sign in sign up
<<
Home , Barodontalgia, Diffusing capacity, Hyperbaric medicine, Oxygen therapy

CRITICAL REVIEW

Hyperbaric : Side Effects Defined and Quantified

Marvin Heyboer III,* Deepali Sharma, William Santiago, and Norman McCulloch Division of Hyperbaric and Wound Care, Department of , SUNY Upstate Medical University, Syracuse, New York.

Significance: Hyperbaric (HBOT) is an important advanced therapy in the treatment of problem wounds, including ulcers and late effect radiation injury. HBOT remains among the safest used today. Nonetheless, there are side effects associated with HBOT. It is impor- tant for providers to be able to identify, understand, and quantify these side effects for prevention, management, and informed consent. Recent Advances: The past two decades have seen significant advancements in our understanding of the underlying mechanisms of HBOT. This has led to Marvin Heyboer III, MD, FACEP, FUHM, FACCWS a better understanding of the underlying reason for clinical benefit. It has also Submitted for publication December 1, 2016. led to a better understanding of its side effects. Moreover, more recent liter- Accepted in revised form January 26, 2017. ature allows for better quantification of these side effects. This review will *Correspondence: Division of and Wound Care, Department of highlight these side effects.

Emergency Medicine, SUNY Upstate Medical Critical Issues: Wound healing in the case of problem nonhealing wounds re- University, 550 East Genesee Street, Suite 103, quires the use of various advanced treatment modalities, including HBOT. Syracuse, NY 13202 (e-mail: [email protected]). HBOT has been shown to significantly improve healing rates in certain problem wounds, including advanced diabetic foot ulcers and late effect radi- ation injury. It is provided in a variety of clinical settings by providers with varying levels of expertise. It is important for those providing this therapy to understand the potential side effects. Future Directions: Research in HBOT has led to significant advancements in the area of wound healing. At the same time, there remains a variety of treatment protocols used at different institutions. It is important to quantify risk and benefit at different treatment and times to better stan- dardize treatment and improve patient care.

Keywords: hyperbaric, oxygen, side, effects

SCOPE AND SIGNIFICANCE usually adverse effect. This review will attempt to describe and quantify these Hyperbaric oxygen therapy (HBOT) side effects. This should lead to better has been identified as a useful advanced consideration of risk and benefit in dis- adjunctive therapy in the promotion of cussions with the patient when consid- healing in certain problem wounds in ering HBOT. addition to its application to a variety of other medical conditions. As with all medical treatments, HBOT has known TRANSLATIONAL RELEVANCE potential side effects as a result of HBOT works through both pri- treatment. A side effect here is consid- mary and secondary effects. Primary ered a known potential secondary and effects involve both increased pres-

210 ADVANCES IN WOUND CARE, VOLUME 6, NUMBER 6 j Copyright ª 2017 by Mary Ann Liebert, Inc. DOI: 10.1089/wound.2016.0718 HYPERBARIC OXYGEN SIDE EFFECTS 211

sure and . Secondary effects as a result of result of increased local growth factors and release a controlled oxidative stress include antimicrobial of autologous progenitor stem cells.7 effects, blunting of ischemia–reperfusion injury, It is these very same primary and secondary ef- and wound healing. Wound healing is the result fects that can cause the side effects associated with of both local and systemic effects. Local effects HBOT. These include various forms of , include a steepened oxygen gradient, macrophage central nervous system (CNS) and pulmonary ox- recruitment, and release of multiple growth fac- ygen toxicity, and ocular side effects. There are tors. Systemic effects result in progenitor stem cell additionally issues of claustrophobia. It is impor- mobilization and release from bone marrow in ad- tant to understand and quantify these side effects. dition to improved homing to the site of injury by This assists with creating protocols to minimize these cells.1–4 The results of both local and systemic risk in addition to better weighing risk and benefit effects include neovasculogenesis and collagen of treatment for the patient. It is important to note formation, which promote wound healing.1–4 These that HBOT remains among the safest therapies same mechanisms that result in HBOT beneficial used today.8 The following is an exhaustive list of effects can also cause the known side effects in potential side effects, some of which are more com- some patients. mon (middle barotraumas [MEB], claustropho- bia) and others that are theoretical risks unlikely to CLINICAL RELEVANCE occur clinically with appropriate screening precau- tions (pulmonary barotrauma [PBT]). The use of HBOT has grown significantly in the past 2 decades. Its application has a variety of recognized indications as outlined by the Undersea DISCUSSION and Hyperbaric Medicine Society,5 although a Effects of majority of patients are receiving treatment for HBOT by definition means treatment with 100% late effect radiation injury and problem wounds oxygen at higher than where (primarily advanced diabetic foot ulcers). Treat- increased pressures depend on treatment guide- ment is provided in a variety of clinical settings by lines and indications. Hence, the side effects of providers and staff with differing levels of exper- HBOT are based on the physiologic response to this tise. Having an understanding of the potential side high pressure–high oxygen environment and the effects of HBOT is critical to providing safe medical psychological response that patients experience care with complete patient informed consent. from the closed confines of the treatment chamber— monoplace or multiplace. Boyle’s Law states that BACKGROUND AND OVERVIEW the volume of a gas at a fixed is in- HBOT is the treatment of patients with 100% versely proportional to the . Low- 1 ering the ambient pressure causes increased gas oxygen at higher than atmospheric pressure. This is provided in either a monoplace (single person) volume; the converse is also true (Fig. 1). These chamber typically compressed with oxygen or a effects of pressure are experienced within physio- logic and pathologic air cavities, including the mid- multiplace chamber (multiple persons) compressed with air where oxygen is delivered by either a hood dle ear, paranasal sinuses, pathologic dental spaces, or mask. The benefits of treatment are the result of and emphysematous bulla. both primary and secondary effects. Primary ef- fects are the result of increased pressure and hy- peroxia. Indeed, PaO2 can increase from less than 200 mmHg at 1 atmospheres absolute (ATA) room air to more than 2,000 mmHg at 3 ATA. This also translates into significant increases in tissue oxy- gen .6 Meanwhile, secondary ef- fects are the result of a controlled oxidative stress. HBOT produces reactive oxygen species (ROS) and reactive nitrogen species, which function as sig- naling molecules in multiple pathways, including those involved in wound healing.1 The result is an array of secondary effects that include improved leukocyte function, amelioration of ischemia– Figure 1. Gas volume change with pressure. reperfusion injury, and neovascularization as a 212 HEYBOER ET AL.

