ACTiVE — Automated Closed-Loop vs Protocolized Conventional Ventilation

1. Publication

• Title: Effect of Automated Closed-Loop Ventilation vs Protocolized Conventional Ventilation on Ventilator-Free Days in Critically Ill Adults: A Randomized Clinical Trial
• Acronym: ACTiVE
• Year & Journal: JAMA, published online December 8, 2025 (print: 2026;335(10):874-884)
• Citation: Sinnige JS, Buiteman-Kruizinga LA, Horn J, et al; ACTiVE Investigators and the Protective Ventilation Network. Effect of Automated Closed-Loop Ventilation vs Protocolized Conventional Ventilation on Ventilator-Free Days in Critically Ill Adults: A Randomized Clinical Trial. JAMA. 2026;335(10):874-884. doi:10.1001/jama.2025.24384

2. Context & Rationale

Background: Automated closed-loop ventilation systems (e.g., INTELLiVENT-ASV) continuously adjust ventilator settings based on real-time physiologic feedback, theoretically optimizing lung-protective ventilation more consistently than clinician-driven protocols, especially given variable clinician expertise and workload across shifts. Whether this translates into improved patient-centered outcomes had remained uncertain.

Research Question/Hypothesis: In critically ill mechanically ventilated adults, does early initiation of automated closed-loop ventilation (INTELLiVENT-ASV) increase ventilator-free days at day 28 compared with protocolized conventional ventilation delivered by experienced teams?

Why This Matters: Tests whether automation can match or exceed high-quality, protocol-driven human-delivered ventilation — directly relevant given ongoing ICU staffing pressures and interest in reducing clinician/nursing workload while maintaining safe, lung-protective ventilation.

3. Design & Methods

• Study Type: International, multicenter, randomized clinical trial
• Setting & Centers: 7 ICUs, Netherlands and Switzerland; enrolled October 2020 – June 2025, final follow-up at 90 days
• Population:
• Inclusion: Adults <1 hour after initiation of invasive ventilation, expected to require ventilation ≥24 hours
• Exclusions: Unavailability of INTELLiVENT-ASV-capable ventilator
• Intervention: Automated closed-loop ventilation using INTELLiVENT adaptive support ventilation (n=602)
• Comparator: Protocolized conventional ventilation, both groups following standardized ventilation management, sedation, and weaning protocols (n=599)
• Randomization: 1:1, 1201 total patients
• Blinding: Open-label (inherent to ventilator-mode comparison)
• Statistical Power & Follow-Up: Primary outcome: ventilator-free days at day 28 (days alive and free from invasive ventilation). Secondary: mortality, duration of ventilation.

4. Key Results

1201 patients randomized (602 closed-loop, 599 conventional).

Key interpretive point: The trial establishes that automated closed-loop ventilation is safe and achieves outcomes comparable to high-quality, protocol-driven conventional ventilation — it did not demonstrate superiority, but importantly also showed no inferiority/harm.

5. Internal Validity Assessment

• Randomization & Allocation: International randomization across 7 ICUs in 2 countries; specific concealment mechanics not detailed in available trial text.
• Protocol Adherence & Separation: Both groups followed standardized ventilation management, sedation, and weaning protocols — an important design feature ensuring the comparison isolates the ventilation mode itself, not overall care quality/protocolization.
• Blinding & Detection Bias: Open-label (inherent to comparing an automated system against manual ventilator adjustment); the primary outcome (ventilator-free days) is objective.
• Missing Data & Sensitivity Analyses: Long, nearly 5-year enrollment period (2020-2025) reflects a challenging but thorough recruitment process, likely including pandemic-era disruptions.
• Overall Internal Validity Conclusion: Strong — adequately sized (1201-patient), rigorously designed trial with standardized co-interventions in both arms, ensuring a clean test of the ventilation mode itself rather than confounded by differing overall care quality.

