High-flow nasal cannula for reducing hypoxemic events in patients undergoing bronchoscopy: A systematic review and meta-analysis of randomized trials.

BACKGROUND: Patients undergoing bronchoscopic procedures may develop hypoxemia and severe complications. High-flow nasal cannula (HFNC) may prevent hypoxemic events during bronchoscopy. We conducted a systematic review of randomized controlled trials (RCTs) to evaluate the effectiveness of HFNC in these patients.
METHODS: We conducted a search in PubMed, Embase, and the Cochrane Library for RCTs published before November 2021. Individual effect sizes were standardized, and a meta-analysis was performed to calculate the pooled effect size using random-effects models. The primary outcome was the incidence of hypoxemic events (oxygen saturation [SpO2] < 90%) during bronchoscopy. Secondary outcomes included the incidence of interrupted bronchoscopy due to desaturation, lowest SpO2 during bronchoscopy, partial pressure of oxygen (PaO2), partial pressure of carbon dioxide (PaCO2), end-tidal CO2 (EtCO2) at the end of bronchoscopy, and the incidence of intubation after the procedure.
RESULTS: Five trials involving 257 patients were reviewed. The incidence of hypoxemic events was lower in the HFNC group than in the conventional oxygen therapy group (risk ratio, 0.25; 95% confidence interval [CI], 0.14-0.42). The lowest SpO2 during the procedure was significantly higher in the HFNC group than in the conventional oxygen therapy group (weighted mean difference [WMD], 7.12; 95% CI, 5.39-8.84). PaO2 at the end of the procedure was significantly higher in the HFNC group than in the conventional oxygen therapy group (WMD, 20.36; 95% CI, 0.30-40.42). The incidence of interrupted bronchoscopy due to desaturation, PaCO2 and EtCO2 at the end of the procedure, and the incidence of intubation after the procedure were not significantly different between groups.
CONCLUSIONS: HFNC may reduce the incidence of hypoxemic events and improve oxygenation in patients undergoing bronchoscopy.

Introduction

Hypoxemia is one of the complications in patients undergoing bronchoscopy. Sedation and occlusion of the bronchi during the procedure reduce the respiratory drive and lead to hypoventilation [1]. Patients with pulmonary complications after bronchoscopic procedures occasionally have a risk of hypoxemic events that require rescue airway interventions [2]. Complications of bronchoscopy, such as refractory hypoxemia and respiratory depression, can be debilitating without careful monitoring [2-4]. Therefore, oxygen supplementation during bronchoscopy is crucial for these patients.

In the past, conventional oxygen therapy was usually adopted for patients undergoing diagnostic or therapeutic bronchoscopy, but desaturation would occasionally occur due to impaired respiratory drive and hypoventilation [2-4]. For safer bronchoscopic procedures, high-flow nasal cannula (HFNC) may replace conventional oxygen supply due to the more consistent fraction of inspired oxygen [5, 6]. According to a previous study, in patients using conventional oxygen therapy, the complication rate can reach 35% after bronchoscopy [7]. Thus, conventional oxygen therapy may not be as useful as expected for maintaining oxygenation.

Currently, HFNC is used to prevent respiratory failure. HFNC enhances secretion clearance and reduces bronchoconstriction by using heated and humidified gas [8], decreases dead space [9], and restores functional residual capacity to improve ventilation/perfusion mismatch (V/Q mismatch) [10]. In the past, several feasibility studies and reviews have assessed whether HFNC can maintain oxygenation and avoid endotracheal intubation in patients undergoing bronchoscopy [7, 11, 12]. Since then, several randomized controlled trials (RCTs) have been reported [13-17], but no systematic review or meta-analysis has encompassed them all. Thus, the aim of this systematic review was to compare the efficacy of HFNC with conventional oxygen therapy in maintaining oxygenation (SpO2 ≥ 90%) and avoiding endotracheal intubation in patients undergoing bronchoscopy.

Materials and methods

Inclusion criteria

RCTs that compared HFNC with conventional oxygen therapy in patients undergoing bronchoscopy were included in the analysis. We excluded trials in which (1) patients were <18 years old, (2) patients underwent bronchoscopy for intubation, (3) comparisons different from the one of interest were performed, or (4) duplicate patient cohorts were reported.

Search strategy and study selection

Relevant trials published before November 2021 were identified from the PubMed, Embase, and Cochrane Library databases. The following Medical Subject Headings (MeSH) were used in the search: “HFNC”, “high flow nasal cannula,” “high flow oxygen,” “high flow nasal oxygen,” “bronchoscopy,” and “bronchoscope.” These were combined into the search strategy detailed in S1 Appendix. No language restrictions were imposed. The ClinicalTrials.gov registry was searched for ongoing trials. This systematic review was registered in the online PROSPERO International Prospective Register of Systematic Reviews of the National Institute for Health Research (registration number CRD42021254176). The completed PRISMA checklist was provided in S2 Appendix.

Data extraction

Two authors independently extracted baseline and outcome data, study designs, study population characteristics, inclusion and exclusion criteria, HFNC settings, sedative or anesthetic agents, and post-treatment parameters from the studies retrieved by the database search. The reviewers’ individually recorded decisions were compared, and disagreements concerning data extraction were resolved through discussion with a third reviewer.

Methodological quality appraisal

Two reviewers independently assessed the methodological quality of each study using the risk-of-bias tool, version 2, as recommended by the Cochrane Collaboration [18]. For randomized trials, we assessed allocation, performance, attrition, measurement, reporting, and overall bias. Disagreements regarding the assessment of risk of bias were resolved through a comprehensive discussion.

Outcomes

The primary outcome was the incidence of hypoxemic events during bronchoscopy (oxygen saturation [SpO2] < 90%). Secondary outcomes included the incidence of interrupted bronchoscopy due to desaturation, lowest SpO2 during bronchoscopy, partial pressure of oxygen (PaO2), partial pressure of carbon dioxide (PaCO2), end-tidal CO2 (EtCO2) at the end of bronchoscopy, and the incidence of intubation after the procedure.