Middle ear barotrauma. MEB is one of the most Causes of ET dysfunction may be inherent cra- common side effects of HBOT. Patients may report niofacial features such as palatal muscle anomalies difficulty with ear equalization, a feeling of pres- or a result of infectious or allergic reactions. These sure, ear pain, and discomfort during compression, include upper respiratory infections, environmen- which is the initial phase of HBOT.9 tal allergies, or enlarged adenoids, to name a few.14 If not attended to, this can lead to edema in the The reported incidence of MEB in patients un- middle ear, retraction, and in rare cases, rupture of dergoing HBOT varies significantly from *2% to the tympanic membrane with conductive hearing 84% in nonintubated and upward of 94% in in- deficit. In rare cases, MEB can be transmitted to tubated patients, making MEB one of the most the inner ear, with risk of rupture of the round or common side effects of HBOT.8,15 The wide range oval window membranes and impairment of inner of incidence is due to varying criteria used to de- ear function, causing and sensorineural fine MEB, variations in patient population, and hearing loss.10 MEB is most commonly classified variation in patient instruction of how to equalize using the modified TEED score (Table 1). More pressure in the middle ear.8 A recent publication recently, the O’Neill grading system was proposed of a large number of patient treatments demon- as a newer and more practical grading system.11 strated an overall incidence of 43%. The vast ma- For effective air equalization in the middle ear jority of cases were minor—84% were TEED 1 (TM to occur, the Eustachian tube (ET), which connects injection/retraction) or TEED 2 (TM slight hemor- the middle ear to the nasopharynx, positioned su- rhage) with no episodes of TM rupture.8 perior, posterior, and lateral to the nasopharynx, Rate of compression does play a role in risk of needs to be open and functioning (Fig. 2).12 The ET MEB. A previous study demonstrated that a high is collapsed at rest and needs to be actively opened rate of compression (4.1 psi/min) increased risk of by the patient using valsalva maneuvers, swal- MEB.16 On the other hand, a more recent study lowing, chewing, or by attempting to create posi- suggested that a very slow rate of compression tive pressure by blowing air against the pinched (1 psi/min) also increases risk of MEB. It found nares, thereby opening the collapsed ET.10 During that 2 psi/min was the best compression rate for compression, the relative negative middle ear minimizing MEB.8 There is an increased risk of pressure (compared with the dive chamber pres- MEB during initial treatments and no increased sure) causes collapse and closure of the ET.13 In- risk associated with a longer treatment course.8,17 ability to open the ET prevents equalization of the Other risk factors indentified include intuba- middle ear pressure with the higher outside pres- tion, active upper respiratory infection, sure. This results in gas volume contraction in (presumptively due to neuropathy), and a history the middle ear, which initially causes pain. Sub- of head and neck malignancy.8,15,18 Intuitively, sequent inward retraction of the tympanic mem- there is higher risk of MEB in intubated patients brane and adjoining ossicles, followed by middle with mixed evidence in the literature supporting ear mucosal swelling, capillary dilation, and tran- this.8,19,20 sudate leakage, causes fluid extravasation into the MEB can be avoided and its incidence reduced. middle ear space, with vessel rupture re- Adequate patient education, training, and assis- sulting in hemotympanum and possible tympanic tance through active coaching during compres- membrane perforation.10,13 sion can help mitigate MEB cases. In instances Alternatively, if air equalization on either side of wherepatientsareunabletosuccessfullyequalize the tympanic membrane (TM) does not occur during air pressure across the middle ear, needle myr- , positive pressure increase in the ingotomy may be performed for emergent patients middle ear may also lead to similar middle ear trau- or tympanostomy tubes placed for the duration of ma, although less likely since the positive pressure extended treatments.10 For patients with inher- helps to open the ET. ent ET dysfunction with known allergic or in- flammatory etiology, the use of decongestants and Table 1. Modified TEED score antihistamines can reduce obstruction and facili- Grade Findings on Otoscopy tate successful pressure equalization. Most cases of MEB resolve in the absence of re- 0 Normal examination 8 1 TM injection or retraction petitive trauma. Long-term sequelae from MEB 2 Slightly hemorrhagic TM during HBOT are rare. The sequelae reported in- 3 Grossly hemorrhagic TM clude sensorineural hearing loss, ossicular dis- 4 Hemotympanum ruption, and perilymphatic fistula. Management 5 TM perforation requires referral to otolaryngology for possible HYPERBARIC OXYGEN SIDE EFFECTS 213

Figure 2. Anatomy of the ear (D.S.). surgical interventions such as tympanoplasty or tive pressure gradient causes inflammation of the surgical repair of the round or oval window.10 mucosal surfaces of sinuses and osteal openings, Most injuries, including tympanic membrane thereby occluding these sinuses. This compression rupture, serous otitis, and tympanic membrane of the sinus space leads to congestion and edema, edema, heal spontaneously and medications such which is accompanied by facial pain and relieved as as antibiotics, decongestants, and steroids are not the pressure is eliminated (Fig. 3).21 The resulting indicated. Although MEB is the most common of edema can create a closed air space within the si- HBOT side effects, it is also most easily and effec- nuses, resulting in paradoxical pain during cham- tively ameliorated with patient coaching, topical ber decompression as the air volume expands, but medications, and (in less common circumstances) is unable to escape. relatively benign surgical intervention. Barosinusitis can lead to epistaxis, although such cases are rare, with incidence reported at 1 Sinus/paranasal barotrauma. Sinus and para- case per 10,000 treatments.15 The pressure nasal barotrauma is the second most common changes that occur during HBOT are similar to manifestation of barotrauma after MEB often oc- pressure changes that occur during underwater curring in the setting of upper respiratory infec- up to 60 feet in sea water (2.8 tions or allergic rhinitis.15 ATA). A case report for optic neuropathy was re- Barotrauma of the paranasal sinuses is charac- ported from possible ethmoidal and sphenoidal terized by pressure sensation, most commonly felt barotrauma after recreational diving, with reso- over the frontal sinuses, resulting in barosinusitis. lution of symptoms.22 The ostea draining the sinuses into the nasal cavity There is a propensity for barosinusitis to occur in are small in diameter compared with the spaces the setting of upper airway inflammation due to they drain. With HBOT, changes in pressure occur underlying upper respiratory infections, allergic during the compression phase inside sinus cavities, rhinitis, or mucociliary dysfunction. Indeed, acute similar to those described in MEB above. A nega- upper respiratory infection is a relative contraindi- 214 HEYBOER ET AL.

Figure 3. Anatomy of sinuses (D.S.).

cation to elective HBOT. When HBOT is provided, majority of studies evaluating this side effect come symptoms should be controlled with a regimen of from aviation and dive medicine. It has been re- decongestant nasal spray, antihistamines, and/or ported during flying at altitudes higher than 600 m steroid nasal spray just before compression.15 and during diving at depths of more than 10 m, with incidence at 0.26–2.8% in aircraft personnel, Dental barotrauma. Dental barotrauma (- air passengers, and divers.23 has odontalgia/odontocrexis), which is commonly called been reported by 9.2–21.6% of American and Aus- tooth squeeze, is pain in a tooth caused by a change tralian civilian divers.25 in atmospheric pressure. This phenomenon was Preventive measures should include a dental first observed in air crews during World War II and examination by the hyperbaric medicine physi- subsequently reported in divers.23 cian before HBOT and treatment of carious lesions Dental pain can occur during either compression and defective restorations when known before or decompression. It is classically experienced as a HBOT.23 decrease in pressure during decompression causes expansion of air bubbles trapped under a root fill- Pulmonary barotrauma. As previously men- ing or against dentin activating nociceptors. It can tioned, Boyle’s Law states that the volume of a gas also be referred to pain with stimulation of noci- at a fixed temperature is inversely proportional to ceptors in the maxillary sinuses. If expanding the ambient pressure. Similar volume changes can trapped gas results in dental stress, it may cause be seen in the of patients undergoing HBOT tooth fracture, a process called odontecrexis (tooth if a closed system is created. Normally, there is no explosion in Greek).24 Possible etiologies include risk of PBT in patients with normal lungs and an dental infections, sinusitis, differences in the ex- open glottis. The potential exists for PBT from pansion behavior of dental enamel and pulp, and overinflation for patients at risk for air trapping pressure-induced movement of fluids from exposed during decompression ( or chronic obstruc- dentine to the pulp.23 tive pulmonary disease [COPD] with active bron- Barodontalgia can occur as a result of any chospasm, mucous plugging, and bullous lung change in pressure, including HBOT. However, the disease) and those with a prolonged closed glottis. HYPERBARIC OXYGEN SIDE EFFECTS 215

