Adverse Effects of Hyperbaric Oxygen Therapy: a systematic review and meta-analysis

doi:10.21203/rs.3.rs-2453696/v1

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Method Article

Adverse Effects of Hyperbaric Oxygen Therapy: a systematic review and meta-analysis

https://doi.org/10.21203/rs.3.rs-2453696/v1

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Objective

Hyperbaric oxygen therapy is one of the common clinical treatments, but adverse effects have hampered and limited the clinical application and promotion of hyperbaric oxygen therapy. We conducted a systematic review and meta-analysis of the adverse effects of hyperbaric oxygen therapy to provide a theoretical basis for clinical treatment.

Methods

Three electronic databases (Pubmed, Web of Science, Cochrane) were comprehensively searched for randomized clinical trials (RCTs) from March, 2012 to October, 2022. Two reviewers independently screened titles and abstracts for eligibility and assessed the quality of the included studies. The meta-analysis was performed using RevMan 5.3.

Results

A total of 26 RCTs involving 1497 participants were identified. ①HBOT group reported more adverse effects (29.81% vs 10.34%, P < 0.05). ②The most frequent side effect of HBOT is ear discomfort (124 cases). ③When the courses of hyperbaric oxygen was > 7 sessions, the incidence of adverse effects was higher than that of the control group; when the course of HBOT was ≤ 7 sessions, the adverse effects caused by hyperbaric oxygen were comparatively lower.④ When chamber pressures are above 2.0 ATA, the incidence of adverse effects is higher than that of the control group; when chamber pressure is below 2.0 ATA, HBOT is relatively safe.

Conclusion

HBOT is more likely to cause adverse reactions when the course of HBOT is > 7 sessions and chamber pressure is above 2.0 ATA.

Randomized controlled trial

Systematic review

Meta-analysis

Hyperbaric Oxygen Therapy

Adverse Effects

Safety

Hyperbaric oxygen therapy (HBOT), a technique through which 100% oxygen is provided at a pressure higher than 1 atm absolute (ATA), has become a well-proven treatment modality for multiple conditions ¹. The clinical application of HBOT is becoming more widespread and currently approved indications include air or gas embolism, acute thermal burn injury, carbon monoxide poisoning, central retinal artery occlusion, clostridial myositis and myonecrosis, decompression sickness, delayed radiation injury, idiopathic sudden sensorineural hearing loss, intracranial abscess, necrotizing soft tissue infections, etc. In addition to approved indications, further studies have demonstrated the potential applications and translation of HBOT in the field of inflammatory and systemic conditions, cancer, COVID-19 and other conditions are summarized².

During the application of HBOT, a few adverse effects have been identified, for instance, middle ear barotrauma, sinus and paranasal sinus barotrauma, ocular side effects, hypoglycemia, epilepsy, claustrophobia, etc. ³ The occurrence of these adverse effects affects the application and promotion of HBOT. Systematic reviews and meta-analyses of the adverse effects of HBOT are still lacking. We conducted a systematic review and meta-analysis of the adverse effects of HBOT to provide a theoretical basis for clinical treatment.

Therefore, the research question for this systematic review was:

Does Hyperbaric oxygen therapy cause more adverse effects when compared with sham therapy or another intervention?

This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.⁴ We have registered this review in PROSPERO (registered ID CRD42022316605).

Search Strategy and Selection of Studies:

Three electronic databases (Pubmed, Web of Science, Cochrane) were comprehensively searched for randomized controlled trials (RCTs) from March, 2012 to October, 2022 by two authors independently, with no language restriction. Taking PubMed as an example, the following search terms were used for study retrieval: ((((((((((Hyperbaric Oxygenations) OR (Oxygenations, Hyperbaric)) OR (Hyperbaric Oxygen Therapy)) OR (Hyperbaric Oxygen Therapies)) OR (Oxygen Therapies, Hyperbaric)) OR (Oxygen Therapy, Hyperbaric)) OR (Therapies, Hyperbaric Oxygen)) OR (Therapy, Hyperbaric Oxygen)) OR (Oxygenation, Hyperbaric)) OR (HBO)) OR (HBOT).

