ABSTRACT
Hyperbaric oxygen (HBO) therapy appears to be a promising adjunctive medication for a variety of equine disorders, including laminitis and other ischemic injuries. Hyperbaric oxygen is a high-dose oxygen inhalation therapy that is achieved by having the patient breathe 100 percent 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. 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.
The use of HBO by veterinary medical hospitals is in its infancy. Our clinic has conducted > 7,500 dives in our hyperbaric oxygen chamber. Patients included pregnant animals and neonatal foals, with no adverse effects noted. Patients have been pressurized from 1.5 to 3 ATA ranging from 45-90 minutes at treatment pressure (depth). Hagyard Equine Medical Institute has used HBO as adjunctive therapy for fungal disease (fungal pneumonia), thermal burns, carbon monoxide, smoke inhalation, closed head injuries, ileus, CNS edema/perinatal asphyxia, peripheral neuropathies, sports injuries (exertional rhabdomyolysis), cellulitis, compartment syndrome, and 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.
Hyperbaric oxygen (HBO) is a high-dose oxygen inhalation therapy that is achieved by having the patient breathe 100 percent 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.
The principal source of oxygen transport is the red blood cell in the form of oxyhemoglobin (Hbg02). At normal sea level pressure, where alveolar oxygen pressure is at 100 mmHg, hemoglobin is about 97% saturated and yields an oxygen content of about 19.8 mL of oxygen per dL of 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 a physical solution in plasma. HBO does not significantly increase hemoglobin’s transport of oxygen, but it elevates the capillary plasma oxygen transport. 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 hyperbaric oxygen therapy in lab animals and humans and introduces to the practitioner the potential use of this treatment modality for our equine patient.
HISTORY OF HYPERBARIC CHAMBERS
In 1662, a British clergyman named Henshaw, without scientific basis, thought it would be a clever 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 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 sprawl around the European continent. These large chambers were often able to accommodate more than one person and could sustain pressures of two or more atmospheres. These pneumatic institutes began to rival the popularity of the mineral water spas.
It was not until 1879 that semi-scientific efforts were made regarding 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 anesthetic. Dr. Fontaine noted that he could achieve deep surgical anesthesia because it increased the effective percentage of nitrous oxide in the patient’s body 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: pressure-volume relationship) and the patients were not their normal cyanotic color when coming out of anesthesia. Compressed air therapy was first introduced into the United States in 1871 by Dr. J.L. Corning. In the early 1900’s 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 when compared to sea level. With these observations, Dr. Cunningham postulated that increased atmospheric pressure would be beneficial for patients with heart disease. In 1918, he placed a young resident physician suffering from the flu into a chamber used for animal studies to test his hypothesis. The physician was successfully oxygenated during his hypoxic crisis when compressed to 2 ATM. Dr. Cunningham, realizing that his concepts were sound, built an 88-foot-long chamber, 10 feet in diameter, in Kansas City and began treating a multitude of diseases, most of them without scientific rationale. The 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 hyperbaric oxygen in modern clinical medicine began in 1955 with the work of Churchill-Davis, who helped attenuate 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 hyperbaric oxygen (HBO) in cardiac surgery to help prolong the patients’ 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, Dr. Boerma published a study on “life without blood”. The study involved exsanguinating pigs and removing their erythrocytes before exposing them to 3 ATM of HBO. These pigs were noted to have sufficient oxygen in the plasma to sustain life when they were given HBO at 3 ATA.
It has frequently been said that the history of “hyperbaric oxygenation” goes back “over 300 years” referring to the work of Henshaw. This is incorrect, as oxygen was not discovered until 1775 by Priestly. All the early chambers were pressurized with compressed air, and oxygen was not a consideration. Clinical hyperbaric oxygen goes back only about 50 years, beginning with the work of Churchill-Davidson and Boerma.
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 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 Preventive Medicine started to offer board certification in Undersea and Hyperbaric Medicine in 1999, which 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 in 1991, and for hyperbaric nursing in 1995.
There are currently numerous human fellowships available in the United States in Clinical Hyperbaric Medicine.
PHYSIOLOGICAL EFFECTS
Pressure of gases is defined as a force per unit area. The pressure of one atmosphere (ATM) is equal to 14.7 pounds per square inch (PSI). This pressure results from the air’s weight producing a force on the Earth’s surface. Weather forecasters usually refer to this pressure as “barometric pressure” which is measured in inches of mercury (29.9 inches of mercury = 760 mm mercury = 1 atmosphere). The term “atmospheres” when used refers to absolute atmospheres. 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 feet in seawater (FSW), one is at an absolute pressure of 2 ATM. This is exampled by the fact that 33 feet is equal to a gauge pressure of 14.7 pounds per square inch as read on the gauge. Absolute pressure equals gauge pressure plus atmospheric pressure (i.e., 1 ATM + 1 ATM = 2 ATM).
