links.lww.com/CCM/F294

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Supplementary Table 1: Individual Study Risk of Bias

Study (author, year)

Randomization sequence generation

Randomization concealment

Blinding Incomplete data

Selective reporting

Other Overall ROB for mortality

Heinrich, 2014 Low Probably low High Low Low Probably low Low

Jaber, 2016 Low Low High Low Low Low Low

Mir, 2017 Low Low High Low Low Probably low Low

Ng, 2018 Low Low High Low Low Low Low

Simon, 2016 Low Low High Low Low Low Low

Vourc'h 2015 Low Low High Low Low Low Low

Lodenius 2018 Low High High Low Probably low Low High

Guitton 2019 Low Low High Low Probably low Low Low

Frat, 2019 Low Low High Low Low Low Low

Vourc’h 2019 Low Low High Low Low Low Low

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Supplementary Table 2: Summary of Findings

Certainty assessment № of patients Effect

Certainty Importan

№ of ce studi es

Study design

Risk of bias

Inconsist ency

Indirect ness

Impreci sion

Other considera

tions HFNC stand

ard thera

py

Relat ive (95%

CI)

Absol ute (95%

CI) Peri-intubation hypoxia (assessed with: Lowest SpO2 below 80%)

7 ^a randomi sed trials

not serio

us

not serious

serious

b

none 72/46 3 (15.6

%) 65/42

1 (15.4

%) RR 0.98 (0.68 to 1.42)

3 fewer

per 1,000

(from 49 fewer to 65 more)

⨁⨁⨁◯

MODERATE

CRITICAL

28 Day Mortality 4 ^c randomi

sed trials

not serio

us

not

serious not

serious serious

b none 114/3

53 (32.3

%) 110/3

12 (35.3

%) RR 0.91 (0.72 to 1.12)

32 fewer

per 1,000

⨁⨁⨁◯

MODERATE

CRITICAL

Peri-intubation complications (assessed with: severe immediate complications including severe hypoxia, significant hypotension and pressor use, and cardiac arrest)

7 ^d randomi sed trials

not serio

us

not

serious serious ^e serious ^f none 206/4 63 (44.5

%) 202/4

21 (48.0

%) RR 0.87 (0.71 to 1.06)

62 fewer

per 1,000

⨁⨁◯◯

LOW

CRITICAL

ICU LOS

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Inconsist

ency Indirect

ness Impreci sion

ard thera

py

Relat ive (95%

CI)

Absol ute (95%

CI) 4 ^c randomi

sed trials

not serio

us

not

serious not

serious serious

b none 353 312 - MD

1.15 lower

(2.45 lower to 0.16 higher

)

⨁⨁⨁◯

MODERATE

CRITICAL

Apneic time (assessed with: seconds) 7 ^g randomi

sed trials

not serio

us

serious ^h not

serious serious ⁱ none 311 299 - MD

10.3 secon

ds highe

r (11 lower

to 31.7 higher

)

⨁⨁◯◯

LOW

IMPORTA NT

PaO2 post intubation (assessed with: mm Hg) 6 ^j randomi

sed trials

not serio

us

not serious ^k

not serious

serious ⁱ none 162 167 - MD 27

mm Hg highe

r (13.2 lower to 67.2 higher

)

⨁⨁⨁◯

MODERATE

IMPORTA NT

PaO2 after pre-oxygenation (assessed with: mm Hg)

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Inconsist

ency Indirect

ness Impreci sion

ard thera

py

Relat ive (95%

CI)

Absol ute (95%

CI) 7 ^l randomi

sed trials

not serio

us

not

serious ^m not

serious serious ⁱ none 408 378 - MD

3.6 mm Hg highe

r (3.5 lower

to 10.7 higher

)

⨁⨁⨁◯

MODERATE

IMPORTA NT

PaCO2 post intubation (assessed with: mm Hg) 4 ⁿ randomi

sed trials

not serio

us

serious ^o not

serious serious

b none 105 103 - MD

0.6 mm Hg lower

(3.4 lower to 2.2 higher )

