Injuries, Acute BrainPROLABINCT01690819
Protective Ventilatory Strategy in Severe Acute Brain Injury
A study testing Conventional Ventilatory Strategy and Protective Ventilatory Strategy in people with Injuries, Acute Brain, run by University of Turin, Italy at 1 site in Italy.
Trial summary
Acute respiratory distress syndrome (ARDS) occurs in almost 20% of patients with severe acute brain injury and is associated with increased morbidity and mortality. A massive increase in sympathetic activity and an increased production of proinflammatory cytokines released into the systemic circulation are the most… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Injuries, Acute Brain
- What is being tested?
- Conventional Ventilatory Strategy and Protective Ventilatory Strategy
- Type of treatment
- Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 524 participants
- Where
- 1 siteItaly
- Study dates
- Oct 2013to Dec 2021
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Patients with severe acute brain injury (traumatic brain injury, subarachnoid haemorrhage, intra-cerebral haemorrhage, and ischemic stroke)
- Patients with not obey commands and do not open eyes on GCS (Glasgow Coma Scale)
- Less than 24 hours of mechanical ventilation (expected >72 hours)
Who cannot join
- Age < 18 years
- Diagnosis of ARDS before randomization.
- Patients unlikely to survive for the next 24 hours in the opinion of ICU consultant.
- Pregnancy
- Post-anoxic coma
- Metabolic or toxic encephalopathy
- Lack of Informed Consent.
Trial locations and contacts
1 site in 1 country.
Italy1 site
University of Turin - Department of Anesthesia and Intensive care Medicine
Turin, 10126
About this study
Official title: Protective Ventilatory Strategy in Severe Acute Brain Injury: Randomized Multi-center Controlled Trial
Acute respiratory distress syndrome (ARDS) occurs in almost 20% of patients with severe acute brain injury and is associated with increased morbidity and mortality. A massive increase in sympathetic activity and an increased production of proinflammatory cytokines released into the systemic circulation are the most important recognized mechanisms. Altered blood brain barrier after injury causes spillover of inflammatory mediators from the brain into the systemic circulation leading to peripheral organs damage. The adrenergic surge induces an increase in vascular hydrostatic pressure and lung capillary permeability, causing an alteration of alveolar capillary barrier with fluid accumulation, resulting in ARDS.
The main goal of mechanical ventilation after acute brain injury are the maintenance of optimal oxygenation, and a tight control of carbon dioxide tension, although ventilatory settings to be used to obtain these targets, while avoiding secondary insults to the brain, are not clearly identified.
Read more
Protective ventilatory strategy has been positively evaluated first in patients with ARDS, and then in those undergoing cardiopulmonary bypass or lung resection surgery, or in brain death organ donors, but data on the effect of protective mechanical ventilation on patients with acute brain injury are still lacking even if this is a population with recognized risk factors for ARDS.
Therefore, the primary aim of this multi-center, prospective, randomized, controlled trial is to investigate whether a protective ventilatory strategy, in the early phase after severe acute brain injury, is associated with a lower incidence of ARDS, avoiding any further damage to the brain. Secondary aim is to evaluate if a protective ventilatory strategy is associated with reduced duration of mechanical ventilation, incidence of organ failure, intensive care unit length of stay, and lower concentrations of plasma inflammatory cytokines, without adversely affect in neurological outcome.
Read the detailed description
BACKGROUND Acute respiratory distress syndrome (ARDS) is described as the most common non-neurologic organ dysfunction occurring in the early phase after severe acute brain injury, with a reported incidence of 10-15% and increased morbidity and mortality.
A significant role has been recently proposed for neuro-inflammation in the genesis of ARDS following acute brain injury. The neuro-inflammatory response represents initially a coordinated effort to protect the brain after injury, but may then become altered and be responsible for the activation of the secondary injury cascade leading to single or multiple organ dysfunction. This preclinical event may increase the susceptibility of lungs to the stress of injurious mechanical ventilation. The main targets of ventilatory management of acute brain injury patients are maintenance of an optimal oxygenation, and a tight arterial carbon dioxide control. Actual Guidelines for the management of severe traumatic brain injury, in particular, state that hypoxia (PaO2 <60 mmHg or SaO2 < 90%) should be avoided and PaCO2 level tightly controlled with a target of 35-38 mmHg. However, no published recommendation exists on which ventilator setting, in terms of tidal volume, respiratory rate, and positive end-expiratory pressure (PEEP) levels, should be used to obtain these respiratory targets. In previous studies on patients with ARDS, mechanical ventilation with a low tidal volume and moderate PEEP levels resulted in decreased mortality and increased number of ventilatory free days, and it now represents the standard of care for these patients.
Patients with acute brain injury represent a category at risk to develop ARDS both because of the adrenergic cascade and the inflammatory reaction, and because of the ventilatory strategy implemented to optimize gas exchange. Nevertheless, no clinical trial has been performed to evaluate the effect of protective ventilatory strategies upon severe acute brain injury patients.
