An interventional study of Permissive lung-protective ventilation and Conventional lung-protective ventilation in Invasive Ventilation, Critical Illness and Intensive Care (ICU), sponsored by Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA). Recruiting at 2 sites in Netherlands. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2026-09-23.
Sponsored by Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA) · Not applicable, Interventional, and Treatment
The goal of this clinical trial is to investigate the impact of a ventilation strategy with a lower respiratory rate (RR) (permissive lung-protective ventilation) on clinical outcomes in adult critically ill patients receiving invasive ventilation.
The main question it aims to answer is:
Is a permissive lung-protective ventilation, defined as a strategy that reduces ventilatory intensity by stepwise lowering RR to the lowest level permitted by predefined safety limits, superior to conventional lung-protective ventilation, with respect to the number of days free from ventilation and alive at day 28 (VFD-28) in adult critically ill patients receiving invasive ventilation?
Researchers will compare permissive lung-protective ventilation with conventional lung-protective ventilation to see if it improves clinical outcomes.
Participants will be randomly assigned to one of the two ventilation strategies under investigation and followed up for 28 days.
RATIONALE Injury caused by mechanical ventilation is associated with its intensity, of which the respiratory rate (RR) is a substantial contributor. A permissive ventilation strategy that reduces RR and allows mild hypercapnia, may lower the intensity of ventilation and improve patient-centered outcomes. In this approach, RR is stepwise decreased to the lowest level compatible with predefined safety limits.
OBJECTIVE To compare permissive lung-protective ventilation with a lower RR, to conventional lung-protective ventilation, in adult critically ill patients receiving invasive ventilation.
HYPOTHESIS Permissive lung-protective ventilation, defined as a strategy that reduces ventilatory intensity by stepwise lowering RR to the lowest level permitted by predefined safety limits, is superior to conventional lung-protective ventilation, with respect to the number of days free from ventilation and alive at day 28 (VFD-28) in adult critically ill patients receiving invasive ventilation.
STUDY DESIGN International, multicenter, investigator-initiated, randomized, clinical, superiority trial.
STUDY POPULATION Critically ill patients, aged ≥ 18 years, intubated and expected to receive invasive ventilation for > 24 hours.
INTERVENTION AND COMPARISON Patients are randomized in a 1:1 ratio to permissive lung-protective ventilation with lower RR, or to conventional lung-protective ventilation.
STUDY ENDPOINTS The primary outcome is the number of VFD-28, a composite endpoint of duration of ventilation and death until day 28. The secondary outcomes include the individual components of this composite endpoint, namely duration of ventilation (analyzed separately in survivors and non-survivors) and 28-day mortality. Additional secondary outcomes are intensive care unit (ICU) and hospital length of stay, and ICU-, hospital, and 90-day mortality.
SAMPLE SIZE AND DATA ANALYSIS Based on previous literature, we assumed that the intervention would determine an increase in the number of VFD-28 of 2.4 days, with a standard deviation of 10. The required sample size with a t-test and allowing for a 15% inflation to account for rank-based testing, a power of 90%, an alpha of 0.05 and a drop-out rate of 10% is 926 patients (463 patients per group). Primary analysis will follow the intention-to-treat principle, with additional per-protocol analysis.
NATURE AND EXTENT OF THE BURDEN AND RISKS ASSOCIATED WITH PARTICIPATION, BENEFIT AND GROUP RELATEDNESS Ventilation with lower RR may result in higher PaCO2 and lower arterial pH. When kept within safe limits, evidence suggests that hypercapnia and mild acidosis are safe and do not lead to worse outcomes or severe adverse events. Both ventilation strategies are forms of lung-protective ventilation and are currently variably used as part of standard care. No other interventions are performed. Permissive ventilation is most often reserved for patients with severe lung conditions, where ventilator settings are more complex and ventilation intensity is high. In these patients, permissive ventilation is considered safe, and may even be beneficial. The collection of demographics, ventilation and outcome data causes no harm to patients. Blood is drawn for arterial blood gas analysis, but this is also part of standard care.
1,780 studies on the registry are indexed under Critical Illness; 442 are open to participants now.
This study's planned enrollment of 926 is above the median of 90 across 926 interventional studies indexed under Critical Illness.
Browse Critical Illness studies →Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA) is the lead sponsor of 532 studies on the registry; 181 are open to participants now.
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Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.
Exclusion Criteria:
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
A reason a treatment, test or procedure should not be given to a particular person, such as an allergy, another illness or a medicine they take.
Chronic obstructive pulmonary disease: long-term lung disease that makes it hard to breathe out, including emphysema and chronic bronchitis.