⨁⨁◯◯

LOW

IMPORTA NT

CI: Confidence interval; RR: Risk ratio; MD: Mean difference

Explanations

a. Frat 2019, Guitton 2019, Jaber 2016, Simon 2016, Vourc'h 2015, Lodenius 2018, Vourc’h 2019 b. Wide confidence intervals that don't exclude significant clinical benefit or significant harm c. Frat 2019, Guitton 2019, Jaber 2016, Vourc'h2015

d. Frat 2019, Guitton 2019, Jaber 2016, Simon 2016, Vourc'h 2015, Lodenius 2018, Vourc’h 2019

e. Complications have varying degrees of importance, for example, pressor use is less deleterious than cardiac arrest. Also unclear how carefully complications were examined in both arms of the study.

f. Upper end of confidence interval does not exclude no effect.

g. Guitton 2019, Simon 2016, Vourc'h 2015, Lodenius 2018, Mir 2017, Ng 2018, Vourc’h 2019 h. High Isquared with variable effects across studies

i. Lower end of 95% confidence interval doesn't exclude no effect

j. Jaber 2016, Simon 2016, Vourc'h 2015, Mir 2017, Ng 2018, Heinrich 2014

k. While the Isquared is moderately high, the far majority of the studies show a higher PaO2 with HFNC.

l. Frat 2019, Guitton 2019, Jaber 2016, Simon 2016, Vourc'h 2015, Ng 2014, Heinrich 2014 m. While the Isquared is moderately high, all of the studies show a higher PaO2 with HFNC.

n. Jaber 2016, Simon 2016, Lodenius 2018, Mir 2017

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o. Inconsistent forest plot with no agreement in results.

Supplementary Table 3 – Characteristics of Included Studies

Study Country

Number of Patients

Randomized Population Intervention Details Comparator Details Outcomes Serious Complications

Noted

Heinrich,

2014 Germany 33

Inclusion: elective bariatric surgery patients (BMI ≥ 35 with comorbidities or BMI ≥ 40)

Exclusion: supplemental O2, severe psychiatric comorbidities

(OptiFlow, Fisher & Paykel Healthcare)

Pre-oxygenation Settings:

Flow: 50 L/min FiO2: 100%

Duration: 7 minutes

Face mask or CPAP Pre-oxygenation Settings:

Face mask, flow: 12 L/min

CPAP, PEEP: 7 cmH2O FiO2: 100%

Duration: 7 minutes

Peri-intubation complications, PaO2

after pre-oxygenation, PaO2 post-intubation

Pressor support, epistaxis, aspiration, other

hemodynamic compromise

Jaber,

2016 France 50

Inclusion: ICU patients, intubated, RR > 30 requiring FiO2 ≥ 50% for PF < 300

Exclusion: CV instability

(OptiFlow, Fisher & Paykel Healthcare) + NIV

Pre-oxygenation Settings:

HFNC, Flow: 60 L/min NIV, IPAP/EPAP: 15 cmH2O/5 cmH2O FiO2: 100%

Duration: 4 minutes

NIV

Pre-oxygenation Settings:

IPAP: 15 cmH2O PEEP: 5 cmH2O FiO2: 100%

Duration: 4 minutes

Mortality (28 days), ICU LOS, peri- intubation complications, peri- intubation hypoxemia, PaO2 after pre- oxygenation, PaO2 post- intubation, PaCO2 post- intubation

Severe hypoxemia, severe hemodynamic collapse, cardiac arrest, death

Mir, 2017 United

Kingdom 40

Inclusion: RSI for emergency surgery Exclusion: severe respiratory disease

Pre-oxygenation Settings:

Flow: 70 L/min FiO2: N/A

Duration: 3 minutes

Face mask Pre-oxygenation Settings:

Flow: 12 L/min FiO2: N/A Duration: N/A

Peri-intubation complications, peri- intubation hypoxemia, PaO2 post-intubation, PaCO2 post-intubation, apneic time

Airway emergencies, severe hypoxia

Ng, 2018 Australia 50

Inclusion: neurosurgical patients, ASA status: 1-3 Exclusion: RSI, ↑ICP, BMI ≥ 35, fibreoptic intubation, gas oxygenation

Pre-oxygenation Settings:

Duration: 5 minutes

Face mask with subsequent BMV Pre-oxygenation Settings:

