PLoS ONE
Public Library of Science
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Use of hyperbaric oxygen therapy for preventing delayed neurological sequelae in patients with carbon monoxide poisoning: A multicenter, prospective, observational study in Japan
DOI 10.1371/journal.pone.0253602 , Volume: 16 , Issue: 6 , Pages: 0-0
Article Type: research-article, Article History
Abstract

Background

The purpose of this study was to clarify the practical clinical treatment for acute carbon monoxide (CO) poisoning in Japan and to investigate the efficacy of hyperbaric oxygen (HBO2) therapy in preventing delayed neurological sequelae (DNS) in the acute phase of CO poisoning.

Methods

We conducted a multicenter, prospective, observational study of acute CO poisoning in Japan. Patients with acute CO poisoning were enrolled and their treatment details were recorded. The primary endpoint was the onset of DNS within 2 months of CO exposure. Factors associated with DNS were assessed with logistic regression analysis.

Results

A total of 311 patients from 57 institutions were registered and 255 were analyzed: 171 received HBO2 therapy (HBO2 group) and 84 did not (normobaric oxygen [NBO2] group). HBO2 therapy was performed zero, once, twice, or three times within the first 24 h in 1.8%, 55.9%, 30.9%, and 11.3% of the HBO2 group, respectively. The treatment pressure in the first HBO2 session was 2.8 ATA (47.9% of the HBO2 group), 2.0 ATA (41.8%), 2.5 ATA (7.9%), or another pressure (2.4%). The incidence of DNS was 13/171 (7.6%) in the HBO2 group and 3/84 (3.6%) in the NBO2 group (P = 0.212). The number of HBO2 sessions in the first 24 h was one of the factors associated with the incidence of DNS (odds ratio, 2.082; 95% confidence interval, 1.101–3.937; P = 0.024).

Conclusions

The practical clinical treatment for acute CO poisoning, including HBO2 therapy, varied among the institutions participating in Japan. HBO2 therapy with inconsistent protocols showed no advantage over NBO2 therapy in preventing DNS. Multiple HBO2 sessions was associated with the incidence of DNS.

Introduction

Hyperbaric oxygen (HBO2 ) therapy is thought to be essential for preventing neurological sequelae in patients with carbon monoxide (CO) poisoning, based on the results of a randomized controlled trial (RCT) reported by Weaver et al. [1]. However, the results of RCTs, including subsequent reports, have been conflicting [26], and the effects of HBO2 therapy for patients with CO poisoning remains contentious. A previous meta-analysis did not find beneficial effects of HBO2 therapy or the reduction of adverse neurological outcomes by HBO2 therapy for CO poisoning [7]. Therefore, it is unclear whether HBO2 therapy in the acute phase of CO poisoning prevents neurological sequelae.

Our previous survey, performed by questionnaire, showed that the clinical practice of HBO2 therapy for CO poisoning varied in both its indications and the practice regimens used in Japan [8]. This situation is not specific to Japan and has also been reported in the USA and Europe [9, 10]. These findings suggest that there is no clear clinical consensus about HBO2 therapy for acute CO poisoning. Therefore, we conducted a multicenter, prospective, observational study of acute CO poisoning to clarify the practical clinical treatment for acute CO poisoning in Japan and to investigate the efficacy of HBO2 therapy in preventing DNS in the acute phase of CO poisoning.

Methods

Design and setting

We conducted a multicenter, prospective, observational study of acute CO poisoning in Japan called the COP-J Study to clarify the efficacy of HBO2 therapy in the acute phase of CO poisoning. A cohort of patients with acute CO poisoning from 54 institutions was enrolled in the COP-J Study, which recorded the patients’ data after approval was given by the Ethics Committee of each institution. The COP-J Study was approved by the Japanese Society of Intensive Care Medicine (No. 0011). The therapeutic policies of the majority of these institutions have already been reported [8] and 19 (35.2%) of the 54 institutions involved in this study did not administer HBO2 therapy and performed only normobaric oxygen (NBO2) therapy. The 35 enrolled institutions that had an HBO2 chamber administered HBO2 therapy according to their institutional policies [8]. At the start of the study, there were 568 institutions in Japan that had an HBO2 chamber, of which 115 had a board-certified fellow of the Japanese Society of Hyperbaric and Undersea Medicine.

Data collection and analysis

Patients diagnosed with acute CO poisoning based on any symptoms after CO exposure or on a carboxyhemoglobin (COHb) level exceeding 10%, between October 2015 and September 2018, were enrolled in the study. The medical records of the patients, including the circumstances of CO exposure, prehospital information, physical and laboratory findings upon arrival, and details of treatments, including HBO2 therapy, were recorded by the University Hospital Medical Information Network–Internet Data and Information Center for Medical Research (UMIN–INDICE) web system. The primary endpoint was the onset of delayed neurological sequelae (DNS) within 2 months of CO exposure. DNS was defined as cognitive dysfunction that affected daily life after an improvement in disturbed consciousness. DNS was checked at outpatient consultations or by telephone if the patient did not visit the hospital. In the telephone consultation for DNS, the physician addressed the following questions to the patients or their family: “Is there any hindrance to daily life?”; “Do you have memory problems?”; “Is there any change in your personality?”; “Are there more things you cannot do compared with before?”, and so on. If there was any doubt about the presence of DNS, the physician instructed the patient to visit the hospital. DNS was finally diagnosed by a physician based on all the findings at the time of diagnosis, including results of a cognitive function test, such as the mini-mental state examination, the Wechsler adult intelligence scale, Hasegawa’s dementia scale-revised [11], the trail-making test, or the story recall test. In addition, the physicians were not blinded as to the treatment of acute CO poisoning. The secondary endpoint was the improvement in prolonged consciousness disturbance (PCD), which was defined as prolonged consciousness disturbance after 24 h from admission. The improvement in PCD was checked by a physician at discharge or at 2 months after CO exposure. Before the analysis, we excluded patients with cardiopulmonary arrest upon arrival, or in-hospital death, or who were lost to follow-up. In the analysis, we compared the incidence of DNS and improvement in PCD between patients who received either HBO2 or NBO2 therapy during the acute phase. The factors associated with DNS and unimproved PCD were also identified.

Statistical analyses

Variables are shown as means ± standard deviations or numbers (percentages). Missing values were excluded from all analyses. Univariate analyses were performed with a t test for continuous variables and a χ2 test for categorical variables. Univariate regression and multivariable logistic regression with the stepwise variable selection method were performed to identify factors associated with DNS and unimproved PCD, and the results are presented as odds ratios (ORs) and 95% confidence intervals (CIs). The factors associated with DNS and unimproved PCD in previous reports [1217] were included as variables in the multivariable logistic regression models. Values of P < 0.05 were considered to indicate statistical significance. All analyses were performed with IBM SPSS Statistics for Windows version 22 (IBM SPSS Inc., Chicago, IL).

Results

Patients’ characteristics

A total of 311 patients from 54 institutions were registered and 255 were included in the analysis (Fig 1). Of the patients included, 171 received HBO2 therapy (HBO2 group) and 84 did not (NBO2 group). Patients excluded from the analyses included 12 with cardiopulmonary arrest on arrival (CPAOA), three who died in hospital, and 41 who were lost to follow-up.

Flowchart of patient selection.
Fig 1
HBO2, hyperbaric oxygen; NBO2, normobaric oxygen; CPAOA, cardiopulmonary arrest on arrival.Flowchart of patient selection.

The patients’ characteristics and the physiological and laboratory findings on arrival are shown in Table 1. The mean age was 54 ± 22 years in the NBO2 group and 49 ± 19 years in the HBO2 group (P = 0.063). Almost 60% of the patients were male and half the patients had a history of smoking. The sex ratios and smoking histories did not differ significantly between the NBO2 and HBO2 groups. The total rate of patients who had attempted suicide was 29.8% and the difference between the NBO2 and HBO2 groups was not significant (25.0% vs 32.2%, respectively; P = 0.240). In more than half the patients in both groups, CO poisoning was caused by burning charcoal. In the NBO2 group, the number of cases caused by fires was greater than in the HBO2 group, whereas the number of cases caused by car exhausts was lower. The environmental circumstances of CO exposure was the same in both groups. Almost all the patients arrived at hospital by ambulance and the incidence of loss of consciousness was the same in the NBO2 and HBO2 groups (42.3% vs 48.0%, respectively, P = 0.413). Oxygen was administered by the emergency medical service slightly less frequently in the NBO2 group than in the HBO2 group (84.2% vs 92.4%, respectively; P = 0.064). The estimated time of exposure to CO was 181 ± 376 min in the NBO2 group and 202 ± 256 min in the HBO2 group, and the difference was not significant (P = 0.605). The time from CO exposure to hospitalization was the same between the NBO2 and HBO2 groups (240 ± 382 and 279 ± 350 min, respectively; P = 0.420). In the NBO2 group, 47 (56.0%) patients were transferred to an institution that offered only NBO2 therapy by EMS.