Terms applicable to Hyperbaric exposures:
1) Surface: The normal atmospheric pressure from which a hyperbaric exposure begins. (IE: Ground level or sea level)
2) Dive: Any exposure to hyperbaric pressure, either in water or in a chamber.
3) Descent: Increase pressure, either by going down under water or by adding pressure to a chamber. May be referred to as compression.
4) Depth: The maximum pressure achieved during a hyperbaric exposure. Typically measured in ATA, feet of sea water (fsw) or pounds per square inch (PSI) Also referred as treatment pressure.
5) 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 increase pressure by contracting. Doubling the pressure reduces the gas volume to about half and tripling the pressure reduces it by a third.
Dalton’s Law: Total pressure exerted by a mixture of gases is equal to the sum of the pressures of each of the different gases making up the mixture (PO2=Ptot X FiO2) . Where Fi02 is the fractional concentration of oxygen expressed as a decimal, using Dalton’s Law we would be able to determine the PO2 in mmHg in the chamber while breathing 100% oxygen at 66 fsw. 66 fsw = 3 absolute atmospheres PO2=Ptot X FiO2 PO2=760(3) X 1.0 PO2=2280 mmHg.
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). To help illustrate Henry’s law think about a carbonated drink containing 20cc of dissolved gas at 2 ATA, How much gas remains in solution when the beverage reaches sea level? P1/P2=A1/A2 2/1=20/A2 2A2=20 A2= 10cc.
MECHANICAL EFFECTS
Bubbles and gas-containing cavities within the body are subject to the mechanical effects of changing pressure, which 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 a middle-ear squeeze, a sinus squeeze, and a burst of the 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 approximately 50% when a patient breathes oxygen over a 6-hour period at 2 ATM.
OXYGEN SOLUBILITY
As chamber pressure increases, PO2 in the breathing media also increases. For instance, using Dalton’s Law, air at sea level pressure (760mmHg) contains 21% oxygen with a PO2 of 160 mmHg. When the chamber is pressurized with air to 3 ATA PO2 is 479 mmHg, which is equivalent of breathing 63% oxygen at sea level. As the chamber is pressurized with air to 5 ATA, PO2 exceeds 798 mmHg, 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: bound to hemoglobin and physically dissolved in the plasma. At normal sea level pressure where alveolar oxygen pressure is about 100 mmHg, hemoglobin is already 97% saturated (Oxyhemoglobin) and yields an oxygen content of about 19.8 mL of oxygen per dL of blood. When PAO2 (alveolar oxygen partial pressure) reaches 200 mmHg, hemoglobin then becomes fully saturated with oxygen. Therefore, further increases in pressure will not increase the amount of oxyhemoglobin, thus oxygen transport via hemoglobin is not improved with hyperbaric oxygen therapy.
Instead oxygen is dissolved into the plasma and carried to the tissues in a physical solution. A person breathing air at sea-level pressure has only 1.5% of the oxygen physically dissolved in plasma. Oxygen transport by plasma is the key to hyperbaric oxygen therapy, for even poorly perfused tissue can receive oxygen as the hyperoxygenated plasma seeps across it. As the chamber is pressurized, the elevated alveolar oxygen tension in the lungs drives oxygen into the plasma of the pulmonary circulation and its subsequent transport throughout the body. Unlike hemoglobin saturation, which has an S-shaped curve, the amount of dissolved oxygen increases linearly as PO2 increases.
Oxygen solubility is defined by Henry’s Law, which looks at the relative quantity of gas entering solution as related to the PAO2 but does not define the absolute amount of gas in solution. The absolute amount of gas 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 of O2 per dL of blood per mmHg PAO2. Breathing air at sea level, arterial oxygen tension is about 100 mmHg, therefore, the blood carries about 0.31 mL of dissolved oxygen per dL of whole blood. When breathing 100% oxygen at sea level the amount of dissolved oxygen increases to about 2.1 ml of O2 per dL of blood. Breathing 100 percent oxygen at 2 ATA results in a PAO2 of 1433 mmHg (4.4 mL of dissolved oxygen per dL of blood).
At 3 ATA provides a PAO2 of about 2200 mmHg and adds about 6.8 mL O2 to each dL of blood. A healthy adult human at rest uses about 6 mL of oxygen per dL of circulating blood. Thus HBO at 3 ATA provides sufficient plasma oxygen to exceed the body’s total metabolic requirement. The dissolved content of 6 mL oxygen per dL of blood is equivalent to the sea level oxygen capacity of 5 grams of hemoglobin. This phenomenon is the reason Dr. Boerma was able to sustain pigs’ life without blood in his study “Life Without Blood”.
