation and collagen synthesis are oxygen dependent,[12] and collagen is the foundational matrix for angiogenesis. In addition, HBOT likely stimulates growth factors involving angiogenesis and other mediators of the wound healing process.[49] Hyperbaric oxygen also has been shown to have direct and indirect antimicrobial activity. In particular, it increases intracellular leukocyte killing.[14, 15, 13]

Diabetic lower extremity ulcers have been the focus of most wound research in hyperbaric medicine, since the etiology of these wounds is multifactorial, and HBOT can address many of these factors. Several randomized controlled clinical trials have studied HBOT for the treatment of diabetic lower extremity wounds.[50, 51, 52, 53] Additionally, many more prospective, noncontrolled clinical trials and retrospective trials have been completed. Based on the body of evidence, major insurance carriers around the world now endorse the use of HBOT for the treatment of diabetic lower extremity wounds that show evidence of deep soft tissue infection, osteomyelitis, or gangrene. HBOT has been shown to reduce the amputation rate in patients with diabetic ulcers as well.[50, 51, 53]

In an effort to select patients appropriately for HBOT, various objective vascular evaluation methods have been used, including transcutaneous oximetry, capillary perfusion pressure, laser Doppler, and other types of vascular studies. Debate is ongoing regarding which method provides the most reliable data and whether these methods are more useful than other clinical markers of wound failure.

Note that HBOT should be used in conjunction with a complete wound healing care plan. As with all chronic wounds, other underlying host factors (eg, large vessel disease, glycemic control, nutrition, infection, presence of necrotic tissue, offloading) must be simultaneously addressed in order to have the highest chance of successful healing and functional capacity.

Because the goals of HBOT for wound healing include cellular proliferation and angiogenesis, HBOT is generally performed daily for a minimum of 30 treatments. Treatment is generally at 2 to 2.4 ATA for a total of 90 minutes of 100% oxygen breathing time. Based on the response to therapy, extended courses of therapy may be indicated.

Previous
Next

Compromised Skin Grafts and Flaps

Most skin grafts and flaps in normal hosts heal well. In patients with compromised circulation, this may not be the case. Patients with diabetes or vasculopathy from another etiology and patients who have irradiated tissue are particularly subject to flap or graft compromise. In these patients, hyperbaric oxygen therapy (HBOT) has been demonstrated to be useful. Unfortunately, if patients are not identified early, the initial flap or graft may be lost. Even in such cases, patients can significantly benefit from HBOT to prepare the wound bed for another graft or flap procedure. The procedure then has a higher chance of success following HBOT.

Over 30 animal studies have documented efficacy of HBOT in preserving both pedicled and free flaps in multiple models. These models looked at arterial, venous, and combined insults in addition to irradiated tissues. While improvement was observed regardless of the type of vascular defect, those with arterial insufficiency and radiation injury demonstrated the greatest improvement.

Human case studies documentng benefit of hyperbaric treatment for flap survival were first reported in 1966. A controlled clinical trial showing improved survival of split skin grafts followed shortly thereafter.[54] This was corroborated by a later clinical trial.[55] Additionally, evidence exists of benefit for flaps in post-irradiated tissue in human subjects.[56]

As the underlying pathophysiology of all compromised grafts and flaps is hypoxia, HBOT benefits patients by reducing the oxygen deficit. A unique mechanism of action of HBOT for preserving compromised flaps is the possibility of closing arteriovenous shunts.[57] Additionally, the same mechanisms of action that improve wound healing, namely, improved fibroblast and collagen synthesis[12] and angiogenesis,[11] also are likely to benefit a compromised graft or flap.

The current standard for HBOT to treat a compromised graft or flap includes twice daily treatment until the graft or flap appears viable and then once per day until completely healed. The initiation of HBOT should be expedited. In general, benefit should be seen by 20 treatments. If it is not, continuation of therapy should be reviewed. However, the cost of creating a complex flap is high, which makes HBOT cost-effective for this diagnosis. Of course, patients with compromised flaps need surgical attention to the arterial and venous supply, appropriate local management, and maximization of medical support.

Previous
Next

Crush Injury and Compartment Syndrome

Acute peripheral traumatic ischemia includes those injuries that are caused by trauma that leads to ischemia and edema; a gradient of injury exists. This category contains crush injuries as well as compartment syndrome. Crush injuries often result in poor outcome because of the body’s attempt to manage the primary injury. The body then develops more injury due to the reperfusion response. Injuries are graded using definite points on a severity scale. The commonly referenced system is the Gustilo classification,[58] but other classification scales are available.

The benefits of hyperbaric oxygen therapy (HBOT) for this indication include hyperoxygenation by increasing oxygen within the plasma. HBOT also induces a reduction in blood flow[59, 60] that allows capillaries to resorb extra fluid, resulting in decreased edema. As a gradient of oxygenation is based on blood flow, oxygen tissue tensions can be returned, allowing for the host defenses to properly function.[12] Animal studies suggest that a decreased neutrophil adherence to ischemic venules is observed with elevated oxygen pressures (2.5 ATA).[16, 17] Reperfusion injury is diminished, as HBOT generates scavengers to destroy oxygen radicals.[61]

Compartment syndrome also is a continuum of injury that occurs when compartment pressures exceed the capillary perfusion pressures. The extent to which the injury has affected tissues is unclear, even after surgical intervention.[62, 59, 63] HBOT is not recommended during the “suspected” stage of injury, when compartment syndrome is not yet present but may be impending. HBOT is beneficial during the impending stage, when objective signs are noted (pain, weakness, pain with passive stretch, tense compartment). With these signs, even if surgery is not elected because of compartment pressures or patient stability, HBOT is indicated. Once the patient has undergone fasciotomy, HBOT can be used to help decrease morbidity.[4]

HBOT should be started as soon as is feasible, ideally within 4-6 hours from time of injury. After emergent surgical intervention, the patient should undergo HBOT at 2-2.5 ATA for 60-90 minutes. For the next 2-3 days, perform HBOT 3 times daily, then twice daily for 2-3 days, and then daily for the next 2-3 days.[2]

Previous
Next

Necrotizing Soft Tissue Infections

These infections may be single aerobic or anaerobic but are more often mixed infections that often occur as a result of trauma, surgical wounds, or foreign bodies, including subcutaneous and muscular injection of contaminated street drugs. They are often seen in compromised hosts who have diabetes or a vasculopathy of another type. These infections are named based on their clinical presentation and include necrotizing fasciitis, clostridial and nonclostridial myonecrosis, and Fournier gangrene.

Regardless of the depth of the tissue invasion, these infections have similar pathophysiology that includes local tissue hypoxia, which is exacerbated by a secondary occlusive endarteritis.[64] Intravascular sequestration of leukocytes is common in these types of infections, mediated by toxins from specific organisms.[65] Clostridial theta toxin appears to be one such mediator. All of these factors together foster an environment for facultative organisms to continue to consume remaining oxygen, and this promotes growth of anaerobes.