Should the lung parenchyma be disrupted from undertaken in circumstances where significant overinflation during decompression, the potential pulmonary disease is present to mitigate any po- manifestations are pneumomediastinum, subcu- tential untoward outcome during HBOT. taneous emphysema, intrapulmonary hemor- rhage, simple (PTX), and tension CNS PTX. Pneumomediastinum and intrapulmonary As we have stated, HBOT is the treatment of hemorrhage are generally self-limited and require patients with 100% oxygen at higher than atmo- only conservative management with supplemen- spheric pressures. HBOT can result in arterial tal oxygen to achieve resolution. PTX, however, is oxygen tensions of greater than 2,000 mmHg and a potentially life-threatening phenomenon espe- tissue levels of 200–400 mmHg and higher.6 HBOT cially given the increased risk of exacerbating a has many of its therapeutic benefits through con- simple PTX into a tension PTX during decom- trolled oxidative stress. Antioxidant defenses are pression in a hyperbaric chamber. Tension PTX usually adequate during the hyperoxic exposure can rapidly lead to cardiovascular collapse and created by a typical clinical hyperbaric oxygen death if not treated quickly with thoracostomy treatment.1 Nonetheless, CNS oxygen toxicity does tube insertion. Cases of tension PTX during hy- occur. The recognized presentation of CNS oxygen perbaric oxygen treatment are very rare, but have toxicity during clinical hyperbaric oxygen treat- been reported.26,27 ment is an oxygen toxicity seizure. The link between Arterial gas embolism (AGE) can result from hyperbaric oxygen and seizure was first recognized PBT when alveolar air passes into the ruptured by in 1878.30,31 Dr. Christian J. Lam- pulmonary vessels. The air bubbles then enter the bertsen described it in this way: ‘The convulsion is left heart and embolize through systemic arteries usually preceded but not always by the occurrence leading, potentially, to vascular occlusion in the of localized muscular twitching. Eventually an brain or heart.28 The most severe clinical mani- abrupt spread of excitation occurs and the rigid festations of AGE include , unconsciousness, ‘‘tonic’’ phase of the convulsions begins. Vigorous and . Other symptoms include loss clonic contractions of the muscle groups of the head of consciousness, confusion, aphasia, dysarthria, and neck, trunk and limbs then occur becoming vertigo, visual disturbance, unilateral sensory and progressively less violent over 1 minute.’32,33 motor changes, and seizure. Cases of PBT resulting The exact underlying pathophysiology is not un- in AGE have been reported in the medical litera- derstood. It appears to be the result of direct oxygen ture.29 Treatment of choice for AGE from any eti- toxicity. The increased ROS and free radical inter- ology is HBOT.5,6 mediates interact with the neuronal cell plasma The lung is an open air space system. As such, membrane.34–36 This causes peroxidation at PBT is not expected with HBOT in the absence of the plasma membrane, resulting in a change in pulmonary disease. As such, all potential candi- brain electrical activity.35 (NO) has dates for HBOT must be thoroughly screened for been implicated as a mediator for CNS oxygen tox- pulmonary disease, which may increase the risk of icity through formation of peroxynitrite (ONOO-). PBT. Screening begins with a thorough history and In addition, there is vasodilation secondary to NO, physical examination. Historical features, includ- which counteracts the cerebral ing COPD, asthma, bronchiectasis, , prior normally seen secondary to hyperoxia.37 Gross re- spontaneous PTX, or prior chest , should tention of (CO2) in brain tissue and prompt further investigation inclusive of, at mini- intense vasoconstriction have been shown to be mum, a chest x-ray. Indeed, an unvented PTX is an unlikely causes.34 absolute contraindication to HBOT due to the po- Prodromal symptoms have been reported, al- tential of creating a tension PTX during the de- though they appear in <50% of cases. These include compression phase of treatment. This requires twitching, staring gaze, auditory hallucinations, treatment to create an open system before any visual changes, nausea, vertigo, , and irri- hyperbaric treatment. Other pulmonary historical tability.38,39 This is rapidly followed by tonic–clonic features may not preclude a potential patient from seizure activity. This is reversible with no residual HBOT, but treatment protocols may need adjust- neurological damage and resolution with a decrease ment such as a slower decompression rate to suit in the inspired partial pressure of oxygen (PO2), 32 the needs of a particular patient. This may be the resulting in a reduced cerebral PO2. The occur- case in a patient with significant blebs who is de- rence of generalized convulsions requires sufficient compressed at a slow 1 psi/min rate. Additionally, a oxygen pressure and duration of exposure. When careful evaluation of risk versus benefit should be this is sufficient, the required length of exposure 216 HEYBOER ET AL.

34 varies inversely with the PO2 breathed. No path- Table 3. Risk factors for oxygen toxicity seizure ologic changes have been found to be associated with Risk Factors Study 36 an isolated oxygen-mediated seizure. 7 An oxygen toxicity seizure is relatively rare at Increased treatment pressure (2 vs. 2.4/2.5 vs. 2.8 ATA) Heyboer et al. Other CNS (brain tumor/STRN brain) typical clinical treatment pressures (2 ATA–3 ATA). Air break It is difficult to predict on an individual basis. It was Increased treatment pressure (2 vs. 2.4 ATA) Banham38 40 Carbon monoxide poisoning traditionally reported at *1 in 10,000 treatments. 47 However, more recent evidence over the past 15 Increased treatment pressure (1.5 vs. 2 vs. 2.4 vs. 2.8 ATA) Hadanny et al. Carbon monoxide poisoning Hampson et al.45 years puts the incidence at *1 in 2,000–3,000 , hyperthyroid Welslau and 7,38,41,42 treatments. The reason for the increased Almeling44 incidence over the past 15–20 years appears to be Hood over mask (multiplace chamber) Yildiz et al.43 related to patient selection (sicker patients with CNS, central nervous system. more comorbid illness) and changes in hyperbaric oxygen treatment protocols.42 Risk factors identified to a combination of the level of PO exposure and include higher treatment pressure, CO retention, 2 2 time. As such, these air breaks limit the interval brain tumor/brain soft tissue radionecrosis, hypo- time exposure and are expected to decrease the risk glycemia, hyperthyroid, and carbon monoxide poi- of oxygen toxicity.34 Indeed, the U.S. Navy has used soning.7,38,43–46 No link to increased risk has been air breaks successfully for many years. Yildiz found identified with monoplace versus multiplace cham- that the use of masks was protective over hoods due ber, neurologic versus non-neurologic treatment to less risk of CO retention when undergoing indication, or past medical history of , diabe- 2 treatment in a multiplace chamber.43 Finally, tes, alcoholism, or epilepsy.7,38,47 Table 2 shows the screening for risk factors and optimizing antiseizure incidence reported in published studies. Table 3 lists medications in known epileptics before hyperbaric risk factors to having an oxygen toxicity seizure that oxygen treatment are thought to be protective. have been identified. There are no long-term sequelae as a result of Preventive measures include the use of air breaks an oxygen toxicity seizure. No pathophysiologic at given intervals during hyperbaric oxygen changes have been found to be associated with . This allows for interval breaks in overt an isolated oxygen-mediated seizure.36 Indeed, pa- exposure to oxygen free radicals and resulting sei- tients who have had an oxygen toxicity seizure zure. While the use of air breaks to decrease the in- may still go on to complete their recommended cidence of CNS oxygen toxicity has not been directly course of treatment. While their risk of subsequent demonstrated, there is a large amount of published oxygen toxicity seizure is increased, it is still less data on the cause of oxygen toxicity related directly than 10%.7,38,44,47 Adjustments can be made to subsequent treatments, including lower treatment Table 2. Incidence of oxygen toxicity seizure pressure and additional air breaks. While oxygen Study Incidence Percent Tx Pressure Indications toxicity seizure is one of the more feared side effects of HBOT, its incidence remains low with no evi- 89 Hart 1987 1 in 12,253 0.008 2–3 ATA All dence of long-term sequelae as a result of an episode. 0.8% per 10,000 Davis40 1 in 10,552 0.01 2.4 ATA All Pulmonary oxygen toxicity 0.95 per 10,000 Continuous exposure of the lungs to elevated levels Welslau and Almeling44 1 in 6,704 0.05 2.4–2.8 ATA All of oxygen, either at atmospheric or hyperbaric pres- 1.5 per 10,000 sure, leads to progressively severe toxic effects as the 41 Plafki et al. 1 in 2,844 0.035 2.4–2.5 ATA All duration of exposure, F O ,orpO increases. Patho- 3.5 per 10,000 i 2 2 logical manifestations of pulmonary oxygen toxicity Hampson and Atik42 1 in 3,388 0.03 2–2.8 ATA All 3 per 10,000 are differentiated into two overlapping phases: the Yildiz et al.43 1 in 40,339 0.0025 2–2.8 ATA All acute exudative phase and the subacute proliferative 0.25 per 10,000 phase. Pulmonary changes in the acute exudative Banham38 1 in 1,651 0.06 1.9–4 ATA All phase include interstitial and alveolar edema, intra- 6 per 10,000 alveolar hemorrhage, fibrinous exudate, hyaline Heyboer et al.7 1 in 2,121 0.05 2–2.8 ATA All membrane swelling, and destruction of capillary en- 5 per 10,000 dothelial cells and type I alveolar epithelial cells. Hadanny et al.47 1 in 8,945 0.011 1.5–2.8 ATA All Interstitial fibrosis, fibroblastic proliferation, and 1.1 per 10,000 hyperplasia of type II alveolar epithelial cells char- 48 ATA, atmospheres absolute. acterize the subacute proliferative phase (Table 4). HYPERBARIC OXYGEN SIDE EFFECTS 217

Table 4. Pathologic manifestations of pulmonary plications of HBOT do not cause pulmonary oxygen toxicity symptoms or clinically significant pulmonary 54 Acute Exudative Phase Subacute Proliferative Phase functional deficits.

