Pulmonary function following hyperbaric oxygen therapy: A longitudinal observational study

Connor T A Brenna; Shawn Khan; George Djaiani; Darren Au; Simone Schiavo; Mustafa Wahaj; Ray Janisse; Rita Katznelson

doi:10.1371/journal.pone.0285830

. 2023 May 31;18(5):e0285830. doi: 10.1371/journal.pone.0285830

Pulmonary function following hyperbaric oxygen therapy: A longitudinal observational study

Connor T A Brenna ¹, Shawn Khan ², George Djaiani ³, Darren Au ⁴, Simone Schiavo ^1,^3,⁴, Mustafa Wahaj ³, Ray Janisse ³, Rita Katznelson ^1,^3,^4,^*

Editor: Eman Sobh⁵

PMCID: PMC10231819 PMID: 37256885

Abstract

Hyperbaric oxygen therapy (HBOT) is known to be associated with pulmonary oxygen toxicity. However, the effect of modern HBOT protocols on pulmonary function is not completely understood. The present study evaluates pulmonary function test changes in patients undergoing serial HBOT. We prospectively collected data on patients undergoing HBOT from 2016–2021 at a tertiary referral center (protocol registration NCT05088772). Patients underwent pulmonary function testing with a bedside spirometer/pneumotachometer prior to HBOT and after every 20 treatments. HBOT was performed using 100% oxygen at a pressure of 2.0–2.4 atmospheres absolute (203–243 kPa) for 90 minutes, five times per week. Patients’ charts were retrospectively reviewed for demographics, comorbidities, medications, HBOT specifications, treatment complications, and spirometry performance. Primary outcomes were defined as change in percent predicted forced expiratory volume in one second (FEV₁), forced vital capacity (FVC), and forced mid-expiratory flow (FEF_25-75), after 20, 40, and 60 HBOT sessions. Data was analyzed with descriptive statistics and mixed-model linear regression. A total of 86 patients were enrolled with baseline testing, and the analysis included data for 81 patients after 20 treatments, 52 after 40 treatments, and 12 after 60 treatments. There were no significant differences in pulmonary function tests after 20, 40, or 60 HBOT sessions. Similarly, a subgroup analysis stratifying the cohort based on pre-existing respiratory disease, smoking history, and the applied treatment pressure did not identify any significant changes in pulmonary function tests during HBOT. There were no significant longitudinal changes in FEV₁, FVC, or FEF_25-75 after serial HBOT sessions in patients regardless of pre-existing respiratory disease. Our results suggest that the theoretical risk of pulmonary oxygen toxicity following HBOT is unsubstantiated with modern treatment protocols, and that pulmonary function is preserved even in patients with pre-existing asthma, chronic obstructive lung disease, and interstitial lung disease.

Introduction

Hyperbaric oxygen therapy (HBOT) has been recognized as a valuable intervention for a variety of acute and chronic conditions (S1 Table) [1, 2]. Treatment protocols include repeated sessions of exposure to 100% oxygen (O₂) at 1.3–2.8 atmospheres absolute (ATA) or 132–284 kPa for a predetermined amount of time per session, with a variable number of sessions per week and up to 60 total sessions depending on the indication. Although individual treatments may incorporate air breaks to avoid potential pulmonary and neurological O₂ toxicity, the cumulative effect of multiple longitudinal sessions of HBOT on pulmonary function is not completely understood.

Pulmonary oxygen toxicity (POT) related to the high partial pressure of O₂ in the alveoli may impair respiratory function [3]. Although the mechanisms of POT (also called the Lorrain Smith effect) [4] remain unclear, the increased production of reactive O₂ species during hyperoxic exposure presents a potential source of damage to lung parenchyma [5, 6]. Clinically, POT presents as tracheobronchiolitis causing coughing, pleuritic chest pain, and dyspnea [7]. Clinical diagnosis is challenging due to a lack of unique objective findings: oftentimes, the only identifiable change in pulmonary function is a highly variable decrease in vital capacity (VC) [8, 9]. Other measures of pulmonary function, such as forced mid-expiratory flow and diffusion capacity (DC), have been proposed as more sensitive markers of HBOT damage, however none of these are highly specific [10].

The aim of the present study was to evaluate serial changes in pulmonary function tests among patients undergoing prolonged courses of HBOT for a variety of clinical indications. We hypothesized that extended regimens of HBOT would be associated with a degree of POT resulting in impairment of pulmonary function tests at several predetermined time intervals during a course of serial treatment.

Methods

Study design and participants

We conducted a retrospective analysis of prospectively collected data on a cohort of patients undergoing HBOT at the University Health Network’s Hyperbaric Medicine Unit in Toronto, ON, Canada, between February 2016 and June 2021. All studied patients provided written consent to undergo HBOT (for a variety of clinical indications), and were scheduled to receive at least ten cycles of treatment at our large referral center during this timeframe. Patients underwent PFT assessment before starting HBOT and following every 20 treatment sessions thereafter.

Research ethics approval for the analysis of these data was provided by the University Health Network (Toronto, ON) Research Ethics Board (CAPCR ID: 19–5081.1). Data were collected retrospectively from the electronic records of enrolled patients, and comprised demographic information, HBOT indication and protocol, treatment complications, and PFT results immediately before the first HBOT session and following every subsequent 20 treatments. The protocol was retrospectively registered during the data collection stage and prior to analysis on Clinicaltrials.gov (trial ID: NCT05088772). We followed the STROBE guidelines for reporting observational cohort studies (S2 Table) [11].

Hyperbaric oxygen therapy protocol

The HBOT protocol utilized at our center has been previously described [12]. HBOT was performed with 100% O₂ at a pressure of 2.4 or 2.0 ATA (243 or 203 kPa) for 90 minutes, with 1–2 air breaks (0.21 fraction of inspired O₂ at the same ATA) per session, five times weekly in one of three mono-place chambers (Sechrist 3600H and Sechrist 4100H, Sechrist Industries Inc., Anaheim, CA, USA; PAH-S1-3200, Pan-America Hyperbarics Inc., Plano, TX, USA) or through a plastic hood in a multi-place chamber (rectangular Hyperbaric System, Fink Engineering PTY-LTD, Warana, Australia).

Pulmonary function testing protocol

Bedside spirometry was performed by a trained respiratory therapist using a KoKo Trek USB Spirometer software and pneumotachometer (KoKo, USA). Pulmonary function tests were completed at the time of consultation (prior to the first HBOT treatment) and following every 20 treatments thereafter. In rare cases when PFTs could not be obtained on the exact date of a 20^th, 40^th, or 60^th treatment (e.g., due to equipment limitations), they were obtained on the nearest possible date of another treatment and rounded to an increment of 20 at the time of data analysis. The spirometry equipment was calibrated at the beginning of each day. Patients were tested in a seated position with nose clips, in accordance with American Thoracic Society testing criteria [13], and results were compared against Knudson reference values [14] to determine their percentage of predicted values based on age, sex, and height. To capture potential restrictive, obstructive, and effort-independent changes, three markers of dynamic lung function were recorded: FEV₁% (percentage of predicted FEV₁), FVC% (percentage of predicted FVC), and FEF_25-75% (percentage of predicted FEF_25-75). The data utilized in this study comprise the highest readings for each of these variables from three satisfactory forced expiratory maneuvers performed as part of each PFT assessment. The primary outcome of this study was change in spirometry performance over the course of HBOT. We additionally classified the degree of any baseline PFT abnormalities on the basis of each independent parameter’s deviation from the predicted value, designating mild abnormality as 70–79%, moderate abnormality as 60–69%, and severe abnormality as less than 60%.

Data collection and statistical analysis

Patient demographic data and past medical history characteristics were summarized using descriptive statistics, and continuous data were expressed as means ± standard deviations. Linear mixed effect regression models were used to estimate the adjusted sample mean scores of PFT outcomes FEV₁%, FVC%, and FEF_25-75% at each timepoint for the cohort. Timepoint was included as the fixed effect and individual subject as the random effect for each outcome for the overall cohort. PFT outcomes were also modeled for subgroups by timepoint interaction for pre-existing respiratory disease, smoking status, and treatment pressure (in ATA). Similarly, individual subjects were included as random effects. The maximum likelihood estimation was used to prepare the mixed models and analyzed under the intention-to-treat principle. Post-hoc pairwise comparisons between timepoints were conducted for each grouping of pre-existing respiratory disease, smoking status, and treatment pressure, for each PFT variable. Pairwise comparisons were adjusted using Tukey’s HSD. The alpha was set to 0.05. All analyses were performed using R version 4.0.3.

Objectives

The primary objective of this study was to evaluate changes in series of pulmonary function tests (PFTs) performed over the course of recurrent HBOT exposures. A secondary study outcome was the incidence of pulmonary complications such as lung barotrauma.