Grading evidence quality

Two reviewers independently assessed the evidence quality for each outcome using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) guidelines [19]. Evidence quality was classified as high, moderate, low, or very low based on the assessed risk of bias, inconsistency, indirectness, imprecision, and publication bias. Discrepancies were resolved by consensus.

Statistical analyses

We analyzed the data using Review Manager version 5.4 (Cochrane Collaboration, Oxford, England) in accordance with the PRISMA guidelines [20]. Risk ratios (RRs) for binary outcomes and weighted mean differences (WMDs) for continuous outcomes with the corresponding 95% confidence intervals (CIs) were computed. Standard deviations were estimated from CI limits or standard errors. If the mean and variance were not reported in a trial, they were estimated from the median, interquartile range (IQR), and sample size if the skewness was acceptable [21]. All outcomes were analyzed using a random-effects model [22]. Cochran’s Q and I2 statistics were calculated to evaluate the statistical heterogeneity and inconsistency of treatment effects, respectively, across trials. Statistical significance was set at p < .10 for Cochran’s Q tests. Statistical heterogeneity across trials was assessed using the I2 test, which quantifies the proportion of total outcome variability across trials [23]. Trial sequential analysis was performed to reduce type I errors, and sensitivity analysis was used to manage heterogeneity [18, 24, 25].

Results

Trial characteristics

Fig 1 illustrates the study selection process. The initial search yielded 371 citations. After removal of duplicates, 308 studies were left, of which 270 did not compare HFNC with conventional oxygen therapy in patients undergoing bronchoscopy. Among these reports, nine registrations that were not retrieved were excluded. After the remaining 29 studies were reviewed, 24 were excluded. Of these, 18 were not RCTs, two included patients aged <18 years, two investigated bronchoscopy for intubation, and two conducted different comparisons. Hence, five trials were eligible for this study [10-14]. The search strategy and list of 23 major exclusions are reported in the S1 Appendix.

Fig 1

Flowchart of study selection.

RCT, randomized controlled trial.

Five trials on patients undergoing bronchoscopy were published between 2012 and 2021 [13-17]. They had sample sizes ranging from 36 to 76, with a total sample size of 257. All the trials enrolled adult patients with indications for diagnostic or therapeutic interventions. Three trials measured baseline oxygenation by examining SpO2 [13-15], one by investigating PaO2 [16], and one by examining PaO2/FiO2 [17]. Ben-Menachem et al. performed local anesthesia with nebulized 2% lidocaine and sedation with midazolam, propofol, and alfentanil [13]. Douglas et al. conducted sedation with midazolam, opioids, or propofol [14]. Irfan et al. conducted moderate sedation with midazolam and alfentanil [15]. Longhini et al. administered an anesthetic spray containing 10% lidocaine [16]. Lucangelo et al. performed local anesthesia nebulized lidocaine 2% through the mouth and nostrils [17]. Notably, Ben-Menachem et al. investigated post-lung transplant patients [13]. All the included trials categorized patients into two groups: those undergoing HFNC and those undergoing conventional oxygen therapy. Regarding intervention timing, HFNC was conducted during bronchoscopy in all trials. The baseline characteristics of the patients in each trial are summarized in Table 1.

Table 1

Characteristics of the selected randomized controlled trials.

Study	Inclusion criteria	No. of patients (% male)	Age, years, mean ± SD	Baseline oxygenation	Sedative or anesthetic agents; duration of bronchoscopy (min)	Interventions
Ben-Menachem [13]	Age ≥ 18 years; lung transplant recipients; undergoing TBLB; able to provide informed consent; English speaking	H: 37 (40.5)	H: 54.9 ± 11.7	H: 98 (97–99)†,a	Local Topicalized anesthesia with nebulized 2% lidocaine and midazolam (1 to 3 mg) sedation with midazolam, propofol (321 mg in intervention group and 337 mg in control group) and alfentanil (586 mcg in intervention group and 691 mcg in control group) to keep ASA score II–III; H: 33 ± 10, C: 34 ± 8	H: FiO2: 100%, flow rate: 30–50 LPM through the nasal cannula
		C: 39 (25.6)	C: 55.8 ± 11.9	C: 98 (97–99)†,a		C: Flow rate: 4–10 LPM through standard oxygen tubing
Douglas [14]	Age ≥ 18 years; able to provide informed consent; sedation planned; English speaking	H: 30 (63)	H: 62.8 ± 14.1	H: 96 (95–99)†,a	Topical 2% lignocaine to patient’s nasopharynx and oropharynx Sedation with midazolam, opioids or propofol to keep MOAA/S = 4; I: 24 (26–28)†, C: 21 (17–32)†	H: FiO2: 100%, flow rate: 30–50 LPM (up to 70 LPM if necessary) through the nasal cannula
		C: 30 (63)	C: 63.4 ± 14.3	C: 96 (94–98)†,a		C: Flow rate: 10 LPM (up to 15 LPM if necessary) through the bite block
Irfan [15]	Age ≥ 18 years; SpO2 ≥ 90%; able to breathe spontaneously throughout the procedure	H: 20 (60)	H: 61.9 ± 12	H: 98.4 ± 2.7a	Local anesthesia sedation with midazolam (5.6 mg in intervention group and 5.5 mg in control group) and alfentanil (300 mcg in intervention group and 287 mcg in control group) varied by assessing purposeful response to verbal and/or tactile stimuli while preserving spontaneous respiratory efforts; NI	H: FiO2: 36%, flow rate: 30 LPM through the nasal cannula
		C: 20 (60)	C: 64.5 ± 14	C: 96.9 ± 1.9a		C: Nasal prong to maintain SpO2 ≥ 94%
Longhini [16]	Age ≥ 18 years; outpatients undergoing flexible bronchoscopy for bronchoalveolar lavage	H: 18 (83)	H: 61.9 ± NI	H: 10.8 (8.7–12.0)†,b	Topical Aanesthetic spray containing 10% lidocaine over tongue and nasopharynx; gargles with 10 mL of 2% lidocaine hydrochloride solution guaranteed further anesthesia of the oropharynx; H: 11 min 30 s ± NI, C: 12 min 50 s ± NI	H: FiO2 set to reach SpO2 ≥ 95%, flow rate: 60 LPM through the nasal cannula
		C: 18 (67)	C: 64.5 ± NI	C: 11.1 (10.5–12.1)†,b		C: Nasal cannula to keep SpO2 ≥ 94%
Lucangelo [17]	Age ≥ 18 years; BMI ranging from 21 to 30	H60: 15 (47)	H60: 64 (63–70)†	H60: 350.9 (304.3–363.8)†,c	Anesthesia by nNebulized 2% lidocaine 2% through the mouth and nostrils to guarantee fully developed local anesthesia; 4mg midazolam in each group delivered as demanded by each patient, reaching a maximum dose of 0.1 mg/kg BW; H60: 15 (9–21)†, H40: 15 (12–16)†, C: 14 (10–16)†	H60: FiO2: 50%, flow rate: 60 LPM through the nasal cannula
		H40: 15 (53)	H40: 70 (61–76)†	H40: 342.8 (295.7–371.9) †,c		H40: FiO2: 50%, flow rate: 40 LPM through the nasal cannula
		C: 15 (60)	C: 68 (62–78)†	C: 322.4 (295.6–374.3)†,c		C: FiO2: 50%, flow rate: 40 LPM through the venturi mask