1.1 Inclusion And Exclusion Criteria

Only RCTs were included in the analysis. Case-control studies, case series and case reports were not considered. All participants in treatment group received HBOT alone or in combination with other therapeutic approaches, with no restriction on age, gender, race and severity of disease. Patients in control group received placebo or other treatments except for HBOT. Studies with a retrospective nature, irrelevant topics, no controls, duplicated data or insufficient data were also excluded. The results included the adverse effects of HBOT.

1.2 Methodological Quality And Risk Of Bias Assessment

Two authors evaluated the risk of bias with regard to adverse event outcomes by using the tool recommended by the Cochrane Collaboration Handbook. Each study was categorized into “low”, “unclear” and “high” risk of bias by two reviewers base on following domains: random sequence generation, allocation concealment, blinding to participants, researchers and outcome evaluators, incomplete data, selective outcome reporting and other sources of bias.

1.3 Data Extraction

A pre-defined Excel form was used for data collection. Extracted information included the first author’s name, year of publication, age, sample size, interventions, follow-up and adverse events. We directly contracted the first or correspondence author by e-mail for insufficient or ambiguous data. Discrepancies were resolved by team discussion.

1.4 Statistical Analysis

Statistical analysis was performed by Review Manager 5.3. For each included study, we calculated risk ratio and 95% confidence interval (95% CI) for incidence rate in the intervention arm compared with that of control, based on the reported number of events and sample size. We used the I² index to examine heterogeneity across trials for each outcome. A fixed-effect model was utilized for meta-analysis if I² < 25% or P > 0.10. Otherwise, a random effect model was used (I² > 25% or P < 0.10). Significance was accepted at P < 0.05. We conducted subgroup analysis by different control groups, different adverse events, different treatment courses, different chamber pressure, and different types of diseases. For subgroup analysis of different adverse effects, when fewer than two studies report a particular adverse effect, the adverse effect was included in the "other adverse effects"; when the study mentioned the adverse event as a barotrauma but did not mention that the barotrauma site, it was not included in the subgroup analysis. For subgroup analyses of different types of diseases, when there were fewer than two researches studying one disease, the disease was not included in the subgroup analysis.

2.1 Summary of the included studies

Totally 1554 articles were identified. We removed 301 duplications and excluded another 1029 records after screening the title and abstract. Thus, 129 full-text articles were further assessed for eligibility. As shown in Fig. 1, we excluded studies with no reporting of adverse effects(n = 174), only report that no adverse events were reported (n = 18), failure to report exact number of adverse events(n = 6). Finally, 26 RCTs^5–30 involving 1497 participants (842 in HBOT group and 745 in control group) were included for meta-analysis.

Detailed characteristics of included trials were descripted in Table 1. All studies were published from 2012 to 2022. The average age of participants ranged from 5 to 70 years. Hyperbaric oxygen therapy was explicitly described by authors in 14 of the trials, including chamber pressures, treatment courses, and eight of them specify the rate of compression. Diseases involved in the studies includes cerebral palsy, childhood autism, stroke, sudden sensorineural hearing loss, fibromyalgia syndrome, persistent postconcussion symptoms, diabetes with nonhealing ulcers of the lower limb, chronic bowel dysfunction after pelvic radiotherapy, prostate cancer, adhesive postoperative small bowel obstruction, chronic venous leg ulcers, radiation-induced cystitis, osteoradionecrosis, mild traumatic brain injury, central airway stenosis after lung transplantation, COVID- 19 severe hypoxaemia, post-traumatic stress disorder and chronic nonhealing ulcer. In all trials, the treatment course was 7–60 sessions, the chamber pressure in HBOT group was 1.45-2.5ATA, and the chamber pressure in control group was 1.03-2.2ATA. The adverse effects mentioned in the study includes ear discomfort, sinus pain, ocular side effects, seizure, claustrophobia, chest pain, gastrointestinal reaction, headache, fatigue, congestive heart failure.