The cornerstones of therapy are wide surgical debridement and aggressive antibiotic therapy. Hyperbaric oxygen therapy (HBOT) is used adjunctively with these measures, as it offers several mechanisms of action to control the infection and reduce tissue loss. First, HBOT is toxic to anaerobic bacteria.[66] Next, HBOT improves polymorphonuclear function and bacterial clearance.[13, 67] Based on results of work related to CO poisoning, HBOT may decrease neutrophil adherence based on inhibition of beta-2 integrin function.[18, 17] Further investigation is needed to see if this mechanism is at work in necrotizing infections as well. In the case of clostridial myonecrosis, HBOT can stop the production of the alpha toxin.[20, 68] Finally, limited evidence indicates that HBOT may facilitate antibiotic penetration or action in several classes of antibiotics, including aminoglycosides,[21] cephalosporins,[23] sulfonamides[22] and amphotericin.[24]

Multiple clinical studies suggest that HBOT is efficacious in the treatment of necrotizing soft tissue infections. These include case series, retrospective and prospective studies, and non-randomized clinical trials. They suggest significant reductions in mortality and morbidity. The reduction in mortality was remarkably similar in two studies: 34% (untreated) vs. 11.9% (treated) in one study;[69] 38% (untreated) vs. 12.5% (treated) in the other.[70] In another study,[71] the treated group had more patients with diabetes and more patients in shock and still had significantly less mortality (23%) than the untreated group (66%). Clinical studies involving patients with Fournier gangrene treated with HBOT bear similar results.

Initial HBOT is aggressively performed at least twice per day in coordination with surgical debridement. Typically, a treatment pressure ranging from 2.0-2.5 ATA is adequate. However, in the specific case of clostridial myonecrosis, 3 ATA is often used to ensure adequate tissue oxygen tensions to stop alpha toxin production. For the same reason, HBOT should be initiated as quickly as possible in this circumstance and performed 3 times in the first 24 h if at all feasible.

Intracranial abscess

The disorders considered in treatment of intracranial abscesses (ICA) include subdural and epidural empyema as well as cerebral abscess.[2] Studies from around the world have reviewed mortality from ICA with a resulting mortality of about 20%.[72] HBOT has multiple mechanisms that make it useful as an adjunctive therapy for ICA.

HBOT induces high oxygen tensions in tissue, which helps to prevent anaerobic bacterial growth, including organisms commonly found in ICA.[73, 74, 75, 76] HBOT can also help reduce increased intracranial pressure (ICP) and its effects are proposed to be more pronounced with perifocal brain swelling.[10, 77, 78] As discussed earlier, HBOT can enhance host immune systems and the treatment of osteomyelitis.[79] Candidates for adjunctive HBOT are patients who have multiple abscesses, who have an abscess that is in a deep or dominant location, whose immune systems are compromised, in whom surgery is contraindicated, who are poor candidates for surgery, and who exhibit inadequate response despite standard surgical and antibiotic treatment.[4]

HBOT is administered at 2.0-2.5 ATA for 60-90 minutes per treatment. HBOT may be 1-2 sessions per day. The optimized number of treatments has not been determined.[4]

Previous
Next

Delayed Radiation Injury

Radiation therapy causes acute, subacute, and delayed injuries. Acute and subacute injuries are generally self-limited. However, delayed injuries are often much more difficult to treat and may appear anywhere from 6 months to years after treatment. They generally are seen after a minimum dose of 6000 cGy. While uncommon, these injuries can cause devastating chronic debilitation to patients. Notably, they can be quiescent until an invasive procedure is performed in the radiation field. Injuries are generally divided into soft tissue versus hard tissue injury (osteoradionecrosis [ORN]).

While the exact mechanism of delayed radiation injury is still being elucidated, the generally accepted explanation is that an obliterative endarteritis and tissue hypoxia lead to secondary fibrosis.[80] Hyperbaric oxygen therapy (HBOT) was first used to treat ORN of the mandible. Based on the foundational clinical research of Marx,[81] multiple subsequent studies supported its use. The success of HBOT in treating ORN then led to its use in soft tissue radionecrosis as well.

Osteoradionecrosis

Marx demonstrated conclusively that ORN is primarily an avascular aseptic necrosis rather than the result of infection.[81] He developed a staging system for classifying and planning treatment,[82] which is largely accepted throughout the oromaxillofacial surgery community. See the following:

  • Stage I - Exposed alveolar bone: The patient receives 30 HBOT treatments and then is reassessed for bone exposure, granulation, and resorption of nonviable bone. If response is favorable, an additional 10 treatments may be considered.
  • Stage II - A patient who formerly was Stage I with incomplete response or failure to respond: Perform transoral sequestrectomy with primary wound closure followed by an additional 10 treatments.
  • Stage III - A patient who fails stage II or has an orocutaneous fistula, pathologic fracture, or resorption to the inferior border of the mandible: The patient receives 30 treatments, transcutaneous mandibular resection, wound closure, and mandibular fixation, followed by an additional 10 postoperative treatments.
  • Stage IIIR - Mandibular reconstruction 10 weeks after successful resolution of mandibular ORN: The patient receives 10 additional postoperative HBOT treatments.

The cornerstone of therapy is to begin and complete (if possible) HBOT prior to any surgical intervention and then to resume HBOT as soon as possible after surgery. Only in this way is adequate time allowed for angiogenesis to support postoperative healing. For patients with a history of significant radiation exposure, but no exposed bone, who require oral surgery, many practitioners suggest 20 HBOT treatments prior to surgery and 10 treatments immediately following surgery. Feldmeier has published an excellent review of this literature.[83]

Soft tissue radionecrosis

While soft tissue radionecrosis also is rare, it causes significant morbidity, depending on the site of injury. All of these injuries lead to significant local pain. Both radiation cystitis and radiation proctitis can result in severe blood loss with symptomatic anemia. Radiation cystitis may also cause obstructive uropathy secondary to fibrosis and blood clot formation. Radionecrosis of the neck and larynx can lead to dysphagia and respiratory obstruction. Irradiated skin develops painful, necrotic wounds that do not heal with standard wound healing care plans.

For each of these subpopulations of soft tissue radionecrosis, published case series and prospective, nonrandomized clinical trials corroborate one another, providing a degree of external validity. Larger studies are warranted. A national registry is currently being evaluated, from which more powerful conclusions may be forthcoming. Currently, the largest group of reported patients treated with HBOT for soft tissue radionecrosis are those with radiation cystitis. At least 15 publications, representing almost 200 patients, report a combined success rate in the 80% range. The two largest studies were published by Bevers[84] and Chong.[85]

HBOT and carcinogenesis

Practitioners and patients are often concerned that HBOT may foster recurrence of malignancy or promote the growth of an existing tumor. This is largely because of the known angiogenic effective of HBOT. Feldmeier has reviewed this subject extensively. Malignant angiogenesis appears to follow a different pathway than angiogenesis related to wound healing. His review of the literature suggests that the risk is low.[86]

Previous
Next

Refractory Osteomyelitis

Refractory osteomyelitis is defined as acute or chronic osteomyelitis that is not cured after appropriate interventions. More often than not, refractory osteomyelitis is seen in patients whose systems are compromised. This condition often results in nonhealing wounds, sinus tracts, and, in the worst case, more aggressive infections that require amputation.