†Data reported as median (IQR); aData reported as SpO2; bData reported as PaO2 in kPa; cData reported as PaO2/FiO2 ratio.

Abbreviations: BMI, body mass index; C, conventional oxygen therapy; H, high-flow nasal cannula; H60, high-flow nasal cannula with flow of 60 LPM; H40, high-flow nasal cannula with flow of 40 LPM; LPM, liters per minute; MOAA/S, Modified Observer’s Assessment of Alertness/Sedation Scale; NI, no information; TBLB, transbronchial lung biopsy.

The methodological quality of the included studies is summarized in Table 2. Regarding allocation bias, one trial presented an imbalance in the comorbidity of pulmonary carcinoma and SpO2 following preoxygenation at baseline [14], one trial showed an imbalance for the diagnosis of metastatic cancer at baseline [15], and one trial did not provide information on age [16]. All trials had acceptable management of performance, attrition, measurement, and reporting biases. Overall, two trials were rated as having a low risk of bias [13, 17], and three trials had some concerns regarding bias [14-16].

Table 2

Methodological quality assessment of the randomized trials.

Randomized controlled trials evaluated using the revised Cochrane Risk of Bias (RoB 2.0) tool
Study	Allocation bias	Performance bias	Attrition bias	Measurement bias	Reporting bias	Overall bias
Ben-Menachem [13]	Low risk	Low riskd	Low risk	Low risk	Low risk	Low risk
Douglas [14]	Some concernsa	Low risk	Low risk	Low risk	Low risk	Some concerns
Irfan [15]	Some concernsb	Low risk	Low risk	Low risk	Low riske	Some concerns
Longhini [16]	Some concernsc	Low risk	Low risk	Low risk	Low risk	Some concerns
Lucangelo [17]	Low risk	Low risk	Low risk	Low risk	Low riske	Low risk

aThe baseline of comorbidity of pulmonary carcinoma, procedural data, and the SpO2 following pre-oxygenation were imbalanced.

bThe baseline of diagnosis of metastatic cancer was imbalanced.

cThe baseline of age was not available.

dOne patient crossed over from the conventional oxygen group to the HFNC group in Ben-Menachem’s trial, but they performed adequate analysis on an intend-to-treat (ITT) basis. Hence, we did not raise the risk of bias.

eAlthough these two trials did not provide protocol registration, they investigated the same outcomes as other trials registered in ClinicalTrials.gov. Obvious selective reporting was not detected. Hence, we did not raise the risk of bias.

Incidence of hypoxemic events during bronchoscopy and of interrupted bronchoscopy due to desaturation

A total of four trials measured the incidence of hypoxemic events after bronchoscopy [13-16]. All trials defined hypoxemic events as SpO2 < 90%. The incidence of hypoxemic events was significantly lower among patients who underwent HFNC than among those who underwent conventional oxygen therapy (RR, 0.25; 95% CI, 0.14–0.42; Fig 2). Furthermore, the results of trial sequential analysis showed that the Z-curve crossed the O’Brien-Fleming boundaries after the fifth cumulative significance testing. These findings indicate that HFNC may reduce hypoxemic events (SpO2 < 90%) in patients undergoing bronchoscopy (S3 Appendix). Two trials measured the incidence of interrupted bronchoscopy due to desaturation [13, 14], which was lower among patients who underwent HFNC than among those who underwent conventional oxygen therapy (RR, 0.19; 95% CI, 0.02–1.86), although the result was not statistically significant (Fig 2).

Fig 2

Forest plot for comparison: High-flow nasal cannula versus conventional oxygen therapy.

Outcomes: incidence of hypoxemic events and incidence of interrupted bronchoscopy due to desaturation. HFNC, high-flow nasal cannula; COT, conventional oxygen therapy; CI, confidence interval; M-H, Mantel-Haenszel.

Lowest SpO2 during bronchoscopy

Four trials measured the lowest SpO2 during the procedure in patients undergoing bronchoscopy [13-16]. The lowest SpO2 was significantly higher in patients on HFNC than in those on conventional oxygen therapy (WMD, 7.12; 95% CI, 5.39–8.84; Fig 3).

Fig 3

Forest plot for comparison: High-flow nasal cannula versus conventional oxygen therapy.