AIMS The aim of this study is to investigate whether the application of a protective ventilatory strategy, defined as low tidal volume and moderate levels of PEEP, improves the combined end point of "event free survival" defined as survival without ventilator dependency or ARDS diagnosis, without adversely affecting neurological outcome.
Secondary aim of this study is to evaluate if protective ventilatory strategy may increase number of ventilator and organ failure free days, reduce intensive care unit (ICU) length of stay, reduce the incidence of ventilator associated pneumonia (VAP), reduce concentrations of plasma inflammatory cytokines (IL-6, TNF-alpha, TNF-RI/II, IL-8, IL-1ra, IL-1beta), without adversely affecting neurological outcome as measured by the Modified Oxford Handicap scale at intensive care unit discharge and the Glasgow Outcome Scale-extended (GOSe) at 6 months.
- Conditions
- Injuries, Acute Brain
- Being tested
- Conventional Ventilatory Strategy, Protective Ventilatory Strategy
- Keywords
- Acute Respiratory Distress Syndrome, Acute Brain Injury
- Medical subject headings
- Brain Injuries, Respiratory Distress Syndrome
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Conventional Ventilatory StrategyProcedure or surgery
The conventional strategy will be the standard of care with a lower limit of tidal volume equal to 8 ml/Kg of predicted body weight and with a PEEP of 4 cmH2O
Protective Ventilatory StrategyProcedure or surgery
The protective strategy will consist of a tidal volume of 6 ml/Kg of predicted body weight, with a PEEP of 8 cmH2O
| Study group | Role | What they receive |
|---|---|---|
| Conventional Ventilatory Strategy | Active comparator | Conventional Ventilatory Strategy Receives: Procedure: Conventional Ventilatory Strategy |
| Protective Ventilatory Strategy | Experimental | Protective ventilatory strategy Receives: Procedure: Protective Ventilatory Strategy |
What is being measured
The primary outcome is the main question the study is designed to answer.
Proportion of event free survival
Combined end point of "event free survival" defined as survival without ventilator dependency or ARDS* diagnosis
*ARDS will be defined according to Berlin definition criteria. If chest x-ray is not immediately available, ARDS diagnosis will be suspected and confirmed later on.
Interpretation of bilateral infiltrates on chest x-ray and of heart failure vs. fluid overload was variable and in a large observational study (LUNGSAFE, JAMA. 2016 Feb 23;315:788-800) hypoxemic patients with new infiltrates were described as a well-defined group with outcome, risk factors, comorbidities and clinical management similar to ARDS. Therefore, in March 2016 the study protocol replaced "ARDS" with "acute hypoxemic respiratory failure" as one of the components of the composite primary endpoint. Acute hypoxemic respiratory failure was defined as PaO2/FiO2 ratio < 300, with presence of infiltrates on chest x-ray, independently of lung opacities distribution and characteristics.
Measured: 28 days
Secondary outcomes (10)
Number of ventilator free days at 28 days
Measured: 28 days
number of ICU free days at day 28 after randomization
Measured: participants will be followed for the duration of ICU stay, an expected average of 3 weeks
Incidence of ventilator associated pneumonia (VAP)
Measured: 28 days
Cumulative SOFA free score from the randomization to day 28
Measured: 28 days
Concentrations of plasma inflammatory cytokines
Measured: 7 days
Modify Oxford Handicap Scale at ICU discharge
Measured: participants will be followed for the duration of ICU stay, an expected average of 3 weeks
Glasgow Outcome Scale extended (GOSe) at 6 months
Measured: at 6 months
Mortality at day 28 after randomization
Measured: 28 days
LOS in ICU
length of stay in intensive care unit
Measured: 20 days (average time)
Hospital length of stay (HLOS)
length of stay in hospital
Measured: 30 days (average time)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted24 Sep 2012 (estimated)
- Study startOct 2013
- Primary completionDec 2018
- Study completionDec 2021 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Injuries, Acute BrainStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 524 participants (estimated)
Sponsor and investigators
- Lead sponsor
- University of Turin, Italy
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Luciana Mascia, University of Turin, Italy
- Investigators
- Luciana Mascia, MD, PhD, Principal investigator, University of Turin, Italy
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01690819
- Sponsor's protocol ID
- PROLABI
- Acronym
- PROLABI
- Status last verified
- Apr 2021
- First submitted
- 12 Sep 2012
- Last updated
- 26 Apr 2021
- Results posted
- No
- Data monitoring committee
- Yes
Publications
Mascia L, Fanelli V, Mistretta A, Filippini M, Zanin M, Berardino M, Mazzeo AT, Caricato A, Antonelli M, Della Corte F, Grossi F, Munari M, Caravello M, Alessandri F, Cavalli I, Mezzapesa M, Silvestri L, Casartelli Liviero M, Zanatta P, Pelosi P, Citerio G, Filippini C, Rucci P, Rasulo FA, Tonetti T. Lung-Protective Mechanical Ventilation in Patients with Severe Acute Brain Injury: A Multicenter Randomized Clinical Trial (PROLABI). Am J Respir Crit Care Med. 2024 Nov 1;210(9):1123-1131. doi: 10.1164/rccm.202402-0375OC.
