Boet Appendix 1-5 52(2)

First author, year

Patients

n

female

n (%)

Age (years)

Mean (SD) or range)

Ethnicity

n (%)

Comorbidities,

n (%)

Cannellotto, 2021

40

14 (35%)

55.2 (9.2)

NR

Chen, 2020

5

1 (20%)

24−69 (mean 47)

Chinese: 5 (100%)

Hypertension: 1 (20%)

Cardiovascular disease: 1 (20%)

Gorenstein, 2020

80

7 (8.8%)

HBOT:

Median = 58

Range = 30−79

Control:

Median = 62

Range = 24−80

White: 23 (28.9%)

Black: 13 (16.3%)

Asian: 7 (8.8%)

Other: 37 (46.3%)

Hypertension: 40 (50%)

Diabetes: 24 (30%)

Cardiovascular disease: 8 (10%)

COPD: 4 (5%)

Guo, 2020

2

0

57 and 64

Chinese: 2 (100%)

Hypertension: 1 (50%)

Diabetes: 1 (50%)

Cardiovascular disease: 1 (50%)

Petrikov, 2021

87

44 (50.6%)

Control:

64.5 (12.7)

HBOT:

58.8 (13.6)

NR

NR

Thibodeaux, 2020

5

4 (80%)

39−63

(median 48)

White: 2 (40%)

Black: 3 (60%)

BMI (Obese): 4(80%)

Hypertension: 4(80%)

Diabetes: 3 (60%)

Zhang, 2020

4

0

56−67

Chinese: 4 (100%)

NR

Zhong, 2020

1

0

87

Chinese

Cardiovascular disease

Chronic obstructive pulmonary disease

First author, year, country

Study design, n patients, single or multi-centre

Inclusion criteria

Exclusion criteria

Intervention planned (type of chamber, pressure, duration, frequency)

Control

Cannellotto, 2021, Argentina

Randomised controlled trial, n = 40 (20 per group), multicentre
(n = 3)

“Patients in emergency department or ICU, > 18 years of age, with confirmed diagnosis of COVID-19 by PCR or nasal swab, with pneumonia with oxygen dependence and no previous hospitalisation within the last six months.”

“Patients unable to give consent, were pregnant or breast feeding, required mechanical ventilation, were unable to maintain prolonged sitting position (≥ 2 h) or had contraindications for HBOT.”

Monoplace, 1.45 atm abs, 90 minutes,
≥ 5, daily

Standard of care

Chen, 2020, China

Case series,
n = 5, single

Progressive hypoxaemia, moderate-severe ARDS, laboratory confirmed COVID-19

NR

Multiplace 2.0 atm abs for one patient, 1.6 atm abs for four patients, 60-90 min, mean five HBOT sessions (range: 3−8)

None

Gorenstein, 2020, United States

Cohort study with propensity score matching,
n = 80 (20 intervention; 60 control), single

Age ≥ 18, laboratory confirmed COVID-19, SaO₂ < 93% on room air

Pregnancy, pneumothorax, positive troponin

Monoplace, 2.0 atm abs, 90 min, once daily for five days

Identified among COVID-19 patients treated contemporaneously at the same hospital using propensity score matching with a 3:1 ratio.

Guo, 2020, China

Case reports, n = 2, single

Laboratory confirmed COVID-19, and one of the following criteria: shortness of breath; respiratory rate
≥ 30 breaths/minute; finger pulse oxygen saturation (SpO₂) ≤ 93% at rest state; and P/F ratio (PaO₂/FiO₂, where PaO₂ is the arterial oxygen partial pressure and FiO₂ is the percentage of inhaled oxygen concentration)
≤ 300 mmHg

Pneumothorax, bullae or other absolute contraindication to HBOT

Monoplace, 1.5 atm abs, 60 min, once daily for seven days

None

Petrikov, 2021, Russia

Randomised controlled trial, n = 87
(57 HBOT group, 30 control group), single

HBOT group divided into two additional subgroups based on start of HBOT after admission:

Group 1
(≤ 7 days):
n = 28

Group 2
(> 7 days):
n =  24

Patient admitted to hospital and clinical diagnosis of COVID-19

NR

Monoplace, 1.4−1.6 atm abs, 40 minutes, NR, NR

Standard of care

Thibodeaux, 2020, United States

Retrospective case series,
n = 5, single

Impending respiratory failure, imminent intubation

NR

Type of chamber not reported;
2.0 atm abs, 90 min; Average five
(range 1−6)

