Noninvasive Ventilation for Preoxygenation during Emergency Intubation.
Gibbs KW, Semler MW, Driver BE, Seitz KP, Stempek SB, Taylor C, Resnick-Ault D, White HD, Gandotra S, Doerschug KC, Mohamed A, Prekker ME, Khan A, Gaillard JP, Andrea L, Aggarwal NR, Brainard JC, Barnett LH, Halliday SJ, Blinder V, Dagan A, Whitson MR, Schauer SG, Walker JE Jr, Barker AB, Palakshappa JA, Muhs A, Wozniak JM, Kramer PJ, Withers C, Ghamande SA, Russell DW, Schwartz A, Moskowitz A, Hansen SJ, Allada G, Goranson JK, Fein DG, Sottile PD, Kelly N, Alwood SM, Long MT, Malhotra R, Shapiro NI, Page DB, Long BJ, Thomas CB, Trent SA, Janz DR, Rice TW, Self WH, Bebarta VS, Lloyd BD, Rhoads J, Womack K, Imhoff B, Ginde AA, Casey JD, PREOXI Investigators and the Pragmatic Critical Care Research Group
- DOI
- 10.1056/NEJMoa2313680
- Record issued
- 2026-08-16
- Engine
- 7.39.0
- Exported
- 2026-09-21
Prepared by Alpha1. This document is confidential: it is intended for the recipient it was shared with and must not be redistributed. The live record at alpha1science.com/verify/c8d34d9e-0a9e-4427-9972-90ad2dbc43f4 is authoritative.
How this rating was calculated
- ClaimsEfficacy rests on an unvalidated surrogate endpoint−0.5★
- ReportingData & code availability partially met−0.25★
- 01Efficacy rests on an unvalidated surrogate endpoint
The primary outcome is hypoxemia during intubation, defined by oxygen saturation <85%, which is a surrogate for clinical outcomes such as cardiac arrest and death. The paper does not provide evidence of target engagement at the tested dose (e.g., PK/PD) nor does it cite validated evidence linking this surrogate to the clinical outcome, although it mentions an association with cardiac arrest and death.
“The primary outcome was hypoxemia during intubation, defined by an oxygen saturation of less than 85% during the interval between induction of anesthesia and 2 minutes after tracheal intubation.”
This Kaimen Rigor review uses Kaimen Rigor reviewers trained on a curated corpus of high-fidelity and retracted papers, with expert supervision and curation. It can still make mistakes; verify each finding against the source before relying on it.
This is a well-conducted and well-reported multicenter randomized trial with a clear scientific premise, rigorous design, and appropriate statistical analysis. The main weakness is the lack of a detailed data availability statement, and minor copyedit issues with hyphenation and software version formatting.
Both reviewers independently scored all eight dimensions and agreed on every status, so no divergence needed reconciliation. The study type is interventional (randomized trial). Non-applicable sub-criteria (e.g., species/strain, housing, antibodies, cell lines) were excluded from scoring. The statistics verification recomputed only 1 test (the primary chi-square) and found it consistent; other reported statistics were not machine-verified and should not be assumed correct.
Numerical inconsistencies
None foundValues that contradict each other or are impossible for the stated sample: recomputed p-values and test statistics, GRIM/GRIMMER checks on summary numbers, percentages against their own counts, totals against their parts, and estimates against their own confidence intervals.
Checked — nothing surfaced.
Recomputed 1 test: 1 consistent, 0 inconsistent; 1 via agent-written checks.
