Publication

• Title: Spontaneous-Breathing Trials with Pressure-Support Ventilation or a T-Piece
• Acronym: TiP-Ex
• Year: 2022
• Journal published in: The New England Journal of Medicine
• Citation: Thille AW, Gacouin A, Coudroy R, et al. Spontaneous-Breathing Trials with Pressure-Support Ventilation or a T-Piece. N Engl J Med. 2022;387:1843-54.

Context & Rationale

• Background

  • Spontaneous breathing trials (SBTs) are a core “readiness test” before extubation, but the tested conditions vary substantially between ICUs (T-piece, low-level pressure support, CPAP/PEEP, automatic tube compensation).
  • T-piece SBTs remove ventilator assistance but retain an endotracheal tube (ETT) load; pressure-support ventilation (PSV) SBTs add inspiratory assistance (often intended to offset ETT resistance) and can reduce work of breathing.
  • Prior physiological and clinical studies suggested PSV may increase “SBT success” and accelerate extubation, but concerns persisted that an easier test could permit premature extubation and increase reintubation.
  • Patients at high risk of extubation failure (older age and/or chronic cardiac/respiratory disease) often receive prophylactic post-extubation support (e.g., NIV and/or high-flow nasal oxygen), which may interact with the SBT strategy by mitigating post-extubation respiratory failure.
• Research Question/Hypothesis

  • In high-risk mechanically ventilated adults deemed ready for extubation assessment, does a PSV-based SBT strategy (vs a T-piece SBT strategy) increase ventilator-free days at day 28, without worsening clinically important harms such as reintubation?
• Why This Matters

  • SBT strategy is a high-frequency ICU decision with potential system-level consequences (time to extubation, ICU throughput, sedation exposure) and patient-level consequences (reintubation, aspiration, ventilator-associated complications).
  • High-risk patients represent a clinically consequential subgroup in whom clinicians often trade off an earlier extubation against fear of extubation failure and the downstream harms of reintubation.
  • A pragmatic, multicentre RCT in this subgroup could standardise practice and inform guideline recommendations where equipoise persists.

Design & Methods

• Research Question: Among adult ICU patients at high risk of extubation failure who were ready for an initial SBT, does an SBT strategy using PSV (vs a T-piece) increase ventilator-free days at day 28?
• Study Type: Multicentre, investigator-initiated, pragmatic, parallel-group, randomised controlled superiority trial; 31 adult ICUs in France; open-label with central web-based randomisation stratified by centre (block size 4).
• Population:
  • Setting: Adult ICUs; patients intubated and invasively ventilated for >24 hours.
  • High-risk definition: Age >65 years and/or chronic cardiac disease and/or chronic respiratory disease.
  • Readiness for initial SBT (key thresholds): Respiratory rate ≤35 breaths/min; SpO₂ ≥90% with FIO₂ ≤40% and PEEP ≤8 cmH₂O (or PaO₂/FIO₂ ≥150 with PEEP ≤8); adequate cough; awake (RASS -2 to +1); no continuous sedation; no vasopressors or minimal doses.
  • Key exclusions (from enrolment flow): Do-not-reintubate decision at time of initial SBT; traumatic brain injury; pre-existing neuromuscular disease; already performed an initial SBT since intubation; other protocol exclusions (e.g., legal protections/consent constraints).
• Intervention:
  • PSV SBT strategy: 1-hour SBT on the ventilator with PSV 8 cmH₂O and PEEP 0 cmH₂O (target FIO₂ ≤0.40).
  • After SBT success: Extubation recommended as soon as possible after reconnection to ventilator for ~1 hour “rest”.
  • If SBT failure: Return to ventilatory support; repeat SBT daily until success.
• Comparison:
  • T-piece SBT strategy: 1-hour SBT with a T-piece, using oxygen flow 4–6 L/min (target FIO₂ ≤0.40).
  • After SBT success / if failure: Same extubation encouragement and repeat-testing approach as intervention.
  • Co-interventions: Post-extubation prophylactic NIV was encouraged in this high-risk cohort; other care per treating clinicians.
• Blinding: Unblinded (clinicians and patients); extubation timing and post-extubation supports were clinician-driven; primary outcome largely objective but decisions around extubation and reintubation could be influenced by treatment allocation.
• Statistics: A total of 900 patients were required to detect an absolute increase of 2 ventilator-free days at day 28 (two-sided alpha 0.05; 80% power); the planned sample size was increased to 1000 to allow for exclusions; the primary analysis was intention-to-treat after post-randomisation eligibility validation by a blinded committee, using a Mann–Whitney U test with a bootstrapped 95% CI for the median difference; secondary outcomes were not adjusted for multiplicity.
• Follow-Up Period: 28 days for the primary outcome; 90 days for mortality and longer-term outcomes.