None

Zhang, 2020, China

Prospective case series,

n = 4, single

Progressive dyspnoea, lung CT lesion area
> 30%, SpO₂
< 90% on air, clear consciousness, able to communicate in words and language, minimal education level of junior high

Pneumothorax, pulmonary bullae

Portable monoplace chamber; 1.5 atm abs, 90 min, once daily for seven days

None

Zhong, 2020, China

Case report,
n = 1, single

Critically ill with pneumonia and tracheal intubation, laboratory confirmed positive for COVID-19 from tracheal aspirate

NR

Multiplace chamber, 1.6−1.8 atm abs for 70−100 min, four sessions

None

First author,
year

Risk of bias arising from the randomisation process

Risk of bias due to deviations from the intended interventions

Risk of bias due to missing outcome data

Risk of bias in measurement of the outcome

Risk of bias in selection of the reported result

Overall risk of bias

GRADE assessment (certainty of evidence)

Cannellotto, 2021

Low risk

Some concerns

Low risk

Low risk

Low risk

Some concerns

 High

Petrikov, 2021

Some concerns

High risk

Low risk

Some concerns

Some concerns

High risk

Moderate

Newcastle Ottawa Scale Risk of Bias Assessment

Selection

Comparability

Outcome/

exposure

Overall quality assessment

GRADE assessment (certainty of evidence)

Gorenstein, 2020

****

**

***

Good

Moderate

First author, year

n patients

Timing of outcome measurement

Number of HBOT sessions received

Results

Clinical outcomes

Biological outcomes

Imaging outcomes

Safety outcomes

Cannellotto, 2021

40
(20 per group)

Within 30 days after admission

Mean 6.2 
(SD 1.2)

Primary outcome: Proportion of patients that recovered from hypoxaemia (SpO₂ ≥ 93%):

Control group:

Day 3:
1 (8%)

Day 5:
8 (40%)

Day 10:
  13 (65%)

Day 15:
16 (80%)

HBOT group:

Day 3:
11 (55%)

Day 5:
19 (95%)

Day 10:
20 (100%)

Day 15:
20 (100%)

OR for recovery from hypoxaemia (SpO₂ ≥93%) for HBOT vs. control group:

Day 3: 23.2 (95% CI 1.6 to 329.6;
P = 0.001)

Day 5: 28.5 (95% CI 1.8 to 447.4;
P < 0.001)

Co-primary outcome: Median time to recovery (P < 0.01):

HBOT: median (IQR) 3 (1.0–4.5) days

Control: 9 (5.5–12.5) days

 Secondary outcomes:

 Acute respiratory distress
(P = 0.61):

Control group: 3 (15%)

HBOT group: 3 (15%)

 Mechanical ventilation
(­P = 0.61):

Control group: 3 (15%)

HBOT group: 1 (5%)

Death
(P = 1.0):

Control group: 1 (5%)

HBOT group: 1 (5%)

NR

NR

Ear discomfort
(n = 1)

Chen, 2020

5

Assessed before and after course of HBOT (average of five sessions per patient)

5 (mean)
3−8 (range)

Oxygen saturation (SpO₂) increased mean (SD) 73 (6)% to 94 (2)%,
P < 0.05)

PaO₂ and SaO₂ increased: numbers NR,
(P < 0.05)

 Lymphocyte count increased, mean (SD): 0.61 (0.35) x 10⁹·L^-1 to 1.09 (0.24) x 10⁹·L^-1 (P < 0.05)

C-reactive protein levels decreased: numbers NR

D-dimer decreased: numbers NR
(P < 0.05)

Fibrinogen decreased: numbers NR
(P < 0.05)

CT improved (qualitatively) 

NR

Gorenstein, 2020

80 (20 HBOT; 60 propensity matched controls)

Assessed at end of study (Patients received up to 5 daily treatments while oxygen still required)

5

In-hospital mortality (primary outcome):

HBOT: two patients (10%) died (none remain hospitalised).

