Seizures during hyperbaric oxygen therapy: retrospective analysis of 62,614 treatment sessions

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1 Seizures during hyperbaric oxygen therapy: retrospective analysis of 62,614 treatment sessions A. Hadanny, M.D. 1,2,3, O. Meir, B.A. 1, Y. Bechor, B.A. 1, G. Fishlev, M.D. 1, J. Bergan, S. Efrati, M.D. 1,2,3,4 1 The Sagol Center for Hyperbaric Medicine and Research, Assaf Harofeh Medical Center, Zerifin, Israel 2 Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel 3 Research and Development Unit, Assaf Harofeh Medical Center, Zerifin, Israel 4 Sagol School of Neuroscience, Tel-Aviv University, Tel-Aviv, Israel CORRESPONDING AUTHORS: Amir Hadanny amir.had@gmail.com and Shai Efrati efratishai@013.net ABSTRACT Introduction: Hyperbaric oxygen (HBO 2 ) therapy is considered to be a generally safe therapy. However, data regarding seizure incidence during HBO 2 therapy as a clinical presentation of central nervous system- (CNS) related oxygen toxicity are conflicting (ranging from 1:10,000 to 1:600 seizures:hyperbaric sessions). The risk for seizures is of significant importance for the growing population of patients suffering from chronic neurological disorders such as traumatic brain injury and stroke who are treated with HBO 2. The aim of this study was to evaluate the incidence of seizures during HBO 2 therapy in a large cohort of patients and determine whether patients with known chronic neurological disorders are at increased risk. Methods: Retrospective analysis of 2,334 patients treated at the Sagol Center of Hyperbaric Medicine and Research, Assaf Harofeh Medical Center, Israel, between June 2010 and December Patients were grouped into one of three categories according to indication for HBO 2 therapy: Category A nonneurological indications; Category B neurological indications; and Category C acute indications. Results: A total of 62,614 hyperbaric sessions, administered to 2,334 patients, were included in the analysis. The overall incidence of seizures during hyperbaric sessions was 0.011% (1:8,945), occurring in seven (0.3%) patients. Only one patient had a clear oxygen toxicity-induced seizure, with an overall incidence of 1:62,614. Conclusions: Seizures induced by oxygen toxicity during HBO 2 therapy are extremely rare. Moreover, in relation to oxygen-induced seizures, HBO 2 therapy can be considered safe for patients suffering with chronic neurological disorders except for uncontrolled epilepsy. Introduction Hyperbaric oxygen (HBO 2 ) therapy is being utilized for a growing number of patients with a wide diversity of comorbid illnesses. In particular, the number of patients with chronic neurological disorders such as traumatic brain injury and stroke has grown significantly. Patients with chronic neurological disorders are being referred for HBO 2 therapy for non-healing wound indications (such as diabetic ulcers and crush injuries) and for the neurotherapeutic effects of HBO 2 therapy [1-3]. The possibility that oxygen can induce hyperactivation of the central nervous system (CNS) was first suggested in 1878 [4]. Breathing hyperbaric oxygen can culminate in grand mal seizures, secondary to so-called oxygen toxicity, with or without preceding symptoms and signs. CNS hyperactivation and the development of seizures depend upon the partial pressure of oxygen and the duration of exposure [5]. The exact mechanism underlying CNS-related oxygen toxicity is not fully understood. One suggested mechanism involves reactive KEYWORDS: hyperbaric oxygenation, hyperbaric oxygen therapy, central nervous system oxygen toxicity, complications, adverse effects, side effects Copyright 2016 Undersea & Hyperbaric Medical Society, Inc. 21

2 oxygen species during HBO 2 therapy that cause membrane lipid peroxidation and enzyme inhibition and/or modulations that lead to alterations in brain metabolism and its related electrical activity [6]. There is no clear evidence that seizures are related to oxygen induced metabolic changes, however, an increase of glucose utilization precedes the onset of electrophysiological manifestations of CNS oxygen-toxicity [5]. Another suggested mechanism relates to increased nitric oxide (NO) levels in the brain, which may cause vasodilation in cerebral vessels and further increase oxygen delivery to the brain [7]. HBO 2 therapy is considered to be a generally safe therapy. However, as clinical presentations of CNSrelated oxygen toxicity, seizures are reported with conflicting incidence range, from 1:10,000 and up to 1:600 seizures:hyperbaric sessions [8]. HBO 2 -induced seizures are defined as brief, oxygen-related, generalized tonic-clonic convulsions usually occurring toward the end of the treatment [5]. Non-oxygen-related seizures in epileptic patients treated with HBO 2 therapy, even though rare, should be differentiated from oxygen toxicity-related seizures [5]. Interestingly, in some cases where there is an epileptic focus secondary to circulatory and metabolic disturbances, HBO 