Interstitial edema Interstitial fibrosis Alveolar edema Fibroblastic proliferation Ocular side effects Intra-alveolar hemorrhage Type II alveolar epithelial Increased partial pressures of oxygen can poten- cell hyperplasia tially pose harm to multiple body tissues, including Fibrinous exudate the eye. Under normoxic conditions, oxygen me- Capillary endothelium destruction Type I alveolar epithelial cell destruction tabolism produces superoxide radicals and other toxic reactive species. Removal of these harmful substances is mediated by superoxide dismutase Pulmonary mechanical function is negatively and other cellular defense mechanisms. Under hy- affected by these pathological changes (Table 5). peroxic conditions, these defense mechanisms may Changes in pulmonary function include decreased become overwhelmed due to the increased free radical production leading to oxygen toxicity and , decrements in inspiratory and 55 expiratory and rates, and decreased subsequent ocular side effects. In addition to the inspired PO2 and exposure CO2 . Progressive reduction in is seen in pulmonary oxygen toxicity. duration, many other variables can play a role in the Indeed, decreased vital capacity remains a consis- development of ocular manifestations of oxygen tent and sensitive manifestation of pulmonary oxy- toxicity. These include the age of the exposed indi- gen toxicity. The rate of pulmonary oxygen toxicity vidual whether advanced age (i.e., cataract promo- tion) or young age (i.e., retrolental fibroplasia), the development correlates with pO2 and the duration of exposure.49 Symptoms of toxicity typically begin method use for oxygen delivery, and the presence of undiagnosed comorbid conditions that may affect after *12–16 h at 1.0 ATA, 8–14 h at 1.5 ATA, and 56,57 3–6 h at 2.0 ATA. Symptoms occur earlier at 2.5 and the patient’s susceptibility to oxygen toxicity.

3.0 ATA, but are milder since exposure time is lim- ited by neurologic oxygen toxicity.48–51 Hyperoxic myopia. Myopia can have direct toxic Symptoms of pulmonary oxygen toxicity are in- effects of oxygen on the crystalline lens and is one of 57,58 sidious in onset and present as mild substernal the most common side effects. An acute myopic chest discomfort accentuated by inspiration. As ox- shift may be due to osmotic changes in the lens of the ygen exposure continues, this progresses to wide- eye, systemic medications (i.e., ), miotic eye spread pleuritic , cough, chest tightness, medications, and ciliary spasm. Under repeated and dyspnea.49,51 The severity of symptoms di- exposures to hyperoxia, hyperoxic myopia is also 59 minishes quickly within the first few hours postex- included in the list of differential diagnoses. posure and the sensation of pulmonary irritation Progressive myopic changes are a known side 59 completely disappears over the next 1–3 days.51 effect of repetitive treatments with HBOT. The Pulmonary oxygen toxicity is not expected from rate of this change has been reported in the liter- routine daily HBOT. The possibility of develop- ature to be *0.25 diopter per week and progressive 60 ment does exist with prolonged exposure most throughout the course of ongoing treatment. typically related to long treatment tables such as Myopia has been reported in 25–100% of patients US Navy Treatment Table 6 used for decompres- undergoing HBOT after several weeks at pressures 61 sion illness, but even these cases would be mild and of 2.0 ATA and greater. The exact mechanisms self-limiting. Pulmonary oxygen toxicity can be for myopic change are not fully known. Proposed avoided if oxygen is provided in the proper dose. hypotheses have included a reduction in back- Humans exposed to hyperoxia at 0.55 ATA for scattered light and lens optical density with hy- 7 days showed no manifestations of pulmonary perbaric oxygen through oxidative damage to the toxicity.52 Likewise, exposure to 0.3 ATA for crystalline structure of the lens proteins and high 30 days produced no toxicity.53 Most ap- partial pressures of oxygen in direct contact with the eye, resulting in oxygen toxicity due to local 62–64 Table 5. Pulmonary function changes in oxygen toxicity hyperoxia. Decreased lung compliance A thorough ocular examination by the diving Decreased inspiratory lung volume and rate and hyperbaric physician can provide an objective Decreased expiratory lung volume and rate assessment of visual status and ocular function Decreased carbon monoxide diffusing capacity before the patient beginning HBOT. If the patient Decreased vital capacity is likely to undergo a prolonged course of treat- 218 HEYBOER ET AL.

ment, one may consider a more thorough exami- occurs when the production of ROS overwhelms the nation by an optometrist or ophthalmologist that normal capacity of antioxidant defense mechanisms includes documentation of corrected and uncor- to facilitate their elimination. Glutathione is an im- rected visual acuity, refraction, color vision, status portant antioxidant that functions to prevent damage of the crystalline lens, and fundus examination. By to cellular structures caused by ROS such as free accurately documenting ocular function, the ben- radicals, peroxides, and lipid peroxides (Fig. 4). Glu- efit of HBOT can be weighed against any adverse tathione, in its reduced form, plays a critical role in effects on visual acuity and thus be used to guide the lens stroma by maintaining the transparency of therapeutic decisions. lens crystalline proteins.70,71 When oxidized, this can Clinical experience suggests that such a change promote abnormal protein cross-linking, increased in a patient’s vision may affect their overall quality of production of insoluble proteins, and abnormal col- life. Their driving habits may be affected, routine orization resulting in nuclear light scatterings—an tasks may become more challenging, and patient earlyfindingincataractformation.69 safety becomes a concern, placing those with mobil- To date, there has only been one report of nu- ity issues at an increased risk of falls and subsequent clear cataract development in a human receiving injury. One may consider optometry evaluation for less than 50 HBOT treatments. This occurred in a temporary visual correction during HBOT when the 49-year-old woman who had received 48 treat- degree of myopia becomes a safety concern. Utilizing ments over a period of 11 weeks.69 This appears to 5-min periods of air breathing every 20–25 min can be an exception to the general observation that reduce the risk of oxygen toxicity.57 In addition, the cataract formation occurs only in treatment series use of mask over hood in a multiplace chamber set- greatly exceeding 20–60 treatments. Undiagnosed ting would theoretically decrease the risk due to a pre-existing conditions may play a role in such lower topical PO2. It is important to note that this circumstances. Increased pO2 in the precorneal gas myopic shift is reversible after discontinuation of space has been reported to play a more significant HBOT usually returning to baseline within 3–6 role than inspired PO2 in determining the physio- weeks, but as long as 6–12 months.59 logic effects of the gas mix on the cornea.72 Thus, the use of a oronasal mask in lieu of a hood as an Cataracts. HBOT leads to an increase in pO2 oxygen delivery device in a multiplace chamber and of ROS in blood and tissues, in- should reduce the amount of oxygen to the eye, cluding the lens stroma of the cornea, where it keeping the precorneal gas closer to normal oxygen plays a role in cataractogenesis.57 The relationship fraction. This was shown to result in a 50% reduc- between senile nuclear cataract formation and tion in myopic shift and overall lenticular oxygen myopia is well known and reported and both can toxicity.63 Patients therefore should be offered the be considered to represent two levels of severity of choice between delivery systems when available lenticular oxygen toxicity. The development of and clinically appropriate. cataracts in humans has been reported only after prolonged exposure to hyperbaric oxygen, usually Retrolental fibroplasia following hyperoxic expo- 150 treatments or more.65 In the , sure. Retrolental fibroplasia also known as reti- de novo cataract genesis is rare as the maximum nopathy of prematurity is a potentially blinding number of treatments rarely exceeds 75.66 condition affecting the retina of premature infants Cataracts remain the leading cause of visual im- caused by exposure to hyperoxia. It is vasoprolifera- pairment and blindness worldwide and usually tive retinopathy that occurs in preterm babies with present after age 65.67 Risk factors include ad- immature retinal vasculature.73,74 In the 1950s, it vanced age, female gender, , diabetes, eth- was associated with the use of high amounts of oxy- anol use, and corticosteroids. Incidence increases genintheprematureinfant.75 over the age of 65. Three types of cataracts have The two factors associated with pathophysio- been identified, which are cortical, subcapsular, and logic development are an incompletely vascular- 68 nuclear, which is the most common. They are ized retina and increased arterial pO2 with relative identified by a yellow-brown discoloration and hazy retinal hyperoxia. Both of these contribute to va- appearance of the lens in conjunction with the vi- soconstriction of the developing retinal vessels and sual changes experienced by the patient. a decrease in growth factors, most notably insulin- The exact mechanism of cataractogenesis is not like growth factor (IGF-1) and vascular endothelial completely understood. As reported, long-term expo- growth factor (VEGF). Consequently, there is ar- sure to HBOT resulting in oxidative damage to the rest of retinal neovascularization and capillary lens proteins plays a critical role.69 Oxidative stress obliteration, leading to a decrease in and HYPERBARIC OXYGEN SIDE EFFECTS 219