Table 1

Details of HBOT studies included in the performance meta-analysis
Study ID	Sample size		Age (years)		Disease	Intervention		Course (session)	Adverse events
Study ID	T	C	T	C	Disease	T	C	Course (session)	T	C
Lacey2012³¹	24	22	6.3 ± 1.3	5.2 ± 2.0	Cerebral palsy	100% oxygen at a pressure (or depth) of 1.5ATA	Room Air(21% oxygen) at 1.5ATA	40	Ear pain (7)	Ear pain (8)
Sampanthavivat2012²⁹	29	29	6.10	5.67	Childhood autism	100% oxygen at a pressure (or depth) of 1.5ATA	Room Air(21% oxygen) at 1.15ATA	20	Minor-grade ear barotrauma (11)	Minor-grade ear barotrauma (3)
Chen2013⁵	33	32	60.3 ± 9.3	60.5 ± 9.5	Progressive cerebral infarction	100% oxygen at a pressure (or depth) of 1.5ATA	Conventional treatment	14	Ear pain (1); gastrointestinal reaction (1)	Rash (1)
Efrati2013⁶	59	29	61 ± 12	63 ± 6.3	Stroke	90 minutes each, 100% oxygen at 2ATA	Conventional treatment	40	Mild-moderate barotrauma of the middle ear (6)	No
Cvorovic2013⁷	25	25	53.6 ± 15.5	47.3 ± 10.8	Sudden sensorineural hearing loss	100% oxygen at a pressure (or depth) of 2.0ATA	Conventional treatment	20	Serous otitis media (3)	No
Efrati2015⁸	48	26	50.4 ± 10.9	48.1 ± 11.1	Fibromyalgia syndrome	90 minutes, 100% oxygen at 2ATA	Conventional treatment	40	Mild barotrauma (13)	No
Miller2015⁹	24	23	32.5	31.4	Persistent postconcussion symptoms	100% oxygen at a pressure (or depth) of 1.5ATA	Room Air(21% oxygen) at 1.2ATA	40	Middle ear pain (1); Inner ear barotrauma (3); Tooth pain (1); Onset migraine headache (2); Transient worsening of myopia (1)	Middle ear pain (1); change in headaches frequency (1); Claustrophobia/anxiety (1); Sinus pain (3)
Fedorko 2016¹⁰	49	54	61	62	Diabetes with nonhealing ulcers of the lower limb	100% oxygen at a pressure (or depth) of 2.4ATA	Room air (21% oxygen)at 1.2ATA	30	Barotraumas (3); Unable to equalize ears (4); Visual changes (4); Anxiety, chest pain (2); Nausea (3); Hypoglycemia (4); Wound infection (2); Pain postmyringotomy (1); Congestive heart failure (1)	Barotraumas (3); Visual changes (3); Nausea (1); Hypoglycemia (1);
Glover2016¹¹	53	28	62.3	62.0	Chronic bowel dysfunction after pelvic radiotherapy	90 minutes, 100% oxygen at 2ATA	Room Air(21% oxygen) at 1.3ATA	40	Myopia (16); Fatigue (2); Ear pain or barotrauma (15)	Myopia (3); Fatigue (3); Ear pain or barotrauma (6)
Chiles2018¹²	40	43	40–65	40–65	Prostate cancer	100% oxygen at a pressure (or depth) of 2.2ATA	Room Air(21% oxygen) at 2.2ATA	10	Immediate urine leak (1); Ear pressure (2); Hypertension (1); Myopia (1); Urinary tract infection (1); Incontinence (1)	Ear pressure (1); Meatal stenosis (1)
Fukami2018¹³	33	40	66	62	Adhesive postoperative small bowel obstruction	100% oxygen at a pressure (or depth) of 2.0ATA	Conservative treatment	7	Mild earache (1)	No
Santema2017¹⁴	53	56	67.6	70.6	Ischemic lower extremity ulcers in patients with diabetes	100% oxygen at a pressure (or depth) of 2.4ATA	Standard care	40	Oxygeninduced seizure (1); Barotraumatic perforation of the tympanic membrane (1); Inability to equalize the pressure of the middle ear (3)	No