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Table 1
Patient characteristics and physiological and laboratory findings upon arrival.
NBO2 (n = 84) HBO2 (n = 171) P-value
Age 54 ±22 49 ± 19 0.063
Sex (male, %) 51 (60.7%) 107 (62.6%) 0.774
Smoking 37 (48.7%) 67 (47.5%) 0.870
Type 0.240
    Accidental 63 (75.0%) 116 (67.8%)
    Intentional 21 (25.0%) 55 (32.2%)
Cause <0.001
    Charcoal 43 (51.2%) 87 (50.9%) 0.963
    Fire 26 (31.0%) 12 (7.0%) <0.001
    Car exhaust 5 (6.0%) 34 (19.9%) 0.002
    Other 10 (11.8%) 38 (22.2%) 0.041
Environment 0.097
    Indoor 68 (81.0%) 122 (71.3%)
    Outdoor 5 (6.0%) 7 (4.1%)
    In a car 11 (13.0%) 42 (24.6%)
Arrived by ambulance 78 (92.9%) 150 (87.7%) 0.210
Loss of consciousness 33 (42.3%) 72 (48.0%) 0.413
Oxygen administration by EMS 64 (84.2%) 122 (92.4%) 0.064
SpCO (%) at scene 26.4 ± 20.9, (n = 8) 30.1 ± 15.7, (n = 40) 0.562
Exposure time (min) 181 ± 376 202 ± 256 0.605
Time from exposure to hospital (min) 240 ± 382 279 ± 350 0.420
No. patients transferred to the institution performing only NBO2 47 (56.0%)
Glasgow Coma Scale on arrival 13 ± 4 13 ± 3 0.445
Systolic blood pressure (mmHg) 138 ± 30 133 ± 23 0.223
Diastolic blood pressure (mmHg) 79 ± 20 77 ± 17 0.497
Heart rate (/min) 100 ± 26 87 ± 19 <0.001
Respiratory rate (/min) 21 ± 7 20 ± 5 0.071
Body temperature (°C) 36.5 ± 0.9 36.7 ± 0.7 0.046
Blood gas analysis (BGA)
Time from arrival to BGA (min) 11.4 ± 12.2 14.0 ± 17.4 0.257
    pH 7.374 ± 0.102 7.409 ± 0.073 0.008
    PaO2 (Torr) 198 ± 103 270 ± 122 <0.001
    PaCO2 (Torr) 37.9 ± 19.4 36.2 ± 6.9 0.342
    HCO3 (mmol/L) 21.0 ± 4.6 22.8 ± 4.1 0.003
    Base excess (mmol/L) -3.2 ± 5.9 -1.3 ± 4.6 0.016
    Lactate (mmol/L) 4.7 ± 3.9 3.5 ± 4.3 0.045
    SaO2 (%) 97.2 ± 5.8 97.2 ± 6.5 0.979
    COHb (%) 19.3 ± 10.2 18.7 ± 11.4 0.682
    MetHb (%) 0.8 ± 0.6 1.2 ± 1.7 0.071
    Hematocrit 41.9 ± 5.8 41.9 ± 5.6 0.980
White blood cell (/μL) 10483 ± 5395 10195 ± 5019 0.685
C-reactive protein (mg/dL) 0.9 ± 3.0 0.7 ± 2.5 0.637
Creatine kinase (IU/L) 361 ± 1000 567 ± 2295 0.446
Creatine kinase MB fraction (IU/L) 14.0 ± 13.3, (n = 40) 13.9 ± 43.0, (n = 89) 0.993
    Above normal range 11 (27.5%), (n = 40) 12 (13.5%), (n = 89) 0.061
Troponin T, positive 7 (29.2%), (n = 24) 18 (22.8%), (n = 79) 0.529
ECG abnormality 18 (22.8%), (n = 79) 33 (20.9%), (n = 158) 0.737
    ST-T change 9 (50.0%) 10 (30.3%)
    AF rhythm 3 (16.7%) 3 (9.1%)
    Other 6 (33.3%) 20 (60.6%)
Abnormal findings on CT 6 (10.7%), (n = 58) 17 (15.9%), (n = 107) 0.368
    Lesion(s) on basal ganglia 1 (16.7%) 11 (64.7%)
    Acute cerebral infarction 1 (16.7%) 0 (0%)
    Chest lesion 3 (50.0%) 1 (5.9%)
    Other 1 (16.7%) 5 (29.4%)
Abnormal findings on head MRI 7 (22.6%), (n = 32) 24 (23.5%), (n = 106) 0.913
    Lesion(s) on basal ganglia or white matter 4 (57.1%) 19 (79.2%)
    Other 3 (42.9%) 5 (20.8%)
NBO2, normobaric oxygen; HBO2, hyperbaric oxygen; EMS, emergency medical service; SpCO, carbon monoxide hemoglobin saturation; COHb, carboxyl hemoglobin; MetHb, methemoglobin; ECG, electrocardiogram; AF, atrial fibrillation; CT, computed tomography; MRI, magnetic resonance imaging.

In the arterial blood gas analyses, PaO2 was significantly lower in the NBO2 group than in the HBO2 group (198 ± 103 vs 270 ± 122 Torr, respectively; P < 0.001) and lactic acidosis was significantly more severe in the NBO2 group than in the HBO2 group. There was no significant difference in COHb levels between the NBO2 and HBO2 groups (19.3 ± 10.2% and 18.7 ± 11.4%, respectively; P = 0.682). Furthermore, in the NBO2 group, the COHb levels were 20.9 ± 10.0% in patients who were transferred to institutions that only offered NBO2 therapy and 17.2 ± 10.1% in patients transferred to institutions that also provided HBO2 therapy (P = 0.101).

Treatment regimens including HBO2 therapy and NBO2 therapy

The number of HBO2 sessions during the first 24 h and the first week in the HBO2 group are shown in Fig 2. HBO2 therapy was performed zero, one, two, or three times within the first 24 h in 1.8%, 55.9%, 30.9%, and 11.3% of the HBO2 group, respectively. In the HBO2 group, 30 patients (17.9% of the group) received HBO2 therapy only once during the first week after admission; 49 patients (29.2% of the HBO2 group) received HBO2 therapy three times in the first week; and the maximum number of treatments during the first week was 15. The average time from arrival to the first HBO2 session was 158 ± 147 min among the patients who were administered HBO2 therapy on the first day.

Number of HBO2 session during the first 24 h and the first week in the HBO2 group.
Fig 2
Number of HBO2 session during the first 24 h and the first week in the HBO2 group.

The treatment pressures in each HBO2 session during the first 24 h are shown in Table 2. The treatment pressure in the first HBO2 session was 2.8 atmospheres absolute (ATA) (47.9% of the HBO2 group), 2.0 ATA (41.8%), 2.5 ATA (7.9%), or another pressure (2.4%). A treatment pressure of 2.0 ATA was used in the majority of patients in both the second and third HBO2 sessions. In addition, HBO2 therapy were not administered during the first 24 h in 2 patients of the HBO2 group and the details of HBO2 therapy were unknown in 4 patents.

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Table 2
Treatment pressure in each HBO2 session during the first 24 h.
Treatment pressure First (n = 165) Second (n = 71) Third (n = 19)
1.5 ATA 1 (0.6%)
2.0 ATA 69 (41.8%) 38 (53.5%) 12 (63.2%)
2.1 ATA 2 (10.5%)
2.4 ATA 2 (1.2%) 11 (15.5%) 4 (21.1%)
2.5 ATA 13 (7.9%) 9 (12.7%)
2.7 ATA 1 (0.6%)
2.8 ATA 79 (47.9%) 13 (18.3%) 1 (5.3%)
ATA, atmospheres absolute.

The number of patients treated with mechanical ventilation was significantly more in the NBO2 group than in the HBO2 group (25.0% vs 4.7%, respectively, P < 0.001; Table 3). The period of oxygen administration during the hospital stay was 344 ± 2128 h and 70 ± 190 h in the NBO2 and HBO2 groups, respectively, which did not differ significantly (P = 0.266; Table 3). ICU days was also significantly longer in the NBO2 group than in the HBO2 groups (4.1 ± 11.0 and 1.3 ± 2.4 days, respectively; P = 0.025; Table 3), but hospital days did not differ between the groups (P = 0.294; Table 3).

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Table 3
Therapeutic periods and incidence of neurological sequelae.
NBO2 (n = 84) HBO2 (n = 171) P value
MV 21 (25.0%) 8 (4.7%) <0.001
Period of MV (h) 557 ± 3157 6 ± 31 0.127
Period of oxygen administration during the hospital stay (h) 344 ± 2128 70 ± 190 0.266
ICU stay (days) 4.1 ± 11.0 1.3 ± 2.4 0.025
Hospital stay (days) 15.2 ± 25.5 11.1 ± 30.2 0.294
DNS 3 (3.6%) 13 (7.6%) 0.212
PCD 5 (6.0%) 14 (8.2%) 0.523
Unimproved PCD 2 (2.4.%) 6 (3.5%) 0.627
NBO2, normobaric oxygen; HBO2, hyperbaric oxygen; MV, mechanical ventilation; ICU, intensive care unit; DNS, delayed neurological sequelae; PCD, prolonged consciousness disturbance.

Incidence of DNS, improvement in PCD, and factors associated with DNS and unimproved PCD

The total incidence of DNS was 16/255 (6.3%) in this study, and did not differ between the NBO2 group and the HBO2 group (3.6% vs 7.6%, respectively; P = 0.212, Table 3). The total incidences of PCD and unimproved PCD were 19/255 (7.5%) and 8/255 (3.1%), respectively. Neither of these measures differed between the NBO2 group and the HBO2 group (PCD: 6.0% vs 8.2%, respectively, P = 0.523; unimproved PCD: 2.4% vs 3.5%, respectively, P = 0.627; Table 3).

Concerning the association between the number of HBO2 sessions in the first 24 h and the incidence of DNS, a greater number of HBO2 sessions in the first 24 h was associated with a greater incidence of DNS (P = 0.020; Table 4). The incidence of unimproved PCD was not associated with the number of HBO2 sessions in the first 24 h (P = 0.735; Table 4).

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Table 4
Number of HBO2 therapy sessions in the first 24 h and incidence of neurological sequelae.
No. of HBO2 sessions in the first 24 h n (%) DNS Unimproved PCD
0 87 (34.5%) 4 (4.6%) 2 (2.3%)
1 94 (37.3%) 3 (3.2%) 4 (4.3%)
2 52 (20.6%) 5 (9.6%) 2 (3.8%)
3 19 (7.5%) 4 (21.1%) 0 (0%)
P = 0.020 P = 0.735
HBO2, hyperbaric oxygen; DNS, delayed neurological sequelae; PCD, prolonged consciousness disturbance.

The treatment pressures in the first HBO2 session were 2.8 ATA (n = 7), 2.5 ATA (n = 1), and 2.0 ATA (n = 4) in the DNS patients in the HBO2 group, and 2.8 ATA (n = 6) and 2.0 ATA (n = 1) in the unimproved PCD patients in the HBO2 group.