Figure 4. Oxygen free radical effect on ocular lens.

subsequent retinal ischemia and . Normal the incidence, retinopathy of prematurity remains response to these changes is an upregulation of prevalent among small premature infants.77,78 various growth and angiogenic factors, including About 4.5% of surviving babies weighing less than IGF-1 and VEGF (Fig. 5). If this response is exag- 1 kg are legally blind with a larger percentage ex- gerated, abnormal and disorganized hibiting significant visual impairment. Neurocogni- may ensue leading to inflammation, proliferative tive and developmental abnormalities may also be retinopathy, significant fibrosis, and ultimately seen leading to profound disability, including the irreversible retinal detachment and permanent inability to provide self-care, incontinence, motor blindness.76 disabilities, and altered social–personal skills.76 The incidence in premature infants in Western The discussion of HBOT in the setting of retro- countries has been reported to vary between 35% and lental fibroplasia should include two factors: hyper- 60%.74 Despite current neonatal care management oxia and neovascularization through angiogenesis. maintaining moderate oxygenation with arterial pO2 Oxygen saturations of 88–95% will maintain an in the range of 60–80 mmHg in attempts to curb arterial pO2 above 45 mmHg and usually less than

Figure 5. Retrolental fibroplasia. 220 HEYBOER ET AL.

75–80 mmHg. Targeting between anxiety in monoplace chambers is reported at 8 88% and 93% has been shown to result in a signifi- events per 10,000 treatments.15 cant reduction in retinopathy of prematurity.77 Mild confinement anxiety is easily controlled Arterial pO2 is 90 to 110 mmHg at sea level. HBOT with sedation before treatments such that individ- 15 has been shown to increase the arterial pO2 to well uals may continue to receive daily HBOT. More above 2,000 mmHg.57 Such high partial pressures severe cases may need referral to a psychiatrist or (and oxygen saturations) could potentially increase a psychologist, and cognitive-behavioral therapy, the risk of development. As discussed previously, an relaxation exercises, and/or long-term drug therapy abnormal angiogenic process occurs in the retina in might be necessary.79 Preventive measures with response to decreased perfusion and hypoxia. HBOT adequate patient history, patient education, reas- has been shown to increase angiogenesis through surance, and coaching are the most effective means upregulation of VEGF production. These two bene- of anticipating episodes of claustrophobia and fits of HBOT not only play a central role in other treating them effectively before HBOT. conditions (i.e., wound healing) but have also been the focus of discussion and the cornerstone of re- Other side effects of HBOT search for therapeutic options in the setting of ret- Blood pressure effects. HBOT causes an in- rolental fibroplasias. crease in both systolic and diastolic blood pressure Retrolental fibroplasia remains an unfortunate (DBP). This holds true for both hypertensive and growing global problem and a devastating compli- nonhypertensive patients.81,82 Overall, the effect cation of premature infants in both industrialized on blood pressure is mild. One study reported an and developing nations. When severe, visual out- overall increase in systolic blood pressure (SBP) of comes are unfavorable even with treatment and it 6% and DBP of 12%.81 Another study reported in- still remains the most common cause of blind- creases in SBP of 7 mmHg, DBP of 4 mmHg, and ness.76 Prevention lies with a focus on research MAP of 5 mmHg.82 No patients experienced signs of investigating preventative treatments that can hypertensive urgency or emergency in these stud- modulate angiogenesis, for example, and sound ies.81,82 The effect diminished with each additional clinical practice regarding oxygen supplementa- treatment (protective).82 Calcium channel blockers tion and delivery in the premature infant. and beta-blockers exacerbated HBOT effect on blood pressure.81,82 Proposed mechanisms include in- Claustrophobia creased systemic vascular resistance through alpha- Claustrophobia is the fear of being enclosed in receptor-induced vasoconstriction. Endothelin-1 is smallspaceswithnoescapeandmaybetriggeredby elevated during HBOT and endothelin-1-induced different stimuli in the daily environment such as vasoconstriction may be involved.82–84 elevators, tunnels, small windowless rooms, base- ments, or even tight clothing. Symptoms may include . There is a theoretical risk sweating, palpitations, hyperventilation, light- of pulmonary edema in patients with compromised headedness, choking, chest tightness, increased blood left ventricular function who are undergoing pressure, trembling, anxiety, headache, confusion, or HBOT. There are limited published data, although even disorientation. Claustrophobia is thought to be the risk is low based off the data available. Two caused by classical conditioning, a result of past studies reported their incidence at 1 in 1,000 (0.1%) (usually childhood) experience or a learned behavior and 1 in 4,500 (0.02%).83,84 While the etiology is not from parents or peers. Other theories attribute the fully known, it appears to be related to hyperbaric size of the amygdala to a person experiencing claus- oxygen, inducing increased systemic vascular re- trophobia, with persons suffering from disor- sistance and decreased cardiac output.83,85 A re- ders having smaller amygdala.79 cent study evaluating the effects of hyperbaric Psychological effects of claustrophobia are expe- oxygen at 243 kPa found a reduction in cardiac rienced by some patients when placed in the tube- output due only to a decrease in heart rate with no like cylindrical monoplace chambers or under hoods impact on other cardiac function.86 Other potential and face masks in multiplace chambers. Between mechanisms of hyperbaric-induced pulmonary 15% and 37% of people worldwide are affected by edema include increased pulmonary capillary claustrophobia, with 5–7% affected by severe wedge pressure, myocardial damage, or consump- claustrophobia.80 It appears to be present in about tion of endothelial-derived NO by oxygen free 2% of the general patient population and may cause radicals, or cardiac output imbalance between the some degree of confinement anxiety, even in a right and left heart.84 Noncardiac acute pulmonary multiplace chamber. Incidence of confinement edema is not expected in patients with normal HYPERBARIC OXYGEN SIDE EFFECTS 221