Outcome: lowest SpO2 during bronchoscopy. HFNC, high-flow nasal cannula; COT, conventional oxygen therapy; CI, confidence interval; SD, standard deviation.

PaO2 at the end of bronchoscopy

Two trials measured PaO2 at the end of the procedure in patients undergoing bronchoscopy [16, 17]. We compared the HFNC group with a flow rate of 60 liters per minute (LPM) with the conventional oxygen therapy group in Lucangelo’s study [17]. The unit was converted from kPa to mmHg. PaO2 was significantly higher in patients on HFNC than in those on conventional oxygen therapy (WMD, 20.36; 95% CI, 0.30–40.42; Fig 4).

Fig 4

Forest plot for comparison: High-flow nasal cannula versus conventional oxygen therapy.

Outcome: PaO2 at the end of bronchoscopy. HFNC, high-flow nasal cannula; COT, conventional oxygen therapy; CI, confidence interval; SD, standard deviation.

PaCO2 and EtCO2 at the end of the procedure

Two trials each measured PaCO2 [16, 17] and EtCO2 [14, 15] at the end of the procedure in patients undergoing bronchoscopy. We compared the HFNC group with a flow rate of 60 LPM with the conventional oxygen therapy group in Lucangelo’s study [17]. The unit was converted from kPa to mmHg. PaCO2 was higher among patients on conventional oxygen therapy than among those on HFNC (WMD, −0.02; 95% CI, −2.31–2.27). EtCO2 was also higher in the conventional oxygen therapy group than in the HFNC group (WMD, −0.12; 95% CI, −4.19–3.94). However, these differences were not significant (Fig 5).

Fig 5

Forest plot for comparison: High-flow nasal cannula versus conventional oxygen therapy.

Outcomes: PaCO2 and EtCO2 at the end of the procedure. HFNC, high-flow nasal cannula; COT, conventional oxygen therapy; CI, confidence interval; SD, standard deviation.

Incidence of intubation after the procedure

Two trials measured the incidence of intubation after bronchoscopy [14, 15]. No adverse events of endotracheal intubation were reported in either group. The incidence of intubation in both arms was 0.

GRADE evidence quality

The GRADE evidence quality for each main outcome is shown in Table 3. In the risk-of-bias domain, all items were rated as serious because of the risk of bias in allocation. In the inconsistency and indirectness domains, all items were rated as having low risk because heterogeneity was acceptable among the trials, and all used head-to-head comparison. In the imprecision domain, the incidence of interrupted bronchoscopy due to desaturation and PaO2, PaCO2, and EtCO2 at the end of the procedure were rated as serious due to imprecision attributable to an insufficient number of trials with a wide 95% confidence interval. No publication bias was observed. Thus, we obtained evidence of low quality for the incidence of interrupted bronchoscopy due to desaturation and PaO2, PaCO2, and EtCO2 at the end of the procedure and of moderate quality for the incidence of hypoxemic events (SpO2 < 90%) and lowest SpO2 during bronchoscopy.

Table 3

Summary of findings compiled using GRADE methodology.

Outcome	No. of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Publication bias	Effect size	Certainty	Importance
								(95% CI)
Incidence of hypoxemic events (SpO2 < 90%)	4	RCT	Seriousa	Not serious	Not serious	Not serious	Undetected	RR: 0.25	⨁⨁⨁◯	Critical
								(0.14−0.42)	Moderate
Incidence of interrupted bronchoscopy due to desaturation	2	RCT	Seriousa	Not serious	Not serious	Seriousb	Undetected	RR: 0.19	⨁⨁◯◯	Important
								(0.02−1.86)	Low
Lowest SpO2 during bronchoscopy	4	RCT	Seriousa	Not serious	Not serious	Not serious	Undetected	WMD: 7.12	⨁⨁⨁◯	Important
								(5.39–8.84)	Moderate
PaO2 at the end of bronchoscopy	2	RCT	Seriousa	Not serious	Not serious	Seriousb	Undetected	WMD: 20.36	⨁⨁◯◯	Important
								(0.30–40.42)	Low
PaCO2 at the end of bronchoscopy	2	RCT	Seriousa	Not serious	Not serious	Seriousb	Undetected	WMD: −0.02	⨁⨁◯◯	Important
								(−2.31–2.27)	Low
EtCO2 at the end of bronchoscopy	2	RCT	Seriousa	Not serious	Not serious	Seriousb	Undetected	WMD: −0.12	⨁⨁◯◯	Important
								(−4.19–3.94)	Low

Abbreviations: CI, confidence interval; GRADE, quality of evidence grade; NI, no information; RCT, randomized controlled trial; RR, risk ratio; WMD, weighted mean difference; ⨁⨁⨁◯, moderate certainty; ⨁⨁◯◯, low certainty.

aData reported as downgraded because of some concerns of bias.

bData reported as downgraded because of wide CI or insufficient studies.

Discussion

Our findings indicate that in patients undergoing bronchoscopy, regardless of the sedative or anesthetic agents used, HFNC resulted in a lower incidence of hypoxemic events (SpO2 < 90%) when compared with conventional oxygen therapy, and it improved the values of the lowest SpO2 during bronchoscopy and PaO2 at the end of the procedure. The incidence of interrupted bronchoscopy, PaCO2, EtCO2, and the incidence of intubation did not differ significantly between groups. However, the evidence was limited by the low to moderate quality of these studies as assessed by the GRADE system.

Patients undergoing bronchoscopy are more vulnerable to desaturation resulting from hypoventilation [2-4]. To overcome the patients’ peak inspiratory demand flow and relieve their respiratory distress during bronchoscopy, a high-flow system can provide additional support [26, 27]. First, the heated humidification of inhaled gas may enhance bronchial hygiene and reduce bronchoconstriction [8]. Second, washout of the upper airway may reduce dead space [9]. Third, positive airway pressure may restore atelectatic lung regions [10]. Fourth, decreased entrainment of ambient air may increase oxygen supply [27]. Thus, HFNC may be a safe alternative to conventional oxygen therapy in patients undergoing bronchoscopy.