Results

A total of 86 patients receiving HBOT during the study period were included in the analysis, all of whom received baseline spirometry and 20 or more individual treatments as illustrated in a modified CONSORT diagram [15] in Fig 1. Patients were included in the analysis if they underwent baseline spirometry prior to first treatment, as well as subsequent PFTs at one or more appropriate intervals (i.e., after 20, 40, and/or 60 treatments). A descriptive analysis of the cohort is provided in Table 1.

Fig 1 — Modified CONSORT diagram illustrating the disposition of study participants. Illustrated are the number of patients who were enrolled in the study, who underwent baseline testing, who underwent hyperbaric oxygen therapy, who underwent follow-up testing after 20, 40, and/or 60 treatments, and who were therefore including in the analysis.

Table 1. Descriptive analysis of patients included in the current study.

Characteristic	No. of Patients (n = 86)	Percent
Sex
Female	33	38
Male	53	62
Age (years)
Mean ± SD	57.5 ± 15.4
Age Groups
0–40	13	14
41–60	33	36
61–80	35	44
81+	5	6
Body Mass Index^*
Mean ± SD	27.1 ± 10.3
Body Mass Index Groups
15.0–18.5	4	7
18.6–25.0	25	43
25.1–35.0	22	38
35.1+	7	12
Comorbidities
Hypertension	32	37
Coronary Artery Disease	10	12
Congestive Heart Failure	5	6
Left Ventricular Hypertrophy	1	1
Valvular Disease	4	5
Atrial Fibrillation	5	6
Peripheral Vascular Disease	17	20
Type II Diabetes	15	17
Chronic Obstructive Pulmonary Disease	7	8
Asthma	7	8
Interstitial Lung Disease	2	2
Kidney Failure	12	14
Previous Organ Transplant	6	7
Medications
Angiotensin-Converting Enzyme Inhibitor or Angiotensin Receptor Blocker	15	17
Beta Blocker	13	15
Calcium Channel Blocker	11	15
Diuretic	6	7
Digoxin	1	1
Opioid	20	28
Steroid (Systemic)	15	17
Anti-Platelet Agent	19	23
Anticoagulant	6	8
Beta Agonist (Inhaler)	7	9
Steroid (Inhaler)	2	3
Smoking
Current Smoker	23	27
Former Smoker	16	19
Never Smoker	47	55
Pack Years^**
Mean ± SD	19.5 ± 13.2

Open in a new tab

Descriptive analysis of patients included in this study (n = 86), including demographic information (sex, age, body mass index), pre-existing comorbidities and medications, and smoking behavior. Abbreviations: SD = standard deviation.

*n = 58 for BMI calculations.

**n = 22 for current and former smokers for whom there was enough information to calculate pack years of smoking history.

Patients underwent an average of 43 ± 15 (range of 20–118) HBOT sessions, detailed in Table 2. The most common indication for HBOT was soft tissue radiation injury (n = 25; 29%), and the most common complication was ear barotrauma (n = 17; 26%). No patients in the cohort experienced pulmonary barotrauma. The total number of HBOT treatments was 3666.

Table 2. Hyperbaric oxygen therapy details and complications.

Variable	No. of Patients (n = 86)	Percent
Treatment Cycles (#)
Mean ± SD	42.5 ± 15.0
20–40	58	67
41–60	22	26
61+	6	7
Pressure (ATA)
Mean ± SD	2.2 ± 0.2
2.4	49	57
2.0	37	43
Air Breaks (#)
Mean ± SD	1.5 ± 0.5
2	44	51
1	42	49
Indication
Diabetic Foot Ulcer	9	10
Soft Tissue Radiation Injury	25	29
Osteoradionecrosis	12	14
Osteomyelitis	7	8
Idiopathic Sudden Sensorineural Hearing Loss	3	3
Arterial Insufficiency	2	2
Necrotizing Infections	1	1
Calciphylaxis	2	2
Inflammatory Bowel Disease	2	2
Compromised Wound	12	14
Treatment Complications
Ear Barotrauma	17	26
Lung Barotrauma	0	0
Seizure	2	2
Ocular Changes	15	17
Anxiety	18	21
Congestive Heart Failure	1	1

Open in a new tab

Breakdown of hyperbaric oxygen therapy treatment protocols for all patients included in the cohort (n = 86), including the number of cycles, the treatment pressure, and the number of air breaks, as well details regarding complications of treatment. Abbreviations: SD = standard deviation.

Due to individual variation in treatment duration, each timepoint has a unique sample size. The results of PFTs performed at baseline (n = 86) and after 20 (n = 81), 40 (n = 52), and 60 (n = 12) treatments are illustrated in Fig 2. There was no significant change in FEV₁%, FVC%, or FEF_25-75% across the four timepoints. A subgroup analysis comparing patients with and without pre-existing respiratory disease is presented in Fig 3. Among those with pulmonary comorbidities, 14 patients completed PFTs at baseline, 14 after 20 treatments, and 11 after 40 treatments. No patients in this group underwent 60 treatments. Among those without pulmonary comorbidities, 72 completed PFTs at baseline, 67 after 20 treatments, 41 after 40 treatments, and 12 after 60 treatments. Neither subgroup had a significant change in FEV₁%, FVC%, or FEF_25-75% across these timepoints. A post-hoc pairwise comparison similarly identified no interval change in FEV₁%, FVC%, or FEF_25-75% values between individual study timepoints (S2 Table).

Fig 2 — Measurements of pulmonary function before (n = 86) hyperbaric oxygen therapy (Pre-HBOT) and after 20 (n = 81), 40 (n = 52), and 60 (n = 12) treatment sessions. Circles, triangles, and squares represent cohort means of FEV1%, FVC%, and FEF25-75% at each timepoint, and bars delineate a confidence limit of 95%. Abbreviations: FEV1% = percentage of predicted forced expiration volume in one second; FVC% = percentage of predicted forced vital capacity; FEF25-75% = percentage of predicted mid-expiratory flow.

Fig 3 — Measurements of pulmonary function among patients stratified by pulmonary disease. Circles represent patients without known pulmonary disease before (n = 72) hyperbaric oxygen therapy (Pre-HBOT) and after 20 (n = 67), 40 (n = 41), and 60 (n = 12) treatment sessions, and triangles represent patients with pre-existing respiratory disease before (n = 14) hyperbaric oxygen therapy (Pre-HBOT) and after 20 (n = 14) and 40 (n = 11) treatment sessions. FEV1% is represented in panel A, FVC% in panel B, and FEF25-75% in panel C. Points represent subgroup means at each timepoint, and bars delineate a confidence limit of 95%. Abbreviations: FEV1% = percentage of predicted forced expiration volume in one second; FVC% = percentage of predicted forced vital capacity; FEF25-75% = percentage of predicted mid-expiratory flow.

A second subgroup analysis of patients stratified by smoking status is presented in Fig 4. Pre-HBOT PFT data were available for 47 patients with no smoking history, and for 44 after 20 treatments, 31 after 40 treatments, and 10 after 60 treatments. Pre-HBOT PFT data were available for 16 patients who had formerly smoked but quit, and for 14 patients after 20 treatments, 11 patients after 40 treatments, and one patient after 60 treatments. Finally, pre-HBOT PFT data were available for 23 patients who were current smokers, and for 23 after 20 treatments, 10 after 40 treatments, and one after 60 treatments. There was no significant change in FEV₁%, FVC%, or FEF_25-75% across these timepoints, in any of the three subgroups. A final subgroup analysis comparing patients treated at 2.4 and 2.0 ATA (243 and 203 kPa) is presented in Fig 5. Among those treated at 2.4 ATA (243 kPa), 49 patients completed PFTs at baseline, 46 after 20 treatments, 32 after 40 treatments, and 6 after 6 treatments. Among those treated at 2.0 ATA (203 kPa), 37 completed PFTs at baseline, 35 after 20 treatments, 20 after 40 treatments, and 6 after 60 treatments. Neither subgroup had a significant change in FEV₁%, FVC%, or FEF_25-75% across these timepoints. Similarly, a post-hoc pairwise comparison identified no interval PFT change between timepoints in these subgroups.

Fig 5 — Measurements of pulmonary function among patients stratified by treatment pressure. Circles represent patients treated at 2.0 ATA before (n = 37) hyperbaric oxygen therapy (Pre-HBOT) and after 20 (n = 35), 40 (n = 20), and 60 (n = 6) treatment sessions, and triangles represent patients treated at 2.4 ATA before (n = 49) hyperbaric oxygen therapy (Pre-HBOT) and after 20 (n = 46), 40 (n = 32), and 60 (n = 6) treatment sessions. FEV1% is represented in panel A, FVC% in panel B, and FEF25-75% in panel C. Points represent subgroup means at each timepoint, and bars delineate a confidence limit of 95%. Abbreviations: FEV1% = percentage of predicted forced expiration volume in one second; FVC% = percentage of predicted forced vital capacity; FEF25-75% = percentage of predicted mid-expiratory flow.

