Safety and Tolerability of Hyperbaric Oxygen Therapy in Cats and Dogs
ABSTRACT
This prospective clinical trial was designed to evaluate the safety of hyperbaric oxygen therapy (HBOT) in a population of cats and dogs with a variety of naturally occurring diseases. Seventy-eight dogs and twelve cats with various naturally occurring disease conditions, who had the potential to benefit from HBOT, were enrolled in the study. These patients were treated with HBOT in a monoplace hyperbaric oxygen chamber at 2 air pressure absolute for a treatment length of either 45 min or 60 min. There were 230 hyperbaric oxygen treatments performed during the study period. No major adverse effects were observed. There were 76 minor adverse effects recorded, which were not considered to be of clinical significance. Hyperbaric oxygen therapy was well tolerated and there were no major adverse effects recorded during treatment.
Introduction
Hyperbaric oxygen therapy (HBOT) is the therapeutic use of oxygen inhaled inside a chamber pressurized above atmospheric pressure.1–3 In HBOT, the pressure used is expressed in multiples of atmospheric pressure at sea level, which is 1 atmosphere of air pressure absolute (ATA).2–4 One hundred percent oxygen at 2 or 3 ATA can result in arterial oxygen tension in excess of 2,000 mm Hg and oxygen tension in tissues at approximately 400 mm Hg.2 The dissolved oxygen concentration in blood at these pressures approaches 60 mL/L of plasma, which is almost sufficient to supply the resting total oxygen requirement of many tissues without the contribution of oxygen bound to hemoglobin.1 This hyperoxia has many potential benefits and is the basis of HBOT.1,2,4
Currently, the Undersea and Hyperbaric Medical Society lists 14 indications for HBOT in humans: air or gas embolism, carbon monoxide poisoning, clostridial myositis and myonecrosis, crush injury or other acute trauma ischemia, decompression sickness, arterial insufficiencies, severe anemia, intracranial abscess, necrotizing soft tissue infections, refractory osteomyelitis, delayed radiation injury, compromised skin flaps or grafts, and idiopathic sudden sensorineural hearing loss.5 The Cochrane reviews are a key resource in evidence-based medicine in the human literature.6–12 They form a database of systemic reviews and meta-analyses with a focus on reporting results of well-conducted and controlled trials.6–12 There are several Cochrane reviews on the use of HBOT. In the following conditions, HBOT was considered to improve outcomes or reduce the risk of mortality: traumatic brain injury, late radiation tissue injury, acute idiopathic sudden sensorineural hearing loss, tumor sensitization to radiotherapy, skin grafting, skin trauma, acute migraines, and Bell’s palsy.6–12 As such, HBOT is considered a promising adjunctive therapy for a variety of surgical and medical disorders.
There are several proposed mechanisms for the reported physiological benefits of hyperbaric oxygen:
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Plasma oxygen carriage. The high level of dissolved oxygen in the patients’ plasma during treatment allows tissues to preferentially use the oxygen in the plasma rather than the oxygen bound to hemoglobin, which helps to relieve hypoxic stress.1,5 This is particularly advantageous in the treatment of severe anemia and carbon monoxide poisoning.1,5
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Tissue hyperoxia. Normal wound healing proceeds through an orderly sequence of steps.5 The main stages of wound healing involve control of contamination and infection, inflammation, regeneration of the connection tissue matrix, neovascularization, wound contraction, and resurfacing.5 Many of these steps are critically dependent on adequate perfusion and oxygen availability.5,13 Hypoxia inhibits the formation of collagen matrix, which is essential for angiogenesis and wound healing.4,5,13 Hence, the oxygen-rich environment in HBOT is beneficial in wound healing.