cardiac function treated with HBOT. Nonetheless, SUMMARY it may occur in those with compromised baseline HBOT is an important advanced adjunctive cardiac function. Patients with a history of con- therapy in the treatment of certain problem gestive should have a baseline echo- wounds, primarily those as a result of late effect cardiogram before HBOT and caution should be radiation injury and diabetes. HBOT remains taken in patients with a low ejection fraction (EF) among the safest therapies used today. The side (i.e., <35–40%). Patients should not be fluid over- effects that have been described are self-limiting loaded. In addition, consideration should be given and often can be avoided with adequate screening. to treatment in a multiplace chamber in these pa- One of the most common side effects related to tients where they can sit upright and a tender is pressure changes is MEB. While it is commonly 84 immediately available. encountered, it is typically mild and self-limiting, and it can be prevented by ongoing teaching of Hypoglycemia in diabetics. HBOT stimulates middle techniques and appropriate residual insulin secretion in diabetics and increases compression rates. PBT is unlikely and can be 81 glucose utilization in the brain. This combination, avoided with appropriate pretreatment screening. along with other potential mechanisms, can theo- Oxygen toxicity is rare and most commonly en- retically lead to hypoglycemia in diabetic patients countered as a CNS oxygen toxicity seizure. This undergoing HBOT. As a result, hyperbaric medicine resolves with withdrawal of oxygen and does not facilities set minimum pretreatment serum glucose have any permanent implications. In addition, levels to undergo treatment. These minimum levels further HBOT is typically tolerated. Adjustment are as high as 150 mg/dL to as low as 100 mg/dL. of the treatment protocol to decrease maximum Overall published data suggest an overall mean pressure and provide additional air breaks may be decrease in the serum glucose levels for diabetics undertaken, but is not required. Pulmonary oxy- undergoing HBOT, but with a large range and a gen toxicity is not seen with typical elective treat- high percentage of patients who actually had an ments provided for problem wounds. Ocular side increase in their serum glucose. These include a effects should be monitored. Hyperoxic myopia, relatively low number of clinically relevant post- which is one of the most common side effects, is HBOT hypoglycemia episodes with no poor out- considered reversible. Providers should monitor comes reported. Finally, there are no clear risk the degree of change during treatment to assure factors for development of hypoglycemia, although safety with driving and instruct patients to avoid a lack of control appears to be a consistent new permanent prescription until at least 8 weeks 81,87,88 theme. One study had post-treatment serum after treatment is completed. Claustrophobia may glucose levels higher in 54% of treatments and be managed with coaching and anxiolytic medica- lower in 46% of treatments. They had only 1.5% tions. Intolerance of a monoplace chamber may <70 mg/dL, only 0.19% symptomatic, and no ex- warrant referral to the closest multiplace chamber treme hypoglycemia requiring assistance with facility. Hypoglycemia during HBOT is a legiti- 87 treatment. Another study had a median change mate concern, but clinically relevant hypoglycemia in serum glucose of -25 mg/dL, but with a range of is not common. Minimum pretreatment thresholds +240 mg/dL to -374 mg/dL. Only 1.2% of treat- should not be too laboriously high and overall in- ments had a post-treatment serum glucose <90 mg/ dividual patient glycemic control and day of treat- 88 dL and no one was symptomatic. Another had an ment trend should be of greater importance than average drop of 22%, but only 0.3% of cases where the absolute number. Finally, HBOT effects on BP 81 patients had symptomatic hypoglycemia. are not typically of clinical relevance except in the In light of these findings, current protocols may case of patients with a low EF or severe aortic require too high a minimum serum glucose level stenosis. Care should be taken in consideration of before treatment, although further evidence would treatment in these patients to avoid acute pulmo- be helpful. This is important since HBOT is an nary edema. adjunctive therapy to standard care, which in- cludes tight glycemic control for these patients. An absolute pretreatment minimum level of 100 mg/ ACKNOWLEDGEMENTS dL appears to be sufficient.87 In addition, the de- AND FUNDING SOURCES cision to pretreat with glucose and/or abort HBOT There were no funding sources related to the should include consideration of a patient’s docu- work presented. The authors thank the Upstate mented level of control and serum glucose trend on University Hospital staff, including Kimberly day of treatment. Rouselle and Sarah Seargent, for their support and 222 HEYBOER ET AL.

assistance in various studies, in- TAKE-HOME MESSAGES cluding quality studies that have been carried out. The authors also HBOT remains among the safest therapies used today. thank Susan Wojcik, PhD, and Wil- HBOT is the treatment of patients with 100% oxygen at liam Grant, EDD, from the De- higher than atmospheric pressure. It is both the primary and partment of Emergency Medicine, secondary effects that result in its beneficial effects and side SUNY Upstate Medical University, effects. for their assistance in study design One of the most common side effects identified in the peer- and statistical analysis. reviewed literature is MEB. It is typically mild and self- limited. Patient instruction on middle ear clearing, daily monitoring with otoscopic examination, and appropriate AUTHOR DISCLOSURES compression rates are important to its prevention. AND GHOSTWRITING Oxygen toxicity seizure is one of the most feared side effects The authors do not have any of HBOT. It is important to remember that this is an un- commercial conflicts of interest. The common and self-limiting side effect. It is resolved with article was written exclusively by withdrawal of 100% oxygen and has no long-term implica- the authors. tions. Continued HBOT is permissible and may be done with adjustment to maximum pressure and addition of air breaks. ABOUT THE AUTHORS Higher occurrence rates have been linked to higher treat- Marvin Heyboer III, MD, ment pressures. FACEP, FUHM, FACCWS, is an Associate Professor of Emergency Medicine at SUNY Upstate Medical University. He is board certified in Care physician and an Emergency Medicine physi- Undersea and Hyperbaric Medicine and Emergency cian at Upstate University Hospital. Norman Mc- Medicine. He is the Medical Director of Upstate Culloch, MD, MBA, is board certified in Internal University Hospital Hyperbaric Medicine and Medicine. He is fellowship trained in Undersea and

Wound Care Center and the Director of the Fellow- Hyperbaric Medicine and board eligible in Undersea ship in Undersea and Hyperbaric Medicine. He is and Hyperbaric Medicine with the American Board actively involved in research and has published of Preventive Medicine. He is also an NOAA Dive multiple articles in the areas of hyperbaric medicine Medical Officer. Deepali Sharma, MD, is a Fellow and wound care. William Santiago, MD, is an As- in Undersea and Hyperbaric Medicine at SUNY sistant Professor of Emergency Medicine at SUNY Upstate Medical University. She is residency trained Upstate Medical University. He is board certified in in Emergency Medicine. She is a practicing Emer- Undersea and Hyperbaric Medicine and Emergency gency Medicine physician at Upstate University Medicine. He is a Hyperbaric Medicine and Wound Hospital.

REFERENCES 1. Thom SR. Hyperbaric oxygen–its mechanism and 5. Weaver LK. Hyperbaric Oxygen Therapy Indica- 10. Shupak A, Gilbey P. Effects of pressure. In: Neuman efficacy. Plast Reconstr Surg 2011;127(S1):131S– tions, 13th ed. North Palm Beach, FL: Best Pub- TS, Thom SR. Physiology and Medicine of Hy- 141S. lishing Company, 2014. perbaric Oxygen Therapy. Philadelphia, PA: Saunders Elsevier, 2008:513–526. 2. Thom SR, Bhopale VM, Velazquez OC, Goldstein 6. Thom SR. Hyperbaric oxygen therapy. J. Intensive LJ, Thom LH, Buerk DG. Stem cell mobilization by Care Med 1989;4:58–74. 11. O’Neill OJ, Weitzner ED. The O’Neill grading hyperbaric oxygen. Am J Physiol Heart Circ Phy- system for evaluation of the tympanic membrane: siol 2006;290:1378–1386. 7. Heyboer III M, Jennings S, Grant WD, Ojevwe C, Byrne J, Wojcik SM. Seizure incidence by treat- a practical approach for clinical hyperbaric pa- tients. UHM 2015;42:265–271. 3. Goldstein LJ, Gallagher KA, Bauer SM, et al. En- ment pressure in patients undergoing hyperbaric dothelial progenitor cell release into circulation is oxygen therapy. UHM 2014;41:380–385. triggered by hyperoxia-induced increases in bone 12. Bluestone CD. Eustachian Tube Structure, Function, marrow nitric oxide. Stem Cells 2006;24:2309–2318. 8. Heyboer III M, Wojcik S, Grant WD, Chambers P, Role in Otitis Media. Hamilton, ON: BC Decker, Inc., Jennings S, Adcock P. Middle ear barotrauma in hy- 2005. 4. Liu ZJ, Velazquez OC. Hyperoxia, endothelial perbaric oxygen therapy. UHM 2014;41:359–363. progenitor cell mobilization, and diabetic wound 13. Beuerlein M, Nelson RN, Wellin DB. Inner and healing. Antioxid Redox Signal 2008;10:1869– 9. Jain KK. Textbook of Hyperbaric Medicine, 5th ed. middle ear hyperbaric oxygen-induced baro- 1882. Cambridge, MA: Hogrefe Publishing, 1999. trauma. Laryngoscope 1997;107:1350–1356. HYPERBARIC OXYGEN SIDE EFFECTS 223