Discussion

Overall, we did not appreciate a significant change in PFTs among patients undergoing serial HBOT with a protocol of five weekly treatments of 90 minutes at 2.4 or 2.0 ATA (243 or 203 kPa) with 1–2 air breaks. This study is among the largest describing PFT changes in patients undergoing repetitive HBOT, and we report on a representative sample which is broadly generalizable to other conventional HBOT treatment facilities. Subgroup analysis identified that patients with pre-existing lung disease and those who currently or formerly smoked tended to have a greater degree of mild-to-moderate PFT abnormality at baseline; despite this, there were no significant changes in PFT trends during HBOT among these subgroups. Patients treated at 2.0 ATA (203 kPa) similarly exhibited a greater degree of mild abnormality at baseline (in all three parameters, although most markedly in FEV₁%, reflecting baseline differences in large airway performance). The reason for this is unclear; we speculate that providers may have elected to use more conservative treatment protocols among patients with high-risk features or whose pulmonary function already exhibited some degree of impairment prior to treatment.

Reports describing pulmonary function among human subjects undergoing HBOT are scarce, heterogenous, and divergent in their results. Pott and colleagues reported no change in forced vital capacity (FVC) or DC following 30 daily, 90-minute, uninterrupted sessions of HBOT at a pressure of 2.4 ATA (243 kPa), even among patients with significant smoking histories [16]. Thorsen and colleagues found that a treatment regimen of 21 daily, 90-minute sessions at 2.4 ATA (243 kPa), with two five-minute air breaks, considerably reduced FEV₁ and FEF_25-75 that did not return to baseline values [17]. In contrast, Hadanny and colleagues reported that 60 daily, 90-minute sessions at 2 ATA (203 kPa) with three, five-minute air breaks at 1 ATA (101 kPa) improved peak expiratory flow (PEF) and FVC [18]. Comert and colleagues also reported an increase in dynamic lung volumes including total lung capacity (TLC), VC, and residual volume (RV) following HBOT at 2.4 ATA (243 kPa) for 90 minutes in a cohort of 22 patients [19]. Finally, some studies have reported pulmonary function measurements among hyperbaric chamber attendants, although the frequency and duration of exposure in this population differs from that of patients undergoing HBOT. A recent observational study describes small decreases in FEV₁, FVC, FEF_25-75, and peak expiratory flow, with unclear clinical significance, among 68 attendants with a mean follow-up of almost ten years [20].

Our results are in agreement with those of Pott and colleagues, who similarly protocoled treatments of daily 90-minute sessions at 2.4 ATA (243 kPa), and reported no significant change in FVC after 30 treatments [16]. Our findings disagree with Thorson and colleagues who, despite following a similar protocol of 21 daily, 90-minute sessions at 2.4 ATA (243 kPa), reported a decrease in FEV₁ [17]. We also did not confirm the finding of Hadanny et al. or Comert et al. who reported a small increase (2.40%) in FVC% after 60 sessions of HBOT at 2.0 ATA (203 kPa) and statistically significant improvements in dynamic lung volumes with HBOT at 2.4 ATA (243 kPa), respectively (the degree of improvement, and exactly which volumes were measured, were not specified) [18, 19]. These latter studies, combined with emerging evidence based on exhaled compounds after HBOT [8], have challenged the paradigm ascribing pulmonary risks to HBOT. However, they are potentially biased by the exclusion of patients with significant pre-existing lung disease [19] or who were actively smoking [18]. The exclusion of these patients is not reflective of clinical practice, which is important as they may theoretically be among those at highest risk of pulmonary change during HBOT. The practice at our large North American referral center also differs from many of those described in these studies, frequently using treatment regimens with greater cumulative hyperoxic exposure, and the risk of POT with these protocols has not been thoroughly characterized.

The safe threshold for hyperoxic exposure in humans before risking impairment in pulmonary function appears to be approximately double the ambient air pressure at sea level (0.21 ATA or 21 kPa) [21, 22]. However, this risk is proportional to both the inspired pressure and the duration of exposure [21, 22], so that with multiple longitudinal exposures, even small elevations of ATA above that threshold may pose considerable risks. Early, exploratory studies on human subjects reported that reversible symptoms of POT and associated changes in dynamic pulmonary function develop within approximately 3–16 hours of continuous exposure to 100% O₂ using ATAs in a range of 1.0–3.0 (101–304 kPa) [23–26]. These changes correspond to two descriptions of two discrete phases of acute POT based on pathology of the lower respiratory tract: an acute, exudative phase characterized by reversible capillary endothelial cell damage, parenchymal edema, and the infiltration of inflammatory cells [27]; and a subacute, proliferative phase in which type II pneumocytes and fibroblasts multiply and cause irreversible derangement of the lung architecture, including marked thickening of the blood-air barrier and pulmonary fibrosis with impaired gas exchange [9, 28].

In order to quantify POT, a unit of pulmonary toxic dose (UPTD) has been introduced to predict impairment of pulmonary function [29]. As an example, hyperoxic exposures might be limited to 450 UPTD per day and 2250 UPTD per week [9] where each UPTD is the equivalent of one minute at 1 ATA (101 kPa) of 100% O₂. However, this model has several limitations including a need for cumulative dose calculations to account for periods of recovery between exposures, hence alternative metrics such as a POT index have been proposed [30]. Currently, there is no available metric which has been validated for modern HBOT protocols, that include daily treatment sessions at variable pressures (and with or without air breaks) over protracted intervals of time.

The UPTD of treatment protocols in our study varies with number of sessions, and between patients treated at 2.0 or 2.4 ATA (203 or 243 kPa). However, the study group with the largest exposure in our cohort (those undergoing 60 treatment sessions at 2.4 ATA or 243 kPa) would have exposure to approximately 274 UPTD per session and 16,440 UPTD in total (using the formula UPTD = t × [0.5/(PO₂−0.5)]^−5/6, where t is time in minutes and PO₂ is treatment pressure in ATA) [9]. Hadanny and colleagues calculated UPTDs for their study of 224/session and 13,489 total, as well as for the studies by Pott et al. (273/session, 8,213 total) and Thorsen et al. (273/session, 5,749 total) [18]. Using the POT index derived by Arieli [30], we calculate a safe index of 116 following an individual 90-minute treatment at 2.4 ATA (243 kPa), with essentially complete recovery over the following 22.5 hours to a negligible toxicity index of 0.001 before each subsequent treatment. Our results therefore validate the use of HBOT at both 2.0 and 2.4 ATA or 203 and 243 kPa (with a larger cumulative exposure than previously published studies), even with the inclusion of patients harboring pre-existing lung disease and/or significant smoking histories, without concerns of pulmonary dysfunction in these groups.

A secondary outcome of our study explored respiratory complications of HBOT, which are uncommon but may result from exposure of the lungs to high partial pressures of O₂. During the decompression phase of treatment, acute pressure changes can cause pulmonary edema [31, 32] or pulmonary barotrauma, which may lead to arterial gas embolism [33], pneumomediastinum [34], or tension pneumothorax [35], although barotraumatic lung injury is very rare in the absence of high-risk features such as pre-existing respiratory disease [36]. We did not identify any cases of pulmonary complications within our cohort, consistent with the rarity of these events reported in the current literature [37]. Our study findings therefore support the safety profile of modern HBOT.

Limitations

While our study reports PFT measures from a large, representative cohort of patients undergoing HBOT, it is constrained by several limitations. These include a lack of DC measurement (which could not be performed with our bedside spirometry devices), and the high degree of variability inherent in pulmonary function evaluation. A limited number of patients in our cohort missed testing at an eligible timepoint due to various resource limitations at our testing center (e.g., respiratory therapist not available to perform spirometry testing), and so may not have had PFTs performed either after 20, 40, and/or 60 treatments. Finally, our study does not include long-term follow-up to assess for possible delayed effects of HBOT on lung parenchyma and pulmonary function after the completion of treatment.

Conclusions

The present study provides further evidence for the safety profile of HBOT, both with respect to potentially insidious consequences of treatment on pulmonary function and to acute iatrogenic injury. Our analysis of a large cohort of patients undergoing serial HBOT with periodic PFTs offers clarity to conflicting reports in the extant literature, demonstrating no significant changes in critical markers of dynamic lung function over the course of treatment. Our data also illustrate this finding in patients with prior respiratory disease or smoking histories. Future directions for this work include dose-finding studies for the safe maximum treatment pressure and duration to maximize therapeutic possibilities without impairing pulmonary function, investigations of possible delayed effects of HBOT on pulmonary function in the long term, and experiments to further characterize parenchymal changes in the hyperoxic response which may take place at the sub-clinical level.