Mader and Niinikoski showed that hyperbaric oxygen therapy (HBOT) is capable of elevating oxygen tension in infected bone to normal or above normal levels.[87, 13] Since polymorphonuclear (PMN) function requires adequate oxygen concentration, this is a significant mechanism by which HBOT helps to control osteomyelitis, as demonstrated by Mader in the same study.[13]

A unique mechanism by which HBOT is beneficial in osteomyelitis is in promoting osteoclast function. The resorption of necrotic bone by osteoclasts is oxygen-dependent. This has best been demonstrated in animal models of osteomyelitis.[88]

Additionally, as previously mentioned, HBOT facilitates the penetration or function of antibiotic drugs. Other properties of HBOT previously discussed, such as neovascularization and blunting the inflammatory response, likely provide additional benefit.

Convincing animal evidence supports the use of HBOT in the treatment of osteomyelitis. Clinical studies are somewhat problematic, however, because osteomyelitis has so many different presentations that comparisons become difficult. This is compounded by the small study sizes found in the literature. However, these observations do suggest benefit of HBOT for refractory osteomyelitis in humans.

One specific subset of osteomyelitis that merits special attention is malignant otitis externa. This progressive pseudomonal osteomyelitis of the ear canal can spread to the skull base and become fatal. Davis et al published a study of 17 patients with malignant otitis externa, all of whom demonstrated dramatic improvement with the addition of HBOT to standard surgical debridement and antibiotic therapy.[89]

Previous
Next

Thermal Burns

Thermal burns present a multifactorial tissue injury that culminates in a marked inflammatory response with vascular derangement from activated platelets and white cell adhesion with resultant edema, hypoxia, and vulnerability to severe infection. Poor white cell function caused by the local environment exacerbates this problem. Hyperbaric oxygen therapy (HBOT) addresses each of these pathophysiological derangements, and can, therefore, make a significant difference in patient outcomes. These mechanisms of action have been discussed above.

Multiple animal studies support the utility of HBOT for treatment of thermal burns. Human studies ranging from case series to randomized clinical trials have supported the potential benefit of HBOT in burn treatment. These include a small randomized study by Hart[90] that demonstrated improved healing and decreased mortality. Niezgoda[91] showed increased healing in a standardized human burn model. In a series of publications, Cianci[92, 93] suggests significant reduction in length of hospital stay, need for surgery, and cost.

Because of the goals of therapy, HBOT is begun as soon as possible after injury, with a goal of three treatments within the first 24 hours and then twice daily. Length of treatment depends on the clinical impairment of the patient and the extent of and response to grafting. Special attention must be given to fluid management and chamber and patient temperature to avoid undue physiologic stress to the patient as well as potential complications of treatment (ie, oxygen toxicity).

Previous
Next

Exceptional Anemia

Patients who develop exceptional anemia have lost significant oxygen carrying capacity in the blood. These patients become candidates for hyperbaric oxygen therapy (HBOT) when they are unable to receive blood products because of religious or medical reasons. The major oxygen carrier in human blood is hemoglobin, transporting 1.34 mL of oxygen per gram. Borema performed an experiment in the 1960s in which exsanguinated pigs (who had only plasma in their vasculature) were able to sustain life under hyperbaric conditions.[6]

The body generally uses 5-6 vol% (mL of O2 per 100 mL of blood);[94] under 3 ATA, 6 vol% of molecular oxygen can be dissolved into the plasma.[95] The CNS and cardiovascular systems are the two most oxygen-sensitive systems in the human body.[94, 96] Oxygen debt is one way of determining a patient’s need to start or continue HBOT. A cumulative oxygen debt is the time integral of the volume of oxygen consumption (VO2) measured during and after shock insult minus the baseline VO2 required during the same time interval.[4] Patients who have a debt >33 L/m2 do not survive, whereas patients with debts ≤9 usually recover.[2]

HBOT is administered at 2-3 ATA for periods of up to four hours per treatment. As many as 3-4 sessions a day may be necessary, depending on a patient’s clinical picture. Treatments should continue until the patient can receive blood products, no longer demonstrates end stage organ failure, or no longer has a calculated oxygen debt.[4]

Previous
Next

Central Retinal Artery Occlusion

Central retinal artery occlusion (CRAO) is a sudden, painless loss of vision caused by obstruction of the central retinal artery and, although infrequent, can cause permanent visual loss.[97, 98] CRAO is the most recently approved indication by the Undersea and Hyperbaric Medicine Society (UHMS) for HBOT.[99] CRAO is caused by the obstruction of the central retinal artery and, although an infrequent cause of visual loss,[97] leads to permanent visual loss. Current treatment for CRAO consists of attempts to lower intraocular pressure and movement of a potential embolus downstream, ocular massage, anterior chamber paracentesis, and medications (both eye drops and oral). Most modalities have proven inefficacious.[100]

A small study by Hertzog et al evaluated HBOT with CRAO. Patients were divided into groups based on time of onset of CRAO to HBOT. The study noted that HBOT was most useful in preserving vision if instituted within eight hours.[101] Another retrospective study published by Beiran compared patients from a facility where HBOT was available to a facility that did not have HBOT. The patients who received HBOT demonstrated visual improvement (82% HBOT vs 29.7% control).[102]

Patient selection for HBOT should meet the following criteria: < 24 hours of painless vision loss, no history of flashes or floaters prior to vision loss, visual acuity 20/200 or worse, even with pinhole testing, age >40 years, and no recent eye surgery or trauma.[99] Visual improvement has been reported even with delay of HBOT.[103]

HBOT is administered at two ATA on 100% oxygen. If no response is noted, pressure should be increased to 2.8 ATA. If vision is still not improved after 20 minutes, US Navy treatment Table 6 is indicated. If vision is improved, continue at treatment depth for 90 minutes bid. Continue daily bid compression until resulting in three days without visual improvement. If the patient responds to 100% oxygen via nonrebreather (NRB) mask itself, HBOT is not needed, and the patient should be maintained on surface 100% oxygen for 12 hours.[99]

Previous
Next

Idiopathic Sudden Sensorineural Hearing Loss

Sudden sensorineural hearing loss (SSHL) is a relatively rare cause of sensorineural hearing loss of at least 30 dB in three contiguous frequencies over three days. An associated common complaint in 90% of patients is tinnitus, usually unilateral.[104] Patients can also present with a sensation of fullness or a blocked ear[105] or vertigo.[106]

SSHL has many causes, but idiopathic SSHL still predominates. Numerous etiologies have been proposed with about as many treatments. SSHL is thought to be related to inner ear hypoxia because the cochlea requires a high O2 supply.[107] HBOT increases the partial pressure of oxygen (pO2) in the inner ear. A Cochrane Review concluded a significant mean improvement in patients treated with HBOT.[108]

Candidates for HBOT demonstrate significant SSHL within 14 days of onset. The patient should undergo evaluation that includes audiology and imaging studies. If no contraindications are noted, oral steroids are also recommended. HBOT should ensue at 1.5-2.5 ATA for 90 minutes daily for 15-20 treatments.[109]

Previous
Next

Complications and Special Concerns

As with any medical therapy, treatment brings both risks and benefits. One of the more frequently seen injuries caused by hyperbaric oxygen therapy (HBOT) is barotrauma (ie, injuries caused by pressure as a result of an inability to equalize pressure from an air-containing space and the surrounding environment).[2, 4]