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Contraindication
A reason a treatment, test or procedure should not be given to a particular person, such as an allergy, another illness or a medicine they take.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
COPD
Chronic obstructive pulmonary disease: long-term lung disease that makes it hard to breathe out, including emphysema and chronic bronchitis.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Informed consent
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
The goal is to achieve the lowest possible respiratory rate (RR) according to a guideline.
Other: Permissive lung-protective ventilation
The respiratory rate is set according to standard of care.
Other: Conventional lung-protective ventilation
The goal is to achieve the lowest possible respiratory rate (RR) guided by a nomogram, that integrates baseline RR with arterial blood gas analysis (ABG) results, to stay within safety limits of PaCO2 and pH. The lowest RR possible is determined by the maximum acceptable PaCO2 of ≤ 8.5 kPa (64 mmHg) and limited by the lowest acceptable pH of \> 7.20, depending on the combination. The nomogram provides guidance on RR reductions based on these safety limits. The first target RR is determined using the baseline RR and the first ABG, obtained within 1 hour after randomization. The set RR is gradually decreased in steps of 2 breaths, approximately every 10 to 20 minutes, and downtitration is intended to be completed between 4 to 6 hours. Other ventilator settings are set according to lung-protective ventilation, following international guidelines.
The respiratory rate (RR) is set according to standard of care, starting to target a normal PaCO2 (4.7-6.4 kPa or 35-48 mmHg) and/or a normal arterial pH (7.35-7.45). Other ventilator settings according to lung-protective ventilation, following international guidelines.
Number of days free from ventilation and alive at day 28 (VFD-28)
Ventilator-free days at day 28 (VFD-28) is defined as: * VFD-28 = 0 if a subject dies within 28 days of start of invasive ventilation; * VFD-28 = 0 if a subject is invasively ventilated for ≥28 days; * VFD-28 = 28 - X days after tracheal intubation if a subject is successfully liberated from ventilation.
Time frame: From start of invasive ventilation to successful liberation from ventilation, death or day 28, whichever occurs first
Duration of ventilation
Time difference between the date and time of the last successful liberation from invasive ventilation episode and the date and time of intubation.
Time frame: From start of invasive ventilation to successful liberation from ventilation, death or day 28, whichever occurs first.
28-day mortality
Death for any cause within 28 days
Time frame: from randomization to day 28
Intensive Care Unit (ICU) length of stay
Time difference between the date time of ICU discharge and the date and time of randomization
Time frame: from randomization to ICU discharge, death or day 90, whichever occurs first.
Hospital length of stay
Time difference between the date time of hospital discharge and the date and time of randomization
Time frame: from randomization to hospital discharge, death or day 90, whichever occurs first.
Successful switch to pressure support ventilation
ventilation in pressure support mode at two consecutive time points
Time frame: from start of invasive ventilation to successful liberation from ventilation, death or day 28, whichever occurs first.
Intensive Care Unit (ICU) mortality
death from any cause in ICU
Time frame: from randomization to day 90
Hospital mortality
death from any cause in hospital
Time frame: from randomization to day 90
Incidence of Acute Respiratory Distress Syndrome (ARDS)
ARDS is defined according to the Berlin definition.
Time frame: from randomization to day 28
Incidence of Acute Kidney Injury (AKI)
AKI is defined according to the KDIGO guidelines
Time frame: from randomization to day 28
Incidence of severe hypercapnia
Severe hypercapnia is defined as PaCO2 \> 9.3 kPa (70 mmHg) with severe acidemia defined as pHa \< 7.20
Time frame: from randomization to end of the intervention
Incidence of severe hypoxemia
Severe hypoxemia is defined as PaO2 \< 8 kPa (60 mmHg)
Time frame: from randomization to end of the intervention
Incidence of ventilation-associated complications
Ventilator-associated complications are: (1) air leaks, (2) severe atelectasis, (3) ventilator-associated pneumonia, (4) acute cor pulmonale.
Time frame: from randomization to end of the intervention
Plan to share: Undecided
No publications or documents are linked to this record.
Start is estimated for Sep 2026; primary completion for Mar 2029, 30 months later.
Of 399 non-industry interventional studies with no phase under Critical Illness, half reached primary completion within 21 months of starting (the median), counting those still running; a quarter within 12 and three quarters within 40. This study's planned 30 months is above that.
Counting every sponsor, half of 403 studies reached it within 21 months; a quarter within 12 and three quarters within 40.
Critical Illness covers many different conditions, not one, so the studies compared here vary widely. Read these figures as a rough guide.
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