Supporting information

S1 Table. Approved indications for hyperbaric oxygen therapy in Canada and the United States.

Hyperbaric oxygen therapy indications approved by Health Canada (*) or the US Food and Drug Administration (†). Unlabeled items are approved by both agencies.

(DOCX)

Click here for additional data file.^{(13.5KB, docx)}

S2 Table. STROBE statement for cohort studies.

Guidelines for reporting observational studies, and the page location of critical elements in the submitted manuscript.

(DOCX)

Click here for additional data file.^{(19.4KB, docx)}

S3 Table. Post-hoc pairwise comparisons.

Data resulting from a secondary analysis of the full cohort, which evaluated interval change in pulmonary function test performance between study timepoints. Abbreviations: FEV1% = percentage of predicted forced expiration volume in one second; FVC% = percentage of predicted forced vital capacity; FEF25-75% = percentage of predicted mid-expiratory flow; DE = difference estimate; LCL = lower confidence limit; UCL = upper confidence limit.

(DOCX)

Click here for additional data file.^{(14.5KB, docx)}

Abbreviations

HBOT: hyperbaric oxygen therapy
O₂: oxygen
POT: pulmonary oxygen toxicity
ATA: atmosphere absolute
PFT: pulmonary function test
FEV₁: percentage of predicted forced expiration volume in one second
FVC: percentage of predicted forced vital capacity
FEF_25-75%: percentage of predicted mid-expiratory flow
DC: diffusion capacity
PEF: peak expiratory flow
RV: residual volume
TLC: total lung capacity
VC: vital capacity
UPTD: unit of pulmonary toxic dose

Data Availability

The source data from our study cannot be shared publicly, in full, because of an ethical restriction levied by our institutional research ethics board. This is because the data contains sensitive information from patient’s medical charts (e.g., birth dates and personal health information). Taken together, this information may allow for the identification of individual study participants. We offer that an anonymized minimal data set can be prepared in aggregate and made available upon reasonable request via email to the study’s first author (connor.brenna@mail.utoronto.ca) or the Hyperbaric Medicine Unit, Toronto General Hospital, Toronto, Ontario, Canada (hyperbaricmedicineunit@uhn.ca).

Funding Statement

CTAB gratefully acknowledges the William S. Fenwick Research Fellowship received from the University of Toronto Temerty Faculty of Medicine in support of this study.

References

1.Hyperbaric Oxygen Therapy—Canada.ca. https://www.canada.ca/en/health-canada/services/healthy-living/your-health/medical-information/hyperbaric-oxygen-therapy.html
2.Hyperbaric Oxygen Therapy: Get the Facts | FDA. https://www.fda.gov/consumers/consumer-updates/hyperbaric-oxygen-therapy-get-facts
3.Jackson RM. Pulmonary Oxygen Toxicity. Chest. 1985;88(6):900–905. doi: 10.1378/chest.88.6.900 [DOI] [PubMed] [Google Scholar]
4.Smith JL. The pathological effects due to increase of oxygen tension in the air breathed. J Physiol. 1899;24(1):19. doi: 10.1113/jphysiol.1899.sp000746 [DOI] [PMC free article] [PubMed] [Google Scholar]
5.Klein J. Normobaric pulmonary oxygen toxicity. Anesth Analg. 1990;70(2):195–207. doi: 10.1213/00000539-199002000-00012 [DOI] [PubMed] [Google Scholar]
6.Fisher AB, Forman HJ, Glass M. Mechanisms of pulmonary oxygen toxicity. Lung 1984 162:1. 1984;162(1):255–259. doi: 10.1007/BF02715655 [DOI] [PubMed] [Google Scholar]
7.van Ooij PJAM, Sterk PJ, van Hulst RA. Oxygen, the lung and the diver: friends and foes? Eur Respir Rev. 2016;25(142):496–505. doi: 10.1183/16000617.0049-2016 [DOI] [PMC free article] [PubMed] [Google Scholar]
8.Wingelaar TT, Brinkman P, van Ooij PJAM, et al. Markers of pulmonary oxygen toxicity in hyperbaric oxygen therapy using exhaled breath analysis. Front Physiol. 2019;10(APR):475. doi: 10.3389/fphys.2019.00475 [DOI] [PMC free article] [PubMed] [Google Scholar]
9.Wingelaar TT, van Ooij PJAM, van Hulst RA. Oxygen toxicity and special operations forces diving: Hidden and dangerous. Front Physiol. 2017;8(JUL):1263. doi: 10.3389/fpsyg.2017.01263 [DOI] [PMC free article] [PubMed] [Google Scholar]
10.Edmonds C, Bennett M, Lippmann J, Mitchell S. Oxygen Toxicity. In: Diving and Subaquatic Medicine. 5th ed. CRC Press; 2015:242. [Google Scholar]
11.von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: Guidelines for reporting observational studies. Ann Intern Med. 2007;147(8):573–577. doi: 10.7326/0003-4819-147-8-200710160-00010 [DOI] [PubMed] [Google Scholar]
12.Schiavo S, Djaiani C, DeBacker J, et al. Magnitude and Clinical Predictors of Blood Pressure Changes in Patients Undergoing Hyperbaric Oxygen Therapy: A Retrospective Study. Int J Environ Res Public Health. 2020;17(20):1–14. doi: 10.3390/ijerph17207586 [DOI] [PMC free article] [PubMed] [Google Scholar]
13.Graham BL, Steenbruggen I, Miller MR, et al. Standardization of Spirometry 2019 Update. An Official American Thoracic Society and European Respiratory Society Technical Statement. Am J Respir Crit Care Med. 2019;200(8):E70–E88. doi: 10.1164/rccm.201908-1590ST [DOI] [PMC free article] [PubMed] [Google Scholar]
14.Knudson RJ, Lebowitz MD, Holberg CJ, Burrows B. Changes in the normal maximal expiratory flow-volume curve with growth and aging. American Review of Respiratory Disease. 1983;127(6):725–734. doi: 10.1164/arrd.1983.127.6.725 [DOI] [PubMed] [Google Scholar]
15.Schulz KF, Altman DG, Moher D. CONSORT 2010 Statement: updated guidelines for reporting parallel group randomised trials. Trials. 2010;11(1):1–8. doi: 10.1186/1745-6215-11-32 [DOI] [PMC free article] [PubMed] [Google Scholar]
16.Pott F, Westergaard P, Mortensen J, Jansen EC. Hyperbaric oxygen treatment and pulmonary function. Undersea and Hyperbaric Medicine. 1999;26(4):225–228. [PubMed] [Google Scholar]
17.Thorsen E, Aanderud L, Aasen TB. Effects of a standard hyperbaric oxygen treatment protocol on pulmonary function. European Respiratory Journal. 1998;12(6):1442–1445. doi: 10.1183/09031936.98.12061442 [DOI] [PubMed] [Google Scholar]
18.Hadanny A, Zubari T, Tamir-Adler L, et al. Hyperbaric oxygen therapy effects on pulmonary functions: A prospective cohort study. BMC Pulm Med. 2019;19(1):148. doi: 10.1186/s12890-019-0893-8 [DOI] [PMC free article] [PubMed] [Google Scholar]
19.Comert S, Sumen SG, Caglayan B. Effects of a standard hyperbaric oxygen treatment protocol on pulmonary functions and diaphragm. In: European Respiratory Journal. Vol 50. European Respiratory Society (ERS); 2017:PA730. doi: 10.1183/1393003.congress-2017.pa730 [DOI] [PubMed] [Google Scholar]
20.Demir L, Avci M. Effect of hyperbaric exposure on pulmonary functions in hyperbaric chamber inside attendants. Undersea & hyperbaric medicine. 2022;49(2):161–169. doi: 10.22462/03.04.2022.1 [DOI] [PubMed] [Google Scholar]
21.Miller JN, Winter PM. Clinical manifestations of pulmonary oxygen toxicity. Int Anesthesiol Clin. 1981;19(3):179–199. doi: 10.1097/00004311-198119030-00011 [DOI] [PubMed] [Google Scholar]
22.Schaefer KE. Oxygen in Closed Environmental Systems. In: Gilbert DL, ed. Oxygen and Living Processes. Springer; 1981:343–357. doi: 10.1007/978-1-4612-5890-2_15 [DOI] [Google Scholar]
23.Clark JM, Lambertsen CJ, Gelfand R, et al. Effects of prolonged oxygen exposure at 1.5, 2.0, or 2.5 ATA on pulmonary function in men (predictive studies V). J Appl Physiol (1985). 1999;86(1):243–259. doi: 10.1152/jappl.1999.86.1.243 [DOI] [PubMed] [Google Scholar]
24.Fisher AB, Hyde RW, Puy RJ, Clark JM, Lambertsen CJ. Effect of oxygen at 2 atmospheres on the pulmonary mechanics of normal man. J Appl Physiol. 1968;24(4):529–536. doi: 10.1152/jappl.1968.24.4.529 [DOI] [PubMed] [Google Scholar]
25.Clark JM, Lambertsen CJ. Rate of development of pulmonary O2 toxicity in man during O2 breathing at 2.0 Ata. J Appl Physiol. 1971;30(5):739–752. doi: 10.1152/jappl.1971.30.5.739 [DOI] [PubMed] [Google Scholar]
26.Clark JM, Jackson RM, Lambertsen CJ, Gelfand R, Hiller WDB, Unger M. Pulmonary function in men after oxygen breathing at 3.0 ATA for 3.5 h. J Appl Physiol (1985). 1991;71(3):878–885. doi: 10.1152/jappl.1991.71.3.878 [DOI] [PubMed] [Google Scholar]
27.Davis WB, Rennard SI, Bitterman PB, Crystal RG. Pulmonary oxygen toxicity. Early reversible changes in human alveolar structures induced by hyperoxia. N Engl J Med. 1983;309(15). doi: 10.1056/NEJM198310133091502 [DOI] [PubMed] [Google Scholar]
28.Robinson FR, Casey HW, Weibel ER. Animal model: Oxygen toxicity in nonhuman primates. Am J Pathol. 1974;76(1):175. [PMC free article] [PubMed] [Google Scholar]
29.Harabin AL, Homer LD, Weathersby PK, Flynn ET. An analysis of decrements in vital capacity as an index of pulmonary oxygen toxicity. J Appl Physiol (1985). 1987;63(3):1130–1135. doi: 10.1152/jappl.1987.63.3.1130 [DOI] [PubMed] [Google Scholar]
30.Arieli R. Calculated risk of pulmonary and central nervous system oxygen toxicity: a toxicity index derived from the power equation. Diving Hyperb Med. 2019;49(3):154. doi: 10.28920/dhm49.3.154-160 [DOI] [PMC free article] [PubMed] [Google Scholar]
31.Weaver LK, Churchill S. Pulmonary edema associated with hyperbaric oxygen therapy. Chest. 2001;120(4):1407–1409. doi: 10.1378/chest.120.4.1407 [DOI] [PubMed] [Google Scholar]
32.Obiagwu C, Paul V, Chadha S, Hollander G, Shani J. Acute pulmonary edema secondary to hyperbaric oxygen therapy. Oxf Med Case Reports. 2015;2015(2):183–184. doi: 10.1093/omcr/omv002 [DOI] [PMC free article] [PubMed] [Google Scholar]
33.Rivalland G, Mitchell SJ, van Schalkwyk JM. Pulmonary Barotrauma and Cerebral Arterial Gas Embolism During Hyperbaric Oxygen Therapy. Aviat Space Environ Med. 2010;81(9). doi: 10.3357/ASEM.2783.2010 [DOI] [PubMed] [Google Scholar]
34.Jaeger N, Brosious J, Gustavson R, et al. Pneumomediastinum following hyperbaric oxygen therapy for carbon monoxide poisoning: case report. Undersea & Hyperbaric Medicine. 2013;40(6):521–523. [PubMed] [Google Scholar]
35.Unsworth I. Pulmonary barotrauma in a hyperbaric chamber. Anaesthesia. 1973;28(6):675–678. doi: 10.1111/J.1365-2044.1973.TB00555.X [DOI] [PubMed] [Google Scholar]
36.Brenna CTA, Khan S, Djaiani G, Buckey JC, Katznelson R. The role of routine pulmonary imaging before hyperbaric oxygen treatment. Diving Hyperb Med. 2022;52(3):197–207. doi: 10.28920/dhm52.3.197-207 [DOI] [PMC free article] [PubMed] [Google Scholar]
37.Hadanny A, Meir O, Bechor Y, Fishlev G, Bergan J, Efrati S. The safety of hyperbaric oxygen treatment—retrospective analysis in 2,334 patients. Undersea Hyperb Med. 2016;43(2):113–122. [PubMed] [Google Scholar]