Table 4. Complications to Hyperbaric Oxygen Therapy (Open Table in a new window)

Complication Presentation Treatment
Barotrauma
  Middle ear (URI, Eustachian tube dysfunction) Ear pain, fullness



Muffled hearing



Autoinflation technique



Pseudoephedrine/oxymetazoline



Tympanostomy tubes



Wait for URI resolution



Sinus Sinus pain or bleeding Oxymetazoline/pseudoephedrine



Antihistamines



Steroid nasal spray



Dental Tooth pain Replacement of filling or crown (allows trapped air bubble to escape)
Pulmonary Dry cough



Chest pain or burning



Decreased vital capacity



No breath-holding



Thoracostomy (if pneumothorax)



Increase decompression time



Round or oval window blowout Immediate deafness



Tinnitus



Nystagmus, vertigo, or both



Discontinue Valsalva



Refer to ENT



Visual refraction change
  Lens morphology Progressive myopia with prolonged number of treatments Most resolve spontaneously when treatment finished
Cataracts Clouding of vision Prescreen for existing cataracts



HBOT generally does not influence cataract formation, except after prolonged (>100) treatments



Oxygen toxicity
  CNS (Incidence 0.7 per 10,000 treatments at 2.4 ATA) Seizure Removal from oxygen source



Resume HBOT with shorter oxygen treatment periods



Does not require medication



Treat hypoglycemia if present



Treat fever if present



Pulmonary Dry cough



Chest pain or burning



Decreased vital capacity



Decrease total oxygen exposure time (including outside HBOT)

 

Pediatric considerations

Pediatric patients also have special concerns. The proportion of surface area to body mass is much greater in children than in adults. As temperature in the chamber can fluctuate, care must be taken to ensure the child remains warm without causing hyperthermia. This can be more difficult in a monoplace chamber because the patient cannot be physically reached from outside the chamber to provide blankets or warmed water as heat sources. Unless children can focus and equalize their ears, consideration for placement of tympanostomy tubes should be discussed with the parents to prevent middle ear barotrauma.

Oxygen administration is easy in a monoplace chamber because the chamber is pressurized with oxygen. Multiplace chambers can fashion equipment to fit the child. A neck ring can be fitted over the child’s torso, or, if the child is small enough, 2 hoods can be placed together to form a capsule around the child. Care must be taken when treating patients with ductal dependent lesions, as oxygen is a signal for ductus arteriosus closure. This has not been a documented problem in pregnancy. Bronchopulmonary dysplasia in a preterm infant, as is associated with mechanical ventilation and elevated oxygen tensions, can be accelerated with HBOT.[2]

Previous
Next

Potential New Indications for Hyperbaric Oxygen Therapy

Bisphosphonate-associated osteonecrosis

Bisphosphonates are used widely for the management of metastatic cancer in bone, osteoporosis, Paget disease of bone, and acute hypercalcemia. The exact mechanism of the pathophysiology that lead to osteonecrosis is unknown. However, bisphosphonates bind to bone and incorporate in the osseous matrix. During bone remodeling, they are taken up by osteoclasts, which induces cell death. They also inhibit osteoblast-mediated osteoclastic resorption and have antiangiogenic properties. As a result, bone turnover is suppressed; therefore, little physiologic remodeling occurs. The most vulnerable site appears to be the jaw.

No reliable treatment for this condition is currently available. Case studies using HBOT to treat bisphosphonate-associated osteonecrosis prompted a pilot study with favorable results. Therefore, a randomized clinical trial is currently underway to evaluate the efficacy of HBOT for this condition.[110]

Previous
 
Contributor Information and Disclosures
Author

Emi Latham, MD, FACEP, FAAEM Assistant Clinical Professor of Emergency Medicine, Hyperbaric Medicine Physician, University of California, San Diego, School of Medicine

Emi Latham, MD, FACEP, FAAEM is a member of the following medical societies: American Academy of Emergency Medicine, American College of Emergency Physicians, Undersea and Hyperbaric Medical Society, Wilderness Medical Society

Disclosure: Nothing to disclose.

Coauthor(s)

Michael Neumeister, MD, FRCSC, FACS Chairman, Professor, Division of Plastic Surgery, Director of Hand/Microsurgery Fellowship Program, Chief of Microsurgery and Research, Institute of Plastic and Reconstructive Surgery, Southern Illinois University School of Medicine

Michael Neumeister, MD, FRCSC, FACS is a member of the following medical societies: American Association for Hand Surgery, American Burn Association, American College of Surgeons, American Medical Association, American Society for Surgery of the Hand, American Society of Plastic Surgeons, American Society for Reconstructive Microsurgery, Canadian Society of Plastic Surgeons, Illinois State Medical Society, Illinois State Medical Society, Ontario Medical Association, Plastic Surgery Research Council, Royal College of Physicians and Surgeons of Canada, Society of University Surgeons, American Council of Academic Plastic Surgeons

Disclosure: Nothing to disclose.

Marc A Hare, MD Assistant Clinical Professor, Department of Emergency Medicine, University of California San Diego Medical Center; Medical Director, Center for Wound Healing and Hyperbaric Medicine, Paradise Valley Hospital

Marc A Hare, MD is a member of the following medical societies: American College of Emergency Physicians, Undersea and Hyperbaric Medical Society

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Chief Editor

Ryland P Byrd, Jr, MD Professor of Medicine, Division of Pulmonary Disease and Critical Care Medicine, James H Quillen College of Medicine, East Tennessee State University

Ryland P Byrd, Jr, MD is a member of the following medical societies: American College of Chest Physicians, American Thoracic Society

Disclosure: Nothing to disclose.

Additional Contributors

Erik D Schraga, MD Staff Physician, Department of Emergency Medicine, Mills-Peninsula Emergency Medical Associates

Disclosure: Nothing to disclose.

Acknowledgements

Multiplace hyperbaric chamber photos courtesy of OxyHeal Health Group, Inc.

Monoplace hyperbaric chamber photos courtesy of Sechrist Industries, Inc.

References
  1. Henshaw IN, Simpson A. Compressed Air as a Therapeutic Agent in the Treatment of Consumption, Asthma, Chronic Bronchitis and Other Diseases. 1857.

  2. Kindwall E, Whelan H. Hyperbaric Medicine Practice. 2nd ed. Flagstaff, AZ: Best Publishing Company; 2004. chap 1, 18, 19, 20, 25, 29, 30.

  3. Chin W, Jacoby L, Simon O, Talati N, Wegrzyn G, Jacoby R, et al. Hyperbaric programs in the United States: Locations and capabilities of treating decompression sickness, arterial gas embolisms, and acute carbon monoxide poisoning: survey results. Undersea Hyperb Med. 2016 Jan-Feb. 43 (1):29-43. [Medline].

  4. Feldmeier J. Hyperbaric Oxygen 2003: Indications and Results- The Hyperbaric Oxygen Therapy Committee Report. Kensington, Maryland: Undersea and Hyperbaric Medical Society, Inc.; 2003. chap 1, 2, 4, 5, 7, 8.