GAS EXCHANGE AND OXYGEN DIFFUSION
An increase in oxygen tension causes oxygen to diffuse further from the functioning capillaries. Tissue oxygen content depends on 3 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 breathing air at 1 ATA, oxygen diffuses about 64 micrometers (about the thickness of 1 sheet of typing paper) at the arterial end of the capillary. During oxygen breathing at 3 ATA, oxygen diffuses about 250 micrometers (about the thickness of 3 sheets of typing paper).
In a hypoxic environment HBO may be able to restore P02 to normal or slightly elevated levels (it depends 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 mmHg but cannot migrate in < 10 mmHg. Fibroblasts also do not divide in < 22 mmHg and do not form collagen in < 28 mmHg.
Interestingly, it has been reported that if oxygen tension is held continuously at 290-560 mmHg fibroblastic replication was halted. When oxygen tension was returned to normal, the replication process continued. Therefore, daily high doses are needed to correct the hypoxic environment but must be delivered in an intermittent pattern to avoid side effects of the cells.
Therapeutic Effects of hbo
1) Reverse Hypoxia – Increases the amount of dissolved oxygen in the plasma
2) Alter ischemic effect
3) Influence vascular reactivity – Decreased neutrophil adhesion and subsequent release
of free radicals is an important early event leading to endothelial damage and microcirculatory failure associated with I-R Injury. HBO reversibly inhibits the ß2 Integrins therefore inhibiting the neutrophil- endothelial adhesion. Decrease adherence of neutrophils to the microvasculature.
4) Reduce edema – Hyperoxygenation will cause vasoconstriction. Although
vasoconstriction may be present, there is more oxygen
delivered to the tissues.
5) Modulate nitric oxide production – An increase of nitric oxide leads to vasodilation while a decrease of nitric oxide (NO) leads to vasoconstriction. Carbon dioxide increases NO production and oxygen decreases NO production by the endothelial cells.
6) Modify growth factors and cytokine effect by regulating their levels and/or receptors – Vascular Endothelial Growth Factor (VEGF) is important for the growth and survival of endothelial cells, and is
found in plasma, serum, and wound exudates. Under normobaric conditions, VEGF is stimulated by hypoxia, lactate, nitric oxide 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) Induce changes in membrane proteins affecting ion exchange and gaiting mechanisms
8) Promote cellular proliferation
9) Accelerate collagen deposition
10) Stimulate capillary budding and arborization
11) Accelerate microbial oxidative killing
12) Improve select antibiotic exchange across membranes– 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 potentiate the activity of certain antimicrobials by inhibiting biosynthetic reactions in bacteria. Interfere with bacterial disease propagation by denaturing toxins
13) Modulate the immune system response
14) Enhance oxygen radical scavengers thereby decreasing ischemia- reperfusion injury. HBOT increases the amount and activity of the free radical scavenger superoxide dismutase
Complications and Side Effects
Although any therapeutic application of hyperbaric oxygenation 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. CNS oxygen toxicity can occur at levels of 3 ATA for one to two hours.
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 within four to six hours
at 2.0 ATA. 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 no 100% oxygen at pressures greater than 3 ATA.
Doxorubicin has been shown to cause severe cutaneous necrosis if extravasation occurs during treatment. In human medicine, researchers looked to see if HBOT can help decrease the severity of tissue necrosis. To the researchers’ surprise, 87% mortality were noted in rats when HBOT was used. Cardiotoxicity was also noted when Doxorubicin was combined with HBOT.
It is therefore strongly recommended that horses treated with Doxorubicin do not have HBOT. Contraindications for HBO therapy are unknown for horses but may include untreated pneumothorax, high fevers (predispose to oxygen toxicity), emphysema and upper airway occlusions. In cases of severe necrotizing pneumonia a bronchopleural fistula may develop which when exposed to HBOT can result in a tension pneumothorax.
It is unknown if HBOT will cause congenital defects in horses. In human studies it has not been shown to have adverse effects. During the late 1970’s and early 1980’s, Russian scientists looked at 700 pregnant women at all different stages of their gestation who were treated with HBOT and failed to identify any maternal or fetal complications or mortality. In our hyperbaric center we do not hesitate to treat a mare with HBOT, especially when the benefits outweigh the risks. It is not unusual in our clinic to allow the mare of a patient (foal) to be allowed in the chamber during treatments to aid in the relaxation of the foal.