Key Results

This trial was not stopped early. 983 patients were randomised and 969 (484 PSV; 485 T-piece) were included in the primary analysis.

• PSV SBTs increased initial SBT success (79.1% vs 71.7%) and reduced prolonged weaning (>7 days: 2.3% vs 5.6%), but did not improve ventilator-free days at day 28 (median 27 vs 27; median difference 0; 95% CI -0.5 to 1; P=0.31).
• Extubation and safety outcomes were broadly similar: reintubation ≤7 days 14.9% vs 13.6% (absolute difference 1.3 pp; 95% CI -3.1 to 5.8).
• Hypercapnic coma as a reintubation indication occurred only in the PSV arm (7/78 vs 0/71; P=0.01), a signal that was not a pre-specified primary safety endpoint and should be interpreted cautiously given multiple comparisons.

Internal Validity

• Randomisation and Allocation:
  • Central, web-based randomisation stratified by centre with concealed allocation (block size 4).
  • Post-randomisation eligibility validation by a blinded committee; 969/983 (98.6%) retained for the primary analysis (484 PSV; 485 T-piece).
• Dropout / exclusions:
  • 14/983 randomised patients were excluded after randomisation (6 PSV; 8 T-piece), including deaths before SBT, withdrawals, self-extubation, transfer before initial SBT, and missing data.
  • Because the exclusion process occurred after randomisation (even if blinded), this is best interpreted as a modified intention-to-treat population and could introduce bias if exclusions were imbalanced in unmeasured ways.
• Performance and detection bias:
  • Open-label intervention; clinicians knew assignment and determined timing of extubation and adjunctive supports.
  • Primary outcome (ventilator-free days) and reintubation are largely objective, but decisions to terminate SBTs, extubate, and reintubate can still be susceptible to expectation and local culture.
• Protocol adherence:
  • Crossovers were uncommon: 6/484 (1.2%) in the PSV arm received at least one T-piece SBT; 10/485 (2.1%) in the T-piece arm received at least one PSV SBT.
  • Mean SBT settings achieved separation consistent with the protocol: PSV arm mean PSV 8±1 cmH₂O and PEEP 0±1; T-piece arm mean oxygen flow 4±4 L/min.
• Baseline characteristics:
  • Groups were broadly balanced in illness severity and comorbidity burden (e.g., age 69±9 vs 68±9; SAPS II 53±17 vs 53±18; chronic cardiac disease 46.9% vs 48.2%; chronic respiratory disease 24.8% vs 27.0%).
  • A substantial minority had COVID-19 as a primary reason for admission (23.3% vs 24.5%), anchoring the trial in a pandemic-era case-mix.
• Heterogeneity:
  • 31 ICUs improves representativeness and reduces single-centre idiosyncrasy, but local thresholds for extubation/reintubation and post-extubation supports could still vary.
  • Given the null effect on the primary outcome and generally consistent directions across key secondary outcomes, there is no strong signal of major between-centre heterogeneity in headline effects (formal centre-level heterogeneity was not reported).
• Timing:
  • SBT duration was fixed at 1 hour in both arms, standardising exposure time.
  • Among patients with successful initial SBT, extubation occurred at a median of 2.8 h (2.0 to 4.2) vs 2.7 h (2.0 to 3.7) (median difference 0.1 h; 95% CI -0.1 to 0.3), suggesting extubation decisions were not materially delayed differentially by group assignment once the initial SBT was passed.
• Dose:
  • PSV level (8 cmH₂O) with zero PEEP was a deliberate “ETT-compensating” strategy, but may represent a relatively assistive SBT compared with common ICU practice (e.g., PSV 5 cmH₂O with PEEP 5 cmH₂O), raising the possibility of physiological under-challenge in some patients.
• Separation of the variable of interest:
  • Initial SBT success: 383/484 (79.1%) vs 348/485 (71.7%) (absolute difference 7.4 pp; 95% CI 2.0 to 12.8).
  • Prolonged weaning: 11/484 (2.3%) vs 27/485 (5.6%) (absolute difference -3.3 pp; 95% CI -5.9 to -0.8).
  • Ventilator-free days at day 28: 27 (24 to 27) vs 27 (23 to 27) (median difference 0; 95% CI -0.5 to 1).
• Adjunctive therapy use:
  • Among 958 patients with at least one extubation attempt, prophylactic post-extubation NIV was used in 750/958 (78.3%) and high-flow nasal oxygen in 388/958 (40.5%); group-specific utilisation was not reported in the main trial tables.
• Outcome assessment and statistical rigour:
  • The primary endpoint (ventilator-free days at day 28) is a composite of survival and duration of invasive ventilation, with a hard upper bound of 28 days and death scored as 0; non-parametric methods were appropriately used for a skewed/censored distribution.
  • Secondary outcomes were not adjusted for multiplicity and many p values were not reported; secondary signals should be treated as hypothesis-generating rather than confirmatory.