- CONSISTENTreported p < .001 · recomputed p = <.001Reviewers 1, 2Primary outcome chi-square test p-value
“Hypoxemia during the interval between induction of anesthesia and 2 minutes after intubation (the primary outcome) occurred in 57 of 624 patients (9.1%) in the noninvasive-ventilation group and in 118 of 637 patients (18.5%) in the oxygen-mask group (absolute risk difference, −9.4 percentage points; 95% CI, −13.2 to −5.6; P<0.001)”
Taken as given: The numbers 57 and 624 are the event count and group total for the noninvasive-ventilation group.; The numbers 118 and 637 are the event count and group total for the oxygen-mask group.; The test is a two-sided Pearson chi-square test with 1 degree of freedom.Method: Pearson chi-square test on the 2x2 table of events and non-events.How we recomputed it: pChi2x2(57, 624-57, 118, 637-118)
Overstated conclusions
2 findings · worst highConclusions that reach past what the paper's own results support — including a significance claim that no longer holds when the statistic is recomputed, and efficacy resting on an unvalidated surrogate endpoint.
- Efficacy rests on an unvalidated surrogate endpointAssessed
- Conclusions only partially backed by the presented evidenceAssessed
3 major claims checked against the paper's own evidence: 1 only partially supported (evidence backs part of the claim; gaps or caveats remain); the rest adequately supported.
- partialReviewers 1, 2The effect of noninvasive ventilation on the incidence of hypoxemia appeared to be greater among patients with a higher body-mass index.The subgroup analysis suggests a possible interaction, but the paper notes it is exploratory and not definitive.Evidence: Subgroup analysis in Figure 2 shows a greater effect in higher BMI categories, but no formal interaction test result is reported in the text.
The effect of noninvasive ventilation on the incidence of hypoxemia appeared to be greater among patients with a higher body-mass index.
Resultsreviewer’s wording - supportedReviewers 1, 2Preoxygenation with noninvasive ventilation resulted in a lower incidence of hypoxemia during intubation than preoxygenation with an oxygen mask.The primary outcome result directly supports this claim with a statistically significant difference.Evidence: Primary outcome: 57/624 (9.1%) vs 118/637 (18.5%), difference -9.4 percentage points, 95% CI -13.2 to -5.6, P<0.001.
“Among critically ill adults undergoing tracheal intubation, preoxygenation with noninvasive ventilation resulted in a lower incidence of hypoxemia during intubation than preoxygenation with an oxygen mask.”
ConclusionFind in source - supportedReviewers 1, 2Preoxygenation with noninvasive ventilation did not appear to increase the incidence of aspiration.The safety outcome for aspiration shows no significant difference, supporting the claim.Evidence: Aspiration occurred in 6/645 (0.9%) vs 9/656 (1.4%), difference -0.4 percentage points, 95% CI -1.6 to 0.7.
“Preoxygenation with noninvasive ventilation did not appear to increase the incidence of aspiration.”
Discussion ¶2Find in source
Premise concern: surrogate not validated for clinical benefit.
- INADEQUATESurrogate endpointThe primary outcome is hypoxemia during intubation, defined by oxygen saturation <85%, which is a surrogate for clinical outcomes such as cardiac arrest and death. The paper does not provide evidence of target engagement at the tested dose (e.g., PK/PD) nor does it cite validated evidence linking this surrogate to the clinical outcome, although it mentions an association with cardiac arrest and death.
“The primary outcome was hypoxemia during intubation, defined by an oxygen saturation of less than 85% during the interval between induction of anesthesia and 2 minutes after tracheal intubation.”
- ADEQUATEEffect sizeThe effect size is a reduction in hypoxemia from 18.5% to 9.1%, an absolute risk difference of -9.4 percentage points (95% CI -13.2 to -5.6, P<0.001). This is a clinically meaningful reduction, halving the incidence of a serious complication, and is statistically robust.
“hypoxemia occurred in 57 of 624 patients (9.1%) in the noninvasive-ventilation group and in 118 of 637 patients (18.5%) in the oxygen-mask group (difference, −9.4 percentage points; 95% confidence interval [CI], −13.2 to −5.6; P<0.001).”
Data authenticity concerns
None foundAn adversarial read for patterns associated with data that may not be genuine: results that look too clean, implausibly large effects, duplicated data or images, and methods that do not match the results reported.
Checked — nothing surfaced.