Among 35 patients with abnormal findings in CT or MRI, DNS was observed in 2 (22.2%) and 8 (30.8%) patients in the NBO2 group (n = 9) and the HBO2 group (n = 26), respectively. There was no significant difference in the incidence of DNS between the groups (P = 0.625). Unimproved PCD was observed in 2 (22.2%) and 6 (23.1%) patients in the NBO2 group and the HBO2 group, respectively. There was no significant difference between the groups (P = 0.958).

The following variables, previously reported to be associated with DNS and unimproved PCD [1217], were included in the univariate and multivariable logistic regression models to identify factors associated with the incidence of DNS and unimproved PCD: age, sex, type of CO poisoning, cause, consciousness loss at the scene, estimated exposure time, time from exposure to hospital, Glasgow Coma Scale (GCS) score on arrival, COHb, lactate level, white blood cell count, and number of HBO2 sessions and maximum therapeutic pressure in the first 24 h.

In the univariate regression analysis for the incidence of DNS, type of CO poisoning (intentional), cause (charcoal), consciousness loss at the scene, estimated exposure time, time from exposure to hospital, GCS score on arrival, white blood cell count, and number of HBO2 sessions in the first 24 h were statistically significant (Table 5). The exposure time (OR, 1.003; 95% CI, 1.001–1.004; P < 0.001), GCS score (OR, 0.803; 95% CI, 0.695–0.927; P = 0.003), and the number of HBO2 sessions in the first 24 h (OR, 2.082; 95% CI, 1.101–3.937; P = 0.024) were independently associated with the incidence of DNS in the multivariable logistic regression model (Table 5).

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Table 5
Factors associated with the incidence of delayed neurological sequelae (DNS).
Univariate regression analysis Multivariable logistic regression analysis
OR 95% CI P value OR 95% CI P value
Age (years) 1.010 0.985–1.036 0.446
Sex, male 1.911 0.598–6.102 0.274
Type, intentional 0.170 0.057–0.507 0.002
Cause
Charcoal 16.174 2.103–124.398 0.007
Fire 0.364 0.047–2.840 0.335
Car exhaust 0.000 0.000 0.993
Other 0.000 0.000 0.997
Consciousness loss at the scene 3.839 1.199–12.290 0.023
Estimated exposure time (min) 1.004 1.002–1.005 <0.001 1.003 1.001–1.004 <0.001
Time from exposure to hospital (min) 1.002 1.001–1.003 <0.001
Glasgow Coma Scale on arrival 0.791 0.710–0.883 <0.001 0.803 0.695–0.927 0.003
COHb (%) 1.020 0.974–1.068 0.406
Lactate (mmol/L) 1.039 0.931–1.159 0.495
White blood cells (×103/μL) 1.116 1.039–1.193 0.003
Number of HBO2 sessions in the first 24 h 1.891 1.120–3.192 0.017 2.082 1.101–3.937 0.024
Maximum therapeutic pressure in first 24 h 1.476 0.725–3.008 0.283
OR, odds ratio; CI, confidence interval; COHb, carboxyl hemoglobin; HBO2, hyperbaric oxygen.

In the univariate regression analysis for unimproved PCD, estimated exposure time, time from exposure to hospitalization, and GCS score on arrival were statistically significant (Table 6). The time from exposure to hospital (OR, 1.002; 95% CI, 1.001–1.004; P = 0.007) was independently associated with unimproved PCD in the multivariable logistic regression model (Table 6).

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Table 6
Factors associated with the incidence of unimproved PCD.
Univariate regression analysis Multivariable logistic regression analysis
OR 95% CI P value OR 95% CI P value
Age (year) 0.993 0.970–1.016 0.535
Sex, male 0.661 0.258–1.689 0.387
Type, intentional 0.914 0.334–2.501 0.860
Cause
Charcoal 2.205 0.810–6.001 0.122
Fire 1.119 0.309–4.054 0.864
Car exhaust 0.281 0.036–2.166 0.223
Other 0.484 0.108–2.170 0.864
Consciousness loss at the scene 2.516 0.910–6.958 0.075
Estimated exposure time (min) 1.002 1.001–1.004 <0.001
Time from exposure to hospitalization (min) 1.001 1.000–1.002 0.003 1.002 1.001–1.004 0.007
Glasgow Coma Scale on arrival 0.876 0.788–0.974 0.015
COHb (%) 0.960 0.916–1.005 0.083
Lactate (mmol/L) 1.051 0.949–1.163 0.338
White blood cells (×103/μL) 1.001 0.999–1.097 0.987
Number of HBO2 session in first 24 h 1.353 0.834–2.196 0.221
Maximum therapeutic pressure in first 24 h 1.954 0.969–3.940 0.061
PCD, prolonged consciousness disturbance; OR, odds ratio; CI, confidence interval; COHb, carboxyl hemoglobin; HBO2, hyperbaric oxygen.

Discussion

In this study, it has been shown that the clinical practice for acute CO poisoning varies in Japan, and that the application of and protocols for HBO2 therapy are not consistent. HBO2 therapy with inconsistent protocols showed no advantage over NBO2 therapy in preventing DNS and unimproved PCD. Furthermore, a greater number of HBO2 sessions in the first 24 h was associated with a higher incidence of DNS.

In clinical practice, the treatment for acute CO poisoning, including HBO2 therapy, varied in the present study, as in our previous report [8]. In particular, the profiles of HBO2 therapy, including the number of treatments given and the therapeutic pressures used, were not consistent. These results are similar to reports from Europe and the USA [9, 10], and may indicate that there is no global consensus on an effective regimen of HBO2 therapy for CO poisoning. Further research, including RCTs, is required to establish consensus on these issues.

In the present study, the total incidence of DNS was only 6.3%, which is lower than that in other studies [16]. In our study, all of the patients with any symptoms after CO exposure or with a COHb level exceeding 10% were registered and analyzed, except for 12 CPAOA patients and three patients who died in hospital (Fig 1). The patients in this study might have had milder conditions than those in other studies because the entry criteria were less restrictive. Furthermore, in this study, DNS was only defined as cognitive dysfunction that affected daily life after an improvement in disturbed consciousness and did not include minor symptoms, such as tinnitus or headache. Therefore, patients with mild symptoms or with symptoms other than cognitive dysfunction were not included. Furthermore, 40% of the patients without DNS were only diagnosed by telephone, so patients with mild symptoms might have been overlooked. These aspects of our study may have influenced the lower incidence of DNS.

Although the protocol for HBO2 therapy varied, incidences of DNS and unimproved PCD did not differ between the patients treated with NBO2 only and those treated with HBO2, and the incidence of DNS tended to be lower in patients treated with NBO2 only than in those treated with HBO2 in this study (Table 3). Many RCTs have tried to clarify the efficacy of HBO2 therapy in preventing DNS after CO poisoning [16], and half of them have shown no beneficial effects of HBO2 therapy in this context [2, 3, 6]. In contrast, several reports have claimed that therapeutic pressure less than 2.5 ATA does not produce the beneficial effects of HBO2 therapy [18, 19]. Thom et al. reported that the adherence of activated neutrophils, which is one of the mechanisms underlying the development of DNS after CO poisoning, was suppressed experimentally at 2.5 or 3.0 ATA, but not at 2.0 ATA [18]. The therapeutic pressures in the RCTs that demonstrated the beneficial effects of HBO2 therapy exceeded 2.5 ATA [1, 4, 5, 20]. Birmingham and Hoffman claimed that inadequate pressure during HBO2 therapy may only enhance oxygen toxicity, without the benefit offered by HBO2 at higher pressures [19]. In the present study, only 60% of the patients in the HBO2 group were administered the first session of HBO2 therapy at pressures of more than 2.5 ATA (Table 2) and the same rate was observed in the DNS patients treated with HBO2 therapy at pressures of more than 2.5 ATA. Therefore, in this study, insufficient treatment pressure might also have affected the number of patients with DNS.

Oxidative stress is a key mechanism in DNS [2025]. HBO2 reduced oxidative stress in an animal model of CO poisoning [26] and its beneficial effects included inhibition of leukocyte beta-2 integrins [18], reversal of CO-cytochrome c oxidase binding [27], and recovery of energy metabolism [28]. However, there have been reports that HBO2 therapy itself induces oxidative stress [2932]. Experimental data have shown that HBO2 induces oxidative stress in healthy rat brains, measured as the lipid peroxidation products in brain cortex homogenates [2931]. This HBO2-induced oxidative stress is related to the HBO2 pressure [29] or the exposure time [30]. It has also been reported that a single session of HBO2 (2.4 kPa, 131 min) reduced plasma vitamin C and increased plasma lipid peroxides and urinary 8-oxo-deoxyguanosine excretion in healthy volunteers [32]. Although HBO2 therapy has beneficial effects, it should be considered that there are concerns about adverse effects of HBO2 therapy such as HBO2-induced oxidative stress.

A greater number of HBO2 sessions in the first 24 h was associated with a higher incidence of DNS (Tables 4 and 5). Two RCTs have reported that two HBO2 sessions at 2.0 ATA were neither more beneficial nor more harmful than one session [2, 3], although multiple HBO2 sessions at 2.5 to 2.8 ATA had beneficial effects on preventing DNS [1, 4, 5]. Annane et al. [2] reported that two HBO2 sessions at 2.0 ATA were associated with worse outcomes than one HBO2 session in comatose patients with acute CO poisoning, and that there was no evidence of the superiority of HBO2 over NBO2 in patients with transient loss of consciousness. Raphael et al. [3] reported that two of HBO2 sessions at 2.0 ATA showed no beneficial effects versus one session in patients with CO poisoning who experienced sustained loss of consciousness. Further, one HBO2 session was also ineffective versus NBO2 therapy in patients who did not experience sustained loss of consciousness [3]. A recent meta-analysis of the therapeutic effects of different numbers of HBO2 sessions found that HBO2 therapy at a therapeutic pressure of 2.0 ATA was associated with a lower risk of memory impairment than NBO2 therapy, but that two HBO2 sessions was associated with a higher risk of memory impairment than one session [33]. However, as mentioned above, the therapeutic pressure of 2.0 ATA was considered to be insufficient to produce its beneficial effects [19]. Therefore, multiple HBO2 sessions with insufficient therapeutic pressure should be administered cautiously because of the possibility of worsening symptoms. However, the present data could not rule out the possibility that more severely affected patients had received more HBO2 sessions because the HBO2 therapy protocols were not consistent and depended on each institutions’ policies [8].