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Barometric effects. Hyperbaric oxygen therapy is useful in the treatment of decompression sickness and arterial gas embolism due to the principle of Boyle’s law.1,2,4 Boyles law states that the volume of gas in an enclosed space is inversely proportional to the pressure exerted on it.1,2,4 Therefore, the intravascular bubbles causing obstruction in these disease conditions reduce in size during HBOT and move to smaller vessels.1,5 This reduces extravascular tissue damage.1,5 In humans, HBOT remains the definitive treatment for arterial gas embolism.5
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Immunomodulation. Hyperbaric oxygen therapy is reported to benefit the immune system by restoring neutrophil-mediated bacterial killing in previously hypoxic tissues and reducing leucocyte adhesion in reperfusion injury.4,5 This prevents the release of proteases and free radicals.5 Hyperbaric oxygen is synergistic with some antibiotic therapy because it improves oxygen transport of the antibiotic across cell walls and allows better penetration of the target bacteria.5
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Relief of oxidative stress. In ischemic stroke, HBOT has been shown to increase oxygen content, stabilize the blood–brain barrier, decrease intracranial pressure, and relieve cerebral oedema.14–18 Hyperbaric oxygen therapy can effectively alleviate oxidative stress.14 Oxidative stress is considered to be an important contributing factor to the development of cerebral ischemic–reperfusion injury.14 Hyperbaric oxygen therapy is reported to increase the expression of brain-derived neurotrophic factor, glial-derived neurotrophic factor, and nerve growth factor, which can promote the proliferation and restoration of the neuron.14
In humans, HBOT is considered safe at 1.5–2.0 ATA with a treatment length less than 120 min.1,2,4,19 Reported complications during HBOT in humans include reversible middle ear barotrauma, sinus pain, reversible optic symptoms including myopia, pulmonary barotrauma, oxygen toxicity, claustrophobia, and vomiting.1,4,19–21
There are various manifestations of oxygen toxicity seen in human patients during HBOT. Pulmonary and central nervous system toxicity occurs due to the generation of reactive oxygen species.22 The development of pulmonary and central nervous system toxicity is dependent on the partial pressure and duration of exposure.22 In the acute setting, pulmonary toxicity can result in alveolar and interstitial edema and alveolar hemorrhage.22 Long-term complications can include fibrosis and emphysema.22 Central nervous system toxicity can present with various clinical signs including nausea, diaphragmatic spasms, behavior changes, vertigo, facial twitching, change in visual field, syncope, and seizures.22 Hyperoxia may lower the seizure threshold; however, HBOT-related seizures are rare and self-limiting and have not been reported to cause permanent brain injury.4,19
A fatal complication of HBOT is explosion of the hyperbaric chamber due to ignition of the pressurized oxygen within the chamber.23,24
Hyperbaric oxygen therapy is regarded in the human literature as a procedure with an acceptable rate of complications as long as safety guidelines concerning pre-examinations, contraindications, and close monitoring of the patients during therapy are followed.19 Contraindications for hyperbaric oxygen therapy in humans include pneumothorax, upper respiratory infections, emphysema with carbon dioxide retention, pulmonary blebs, pregnancy, recent ear surgery, and severe claustrophobia.19–21
Currently, the veterinary literature on HBOT for dogs and cats consists of textbook chapter reviews, published review articles, conference proceedings, small population studies, case reports, and anecdotal reports of its clinical use.25–33 Since the 1960s, there have been several experimental studies performed on laboratory animals including dogs, pigs, cats, gerbils, rats, and rabbits, investigating the various benefits of HBOT in a number of different disease states.34–47 It has been hypothesized that veterinary patients with skin wounds, sepsis, peritonitis, spinal cord injury, neurologic disease, and anemia and those at risk of ischemic events would benefit from HBOT.25,27,28
There are a number of hyperbaric oxygen chambers installed in small animal hospitals across the United States.25–28 Despite the relatively common use of hyperbaric oxygen chambers, the safety of HBOT in cats and dogs is not well documented and to the authors’ knowledge there are no reported veterinary studies with large treatment numbers describing the adverse effects seen during clinical HBOT in dogs and cats.
This prospective clinical trial was designed to evaluate the incidence of adverse effects (either major or minor) during HBOT in a population of cats and dogs with a variety of naturally occurring diseases. We hypothesized that HBOT would be well tolerated and the rate of adverse effects would be low.