  5. Leslie CA, Sapico FL, Ginunas VJ, Adkins RH. Randomized controlled trial of topical hyperbaric oxygen for treatment of diabetic foot ulcers. Diabetes Care. 1988 Feb. 11(2):111-5. [Medline].

  6. Boerema I, et al. Life without blood. A study of the influence of high atmospheric pressure and hypothermia on dilution of the blood. J Cardiovascular Surg. 1960. 1:133-146.

  7. Bassett BE, Bennett PB. Introduction to the physical and physiological bases of hyperbaric therapy. Hunt TK, Davis JC. Hyperbaric Oxygen Therapy. Bethesda, MD: Undersea Medical Society; 1977. 11-24.

  8. Bird AD, Telfer AB. Effect of Hyperbaric Oxygen on Limb Circulation. Lancet. 1965 Feb 13. 1(7381):355-6. [Medline].

  9. Nylander G, Lewis D, Nordstrom H, et al. Reduction of postischemic edema with hyperbaric oxygen. Plast Reconstr Surg. 1985 Oct. 76(4):596-603. [Medline].

  10. Sukoff MH, Ragatz RE. Hyperbaric oxygenation for the treatment of acute cerebral edema. Neurosurgery. 1982 Jan. 10(1):29-38. [Medline].

  11. Knighton DR, Silver IA, Hunt TK. Regulation of wound-healing angiogenesis-effect of oxygen gradients and inspired oxygen concentration. Surgery. 1981 Aug. 90(2):262-70. [Medline].

  12. Hunt TK, Pai MP. The effect of varying ambient oxygen tensions on wound metabolism and collagen synthesis. Surg Gynecol Obstet. 1972 Oct. 135(4):561-7. [Medline].

  13. Mader JT, Brown GL, Guckian JC, et al. A mechanism for the amelioration by hyperbaric oxygen of experimental staphylococcal osteomyelitis in rabbits. J Infect Dis. 1980 Dec. 142(6):915-22. [Medline].

  14. Park MK, Myers RA, Marzella L. Oxygen tensions and infections: modulation of microbial growth, activity of antimicrobial agents, and immunologic responses. Clin Infect Dis. 1992 Mar. 14(3):720-40. [Medline].

  15. Mandell GL. Bactericidal activity of aerobic and anaerobic polymorphonuclear neutrophils. Infect Immun. 1974 Feb. 9(2):337-41. [Medline].

  16. Zamboni WA, Roth AC, Russell RC, et al. The effect of acute hyperbaric oxygen therapy on axial pattern skin flap survival when administered during and after total ischemia. J Reconstr Microsurg. 1989 Oct. 5(4):343-7; discussion 349-50. [Medline].

  17. Thom SR. Effects of hyperoxia on neutrophil adhesion. Undersea Hyperb Med. 2004 Spring. 31(1):123-31. [Medline].

  18. Thom SR. Functional inhibition of leukocyte B2 integrins by hyperbaric oxygen in carbon monoxide-mediated brain injury in rats. Toxicol Appl Pharmacol. 1993 Dec. 123(2):248-56. [Medline].

  19. Thom SR. Antagonism of carbon monoxide-mediated brain lipid peroxidation by hyperbaric oxygen. Toxicol Appl Pharmacol. 1990 Sep 1. 105(2):340-4. [Medline].

  20. Van Unnika. Inhibition of toxin Production in Clostridium Perfringens in Vitro by Hyperbaric Oxygen. Antonie Van Leeuwenhoek. 1965. 31:181-6. [Medline].

  21. Mirhij NJ, Roberts RJ, Myers MG. Effects of hypoxemia upon aminoglycoside serum pharmacokinetics in animals. Antimicrob Agents Chemother. 1978 Sep. 14(3):344-7. [Medline].

  22. Keck PE, Gottlieb SF, Conley J. Interaction of increased pressures of oxygen and sulfonamides on the in vitro and in vivo growth of pathogenic bacteria. Undersea Biomed Res. 1980 Jun. 7(2):95-106. [Medline].

  23. Mendel V, Reichert B, Simanowski HJ, et al. Therapy with hyperbaric oxygen and cefazolin for experimental osteomyelitis due to Staphylococcus aureus in rats. Undersea Hyperb Med. 1999 Fall. 26(3):169-74. [Medline].

  24. Muhvich KH, Anderson LH, Criswell DW, et al. Hyperbaric hyperoxia enhances the lethal effects of amphotericin B in Leishmania braziliensis panamensis. Undersea Hyperb Med. 1993 Dec. 20(4):321-8. [Medline].

  25. Harvey EN. Decompression sickness and bubble formation in blood and tissues. Bull NY Acad Med. 1945. 21:505-36.

  26. Brubakk A, Neuman T. Bennett and Elliott's Physiology and Medicine of Diving. 5th ed. Great Britain: Elsevier Science Limited; 2003. chap 10.

  27. Bove A. Bove and Davis' Diving Medicine. 4th ed. Elsevier Inc.; 2004. chap 8, 10.

  28. Neuman TS. Arterial gas embolism and decompression sickness. News Physiol Sci. 2002 Apr. 17:77-81. [Medline].

  29. Navy Department. Diving Medicine and Recompression Chamber Operations. US Navy Diving Manual. Rev 4. Washington DC: 1999. 5:

  30. Spencer MP. Decompression limits for compressed air determined by ultrasonically detected blood bubbles. J Appl Physiol. 1976 Feb. 40(2):229-35. [Medline].

  31. Butler BD, Hills BA. Transpulmonary passage of venous air emboli. J Appl Physiol. 1985 Aug. 59(2):543-7. [Medline].

  32. Abernathy CM, Dickinson TC. Massive air emboli from intravenous infusion pump: etiology and prevention. Am J Surg. 1979 Feb. 137(2):274-5. [Medline].

  33. Khan M, Schmidt DH, Bajwa T, Shalev Y. Coronary air embolism: incidence, severity, and suggested approaches to treatment. Cathet Cardiovasc Diagn. 1995 Dec. 36(4):313-8. [Medline].

  34. Michenfelder JD, Martin JT, Altenburg BM, et al. Air embolism during neurosurgery. An evaluation of right-atrial catheters for diagnosis and treatment. JAMA. 1969 May 26. 208(8):1353-8. [Medline].

  35. Fong J, Gadalla F, Gimbel AA. Precordial Doppler diagnosis of haemodynamically compromising air embolism during caesarean section. Can J Anaesth. 1990 Mar. 37(2):262-4. [Medline].

  36. Davies JM, Campbell LA. Fatal air embolism during dental implant surgery: a report of three cases. Can J Anaesth. 1990 Jan. 37(1):112-21. [Medline].

  37. Brown SD, Piantadosi CA. Recovery of energy metabolism in rat brain after carbon monoxide hypoxia. J Clin Invest. 1992 Feb. 89(2):666-72. [Medline].

  38. Thom SR, Taber RL, Mendiguren II, et al. Delayed neuropsychologic sequelae after carbon monoxide poisoning: prevention by treatment with hyperbaric oxygen. Ann Emerg Med. 1995 Apr. 25(4):474-80. [Medline].

  39. Goulon MA, Barios M, Rapin M, Mouilhat F, Grobuis S, Labrousse J. Intoxicationoxy carbonee at anoxie aique par inhalation de gay de charbon et d'hydrocarbures. (English Translation). J Hyperbaric Med. 1986. 1:23-41.