Conclusion on Internal Validity: Overall, internal validity appears moderate to strong: randomisation and allocation concealment were robust and crossovers were rare, with clear separation in initial SBT success; the main limitations arise from the open-label nature of the intervention, post-randomisation eligibility exclusions, and reliance on a bounded composite primary endpoint sensitive to distributional ceiling effects.

External Validity

• Population representativeness:
  • The trial enrolled a broadly defined “high-risk” cohort (age >65 and/or chronic cardiorespiratory disease) with a median of 6 days of ventilation before initial SBT, reflecting typical medical ICU trajectories.
  • Exclusions and non-enrolment were substantial: of 1,476 eligible, 381 were not randomised due to staff unavailability/logistics and 112 declined participation, which may select for centres/patients with more robust research infrastructure or more protocolised liberation practices.
• Applicability:
  • Practice environment: 31 French ICUs during the COVID-19 era; the high use of prophylactic NIV/HFNC after extubation suggests results may be most applicable to systems with ready access to post-extubation respiratory supports.
  • SBT technical details: PSV 8 cmH₂O with PEEP 0 and 1-hour duration may not match local “low pressure support” norms, potentially affecting transportability.
  • Exclusion of traumatic brain injury and neuromuscular disease limits direct extrapolation to neurocritical care and neuromuscular ventilator-dependence phenotypes.

Conclusion on External Validity: Generalisability is moderate: findings are highly relevant to adult ICUs caring for older patients with cardiorespiratory comorbidity, particularly where prophylactic NIV/HFNC is commonly used, but may not fully extend to resource-limited settings, neurocritical care populations, or ICUs using substantially different SBT settings/durations.

Strengths & Limitations

• Strengths:
  • Pragmatic multicentre RCT in a clinically important, high-risk extubation population.
  • Clear operationalisation of SBT strategies (fixed 1-hour duration; PSV 8/PEEP 0 vs T-piece), producing measurable intervention separation.
  • High retention into the primary analysis (969/983 randomised) and low crossover.
  • Use of ventilator-free days at day 28 provides a patient-centred composite balancing earlier extubation against potential harm from reintubation and death.
• Limitations:
  • Open-label design with clinician-determined extubation and reintubation decisions, potentially introducing performance bias.
  • Post-randomisation eligibility exclusions create a modified intention-to-treat analysis set.
  • Primary outcome distribution was heavily bounded (median 27/28 days in both arms), reducing sensitivity to detect operationally important but small differences in liberation timing.
  • High prevalence of post-extubation prophylactic respiratory support may have reduced event rates and interacted with the SBT strategy, limiting transportability to ICUs with different extubation support practices.
  • Secondary outcomes were not adjusted for multiplicity; many p values were not reported, limiting inferential certainty for secondary signals such as hypercapnic coma as a reintubation reason.