A reduced incidence of hazardous hypoxemic events (SpO2 < 90%) has been observed in both therapeutic and diagnostic bronchoscopy [13-16]. In our systematic review, Douglas et al. and Irfan et al. evaluated the efficacy of HFNC in patients undergoing endobronchial ultrasound procedure [14, 15], and Longhini et al. and Lucangelo et al. investigated the efficacy of HFNC in patients undergoing bronchoscopy for bronchoalveolar lavage (BAL) [16, 17]. The procedure duration varied among the trials and ranged from 11 min 30 s to 34 min. Regardless of the procedure performed, the lowest SpO2 during bronchoscopy and the PaO2 at the end of the procedure were higher in the HFNC group than in the conventional oxygen therapy group. Notably, with the exception of the trials by Douglas et al. and Lucangelo et al. [14, 17], all included trials showed that the lowest SpO2 values were less than 90% in the control groups. Thus, the pooled results indicated that HFNC may improve patient safety and provide clinical benefits to patients undergoing bronchoscopy.

Both low and high pulmonary risk patients undergoing bronchoscopy may benefit from HFNC according to our inclusion criteria, because desaturation may occur at any level of forced expiratory volume 1 (FEV1), even without sedation [28]. Among our included trials, Ben-Menachem et al. investigated the same issues in patients after lung transplantation [13], who were at significantly higher risk of hypoxemia or adverse events during bronchoscopy due to a higher incidence of hypoxemic events (SpO2 < 90%) than the other four trials (Fig 2), indicating the value of HFNC during invasive bronchoscopy in more vulnerable patients. Hence, a comprehensive algorithm for choosing HFNC or conventional oxygen therapy in patients undergoing bronchoscopy should be established, especially in patients with underlying severe lung disease. In the past, several studies have suggested that patients with (1) SpO2 on room air pre-procedure < 90% [28]; (2) moderate sedation [29]; (3) obstructive sleep apnea (OSA) [30]; or (4) requiring long-term oxygen therapy, such as for congestive heart failure (CHF) [31], chronic obstructive pulmonary disease (COPD) [32], or interstitial lung disease (ILD) [33], may benefit from HFNC treatment. However, this need to be validated by more evidence.

Although there is substantial effort to detect the hypoxemic events in patients undergoing bronchoscopy, PaCO2 or EtCO2 are also important for clinicians to assess the lung condition. One previous study indicated the effectiveness of HFNC for CO2 removal [27]; however, our systematic review showed that HFNC was not as effective as expected. All the trials presented lower PaCO2 or EtCO2 in the control group than in the HFNC group, except for the trial by Douglas et al. [14]. There are several reasons for this discrepancy. First, the number of trials was small. Second, these trials enrolled patients without severe pulmonary illnesses. A conclusive result cannot be obtained because the severity of pulmonary disease may influence the extent of CO2 clearance. Hence, more evidence is required to evaluate the effectiveness of HFNC for CO2 removal.

Several clinical factors across the trials induced heterogeneity in our meta-analysis. First, the approaches to intervention varied in terms of flow intensity and FiO2. Second, different devices were used for the control groups, making exact FiO2 measurement difficult, because it was influenced by the peak respiratory flow and the design of each low-flow system. Third, the study population in the trial by Ben-Menachem et al. differed from that of the other trials [13]. Fourth, the use of sedative or anesthetic agents varied among the trials. To take such diversity into account, we utilized sensitivity analysis, with results shown in the S4 Appendix.

Our study has several limitations. First, the trials had small sample sizes for each group. Hence, the certainty of imprecision was downgraded accordingly. Second, the number of RCTs in patients with HFNC undergoing bronchoscopy was insufficient for conducting comprehensive analyses. Third, there is still debate over the routine use of oxygen supplementation during bronchoscopy [28]. Not all centers gave oxygen to patients, unless desaturation occurs. Fourth, we did not obtain PaCO2 and EtCO2 values during bronchoscopy, which prevented us from performing a more precise analysis. Fifth, according to the inclusion criteria, no suspected cancer patients or patients at high specified pulmonary risk were included in our systematic review, limiting the external validity of the results.

Conclusion

Our meta-analysis revealed that HFNC may provide consistent oxygenation (SpO2 ≥ 90%) and safer invasive procedures in patients undergoing bronchoscopy when compared with conventional oxygen therapy.

Search strategy.

(DOCX)

Click here for additional data file.

PRISMA checklist.

(DOCX)

Click here for additional data file.

Trial sequential analysis.

(TIF)

Click here for additional data file.

Sensitivity analysis.

(DOCX)

Click here for additional data file.

11 Aug 2021

PONE-D-21-21235

High-flow nasal cannula for reducing hypoxic events in patients receiving bronchoscopy: A systematic review and meta-analysis of randomized trials

PLOS ONE

Dear Dr. Hu,

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

Please submit your revised manuscript by Sep 25 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

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

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

We look forward to receiving your revised manuscript.

Kind regards,

Alessandro Putzu, M.D.

Academic Editor

PLOS ONE

Journal requirements:

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

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

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

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

2. PLOS requires an ORCID iD for the corresponding author in Editorial Manager on papers submitted after December 6th, 2016. Please ensure that you have an ORCID iD and that it is validated in Editorial Manager. To do this, go to ‘Update my Information’ (in the upper left-hand corner of the main menu), and click on the Fetch/Validate link next to the ORCID field. This will take you to the ORCID site and allow you to create a new iD or authenticate a pre-existing iD in Editorial Manager. Please see the following video for instructions on linking an ORCID iD to your Editorial Manager account: https://www.youtube.com/watch?v=_xcclfuvtxQ

Additional Editor Comments :

A number of issues have been identified in the review process. While we feel that this manuscript shows promise, we also think that a major revision is needed. Before we can make a final decision about this manuscript we want to offer you the opportunity to revise and resubmit the manuscript.