  40. Weaver LK, Hopkins RO, Chan KJ, et al. Hyperbaric oxygen for acute carbon monoxide poisoning. N Engl J Med. 2002 Oct 3. 347(14):1057-67. [Medline].

  41. Raphael JC, Elkharrat D, Jars-Guincestre MC, et al. Trial of normobaric and hyperbaric oxygen for acute carbon monoxide intoxication. Lancet. 1989 Aug 19. 2(8660):414-9. [Medline].

  42. Scheinkestel CD, Bailey M, Myles PS, et al. Hyperbaric or normobaric oxygen for acute carbon monoxide poisoning: a randomised controlled clinical trial. Med J Aust. 1999 Mar 1. 170(5):203-10. [Medline].

  43. Ducasse JL, Celsis P, Marc-Vergnes JP. Non-comatose patients with acute carbon monoxide poisoning: hyperbaric or normobaric oxygenation?. Undersea Hyperb Med. 1995 Mar. 22(1):9-15. [Medline].

  44. Grace TW, Platt FW. Subacute carbon monoxide poisoning. Another great imitator. JAMA. 1981 Oct 9. 246(15):1698-700. [Medline].

  45. Barret L, Danel V, Faure J. Carbon monoxide poisoning, a diagnosis frequently overlooked. J Toxicol Clin Toxicol. 1985. 23(4-6):309-13. [Medline].

  46. Garland H, Pearce J. Neurological complications of carbon monoxide poisoning. Q J Med. 1967 Oct. 36(144):445-55. [Medline].

  47. Winter PM, Miller JN. Carbon monoxide poisoning. JAMA. 1976 Sep 27. 236(13):1502. [Medline].

  48. Hunt TK, Twomey P, Zederfeldt B, et al. Respiratory gas tensions and pH in healing wounds. Am J Surg. 1967 Aug. 114(2):302-7. [Medline].

  49. Sheikh AY, Gibson JJ, Rollins MD, et al. Effect of hyperoxia on vascular endothelial growth factor levels in a wound model. Arch Surg. 2000 Nov. 135(11):1293-7. [Medline].

  50. Faglia E, Favales F, Aldeghi A, et al. Adjunctive systemic hyperbaric oxygen therapy in treatment of severe prevalently ischemic diabetic foot ulcer. A randomized study. Diabetes Care. 1996 Dec. 19(12):1338-43. [Medline].

  51. Doctor N, Pandya S, Supe A. Hyperbaric oxygen therapy in diabetic foot. J Postgrad Med. 1992 Jul-Sep. 38(3):112-4, 111. [Medline].

  52. Abidia A, Laden G, Kuhan G, et al. The role of hyperbaric oxygen therapy in ischaemic diabetic lower extremity ulcers: a double-blind randomised-controlled trial. Eur J Vasc Endovasc Surg. 2003 Jun. 25(6):513-8. [Medline].

  53. Kalani M, Jorneskog G, Naderi N, et al. Hyperbaric oxygen (HBO) therapy in treatment of diabetic foot ulcers. Long-term follow-up. J Diabetes Complications. 2002 Mar-Apr. 16(2):153-8. [Medline].

  54. Perrins DJ. Influence of hyperbaric oxygen on the survival of split skin grafts. Lancet. 1967 Apr 22. 1(7495):868-71. [Medline].

  55. Monies-Chass I, Hashmonai M, Hoere D, et al. Hyperbaric oxygen treatment as an adjuvant to reconstructive vascular surgery in trauma. Injury. 1977 May. 8(4):274-7. [Medline].

  56. Greenwood TW, Gilchrist AG. Hyperbaric oxygen and wound healing in post-irradiation head and neck surgery. Br J Surg. 1973 May. 60(5):394-7. [Medline].

  57. Reinisch JF. The pathophysiology of skin flap circulation. The delay phenomenon. Plast Reconstr Surg. 1974 Nov. 54(5):585-98. [Medline].

  58. Gustilo RB, Mendoza RM, Williams DN. Problems in the management of type III (severe) open fractures: a new classification of type III open fractures. J Trauma. 1984 Aug. 24(8):742-6. [Medline].

  59. Skyhar MJ, Hargens AR, Strauss MB, et al. Hyperbaric oxygen reduces edema and necrosis of skeletal muscle in compartment syndromes associated with hemorrhagic hypotension. J Bone Joint Surg Am. 1986 Oct. 68(8):1218-24. [Medline].

  60. Schraibman IG, Ledingham IM. Hyperbaric oxygen and local vasodilatation in peripheral vascular disease. Br J Surg. 1969 Apr. 56(4):295-9. [Medline].

  61. Illingworth CFW, Smith G, Lawson DD, et al. Surgical and physiological observations in an experimental pressure chamber. Br J Surg. 1961. 49:222-227.

  62. Bartlett RL. Stroman RT, Nickels M, et al. Rabbit model of the use of fasciotomy and hyperbaric oxygenation in the treatment of compartment syndrome. UHMS (Suppl.). 1998. 25:1095-1100.

  63. Strauss MB, Hargens AR, Gershuni DH, Hart GB, Akeson WH. Delayed use of hyperbaric oxygen for treatment of a model anterior compartment syndrome. J Orthop Res. 1996. 4:108-111.

  64. Sonoda A, Maekawa Y, Arao T, et al. Spontaneous gangrene of the scrotum and penis (Fournier's gangrene). J Dermatol. 1980 Oct. 7(5):371-5. [Medline].

  65. Stevens DL, Tweten RK, Awad MM, et al. Clostridial gas gangrene: evidence that alpha and theta toxins differentially modulate the immune response and induce acute tissue necrosis. J Infect Dis. 1997 Jul. 176(1):189-95. [Medline].

  66. Knighton DR, Halliday B, Hunt TK. Oxygen as an antibiotic. The effect of inspired oxygen on infection. Arch Surg. 1984 Feb. 119(2):199-204. [Medline].

  67. Knighton DR, Fiegel VD, Halverson T, et al. Oxygen as an antibiotic. The effect of inspired oxygen on bacterial clearance. Arch Surg. 1990 Jan. 125(1):97-100. [Medline].

  68. Kaye D. Effect of hyperbaric oxygen on Clostridia in vitro and in vivo. Proc Soc Exp Biol Med. 1967 Feb. 124(2):360-6. [Medline].

  69. Escobar SJ, Slade JB Jr, Hunt TK, et al. Adjuvant hyperbaric oxygen therapy (HBO2)for treatment of necrotizing fasciitis reduces mortality and amputation rate. Undersea Hyperb Med. 2005 Nov-Dec. 32(6):437-43. [Medline].

  70. Gozal D, Ziser A, Shupak A, et al. Necrotizing fasciitis. Arch Surg. 1986 Feb. 121(2):233-5. [Medline].

  71. Riseman JA, Zamboni WA, Curtis A, et al. Hyperbaric oxygen therapy for necrotizing fasciitis reduces mortality and the need for debridements. Surgery. 1990 Nov. 108(5):847-50. [Medline].