Interpretation & Why It Matters

• Clinical practice

  In high-risk patients, a PSV-based SBT strategy improved the probability of passing the initial SBT and reduced prolonged weaning, but did not translate into more ventilator-free days or lower reintubation; either strategy can be defended as clinically acceptable when embedded in a protocolised liberation pathway.
• Physiology vs outcomes

  The trial illustrates that “easier” physiological testing (PSV) can alter process metrics (SBT success and weaning category) without changing net patient-centred outcomes, particularly when downstream supports (e.g., NIV/HFNC) may buffer post-extubation vulnerability.
• Endpoint selection

  Ventilator-free days at day 28 is attractive but sensitive to ceiling effects; when most patients are extubated early, the endpoint may be insufficiently granular to detect clinically meaningful shifts in extubation timing and durability.

Controversies & Subsequent Evidence

• Ceiling effects and endpoint sensitivity: The median ventilator-free days at day 28 was 27 (IQR near the upper bound) in both arms, raising concerns that a bounded composite outcome may have limited sensitivity to detect differences in extubation timing; this issue was explicitly highlighted in post-publication correspondence.²
• Event rates, co-interventions, and generalisability: The accompanying editorial emphasised that the reintubation signal and other outcomes should be interpreted in the context of modern, protocolised care (including frequent prophylactic NIV/HFNC), which can reduce extubation failure rates and potentially attenuate the effect of the SBT strategy.¹
• Protocol assumptions vs realised distribution: The published trial protocol anticipated an absolute increase of 2 ventilator-free days at day 28 and powered the study accordingly; the observed distribution concentrated near the maximum suggests that future weaning trials may require alternative primary outcomes (e.g., time-to-successful extubation) or different analytic strategies for bounded composites.³
• Consistency with prior RCT evidence: In a mixed-risk ICU population, a large RCT comparing PSV vs T-piece SBTs found higher rates of successful extubation with PSV without a clear increase in reintubation, supporting PSV as a reasonable approach in many settings; TiP-Ex suggests that in high-risk patients, the process benefits of PSV do not necessarily translate into improved ventilator-free days.⁴
• Evidence synthesis and guidance: A recent systematic review and meta-analysis reported associations between SBT technique and extubation success outcomes across heterogeneous ICU populations, and contemporary guidance emphasises protocolised readiness screening and consistent extubation criteria while allowing flexibility in SBT modality selection based on local practice and patient physiology.⁵⁶

Summary

• In 969 high-risk ICU patients, a PSV-based SBT strategy did not increase ventilator-free days at day 28 compared with a T-piece strategy (median 27 vs 27; median difference 0; 95% CI -0.5 to 1; P=0.31).
• PSV increased the likelihood of passing the initial SBT (79.1% vs 71.7%) and reduced prolonged weaning (>7 days: 2.3% vs 5.6%).
• Reintubation ≤7 days after extubation was similar (14.9% vs 13.6%), and mortality by day 90 was similar (16.5% vs 18.7%).
• Post-extubation care commonly included prophylactic NIV (78.3% overall among extubated patients), which may have buffered differences between SBT strategies.
• A signal for hypercapnic coma as a reintubation indication occurred only in the PSV group (7/78 vs 0/71; P=0.01), warranting cautious interpretation given multiple testing and low event counts.

Overall Takeaway

TiP-Ex is a landmark pragmatic trial because it tested a ubiquitous ICU decision (how to perform the SBT) in a high-risk population and demonstrated that improving early physiological “pass rates” with PSV does not necessarily translate into more ventilator-free days or fewer reintubations. The findings support flexibility in SBT modality choice within protocolised liberation pathways, while highlighting how endpoint selection and modern post-extubation supports can shape detectability and interpretation of weaning interventions.

Bibliography

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• 3.Thille AW, Gacouin A, Coudroy R, et al. T-piece versus pressure-support ventilation for spontaneous breathing trial before extubation: protocol for a multicentre randomised trial. BMJ Open. 2020;10:e042619.
• 4.Subirà C, Hernández G, Vázquez A, et al. Effect of pressure support vs T-piece ventilation strategies during spontaneous breathing trials on successful extubation among patients receiving mechanical ventilation: a randomised clinical trial. JAMA. 2019;321(22):2175-2182.
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