2 may even abort seizures by correcting these abnormalities [9]. CNS-related oxygen toxicity risk factors include fever, hypoglycemia, carbon monoxide poisoning, hypercapnia, alcohol dependence and several medications (such as antidepressants, disulfiram, tramadol and cephalosporins) [5,10]. In addition, neurological disorders such as cerebral palsy, head trauma, stroke, autism and others are thought to lower seizure threshold [5,11]. The aim of this study was to evaluate the incidence of seizures during HBO 2 therapy in a large cohort of patients and determine whether patients with known neurological disorders are at increased risk. Methods The study included all patients treated in the Sagol Center of Hyperbaric Medicine and Research, Assaf Harofeh Medical Center, Israel, between June 2010 and December 2014 (since June 2010, adverse effects were strictly recorded in the medical records). Data collected retrospectively from patients medical files included age, sex, chronic diseases, medications, indication for HBO 2, HBO 2 protocol (pressure and duration), number of sessions, side effects and reason for stopping treatment. The study was approved by the Helsinki Ethics Committee of Assaf Harofeh Medical Center. Patient categorization Patients were categorized into one of the following three groups: Category A Patients with non-neurological indications including non-healing wounds, nonneurological radiation injury, osteomyelitis, avascular necrosis (AVN), complex fractures, Crohn s disease and idiopathic hearing loss. Category B Patients with neurological disorders due to stroke (both ischemic and hemorrhagic), traumatic brain injury, cerebral palsy, pervasive developmental disorder and radiation injury to the brain. Category C Patients with acute indications for HBO 2 including decompression sickness, carbon monoxide (CO) poisoning, acute limb ischemia or central retinal artery occlusion. Pre-HBO 2 therapy evaluation Prior to the first session all patients were evaluated by a hyperbaric physician. Chest X-ray was obtained for each patient. Electrocardiogram (ECG) was performed in patients with a history of cardiovascular disease. History of epilepsy or seizures mandated a seizure-free interval of at least six months and a normalized electroencephalogram (EEG). Before each session, heart rate, blood pressure and temperature were obtained in all patients. Blood glucose was measured before each session in diabetic patients. Contraindication for HBO 2 therapy Closed pneumothorax was a contraindication for HBO 2 therapy. Relative contraindications included active uncontrolled bronchial asthma, severe obstructive pulmonary disease and pregnancy (depending on the urgency of the indication for HBO 2 therapy). Patients with fever did not receive HBO 2 therapy until the fever was under control with antipyretic medications or resolved. 22 Hadanny A, Meir O, Bechor Y, et al.

3 HBO 2 therapy protocols HBO 2 therapy was performed in a multiplace chamber equipped with video cameras and an intercom for patient observation. In addition, a registered nurse certified as a hyperbaric attendant was present inside the chamber during each session for patients care. Patients were treated five times per week with different protocols depending on the indication: 100% oxygen at 1.5 atmospheres absolute (atm abs) for 60 minutes with no air breaks and 0.8-meter-per-minute compression and decompression; 100% oxygen at 2 atm abs for 90 minutes with five-minute air breaks every 30 minutes and 1-meter-per-minute compression and decompression; and 100% oxygen at 2.4 atm abs for 90 minutes with five-minute air breaks every 30 minutes and 1-meter-per-minute compression and decompression. In addition, decompression sickness HBO 2 treatments were performed according to U.S. Navy Treatment Tables: USN 5, USN 6, USN 6A [12]. Oxygen was supplied via masks or hoods. In-chamber seizure protocol In cases of suspected seizures during the treatment, the nurse attendant removed the patient s mask or hood, examined the patient by advanced cardiac life support (ACLS) protocols and checked the patient s blood glucose. The on-site physician then decided whether anti-convulsions drugs such as benzodiazepines should be given. Whether these medications were given or they were not, the patient was immediately decompressed and removed from the chamber for further evaluation. Statistical analysis Data are expressed as frequencies and percentages for non-parametric variables. Univariate analysis was performed using chi-square/fisher s exact test to identify significant variables (p<0.05). Numeric variables analysis was performed using one-way ANOVA and Bonferroni post-hoc multiple comparison. Methods were performed using the SPSS v.21 software (SPSS Inc., Chicago, Illinois). Results A total of 62,614 hyperbaric sessions, administered to 2,334 patients, were included in the analysis. The mean age of the patients was 52.3 ± 22.5 years, while 240 (10.3%) were children under the age of 16 years. The