  72. Palmer JD. Neurosurgery 96. New York: Churchill Livingstone; 1996. 875-79.

  73. Alderson D, Strong AJ, Ingham HR, et al. Fifteen-year review of the mortality of brain abscess. Neurosurgery. 1981 Jan. 8(1):1-6. [Medline].

  74. Brook I. Bacteriology of intracranial abscess in children. J Neurosurg. 1981 Apr. 54(4):484-8. [Medline].

  75. Yang SY. Brain abscess: a review of 400 cases. J Neurosurg. 1981 Nov. 55(5):794-9. [Medline].

  76. Dohrmann PJ, Elrick WL. Observations on brain abscess. Review of 28 cases. Med J Aust. 1982 Jul 24. 2(2):81-3. [Medline].

  77. Miller JD, Fitch W, Ledingham IM, et al. The effect of hyperbaric oxygen on experimentally increased intracranial pressure. J Neurosurg. 1970 Sep. 33(3):287-96. [Medline].

  78. Moody RA, Mead CO, Ruamsuke S, et al. Therapeutic value of oxygen at normal and hyperbaric pressure in experimental head injury. J Neurosurg. 1970 Jan. 32(1):51-4. [Medline].

  79. Lampl L, Frey G, Bock KH. Hyperbaric oxygen in intracranial abscesses - update of a series of 13 patients. Undersea Biomed Res (Suppl.). 1992. 19:83.

  80. Rubin P. The Franz Buschke lecture: late effects of chemotherapy and radiation therapy: a new hypothesis. Int J Radiat Oncol Biol Phys. 1984 Jan. 10(1):5-34. [Medline].

  81. Marx RE. Osteoradionecrosis: a new concept of its pathophysiology. J Oral Maxillofac Surg. 1983 May. 41(5):283-8. [Medline].

  82. Marx RE. A new concept in the treatment of osteoradionecrosis. J Oral Maxillofac Surg. 1983 Jun. 41(6):351-7. [Medline].

  83. Feldmeier JJ, Hampson NB. A systematic review of the literature reporting the application of hyperbaric oxygen prevention and treatment of delayed radiation injuries: an evidence based approach. Undersea Hyperb Med. 2002 Spring. 29(1):4-30. [Medline].

  84. Bevers RF, Bakker DJ, Kurth KH. Hyperbaric oxygen treatment for haemorrhagic radiation cystitis. Lancet. 1995 Sep 23. 346(8978):803-5. [Medline].

  85. Chong KT, Hampson NB, Corman JM. Early hyperbaric oxygen therapy improves outcome for radiation-induced hemorrhagic cystitis. Urology. 2005 Apr. 65(4):649-53. [Medline].

  86. Feldmeier J, Carl U, Hartmann K, et al. Hyperbaric oxygen: does it promote growth or recurrence of malignancy?. Undersea Hyperb Med. 2003 Spring. 30(1):1-18. [Medline].

  87. Niinikoski J, Hunt TK. Oxygen tensions in healing bone. Surg Gynecol Obstet. 1972 May. 134(5):746-50. [Medline].

  88. Strauss MB, Malluche HH, Faugere MC. Effect of hyperbaric oxygen on bone resorption in rabbits. Seventh Annual Conference on Clinical Application of HBO. June 1982. Anaheim, California:8-18.

  89. Davis JC, Gates GA, Lerner C, et al. Adjuvant hyperbaric oxygen in malignant external otitis. Arch Otolaryngol Head Neck Surg. 1992 Jan. 118(1):89-93. [Medline].

  90. Hart GB, O'Reilly RR, Broussard ND, et al. Treatment of burns with hyperbaric oxygen. Surg Gynecol Obstet. 1974 Nov. 139(5):693-6. [Medline].

  91. Niezgoda JA, Cianci P, Folden BW, et al. The effect of hyperbaric oxygen therapy on a burn wound model in human volunteers. Plast Reconstr Surg. 1997 May. 99(6):1620-5. [Medline].

  92. Cianci P, Lueders HW, Lee H, et al. Adjunctive hyperbaric oxygen therapy reduces length of hospitalization in thermal burns. J Burn Care Rehabil. 1989 Sep-Oct. 10(5):432-5. [Medline].

  93. Cianci P, Williams C, Lueders H, et al. Adjunctive hyperbaric oxygen in the treatment of thermal burns. An economic analysis. J Burn Care Rehabil. 1990 Mar-Apr. 11(2):140-3. [Medline].

  94. Ketty SS, Schmidt CF. The effects of altered arterial tensions of carbon dioxide and oxygen on cerebral blood flow and cerebral oxygen consumption of normal young men. J Clin Investigation. 1978. 27:484-492.

  95. Lambertsen CJ, Kough RH, Cooper DY, et al. Oxygen toxicity; effects in man of oxygen inhalation at 1 and 3.5 atmospheres upon blood gas transport, cerebral circulation and cerebral metabolism. J Appl Physiol. 1953 Mar. 5(9):471-86. [Medline].

  96. Brozak J, Grande F. Body composition and basal metabolism in man correlation analysis versus physiologic approach. Human Biol. 1955. 27:22-31.

  97. Rumelt S, Brown GC. Update on treatment of retinal arterial occlusions. Curr Opin Ophthalmol. 2003 Jun. 14(3):139-41. [Medline].

  98. Canan H, Ulas B, Altan-Yaycioglu R. Hyperbaric oxygen therapy in combination with systemic treatment of sickle cell disease presenting as central retinal artery occlusion: a case report. J Med Case Rep. 2014 Nov 17. 8(1):370. [Medline]. [Full Text].

  99. Murphy-Lavoie H, Butler FK, Hagan CE. Hyperbaric oxygen therapy in the management of central retinal artery occlusion. Undersea and Hyperbaric Medicine Society. 2008.

  100. Hayreh SS, Zimmerman MB. Central retinal artery occlusion: visual outcome. Am J Ophthalmol. 2005 Sep. 140(3):376-91. [Medline].

  101. Hertzog LM, Meyer GW, Carson S, et al. Central retinal artery occlusion treated with hyperbaric oxygen. J Hyperbaric Medicine. 1992. 7:33-42.

  102. Beiran I, Goldenberg I, Adir Y, Tamir A, Shupak A, Miller B. Early hyperbaric oxygen therapy for retinal artery occlusion. Eur J Ophthalmol. 2001 Oct-Dec. 11(4):345-50. [Medline].

  103. Weiss JN. Hyperbaric oxygen treatment of nonacute central retinal artery occlusion. Undersea Hyperb Med. 2009 Nov-Dec. 36(6):401-5. [Medline].

  104. Fetterman BL, Luxford WM, Saunders JE. Sudden bilateral sensorineural hearing loss. Laryngoscope. 1996 Nov. 106(11):1347-50. [Medline].

  105. Stachler RJ, Chandrasekhar SS, Archer SM, et al. Clinical practice guideline: sudden hearing loss. Otolaryngol Head Neck Surg. 2012 Mar. 146(3 Suppl):S1-35. [Medline].

  106. Rambold H, Boenki J, Stritzke G, et al. Differential vestibular dysfunction in sudden unilateral hearing loss. Neurology. 2005 Jan 11. 64(1):148-51. [Medline].