In the present study, abnormal CT or MRI findings tended to be less frequent in the NBO2 group than in the HBO2 group, although the amount of data obtained was limited (Table 2). Previous studies have reported that imaging abnormalities are a risk factor for DNS [34, 35]. We could not include the abnormal CT or MRI findings as a variable in the logistic regression analyses to identify factors associated with the incidence of DNS and unimproved PCD because of the limited amount of data obtained in this study. However, the lower incidence of abnormal CT or MRI findings in the NBO2 group than in the HBO2 group may suggest that the patients in the HBO2 group were more severely affected than those in the NBO2 group. Myocardial injury is also associated with increased long-term mortality after CO poisoning [36]. In the present study, all the data related to myocardial injury, including the creatine kinase MB fraction, troponin T, and ECG abnormalities, tended to be worse in the NBO2 group than in the HBO2 group, although the amount of data was limited (Table 2). These results were inconsistent with the incidence of abnormal in CT or MRI findings. Data, including imaging findings and myocardial injury, were missing for some patients; therefore, it was unclear whether the severity differed between the two groups.

The number of patients treated with mechanical ventilation was significantly higher in the NBO2 group than in the HBO2 group (Table 1) and PaO2 on arrival was significantly lower in the NBO2 group than in the HBO2 group (Table 3). This might have been related to the greater number of patients affected by fire in the NBO2 group (Table 1). Patients affected by fires were more likely to suffer from smoke inhalation, and subsequently require intubation and ventilation because of their low PaO2/fraction of inspiratory oxygen ratio. Intubated patients could not be treated with HBO2 in a monoplace chamber, which may explain the large number of mechanically ventilated patients in the NBO2 group. It was reported that fire causes cyanide poisoning concurrently with CO poisoning [37]. This might also be associated with the higher lactate levels in the NBO2 group. More mechanically ventilated patients in the NBO2 group also experienced longer ICU stays in the NBO2 group. However, a sub-analysis after excluding mechanically ventilated patients yielded the same result, as HBO2 therapy offered no advantage over NBO2 therapy in the prevention of DNS, and multiple HBO2 sessions on day 1 were still associated with a greater incidence of DNS.

Some retrospective studies have found that HBO2 therapy has beneficial effects on the survival rate [38, 39] or activities of daily living (ADL) in patients with CO poisoning [40]. Rose et al. reported that HBO2 therapy was associated with reduced in-hospital mortality and reduced 1-year mortality [38] and Huang et al. reported a lower 4-year mortality rate after treatment for CO poisoning [39]. In the present study, among 311 patients, there were three cases of CPAOA and three in-hospital deaths, but there were no deaths during the follow-up periods, although 41 patients were lost to follow-up. Regarding the effect of HBO2 therapy on the survival rate after CO poisoning, our data did not reveal any evidence to support the previous reports [38, 39] because the follow-up period was only 2 months and 41 patients were lost to follow-up. Nakajima et al. reported that HBO2 therapy was associated with a favorable consciousness level and ADL at discharge in patients with CO poisoning [40]. In the present study, cognitive dysfunction was only checked for 2 months after CO poisoning and there was no significant difference between the NBO2 group and the HBO2 group (Table 3). Therefore, further investigation is needed to explore the long-term beneficial effects of HBO2 therapy.

There were several limitations to the present study. First, it was an observational study. Although there was no significant difference in the severity of poisoning among the subgroups defined by the number of HBO2 sessions received during first 24 h, the more severely affected patients, as assessed by the clinicians, may have received more HBO2 sessions during the first 24 h. Second, the protocols for HBO2 therapy, including the treatment pressure, number of sessions, their timing, and their duration, were not consistent. Third, as mentioned above, an equality of the groups was not maintained in some parts because this was an observational study. Fourth, there might be some selection bias because only 44% of patients in the NBO2 group were transferred to hospitals where HBO2 therapy was available. In those patients, mild cases might have received NBO2 therapy, although the COHb levels in the NBO2 group were not significantly different between patients transferred to institutions that only offered NBO2 therapy (20.9 ± 10.0%) and patients transferred to institutions that also provided HBO2 therapy (17.2 ± 10.1%, P = 0.101). Furthermore, there may have been a selection bias on the part of the EMS, which may have sent less severely affected patients to institutions that only offered NBO2 therapy. Finally, 40% of the patients without DNS were only diagnosed by telephone, so patients with mild symptoms might have been overlooked.

Shortcomings

As mentioned above, there were some selection biases for non-randomized observational studies. In addition, the lack of a protocol for HBO2 treatment made it difficult to interpret results such as dose-response between the number of HBO2 treatments and the incidence of DNS. There were several issues with assessing DNS, including non-blinded evaluators, 13.8% of loss of follow-up, and the possibility of oversight of patients with mild symptoms.

Conclusions

The practical clinical treatment for acute CO poisoning, including HBO2 therapy, varied among the institutions participating in Japan. HBO2 therapy with inconsistent protocols showed no advantages over NBO2 therapy in the prevention of DNS or the improvement in PCD after CO poisoning. Furthermore, multiple HBO2 sessions on the first day of hospitalization were associated with a greater incidence of DNS. Further research is required to clarify the efficacy of HBO2 therapy in preventing DNS after CO poisoning.

Acknowledgements

Members of the COP-J Study Investigators are given below: Yamaguchi University Hospital, Ube (RT, MF, MT, KK), Kameda Medical Center, Kamogawa (SS), Tokai University School of Medicine, Isehara (SW), Hyogo Emergency Medical Center, Kobe (SK), Japanese Red Cross Maebashi Hospital, Maebashi (SS), Chiba University Graduate School of Medicine, Chiba (NH), Tokyo Medical and Dental University, Tokyo (KY), Japan Self Defense Forces Hospital Yokosuka, Yokosuka (KK), Hokkaido University, Sapporo (Tomonao Yoshida), Gunma University Hospital, Maebashi (Hiroaki Matsuoka), Kagawa University, Kagawa (Kenya Kawakita), Saiseikai Kumamoto Hospital, Kumamoto (Tadashi Kikuchi), Hiroshima University Hospital, Hiroshima (Satoshi Yamaga), St.Mary’s Hospital, Kurume (Kazuhito Tamehiro), Tajima Emergency and Critical Care Medical Center, Toyooka Hospital, Toyooka (Osamu Fujisaki), Asahikawa Medical University Hospital, Asahikawa (Yuka Eto), Iwate Medical University, Morioka (Makoto Onodera), Ibaraki Prefectural Central Hospital, Kasama (Yoshimoto Seki), Tokushima Red Cross Hospital, Komatsushima (Yasushi Fukuta), Kumamoto Red Cross Hospital, Kumamoto (Ken Kuwahara), Showa University, Tokyo (Kenichiro Fukuda), Nagano Red Cross Hospital, Nagano (Koji Yamakawa), Osaka University Graduate School of Medicine, Suita (Ryosuke Takegawa), Gifu University Graduate School of Medicine, Gifu (Tomoaki Doi), Yokohama City University Medical Center, Yokohama (Takuma Sakai), St. Luke’s International Hospital, Tokyo (Shutaro Isokawa), Kanmon Medical Center, Shimonoseki (Shinichiro Tanaka), Tokuyama Central Hospital, Shunan (Susumu Yamashita), Kawasaki Medical School, Kurashiki (Yasukazu Shiino), Kumamoto University Hospital, Kumamoto (Tadashi Kaneko), Jichi Medical University, Tochigi (Chikara Yonekawa), National Hospital Organization Kumamoto Medical Center, Kumamoto (Masahiro Harada), Kindai University, Osaka (Takami Nakao), Tamaki Hospital, Hagi (Hideki Tamaki), Almeida Memorial Hospital, Oita (Nobuhiro Inagaki), Kanazawa University Hospital, Kanazawa (Masaki Okajima), Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima (Yasuyuki Kakihana), Aso Iizuka Hospital, Iizuka (Hiroshi Adachi), Nagasaki University Hospital, Nagasaki (Tomohito Hirao), Hiroshima Prefectural Hospital, Hiroshima (Masahiko Iseki), Saiseikai Matsuyama Hospital, Matsuyama (Katsusuke Kusunoki), Yamaguchi Prefectural Grand Medical Center, Hofu (Takeshi Inoue), Kurashiki Central Hospital, Kurashiki (Shinichiro Ienaga), Saiseikai Yamaguchi Hospital, Yamaguchi (Takashi Tamura), St Marianna University School of Medicine, Kawasaki (Nobuhiko Simozawa), Kochi Health Science Center, Kochi (Go Nojima), University Hospital of the Ryukyus, Okinawa (Kiyotaka Kohshi), Kohsei General Hospital, Mihara (Kenjiro Fujiwara), Kizawa Memorial Hospital, Minokamo (Mikito Yamada), Kagawa Rosai Hospital, Marugame (Kimihiro Yoshino), Osaka National Hospital, National Hospital Organization, Osaka (Daikai Sadamitsu), National Hospital Organization Medical Center, Tachikawa (Takashi Kanemura), Jichi Children’s Medical Center Tochigi, Shimotsuke (Hidetaka Iwai), Ina Central Hospital, Ina (Aya Hori).