PubMed 39288368
Study at a glance
From the registry record, last updated by the sponsor on 26 Apr 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Protective Ventilatory Strategy in Severe Acute Brain Injury: Randomized Multi-center Controlled Trial
- ClinicalTrials.gov ID
- NCT01690819
- Acronym / sponsor ID
- PROLABI / PROLABI
- Conditions
- Injuries, Acute Brain
- Keywords
- Acute Respiratory Distress Syndrome, Acute Brain Injury
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 524 participants (estimated)
- Lead sponsor
- University of Turin, ItalyUniversity, hospital or other
- Study start
- Oct 2013
- Primary completion
- Dec 2018 (actual)
- Study completion
- Dec 2021 (estimated)
- First posted
- 24 Sep 2012 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Acute respiratory distress syndrome (ARDS) occurs in almost 20% of patients with severe acute brain injury and is associated with increased morbidity and mortality. A massive increase in sympathetic activity and an increased production of proinflammatory cytokines released into the systemic circulation are the most important recognized mechanisms. Altered blood brain barrier after injury causes spillover of inflammatory mediators from the brain into the systemic circulation leading to peripheral organs damage. The adrenergic surge induces an increase in vascular hydrostatic pressure and lung capillary permeability, causing an alteration of alveolar capillary barrier with fluid accumulation, resulting in ARDS.
The main goal of mechanical ventilation after acute brain injury are the maintenance of optimal oxygenation, and a tight control of carbon dioxide tension, although ventilatory settings to be used to obtain these targets, while avoiding secondary insults to the brain, are not clearly identified.
Protective ventilatory strategy has been positively evaluated first in patients with ARDS, and then in those undergoing cardiopulmonary bypass or lung resection surgery, or in brain death organ donors, but data on the effect of protective mechanical ventilation on patients with acute brain injury are still lacking even if this is a population with recognized risk factors for ARDS.
Therefore, the primary aim of this multi-center, prospective, randomized, controlled trial is to investigate whether a protective ventilatory strategy, in the early phase after severe acute brain injury, is associated with a lower incidence of ARDS, avoiding any further damage to the brain. Secondary aim is to evaluate if a protective ventilatory strategy is associated with reduced duration of mechanical ventilation, incidence of organ failure, intensive care unit length of stay, and lower concentrations of plasma inflammatory cytokines, without adversely affect in neurological outcome.
Detailed description
BACKGROUND Acute respiratory distress syndrome (ARDS) is described as the most common non-neurologic organ dysfunction occurring in the early phase after severe acute brain injury, with a reported incidence of 10-15% and increased morbidity and mortality.
A significant role has been recently proposed for neuro-inflammation in the genesis of ARDS following acute brain injury. The neuro-inflammatory response represents initially a coordinated effort to protect the brain after injury, but may then become altered and be responsible for the activation of the secondary injury cascade leading to single or multiple organ dysfunction. This preclinical event may increase the susceptibility of lungs to the stress of injurious mechanical ventilation. The main targets of ventilatory management of acute brain injury patients are maintenance of an optimal oxygenation, and a tight arterial carbon dioxide control. Actual Guidelines for the management of severe traumatic brain injury, in particular, state that hypoxia (PaO2 <60 mmHg or SaO2 < 90%) should be avoided and PaCO2 level tightly controlled with a target of 35-38 mmHg. However, no published recommendation exists on which ventilator setting, in terms of tidal volume, respiratory rate, and positive end-expiratory pressure (PEEP) levels, should be used to obtain these respiratory targets. In previous studies on patients with ARDS, mechanical ventilation with a low tidal volume and moderate PEEP levels resulted in decreased mortality and increased number of ventilatory free days, and it now represents the standard of care for these patients.
Patients with acute brain injury represent a category at risk to develop ARDS both because of the adrenergic cascade and the inflammatory reaction, and because of the ventilatory strategy implemented to optimize gas exchange. Nevertheless, no clinical trial has been performed to evaluate the effect of protective ventilatory strategies upon severe acute brain injury patients.
AIMS The aim of this study is to investigate whether the application of a protective ventilatory strategy, defined as low tidal volume and moderate levels of PEEP, improves the combined end point of "event free survival" defined as survival without ventilator dependency or ARDS diagnosis, without adversely affecting neurological outcome.