6. External Validity Assessment

• Population Representativeness: General mechanically ventilated ICU population (Netherlands and Switzerland) expected to require ventilation ≥24 hours — broadly representative of typical ICU ventilation populations.
• Practice Context: Requires INTELLiVENT-ASV-capable ventilator hardware, a real infrastructure/cost consideration for adoption; the comparator arm reflects high-quality, protocol-driven conventional ventilation (not lower-resource, less-protocolized care), which may understate the automated system's relative advantage in settings with less consistent human-delivered protocol adherence.
• Overall External Validity Conclusion: Good for high-resource ICUs with access to closed-loop ventilator hardware and already delivering high-quality protocolized conventional care; the relative advantage of automation might differ in settings with less consistent protocol adherence, though this trial cannot directly address that scenario.

7. Strengths & Limitations

Strengths:

• Adequately powered (1201-patient), international, multicenter trial
• Standardized co-interventions (sedation, weaning) in both arms isolate the ventilation-mode comparison specifically
• Establishes safety of automated closed-loop ventilation — an important prerequisite finding even absent superiority
• Directly relevant to current ICU staffing/workload pressures

Limitations:

• Open-label design (inherent to the comparison)
• Comparator arm was high-quality, protocol-driven conventional ventilation — may understate automation's potential advantage over less consistent real-world practice
• Requires specific, potentially costly ventilator hardware for implementation even if adopted

8. Interpretation & Practice Impact

• Clinical Implications: Automated closed-loop ventilation does not improve ventilator-free days compared with high-quality, protocol-driven conventional ventilation — does not support routine adoption purely for improved patient-centered ventilation-duration outcomes, though it establishes automation as a safe alternative.
• Mechanistic Coherence: The null result against a high-quality conventional-ventilation comparator (not a weak control) suggests automation may match, but not clearly exceed, excellent human-delivered protocolized care — an important nuance for interpreting the result.
• Systems-Level Takeaway: Per the accompanying editorial ("Automated Modes to Improve Mechanical Ventilation Outcomes — The Ghost in the Machine"), automated closed-loop ventilation could still reduce clinician/nursing workload while maintaining safe ventilation quality — a potentially valuable systems-level benefit distinct from the null patient-centered-outcome result, opening the door to future research on workload and safety endpoints specifically.

9. Controversies & Subsequent Evidence

• Editorial Commentary: The accompanying JAMA editorial, provocatively titled "Automated Modes to Improve Mechanical Ventilation Outcomes — The Ghost in the Machine," frames the trial as establishing safety and opening avenues for future research on workload reduction rather than a simple negative verdict on automation's value.
• Guideline Integration: Contributes to a broader, evolving evidence base on closed-loop ventilation systems (including a related systematic review of INTELLiVENT-ASV effectiveness/safety); not yet a guideline-changing result but an important safety-establishing data point.

10. Summary & Executive Takeaway

Summary: ACTiVE randomized 1201 mechanically ventilated adults across 7 ICUs in the Netherlands and Switzerland to automated closed-loop ventilation (INTELLiVENT-ASV) or protocolized conventional ventilation, with standardized sedation/weaning protocols in both arms. Ventilator-free days at day 28, mortality, and ventilation duration showed no significant differences between groups.

Overall Takeaway: Automated closed-loop ventilation does not outperform high-quality, protocol-driven conventional ventilation on patient-centered outcomes, but establishes automation as a safe alternative — opening the door to future research specifically targeting clinician workload reduction as the more relevant potential benefit of automated ventilation systems, rather than expecting superior patient-centered outcomes over already-excellent human-delivered care.

11. Bibliography

• Botta M, Wenstedt EFE, Tsonas AM, et al. Effectiveness, safety and efficacy of INTELLiVENT-adaptive support ventilation, a closed-loop ventilation mode for use in ICU patients — a systematic review. Ann Intensive Care. 2021.
• [Editorial] Automated Modes to Improve Mechanical Ventilation Outcomes — The Ghost in the Machine. JAMA. 2026.