14. Bluestone CD. Studies in otitis media: Children’s during hyperbaric oxygen therapy. Aviat Space 47. Hadanny A, Meir O, Bechor Y, Fishlev G, Bergan J, Hospital of Pittsburgh-University of Pittsburgh prog- Environ Med 2010;81:888–890. Efrati S. Seizures during hyperbaric oxygen ther- ress report—2004. Laryngoscope 2004;114(S105): apy: retrospective analysis of 62,614 treatment 30. Kellogg RH. La pression barometrique: paul bert’s 1–26. sessions. UHM 2016;43:21–28. hypoxia theory and its critics. Respir Physiol 1978; 15. Camporesi EM. Side effects of hyperbaric oxygen 34:1–28. 48. Clark JM, Lambertsen CJ. Pulmonary oxygen therapy. UHM 2014;41:253–257. toxicity: a review. Pharmacol Rev 1971;23:37–133. 31. Bert P. La Pression Barome´trique. Paris: Masson 16. Vahidova D, Sen P, Papesch M, Zein-Snachez M, et Cie, 1878. 49. Clark JM, Lambertsen CJ, Gelfand R, et al. Effects Mueller P. Does the slow compression technique of prolonged oxygen exposure at 1.5, 2.0; or 2.5 32. Lambertsen CJ. Effects of oxygen at high partial of hyperbaric oxygen therapy decrease the inci- ATA on pulmonary function in men (Predictive pressure. In: Fenn WO, Rahn H, eds. Handbook of dence of middle-ear barotraumas? J Laryngol Otol Studies V). J Appl Physiol 1999;86:243–259. Physiology. Bethesda, MD: Am Physiol Soc, 1965: 2006;120:446–449. 1027–1046. 50. Comroe JH, Dripps RD, Dumke PR, Deming M. The 17. Fitzpatrick D, Franck B, Mason K, Shannon S. Risk effect of of high of ox- 33. Bitterman N. CNS oxygen toxicity. UHM 2004;31: factors for symptomatic otic and sinus barotrauma ygen for twenty-four hours on normal men at sea 63–72. in a multiplace hyperbaric chamber. Undersea Hy- level and at a simulated altitude of 18,000 feet. perb Med 2010;37:203–208. 34. Lambertsen CJ, Kough RH, Cooper DY, Emmel GL, JAMA 1945;128:710–717. Loeschcke HH, Schmidt CF. Oxygen toxicity. Ef- 18. Clements KS, Vrabee JT, Mader JT. Complications 51. Clark JM, Lambertsen CJ. Rate of development of fects in man of oxygen inhalation at 1 and 3.5 of tympanostomy tubes inserted for facilitation of pulmonary O2 toxicity in man during O2 breathing atmospheres upon blood gas transport, cerebral hyperbaric oxygen therapy. Arch Otolaryngol Head at 2.0 atm abs. J Appl Physiol 1971;30:739–752. circulation and cerebral . Jr Applied Neck Surg 1998;124:278. Phys 1953;5:471–486. 52. Michel EL, Langevin RW, Gell CF. Effect of continuous 19. Presswood G, Zamboni WA, Stephenson LL, Santos human exposure to oxygen tension of 418 mmHg for 35. Torbati D, Church DF, Keller JM, Pryor W. Free PM. Effect of artificial airway on ear complications 168 hours. Aerosp Med 1960;31:138–144. radical generation in the brain precedes hyper- from hyperbaric oxygen. Laryngoscope 1994;104: baric oxygn-induced convulsions. Free Radic Biol 53. Herlocher JE, Quigley DG, Behar VS, et al. Phy- 1383–1384. Med 1992;13:101–106. siologic response to increased oxygen partial 20. Bessereau J, Tabah A, Genotelle N, Francais A, pressure. I. Clinical observations. Aerosp Med 1964; 36. Clark JM. Oxygen toxicity. In: Neuman TS, Thom Coulange M, Annane D. Middle-ear barotraumas 35:613–618. SR, eds. Physiology and Medicine of Hyperbaric after hyperbaric oxygen therapy. UHM 2010;37: Oxygen Therapy. Philadelphia, PA: Saunders 54. Thorsen E, Aanderud L, Aasen TB. Effects of a stan- 203–208. Elsevier, 2008:527–564. dard hyperbaric oxygen treatment protocol on pul- 21. Skevas T, Baumann I, Bruckner T, Clifton N, monary function. Eur Respir J 1998;12:1442–1445. 37. Chavko M, Auker CR, McCarron RM. Relationship Plinkert PK, Klingmann C. Medical and surgical between protein nitration and oxidation and de- treatment in divers with chronic rhinosinusitis and 55. Butler FK. Diving and Hyperbaric ophthalmology. velopment of hyperoxic seizures. Nitric Oxide 2003; paranasal sinus barotrauma. Eur Arch Otorhino- Surv Ophthalmol 1995;39:347–396. 9:18–23. laryngol 2012;269:853–860. 56. Nichols CW, Lambertsen CJ. Effects of high oxygen 38. Banham NDG. Oxygen toxicity seizures: 20 years 22. Gunn DJ, O’Hagan S. Unilateral optic neuropathy pressures on the eye. N Engl J Med 1969;281:25–30. experience from a single hyperbaric unit. Diving from possible sphenoidal sinus barotrauma after Hyperb Med 2011;41:202–210. 57. McMonnies CW. Hyperbaric oxygen therapy and recreational : a case report. UHM 2013; the possibility of ocular complications or contra- 40:81–86. 39. Donald KW. Oxygen poisoning in man. BMJ 1947; dictions. Clin Exp Optom 2015;98:122–125. 1:712–717. 23. Stoetzer M, Kuehlhorn C, Ruecker M, Ziebolz 58. Tibbles PM, Edelsberg JS. Hyperbaric-oxygen D, Gellrich NC, von See C. Pathophysiology of 40. Davis JC. Hyperbaric oxygen therapy. J Intensive therapy. N Engl J Med 1996;334:1642–1648. barodontalgia: a case report and review of Care Med 1989;4:55–57. the literature. Case Rep Dent 2012;2012: 59. Butler FK, Hagan C. Ocular complications in hy- 41. Plafki C, Peters P, Almeling M, Welslau W, Busch 453415. perbaric oxygen therapy. In: Neuman TS, Thom R. Complications and side effects of hyperbaric SR, eds. Physiology and Medicine of Hyperbaric 24. Robichaud R, McNally ME. Barodontalgia as a oxygen therapy. Aviat Space Environ Med 2000;71: Oxygen Therapy. Philadelphia, PA: Saunders Elsevier, differential diagnosis: symptoms and findings. J 119–124. 2008:565–572. Can Dent Assoc 2005;71:39–42. 42. Hampson N, Atik D. Central nervous system oxy- 60. Anderson B, Farmer JC. Hyperoxic myopia. Trans 25. Zadik Y, Drucker S. Diving dentistry: a review of gen toxicity during routine hyperbaric oxygen the dental implications of scuba diving. Australian therapy. UHM 2003;30:147–153. Am Ophthalmol Soc 1978;76:116–124. Dent J 2011;56:265–271. 43. Yildiz S, Aktas S, Cimsit M, Ay H, Togrol E. Sei- 61. Churchill S, Deru K, Wilson G, Cable R, Bell JE, 26. Cakmak T, Battal B, Kara K, et al. A case of zure incidence in 80,000 patient treatments with Weaver LK. Rates of visual acuity change in pa- tension pneumothorax during hyperbaric oxygen hyperbaric oxygen. Aviat Space Environ Med 2004; tients receiving hyperbaric oxygen in monoplace therapy in an earthquake survivor with crush 75:992–994. and multiplace chambers. UHM 2016:43:217–223. injury complicated by ARDS (adult respiratory 44. Welslau W, Almeling M. Toxicity of hyperbaric oxygen 62. Evanger K, Pierscionek BK, Vaagbo G, Thorsen E, distress syndrome). Undersea Hyperb Med (HBO)–incidence of major CNS-intoxications. Strah- Haugen OH. Myopic shift during hyperbaric oxy- 2015;42:9–13. lenther Onkol 1996;172(S2):10–12. genation attributed to lens index changes. Optom 27. Unsworth IP. Pulmonary barotrauma in a hyper- Vis Sci 2015;92:1076–1084. 45. Hampson NB, Simonson SG, Kramer CC, Pianta- baric chamber. 1973;28:675–678. dosi CA. Central nervous system oxygen toxicity 63. Evanger K, Haugen OH, Irgens A, Aanderud L, 28. Wolf HK, Moon RE, Mitchell PR, Burger PC. Bar- during hyperbaric treatment of patients with car- Thorsen E. Ocular refractive changes in patients otrauma and in hyperbaric oxygen bon monoxide poisoning. UHM 1996;23:215–219. receiving hyperbaric oxygen administered by or- therapy. Am J Forensic Med Pathol 1990;11:149– onasal mask or hood. Acta Ophthalmol Scand 2004; 46. Sanders RW, Katz KD, Suyama J, et al. Seizure 153. 82:449–453. during hyperbaric oxygen therapy for carbon 29. Rivalland G, Mitchell SJ, Van Schalkwyk JM. monoxide toxicity: a case series and five-year 64. Giblin FJ, Padgaonkar VA, Leverenz VR, et al. Pulmonary barotrauma and cerebral gas embolism experience. J Emerg Med 2012;42:e69–e72. Nuclear light scattering, disulfide formation and 224 HEYBOER ET AL.

