🧭 REBEL Rundown
🗝️ Key Points
- 📚Looked at 15 studies involving 3420 patients compares high-flow nasal cannula (HFNC), non-invasive positive pressure ventilation (NIPPV), and facemask oxygen.
- 🫁NIPPV likely reduces hypoxemia during intubation compared to both HFNC and facemask oxygen
- 🚫No significant differences were found in successful intubation on the first attempt or all-cause mortality across the strategies.
📝 Introduction
Peri-intubation hypoxemia continues to remain a significant barrier to safe and effective care of critically ill patients in the ED and ICU. The concept of preoxygenation has been implemented to mitigate peri-intubation hypoxemia by increasing patient oxygen reserves and extending safe apnea time. Traditionally this has been achieved with the use of conventional facemask oxygenation with bag-valve mask (BVM) (PreVent trial), non-rebreather mask (NRB), or simple facemask. These can also be further supplemented with nasal cannula (NC). Recently, with the advent of humidified high flow nasal cannula systems (HFNC), several studies have examined the efficacy of HFNC in the setting of hypoxia (FLORALI trial) and preoxygenation (FLORALI-2 trial). Both these studies also included non-invasive positive pressure ventilation (NIPPV) as a comparator. The recent PREOXI trial looked at NIPPV vs traditional non-ventilating mask apparatus with a clear benefit for NIPPV in preoxygenation. However, this trial did not address the relative efficacy of HFNC vs NIPPV as both intervention arms were allowed to have O2 supplementation with NC or HFNC.
🧾 Paper
Pitre T, et al. Preoxygenation strategies for intubation of patients who are critically ill: a systematic review and network meta-analysis of randomised trials. Lancet Respir Med. 2025;13(7):585-596. PMID: 40127663
🔙PREVIOUSLY COVERED ON REBEL EM:
- PreVent Trial: Bag-Mask Ventilation Prior to Intubation
- FLORALI-2: NIV vs HFNC as Pre-Oxygenation Prior to Intubation
- The PREOXI Trial: Pre-Oxygenation with NIV vs Facemask
- Racial Bias with Pulse Oximetry?
⚙️ What They Did
📈 Results
- 4153 unique reports and, after screening, 15 eligible trials were included in systematic review and network meta-analysis
- Included studies enrolled patients from nine countries, with seven of 15 included studies being conducted in France
💥 Critical Results
- No evidence of an increased risk of cardiac arrest or aspiration with NIPPV compared with alternative preoxygenation methods, however data for the association between preoxygenation strategy and the incidence of cardiac arrest or aspiration were limited
- Subgroup analysis based on all a priori variables did not show evidence of effect modification on any outcomes of interest
- Post-hoc analyses
- Age, sex, and separation of bag-valve mask from facemask for preoxygenation did not show any important differences for all-cause mortality or hypoxemia
- Post-hoc multivariate Bayesian meta-regression modelling incorporating covariates of age, sex, and BMI did not show evidence of treatment modification
💪🏽 Strengths
- Large aggregated sample size: This paper included 15 randomised controlled trials with 3420 patients aggregated between all the trials
- Strong external validity: The studies included patients from nine countries (seven studies conducted in France)
- Recent trials included: Includes the recent PREOXI trial, thus making this the most comprehensive review of the evidence in this topic to date
- All stages of the process: Pragmatic meta-analysis given trials included preoxygenation strategies across all stages of intubation, including before medication administration all the way through intubation
- Well defined parts of methodology: heterogeneity was mitigated given well defined parameters for what constituted hypoxemia and HFNC and excluded trials that did not included HFNC or NIPPV as means of preoxygenation
- Rigorous adherence to international guidelines: This analysis adhered to PRISMA guidelines and used updated GRADE guidance and carefully explored assumptions of transitivity to minimize bias
- Robust statistical analyses: thorough statistical methods with appropriate a priori subgroup delineation, regression analyses, and overall appropriate selection of a network meta-analysis framework
- Relevant clinical outcomes: outcomes were well chosen and clinically practical
⚠️ Limitations
- Trial heterogeneity: As is the concern with most systematic reviews and meta-analyses, there is clinical and methodological heterogeneity among the included trials including variability in patient populations and clinical settings
- Uneven distribution of sample size: some studies had small sample sizes which can introduce sparse-data bias
- Not all types of NIPPV included in studies: Helmet NIPPV was not delineated in any of these studies (all NIPPV was mask-based)
- Facemask definition not standardized: Grouped together bag-valve mask, simple facemask, and non-rebreather mask into one treatment node (although authors did do post-hoc subgroup analysis where BMV and NRB were separated out)
- Transitivity assumption: Assumption in network meta-analyses that all direct comparisons must be sufficiently similar in patient characteristics and study methods for indirect comparisons to be valid, which may introduce confounding and bias
- No control of apneic oxygenation strategies: Many of the included studies did not include protocols for nasal cannula apenic oxygenation, or allowed for physician discretion of its application