Materials and Methods
Patient Selection
Privately-owned canine and feline patients with HBOT as part of their treatment protocol were eligible for inclusion in this prospective clinical trial performed between July 2013 and May 2014 at Brisbane Veterinary Specialist Centre. Owner consent was obtained prior to HBOT therapy. Specific ethics approval was not required because this was an observational study and did not require any alterations to standard treatment protocols for the patients enrolled.
The decision to perform HBOT as part of the patient’s treatment plan was at the discretion of the primary clinician. Hyperbaric oxygen therapy was not performed on patients suspected to have the following: requirement for artificial ventilation, uncontrolled seizures, pneumothorax, pneumomediastinum, or a high risk of aspiration. Hyperbaric oxygen therapy is contraindicated in untreated pneumothorax or pneumomediastinum because of concerns of expansion of trapped gas. Patients at a high risk of aspiration or uncontrolled seizures were not considered suitable patients for HBOT because of concerns that immediate intervention could not be instituted if required. Patients with a pacemaker were also considered unsuitable patients because of the uncertainly of device function at 2.0 ATA.
Treatments
Hyperbaric oxygen therapy was performed in a monoplace chambera with two patient-viewing windows. Hyperbaric oxygen treatment for a patient was standardized to either a single 60-min treatment at 2.0 ATA or two 45-min treatments at 2.0 ATA within a 24-hr period. Oxygen concentration within the chamber during treatment was 85–90%.
A single 60-min treatment per 24 hr was the standard treatment protocol used at our facility. Two 45-min treatments in a 24-hr period were recommended for patients with acute clinical signs and a disease that is considered to respond favorably to HBOT.
To prevent the risk of spark formation and fire ignition in the chamber, the following precautions were taken: in all hyperbaric oxygen treatments performed at our facility, no electrical equipment was allowed inside the chamber, metallic collars and leads were removed from the patient, any electrocardiogram pads on the patient were wrapped in bandaging material, no nylon material was allowed inside the chamber, and only cotton blankets were allowed for patient comfort. Intravenous catheters were wrapped in bandaging material to prevent dislodgement during the treatment.
Patients were not routinely sedated or treated with anxiolytics prior to entering the hyperbaric oxygen chamber. The decision to administer a sedative or treat with an anxiolytic was at the discretion of the patient’s primary clinician.
Any supplementary oxygen therapy the patient was receiving prior to HBOT was discontinued throughout the duration of the HBOT treatment session.
Only staff who had received in-house training and passed an in-house competency examination operated the chamber.
Patients were continuously monitored through the chamber window during the compression and decompression phases. The standard time for compression and decompression in the chamber was 9 min for each pressurization change. If emergency decompression was required, then this could be performed over 3 min.
Maximum oxygen saturation was maintained for either 45 min or 60 min depending on the desired treatment length. The chamber operator or primary attending veterinarian determined the frequency of patient observation or the need for continuous patient monitoring during the maximum oxygen saturation phase. For inclusion in this study, the patient was observed at least five times throughout the maximum oxygen saturation phase for at least 1 min.
Treatments included in this study had the following information recorded: patient name, patient identification number, disease condition, concurrent drug therapy, and a description of adverse effects recorded during the treatment as well as the number of adverse effects.
Adverse effects were defined as either minor or major using predefined criteria. Minor adverse effects were defined as those that caused minimal patient distress and were unlikely to cause persistent patient morbidity. Major adverse effects were defined as those that contributed to mortality or persistent patient morbidity, caused significant distress, or required emergency decompression. In our previous experience of HBOT at our facility, patients commonly have intermittent head shaking, ear flicks, and vocalization. For the purpose of this study, an intermittent head shake, ear flick, or vocalization was classified as a minor adverse effect if the duration was for less than 2 min and occurred fewer than five times in a single treatment session.