membrane damage in lenses of older guinea pigs 77. Chow LC, Wright KW, Sola A. Can changes in 87. Stevens SL, Narr AJ, Claus PL, et al. The inci- treated with hyperbaric oxygen. Exp Eye Res 1995; clinical practice decrease the incidence of severe dence of hypoglycemia during HBO therapy: a 60:219–235. retinopathy of prematurity in very low birth retrospective review. UHM 2015;42:191–196. infants? Pediatrics 2003;111:339–345. 65. Palmquist BM, Philipson B, Barr PO. Nuclear cat- 88. Swaby J, Heyboer M, Wojcik S, Grant W. Effects aract and myopia during hyperbaric oxygen ther- 78. Weinberger B, Laskin DL, Heck DE, Laskin JD. of hyperbaric oxygen therapy on diabetic serum apy. B J Ophthalmol 1984;68:113–117. Oxygen toxicity in premature infants. Toxicol Appl glucose levels: an extended study. Undersea Hy- Pharmacol 2002;181:60–67. perb Med J 2015;42:190. 66. Kindwall EP, Whelan HT. Hyperbaric Medicine Practice, 3rd ed. Flagstaff, AZ: Best Publishing 79. Paddock M. Claustrophobia: causes, symptoms 89. Hart GB, Strauss MB. Central nervous system Company, 2008. and treatments. June 25, 2015. www.medical oxygen toxicity in a clinical setting. In: Bove newstoday.com/articles/37062 (last accessed AA, Bachrach AJ, Greenbaum LJ, eds. Under- 67. Solomon R, Donnenfeld ED. Recent advances and November 7, 2016). sea and Hyperbaric Physiology IX. Proceedings future frontiers in treating age-related cataracts. of the Ninth International Symposicum on Under- JAMA 2003;290:248–251. 80. Davey GC. Phobias: A Handbook of Theory, Re- water and Hyperbaric Physiology. Bethesda, MD: search and Treatment, 1st ed. West Sussex, Undersea and Hyperbaric Medical Society, 1987: 68. Allen D, Vasavada A. Cataract and surgery for England: John Wiley & Sons Ltd, 1997. cataract. BMJ 2006;333:128–132. 695–699. 81. Al-Waili NS, Butler GJ, Beale J, et al. Influences of 69. Gesell LB, Trott A. De Novo cataract development hyperbaric oxygen on blood pressure, heart rate and following a standard course of Hyperbaric Oxygen blood glucose levels in patients with diabetes mel- Therapy. UHM 2007;34:389–392. litus and hypertension. Arch Med Res 2006;37:991– Abbreviations and Acronyms 997. 70. Weikel KA, Garber C, Baburins A, Taylor A. Nutritional AGE ¼ arterial gas embolism modulation of cataract. Nutr Rev 2014;72:30–47. 82. Heyboer III M, Smith G, Santiago W, Wojcik SM. ATA ¼ atmospheres absolute CNS central nervous system 71. Giblin FJ. Glutathione: a vital lens antioxidant. J Effect of hyperbaric oxygen therapy on blood ¼ CO carbon dioxide Ocul Phamacol Ther 2000;16:121–135. pressure. UHM;.Accepted September 27, 2016. 2 ¼ COPD ¼ chronic obstructive pulmonary 72. Butler FK. The eye in the wilderness. In: Auerbach 83. Abel FL, Mcnamee JE, Cone DL, Clarke D, Tao J. disease P, eds. Wilderness Medicine, 5th ed. St Louis: Effects of hyperbaric oxygen on ventricular DBP ¼ diastolic blood pressure Mosby, 2007:604–624. performance, pulmonary blood volume, and EF ¼ ejection fraction systemic and pulmonary vascular resistance. ET ¼ Eustachian tube 73. Ashton N, Ward B, Serpell G. Role of oxygen in UHM 2000;27:67–73. HBOT ¼ hyperbaric oxygen therapy the genesis of retrolental fibroplasia: a prelimi- IGF-1 ¼ insulin-like growth factor nary report. Br J Ophthalmol 1953;37:513–520. 84. Weaver LK, Churchill S. Pulmonary edema asso-

MEB ¼ middle ear barotrauma ciated with hyperbaric oxygen therapy. Chest NO ¼ nitric oxide 74. Teoh SL, Boo NY, Ong LC, Nyein MK, Lye MS, Au 2001;120:1407–1409. ONOO- ¼ peroxynitrite MK. Duration of oxygen therapy and exchange PaO ¼ partial pressure of oxygen in transfusion as risk factors associated with reti- 85. Whalen RE, Saltzman HA, Holloway DH Jr, et al. 2 arterial blood nopathy of prematurity in very low birth weight Cardiovascular and blood gas response to hy- PBT ¼ pulmonary barotrauma infants. Eye 1995;9:733–737. perbaric oxygenation. Am J Cardiol 1965;15:638– pO partial pressure of oxygen 646. 2 ¼ 75. Patz A. The role of oxygen in retrolental fibro- PTX ¼ pneumothorax plasia. Tr Am Ophth Soc 1968;66:940–985. 86. Gawthrope IC, Playford DA, King B, Brown K, ROS ¼ reactive oxygen species Wilson C, McKeown B. The cardiac effects of SBP ¼ systolic blood pressure 76. Sola A, Chow L, Rogido M. Retinopathy of pre- hyperbaric oxygen at 243 kPa using inchamber TM ¼ tympanic membrane maturity and oxygen therapy: a changing relation- echocardiography. Diving Hyperb Med 2014;44: VEGF ¼ vascular endothelial growth factor ship. An Pediatr (Barc) 2005;62:48–61. 141–145.