Review of Hyperbaric Medicine

Because it works through multiple mechanisms of action, hyperbaric oxygen (HBO) therapy proves to be an excellent adjunctive therapy for a variety of medical and surgical disorders.

1. Introduction

Hyperbaric oxygen (HBO) is a high-dose oxygen inhalation therapy that is achieved by having the patient breathe 100% oxygen inside a pressurized hyperbaric chamber. The delivery of oxygen to the tissues is through respiration, because there is insufficient absorption of oxygen through the skin [1,2]. The principal source of oxygen transport is the red blood cell in the form of oxyhemoglobin (HbgO2). At normal sea-level pressure where alveolar oxygen pressure is at 100 mmHg, hemoglobin is ~97% saturated and yields an oxygen content of ~19.8 ml oxygen/dl blood. When alveolar oxygen pressure is at 200 mmHg, hemoglobin becomes fully saturated with oxygen. After hemoglobin is fully saturated, additional oxygen is carried to the tissues in the physical solution in plasma. HBO does not significantly increase hemoglobins transport of oxygen, but it does elevate the capillary plasma oxygen transport [3,4]. The benefits of HBO are derived from both the physiological and pharmacological effects of high-dose oxygen. HBO is based on two physical factors related to the hyperbaric environment:mechanical effects of pressure and increased oxygenation of tissues. This paper reviews scientific and clinical literature regarding HBO therapy in lab animals and humans and introduces the potential use of this treatment modality for our equine patient.

2. History of Hyperbaric Chambers

In 1662, a British clergyman named Henshaw, without scientific basis, thought it would be a good idea to raise the ambient pressure around a patient for therapeutic purposes. He later built the "domicilium," which was a sealed chamber that could either raise or lower pressure depending on the adjustment of the valves. Henshaw reported that acute diseases of all kinds would respond to increased ambient pressure. In the 19th century, following Henshaw's ideology, pneumatic institutes began to spread around the European continent. These large chambers were often able to accommodate more than one person and could sustain pressures of ≥2 atmospheres (ATM). These pneumatic institutes started to rival the popularity of the mineral-water spas [5].

It was not until 1879 that semi-scientific efforts where made in regards to the air. A French surgeon named Fontaine built a mobile operating room on wheels that could be pressurized. He performed over 20 surgeries in the unit using nitric oxide as the anesthetic. Dr. Fontaine noted that he could achieve deep surgical anesthesia, because the pressurized room increased the effective percentage of nitrous oxide in the patient's body and was accompanied by a higher oxygen partial pressure (i.e., compressed air at two atmospheres given an effective level of 42% inhaled oxygen). Dr. Fontaine also noted that hernias were seen to reduce more easily (Boyle's law or pressure volume relationship) and that the patients were not their normal cyanotic color when coming out of anesthesia [5].

Compressed air therapy was first introduced in the United States in 1871 by Dr. J. L. Corning, and he was the first to operate his compressor with electric power. In the early 1900s, Dr. Orville Cunningham, a professor of anesthesia at the University of Kansas, noted that patients with heart disease and other circulatory disorders had difficulties acclimating at high altitudes compared with sea level. Using these observations, Dr. Cunningham postulated that increased atmospheric pressure would be beneficial for his patients with heart disease. In 1918, he tested his hypothesis by placing a young resident physician suffering from the flu into a chamber used for animal studies. The physician was successfully oxygenated during his hypoxic crisis when compressed to 2 ATM. Dr. Cunningham, realizing that his concepts were sound, built a 88-ft-long chamber that was 10 ft in diameter. He began treating a multitude of diseases, most of them without scientific rationale [5]. The American Medical Association (AMA) and the Cleveland Medical Society, failing to receive any scientific evidence for his rationale, forced him to close his facility in 1930.

The advent of the use of HBO in modern clinical medicine began in 1955 with the work of Churchill-Davis, who helped to attenuate the effects of radiation therapy in cancer patients using high-oxygen environments. That same year, Dr. Ite Boerma, a professor of surgery at the University of Amsterdam in Holland, proposed using HBO in cardiac surgery to help prolong the patient's tolerance to circulatory arrest. He conducted surgical operations under pressure, including surgical corrections of transposition of the great vessels, tetralogy of fallot, and pulmonic stenosis. In 1960, Boerma et al [6] published a study called "Life Without Blood". For the study, the erythrocytes of pigs were removed from their exsanguinated blood, and there was sufficient oxygen in the plasma to sustain life when they where given HBO at 3 ATM.