Thistlethwaite2018¹⁵	15	15	70	70	Chronic venous leg ulcers	100% oxygen at a pressure (or depth) of 2.4ATA	Room Air(21% oxygen) at 1.2ATA	30	Otic barotraumas (2)	No
Oscarsson2019¹⁶	41	38	64.0	64.8	Radiation-induced cystitis	100% oxygen at a pressure (or depth) of 2.5ATA	Standard care	30–40	Ear pain (6); myopia (5); Barotrauma (4)	Cardiac failure (1)
Shaw2019¹⁷	47	53	58.3	58.2	Osteoradionecrosis	100% oxygen at a pressure (or depth) of 2.4ATA	Conventional treatment	30	Hearing impaired (1); Ear barotrauma (4); Eye disorders (1); Fatigue (1); Chest wall pain (1); seizure (1); Epistaxis (1); Hypotension (1)	No
Weaver2019¹⁸	60	58	34.8(BIMA)/32.5(HOPPS)	30.8(BIMA)/31.4(HOPPS)	Mild traumatic brain injury	100% oxygen at a pressure (or depth) of 1.5ATA	Room Air(21% oxygen) at 1.2ATA	40	Ear discomfort (15); Sinus pain (5); Dizziness (1); Vertigo (1); Headache (1); Somnolent (1); Dyspnea (2); Hyperventilation (1); Eye disorders (1); Anxiety (1)	Ear discomfort (6); Sinus pain (4); Dizziness (1); Headache (2); Somnolent (1); Eye disorders (2); Vertigo (1)
Hadanny2020¹⁹	30	33	70.68 ± 3.64	68.81 ± 3.34	Healthy older adults	100% oxygen at a pressure (or depth) of 2.0ATA	Conventional treatment	60	Mild middle ear barotrauma (4); Visual acuity changes (15)	Visual acuity changes (10)
Harch2020²⁰	50	27	42.7 ± 10.7	42.3 ± 11.2	Mild traumatic brain injury	100% oxygen at a pressure (or depth) of 1.5ATA	Conventional treatment	40	Fatigue (2); Mild reversible middle Ear barotrauma (1); A multiply previously perforated tympanic membrane (1)	No
Schiavo2020²¹	13	11	62 ± 11	61 ± 10	Stroke	100% oxygen at a pressure (or depth) of 2.0ATA	Conventional treatment	40	Middle-ear barotrauma (4); Chest pain (1)	No
Curtis2021²²	17	8	45.7 ± 14.2	51.8 ± 14.5	Fibromyalgia	100% oxygen at a pressure (or depth) of 2.0ATA	Conventional treatment	40	Mild middle-ear barotrauma (3); New-onset myopia (4)	No
Kraft2021²³	10	10	59.7	54.5	Central airway stenosis after lung transplantation	100% oxygen at a pressure (or depth) of 2.0ATA	Standard care	20	Claustrophobia (1)	No
Cannellotto2022²⁴	20	20	52.8 ± 8.5	57.7 ± 9.3	COVID- 19 severe hypoxaemia	100% oxygen at a pressure (or depth) of 1.45ATA	Conventional treatment	7	Ear discomfort (1)	No
Doenyas-Barak2022²⁵	14	15	39.3 ± 8.1	32.4 ± 9.2	Post-traumatic stress disorder	100% oxygen at a pressure (or depth) of 2.0ATA	Conventional treatment	60	Middle ear barotrauma (7)	No
Hadanny2022²⁶	15	10	11.99 ± 2.32	11.00 ± 2.32	Post‑concussion syndrome	100% oxygen at a pressure (or depth) of 1.5ATA	Room Air(21% oxygen) at 1.03ATA	60	Ear pain (2); Mild-moderate barotrauma (9); Headache (2)	Ear pain (5); Mild-moderate barotrauma (4)
Wolf2018²⁷	25	25	28.3 ± 8.1	28.4 ± 7.4	Traumatic Brain Injury	100% oxygen at a pressure (or depth) of 2.4ATA	Room Air(21% oxygen) at 1.3ATA	30	Ear disorders(10)	Ear disorders(4)
Kaur2012²⁸	15	15	46.9 ± 11.8	47.4 ± 12.5	Chronic nonhealing ulcer	100% oxygen at a pressure (or depth) of 2.5ATA	conventional treatment	30	Ear discomfort/pain (3); Claustrophobia (2); Headache (1); Tinnitus (1)	No