Reporting gaps
1 finding · worst mediumRequired detail the manuscript never states — study design, biological variables, ethics approval and consent, key resources, statistical reporting, data and code availability, and overall transparency.
- Data/code availability incompleteAssessed
The introduction cites prior trials and guidelines, explains the physiological rationale for noninvasive ventilation, and notes the limitations of previous small trials. The hypothesis follows logically from the cited evidence.
“Two small, randomized trials have compared noninvasive ventilation with oxygen masks for preoxygenation in critically ill adults. One trial suggested that the risk of hypoxemia was lower with noninvasive ventilation than with an oxygen mask for preoxygenation, although the other trial did not show a significant difference.”
“We conducted the Pragmatic Trial Examining Oxygenation Prior to Intubation (PREOXI) trial to determine the effect of preoxygenation with noninvasive ventilation, as compared with pre-oxygenation with an oxygen mask, on the incidence of hypoxemia during tracheal intubation among critically ill adults. We hypothesized that the incidence would be lower with noninvasive ventilation.”
“These trials focused on a narrow population of patients with acute hypoxemic respiratory failure undergoing tracheal intubation in an ICU, included fewer than 300 patients (combined), and showed in-conclusive results.”
“Two small, randomized trials have compared noninvasive ventilation with oxygen masks for preoxygenation in critically ill adults. One trial suggested that the risk of hypoxemia was lower with noninvasive ventilation than with an oxygen mask for preoxygenation, although the other trial did not show a significant difference.”
“We hypothesized that the incidence would be lower with noninvasive ventilation.”
Randomization used permuted blocks with concealed allocation. The trial was unblinded, which is acknowledged and justified by the nature of the intervention. A priori sample size calculation is provided. Inclusion/exclusion criteria are described. Missing data handling is described for the primary analysis.
“Randomization was performed with the use of permuted blocks of variable size and was stratified according to trial site. Trial-group assignments were placed in sequentially numbered, opaque envelopes and remained concealed until after enrollment.”
“Given the nature of the intervention, clinicians and research personnel were aware of trial-group assignments after randomization.”
“Assuming an incidence of hypoxemia of 17% in the oxygen-mask group, 85% statistical power, and a two-sided alpha level of 0.05, we calculated that a sample of 1264 patients would be needed to detect an absolute between-group difference of 6 percentage points in the incidence of hypoxemia.”
“Randomization was performed with the use of permuted blocks of variable size and was stratified according to trial site. Trial-group assignments were placed in sequentially numbered, opaque envelopes and remained concealed until after enrollment.”
“Assuming an incidence of hypoxemia of 17% in the oxygen-mask group, 85% statistical power, and a two-sided alpha level of 0.05, we calculated that a sample of 1264 patients would be needed to detect an absolute between-group difference of 6 percentage points in the incidence of hypoxemia.”
“Given the nature of the intervention, clinicians and research personnel were aware of trial-group assignments after randomization.”
The paper reports sex, age, race/ethnicity, and multiple clinical characteristics in Table 1. Since both sexes are enrolled, sex_justified is not applicable. Species/strain and housing conditions are not applicable for a human trial.
“Female sex — no. (%) | 255 (39.5) | 260 (39.6)”
“Median APACHE II score (IQR) | 17 (12–23) | 17 (12–23)”
“Female sex — no. (%) | 255 (39.5) | 260 (39.6)”
The trial was approved by a named IRB (Vanderbilt University Medical Center) with secondary concurrence. Informed consent was waived with justification, and a patient information sheet was provided. Regulatory compliance is stated.
“The trial was initiated by the investigators and approved by the institutional review board at Vanderbilt University Medical Center, with secondary concurrence by the Office of Human Research Oversight of the Defense Health Agency.”
“The requirement for written informed consent was waived; patients were provided a patient information sheet about the trial after enrollment”
“The informed consent of the patients who participated in this trial was addressed as required by 32 CFR 219 and DODI 3216.02_AFI 40-402”
“The trial was initiated by the investigators and approved by the institutional review board at Vanderbilt University Medical Center, with secondary concurrence by the Office of Human Research Oversight of the Defense Health Agency.”