- Unaware racial bias: Did not collect data on race or ethnicity because the authors assumed these do not have a significant effect on pre-oxygenation when prior studies we’ve reviewed here show how race may affect pulse oximetry
🗣️ Discussion
- Both NIPPV and HFNC decreased incidence of hypoxemia during intubation when used for preoxygenation before intubation of adults who were critically ill when compared to traditional facemask oxygen
- The effect size for this was larger for NIPPV than for HFNC
- No differences in first pass success for intubation between preoxygenation strategies indicating preoxygenation may not play a role in mechanics of intubation
- NIPPV seems to reduce the incidence of serious adverse events (although the definition of serious adverse events varied across included studies)
- In congruence with findings from recent trials, there was no evidence of an increased risk of aspiration with NIPPV
- Interestingly, one study included in the analysis looked at NIPPV + HFNC (with apenic oxygenation) versus NIPPV alone (OPTINIV trial) which showed a trend towards superiority of this dual therapy method across the primary outcomes (although all CIs crossed midline due to the low sample size of the study)
- It is interesting that the authors did not factor in race and ethnicity as there is sufficient data to show pulse-oximetry varies with melanin concentrations and can lead to occult hypoxemia not being identified in patients with darker skin pigmentation and further study should be done here to elucidate if optimal preoxygenation strategies can be utilized more in certain subpopulations
- The confluence of data presented here further reinforces the notion that NIPPV and HFNC are effective and safe methods of preoxygenation and superior to traditional facemask strategies in critically ill hypoxemic patients, and has become standard in my practice coupled with apneic oxygenation
- Traditional facemask strategies are likely still appropriate in patients requiring intubation who are not critically ill and hypoxemic, such as in scenarios involving intubation strictly for airway protection
- This strategy should be disseminated in EM and CCM practice amongst providers and RTs and become standard of care
📘 Author's Conclusion
“Preoxygenation with NIPPV or HFNC rather than facemask oxygen might prevent hypoxaemia during tracheal intubation of adults who are critically ill. Compared with HFNC, NIPPV probably decreases the incidence of hypoxaemia during intubation.”
💬 Our Conclusion
This systematic review and network meta-analysis does a good job of summarizing all the relevant data on preoxygenation strategies and includes the most recent large RCT, the PREOXI trial. Overall, it points to a notion we all intuitively probably already hold which is that NIPPV holds an advantage over all other forms of preoxygenation with its superior ability to provide high levels of PEEP and thus engage in alveolar recruitment in such a way that is unique to it. The aggregated data presented in this article continues to reinforce the benefits of NIPPV for preoxygenation, as well as its safety profile. The article also further bolsters prior data showing HFNC as an effective preoxygenation device when compared to traditional facemask strategies. The effects of these interventions are likely augmented in patients with baseline hypoxemia prior to intubation. There seems to be minimal (if any) harm in implementing these strategies and while a mortality benefit is not necessarily elucidated, all-cause mortality may not be the most relevant or practical outcome with regards to preoxygenation techniques. It would be interesting to see a larger RCT looking at facemask versus BVM versus HFNC versus NIPPV implementing standardized apenic oxygenation with 15L of flow through a NC for all the preoxygenation arms (except for the HFNC arm for obvious reasons) and see if any differences in relevant outcomes still manifest.
🚨 Clinical Bottom Line
NIPPV and/or HFNC should be routinely utilized as preoxygenation strategies for critically ill and/or hypoxemic patients prior to intubation and can be done so with minimal concern for adverse events related to their use. The sum of data to this point clearly indicates that this should become standard of care.
📚 References
- Pitre T, et al.
Preoxygenation strategies for intubation of patients who are critically ill: a systematic review and network meta-analysis of randomised trials. Lancet Respir Med. 2025;13(7):585-596.
PMID: 40127663 - Gibbs KW et al.
Noninvasive Ventilation for Preoxygenation During Emergency Intubation. NEJM 2024. PMID: 38869091 - Frat JP et al.
Non-Invasive Ventilation Versus High-Flow Nasal Cannula Oxygen Therapy with Apnoeic Oxygenation for Preoxygenation Before Intubation of Patients with Acute Hypoxaemic Respiratory Failure: A Randomised, Multicentre, Open-Label Trial. Lancet Respir Med 2019.
PMID: 30898520 - Casey JD et al.
Bag-Mask Ventilation During Tracheal Intubation of Critically Ill Adults. NEJM 2019. PMID: 30779528 - Jaber S, et al.
Apnoeic oxygenation via high-flow nasal cannula oxygen combined with non-invasive ventilation preoxygenation for intubation in hypoxaemic patients in the intensive care unit: the single-centre, blinded, randomised controlled OPTINIV trial. Intensive Care Med. 2016;42(12):1877-1887.
PMID: 27730283 - Frat JP, et al.
High-flow oxygen through nasal cannula in acute hypoxemic respiratory failure. N Engl J Med. 2015;372(23):2185-2196.
PMID: 25981908
Post Peer Reviewed By: Mark Ramzy, DO (X: @MRamzyDO), and Marco Propersi, DO (X: @Marco_Propersi)