PLoS One. doi: 10.1371/journal.pone.0285830.r001

Decision Letter 0

Eman Sobh

30 Jan 2023

PONE-D-22-30287Heavy breathing: a longitudinal observational study of pulmonary function following hyperbaric oxygen therapyPLOS ONE

Dear Dr. Brenna,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

==============================

please indicate the reference for heavy breathing expression used in title as it seems a plain language rather than scientific one. The study is iteresting but what about confounders? did you considered any factors that may be associated with decreased PFT during the study period?.

==============================

Please submit your revised manuscript by Mar 16 2023 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Eman Sobh, M.D.

Academic Editor

PLOS ONE

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2. Please provide additional details regarding participant consent. In the ethics statement in the Methods and online submission information, please ensure that you have specified what type you obtained (for instance, written or verbal, and if verbal, how it was documented and witnessed). If your study included minors, state whether you obtained consent from parents or guardians. If the need for consent was waived by the ethics committee, please include this information.

3. Thank you for stating the following in the Competing Interests section:

"I have read the journal's policy and the authors of this manuscript have the following competing interests: RK is a shareholder in the Rouge Valley Hyperbaric Medical Center, Toronto, ON."

Please confirm that this does not alter your adherence to all PLOS ONE policies on sharing data and materials, by including the following statement: "This does not alter our adherence to PLOS ONE policies on sharing data and materials.” (as detailed online in our guide for authors http://journals.plos.org/plosone/s/competing-interests). If there are restrictions on sharing of data and/or materials, please state these. Please note that we cannot proceed with consideration of your article until this information has been declared.

Please include your updated Competing Interests statement in your cover letter; we will change the online submission form on your behalf.

4. In your Data Availability statement, you have not specified where the minimal data set underlying the results described in your manuscript can be found. PLOS defines a study's minimal data set as the underlying data used to reach the conclusions drawn in the manuscript and any additional data required to replicate the reported study findings in their entirety. All PLOS journals require that the minimal data set be made fully available. For more information about our data policy, please see http://journals.plos.org/plosone/s/data-availability.

Upon re-submitting your revised manuscript, please upload your study’s minimal underlying data set as either Supporting Information files or to a stable, public repository and include the relevant URLs, DOIs, or accession numbers within your revised cover letter. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories. Any potentially identifying patient information must be fully anonymized.

Important: If there are ethical or legal restrictions to sharing your data publicly, please explain these restrictions in detail. Please see our guidelines for more information on what we consider unacceptable restrictions to publicly sharing data: http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions. Note that it is not acceptable for the authors to be the sole named individuals responsible for ensuring data access.

We will update your Data Availability statement to reflect the information you provide in your cover letter.

5. Please include your full ethics statement in the ‘Methods’ section of your manuscript file. In your statement, please include the full name of the IRB or ethics committee who approved or waived your study, as well as whether or not you obtained informed written or verbal consent. If consent was waived for your study, please include this information in your statement as well.

6. Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Partly

Reviewer #4: Yes

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: I Don't Know

Reviewer #2: I Don't Know

Reviewer #3: N/A

Reviewer #4: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: No

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Table1 - BMI 15-25 should be divided into under and normal weight

Table2 - ATA 48+36 = 84 implying that there are 2 missing data - please address this accordingly

Line224 "in in" - should be "in"

I wonder if we analyze interval change of PFT between time points of each subjects - will the same conclusions be drawn? (It sems to me that analyzing group data of PFT between time points maybe subject to "the stronger lives longer" kind of bias)

Reviewer #2: Thanks for conducting this important study to investigate the pulmonary function test changes in patients undergoing HBOT especially those with prior respiratory diseases or smoking histories.

I have 1 comment regarding the discussion part (265) where you stated that "Patients treated at 2.0 ATA similarly exhibited a great degree of mild abnormality at baseline" I would appreciate if you could write more details on how you categorized the PFT abnormalities. This will make it easier for the readers and other researchers too.

Reviewer #3: The subject is interesting, title is informative, aim is specific

The results support the aim and illustrative and the discussion is meticulous and answered the research question clearly.

The manuscript is well written

Reviewer #4: 1. Case Control Study were not made to determine the possible exposure factors/disease incidence

both the relative risk and odds ratio are relevant in this retrospective cohort studies.

2. The CONSORT diagram (fig-1) is not done as per the flow of data need to consider the elements of flow of subjects.

3. n=22 for smoker history. what about the others participated in this study?

and why not exclused

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: Yes: Abdullah A. Almojaibel

Reviewer #3: Yes: Aliae Mohamed Hussein

Reviewer #4: No

**********

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

PLoS One. 2023 May 31;18(5):e0285830. doi: 10.1371/journal.pone.0285830.r002

Author response to Decision Letter 0

13 Feb 2023

Editorial Team Comments:

please indicate the reference for heavy breathing expression used in title as it seems a plain language rather than scientific one. The study is interesting but what about confounders? did you considered any factors that may be associated with decreased PFT during the study period?.