2.2 Meta-analysis Results

2.2.1 Incidence of adverse effects

There was a heterogeneity between studies(P = 0.06,I² = 33%), therefore a random-effect model was performed. The results indicated that the incidence of AEs in HBOT group was higher than that in control group (29.81% vs 10.34%, RR = 2.88,95%CI: 1.78–3.32,P < 0.05;Figure 3).

2.2.2 Subgroup Analysis

2.2.2.1 Effect of different control groups

In eight studies, participants in control group received sham therapy. Compared with patients in control group, patients in HBOT group were more likely to have AEs (43.11 22.47 RR = 1.92,95%CI: 1.13–2.55, P = 0.01; Fig. 4), with high heterogeneity (P = 0.010,I² = 68%).In fifteen studies, patients in control group received conventional treatment. The results indicated that the incidence of AEs was higher in HBOT than in the control group(21.06 2.740RR = 7.69,95%CI༚2.56–7.61, P༜0.00001; Fig. 4), with low heterogeneity(P = 0.38,I² = 7%).

2.2.2.2 Effect Of Different Adverse Events

Table 2 summarizes the results of subgroup analysis of different adverse events. We found significantly increased risk ratios with HBOT compared to control group for two specific adverse events: ear discomfort, and ocular side effects.

Ear discomfort: Twenty-four studies^{5–7, 9-22, 24–29,31}reported ear discomfort. The risk of ear discomfort was increased in participants treated with HBOT compared to neither sham therapy nor other conventional treatment(RR = 3.30,95%CI: 1.96–3.70,P༜0.01),with moderate heterogeneity(P = 0.15,I² = 23%).

Sinus pain: Three studies^9,17,18reported sinus pain. The incidence of sinus pain was higher in HBOT than in the control group, with low heterogeneity(P = 0.28,I² = 21%). The difference was not statistically significant(RR = 0.88,95%CI: 0.32–2.29,P > 0.05).

Ocular side effects: Nine studies^{9–12, 16-19,22}reported ocular side effects. The risk of ocular side effects was increased in participants treated with HBOT compared to neither sham therapy nor other conventional treatment(RR = 2.37,95%CI: 1.29–3.32,P༜0.05),with no heterogeneity(P = 0.83,I² = 0%).

Seizure: Two studies^14,17reported seizure. The incidence of seizure was higher in HBOT than in the control group, with no heterogeneity(P = 0.98,I² = 0%). The difference was not statistically significant(95%CI: 0.35–30.92,P > 0.05).

Claustrophobia: Three studies^9,23,28reported claustrophobia. The incidence of claustrophobia was higher in HBOT than in the control group, with no heterogeneity(P = 0.42,I² = 0%). The difference was not statistically significant(RR = 2.94,95%CI: 0.40–7.94,P > 0.05).

Chest pain: Three studies^10,17,21reported chest pain. The incidence of chest pain was higher in HBOT than in the control group, with no heterogeneity(P = 0.94,I² = 0%). The difference was not statistically significant(95%CI: 0.64–22.13,P > 0.05).

Gastrointestinal reaction: Two studies^5,10reported gastrointestinal reaction. The incidence of gastrointestinal reaction was higher in HBOT than in the control group, with no heterogeneity(P = 0.95,I² = 0%). The difference was not statistically significant(RR = 4.22,95%CI: 0.15–19.60,P > 0.05).

Headache: Four studies^9,18,26,28reported headache. The incidence of headache was lower in HBOT than in the control group, with no heterogeneity(P = 0.70,I² = 0%). The difference was not statistically significant(RR = 1.86,95%CI: 0.46–5.28,P > 0.05).

Fatigue: Three studies^11,17,20reported fatigue. The incidence of chest pain was higher in HBOT than in the control group, with no heterogeneity(P = 0.31,I² = 15%). The difference was not statistically significant(RR = 1.20,95%CI༚0.29–3.10,P > 0.05).

Congestive heart failure: Two studies^10,16reported congestive heart failure. The incidence of congestive heart failure was higher in HBOT than in the control group, with no heterogeneity(P = 0.30,I² = 6%). The difference was not statistically significant( RR = 1.02,95%CI:0.15–6.77,P > 0.05).

Other AEs: Other AEs caused by HBOT included hypoglycemia, vertigo, tooth pain, somnolence, anxiety, dyspnea, hyperventilation, urinary incontinence, urinary tract infection, hypotension, and hypertension, as shown in Table 3.