Accepted Indications for HBOT in humans that will be covered by health insurance:
1) Air or gas Embolism
2) Carbon Monoxide poisoning
3) Clostridial myositis and myonecrosis
4) Crush injury, compartment syndrome, and other acute ischemia
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 steadily growing. Patients included pregnant animals, as well as neonatal foals with no adverse effects noted. Patients have been pressurized from 1.5 to 3 ATA ranging from 60-90 minutes at treatment pressure (depth). We have used HBO as adjunctive therapy for:
- Fungal disease (Fungal Pneumonia)
- Thermal burns, carbon monoxide, smoke inhalation
- Closed head injuries
- Ileus
- CNS edema/perinatal asphyxia
- Peripheral neuropathies
- Sports injuries (Exertional rhabdomyolysis)
- Cellulitis, compartment syndrome
- Ischemic injuries (Large Colon Torsions or Small Intestine Volvulus, laminitis)
In carefully selected patients, the addition of HBO therapy to standard measures may improve clinical outcomes. More research is needed in equine HBO medicine. The current cost for HBO is $400-500 per treatment.
EXAMPLE TREATMENT PROTOCOLS FOR EQUINE PATIENTS
These are used at the Hagyard Equine Medical Institute’s Hyperbaric Facility:
Fracture Healing
3 ATA for 60-90 minutes 1x daily 15-20 treatments may be required
Septic Arthritis
2.5 ATA for 60 minutes 1x daily 10-15 consecutive treatments. Osteomyelitis 2.5 to 3.0 ATA for 60-90 minutes 1 to 2 x daily 15-25 consecutive treatments. MUST NOT HAVE RESPIRATORY COMPROMISE (SEE ABOVE STATEMENT ON HYPEROXIA).
Improve tissue oxygenation, salvage potential medullary necrosis, improve antimicrobial delivery and enhance antimicrobial effects.
Tendon /Suspensory Injury
2.5 ATA for 90 minutes 1x daily 10-20 treatments. Best if started on the acute injury.
Pneumonia
1.5-2.0 ATA for 60 minutes 5-20 treatments 1x daily in conjunction with appropriate antibiotics. Lower airway pressure due to concern for respiratory depression with hyperoxia in severe cases.
HBOT is used for pneumonias that do not appear to be resolving to appropriate antimicrobial therapy. WE DO NOT USE THIS AS A PRIMARY THERAPEUTIC OPTION.
Lung Abscesses
3 ATA for 60 minutes 10-20 treatments 1x daily.
Exercise Induced Pulmonary Hemorrhage
2.0 ATA for 60 minutes 1x daily for 5 days and then 2.0 ATA every other day for 5 treatments.
Effect of HBOT on pulmonary pathophysiology is unknown in this condition. HBOT may work by mobilizing stem cells into circulation which move to injured lung parenchymal sites. HBOT also enhances angiogenesis and improves connective tissue repair.
Exertional Rhabdomyolysis
2.5 ATA for 60 minutes 1 to 2x daily (Depending on severity) 3-5 treatments. Best if done < 48 hours after injury.
Anti-inflammatory effects, reduction of tissue swelling, improved oxygen delivery/circulation to injured muscles, decreased recovery time.
Post Operative Gastrointestinal Surgery/Ischemic Reperfusion Injury
2.0-2.5 ATA for 60 minutes 3-10 consecutive treatments 1-2x daily immediately post operatively. Reduce edema, accelerates enterocyte turnover and improves intestinal recovery following Ischemia-Reperfusion injury. Reduce the expression of ICAM-1 and Integrin b2, reduce the production of interleukins, TNFα and PAF.
Closed Head Injuries
1.5 to 2.0 ATA for 60 minutes
- Decreased intracerebral pressure
- Improve the mitochondrial redox function
- Improve Glucose metabolism
- Injured brain could not tolerate exposures > 2 ATA
Cellulitis
2.0 to 3.0 ATA SID or BID for 60 minutes - Continue until resolution. If diagnosed early the
resolution can occur within 3-5 days
Perinatal Asphyxia Syndrome
1.3-1.5 ATA for 60 minutes for 4-10 consecutive treatments. Neuroprotective, maintain Tissue ATP, protect mitochondrial function, inhibit conversion of xanthine dehydrogenase to xanthine oxidase, inhibit arachidonic acid cascade and avoid the production of reactive oxygen species.
About the Author
Nathan Slovis, DVM, DACVIM, CHT
Dr. Nathan Slovis is the Director of the McGee Medical and Critical Care Center at the Hagyard Equine Medical Institute located in Lexington, Kentucky. He is a native of Annapolis, Maryland. He received his Bachelor of Science from Radford University, Doctor of Veterinary Medicine from Purdue University, interned at Arizona Equine Center and completed his residency in Internal Medicine at the University of California, Davis.
Dr. Slovis has published over 60 manuscripts in both national and international peer-reviewed veterinary journals. He is the Editor of both the Atlas of Equine Endoscopy and The Atlas of Diseases/Disorders of the Foal, both distributed by Elsevier. He implemented the current Infectious Disease and Equine Emergency Response Programs at Hagyard Equine Medical Institute and holds the position of Infectious Disease Officer He is also a Certified Hyperbaric Technologist for humans and animals.