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6 Jan 2021

PONE-D-20-36680

Use of hyperbaric oxygen therapy for preventing delayed neurological sequelae in patients with carbon monoxide poisoning: a multicenter, prospective, observational study in Japan

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Reviewer #1: The study by Dr. Fujita and his team is a case series that included 255 patients with CO poisoning of a total 311 initially registered. In the group of 255, 171 received hyperbaric oxygen (HBO2) 1-3 times in the first 24 hours; the remaining patients (84) received normobaric oxygen (NBO2). Delayed neurological sequelae (DNS) occurred in 7.6% of the HBO2 group and 3.6% of the NBO2 group. The authors conclude that HBO2 therapy has no advantage over NBO2 therapy for the prevention of DNS or improving prolonged impaired consciousness. Interestingly, a factor associated with the incidence of DNS in this study is the number of HBO2 sessions in the first 24 h, suggesting that more HBO2 may worsen outcome. The finding of this retrospective analysis is surprising given the opposite conclusion of several randomized, blinded studies with HBO2 administered at what are believed to be therapeutic doses (2.4-2.8 ATA). If correct, the current paper could be an important finding that may affect current practice.

This is a moderately large case series, of the size needed to address this important question, and the paper is easy to read. There are a few minor points that need to be addressed. In addition, the data do not adequately support the authors’ conclusions.

The authors have made an effort to elaborate the patients’ initial conditions. However there are important differences in the two groups that may have affected outcomes. For example, there were differences in the percentages of patients who lost consciousness (42.3% vs. 48.0%, NBO2 vs. HBO2), SpCO at the scene (26.4% vs. 30.1%). These differences were not statistically significant but that does not exclude a possible effect on outcome. In this case the authors used multivariable logistic regression to sort that our, however they need to state how they chose the variables that were in their regression model. It would be helpful to have a table that includes both univariable and multivariable risk factors for outcome.

Another important factor that suggests selection bias is that only 44% of patients in the NBO2 group were transferred to hospitals where HBO2 was available. It is therefore plausible that initial evaluation at those hospitals triaged to NBO2 those patients who were a priori expected to do well without HBO2, thus enhancing the outcome of the NBO2 group. It is also conceivably there may have been a selection bias on the part of the EMS to send less severely affected patients to NBO2 hospitals. Please could the authors comment. Among those patients who were referred to a hospital with hyperbaric facilities, it would be useful for information on the indications for treatment in that subgroup.

The fact that SpCO wat the scene was 26.4% (NBO2) and 30.1% (HBO2), yet despite long times between exposure and hospital arrival (average of around 4 half times if the patients were breathing oxygen), COHb was decreased only to 19.3% and 18.7% in the two groups. Please could the authors comment.

In addition for the potential for selection bias, it is also possible that the relatively low numbers of adverse outcomes indicates that the study is underpowered to detect a difference. DNS was assessed either during a hospital visit or by phone. The relatively low rate of sequelae in this study compared with previous reports (e.g. Gorman et al, Anaesth Intensive Care. 1992;20:311-6, refs. 1 and 4) may have been because phone assessment is less sensitive than formal neuropsychological testing).

There were differences between groups regarding CT findings, which should be described, along with information on abnormal MRI findings. Previous studies have observed imaging abnormalities as risk factors for DNS (e.g. Jeon, et al. JAMA Neurol. 2018;75:436-443). It would be helpful to include an analysis of the subset of patients with CT or MRI abnormalities should be included.

In any retrospective analysis it is impossible to account for therapeutic decisions made based upon real-time assessment of patients, for example the observation that a greater number of HBO2 sessions in the first 24 hours was associated with a greater incidence of DNS. From this, the authors conclude: “Therefore, multiple rounds of HBO2 therapy should be administered with caution, because it is possible that symptoms will worsen.” Of the two factors here (number of treatments and clinical outcome), it is important to consider which one is cause and which one is effect. Contrary to the authors’ conclusion, it is more plausible that additional HBO2 was administered to patients who were not responding well.

The following is an overstatement: “Moreover, Scheinkestel et al. [6] reported harmful effects of HBO2 therapy in patients suffering acute CO poisoning.” It is also noteworthy that while this study reported fewer sequelae with normobaric vs. hyperbaric oxygen, if their protocol is to be the basis for treating CO poisoning, then 3-6 days of inpatient treatment are required.

The following statement, “Experimental data have shown that HBO2 induces oxidative stress in healthy rat brains, measured as the lipid peroxidation products in brain cortex homogenates [24–26]” should be amended to include the observation that in CO poisoning HBO2 actually reduces oxidative stress (Thom SR. Toxicol Appl Pharmacol 1993;123:248-56). It is also of note that other animal studies of CO poisoning have revealed other beneficial effects of HBO2, including inhibition of leukocyte beta-2 integrins (reference 28), reversal of CO-cytochrome c oxidase binding (Adv Exp Med Biol 1989;248:747-54) and recovery of energy metabolism (J Clin Invest 1992;89: 666-72).

The review of the literature in Conclusions suggests that all studies of HBO2 are equivalent, which they are not. Raphael’s and Annane’s studies were performed at 2 ATA, which as the authors point out is considered by many experts to be inadequate. In Raphael’s study the only comparison between NBO2 and HBO2 was in mild cases. Scheinkestel’s study utilized 3-6 days of therapy, which is usually considered impractical. On the other hand, studies at 2.5-2.8 ATA by Thom, Mathieu and Weaver have shown better outcome for HBO2. These details need to be included explicitly in the Discussion. The following statement pertains to a meta-analysis, “A recent meta-analysis of the therapeutic effects of different numbers of HBO2 sessions found that HBO2 therapy was associated with a lower risk of memory impairment than NBO2 therapy, but that two sessions of HBO2 therapy were associated with a higher risk of memory impairment than one session [30].” It is noteworthy that this meta-analysis also assumed equivalence of the various doses.

Reviewer #2: Thank you for allowing me to review this study by Motoki Fujita et al. I previously reviewed this manuscript for another journal. I feel like the manuscript is much improved from the prior version I reviewed.

The question of hyperbaric oxygen therapy efficacy to prevent delayed neurological sequelae in CO poisoning is very important. There has been much controversy over the topic. As the manuscript refers to, probably the best designed study - reported in Weaver et al NEJM 2002 - showed quite a positive benefit of using HBO2 in CO poisoning patients. When looking at the most up-to-date meta-analysis, however, combined, 6 studies show no benefit. The most recent one - performed in 2011 - actually showed some trend towards harm.

Regardless of the stance on HBO2 therapy effectiveness, even presuming it is effective, time delays to therapy (>5 hours in the Weaver study) could certainly limit the benefit of the therapy. Many centers do not offer emergent HBO2. Further studies in this situation are critical.

The authors present a prospective, multi-center clinical study on the use of HBO2 in acutely CO poisoned patients. This is valuable and a fairly large size.

There are some major limitations to the study in its design that could limit further applicability – this was not a randomized trial, there was not set HBO2 protocol (and many patients received non standard therapy previously tested it appears), and the definition of neurocognitive deficits was a bit murky. That said, this was an interesting study that is important to publish.

I am going to reveal my prior critiques and comment on responsiveness to those. I have some additional comments based on the new manuscript.

Prior review:

Major Issues:

1) How did providers determine who was to receive HBO2 therapy? This is not specified. I think if it was up to the provider, more analysis of the decisions/trends of the patients need to be identified. Did they use a general criteria for the trial? Did they go with a professional organization recommendation? The American College of Emergency Physicians does not provide specific recommendations, of note.

-> There was quite a bit of discussion around how many patients received what therapy. It was quite non standard but it was sufficiently reported here. Some were very strange (15 HBO2 sessions over a week), so not sure how to interpret these.

2) Mechanically ventilated patients were not included in the analysis. This is a major limitation. By my calculation, only 4.6% of the HBO2 patients required mechanical ventilation, whereas, 19.5% of the NBO2 group required mechanical ventilation. These patients were then not analyzed. This is a major limitation as these would be the most severely ill patients. Ideally, there is some sensitivity analysis that would include these patients. This may be why the delayed neurological sequelae are so low in the NBO2 group - the sickest were eliminated (19.5%). I do agree to not include patients that had an arrest upon arrival for this study.

-> The authors included mechanical ventilation patients in the analysis. This was a great improvement in the study and makes it much more applicable.

3) The definition of DNS is very vague. Page 7 refers to patients were "checked by a physician if any doubt". What does this mean? This needs to be listed very specifically how DNS was determined as it is a primary outcome of the study. If some of the list or discussion of the DNS determination algorithm needs to be in supplemental materials, that is fine. The exact method needs to be reported.

-> Clearer algorithm certainly. Still some limits. Is the screening questions asked ever been standardized or validated previously? With the 4x mental status exams, did the patient need to have an abnormality on any one of these or multiple tests? If it is only one deficit on a single test this could be a biased definition. The opposite is true as well – if very strict on defining (for instance, patients had to have all 4 with a deficit, then could be biased the other way (not reporting the DNS enough). I would clarify. This is much improved already though.

4) No reports on mortality in this group. I think it would be helpful. The size of the study and exclusion of cardiac arrest upon arrival patients does not warrant this being an outcome measure; however, the numbers should be reported.

-> better commentary on mortality overall

5) Exposure distribution was unique - the most common causes of CO poisoning are generally motor vehicle exhaust and fires. Here, >50% of patients were exposed to burning charcoal. Is this the most common form of poisoning in Japan? This should be discussed more. Related, a lot more of the NBO2 group was exposed to fire, generally felt as the most severe form of exposure. This would provide that the effect seen is even more surprising.

-> much clearer. I would use term “intentional” not “suicide”. For the statistical comparison, I would do statistics for each exposure type (fire, exhaust, coal) instead of exposure in general.

6) Why were the DNS events so low. Most reported prevalence is between 20-40% long term. Why was there only one DNS event in the NBO2 group? Is this because mechanical ventilated patients are excluded from the analysis? Again, I think this data needs to be reported at least in a sensitivity analysis if available. Else, should be listed as a major limitation.

-> Now addressed mechanical ventilation issue. Still quite low though. Any reason why you suspect? Perhaps points above about definition of DNS would be helpful to learn.

7) Why was the PaO2 higher in the HBO2 group? When was this lab taken? Was it prior to HBO2 initiation?

-> This was discussed a bit. Not sure why it is higher but not sure clinical meaningfulness.