It has frequently been said that the history of HBO goes back over 300 yr, which probably refers to the work of Henshaw. This is incorrect, because oxygen was not discovered until 1775 by Priestly. All the early chambers were pressurized with compressed air, and oxygen was not a consideration. Clinical HBO goes back only ~50 yr, beginning with the work of Churchill-Davidson and Boerma [5].

In 1967, the Undersea Medical Society (UMS) was founded by six U. S. Navy Diving and Submarine medical officers as an organization dedicated to diving and undersea medicine. The UMS was later renamed the Undersea and Hyperbaric Medical Society (UHMS) in 1986. This professional society was established for those practicing hyperbaric medicine or diving medicine. They are responsible for publishing approved indications for HBO treatments.

The American Board of Preventative Medicine offered board certification in undersea and hyperbaric medicine in 1999, and this program was later co-sponsored by the American Board of Emergency Medicine in 2001. The National Board on Diving and Hyperbaric Medical Technology offered board certification in hyperbaric technology starting in 1991 and hyperbaric nursing starting in 1995.

There are currently numerous fellowships available in the United States in clinical hyperbaric medicine.

3. Physiological Effects

Pressure of gases is defined as a force per unit area. The pressure of 1 ATM is equal to 14.7 lb/in2 (PSI). This pressure results from the weight of the air producing a force on the surface of the earth. Weathermen usually refer to this pressure as "barometric pressure," which is measured in mercury in (29.9 in Hg = 76 mm Hg = 1 ATM). The term "atmospheres" refers to atmospheres absolute. Absolute pressure equals the gauge pressure plus the ambient air pressure on the surface at sea level (i.e., 1 ATM). For example, if one descends 33 ft in sea water (FSW), one is at an absolute pressure of 2 ATM (33 ft is equal to a gauge pressure of 14.7 PSI as read on the gauge). Absolute pressure equals gauge pressure plus atmospheric pressure (i.e., 1 ATM + 1 ATM = 2 ATM) [7].

Terms applicable to hyperbaric exposures [8]:

• Surface: The normal atmospheric pressure from which a hyperbaric exposure begins (i.e., ground level or sea level).
• Dive: Any exposure to hyperbaric pressure, either in water or in a chamber.
• Descent: An increase in pressure, either by going underwater or by adding pressure to a chamber. May be referred to as compression.
• Depth: The maximum pressure achieved during a hyperbaric exposure. Typically measured in ATA, FSW, or PSI; may also be referred to as treatment pressure.
• Ascend: Decrease in pressure. May be referred to as decompression gas laws.
• Boyle's Law (Table 1): Pressure-volume relationship. With pressure constant, the volume of gas is inversely proportional to the pressure (P1/P2 = V2/V1). When a chamber is pressurized, the volume of gas in enclosed body areas such as the ears, sinuses, lungs, gastrointestinal tract etc. respond to increased pressure by contracting. Doubling the pressure reduces the gas volume to about one-half, and tripling the pressure reduces it by one-third.
• Dalton's Law: The total pressure exerted by a mixture of gases is equal to the sum of the pressure of each of the different gases making up the mixture (PO2 = Ptot × FiO2), where FiO2 is the fractional concentration of oxygen expressed as a decimal. Using Dalton's law, one can determine the PO2 in mm Hg in the chamber while breathing 100% oxygen at 66 FSW (66 FSW = 3 absolute ATM).
          PO2 = Ptot × FiO2
          PO2 = 760(3) × 1.0
          PO2 = 2280 mm Hg
• Henry's Law: Gas in solution. The amount of gas dissolved in a liquid is directly proportional to the partial pressure of the dissolved gas (P1/P2 = A1/A2). If a carbonated drink contains 20 ml of dissolved gas at 2 ATA, one can determine how much gas remains in solution when the beverage reaches sea level.
          (P1)/(P2)=(A1)/(A2)
          (2)/(1)=(20)/(A2)
          2A2 = 20
          A2 = 10 ml

Mechanical Effects

Bubbles and gas-containing cavities within the body are subject to the mechanical effects of changing pressure that follows Boyle's law. Volume is changed in a geometric progression related to pressure change; large reductions take place near the surface, with subsequent reductions becoming smaller at higher pressure (Table 1). These mechanical effects are responsible for unwanted barotraumas that may result in middle-ear squeeze, sinus squeeze, and burst of lung if the patient holds their breath during decompression. If a patient is suffering from gaseous distention of the bowel, compression in the chamber will ease the discomfort, while the inhalation of oxygen will form a high gradient for the removal of nitrogen from the distended gut. Gas trapped in the bowel decreases by ~50% when a patient breathes oxygen over a 6-h period at 2 ATM [3,9,10].