male-to-female ratio was 1.8:1. Regarding the indication for treatment: 25,072 sessions (783 patients) were under Category A; 36,195 sessions (1,236 patients) were under Category B, which included neurological indications; 1,347 sessions (310 patients) were under Category C, which included emergency indications. Most of the non-emergent treatments were carried out at 2 atm abs (99% in Category A and 78% in Category B), while the majority (92%) of emergent exposures were at 2.4 atm abs or higher pressures. Table 1 summarizes patients characteristics. The overall incidence of seizures during hyperbaric sessions was 0.011% (1:8954), occurring in seven (0.3%) patients. Of the seven patients who developed seizures during HBO 2 therapy: Five patients had a history of seizures prior to HBO 2 therapy. Three of the five patients treated urgently for an acute air embolism suffered from seizures a few minutes to several hours prior to the hyperbaric exposure secondary to their primary diagnosis of acute air embolism. They experienced similar seizures during HBO 2 therapy. The seizures were treated with intravenous benzodiazepines and phenytoin. Two of the five patients had a history of epilepsy prior to HBO 2 therapy, and their epilepsy was treated with anti-epileptic medications prior to HBO 2 initiation. One patient was being treated for a traumatic brain injury and the other for a nonhealing wound. During HBO 2 therapy, they both had seizures episodes very similar to those they typically suffer from. The seizures were treated in the chamber using intravenous benzodiazepines. Two patients were seizure-naïve, i.e., without any record or history of prior seizures. One patient was being treated for a non-healing wound and experienced a seizure at her home, 34 hours after her eighth session, which excluded oxygen toxicity as a possibility. The other patient was being treated for stroke-related neurological damage and suffered a true oxygen toxicity seizure during her second hyperbaric session (100% at 2 atm abs). The seizure stopped after mask removal and the patient regained consciousness after 10 minutes. The seizure incidence per group is summarized in Figure 1. Hadanny A, Meir O, Bechor Y, et al. 23

4 Table1: Patients baseline characteristics total A B C comparison comparison between between A-B Groups # A-B-C Groups # number of patients sessions 62,614 25,072 36, mean sessions 26.8 ± ± ± ± 4.9 *0.01 *< per patient age 52.3 ± ± ± ± 21.9 *0.017 *< children (10.3%) 18 (2.3%) 190 (15.3%) 32 (10.3%) *< *< sex males 1495 (64%) 455 (57.9%) 8727 (66.8%) 213 (68.7%) *< *< females 839 (36%) 321 (42.1%) 411 (33.2%) 97 (31.3%) treatment protocol 1.5 atm abs 271 (11.6%) (21.8%) 0 *< *< atm abs 1768 (75.7%) 270 (99%) 968 (78.2%) 23 (7.4%) 2.4 atm abs 295 (12.6%) 8 (1.0%) 0 (0%) 287(92.6%) Category A included patients with non-healing wounds, non-neurological radiation injury, osteomyelitis, AVN, fractures, Crohn s disease, idiopathic hearing loss. Category B included patients with stroke (both ischemic and hemorrhagic), traumatic brain injury, cerebral palsy, autism and radiation injury to the brain. Category C included patients with acute indications including decompression sickness, CO poisoning, acute limb ischemia, central retinal artery occlusion. Inter-group differences significance was calculated using chi-square test for non-para-metric variables and one-way ANOVA for continuous parameters. Category C patients, treated for emergency indications, were significantly different from the chronic subgroups A and B. accordingly, post-hoc analysis comparing subgroups A and B was performed. Continuous parameters are expressed as mean ± SD. Statistical significance was considered as p<0.05. # Comparison between A-B-C groups were by chi-square and ANOVA tests and comparison between A-B groups were by chi-square and Bonferroni post-hoc tests. * Statistical significance (p<0.05) The overall incidence of clear oxygen toxicity seizures was 1:62,614. At hyperbaric pressure of 1.5 atm abs no seizure events were recorded (0:12,303). At 2 atm abs, the seizure incidence was 4:49,049, from which clear oxygen toxicity was 1:49,049. At 2.4 atm abs or higher pressure, the incidence of seizures increased to 1:419, but none could be attributed to clear oxygen toxicity (0:1,259) (Figure 2). There was no significant difference in seizures incidence between neurological and non-neurological indications (Fisher s exact test=1). Discussion This study summarizes one of the largest cohorts of patients treated with HBO 2 therapy. From a total of 62,614 HBO 2 sessions, seven seizure events were recorded while only one case could be considered to be true oxygen toxicity seizure a calculated incidence of 1.59:100,000. Based on these numbers, HBO 2 therapy can thus be considered to be safe for all treatment categories including in patients with neurologic disorders such as traumatic brain injury, stroke, cerebral palsy, autism and radiation injury to the brain. 24 Hadanny A, Meir O, Bechor Y, et al.