Duration: 5 minutes

Peri-intubation complications, peri- intubation hypoxemia, PaO2 after pre- oxygenation, PaO2 post- intubation, apneic time

Airway emergencies, severe hypoxia, cardiovascular collapse

Simon, 2016

Germany 40 Inclusion: ICU patients, PF < 300

Exclusion: RSI

Pre-oxygenation Settings:

BMV

3 minutes

Peri-intubation complications, peri- intubation hypoxemia, , PaO2 after pre- oxygenation, PaO2 post-

Airway emergencies, severe hypoxia, cardiovascular collapse

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Duration: 3 minutes intubation, PaCO2 post- intubation, apneic time

Vourc'h,

2015 France 119

Inclusion: ICU patients, RSI, RR > 30 on FiO2 ≥ 50% for SpO2 ≥ 90% and PF < 300

Exclusion: cardiac arrest, asphyxia

Pre-oxygenation Settings:

Duration: 4 minutes

Mortality (28 days), ICU LOS, peri- intubation complications, peri- intubation hypoxemia, PaO2 after pre- oxygenation, PaO2 post- intubation, apneic time

Desaturation <80 %; cardiovascular collapse, systolic blood pressure < 80 mmHg, vasopressor introduction or increasing doses more than 30 %

Lodenius,

2018 Sweden 80

Inclusion: emergency surgery patients, RSI Exclusion: BMI > 35, urgent NIV

Pre-oxygenation Settings:

Flow: 40 L/min, 70 L/min when apneic

FiO2: 100%

Duration: 3 minutes

Peri-intubation complications, peri- intubation hypoxemia, PaCO2 post-intubation, apneic time

Severe cardiovascular compromise, hemodynamic collapse, cardiac arrest, desaturation <80%

Guitton,

2019 France 192

Inclusion: ICU patients Exclusion: PF < 200, RSI, respiratory arrest, cardiorespiratory arrest, fiberoptic intubation, asphyxia

Pre-oxygenation Settings:

Duration: 4 minutes

BMV

Duration: 4 minutes

Mortality (28 days), ICU LOS, peri- intubation complications, peri- intubation hypoxemia, PaO2 after pre- oxygenation, apneic time

At least one severe complication (death, cardiac arrest, SpO2

< 80%, severe hypotension defined by systolic blood pressure < 80 mmHg or vasopressor initiation or 30% dose increment)

Frat, 2019 France 313

Inclusion: ICU patients, RR > 25 or signs of respiratory distress or PF

< 300

Exclusion: cardiac arrest, GCS < 8, SaO2

unavailable

Pre-oxygenation Settings:

Duration: 3-5 minutes

BiPAP

Flow: 6-8 mL/kg/min FiO2: 100%

Duration: 3 – 5 minutes

Mortality (28 days), ICU LOS, peri- intubation complications, peri- intubation hypoxemia, PaO2 after pre- oxygenation

Immediate complications (arterial hypotension, sustained cardiac arrhythmia, bradycardia, cardiac arrest, death, oesophageal intubation, regurgitation, gastric distension, dental injury and new infiltrate on chest radiograph)

Vourc’h, 2019

France 100 Inclusion: BMI ≥ 35 and planned pre-op RSI Exclusion: SpO2 <90%

on room air,

haemodynamic instability, burns, anticipated intubation without

Pre-oxygenation Settings:

Duration: 4 minutes

BiPAP

IPAP: 15 cmH2O PEEP: 5 cmH2O FiO2: 100%

Duration: 4 minutes

Peri-intubation complications, peri- intubation hypoxemia, apneic time

At least one severe complication (death, cardiac arrest, SpO2

< 80%, systolic blood pressure <80 mmHg or vasopressor initiation)

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laryngoscopy,

Grade 4 glottis exposure previously documented

______________________

ASA = American Society of Anesthesiologists BMI = Body mass index

CV = Cardiovascular ICP = Intracranial pressure

PEEP = Positive end-expiratory pressure PF = PaO2:FiO2 ratio

RR = Respiratory rate

RSI = Rapid sequence intubation

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Supplementary Figure Legend

Supplementary Figure 1: Peri-intubation hypoxia forest plot subdivided by comparator Supplementary Figure 2: Peri-intubation hypoxia forest plot subdivided by risk of bias Supplementary Figure 3: Trial Sequential Analysis of peri-intubation hypoxia