Controls: 13 (22%) died (3 [5%] remained hospitalised at end of study period)

Need for mechanical ventilation (secondary outcome):

HBOT: two (10%) patients intubated

Controls: 18 (30%) intubated

Adjusted sub-distribution hazard ratios:

Inpatient mortality
= 0.37
(P = 0.14); Mechanical ventilation
= 0.26
(P = 0.046)

Secondary outcome of days on mechanical ventilation was not analysed

NR

NR

Claustrophobia, ear pain (n NR)

Hypoxic arrest in unclear circumstances after patient transfer
(n = 1)

Guo, 2020

2

Assessed over 7-day course of HBOT

7

Dyspnoea eliminated immediately after the first HBOT session

Respiratory rate decreased daily; no need for mechanical ventilation

SpO₂ > 93% after the first session and continued to improve

D-dimers reduced

Lymphocyte counts improved

Arterial blood gas indices (PaO₂, P/F ratio, bicarbonate, lactate) improved

Liver function improved

Numbers NR for any outcomes

On CT pulmonary inflammation gradually improved

No adverse effects

Petrikov, 2021

87; 57 randomised to HBOT, 30 randomised to control

HBOT group divided into two additional subgroups based on start of HBOT after admission:

Group 1
(≤ 7 days): 
n = 28

Group 2
(> 7 days): n = 24

Assessed over course of HBOT

(7 sessions)

Mean (SD)

Subgroup 1: 5.1(2.5)

Subgroup 2: 4.2 (2.0)

SpO₂ increased day 14 from baseline and compared to control
P < 0.05, mean (SD)

Control group:

Day 1:
92.6 (4.2)

Day 3:
90.4 (4.9)

Day 7: 91.3 (4.8)

Day 14:
93.4 (4.7)

HBOT subgroup 1:

Day 1:
91.9 (5.3)

Day 3:
91.4 (3.8)

Day 7:
92.1 (3.9)

Day 14:
96.1 (2.8)

NEWS2 decreased from  baseline in the HBOT group and compared to control group (P < 0.05),
mean (SD)

Control group:

Day 4:
4.7 (2.3) points

Day 10:
4.0 (2.3) points

HBOT subgroup 1:

Before:4.4 (2.2) points

After: 1.2 (1.7) points

Ordinal scale for clinical improvement score decreased
(P < 0.05) from baseline in the HBOT group and compared to the control group, mean (SD)

Control group:

Day 4: 4.1 (0.7) points

Day 10: 3.9 (0.8) points

HBOT subgroup 1:

Before: 4.2 (0.7) points

After: 3.0 (0.6) points

Respiratory support, defined as oxygen through the nasal  cannula or face mask with a flow of
3–6 l·min^-1, in severe cases using HFOT or NILV,

P-value NR:

Control group:

Day 4:
10 (33.3%)

Day 10:
8 (26.7%)

HBOT subgroup 1:

Before:
9 (32.1%)

After:
0 (0%)

Oxygen flow rate 3−6 l·min^-1,
P-value NR:

Control group:

Day 4:
14 (46.7%)

Day 10:
13 (43.3%)

HBOT subgroup 1:

Before:
15 (53.6%)

After:
5 (17.9%)

No respiratory support required,
P-value NR:

Control group:

Day 4:
6 (20%)

Day 10:
9 (30%)

HBOT subgroup 1:

Before:
4 (14.3%)

After:
23 (82.1%)

Blood malondialdehyde decreased (HBOT group), mean (SD) from 4.34 (0.52) μmol·l^-1 prior to HBOT to 3.98 (0.48) μmol·l^-1 at day 7

Total antioxidant activity decreased (HBOT group),  mean (SD) from 1.26 (0.28) to 1.21 (0.05) mmol·l^-1

Open circuit potential of platinum electrode decreased (HBOT group) mean (SD) from -22.78 (24.58) mV to 30.45 (15.32) mV

Apoptotic lymphocytes:
No significant change

NR

Claustrophobia
(n = 1)

Pain in the ears
(n = 4)

Thibodeaux, 2020

5

Assessed before and after HBOT  course

Mean 5
Range 1−6

SpO₂ improved, mean (SD): 96 (3)% to 96 (1)%

All patients recovered without need for mechanical ventilation

Respiratory rate decreased, mean (SD): 35.4 (8.5) to 28.0 (7.6)

Inflammatory markers decreased (reported for one patient, NR for four patients)

NR

No adverse effects

Zhang, 2020

4

Assessed before and after HBOT course

7

SpO₂ increased, mean (SD): 86 (5)% to 92 (4)%
(P = 0.042)

6-minute walking distance (m) improved: 272 (62) to 346 (43)
(P = 0.05)

Shortness of breath improved

Blood gas analysis indexes improved

CT resolution of inflammation to different degrees

NR

Zhong, 2020

1

Assessed before and after HBOT course

4

Oxygenation improved

 Patient was eventually extubated

CO₂ reduced,
coagulation normalised,
renal function improved

NR

NR