5 Figure 1: Hyperbaric pressure and seizures 1,000 n seizures n oxygen toxicity seizures atm abs 2 atm abs 2.4 atm abs number of seizures per 100,000 sessions The calculated seizure incidence per 100,000 sessions in the different hyperbaric pressures. Figure 2: Seizures per diagnosis 1,000 n seizures n oxygen toxicity seizures non-neurological indications neurological indications emergency indications number of seizures per 100,000 sessions The calculated seizure incidence per 100,000 sessions per category. Hadanny A, Meir O, Bechor Y, et al. 25

6 Seizures during HBO 2 therapy should be classified as oxygen toxicity seizures or non-oxygen related seizures. In order to define the seizure as oxygenrelated, a careful history should be obtained in order to rule out seizures/unexplained loss of consciousness prior to HBO 2 therapy. In addition, oxygen toxicity seizures occur during the oxygen exposure itself, and are usually resolved easily once the partial pressure of oxygen is reduced (by removing the patient s mask or hood). Non-oxygen-related seizures are a result of a prior epileptogenic focus, which may be activated in sporadic times irrespective of the hyperbaric oxygen environment. In addition to non-oxygen related seizures, hypoglycemia should also be part of the differential diagnosis. Hypoglycemia can cause alteration in consciousness level and cause tremor or other limb movements that may be misdiagnosed as oxygen toxicity. Hyperbaric exposure increases the risk for hypoglycemia mostly in diabetic patients due to increased metabolism and glucose consumption as well as the temporary fast during treatment [13]. Therefore, patients with suspected seizures during HBO 2 therapy should have their oxygen source removed and their blood glucose tested. In the literature, there are mixed reports regarding the rate of oxygen toxicity seizures. The commonly accepted value of 10 per 100,000 was based on several studies from the 1980s [14,15]. Later studies showed higher rates, which may have reflected changes in patient selection and treatment protocols [8,16-18]. Patient selection Yildiz et al. [11] had the lowest incidence of seizures reported in the literature: 2.4:100,000. This low proportion could be attributed to excluding patients with known neurological pathology due to stroke, head trauma and cerebral palsy from their analysis. In the Yildiz study patients were using masks, not hoods, with five-minute air breaks every 30 minutes. In the current study, while all adult patients were also treated by masks and had air breaks, the very low incidence of oxygen toxicity was preserved even though patients with neurological disorders were included in the analysis. HBO 2 protocol Banham showed that hyperbaric oxygen at pressures higher than 2 atm abs increases the risk for oxygen toxicity seizures [8]. In our study, most of the patients (87%) were treated with atm abs. At treatments with pressures between 1.5 to 2.0 atm abs, no oxygen toxicity seizures were recorded. This is in agreement with a recent work by Heyboer, et al., recording zero seizures in 16,430 sessions at 2 atm abs [19,20]. However, a low incidence of oxygen toxicity was also noticed in hyperbaric pressure exposures higher than 2 atm abs. Our overall low incidence of oxygen toxicity can be explained by several factors. First, one of the key reasons is that hyperbaric oxygen exposure was kept to the lowest dose considered effective. Hyperbaric pressures of up to 2 atm abs were administered in most of the sessions (~97%). The duration of the session did not exceed 90 minutes of continuous oxygen exposure with air breaks, or 60 minutes without air breaks. Second, we used masks instead of hoods: it has been previously suggested that hoods increase oxygen toxicity due to increased oxygen partial pressure and carbon dioxide accumulation [7]. We used tight masks as the default, while only children treated at 1.5 atm abs (0.3%) used hoods. Third, patients with known epilepsy were screened using EEG prior to HBO 2 therapy. Epileptic patients had to be well controlled, with a seizure-free period of at least six months prior to HBO 2 therapy. Emergency indications Emergency indications such as CO poisoning are considered to increase the risk for seizures [8,21]. In our study, no seizures were recorded in this patient population. With regard to CO poisoning, the low rate of seizures might be explained by the treatment protocol used: first session at 2.4 atm abs followed by two 2-atm abs sessions instead of the previously used protocol of atm abs [22,23]. Three patients treated for air emboli, in accordance with USN 6A protocol, who had seizures as part of their clinical presentation before entering the chamber, suffered from seizures during their hyperbaric exposure. Although they were treated with high oxygen pressure (3.0 atm abs at 26 Hadanny A, Meir O, Bechor Y, et al.