Secondary aim of this study is to evaluate if protective ventilatory strategy may increase number of ventilator and organ failure free days, reduce intensive care unit (ICU) length of stay, reduce the incidence of ventilator associated pneumonia (VAP), reduce concentrations of plasma inflammatory cytokines (IL-6, TNF-alpha, TNF-RI/II, IL-8, IL-1ra, IL-1beta), without adversely affecting neurological outcome as measured by the Modified Oxford Handicap scale at intensive care unit discharge and the Glasgow Outcome Scale-extended (GOSe) at 6 months.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Conventional Ventilatory Strategy | Active comparator | Procedure: Conventional Ventilatory StrategyConventional Ventilatory Strategy |
| Protective Ventilatory Strategy | Experimental | Procedure: Protective Ventilatory StrategyProtective ventilatory strategy |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (3 listed)
- Patients with severe acute brain injury (traumatic brain injury, subarachnoid haemorrhage, intra-cerebral haemorrhage, and ischemic stroke)
- Patients with not obey commands and do not open eyes on GCS (Glasgow Coma Scale)
- Less than 24 hours of mechanical ventilation (expected >72 hours)
Key exclusion criteria (7 listed)
- Age < 18 years
- Diagnosis of ARDS before randomization.
- Patients unlikely to survive for the next 24 hours in the opinion of ICU consultant.
- Pregnancy
- Post-anoxic coma
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Conventional Ventilatory StrategyThe conventional strategy will be the standard of care with a lower limit of tidal volume equal to 8 ml/Kg of predicted body weight and with a PEEP of 4 cmH2O | Procedure or surgery | Conventional Ventilatory Strategy |
| Protective Ventilatory StrategyThe protective strategy will consist of a tidal volume of 6 ml/Kg of predicted body weight, with a PEEP of 8 cmH2O | Procedure or surgery | Protective Ventilatory Strategy |
Primary outcome
Proportion of event free survival
Time frame: 28 days
Combined end point of "event free survival" defined as survival without ventilator dependency or ARDS* diagnosis *ARDS will be defined according to Berlin definition criteria. If chest x-ray is not immediately available, ARDS diagnosis will be suspected and confirmed later on. Interpretation of bilateral infiltrates on chest x-ray and of heart failure vs. fluid overload was variable and in a large observational study (LUNGSAFE, JAMA. 2016 Feb 23;315:788-800) hypoxemic patients with new infiltrates were described as a well-defined group with outcome, risk factors, comorbidities and clinical management similar to ARDS. Therefore, in March 2016 the study protocol replaced "ARDS" with "acute hypoxemic respiratory failure" as one of the components of the composite primary endpoint. Acute hypoxemic respiratory failure was defined as PaO2/FiO2 ratio < 300, with presence of infiltrates on chest x-ray, independently of lung opacities distribution and characteristics.
10 secondary outcomes
Number of ventilator free days at 28 days
Time frame: 28 days
number of ICU free days at day 28 after randomization
Time frame: participants will be followed for the duration of ICU stay, an expected average of 3 weeks
Incidence of ventilator associated pneumonia (VAP)
Time frame: 28 days
Cumulative SOFA free score from the randomization to day 28
Time frame: 28 days
Concentrations of plasma inflammatory cytokines
Time frame: 7 days
Modify Oxford Handicap Scale at ICU discharge
Time frame: participants will be followed for the duration of ICU stay, an expected average of 3 weeks
Glasgow Outcome Scale extended (GOSe) at 6 months
Time frame: at 6 months
Mortality at day 28 after randomization
Time frame: 28 days
LOS in ICU
Time frame: 20 days (average time)
Hospital length of stay (HLOS)
Time frame: 30 days (average time)
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 26 Apr 2021.
- Derived from this study: PubMed 39288368Mascia L, Fanelli V, Mistretta A, Filippini M, Zanin M, Berardino M, Mazzeo AT, Caricato A, Antonelli M, Della Corte F, Grossi F, Munari M, Caravello M, Alessandri F, Cavalli I, Mezzapesa M, Silvestri L, Casartelli Liviero M, Zanatta P, Pelosi P, Citerio G, Filippini C, Rucci P, Rasulo FA, Tonetti T. Lung-Protective Mechanical Ventilation in Patients with Severe Acute Brain Injury: A Multicenter Randomized Clinical Trial (PROLABI). Am J Respir Crit Care Med. 2024 Nov 1;210(9):1123-1131. doi: 10.1164/rccm.202402-0375OC.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Luciana Mascia, MD, PhD principal investigator
University of Turin, Italy
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Conventional Ventilatory Strategy and Protective Ventilatory Strategy in people with Injuries, Acute Brain, run by University of Turin, Italy at 1 site in Italy.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 26 Apr 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Proportion of event free survival (time frame: 28 days). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01690819, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 26 Apr 2021.