Response: thank you for your comments on our manuscript.

The original title (“Heavy breathing: a longitudinal observational study of pulmonary function following hyperbaric oxygen therapy”) is a reference to each of the core elements of the study. As noted by reviewer 3, we selected it as a concise, descriptive title for the work, introducing a more substantive subtitle which presents the methodological details of the study. Hyperbaric oxygen therapy fundamentally means breathing high-baricity (dense, pressurized, or heavy) oxygen at supra-atmospheric pressures, and the title links this concept to our primary outcome of pulmonary function/breathing performance over the course of repetitive hyperbaric exposure. With this in mind, if the editor would prefer an alternative title we are willing to modify it to: “Pulmonary function following hyperbaric oxygen therapy: a longitudinal observational study.” We have changed the title in our revised manuscript, and will leave it up to the editorial team to choose which of these two titles they prefer.

With respect to confounders, we identified key subgroups and isolated them for independent statistical analysis (including pre-existing lung disease, treatment pressure, and smoking history). Our data suggest that previous cross-sectional studies could have been confounded by these variables, for example because we see baseline differences in pulmonary function among individuals with prior lung disease that could be misinterpreted as a consequence of HBOT in a single-timepoint study. However, our longitudinal analysis did not report significant pulmonary function changes over the course of serial treatment in study group (i.e., PFT performance was stable throughout the study period), and therefore our data is not suggestive of any confounders.

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

Response: we have confirmed that our manuscript is formatted in accordance with the PLOS ONE style requirements. In particular, we have removed authors’ titles from our original submission and have ensured there are no abbreviations in our author affiliations list (Page 1).

Response: we have clarified in our revised manuscript (Methods section, Page 4, Line 95), as well as in the online submission, that participants provided written consent for treatment (HBOT). The present study did not include minors.

3. Thank you for stating the following in the Competing Interests section:

"I have read the journal's policy and the authors of this manuscript have the following competing interests: RK is a shareholder in the Rouge Valley Hyperbaric Medical Center, Toronto, ON."

Please include your updated Competing Interests statement in your cover letter; we will change the online submission form on your behalf.

We have revised our Competing Interests statement to read:

“I have read the journal's policy and the authors of this manuscript have the following competing interests: RK is a shareholder in the Rouge Valley Hyperbaric Medical Center, Toronto, ON. This does not alter our adherence to PLOS ONE policies on sharing data and materials.”

Thank you for updating this statement in the online submission form on our behalf.

We will update your Data Availability statement to reflect the information you provide in your cover letter.

Response: as we note in our original submission, the source data from our study cannot be shared publicly, in full, because of an ethical restriction levied by our institutional research ethics board. This is because the data contains sensitive information from patient’s medical charts (e.g., birth dates and personal health information). Taken together, this information may allow for the identification of individual study participants. We offer that an anonymized minimal data set can be prepared in aggregate and made available upon reasonable request via email to the study’s first author (connor.brenna@mail.utoronto.ca) or the Hyperbaric Medicine Unit, Toronto General Hospital, Toronto, Ontario, Canada (hyperbaricmedicineunit@uhn.ca).

Response: we have included the Ethics Statement from our online submission in the revised manuscript (please see Page 4, lines 93-98). It now reads:

“All studied patients provided written consent to undergo HBOT (for a variety of clinical indications), and were scheduled to receive at least ten cycles of treatment at our large referral center during this timeframe. Patients underwent PFT assessment before starting HBOT and following every 20 treatment sessions thereafter. Research ethics approval for the analysis of these data was provided by the University Health Network (Toronto, ON) Research Ethics Board (CAPCR ID: 19-5081.1).”

Response: we have reviewed our reference list. It is complete, and our manuscript does not cite any retracted articles.

Reviewer #1 Comments:

Table1 - BMI 15-25 should be divided into under and normal weight

Response: we have divided the “BMI 15-25” category into “normal” (BMI 18.5-25) and “underweight” (15-18.5) as suggested by the reviewer. This change can is reflected in Table 1 (Page 8).

Table2 - ATA 48+36 = 84 implying that there are 2 missing data - please address this accordingly

Response: thank you for identifying this typographical error. We have corrected this in the revision (it should read 49 and 37, respectively) in Table 2 (Page 10). We have also checked that the correct values were used in the subgroup analysis presented in Figure 5.

Line224 "in in" - should be "in"

Response: thank you, this has been corrected in the revision (Page 12, Line 225).

Response: this is an interesting point about the potential for bias in interventional studies. In our study, PFT data was analyzed retrospectively after patients’ treatment was completed, and so spirometry results did not impact clinical decision making. Our study methodology therefore safeguards against this type of survivorship bias.

Nonetheless, we have performed a post-hoc pairwise comparison of the various timepoints to assess for interval change (Page 6, Lines 146-148). The results of this secondary analysis do not alter the findings or conclusion of our report, but we include this analysis of the full cohort in the revision as Supplementary Table 3. We are happy to provide the same analyses for each subgroup as additional supplemental files, if the reviewer feels it could add further value, but have not included these in the revision as each table is quite large (due to the number of variables evaluated).

Reviewer #2 Comments:

Thanks for conducting this important study to investigate the pulmonary function test changes in patients undergoing HBOT especially those with prior respiratory diseases or smoking histories.

Response: thank you for your review of our manuscript. This is an insightful comment, and we have clarified it in the revised text. We selected FEV1, FVC, and FEF25-75 as key outcome variables because they reflect large airway obstruction, lung restriction, and small/medium airway obstruction, respectively. Various classification schema exist to characterize the severity of abnormality in these variables for the purposes of clinical diagnosis, but classically rely on the interpretation of several variables in relation to each other within a single patient’s pulmonary function test. Because these variables comprise only a key subset of a full pulmonary function test, and in order to analyze them in aggregate, we opted to categorize abnormalities in FEV1, FVC, and FEF25-75 as an independent function of each parameter’s deviation from predicted values. We chose to use threshold of 70-79% to designate mild abnormality, 60-69% to designate moderate abnormality, and <60% to designate severe abnormality. However, we use these values only to comment on baseline differences in pulmonary function among subgroups; the more important outcome of our study is the stability of pulmonary function over the course of HBOT treatment, which does not appear to change significantly regardless of a patients’ starting pulmonary function. These thresholds have been clarified in the revision (Page 6, Lines 130-134), and we have added more detail to the Discussion section (Page 14, Lines 264-269) in response to this query.

Reviewer #3 Comments:

The subject is interesting, title is informative, aim is specific

The results support the aim and illustrative and the discussion is meticulous and answered the research question clearly.

The manuscript is well written

Response: Thank you for your time and critical review of our manuscript.

Reviewer #4 Comments:

Case Control Study were not made to determine the possible exposure factors/disease incidence

Response: a case control study would not be feasible to examine the relationship between pulmonary dysfunction and HBOT. Our data illustrates that modern HBOT protocols do not cause significant change in pulmonary function, even over long-term, repetitive treatments or among subgroups of patients who might be considered more vulnerable to pulmonary impairment. Therefore, we suggest that a case control study with modern treatment protocols could not be performed: there are no cases.

both the relative risk and odds ratio are relevant in this retrospective cohort studies.

Response: a RR and OR cannot be calculated given that the methodology does not include a control group (e.g., without exposure to HBOT). It would be possible to calculate RR and OR metrics for variables interrogated in our subgroup analyses (e.g., treatment pressure, pre-existing pulmonary disease, and smoking history); however, because no subgroup demonstrated pulmonary dysfunction with serial treatment, the RR and OR in each of these cases would be 1 indicating an identical risk regardless of the modifying variable. In lieu or relative risk and odds ratio calculations, we present the data in Figures 2 through 5 illustrating that pulmonary function is not compromised by modern HBOT regimens.

2. The CONSORT diagram (fig-1) is not done as per the flow of data need to consider the elements of flow of subjects.

Response: we have revised our modified CONSORT diagram (Figure 1) in the revision to better-represent the flow of subjects through the study. All patients enrolled into the study are accounted for in the updated figure, and it clearly depicts the number of patients whose enrollment continued through each study timepoint.

3. n=22 for smoker history. what about the others participated in this study?

and why not exclused

Response: 23 patients in the study were “current smokers”, 16 were “former smokers”, and 47 were “never smokers”. This comment may refer to the calculation of pack years among current and former smokers enrolled into the cohort, as precise data regarding “pack year” smoking quantity was only available for 22 enrolled patients.