“The requirement for written informed consent was waived; patients were provided a patient information sheet about the trial after enrollment”
The trial uses noninvasive ventilation and oxygen masks as interventions; these are described in detail in the Methods. Statistical software (R version 4.31) is identified. No antibodies, cell lines, or other bench reagents are applicable.
“For the patients in the noninvasive-ventilation group, the operators were instructed to administer noninvasive ventilation using a tight-fitting mask connected to either a conventional mechanical ventilator (a ventilator capable of providing invasive mechanical ventilation) or a dedicated noninvasive ventilator before the induction of anesthesia.”
“All the statistical analyses were performed with the use of R software, version 4.31 (R Foundation for Statistical Computing).”
“All the statistical analyses were performed with the use of R software, version 4.31 (R Foundation for Statistical Computing).”
The primary analysis uses chi-square test, and secondary analyses use mixed-effects models. Exact p-values are reported for the primary outcome. Effect sizes are reported with confidence intervals. Software is identified. Data presentation follows clinical trial norms.
“The primary analysis was an unadjusted, intention-to-treat comparison of the primary outcome between the trial groups that was performed with the use of the chi-square test.”
“Hypoxemia during the interval between induction of anesthesia and 2 minutes after intubation (the primary outcome) occurred in 57 of 624 patients (9.1%) in the noninvasive-ventilation group and in 118 of 637 patients (18.5%) in the oxygen-mask group (absolute risk difference, −9.4 percentage points; 95% CI, −13.2 to −5.6; P<0.001)”
“The primary analysis was an unadjusted, intention-to-treat comparison of the primary outcome between the trial groups that was performed with the use of the chi-square test.”
The paper mentions a data sharing statement is available with the full text, but the specific mechanism is not described in the provided text. No repository deposit or accession numbers are mentioned. Code sharing is not applicable.
“A data sharing statement provided by the authors is available with the full text of this article at NEJM.org”
“A data sharing statement provided by the authors is available with the full text of this article at NEJM.org”
The trial is registered at ClinicalTrials.gov (NCT05267652). Methods are detailed. Limitations are explicitly discussed. Conclusions are proportional to the evidence. Funding and COI are disclosed.
“Our trial also has several limitations. Because patients who were already receiving positive-pressure ventilation at the time of eligibility assessment were excluded, the results of our trial do not inform decisions regarding preoxygenation in this patient population.”
“Supported by the U.S. Department of Defense through the Defense Health Agency Restoral program”
“Our trial also has several limitations. Because patients who were already receiving positive-pressure ventilation at the time of eligibility assessment were excluded, the results of our trial do not inform decisions regarding preoxygenation in this patient population.”
Registered (1 ID: ClinicalTrials.gov). No reporting guideline cited.
Broken references and links
None foundReferences checked against Crossref, OpenAlex and Retraction Watch for retractions and resolvability, plus declared data and code links probed for whether they resolve to content matching the paper.
Checked — nothing surfaced.
Checked 30 references by DOI: 24 verified — 6 no DOI (shown, not verified).
- NO DOIMost frequent procedures performed in U.S. hospitals, 2011No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOINational Hospital Ambulatory Medical Care Survey: 2018 emergency department summary tablesNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIPrinciples of peri-intubation oxygenationNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIRapid sequence intubation in adults for emergency medicine and critical careNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIProtocol and statistical analysis plan for the Pragmatic Trial Examining Oxygenation Prior to Intubation of preoxygenation with noninvasive ventilation vs. oxygen mask in critically ill adultsNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIDifficult tracheal intubation in obstetricsNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
1 data/code link checked; 1 live.
- datahttps://clinicaltrials.gov/ct2/show/NCT05267652LIVEHTTP 200Resolves, but the content could not be matched to the paper.
Copyediting
4 minorWording, consistency and formatting errors that need correcting before submission.
No major wording or formatting errors. 4 minor suggestions below.