Oxygen Solubility

As chamber pressure increases, PO2 in the breathing media also increases. Using Dalton's law, air, at sea level pressure (760 mm Hg), contains 21% oxygen with a PO2 of 160 mm Hg. When the chamber is pressurized with air to 3 ATM, PO2 is 479 mm Hg, which is the equivalent of breathing 63% oxygen at sea level. As the chamber is pressurized with air to 5 ATM, PO2 exceeds 798 mm Hg, which is greater oxygen pressure than can be attained breathing 100% oxygen at sea level!

Oxygen is transported by the blood from the lungs into the tissue by two methods:either by binding to hemoglobin or by physically dissolving in the plasma. At normal sea level pressure, where alveolar oxygen pressure is ~100 mmHg, hemoglobin is already 97% saturated (oxyhemoglobin) and yields an oxygen content of ~19.8 ml oxygen/dl blood. When alveolar oxygen partial pressure (PAO2) reaches 200 mm Hg, hemoglobin then becomes fully saturated with oxygen. Therefore, further increases in pressure will not increase the amount of oxyhemoglobin. Thus, oxygen transport through the hemoglobin is not improved with HBO therapy. Instead, oxygen is dissolved into the plasma and carried to the tissues in physical solution. A person breathing air at sea level pressure has only 1.5% of the oxygen carried in the blood physically dissolved in plasma. Oxygen transport by plasma is the key to HBO therapy, because even poorly perfused tissue can receive oxygen as the hyperoxygenated plasma seeps across it [4]. As the chamber is pressurized, the lung's elevated alveolar oxygen tension drives oxygen into the plasma of the pulmonary circulation or it is subsequently transported throughout the body. Unlike hemoglobin saturation, which has an S-shaped curve, the amount of dissolved oxygen increases linearly as PO2 increases [4].

Oxygen solubility is defined by Henry's law, which looks at the relative quantity of gas entering solution as related to the PAO2. However, it does not define the absolute amount of gas in solution. The absolute amount varies with different fluids and is determined by the solubility coefficient of gas in fluids, which is temperature dependent. Oxygen solubility in whole blood at 37°C is 0.0031 ml oxygen/dl blood/mm Hg PAO2. Breathing air at sea level, arterial oxygen tension is ~100 mmHg; therefore, the blood carries ~0.31 ml dissolved oxygen/dl whole blood. When breathing 100% oxygen at sea level, the amount of dissolved oxygen increases to ~2.1 ml O2/dl blood. Breathing 100% oxygen at 2 ATA results in a PAO2 of 1433 mm Hg or 4.4 ml dissolved oxygen/dl blood. At 3 ATA, 100% oxygen provides a PAO2 of ~2200 mm Hg and adds ~6.8 ml oxygen/dl blood. A healthy adult human at rest uses ~6 ml oxygen/dl circulating blood. Thus, HBO at 3 ATM provides sufficient plasma oxygen to exceed the body's total metabolic requirement. The dissolved content of 6 ml oxygen/dl blood is equivalent to the sea level oxygen capacity of 5 g of hemoglobin. This phenomenon is the reason Boerma et al [4,6] was able to sustain a pig's life without blood.

Gas Exchange and Oxygen Diffusion

The increase in oxygen tension causes oxygen to diffuse farther from the functioning capillaries. Tissue oxygen content depends on three factors:

1. Distance from the functioning capillaries
2. Oxygen demand of the tissue
3. The oxygen tension of the capillary

Using the Krogh Erlang mathematical model, oxygen in air breathed at 1 ATM diffuses ~64 µm (about the thickness of one sheet of typing paper) at the arterial end of the capillary. During oxygen breathing at 3 ATM, oxygen diffuses ~250 µm (about the thickness of three sheets of typing paper) [4,11-13]. In a hypoxic environment, HBO may be able to restore PO2 to normal or slightly elevated levels (depending on the severity of the injury). It enhances epithelization, collagen deposition, fibroplasia, angiogenesis, and bacterial killing. In the presence of tissue hypoxia, some or all of these processes are impaired. Human fibroblasts can survive in 3 mm Hg but cannot migrate in <10 mm Hg. Additionally, they do not divide in <22 mm Hg and do not form collagen in <28 mm Hg. Interestingly, it has been reported that if oxygen tension is held continuously at 290 - 560 mm Hg, fibroblastic replication is halted [4]. When oxygen tension is returned to normal, the replication process continues. Therefore, daily high doses are needed to correct the hypoxic environment, but they must also be delivered in an intermittent pattern to avoid possible side effects on the cells.

Therapeutic Effects of HBO

1. Reverses hypoxia [14]
2. Alters ischemic effect [15]
3. Influences vascular reactivity
4. Reduces edema [16,17]                 

1. Hyperoxygenation will cause vasoconstriction. Although vasoconstriction may be present, there is more oxygen delivered to the tissues.