8) The issue of heterogeneity of therapy needs to be addressed as a major limitation - no standard intervention, multiple different pressures/number of hyperbaric treatments for the patients.

-> this was well discussed.

Applicable Minor issues:

4) 35% of facilities did not have access to HBO2 - this is actually a high percentage of HBO2 capable facilities. The US only has 250-350 nationwide. Is there a lot more hyperbaric centers in Japan or is it more that centers with HBO2 were more likely to enroll in this study? Is there data for how many centers in Japan?

-> related, I would include how many patients required intrafacility transfer for HBO2.

6) Page 10, what does "period of oxygen administration" mean? I am confused by this term. Does that mean time before presentation to hospital on oxygen?

-> I am still not sure about this term. It is clearer how it is used now, but I think general length of stay in hospital is more meaningful. Could probably drop it. We can presume most of the patients received oxygen I think.

7) When discussing controversy around HBO2 being effective or not, I would include the discussion of some of the large retrospective studies that suggest mortality or ADL benefit to HBO2:

a. Rose JJ, Nouraie M, Gauthier MC, et al. Clinical Outcomes and Mortality Impact of Hyperbaric Oxygen Therapy in Patients With Carbon Monoxide Poisoning. Crit Care Med. 2018;46(7):e649-e655. doi:10.1097/CCM.0000000000003135

b. Nakajima M, Aso S, Matsui H, Fushimi K, Yasunaga H. Hyperbaric oxygen therapy and mortality from carbon monoxide poisoning: A nationwide observational study. Am J Emerg Med. 2020;38(2):225-230. doi:10.1016/j.ajem.2019.02.009

-> I would still include this

Additional comments:

1) CK-MB is used for cardiac involvement. What was your cut off? How many had “High” values? Do you have troponin data available?

2) What were the ECG abnormalities seen? 20-22% incidence is quite high.

3) What were the CT abnormalities seen? Head CT or Chest CT?

4) What were MRI abnormalities seen, quite a few in the HBO2 group.

5) Not sure you need a paragraph describing vital signs, we can read table

6) Why was there bed rest prescribed and what is the meaning of it? I did not think we prescribe this in clinical care anymore very much.

7) Give % mortality of overall cohort (included and excluded) when you report the number I think.

**********

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21 Apr 2021

We are grateful to the reviewers for their critical comments and useful suggestions, which have helped us to improve our paper considerably. As indicated in the responses that follow, we have taken all these comments and suggestions into account in the revised version of our paper. In the manuscript, the revised text is shown in red font. We have also provided the page and line numbers corresponding to the revisions in the text.

Reviewer 1

1.The authors have made an effort to elaborate the patients’ initial conditions. However, there are important differences in the two groups that may have affected outcomes. For example, there were differences in the percentages of patients who lost consciousness (42.3% vs. 48.0%, NBO2 vs. HBO2), SpCO at the scene (26.4% vs. 30.1%). These differences were not statistically significant but that does not exclude a possible effect on outcome. In this case the authors used multivariable logistic regression to sort that our, however they need to state how they chose the variables that were in their regression model. It would be helpful to have a table that includes both univariable and multivariable risk factors for outcome.

Response:

We have added the results of the univariate regression analyses of all the factors to Tables 5 and 6. The factors associated with DNS and unimproved PCD in previous reports [12–17] were included as variables in the multivariable logistic regression models. Because of the small numbers of patients whose SpCO at the scene (n = 8 in the NBO2 group and n = 40 in the HBO2 group; Table 1), SpCO at the scene was not included in the univariate or multivariable logistic regression analyses.

2. Another important factor that suggests selection bias is that only 44% of patients in the NBO2 group were transferred to hospitals where HBO2 was available. It is therefore plausible that initial evaluation at those hospitals triaged to NBO2 those patients who were a priori expected to do well without HBO2, thus enhancing the outcome of the NBO2 group. It is also conceivably there may have been a selection bias on the part of the EMS to send less severely affected patients to NBO2 hospitals. Please could the authors comment. Among those patients who were referred to a hospital with hyperbaric facilities, it would be useful for information on the indications for treatment in that subgroup.

Response:

There may be a selection bias because only 44% of patients in the NBO2 group were transferred to hospitals where HBO2 therapy was available. Among these, mildly affected patients may have received NBO2 therapy, although there was no significant difference in the COHb levels of the NBO2 group between patents transferred to institutions that offered only NBO2 therapy and patients transferred to institutions that also provided HBO2 therapy (20.9 ± 10.0% and 17.2 ± 10.1%, respectively, P = 0.101). There may be a selection bias arising from the EMS, as you mentioned, although some emergency centers did not have HBO2 chambers. We have added an explanation of this to the limitations (page 21, line 414) and the COHb levels to the results (page 9, line 187).

3. The fact that SpCO wat the scene was 26.4% (NBO2) and 30.1% (HBO2), yet despite long times between exposure and hospital arrival (average of around 4 half times if the patients were breathing oxygen), COHb was decreased only to 19.3% and 18.7% in the two groups. Please could the authors comment.

Response:

In our study, the numbers of patients with SpCO data were low (n = 8 in the NBO2 group and n = 40 in the HBO2 group; Table 1). This may help explain why COHb did not decrease enough on admission.

4. In addition for the potential for selection bias, it is also possible that the relatively low numbers of adverse outcomes indicates that the study is underpowered to detect a difference. DNS was assessed either during a hospital visit or by phone. The relatively low rate of sequelae in this study compared with previous reports (e.g. Gorman et al, Anaesth Intensive Care. 1992;20:311-6, refs. 1 and 4) may have been because phone assessment is less sensitive than formal neuropsychological testing.

Response:

We had previously described this limitation in the discussion section. We have added more text regarding this point in the discussion (page 16, line 300).

5. There were differences between groups regarding CT findings, which should be described, along with information on abnormal MRI findings. Previous studies have observed imaging abnormalities as risk factors for DNS (e.g. Jeon, et al. JAMA Neurol. 2018;75:436-443). It would be helpful to include an analysis of the subset of patients with CT or MRI abnormalities should be included.

Response:

We have added more text to the discussion describing the abnormal CT or MRI findings (page 18, line 360). However, because the amount of data was limited, we could not include the incidence of abnormal CT or MRI findings as a variable in the multivariable logistic regression models to identify factors associated with the incidence of DNS and unimproved PCD.

6. In any retrospective analysis it is impossible to account for therapeutic decisions made based upon real-time assessment of patients, for example the observation that a greater number of HBO2 sessions in the first 24 hours was associated with a greater incidence of DNS. From this, the authors conclude: “Therefore, multiple rounds of HBO2 therapy should be administered with caution, because it is possible that symptoms will worsen.” Of the two factors here (number of treatments and clinical outcome), it is important to consider which one is cause and which one is effect. Contrary to the authors’ conclusion, it is more plausible that additional HBO2 was administered to patients who were not responding well.

Response:

We have added text regarding this point to the discussion (page 18, line 355).

7. The following is an overstatement: “Moreover, Scheinkestel et al. [6] reported harmful effects of HBO2 therapy in patients suffering acute CO poisoning.” It is also noteworthy that while this study reported fewer sequelae with normobaric vs. hyperbaric oxygen, if their protocol is to be the basis for treating CO poisoning, then 3-6 days of inpatient treatment are required.

Response:

We have deleted this sentence.

8. The following statement, “Experimental data have shown that HBO2 induces oxidative stress in healthy rat brains, measured as the lipid peroxidation products in brain cortex homogenates [24–26]” should be amended to include the observation that in CO poisoning HBO2 actually reduces oxidative stress (Thom SR. Toxicol Appl Pharmacol 1993;123:248-56). It is also of note that other animal studies of CO poisoning have revealed other beneficial effects of HBO2, including inhibition of leukocyte beta-2 integrins (reference 28), reversal of CO-cytochrome c oxidase binding (Adv Exp Med Biol 1989;248:747-54) and recovery of energy metabolism (J Clin Invest 1992;89: 666-72).

Response:

We have added an explanation to the discussion and have reordered the discussion (page 17, line 225).

9. The review of the literature in Conclusions suggests that all studies of HBO2 are equivalent, which they are not. Raphael’s and Annane’s studies were performed at 2 ATA, which as the authors point out is considered by many experts to be inadequate. In Raphael’s study the only comparison between NBO2 and HBO2 was in mild cases. Scheinkestel’s study utilized 3-6 days of therapy, which is usually considered impractical. On the other hand, studies at 2.5-2.8 ATA by Thom, Mathieu and Weaver have shown better outcome for HBO2. These details need to be included explicitly in the Discussion. The following statement pertains to a meta-analysis, “A recent meta-analysis of the therapeutic effects of different numbers of HBO2 sessions found that HBO2 therapy was associated with a lower risk of memory impairment than NBO2 therapy, but that two sessions of HBO2 therapy were associated with a higher risk of memory impairment than one session [30].” It is noteworthy that this meta-analysis also assumed equivalence of the various doses.

Response:

The difference in the therapeutic pressure of the HBO2 therapy has been added to the discussion (page 18, lines 341–343, 347, and 351).

We are grateful to the reviewers for their critical comments and useful suggestions, which have helped us to improve our paper considerably. As indicated in the responses that follow, we have taken all these comments and suggestions into account in the revised version of our paper. In the manuscript, the revised text is shown in red. We have also provided the page and line numbers corresponding to the revisions in the text.

Reviewer 2

Prior review: Major Issues:

1. How did providers determine who was to receive HBO2 therapy? This is not specified. I think if it was up to the provider, more analysis of the decisions/trends of the patients need to be identified. Did they use a general criteria for the trial? Did they go with a professional organization recommendation? The American College of Emergency Physicians does not provide specific recommendations, of note.

-> There was quite a bit of discussion around how many patients received what therapy. It was quite non standard but it was sufficiently reported here. Some were very strange (15 HBO2 sessions over a week), so not sure how to interpret these.

Response:

The HBO2 therapy protocols were not consistent and depended on the practices at each participating institution, as we reported in reference 8.