Regarding the second part of this comment, which asks why patients with smoking history were not excluded, we feel that their inclusion is one of several strengths that our present manuscript offers compared to earlier studies of the effects of HBOT on pulmonary function. We clarify in our revision (Discussion section, Page 16, Lines 296-299) that some prior studies are potentially biased by the exclusion of patients with smoking histories (or pre-existing lung disease); however, their exclusion is not reflective of contemporary practice, as a significant proportion of patients referred for HBOT have a smoking history. Thus, it is important to understand the unique risks that HBOT may bear for these patients in particular, who theoretically may be at heightened risk. For this reason, we present a subgroup analysis of patients disaggregated into the categories of current smoker, former smoker, and never smoker (Figure 4).

We thank the editor and all four reviewers for their time contributed to improving our revised manuscript.

PLoS One. doi: 10.1371/journal.pone.0285830.r003

Decision Letter 1

Eman Sobh

27 Mar 2023

PONE-D-22-30287R1Pulmonary function following hyperbaric oxygen therapy: a longitudinal observational studyPLOS ONE

Dear Dr. Brenna,

==============================

Table 1 page 8 for the age groups and BMI the end point of each category can not be the same as the end point of the previous one (for example age groups 0-40, 40-60, ...) please revise and correct this table.

==============================

Please submit your revised manuscript by May 11 2023 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

We look forward to receiving your revised manuscript.

Kind regards,

Eman Sobh, M.D.

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

Reviewer #4: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #4: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: I Don't Know

Reviewer #2: Yes

Reviewer #4: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #4: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #4: Yes

**********

6. Review Comments to the Author

Reviewer #1: (No Response)

Reviewer #2: (No Response)

Reviewer #4: At page 8 Table 1, need to consider the code structure of age group 0 to 40, 41 to 60, and so on. Also BMI groups.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

Reviewer #4: Yes: ABDUL RAHMAN H ALI

**********

PLoS One. 2023 May 31;18(5):e0285830. doi: 10.1371/journal.pone.0285830.r004

Author response to Decision Letter 1

27 Mar 2023

Reviewer Comments

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

Reviewer #4: All comments have been addressed

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #4: Yes

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: I Don't Know

Reviewer #2: Yes

Reviewer #4: Yes

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #4: Yes

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #4: Yes

6. Review Comments to the Author

Reviewer #1: (No Response)

Reviewer #2: (No Response)

Reviewer #4: At page 8 Table 1, need to consider the code structure of age group 0 to 40, 41 to 60, and so on. Also BMI groups.

Response: please see our earlier response, this has been corrected in Tables 1 and 2 (pages 8 and 10) per the reviewer suggestion.

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

Reviewer #4: Yes: ABDUL RAHMAN H ALI

Response: We thank all three reviewers for their time contributed to reviewing our revised submission to PLOS ONE.

PLoS One. doi: 10.1371/journal.pone.0285830.r005

Decision Letter 2

Eman Sobh

14 Apr 2023

PONE-D-22-30287R2Pulmonary function following hyperbaric oxygen therapy: a longitudinal observational studyPLOS ONE

Dear Dr. Brenna,

==============================

Thanks for responding to the comments. Still table one has age with the same cut off point for 0-40 and 40-60. please revise either 0-less than 40 & 40-60 or 0-40 and 41-60 and check numbers according

==============================

Please submit your revised manuscript by May 29 2023 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

We look forward to receiving your revised manuscript.

Kind regards,

Eman Sobh, M.D.

Academic Editor

PLOS ONE

Journal Requirements:

[Note: HTML markup is below. Please do not edit.]

PLoS One. 2023 May 31;18(5):e0285830. doi: 10.1371/journal.pone.0285830.r006

Author response to Decision Letter 2

14 Apr 2023

Editorial Team Comments

Response: thank you for your close attention to detail in reviewing our revised manuscript, and for identifying this error. In the further-revised manuscript, this has been corrected: the age ranges in Table 1 should have read “0-40”, “41-60”, “61-80” and “81+”. The remaining values in the table are correct without additional changes, and this error in the name of the second group has been adjusted per your suggestion. We have double-checked that our other tables and figures also represent our data correctly.

PLoS One. doi: 10.1371/journal.pone.0285830.r007

Decision Letter 3

Eman Sobh

3 May 2023

Pulmonary function following hyperbaric oxygen therapy: a longitudinal observational study

PONE-D-22-30287R3

Dear Dr. Brenna,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Eman Sobh, M.D.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

PLoS One. doi: 10.1371/journal.pone.0285830.r008

Acceptance letter

Eman Sobh

22 May 2023

PONE-D-22-30287R3

Pulmonary function following hyperbaric oxygen therapy:a longitudinal observational study

Dear Dr. Brenna:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Eman Sobh

Academic Editor

PLOS ONE

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

S1 Table. Approved indications for hyperbaric oxygen therapy in Canada and the United States.

Hyperbaric oxygen therapy indications approved by Health Canada (*) or the US Food and Drug Administration (†). Unlabeled items are approved by both agencies.

(DOCX)

Click here for additional data file.^{(13.5KB, docx)}

S2 Table. STROBE statement for cohort studies.

Guidelines for reporting observational studies, and the page location of critical elements in the submitted manuscript.

(DOCX)

Click here for additional data file.^{(19.4KB, docx)}

S3 Table. Post-hoc pairwise comparisons.

(DOCX)

Click here for additional data file.^{(14.5KB, docx)}

Data Availability Statement

[pone.0285830.ref001] 1.Hyperbaric Oxygen Therapy—Canada.ca. https://www.canada.ca/en/health-canada/services/healthy-living/your-health/medical-information/hyperbaric-oxygen-therapy.html

[pone.0285830.ref002] 2.Hyperbaric Oxygen Therapy: Get the Facts | FDA. https://www.fda.gov/consumers/consumer-updates/hyperbaric-oxygen-therapy-get-facts

[pone.0285830.ref003] 3.Jackson RM. Pulmonary Oxygen Toxicity. Chest. 1985;88(6):900–905. doi: 10.1378/chest.88.6.900 [DOI] [PubMed] [Google Scholar]

[pone.0285830.ref004] 4.Smith JL. The pathological effects due to increase of oxygen tension in the air breathed. J Physiol. 1899;24(1):19. doi: 10.1113/jphysiol.1899.sp000746 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0285830.ref005] 5.Klein J. Normobaric pulmonary oxygen toxicity. Anesth Analg. 1990;70(2):195–207. doi: 10.1213/00000539-199002000-00012 [DOI] [PubMed] [Google Scholar]

[pone.0285830.ref006] 6.Fisher AB, Forman HJ, Glass M. Mechanisms of pulmonary oxygen toxicity. Lung 1984 162:1. 1984;162(1):255–259. doi: 10.1007/BF02715655 [DOI] [PubMed] [Google Scholar]

[pone.0285830.ref007] 7.van Ooij PJAM, Sterk PJ, van Hulst RA. Oxygen, the lung and the diver: friends and foes? Eur Respir Rev. 2016;25(142):496–505. doi: 10.1183/16000617.0049-2016 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0285830.ref008] 8.Wingelaar TT, Brinkman P, van Ooij PJAM, et al. Markers of pulmonary oxygen toxicity in hyperbaric oxygen therapy using exhaled breath analysis. Front Physiol. 2019;10(APR):475. doi: 10.3389/fphys.2019.00475 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0285830.ref009] 9.Wingelaar TT, van Ooij PJAM, van Hulst RA. Oxygen toxicity and special operations forces diving: Hidden and dangerous. Front Physiol. 2017;8(JUL):1263. doi: 10.3389/fpsyg.2017.01263 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0285830.ref010] 10.Edmonds C, Bennett M, Lippmann J, Mitchell S. Oxygen Toxicity. In: Diving and Subaquatic Medicine. 5th ed. CRC Press; 2015:242. [Google Scholar]

[pone.0285830.ref011] 11.von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: Guidelines for reporting observational studies. Ann Intern Med. 2007;147(8):573–577. doi: 10.7326/0003-4819-147-8-200710160-00010 [DOI] [PubMed] [Google Scholar]

[pone.0285830.ref012] 12.Schiavo S, Djaiani C, DeBacker J, et al. Magnitude and Clinical Predictors of Blood Pressure Changes in Patients Undergoing Hyperbaric Oxygen Therapy: A Retrospective Study. Int J Environ Res Public Health. 2020;17(20):1–14. doi: 10.3390/ijerph17207586 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0285830.ref013] 13.Graham BL, Steenbruggen I, Miller MR, et al. Standardization of Spirometry 2019 Update. An Official American Thoracic Society and European Respiratory Society Technical Statement. Am J Respir Crit Care Med. 2019;200(8):E70–E88. doi: 10.1164/rccm.201908-1590ST [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0285830.ref014] 14.Knudson RJ, Lebowitz MD, Holberg CJ, Burrows B. Changes in the normal maximal expiratory flow-volume curve with growth and aging. American Review of Respiratory Disease. 1983;127(6):725–734. doi: 10.1164/arrd.1983.127.6.725 [DOI] [PubMed] [Google Scholar]