Statistical Analysis
Where incidence rates were zero, a 95% confidence interval was calculated around our observed rate of major adverse effects, using the rule of three, to indicate the maximum bounds within which the actual rate of major adverse effects would lie based on our sample size.48 Independence of HBOT treatments was assumed for this calculation. In medical statistics, the rule of three is a commonly used technique derived from the sample size to create a confidence interval when incidence rates of zero are observed.48
Results
Study Population
A total of 230 HBOT treatments were performed over the study period, with 12 cats and 78 dogs being treated.
The median age of cats in the study population was 10 yr (range, 4 mo to 16 yr). There were six purebreed cats and six domestic-breed cats.
The median age of dogs in the study population was 8 yr (range, 2 mo to 14 yr). There were 51 purebreed and 27 mixed-breed dogs.
There were a variety of underlying diseases diagnosed in the study population. There were 29 patients with neurological disorders, 21 patients with gastrointestinal or pancreatic disease, 7 patients with hematopoietic disorders, 8 patients with cardiorespiratory disease, 18 patients with integument disorders, and 7 patients with miscellaneous diseases. Data on disease states in the population are presented in Table 1.
There were several different drugs administered to the patients in the study as part of their treatment in addition to HBOT. The most commonly prescribed medications were opioids, antibiotics, and immunosuppressives. Six of the patients were receiving intranasal or flow-by oxygen therapy as part of their treatment prior to their HBOT.
Treatments and Adverse Effects
The mean number of treatments per patient was 2.55 (range, 1–13). There were one hundred eighty 60-min treatment sessions and fifty 45-min treatment sessions. There were no major adverse effects recorded in the 230 treatments, resulting in an incidence of 0% with a 95% confidence interval of 0–1.3% (or a 95% chance that fewer than 1 in 77 treatments will result in major adverse effects).50 There were 55 minor adverse effects in the 60-min treatment sessions and 21 minor adverse effects in the 45-min treatment sessions.
The mean number of treatments per cat was 3.9 (range, 1–15). There was a total of 47 HBOT treatment sessions for the feline patients; 9 of these treatments were 45-min sessions. Three of the feline patients experienced minor adverse effects. A total of six minor adverse effects were recorded in the feline patients. These six adverse effects were all head shakes.
The mean number of treatments per dog was 2.3 (range, 1–12). There was a total of 183 HBOT treatment sessions for canine patients; 31 of these treatments were 45-min sessions. A total of 70 minor adverse effects were recorded in the canine patients. The most common adverse effects seen in the dog population were head shaking, panting, and swallowing.
A list of the minor adverse effects is recorded in Table 2. The majority of adverse effects occurred during the compression or decompression phase of the hyperbaric treatment.
Discussion
The results of this study support the hypothesis that HBOT is well tolerated by canine and feline patients. No patients in this study required emergency decompression or suffered major adverse effects.
The nature of all the adverse effects recorded in the study was mild. We considered the minor adverse effects as inconsequential compared with the potential benefit of HBOT. The majority of minor adverse effects occurred during pressurization and depressurization; therefore, lengthening the time it takes to compress and decompress could help the patient adjust to pressure changes and may reduce the incidence of adverse effects.
Because continuous monitoring throughout the 2ATA treatment phase was not performed on all patients, it is possible that adverse effects were missed by the observer. In our experience prior to the commencement of the study, the majority of minor adverse effects occur during the compression and decompression phase; therefore, it was a requirement that all patients were continuously monitored in these phases. The lack of continuous monitoring for all the patients is a limitation of our study. However, given the frequency of monitoring it is unlikely that a major adverse effect was missed. It is recommended that all patients are closely monitored during hyperbaric oxygen chamber treatment in case any adverse effects might occur that may require intervention.
There were a relatively small number of cats in the study, which could be considered a limitation. Although the number of cats in the study was small, the mean number of HBOT treatments per cat was higher than the mean number of HBOT treatments per dog. In the 47 HBOT treatments recorded for cats, there were only six minor adverse effects. We feel this data fulfills the objectives of our trial and demonstrates that HBOT is safe in cats.