1- Methods. Please include the new PRISMA 2020 checklist in the supplementary material.

2- Methods. The 4 search strategies should be reported in the supplementary material.

3- Methods. How did you manage missing outcome data? Did you contact corresponding authors?

4- Methods. You should consider to perform a trial sequential analysis for the primary outcome to assess risk of type 1 and 2 errors.

5- Results. The list of 27 major exclusions should be reported in the supplement (reference + reason for exclusion).

6- Results. Instead of Figure 1, please use a PRISMA 2020 flow-chart.

7- Results. Systematic searches found only 157 records. This is correct?

8- Results. You reported that all trials had low risk in the reporting bias item. Do you confirm that all trials had a registered protocol?

9- Results. You reported that all trials had low risk in performance bias. Do you confirm that all studies had ITT analysis?

10- Results. Methodology on GRADE should be moved to the Methods.

11- Results. The GRADE assessment for the primary outcome and lowest SpO2 had no serious concern on imprecision. However, only 4 RCTs reported the outcome.

12- Results. The studies were performed under local anesthesia? Sedation?

13- Discussion. The section should be tempered; GRADE results should be considered.

14- Discussion. The inclusion/exclusion criteria of the RCTs limit the external validity of the results. Please discuss.

15- Abstract. Conclusions of the abstract should be tempered since the certainty of evidence is moderate/low.

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

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

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

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Partly

Reviewer #4: Yes

Reviewer #5: Partly

**********

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

Reviewer #5: N/A

**********

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

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

Reviewer #5: Yes

**********

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

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

Reviewer #1: No

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

Reviewer #5: Yes

**********

5. Review Comments to the Author

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

Reviewer #1: I have reviewed the manuscript that is interesting. However, there are some limitation or concerns requiring discussion.

Comments:

1. English requires an extensive revision by a mother language author or service.

2. Intro: “Sedation and the occlusion of the bronchi during the procedure reduce the respiratory drive and alter the lung condition.” The reviewer agree that sedation may alter the respiratory drive or timing (refer to PMID: 23982026 and 28673877); however, it remains unclear what authors mean for “lung condition”. Please specify.

3. Intro: this section requires more quotation to support all statements.

4. Aim of the study: “we compared the efficacy and safety of HFNC with conventional oxygen”. Please specify what is efficacy and safety, even in the material and methods section

5. I would suggest to add a “take-home message” regarding possible indication on the use of HFNC over COT during bronchoscopy.

Reviewer #2: The study is useful for end-users and the process is well-conducted. The PICO selection should appear in the method section.

Introduction: well balanced

Method: appropriate

Results: standard

Discussion: moderately interesting

Conclusion: based on results

Illustrations: standard

Reviewer #3: This is a registered systematic review & meta-analysis of five RCTs that aimed to evaluate whether high flow therapy (HFT) is more effective at preventing hypoxic events during bronchoscopy. It is a well written manuscript that addresses an important clinical area, however a number of issues must be addressed prior to publication.

Major:

- A definition of hypoxic events must be provided in the methods and referred to throughout the results and discussion, with a clear justification for the chosen definition. Without this, an ambiguous reference to hypoxic events does not have clinical relevance and cannot contribute meaningfully to the evidence base.

- Descriptions of physiological effects of HFNC are clear and useful, however no references have been provided for each effect. Please refer to the relevant clinical and bench studies for each point made (consider reviewing PMID: 33664838 for guidance).

- Ambiguous references to potential adverse events during/following bronchoscopy (in the introduction and discussion) should be replaced with specific outcomes and references.

Minor:

Grammatical and style suggestions have been provided below, which would aid clarity.

ABSTRACT

- Line 26 Suggest “undergoing” rather than “receiving” bronchoscopy

- Use comma not semi-colon when listing results

INTRODUCTION

- First two sentences too ambiguous, need to provide more detail on potential complications of bronchoscopy (remove “respiratory disturbance” and “alter the lung condition”).

- There is not “usually” a high risk of hypoxic events requiring intervention – this is rare during elective procedures.

- What evidence is there that hypoxaemia and respiratory distress are debilitating? Please provide references.

- Line 69 – cardiothoracic surgeons may also perform bronchoscopy, remove “physicians”

- “Although oxygen therapy…” is a nebulous statement, remove or make more specific with dates and a reference.

- Conventional oxygen does not have limited effectiveness (line 73), the point here is that HFNC may be more effective.

- HFNC has many, many more applications than treating hypoxaemic respiratory failure (lines 77-78). Either remove statement or provide specific applications (summarised in aforementioned review PMID: 33664838)

- Do not reference one article for its physiological effects, individual trials need to be referenced for each point.

- Line 82 – not strictly true, the Service paper referenced, which is a feasibility study, did report conclusive results.

- Rephrase line 85 “Thus, through a SR…” to “The aim of this systematic review was to…” and list aims.

METHODS

- Inclusion criterion 3 is unclear – what is meant by “clearly” reporting eligibility criteria? Or medical treatments regimens or severity among the population? Needs to be more specific.

- Hypoxic events must be given a clear definition, particularly since this is the primary aim of the systematic review.

- Outcomes – use commas, not semicolons

RESULTS

- What are the irrelevant trials? This needs to be more specific.

- Line 169 “recruited patients of middle-to-old age” is not appropriate. Either provide the mean ± SD / median (IQR) age or omit.

- Line 169 – what is the relevance of including how studies reported baseline oxygenation? In the results, you describe that 4 studies use SpO2.

- Reference 12 is a very specific population at significantly higher risk of hypoxaemia/adverse events – this needs to be commented on.

- The allocation bias to malignancy is surely acceptable given this procedure is commonly performed to investigate suspected cancer?

- Risk of bias needs to be reported as low, high or unclear, not “Some concerns” (see Cochrane guidance), or the “some” needs to be elaborated on.