[pone.0285830.ref015] 15.Schulz KF, Altman DG, Moher D. CONSORT 2010 Statement: updated guidelines for reporting parallel group randomised trials. Trials. 2010;11(1):1–8. doi: 10.1186/1745-6215-11-32 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0285830.ref016] 16.Pott F, Westergaard P, Mortensen J, Jansen EC. Hyperbaric oxygen treatment and pulmonary function. Undersea and Hyperbaric Medicine. 1999;26(4):225–228. [PubMed] [Google Scholar]

[pone.0285830.ref017] 17.Thorsen E, Aanderud L, Aasen TB. Effects of a standard hyperbaric oxygen treatment protocol on pulmonary function. European Respiratory Journal. 1998;12(6):1442–1445. doi: 10.1183/09031936.98.12061442 [DOI] [PubMed] [Google Scholar]

[pone.0285830.ref018] 18.Hadanny A, Zubari T, Tamir-Adler L, et al. Hyperbaric oxygen therapy effects on pulmonary functions: A prospective cohort study. BMC Pulm Med. 2019;19(1):148. doi: 10.1186/s12890-019-0893-8 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0285830.ref019] 19.Comert S, Sumen SG, Caglayan B. Effects of a standard hyperbaric oxygen treatment protocol on pulmonary functions and diaphragm. In: European Respiratory Journal. Vol 50. European Respiratory Society (ERS); 2017:PA730. doi: 10.1183/1393003.congress-2017.pa730 [DOI] [PubMed] [Google Scholar]

[pone.0285830.ref020] 20.Demir L, Avci M. Effect of hyperbaric exposure on pulmonary functions in hyperbaric chamber inside attendants. Undersea & hyperbaric medicine. 2022;49(2):161–169. doi: 10.22462/03.04.2022.1 [DOI] [PubMed] [Google Scholar]

[pone.0285830.ref021] 21.Miller JN, Winter PM. Clinical manifestations of pulmonary oxygen toxicity. Int Anesthesiol Clin. 1981;19(3):179–199. doi: 10.1097/00004311-198119030-00011 [DOI] [PubMed] [Google Scholar]

[pone.0285830.ref022] 22.Schaefer KE. Oxygen in Closed Environmental Systems. In: Gilbert DL, ed. Oxygen and Living Processes. Springer; 1981:343–357. doi: 10.1007/978-1-4612-5890-2_15 [DOI] [Google Scholar]

[pone.0285830.ref023] 23.Clark JM, Lambertsen CJ, Gelfand R, et al. Effects of prolonged oxygen exposure at 1.5, 2.0, or 2.5 ATA on pulmonary function in men (predictive studies V). J Appl Physiol (1985). 1999;86(1):243–259. doi: 10.1152/jappl.1999.86.1.243 [DOI] [PubMed] [Google Scholar]

[pone.0285830.ref024] 24.Fisher AB, Hyde RW, Puy RJ, Clark JM, Lambertsen CJ. Effect of oxygen at 2 atmospheres on the pulmonary mechanics of normal man. J Appl Physiol. 1968;24(4):529–536. doi: 10.1152/jappl.1968.24.4.529 [DOI] [PubMed] [Google Scholar]

[pone.0285830.ref025] 25.Clark JM, Lambertsen CJ. Rate of development of pulmonary O2 toxicity in man during O2 breathing at 2.0 Ata. J Appl Physiol. 1971;30(5):739–752. doi: 10.1152/jappl.1971.30.5.739 [DOI] [PubMed] [Google Scholar]

[pone.0285830.ref026] 26.Clark JM, Jackson RM, Lambertsen CJ, Gelfand R, Hiller WDB, Unger M. Pulmonary function in men after oxygen breathing at 3.0 ATA for 3.5 h. J Appl Physiol (1985). 1991;71(3):878–885. doi: 10.1152/jappl.1991.71.3.878 [DOI] [PubMed] [Google Scholar]

[pone.0285830.ref027] 27.Davis WB, Rennard SI, Bitterman PB, Crystal RG. Pulmonary oxygen toxicity. Early reversible changes in human alveolar structures induced by hyperoxia. N Engl J Med. 1983;309(15). doi: 10.1056/NEJM198310133091502 [DOI] [PubMed] [Google Scholar]

[pone.0285830.ref028] 28.Robinson FR, Casey HW, Weibel ER. Animal model: Oxygen toxicity in nonhuman primates. Am J Pathol. 1974;76(1):175. [PMC free article] [PubMed] [Google Scholar]

[pone.0285830.ref029] 29.Harabin AL, Homer LD, Weathersby PK, Flynn ET. An analysis of decrements in vital capacity as an index of pulmonary oxygen toxicity. J Appl Physiol (1985). 1987;63(3):1130–1135. doi: 10.1152/jappl.1987.63.3.1130 [DOI] [PubMed] [Google Scholar]

[pone.0285830.ref030] 30.Arieli R. Calculated risk of pulmonary and central nervous system oxygen toxicity: a toxicity index derived from the power equation. Diving Hyperb Med. 2019;49(3):154. doi: 10.28920/dhm49.3.154-160 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0285830.ref031] 31.Weaver LK, Churchill S. Pulmonary edema associated with hyperbaric oxygen therapy. Chest. 2001;120(4):1407–1409. doi: 10.1378/chest.120.4.1407 [DOI] [PubMed] [Google Scholar]

[pone.0285830.ref032] 32.Obiagwu C, Paul V, Chadha S, Hollander G, Shani J. Acute pulmonary edema secondary to hyperbaric oxygen therapy. Oxf Med Case Reports. 2015;2015(2):183–184. doi: 10.1093/omcr/omv002 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0285830.ref033] 33.Rivalland G, Mitchell SJ, van Schalkwyk JM. Pulmonary Barotrauma and Cerebral Arterial Gas Embolism During Hyperbaric Oxygen Therapy. Aviat Space Environ Med. 2010;81(9). doi: 10.3357/ASEM.2783.2010 [DOI] [PubMed] [Google Scholar]

[pone.0285830.ref034] 34.Jaeger N, Brosious J, Gustavson R, et al. Pneumomediastinum following hyperbaric oxygen therapy for carbon monoxide poisoning: case report. Undersea & Hyperbaric Medicine. 2013;40(6):521–523. [PubMed] [Google Scholar]

[pone.0285830.ref035] 35.Unsworth I. Pulmonary barotrauma in a hyperbaric chamber. Anaesthesia. 1973;28(6):675–678. doi: 10.1111/J.1365-2044.1973.TB00555.X [DOI] [PubMed] [Google Scholar]

[pone.0285830.ref036] 36.Brenna CTA, Khan S, Djaiani G, Buckey JC, Katznelson R. The role of routine pulmonary imaging before hyperbaric oxygen treatment. Diving Hyperb Med. 2022;52(3):197–207. doi: 10.28920/dhm52.3.197-207 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0285830.ref037] 37.Hadanny A, Meir O, Bechor Y, Fishlev G, Bergan J, Efrati S. The safety of hyperbaric oxygen treatment—retrospective analysis in 2,334 patients. Undersea Hyperb Med. 2016;43(2):113–122. [PubMed] [Google Scholar]

PERMALINK

Pulmonary function following hyperbaric oxygen therapy: A longitudinal observational study

Connor T A Brenna

Shawn Khan

George Djaiani

Darren Au

Simone Schiavo

Mustafa Wahaj

Ray Janisse

Rita Katznelson

Roles

Abstract

Introduction

Methods

Study design and participants

Hyperbaric oxygen therapy protocol

Pulmonary function testing protocol

Data collection and statistical analysis

Objectives

Results

Fig 1. Modified CONSORT diagram of enrollment.

Table 1. Descriptive analysis of patients included in the current study.

Table 2. Hyperbaric oxygen therapy details and complications.

Fig 2. Pulmonary function testing before and during hyperbaric oxygen therapy.

Fig 3. Pulmonary function testing in patients stratified by pre-existing respiratory disease before and during hyperbaric oxygen therapy.

Fig 4. Pulmonary function testing in patients stratified by smoking status before and during hyperbaric oxygen therapy.

Fig 5. Pulmonary function testing in patients before and during hyperbaric oxygen therapy at different pressures.

Discussion

Limitations

Conclusions

Supporting information

Abbreviations

Data Availability

Funding Statement

References

Decision Letter 0

Eman Sobh

Roles

Author response to Decision Letter 0

Decision Letter 1

Eman Sobh

Roles

Author response to Decision Letter 1

Decision Letter 2

Eman Sobh

Roles

Author response to Decision Letter 2

Decision Letter 3

Eman Sobh

Roles

Acceptance letter

Eman Sobh

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

Similar articles

Cited by other articles

Links to NCBI Databases