7 50 msw and 2.8 atm abs at 18 msw, as per USN 6A protocol) these seizures were probably not related to oxygen toxicity. STRENGTHS AND LIMITATIONS The current study has several strengths and limitations. Most of the limitations are related to the fact that data was collected retrospectively. Retrospective cohort study may increase the risk for selection bias. However, in order to eliminate this risk, all patients treated in our institute in the past four and a half years were included without any exclusions. With regard to strengths, this is one of the largest cohorts of HBO 2 therapy analyzed for seizure incidence that also included patients with known neurological disorders. Conclusion Seizures induced by oxygen toxicity during HBO 2 therapy are rare. Moreover, in relation to oxygeninduced seizures, our findings suggest that HBO 2 therapy can be considered to be safe for all treatment categories including in patients with neurologic indications such as traumatic brain injury, stroke, cerebral palsy, autism and radiation injury to the brain. Conflict of interest The authors have declared that no conflict of interest exists with this submission. n REFERENCES 1. Efrati S, Fishlev G, Bechor Y, et al. Hyperbaric oxygen induces late neuroplasticity in post stroke patients--randomized, prospective trial. PLoS One. 2013;8(1):e Efrati S, Ben-Jacob E. Reflections on the neurotherapeutic effects of hyperbaric oxygen. Expert Rev Neurother. 2014;14(3): Boussi-Gross R, Golan H, Fishlev G, et al. Hyperbaric oxygen therapy can improve post concussion syndrome years after mild traumatic brain injury - randomized prospective trial. PLoS One. 2013;8(11): e Kellogg RH. La pression barometrique: Paul Bert s hypoxia theory and its critics. Respir Physiol. 1978;34(1): Jain KK, Torbati D, Tao HY, Ni GT. Oxygen toxicity. textbook of hyperbaric medicine. 1999; 4th edition: Torbati D, Church DF, Keller JM, Pryor WA. Free radical generation in the brain precedes hyperbaric oxygeninduced convulsions. Free Radic Biol Med. 1992;13(2): Chavko M, Auker CR, McCarron RM. Relationship between protein nitration and oxidation and development of hyperoxic seizures. Nitric Oxide. 2003; 9(1): Banham ND. Oxygen toxicity seizures: 20 years experience from a single hyperbaric unit. Diving Hyperb Med. 2011; 41(4): Wassmann W. [Quantitative indicators of electrical brain activity changes during hyperbaric oxygenation (author s transl)]. EEG EMG Z Elektroenzephalogr Elektromyogr Verwandte Geb. 1980; 11(2): Seidel R, Carroll C, Thompson D, et al. Risk factors for oxygen toxicity seizures in hyperbaric oxygen therapy: case reports from multiple institutions. Undersea Hyperb Med. 2013; 40(6): Yildiz S, Aktas S, Cimsit M, Ay H, Togrol E. Seizure incidence in 80,000 patient treatments with hyperbaric oxygen. Aviat Space Environ Med. 2004; 75(11): U.S Navy Diving Manual. 2008: Revision 6: Peleg RK, Fishlev G, Bechor Y, et al. Effects of hyperbaric oxygen on blood glucose levels in patients with diabetes mellitus, stroke or traumatic brain injury and healthy volunteers: a prospective, crossover, controlled trial. Diving Hyperb Med. 2013; 43(4): Clark JM, Lambertsen CJ. Pulmonary oxygen toxicity: a review. Pharmacol Rev. 1971; 23(2): Clark JM. Oxygen toxicity. The physiology and medicine of diving. 1982; 3rd edition: Plafki C, Peters P, Almeling M, Welslau W, Busch R. Complications and side effects of hyperbaric oxygen therapy. Aviat Space Environ Med. 2000; 71(2): Smerz RW. Incidence of oxygen toxicity during the treatment of dysbarism. Undersea Hyperb Med. 2004; 31(2): Hampson N, Atik D. Central nervous system oxygen toxicity during routine hyperbaric oxygen therapy. Undersea Hyperb Med. 2003; 30(2): Hadanny A, Meir O, Bechor Y, et al. 27

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