- Line 190 – hypoxic events has not been defined. This must be described in the methods for these analyses to have any relevance.

- Line 213 and 223 - “mainly” is inappropriate, an exact description of what was analysed should be reported.

- Incidence of intubation needs to be reported even if not statistically significant.

DISCUSSION

- Line 259 – “lower” not “low” incidence.

- It is crucial that a definition of hypoxaemic event be defined. Without this, the discussion and indeed the study cannot provide a meaningful contribution.

- Line 267 – “respiratory deficits” is unusual wording, consider rephrasing and being more specific.

- Line 270 – what evidence is there that HFNC improves “bronchial hygiene” and what does this mean? Whole paragraph requires references for each physiological effect.

- Line 276 – “hazardous hypoxic events” – definition needed.

- Line 294 – this is not correct. Based on your analyses, it cannot be concluded that HFNC reduces CO2 clearance.

- Paragraph starting line 300 – additional limitation by population of lung transplant data which likely heavily influence results given baseline morbidity.

- Limitations – elaboration needed on the small sample size and how this affects interpretation of results and clinical application. Define “acceptable oxygenation” and why this is an important point in the context of this review.

CONCLUSION

- This conclusion cannot be drawn based on the presented data.

- Needs to be much more comprehensive, cover the primary and secondary objectives, summarise limitations and provide suggestions to improve the quality of current evidence base.

Acknowledgement – what editing was done?

Reviewer #4: Dear authors,

This is an interesting article and addresses an important issue (hypoxemia during bronchoscopy). I have following comments for the manuscript.

1. The statement “Clearly reported patient inclusion and exclusion criteria, medical treatment regimens, severity among the population, and the definition and evaluation of hypoxic events during or after bronchoscopy were included in the analysis.” is not clear. Please rephrase it to clarify.

2. In CONSORT diagram – Records screen 136 and irrelevant trial 105, the number should be 31, instead of 32.

3. Please maintain uniformity in the figures – favour HFNC and favour COT should be consistently on same side. In figure 2 favour HNFC in right side whereas in figure 3 it is on other side.

4. English needs editing

5. Authors should also highlight that there is still debate over routine use of oxygen supplementation during bronchoscopy. Even at some centres, oxygen is only given to patients who have oxygen saturation of less than 96%.

6. Authors, did not comment whether is any risk group which would get more benefits with HFNC.

Reviewer #5: Comments to Author:

I think this study is highly novel regarding whether conventional oxygen therapy (COT) or high flow nasal canula (HFNC) is more effective in preventing hypoxemia for patients with during receiving bronchoscopy. However, there are several comments for this study. I am sorry, but I haven't read any further than the results, as I think there are serious problems with the methodology.

Major points

1. What is your research question? Is the presence or absence of sedation during bronchoscopy part of your question? I think the research question needs to be reconsidered because the presence of sedation is considered very important in the development of hypoxemia. In addition, the presence or absence of sedation can be a source of very large conceptual heterogeneity. Therefore, as I will point out below, I think it is highly likely that the search formula, inclusion and exclusion criteria will need to be reconsidered.

2. Line 62-: How often is sedation used during bronchoscopy? If you want to discuss about hypoxemia during bronchoscopy associated with sedation, I think the frequency of sedation needs to be described.

3. Line 67-: What exactly does “debilitating” mean? Have adverse events associated with hypoxemia been discussed in previous studies? If you want to express the need for oxygen administration, I think it would be more persuasive if you describe a specific description of the serious adverse events associated with hypoxemia.

4. Line 77-: In this paragraph, I think it is necessary to subscribe, for example, that recommendations may change because multiple randomized controlled trials (RCTs) have been reported but no systematic review (SR) or meta-analysis (MA) have not been integrated done. It seems to me that you are now describing why we must do RCTs.

5. Line 95-: If your research question includes the presence or absence of sedation during bronchoscopy, then I think you need to add the presence or absence of sedation to your inclusion or exclusion criteria.

6. Line 101-: Have you done any searches about ongoing studies? In the methods section, the authors stated that ClinicalTrials.gov registry was searched for ongoing trials. However, there was no results of the search in result section. Please explain this point.

7. Line 103-: Is it correct to assume that the following search formula was used: “HFNC” OR “high flow nasal cannula” OR “high flow nasal CPAP” OR “high flow nasal oxygen” AND “bronchoscopy” OR “bronchoscope”. Is this search term sufficient for the search formula? First, it is true that there is no MESH term of HFNC, but bronchoscopy of MESH term. When you search with your search formula, you cannot find all the synonyms, plurals, etc. contained in the MESH term. Second, If the search is to be done as you intend, then I think the following use of () is correct: (“HFNC” OR “high flow nasal cannula” OR “high flow nasal CPAP” OR “high flow nasal oxygen”) AND (“bronchoscopy” OR “bronchoscope”). Third, if you are targeting an RCT, you should use the study design filters which Cochrane recommended. I think that your current search formula is inadequate and does not allow you to perform the correct search. If you can't do the correct search, SA and MA will be completely useless.

8. Line 111-: I think it is necessary to extract and consider the procedure time for bronchoscopy. There is a significant correlation between the procedure time for bronchoscopy and the presence of hypoxemia. If it is not mentioned in each study, then I think it should be mentioned as such in your study.

9. Line 125-: What exactly is the definition of “the incidence of hypoxic events during bronchoscopy” in your study? Is it correct that you consider the outcome of each of the RCTs included in this MA as "the incidence of hypoxic events during bronchoscopy"? I think PaCO2 at the

end of bronchoscopy and EtCO2 at the end of bronchoscopy are different from “the incidence of hypoxic events during bronchoscopy”. After establishing specific clinically meaningful outcomes for hypoxemia, you should decide whether you can integrate the results of each study.