Supplementary Figure 4: PaO2 after intubation forest plot subdivided by patient subtype Supplementary Figure 5: PaCO2 after intubation forest plot

Supplementary Figure 6 – ICU Length of stay forest plot Supplementary Figure 7 – 28-day mortality forest plot

Supplementary Figure 8: PaO2 after pre-oxygenation forest plot subdivided by comparator subtype

Supplementary Figure 9: PaO2 after intubation forest plot subdivided by comparator subtype Supplementary Figure 10: Sensitivity analysis of PaO2 after pre-oxygenation by removing studies that only reported SpO2 forest plot

Supplementary Figure 11: Sensitivity analysis of PaO2 after intubation by removing studies

that only reported SpO2 forest plot

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Section/topic # Checklist item Reported on page # TITLE

Title 1 Identify the report as a systematic review, meta-analysis, or both. 1

ABSTRACT

Structured summary 2 Provide a structured summary including, as applicable: background; objectives; data sources; study eligibility criteria, participants, and interventions; study appraisal and synthesis methods; results; limitations; conclusions and

implications of key findings; systematic review registration number.

1

INTRODUCTION

Rationale 3 Describe the rationale for the review in the context of what is already known. 2

Objectives 4 Provide an explicit statement of questions being addressed with reference to participants, interventions, comparisons,

outcomes, and study design (PICOS). 2

METHODS

Protocol and registration 5 Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if available, provide

registration information including registration number. 2

Eligibility criteria 6 Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered,

language, publication status) used as criteria for eligibility, giving rationale. 3

Information sources 7 Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify

additional studies) in the search and date last searched. 2

Search 8 Present full electronic search strategy for at least one database, including any limits used, such that it could be

repeated. 2

Study selection 9 State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable,

included in the meta-analysis). 3

Data collection process 10 Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes

for obtaining and confirming data from investigators. 3

Data items 11 List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and

simplifications made. 3

Risk of bias in individual

studies 12 Describe methods used for assessing risk of bias of individual studies (including specification of whether this was

done at the study or outcome level), and how this information is to be used in any data synthesis. 3

Summary measures 13 State the principal summary measures (e.g., risk ratio, difference in means). 3-4

Supplementary Table 4 - PRISMA checklist

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Synthesis of results 14 Describe the methods of handling data and combining results of studies, if done, including measures of consistency

(e.g., I

²)

for each meta-analysis. 3-4

Section/topic # Checklist item Reported

on page # Risk of bias across studies 15 Specify any assessment of risk of bias that may affect the cumulative evidence (e.g., publication bias, selective

reporting within studies). 3-4

Additional analyses 16 Describe methods of additional analyses (e.g., sensitivity or subgroup analyses, meta-regression), if done, indicating

which were pre-specified. 3-4

RESULTS

Study selection 17 Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at

each stage, ideally with a flow diagram. 4

Study characteristics 18 For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) and

provide the citations. 4-5

Risk of bias within studies 19 Present data on risk of bias of each study and, if available, any outcome level assessment (see item 12). 4-5

Results of individual studies 20 For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each

intervention group (b) effect estimates and confidence intervals, ideally with a forest plot. 4-5

Synthesis of results 21 Present results of each meta-analysis done, including confidence intervals and measures of consistency. 4-5

Risk of bias across studies 22 Present results of any assessment of risk of bias across studies (see Item 15). 4

Additional analysis 23 Give results of additional analyses, if done (e.g., sensitivity or subgroup analyses, meta-regression [see Item 16]). 5 DISCUSSION

Summary of evidence 24 Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to

key groups (e.g., healthcare providers, users, and policy makers). 5-6

Limitations 25 Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval of

identified research, reporting bias). 5-6

Conclusions 26 Provide a general interpretation of the results in the context of other evidence, and implications for future research. 5-6 FUNDING

Funding 27 Describe sources of funding for the systematic review and other support (e.g., supply of data); role of funders for the

systematic review. N/A

From: Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS

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Med 6(7): e1000097. doi:10.1371/journal.pmed1000097