2. Mechanically ventilated patients were not included in the analysis. This is a major limitation. By my calculation, only 4.6% of the HBO2 patients required mechanical ventilation, whereas, 19.5% of the NBO2 group required mechanical ventilation. These patients were then not analyzed. This is a major limitation as these would be the most severely ill patients. Ideally, there is some sensitivity analysis that would include these patients. This may be why the delayed neurological sequelae are so low in the NBO2 group - the sickest were eliminated (19.5%). I do agree to not include patients that had an arrest upon arrival for this study.

-> The authors included mechanical ventilation patients in the analysis. This was a great improvement in the study and makes it much more applicable.

Response:

Data about mechanically ventilated patients were added to manuscript, as you suggested.

3. The definition of DNS is very vague. Page 7 refers to patients were "checked by a physician if any doubt". What does this mean? This needs to be listed very specifically how DNS was determined as it is a primary outcome of the study. If some of the list or discussion of the DNS determination algorithm needs to be in supplemental materials, that is fine. The exact method needs to be reported.

-> Clearer algorithm certainly. Still some limits. Is the screening questions asked ever been standardized or validated previously? With the 4x mental status exams, did the patient need to have an abnormality on any one of these or multiple tests? If it is only one deficit on a single test this could be a biased definition. The opposite is true as well – if very strict on defining (for instance, patients had to have all 4 with a deficit, then could be biased the other way (not reporting the DNS enough). I would clarify. This is much improved already though.

Response:

DNS was diagnosed by a physician based on all the findings at the time of diagnosis, including a cognitive function test, such as the mini-mental state examination, the Wechsler adult intelligence scale, Hasegawa’s dementia scale-revised, the trail-making test, or the story recall test. We have revised the text in the data collection and analysis section (page 5, line 119).

4. No reports on mortality in this group. I think it would be helpful. The size of the study and exclusion of cardiac arrest upon arrival patients does not warrant this being an outcome measure; however, the numbers should be reported.

-> better commentary on mortality overall

Response:

In the present study, among 311 patients, there were three cases of CPAOA and three in-hospital deaths, but there were no patient deaths recorded during the follow-up period. However, 41 patients were lost to follow-up. We have added this to the discussion (page 20, line 391).

5. Exposure distribution was unique - the most common causes of CO poisoning are generally motor vehicle exhaust and fires. Here, >50% of patients were exposed to burning charcoal. Is this the most common form of poisoning in Japan? This should be discussed more. Related, a lot more of the NBO2 group was exposed to fire, generally felt as the most severe form of exposure. This would provide that the effect seen is even more surprising.

-> much clearer. I would use term “intentional” not “suicide”. For the statistical comparison, I would do statistics for each exposure type (fire, exhaust, coal) instead of exposure in general.

Response:

In previous reports, the most common causes of CO poisoning were internal combustion engines (Weaver et al., NEJM 2002;347: 1057-1067.) or gas water heaters (Annane et al., Intensive Care Med. 2011;3: 486-492). However, it was also reported that charcoal is a major cause of CO poisoning in Asia (Lin et al. J Chin Med Assoc. 2018;81: 682-690; Ku et al. Gen Hosp Psychiatry. 2010;32: 310-4.). Charcoal is still used for heating in northern Japan. We have also replaced the term “suicide” to “intentional” (page 8, Table 1) and have added data for each exposure type (fire, exhaust, coal) to Table 1.

6. Why were the DNS events so low. Most reported prevalence is between 20-40% long term. Why was there only one DNS event in the NBO2 group? Is this because mechanical ventilated patients are excluded from the analysis? Again, I think this data needs to be reported at least in a sensitivity analysis if available. Else, should be listed as a major limitation.

-> Now addressed mechanical ventilation issue. Still quite low though. Any reason why you suspect? Perhaps points above about definition of DNS would be helpful to learn.

Response:

The definition of DNS may partly explain why its incidence was low in this study. We have added a sentence to the discussion to describe this point (page 16, line 300).

7. Why was the PaO2 higher in the HBO2 group? When was this lab taken? Was it prior to HBO2 initiation?

-> This was discussed a bit. Not sure why it is higher but not sure clinical meaningfulness.

Response:

This might have been related to the greater number of patients affected by fires in the NBO2 group (Table 1). Patients affected by fires were more likely to suffer from smoke inhalation, and subsequently require intubation and ventilation (Table 3) because of a low P/F ratio. We have added an explanation of this to the discussion (page 119, lines 377 and 381).

8. The issue of heterogeneity of therapy needs to be addressed as a major limitation - no standard intervention, multiple different pressures/number of hyperbaric treatments for the patients.

-> this was well discussed.

Response:

We have added these points to the limitations (page 21, line 414).

Applicable Minor issues:

1. 35% of facilities did not have access to HBO2 - this is actually a high percentage of HBO2 capable facilities. The US only has 250-350 nationwide. Is there a lot more hyperbaric centers in Japan or is it more that centers with HBO2 were more likely to enroll in this study? Is there data for how many centers in Japan?

-> related, I would include how many patients required intrafacility transfer for HBO2.

Response:

At the start of the study, there were 568 institutions in Japan that had an HBO2 chamber, of which 115 institutions had a board-certified fellow of the Japanese Society of Hyperbaric and Undersea Medicine. We have described this in the methods section (page 4, line 98).

Unfortunately, we have no data about interfacility transfer for HBO2 therapy.

2. Page 10, what does "period of oxygen administration" mean? I am confused by this term. Does that mean time before presentation to hospital on oxygen?

-> I am still not sure about this term. It is clearer how it is used now, but I think general length of stay in hospital is more meaningful. Could probably drop it. We can presume most of the patients received oxygen I think.

Response:

This term refers to the period of oxygen administration during hospital stay; oxygen is not always administered for the entire hospital stay.

3. When discussing controversy around HBO2 being effective or not, I would include the discussion of some of the large retrospective studies that suggest mortality or ADL benefit to HBO2:

a. Rose JJ, Nouraie M, Gauthier MC, et al. Clinical Outcomes and Mortality Impact of Hyperbaric Oxygen Therapy in Patients With Carbon Monoxide Poisoning. Crit Care Med. 2018;46(7):e649-e655. doi:10.1097/CCM.0000000000003135

b. Nakajima M, Aso S, Matsui H, Fushimi K, Yasunaga H. Hyperbaric oxygen therapy and mortality from carbon monoxide poisoning: A nationwide observational study. Am J Emerg Med. 2020;38(2):225-230. doi:10.1016/j.ajem.2019.02.009

-> I would still include this.

Response:

We have escribed the survival rate and ADL of patients with CO poisoning in the discussion (page 20, line 391).

Additional comments:

1. CK-MB is used for cardiac involvement. What was your cut off? How many had “High” values? Do you have troponin data available?

Response:

We have added the number of the patients whose CK-MB was above the normal range to Table 1.

2. What were the ECG abnormalities seen? 20-22% incidence is quite high.

Response:

We have added the details of ECG abnormalities to Table 1.

3. What were the CT abnormalities seen? Head CT or Chest CT?

Response:

We have added the details of CT abnormalities to Table 1.

4. What were MRI abnormalities seen, quite a few in the HBO2 group.

Response:

We have added the details of MRI abnormalities to Table 1.

5. Not sure you need a paragraph describing vital signs, we can read table

Response:

We have deleted the text about vital signs.

6. Why was there bed rest prescribed and what is the meaning of it? I did not think we prescribe this in clinical care anymore very much.

Response:

We thought that bed rest might be related to the prevention of DNS. However, the length of bed rest seems to be affected by the period of mechanical ventilation in the present study. Therefore, we have deleted these data from Table 3.

7. Give % mortality of overall cohort (included and excluded) when you report the number I think.

Response:

We have included the number of deceased patients in the discussion, as you suggested (page 20, line 391).


9 May 2021

PONE-D-20-36680R1

Use of hyperbaric oxygen therapy for preventing delayed neurological sequelae in patients with carbon monoxide poisoning: a multicenter, prospective, observational study in Japan

PLOS ONE

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Reviewer #1: Dr. Fujita and his team have responded appropriately to many of the reviewers’ comments, but several concerns remain.

Lines 325-338: the authors are attempting to make the point that HBO2-induced oxidative stress could the cause of worse outcome in the HBO2 group. In favor of this hypothesis they cite evidence that HBO2 induces oxidative stress. Of course it does. However, so does carbon monoxide exposure, and published evidence indicates that HBO2 reduces it (reference 26). The conclusion in lines 335-338 therefore needs to be amended.

Lines 350-354: “A recent meta-analysis of the therapeutic effects of different numbers of HBO2 sessions, including a different range of therapeutic pressures from 2.0 to 2.8 ATA, found that HBO2 therapy was associated with a lower risk of memory impairment than NBO2 therapy, but that two HBO2 sessions was associated with a higher risk of memory impairment than one session [33].” This particular conclusion of Wang’s meta-analysis is based upon two studies (Raphael and Annane) in which sub-therapeutic HBO2 doses were used, and both mild and moderate sequelae (including memory impairment) were defined only by a patient questionnaire (no formal testing of memory); only 4 patients out of 170 had severe sequelae defined as objective abnormalities. All studies using HBO2 at 2.0 ATA have shown no benefit, while all studies using HBO2 at 2.8-3.0 ATA have shown benefit. Please add a caveat to this discussion.

There were 171 patients in the HBO2 group, however the number who received a first HBO2 treatment (Table 2) totaled only 165. Please explain.

From the previous review: It would be helpful to include an analysis of the subset of patients with CT or MRI abnormalities. What were the outcomes for those individuals with brain abnormalities on either CT or MRI?

The following points need to be addressed in a ‘Shortcomings’ section after the Discussion.