**********

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

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

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

Reviewer #1: No

Reviewer #2: Yes: Marc Leone

Reviewer #3: No

Reviewer #4: No

Reviewer #5: No

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

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

9 Sep 2021

Dear Editors and reviewers :

We wish to submit the revised version of our manuscript “High-flow nasal cannula for reducing hypoxemic events in patients undergoing bronchoscopy: A systematic review and meta-analysis of randomized trials” (PONE-D-21-21235) for publication in PLoS One. The paper was coauthored by Chien-Ling Su, Ling-Ling Chiang, and Ka-Wai Tam.

We sincerely appreciate your review of our manuscript, and we hope that our edits and the responses we provide below satisfactorily address all the issues and concerns you and the reviewers have noted, and that the revised manuscript will now be suitable for publication in your journal.

As stated in the original submission, this manuscript has not been published or presented elsewhere in part or in entirety and is not under consideration by another journal. We have read and understood your journal’s policies, and we believe that neither the manuscript nor the study violates any of these. There are no conflicts of interest to declare.

Thank you for your consideration. We look forward to hearing from you.

Sincerely,

Tzu-Tao Chen and Ming-Chi Hu

Department of Pulmonary Medicine, Shuang Ho Hospital, Taipei Medical University

291, Zhongzheng Road, Zhonghe District, New Taipei City, 23561, Taiwan

Tel: 886-2-22490088 ext. 1251

E-mail: 09330@s.tmu.edu.tw (Tzu-Tao Chen)

E-mail: 20549@s.tmu.edu.tw (Ming-Chi Hu)

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

26 Oct 2021

PONE-D-21-21235R1High-flow nasal cannula for reducing hypoxemic events in patients undergoing bronchoscopy: A systematic review and meta-analysis of randomized trialsPLOS ONE

Dear Dr. Hu,

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

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

Please submit your revised manuscript by Dec 10 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

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

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

We look forward to receiving your revised manuscript.

Kind regards,

Andrea Cortegiani, M.D.

Academic Editor

PLOS ONE

Journal Requirements:

Additional Editor Comments (if provided):

Your modifications improved the manuscript. However, please address the comments from the comments from the reviewers which I agree.

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

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

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

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

Reviewer #3: All comments have been addressed

Reviewer #5: All comments have been addressed

**********

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: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #5: Partly

**********

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #5: Yes

**********

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

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #5: No

**********

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: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #5: Yes

**********

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: I have appreciated the effort of authors to improve the manuscript. I have further comments to be addressed

Reviewer #2: The authors responded to my comments and the study can help the readers. The manuscript is sound and seems ready for publication.

Reviewer #3: Many thanks considering the recommended revisions, which have all been included to provide further clarity and scientific rigor. This is an interesting and useful manuscript.

Reviewer #5: Comments to Author:

Thank you for your sincere response to my comment. I think your revision has made the manuscript of higher quality. However, there are still a few things that need to be revised.

Major points

1. Line 90-: After reading your response, I understand your opinion about not changing the search formula regarding sedation. However, I think it is necessary to include the presence or absence of general anesthesia, including midazolam and propofol, etc. , in the inclusion or exclusion criteria. In other words, the integration of all results should be limited to either local or general anesthesia, or integrated in each. As I pointed out in a previous review, the methods of sedation can be a source of very large conceptual heterogeneity.

2. the section of Results: I think it would be easier to understand if the results of each studies were summarized in a table, which could be added to table 1.

3. the section of Results: In the study of Ben-Menachem [13], the procedure time for bronchoscopy is about 30 minutes, which is about twice as long as the procedure time of other studies. Therefore I considered the possibility that there might be the effect of the study of Ben-Menachem [13] to the results, but since you have done a sensitivity analysis, I am satisfied regarding the results of your analysis of outcomes.

4. Line 194-: You responded, "we considered that PaCO2 and EtCO2 were important for respiratory system assessment". As you said, I also think that EtCO2 and PaCO2 are important for respiratory system assessment. However, I don't think high EtCO2 and SpO2<90% are synonymous. In fact, in the table 1 of the study of Lucangelo [17], the PaO2 for all groups was not less than 60 mmHg and therefore you cannot determine the SpO2 was less than 90%. Therefore, I think the study of Lucangelo [17] should be excluded from the analysis of the primary outcome.

**********

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

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

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

Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

Reviewer #5: No

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

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

12 Nov 2021

Dear Reviewers:

We sincerely appreciate your further review of our manuscript (Ref: PONE-D-21-21235), entitled "High-flow nasal cannula for reducing hypoxemic events in patients undergoing bronchoscopy: A systematic review and meta-analysis of randomized trials."

We have carefully addressed all the reviewers’ comments in our revised manuscript. The main corrections and point-by-point responses to the reviewer comments are provided below, with all corresponding changes marked in red font in the manuscript.

We hope that our responses and revisions have adequately addressed the reviewers’ concerns, and that the revised manuscript will now meet the high standards required for publication in your esteemed journal. We look forward to hearing from you.

Sincerely yours,

Tzu-Tao Chen and Ming-Chi Hu

Department of Pulmonary Medicine, Shuang Ho Hospital, Taipei Medical University

291, Zhongzheng Road, Zhonghe District, New Taipei City, 23561, Taiwan

Tel: 886-2-22490088 ext. 1251

E-mail: 09330@s.tmu.edu.tw (Tzu-Tao Chen)

E-mail: 20549@s.tmu.edu.tw (Ming-Chi Hu)

16 Nov 2021

High-flow nasal cannula for reducing hypoxemic events in patients undergoing bronchoscopy: A systematic review and meta-analysis of randomized trials

PONE-D-21-21235R2

Dear Dr. Hu,

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

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

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

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

Kind regards,

Andrea Cortegiani, M.D.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

18 Nov 2021

PONE-D-21-21235R2

High-flow nasal cannula for reducing hypoxemic events in patients undergoing bronchoscopy: A systematic review and meta-analysis of randomized trials

Dear Dr. Hu:

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

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

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

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

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Andrea Cortegiani

Academic Editor

PLOS ONE