4 copyedit issues flagged: mostly consistency, typo.
- MINORconsistencyAbstract“noninvasive-ventilation group”→ Use consistent hyphenation throughout (e.g., 'noninvasive ventilation group' without hyphen).Hyphenation varies between 'noninvasive-ventilation' and 'noninvasive ventilation'.
- MINORconsistencyMethods, Trial Interventions“non-invasive-ventilation group”→ Standardize to 'noninvasive-ventilation group' or 'noninvasive ventilation group'.Inconsistent use of hyphen in 'non-invasive'.
- MINORtypoAbstract, Results“non-invasive-ventilation”→ noninvasive-ventilationInconsistent hyphenation of 'noninvasive'.
- MINORconsistencyMethods, Statistical Analysis“R software, version 4.31”→ R software, version 4.3.1Version number format inconsistent with standard R versioning.
The published work is robust and trustworthy; an informed reader should weigh the minor data-sharing gap and the unverified subset of statistics. No erratum is warranted for the rigor dimensions, but the authors should consider clarifying the data access mechanism and correcting the minor copyedit issues in any future revision or correction.
- 1.HIGHdata codeIn the Supplementary Material or main text, expand the data sharing statement to specify the exact mechanism for data access (e.g., through a data access committee, a named repository, or a platform like Vivli/YODA) and any conditions or timeframe.The current statement merely points to a statement at NEJM.org without describing how readers can actually obtain the data, which is a reporting gap that undermines reproducibility.
- 2.HIGHdata codeConsider depositing de-identified aggregate data or statistical analysis code in a public repository (e.g., Dryad, Zenodo, or ClinicalTrials.gov) and provide a link or DOI in the manuscript.Providing direct access to data or code would enhance reproducibility and is a common expectation for clinical trials.
- 3.MEDIUMreportingExplicitly state adherence to the CONSORT reporting guideline in the Methods or Supplementary Material, and indicate that the CONSORT checklist is available.Both reviewers noted that reporting guideline adherence is not explicitly mentioned, which is a minor transparency gap for a randomized trial.
- 4.MEDIUMreportingInclude a statement about the availability of the full trial protocol and statistical analysis plan, with a link or DOI if available.Providing access to the protocol and SAP strengthens transparency and allows readers to verify pre-specified analyses.
- 5.MEDIUMcopyeditStandardize the hyphenation of 'noninvasive ventilation' throughout the manuscript (e.g., use 'noninvasive-ventilation group' consistently or remove the hyphen consistently).The copyedit pass flagged inconsistent hyphenation (e.g., 'noninvasive-ventilation' vs 'non-invasive-ventilation') that could distract readers.
- 6.MEDIUMcopyeditCorrect the R software version number from '4.31' to '4.3.1' in the Methods, Statistical Analysis section.The copyedit pass noted that the version format is inconsistent with standard R versioning, which could confuse readers trying to reproduce the analysis.
- 7.LOWdata codeIf possible, provide a direct link to the data sharing statement in the main text rather than only in the supplementary material.Making the data sharing statement more prominent would improve reader awareness of data access procedures.
The star rating is the report’s one-glance summary. Every paper starts at 5★ and loses stars for the concrete problems the review finds — so a rating is never a vague average, it’s a running total you can read line by line under “How this rating was calculated.”
- Reporting — 8 dimensionseach dimension that fully fails−½★
- each dimension partially met−¼★
- Statistics · Integrity · Claimseach serious problem−1★
- each medium problem−½★
- Citationseach retracted or unverifiable reference−¼★
- Copyeditonly when the manuscript needs a full edit−½★
The rating never drops below 1★, and a demonstrable critical failure (an impossible statistic, a proven ethics violation) caps it at 1★ on its own — so the stars can never look healthy when the verdict is CRITICAL.
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Graded against NIH, MDAR, ARRIVE 2.0, CONSORT, EQUATOR, and RRID guidelines. A dimension that doesn’t apply to the study type is skipped, never penalized.
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