Table 2

Results of subgroup analysis of different adverse events
Adverse events	No. of trails	P	RR	95%CI	Test of Heterogeneity
Adverse events	No. of trails	P	RR	95%CI	P	I²%
ear discomfort	24	༜ 0.01	3.30	1.96–3.70	0.15	23
sinus pain	3	0.77	0.88	0.32–2.29	0.28	21
ocular side effects	9	༜ 0.01	2.37	1.29–3.32	0.83	0
seizure	2	0.30	—*	0.35–30.92	0.98	0
claustrophobia	3	0.45	2.94	0.40–7.94	0.42	0
chest pain	3	0.14	—*	0.64–22.13	0.94	0
gastrointestinal reaction	2	0.21	4.22	0.15–19.60	0.95	0
headache	4	0.47	1.86	0.46–5.28	0.70	0
fatigue	3	0.92	1.20	0.29–3.10	0.31	15
congestive heart failure	2	0.99	1.02	0.15–6.77	0.30	6

“*”: the incidence of this adverse effect in the control group was 0. The relative risk could not be calculated. 5.26 2.83

Table 3

Other adverse events during HBOT
Adverse events	Study ID	HBOT		Control
Adverse events	Study ID	events	total	events	total
Hypoglycemia	Fedorko2016¹⁰	4	49	1	54
Dizziness/ vertigo	Weaver2019¹⁸	2	60	2	58
Tooth pain	Miller2015⁹	1	24	0	23
Somnolent	Weaver2019¹⁸	1	60	1	58
Anxiety	Weaver2019¹⁸	1	60	0	58
Dyspnea	Weaver2019¹⁸	2	60	0	58
Hyperventilation	Weaver2019¹⁸	1	60	0	58
Incontinence	Chiles2018¹²	2	40	0	43
Urinary tract infection	Chiles2018¹²	1	40	0	43
Meatal stenosis	Chiles2018¹²	0	40	1	43
Hypotension	Shaw2019¹⁷	1	47	0	53
Hypertension	Chiles2018¹²	1	40	0	43

2.2.2.3effect Of Different Treatment Courses

In two studies, participants in HBOT group received ≤ 7 sessions HBOT. The incidence of AEs was higher in HBOT than in the control group, with no heterogeneity(P = 0.93,I² = 0%). The difference was not statistically significant (95%CI:0.35–30.65, P > 0.05). In five studies, participants in HBOT group received 8–20 sessions HBOT. Compared with patients in control group, patients in HBOT group were more likely to have AEs (RR = 4.06,95%CI:1.60–7.89, P = 0.002), with no heterogeneity(P = 0.97,I² = 0%). In nineteen studies, patients in HBOT group received ༞20 sessions HBOT. Compared with patients in control group, patients in HBOT group were more likely to have AEs (RR = 2.51,95%CI:1.63–4.33, P༜0.05;Figure 5) ,with high heterogeneity(P༜0.00001,I² = 75%).

2.2.2.4 Effect Of Different Chamber Pressure

The studies were divided into two subgroups according to chamber pressure. The result demonstrated heterogeneity in the subgroup with chamber pressures ≥ 2.0ATA (P = 0.11, I² = 34%), which was therefore analyzed using a random-effects model. Due to the high chamber pressure in some of the control groups, the studies with sham therapy control groups were not included in this subgroup analysis. The incidence of adverse effects was higher in HBOT group than in control group for subgroups with chamber pressure ≥ 2.0 ATA, with statistically significant differences in the results (RR = 7.99,95%CI:3.03–14.96, P༜0.0001;Figure 6). The difference in the incidence of adverse effects between the hyperbaric and control groups in the subgroup with pressure < 2.0 ATA was not statistically significant (R = 5.40,95% CI: 0.59–13.84, P > 0.05; Fig. 6).

2.2.2.5 Effect Of Different Types Of Diseases

The studies were divided into traumatic brain injury subgroup, stroke subgroup, and diabetic foot subgroup. Adverse effects were more frequent in HBOT group than in control group in the diabetic foot subgroup (Fig. 7).