5. Modulates nitric oxide production [4,18,19]                 

1. An increase of nitric oxide (NO) leads to vasodilation, whereas a decrease of NO leads to vasoconstriction. Carbon dioxide increases NO production, and oxygen decreases NO production by the endothelial cells.

6. Modifies growth factors and cytokine effects by regulating their levels and/or receptors [20,21]         

1. Vascular endothelial growth factor (VEGF) is important for the growth and survival of endothelial cells, and it is found in plasma, serum, and wound exudates. Under normobaric conditions, VEGF is stimulated by hypoxia, lactate, NO, and nicotinamide adenine dinucleotide (NAD). HBO induces production of VEGF, thereby stimulating more rapid development of capillary budding and granulation formation within the wound bed.

7. Induces changes in membrane proteins that affect ion exchange and gaiting mechanisms
8. Promotes cellular proliferation [2,4,11-13]
9. Accelerates collagen deposition
10. Stimulates capillary budding and arborization
11. Accelerates microbial oxidative killing
12. Improves select antibiotic exchange across membranes [22-24]                 

1. Anoxia decreases the activity of several antibiotics (aminoglycosides, sulfonamides, fluoroquinolone). By raising the PO2 of ischemic tissue to normoxic levels, the activity of these antimicrobials may normalize. In addition, HBO may stimulate the activity of certain antimicrobials by inhibiting biosynthetic reactions in bacteria.

13. Interferes with bacterial disease propagation by denaturing toxins
14. Modulates the immune system response
15. Enhances oxygen radical scavengers, thereby decreasing ischemia-reperfusion injury [25,26].         

1. HBO therapy increases the amount and activity of the free-radical scavenger superoxide dismutase
2. Decreased neutrophil adhesion and subsequent release of free radicals is an important early event leading to endothelial damage and microcirculatory failure associated with ischemia reperfusion (I-R) injury. HBO reversibly inhibits the β2 integrins, which also inhibits the neutrophil-endothelial adhesion.

Complications and Side Effects

Although any therapeutic application of HBO is intrinsically associated with the potential for producing mild to severe side effects, the appropriate use of hyperoxia is one of the safest therapeutics available to the practitioner [27]. CNS oxygen toxicity can occur at levels of 3 ATM for 1 - 2 h. Signs in humans include convulsions, nausea, dizziness, muscle twitching, anxiety, and confusion. Pulmonary oxygen toxicity is usually associated with prolonged exposure to HBO. Onset of symptoms has been noted to occur after 4 - 6 h at 2 ATM. Symptoms include dyspnea, shortness of breath, chest tightness, and difficulties inhaling a deep breath. Possible causes for pulmonary toxicity include thickening of the alveolar membrane and pulmonary surfactant changes. Prevention of side effects includes removal from the oxygen source when first signs occur and not using 100% oxygen at pressures of >3 ATM.

Contraindications for HBO therapy are unknown for horses but may include untreated pneumothorax, high fevers (pre-disposition to oxygen toxicity), emphysema, upper airway occlusions, and thoracic surgery.

Accepted Indications for HBO Therapy in Humans

1. Air or gas embolism
2. Carbon monoxide poisoning
3. Clostridial myositis and myonecrosis
4. Crush injury, compartment syndrome, and other acute ischemias
5. Decompression sickness
6. Enhancement of healing in selected wounds
7. Exceptional anemia
8. Intracranial abscess
9. Necrotizing soft-tissue infections
10. Refractory osteomyelitis
11. Delayed radiation injury (soft-tissue and bony necrosis)
12. Skin grafts and flaps
13. Thermal burns

The use of HBO in veterinary medicine is in its infancy. Our clinic has currently treated >100 patients in our HBO chamber. Patients included pregnant animals as well as neonatal foals, and no adverse effects were noted. Patients have been pressurized from 2 to 3 ATM for times ranging from 60 to 90 min at treatment pressure (depth). We have treated horses with the following ailments and had promising results:

• Exceptional blood-loss anemias (neonatal isoerythrolysis)
• Fungal disease (fungal pneumonia)
• Thermal burns, carbon monoxide poisoning, smoke inhalation
• Closed head injuries
• Ileus
• CNS edema/perinatal asphyxia
• Peripheral neuropathies
• Sports injuries (exertional rhabdomyolysis)
• Fracture non-union
• Cellulitis, compartment syndrome
• Ischemic injuries (laminitis)

In carefully selected patients, the addition of HBO therapy to standard measures may improve clinical outcomes. Further research is needed in the field of equine HBO medicine.