  107. Murphy-Lavoie H, Piper S, Moon RE, Legros T. Hyperbaric oxygen therapy for idiopathic sudden sensorineural hearing loss. Undersea Hyperb Med. 2012 May-Jun. 39(3):777-92. [Medline].

  108. Bennett MH, Kertesz T, Perleth M, Yeung P, Lehm JP. Hyperbaric oxygen for idiopathic sudden sensorineural hearing loss and tinnitus. Cochrane Database Syst Rev. 2012 Oct 17. 10:CD004739. [Medline].

  109. Undersea and Hyperbaric Medical Society. Idiopathic Sudden Sensorineural Hearing Loss. UHMS.org. Available at http://membership.uhms.org/?page=ISSHL. Accessed: February 9, 2013.

  110. Al Hadi H, Smerdon GR, Fox SW. Hyperbaric oxygen therapy accelerates osteoblast differentiation and promotes bone formation. J Dent. 2014 Oct 23. [Medline].

 
Previous
Next
 
Rectangular hyperbaric chamber.
Interior of rectangular chamber.
Cylindrical multiplace chamber.
Monoplace chamber.
Table 1. Physiologic Mechanisms of Hyperbaric Oxygen Therapy
Mechanism References Clinical Application
Hyperoxygenationa Boerema I[6]



Bassett BE[7]



Bird AD[8]



DCS/AGE



CO poisoning



Central retinal artery occlusion



Crush injury/compartment syndrome



Compromised grafts and flaps



Severe blood loss anemia



Decrease gas bubble size Boyle law Air or gas embolism
Vasoconstrictionb Nylander G[9]



Sukoff MH[10]



Crush injury/compartment syndrome



Thermal burns



Angiogenesis Knighton DR[11] Problem wounds



Compromised grafts and flaps



Delayed radiation injury



Fibroblast proliferation/collagen synthesis Hunt TK[12] Problem wounds



Delayed radiation injury



Leukocyte oxidative killingc Mader JT[13]



Park MK[14]



Mandell GL[15]



Necrotizing soft tissue infections



Refractory osteomyelitis



Problem wounds



Reduces intravascular leukocyte adherence Zamboni WA[16]



Thom SR[17, 18]



Crush injury/compartment syndrome
Reduces lipid peroxidation Thom SR[19] CO poisoning



Crush injury/compartment syndrome



Toxin inhibition Van Unnik A[20] Clostridial myonecrosis
Antibiotic synergy Mirhij NJ[21]



Keck PE[22]



Mendel V[23]



Muhvich KH[24]



Necrotizing soft tissue infections



Refractory osteomyelitis



aMost oxygen carried in the blood is bound to hemoglobin, which is 97% saturated at standard pressure. Some oxygen, however, is carried in solution, and this portion is increased under hyperbaric conditions due to Henry's law. Tissues at rest extract 5-6 mL of oxygen per deciliter of blood, assuming normal perfusion. Administering 100% oxygen at normobaric pressure increases the amount of oxygen dissolved in the blood to 1.5 mL/dL; at 3 atmospheres, the dissolved-oxygen content is approximately 6 mL/dL, which is more than enough to meet resting cellular requirements without any contribution from hemoglobin. Because the oxygen is in solution, it can reach areas where red blood cells may not be able to pass and can also provide tissue oxygenation in the setting of impaired hemoglobin concentration or function.



bHyperoxia in normal tissues causes vasoconstriction, but this is compensated by increased plasma oxygen content and microvascular blood flow. This vasoconstrictive effect does, however, reduce posttraumatic tissue edema, which contributes to the treatment of crush injuries, compartment syndromes, and burns.



cHBOT increases the generation of oxygen free radicals, which oxidize proteins and membrane lipids, damage DNA, and inhibit bacterial metabolic functions. HBO is particularly effective against anaerobes and facilitates the oxygen-dependent peroxidase system by which leukocytes kill bacteria.



Table 2. Absolute Contraindications to Hyperbaric Oxygen Therapy
Absolute Contraindications Reason Contraindicated Necessary Conditions Prior to HBOT
Untreated pneumothorax Gas emboli



Tension pneumothorax



Pneumomediastinum



Thoracostomy
Bleomycin Interstitial pneumonitis No treatment for extended time from use of medication
Cisplatin Impaired wound healing No treatment for extended time from use of medication
Disulfiram Blocks superoxide dismutase, which is protective against oxygen toxicity Discontinue medication
Doxorubicin Cardiotoxicity Discontinue medication
Sulfamylon Impaired wound healing Discontinue and remove medication
Table 3. Relative Contraindications to Hyperbaric Oxygen Therapy
Relative Contraindications Reason Contraindicated Necessary Conditions Prior to HBOT
Asthma Air trapping upon ascent leading to pneumothorax Must be well controlled with medications
Claustrophobia Anxiety Treatment with benzodiazepines
Congenital spherocytosis Severe hemolysis None; HBOT for emergencies only
Chronic obstructive pulmonary disease (COPD) Loss of hypoxic drive to breathe Observation in chamber
Eustachian tube dysfunction Barotrauma to tympanic membrane Training, PE tubes
High fever Higher risk of seizures Provide antipyretic
Pacemakers or epidural pain pump Malfunction or deformation of device under pressure Ensure company has pressure-tested device and learn to what depth
Pregnancy Unknown effect on fetus (Previous studies from Russia suggest HBOT is safe.) None, but HBOT may be used in emergencies
Seizures May have lower seizure threshold Should be stable on medications; may be treated with benzodiazepines
Upper respiratory infection (URI) Barotrauma Resolution of symptoms or decongestants
Table 4. Complications to Hyperbaric Oxygen Therapy
Complication Presentation Treatment
Barotrauma
  Middle ear (URI, Eustachian tube dysfunction) Ear pain, fullness



Muffled hearing



Autoinflation technique



Pseudoephedrine/oxymetazoline



Tympanostomy tubes



Wait for URI resolution



Sinus Sinus pain or bleeding Oxymetazoline/pseudoephedrine



Antihistamines



Steroid nasal spray



Dental Tooth pain Replacement of filling or crown (allows trapped air bubble to escape)
Pulmonary Dry cough



Chest pain or burning



Decreased vital capacity



No breath-holding



Thoracostomy (if pneumothorax)



Increase decompression time



Round or oval window blowout Immediate deafness



Tinnitus



Nystagmus, vertigo, or both



Discontinue Valsalva



Refer to ENT



Visual refraction change
  Lens morphology Progressive myopia with prolonged number of treatments Most resolve spontaneously when treatment finished
Cataracts Clouding of vision Prescreen for existing cataracts



HBOT generally does not influence cataract formation, except after prolonged (>100) treatments



Oxygen toxicity
  CNS (Incidence 0.7 per 10,000 treatments at 2.4 ATA) Seizure Removal from oxygen source



Resume HBOT with shorter oxygen treatment periods



Does not require medication



Treat hypoglycemia if present



Treat fever if present



Pulmonary Dry cough



Chest pain or burning



Decreased vital capacity



Decrease total oxygen exposure time (including outside HBOT)
Previous
Next
 
 
 
 
 
All material on this website is protected by copyright, Copyright © 1994-2016 by WebMD LLC. This website also contains material copyrighted by 3rd parties.