The results of this meta-analysis demonstrated that the incidence of adverse effects was higher in the hyperbaric group than the control group. The main adverse effects of HBOT include ear discomfort (e.g., middle ear barotrauma, ear pain, etc.), ocular side effects (e.g., myopia, hyperopia, etc.), sinus barotrauma, epilepsy, claustrophobia, chest pain, headache, fatigue, gastrointestinal reactions, etc. Most adverse effects of hyperbaric oxygen are mild and self-limiting, the most common of which is middle ear barotrauma, an adverse effect that can be prevented by ongoing teaching of middle ear clearing techniques and appropriate compression rates ³.

The results of this meta-analysis revealed that the incidence of adverse effects was higher in HBOT group than in control group, regardless of whether the control group was a sham or conventional treatment group. The adverse effects of HBOT can be divided into two categories: adverse effects of pressure and adverse effects of oxygen. The adverse effect of pressure is barotrauma, which can affect any closed, air-filled cavity (including but not limited to ears, sinus, teeth, lungs, and bowel). The adverse effects of oxygen can further be subdivided into three categories: pulmonary, neurologic, and ophthalmologic ³². Patients in the sham therapy group were mostly treated with normobaric or hyperbaric room air. In Chiles2018¹² and Lacey2012³¹, chamber pressures in control groups were consistent with that of the HBOT groups. The incidence of ear discomfort in these studies was found to be similar in the HBOT groups (14.06%) to the control groups (13.85%). Therefore, the factor of injury for ear discomfort may originate more from pressure rather than oxygen toxicity.

Both ear and ocular adverse effects were more frequent in HBOT than in the control group, while the differences in the incidence of the remaining several adverse effects were not statistically significant. It might be due to several reasons: the exclusion of this adverse effect as a contraindication; the small number of cases involving this adverse effect; and the relatively mild clinical manifestation of the adverse effect, which failed to attract the attention of the participants.

Data analysis indicated that a lower incidence of claustrophobia was found in the HBOT group than in the control group. There is a possibility that this is due to the fact that the control group in Miller2015⁹ was a sham therapy group in which participants would also enter the chamber; in parallel, claustrophobia is one of the contraindications to HBOT and few people have previous claustrophobia that is not detected. Claustrophobia may be managed with coaching and anxiolytic medications. Intolerance of a monoplace chamber may warrant referral to the closest multiplace chamber facility³.

Some adverse effects may also be related to the patient's health condition, for instance participants in Chiles2018¹² experienced adverse effects in the form of urinary incontinence and urinary tract infections, which may be related to undergoing radical prostate cancer surgery. Likewise, cardiovascular adverse effects show a similar pattern. The onset of congestive heart failure in the patients of Fedorko2016¹⁰ and Oscarsson2019¹⁶ in this study may also be associated with the participants' health conditions. With regard to the mechanisms of congestive heart failure, a study by Weaver et al. ³³ suggested that hyperbaric oxygen therapy could increase left ventricular (LV) afterload, increase LV filling pressures, increase oxidative myocardial stress, decrease LV compliance by oxygen radical-mediated reduction in nitric oxide, alter cardiac output between the right and left hearts, and induce bradycardia with concomitant LV dysfunction. Therefore, caution should be exercised in the use of hyperbaric oxygen therapy in patients with heart failure or in patients with reduced cardiac ejection fractions. As regards the effect of HBOT on blood pressure, most researches report an increase in blood pressure. Al-Waili et al.³⁴ pointed out that hyperbaric oxygen can cause hypertension, which was seen in one case of hypertension in the hyperbaric group in Chiles2018 ¹². A different result, however, was seen in Shaw 2019¹⁷, where there was one case of hypotension, but the study did not mention its cause.

Our results revealed that at a course of > 7 sessions, the incidence of adverse effects was greater than that of the control group. When the treatment course was ≤ 7 sessions, the adverse effects were relatively low. The main adverse effects that warranted attention were ear adverse effects, such as ear pain ^13,24. The outcome implies that the course of HBOT is a major influencing factor for the adverse effects, hence we recommend that the course of hyperbaric oxygen treatment should be shortened to less than 7 sessions to reduce the occurrence of side effects.