The most commonly reported adverse effect in people undergoing HBOT is middle ear barotrauma during the compression or decompression phase resulting in pain or discomfort.19 In a study of 11,376 HBOT treatments in people, the reported incidence rate of ear pain or discomfort was 17.8%.19 In the same study, the incidence rate of tympanic membrane rupture was 0.4% and all of these patients had underlying neurological disease.19 Head shaking, swallowing, panting, and ear flicking were the most common of the minor adverse effects recorded in our study during the pressurization changes. These clinical signs in veterinary patients could be suggestive of barotrauma. One of the limitations of our study was that the external ear canal and tympanic membrane was not routinely examined before and after HBOT treatment. The significance of barotrauma in veterinary patients is questionable, similar to the situation in humans, in which this is a transient condition that does not contribute to patient morbidity.
As discussed earlier, the clinical signs of oxygen toxicity in people are varied and can include facial twitching, nausea, and vertigo. It is possible that these complications may manifest as head shaking, ear flicks, and swallowing in our veterinary patients. A neurological examination was not performed immediately prior to and after HBOT and therefore it is difficult to ascertain if any of the patients developed permanent CNS toxicity as a result of treatment. Had the study design included a neurological examination, it is unlikely that it would have detected such subtle symptoms. Further research studies with routine neurological, otoscopic, and retinal examination after HBOT may help to determine the incidence of oxygen toxicity and barotrauma in veterinary patients.
All the adverse effects recorded in this study were considered minor and were transient in their nature. As such, determining the exact pathophysiological mechanism behind their occurrence would be difficult and unlikely to be of clinical significance.
Because of the referral nature of our clinical work load, follow-up examinations of the patients were not consistently performed at our facility, and as such, identification of long-term side effects of hyperbaric oxygen therapy was not possible. The primary aim of our study was to determine the safety and tolerability in canine and feline patients during the HBOT treatment sessions and further studies would be required to assess any long-term side effects of HBOT.
The patients in this study were being treated with a large variety of medical therapies. In the human literature, there is a lack of clinical-based evidence describing the effects of hyperbaric oxygen in conjunction with many commonly prescribed medications.49 Previously, it has been suggested that opioid use in humans may increase the risk of adverse effects.49 Most of the patients in our study population were prescribed opioids as part of the treatment protocol for their naturally occurring disease. There were no major adverse effects seen in patients who were receiving opioid analgesia.
There were only six patients in this study who were receiving supplemental oxygen therapy prior to treatment. Because of the small number, we are unable to determine if supplemental oxygen therapy prior to HBOT treatment increases the risk of oxygen toxicity.
Previously reported complications of HBOT in veterinary patients include hypothermia in small, depressed, or sedated patients; anxiety; and hyperthermia.25 A recent study in which dogs’ rectal temperatures were monitored during four consecutive 45-min HBOT treatments at 2ATA found that the rectal temperature decreased on average by 0.07°C, which suggests that extreme changes in body temperature are uncommon during treatment.50
Anxiolytics were not commonly prescribed to the patients in this study. It is possible that the use of anxiolytics prior to HBOT therapy could reduce the rate of minor adverse effects.
The treatment protocol used in this study was adapted from studies on humans. We believe that the results of our study validate the treatment protocol detailed as safe for canine and feline patients. Other treatment protocols may produce different results.
Many of the patients in this study had multiple HBOT treatments throughout their hospitalization. Our results indicate that multiple HBOT treatments did not appear to increase the risk of a major adverse effect. However, the number of patients in our study receiving more than 10 HBOT treatments was small. We therefore cannot extrapolate from our data whether long-term daily HBOT increases the risk of adverse effects.
Conclusion
In conclusion, we believe that the absence of major adverse effects during our 230 HBOT treatments supports our null hypothesis that HBOT is safe in dogs and cats when following the described protocol. In the future, further studies should be performed assessing the potential therapeutic benefit of HBOT in various disease states.
Contributor Notes