(1). This is not a randomized study, therefore, as pointed out in the previous review, the possibility of selection bias is large, both at the EMS level and within hospitals where HBO2 was available. Indeed, there is evidence that those patients who were treated with hyperbaric oxygen (HBO2) were more severely affected than those who were not. In addition to differences pointed out in the previous review (percentages of patients who lost consciousness, SpCO at the scene), the percentage of patients with abnormal CT, basal ganglia lesions) and MRI (basal ganglia lesions) was higher in the HBO2 group. The lack of statistical significance does not exclude a clinical relationship, particularly since fewer than 60% of patients who received HBO2 in this series were treated at a pressure considered to be therapeutic (≥2.4 ATA).

(2). There is no evidence in the manuscript that the assessors were blinded as to the treatment group (NBO2 vs. HBO2).

(3). An apparent dose-response between number of HBO2 treatments and incidence of delayed neurological sequelae (DNS) is incorrectly interpreted as evidence of possible harm due to HBO2. There is no statistical way to control retrospectively for a clinical observation related to improvement/lack of improvement during therapy. For example, a study of seriously ill infected patients might reveal a relationship between duration of antibiotic therapy and mortality. However on this basis it would be incorrect to conclude that antibiotic therapy is harmful; rather, longer antibiotic therapy was most likely prescribed because of lower clinical response to therapy in more severe infections.

(4). The relatively low statistical power to exclude an effect given the low rate of DNS and the fact that that many patients were not formally tested (the numbers are not stated) and 16% were lost to follow-up.

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Reviewer #1: Yes: Richard Moon

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19 May 2021

We are grateful to the reviewer 1 for his critical comments and useful suggestions, which have helped us to improve our paper considerably. As indicated in the responses that follow, we have taken all these comments and suggestions into account in the revised version of our paper. In the manuscript, the revised text is shown in red font. We have also provided the page and line numbers corresponding to the revisions in the text.

Reviewer 1

1. Lines 325-338: the authors are attempting to make the point that HBO2-induced oxidative stress could the cause of worse outcome in the HBO2 group. In favor of this hypothesis they cite evidence that HBO2 induces oxidative stress. Of course it does. However, so does carbon monoxide exposure, and published evidence indicates that HBO2 reduces it (reference 26). The conclusion in lines 335-338 therefore needs to be amended.

Response:

We have changed the sentence as you mentioned (page 18, line344-346).

2. Lines 350-354: “A recent meta-analysis of the therapeutic effects of different numbers of HBO2 sessions, including a different range of therapeutic pressures from 2.0 to 2.8 ATA, found that HBO2 therapy was associated with a lower risk of memory impairment than NBO2 therapy, but that two HBO2 sessions was associated with a higher risk of memory impairment than one session [33].” This particular conclusion of Wang’s meta-analysis is based upon two studies (Raphael and Annane) in which sub-therapeutic HBO2 doses were used, and both mild and moderate sequelae (including memory impairment) were defined only by a patient questionnaire (no formal testing of memory); only 4 patients out of 170 had severe sequelae defined as objective abnormalities. All studies using HBO2 at 2.0 ATA have shown no benefit, while all studies using HBO2 at 2.8-3.0 ATA have shown benefit. Please add a caveat to this discussion.

Response:

We had already discussed the difference of therapeutic effects between 2.0 ATA and 2.5 to 3.0 ATA in the 3rd paragraph of the discussion (page16-17, line 315-333). We have changed the sentence of the discussion because our interpretation of the recent meta-analysis is incorrect as you mentioned (page 18, line 359-365).

3. There were 171 patients in the HBO2 group, however the number who received a first HBO2 treatment (Table 2) totaled only 165. Please explain.

Response:

In the six patients, HBO2 therapy were not administered during the first 24 h in 2 patients of the HBO2 group and the details of HBO2 therapy were unknown in 4 patents. This was the reason why the number of the patients received a first HBO2 treatment was 165.

We have added the contents to the results sessions of the revised manuscript (page 10, line 211-213).

4. From the previous review: It would be helpful to include an analysis of the subset of patients with CT or MRI abnormalities. What were the outcomes for those individuals with brain abnormalities on either CT or MRI?

Response:

Among 35 patients with abnormal findings in CT or MRI, DNS was observed in 2 (22.2%) and 8 (30.8%) patients in the NBO2 group (n = 9) and the HBO2 group (n=26), respectively. There was no significant difference in the incidence of DNS between the groups (P = 0.625). Unimproved PCD was observed in 2 (22.2%) and 6 (23.1%) patients in the NBO2 group and the HBO2 group, respectively. There was no significant difference between the groups (P = 0.958).

We have added the contents to the results sessions of the revised manuscript (page 13, line 252-257).

5. The following points need to be addressed in a ‘Shortcomings’ section after the Discussion.

(1). This is not a randomized study, therefore, as pointed out in the previous review, the possibility of selection bias is large, both at the EMS level and within hospitals where HBO2 was available. Indeed, there is evidence that those patients who were treated with hyperbaric oxygen (HBO2) were more severely affected than those who were not. In addition to differences pointed out in the previous review (percentages of patients who lost consciousness, SpCO at the scene), the percentage of patients with abnormal CT, basal ganglia lesions) and MRI (basal ganglia lesions) was higher in the HBO2 group. The lack of statistical significance does not exclude a clinical relationship, particularly since fewer than 60% of patients who received HBO2 in this series were treated at a pressure considered to be therapeutic (≥2.4 ATA).

(2). There is no evidence in the manuscript that the assessors were blinded as to the treatment group (NBO2 vs. HBO2).

(3). An apparent dose-response between number of HBO2 treatments and incidence of delayed neurological sequelae (DNS) is incorrectly interpreted as evidence of possible harm due to HBO2. There is no statistical way to control retrospectively for a clinical observation related to improvement/lack of improvement during therapy. For example, a study of seriously ill infected patients might reveal a relationship between duration of antibiotic therapy and mortality. However on this basis it would be incorrect to conclude that antibiotic therapy is harmful; rather, longer antibiotic therapy was most likely prescribed because of lower clinical response to therapy in more severe infections.

(4). The relatively low statistical power to exclude an effect given the low rate of DNS and the fact that that many patients were not formally tested (the numbers are not stated) and 16% were lost to follow-up.

Response:

We have briefly added the ‘Shortcomings’ section after the Discussion because majority of the contents have already addressed as limitations (page 21-22, line 435-441).

Further, we have added the sentence about non-blinded evaluator for DNS in the method session (page 5, line12-124).


9 Jun 2021

Use of hyperbaric oxygen therapy for preventing delayed neurological sequelae in patients with carbon monoxide poisoning: a multicenter, prospective, observational study in Japan

PONE-D-20-36680R2

Dear Dr. Fujita,

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.

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Tai-Heng Chen, M.D.

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PLOS ONE

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: (No Response)

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2. 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: No

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

Reviewer #1: I Don't Know

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Reviewer #1: Yes

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5. 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: No

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6. 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: Dr. Fujita and colleagues have done a tremendous amount of work in this study, however modifications are still needed to communicate the differences between this retrospective study and a randomized, blinded prospective study.

The following paragraph has been edited by the authors, but in a way to focus on possible adverse effects of oxidative stress due to administration of hyperbaric oxygen for CO poisoning (lines 334-346):

“Oxidative stress is a key mechanism in DNS [20–25]…Although HBO2 therapy has beneficial effects, it should be considered that there are concerns about adverse effects of HBO2 therapy such as HBO2-induced oxidative stress.”

However, the biochemical data from animals and humans overwhelmingly point to a reduction in oxidative stress in CO poisoning after hyperbaric oxygen. A more appropriate wording of that paragraph would be:

“Oxidative stress is a key mechanism in DNS [20–25]. However, there have been reports that HBO2 therapy itself induces oxidative stress [29–32]. Experimental data have shown that HBO2 induces oxidative stress in healthy rat brains, measured as the lipid peroxidation products in brain cortex homogenates [29–31]. This HBO2-induced oxidative stress is related to the HBO2 pressure [29] or the exposure time [30]. It has also been reported that a 342 single session of HBO2 (2.4 kPa, 131 min) reduced plasma vitamin C and increased plasma lipid peroxides and urinary 8-oxo-deoxyguanosine excretion in healthy volunteers [32]. Although there are concerns about adverse effects of HBO2 therapy such as HBO2-induced oxidative stress, measurement of oxidative stress in animal models of CO poisoning has demonstrated reduced lipid peroxidation [26], inhibition of leukocyte beta-2 integrins [18], reversal of CO-cytochrome c oxidase binding [27] and recovery of energy metabolism [28]. It should also be noted that markers of oxidative stress in humans poisoned by carbon monoxide are reduced after treatment (https://pubmed.ncbi.nlm.nih.gov/21424975/).”

Lines 364-368 have been edited to address the issue of selection bias: “Therefore, multiple HBO2 sessions with insufficient therapeutic pressure should be administered cautiously because of the possibility of worsening symptoms. However, the present data could not rule out the possibility that more severely affected patients had received more HBO2 sessions because the HBO2 therapy protocols were not consistent and depended on each institutions’ policies [8].” The manuscript should also note that a randomized blinded study of three hyperbaric oxygen treatments vs. one revealed no evidence of increased adverse outcomes (page 155 of Weaver LK. Carbon monoxide poisoning. Undersea Hyperb Med 2020;47(1):151-69).

Lines 439-441: “There were several issues with assessing DNS, including non-blinded evaluators, 13.8% of loss of follow-up, and the possibility of oversight of patients with mild symptoms.” In the manuscript it is stated that 41 patients were lost to follow-up (lines 406, 409). The total number of patients is 255 (Table 1), thus percentage lost is not 13.8% but 16.1%.

The shortcomings section should be formatted per the prior review. Although some of the shortcomings were stated earlier in the manuscript, the reader expects a complete list in the Shortcomings paragraph. It is also not clear what is meant by, “the possibility of oversight of patients with mild symptoms”.

**********

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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: Yes: Richard Moon


11 Jun 2021

PONE-D-20-36680R2

Use of hyperbaric oxygen therapy for preventing delayed neurological sequelae in patients with carbon monoxide poisoning: A multicenter, prospective, observational study in Japan

Dear Dr. Fujita:

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.

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on behalf of

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Academic Editor

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https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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