In the present study, the results indicated that patients received HBOT at chamber pressures above 2.0 ATA had a higher incidence of adverse effects than the control group. The incidence of adverse effects is relatively low with a chamber pressure below 2.0 ATA. The adverse effects to be cautioned about are mainly ear discomfort, ocular side effects, headache, sinus barotrauma, etc. ^{5,9,18,20,24,31} Ajayi et al. ³⁵ suggested that the incidence of adverse effects of HBOT at a chamber pressure of 2.0 ATA was similar to that of 2.4 ATA. As for the incidence of epilepsy, Marvin et al. ³⁶noted there was a statistically significant difference for seizure between the different pressures. They also demonstrated a statistically significant increased risk of seizure with increasing treatment pressure. Research by Resanovic et al. and MijajlovicI et al ^37,38, however, suggested that HBOT with chamber pressures below 3.0 ATA rarely caused adverse effects. It is probably related to the fact that in general the adverse effects of HBOT are mild and mostly self-limiting ³ ,as such many patients do not report even though the adverse effect occur.

It has also been suggested that the incidence of adverse effects related to different time interval and rate (slope) of compression ³⁹. Nevertheless, subgroup analyses were not performed since fewer of the studies explicitly described time interval and rate of compression and did not include them as a categorical or control factor, which may affect the accuracy of the data analysis. Eight of the included studies^{5,7,12,13,15,19,27,31} specify the rate of compression, but valid data statistics could not be performed as the rate of compression in the control group was not mentioned. Also, ten studies ^{10–12, 15,19–22, 25,27} reported time intervals. Owing to the 5-minute time interval in most of the studies and the 0-minute interval in only one study, however, it was infeasible to group the studies for subgroup analysis.

The results of this study revealed that the incidence of adverse effects was higher in patients with diabetic foot when received HBOT. Particular attention is needed to the hypoglycemic occurrence in diabetics received HBOT. It has been documented that in diabetics undergoing HBO₂, severe hypoglycemia is rare and occurs more frequently in Type 1 diabetes. Pre-HBO₂ glucose values may be used to predict subsequent hypoglycemia and reduce the need for routine glucose monitoring during and after HBOT ⁴⁰. Fedorko2016¹⁰, a study of diabetes with nonhealing ulcers of the lower limb, saw an occurrence of hypoglycemia in four of the sixty-one patients in the HBOT group.

Limitations also exist in this study. The small number of cases of partial adverse effects during subgroup analysis may have an implication on the results of the data analysis, especially when the heterogeneity between these small number of studies is relatively high. Exclusion as a contraindication resulted in a significant reduction in the incidence of some adverse reactions, as in claustrophobia, leading to no statistical significance of the difference in the incidence of this adverse effect between the HBOT and control groups.

In conclusion, the main adverse effects of HBOT include ear discomfort (e.g., middle ear barotrauma, ear pain, etc.), ocular side effects (e.g., myopia, hyperopia, etc.), sinus barotrauma, epilepsy, claustrophobia, chest pain, headache, fatigue, and gastrointestinal reactions. HBOT is more likely to cause adverse reactions when the treatment course of hyperbaric oxygen is > 7 sessions and chamber pressure is above 2.0 ATA.

Ethics approval: Not applicable.

Competing interests: Nil.

Source(s) of support: Key R&D Program of Jiangsu Province (grant No. BE2021012-4).

Acknowledgements:

Correspondence: Dian-Huai Meng, Rehabilitation Medicine Center, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China, Email [email protected].

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No competing interests reported.

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Adverse Effects of Hyperbaric Oxygen Therapy: a systematic review and meta-analysis

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Abstract

Objective

Methods

Results

Conclusion

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Introduction

Methods

1.1 Inclusion And Exclusion Criteria

1.2 Methodological Quality And Risk Of Bias Assessment

1.3 Data Extraction

1.4 Statistical Analysis

Results

2.1 Summary of the included studies

2.2 Meta-analysis Results

2.2.1 Incidence of adverse effects

2.2.2 Subgroup Analysis

2.2.2.1 Effect of different control groups

2.2.2.2 Effect Of Different Adverse Events

2.2.2.3effect Of Different Treatment Courses

2.2.2.4 Effect Of Different Chamber Pressure

2.2.2.5 Effect Of Different Types Of Diseases

Discussion

Declarations

References

Additional Declarations

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