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Protective Ventilatory Strategy in Severe Acute Brain Injury (PROLABI)

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ClinicalTrials.gov Identifier: NCT01690819
Recruitment Status : Recruiting
First Posted : September 24, 2012
Last Update Posted : May 9, 2017
Information provided by (Responsible Party):
Luciana Mascia, University of Turin, Italy

Brief 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 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.

Condition or disease Intervention/treatment
Injuries, Acute Brain Procedure: Conventional Ventilatory Strategy Procedure: Protective Ventilatory Strategy

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 Type : Interventional  (Clinical Trial)
Estimated Enrollment : 524 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Protective Ventilatory Strategy in Severe Acute Brain Injury: Randomized Multi-center Controlled Trial
Study Start Date : October 2013
Estimated Primary Completion Date : October 2017
Estimated Study Completion Date : March 2018

Arm Intervention/treatment
Active Comparator: Conventional Ventilatory Strategy
Conventional Ventilatory Strategy
Procedure: Conventional Ventilatory Strategy
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
Experimental: Protective Ventilatory Strategy
Protective ventilatory strategy
Procedure: Protective Ventilatory Strategy
The protective strategy will consist of a tidal volume of 6 ml/Kg of predicted body weight, with a PEEP of 8 cmH2O

Primary Outcome Measures :
  1. 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.

Secondary Outcome Measures :
  1. Number of ventilator free days at 28 days [ Time Frame: 28 days ]
  2. 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 ]
  3. Incidence of ventilator associated pneumonia (VAP) [ Time Frame: 28 days ]
  4. Cumulative SOFA free score from the randomization to day 28 [ Time Frame: 28 days ]
  5. Concentrations of plasma inflammatory cytokines [ Time Frame: 7 days ]
  6. 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 ]
  7. Glasgow Outcome Scale extended (GOSe) at 6 months [ Time Frame: at 6 months ]
  8. Mortality at day 28 after randomization [ Time Frame: 28 days ]
  9. LOS in ICU [ Time Frame: 20 days (average time) ]
    length of stay in intensive care unit

  10. Hospital length of stay (HLOS) [ Time Frame: 30 days (average time) ]
    length of stay in hospital

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • 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)

Exclusion Criteria:

  • 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01690819

Contact: Luciana Mascia, MD, PhD +390116334001 luciana.mascia@unito.it

University of Turin - Department of Anesthesia and Intensive care Medicine Recruiting
Turin, Italy, 10126
Contact: Luciana Mascia, MD, PhD         
Sponsors and Collaborators
University of Turin, Italy
Principal Investigator: Luciana Mascia, MD, PhD University of Turin, Italy

Additional Information:
Responsible Party: Luciana Mascia, MD, PhD, University of Turin, Italy
ClinicalTrials.gov Identifier: NCT01690819     History of Changes
Other Study ID Numbers: PROLABI
First Posted: September 24, 2012    Key Record Dates
Last Update Posted: May 9, 2017
Last Verified: May 2017

Keywords provided by Luciana Mascia, University of Turin, Italy:
Acute Respiratory Distress Syndrome
Acute Brain Injury

Additional relevant MeSH terms:
Wounds and Injuries
Brain Injuries
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Craniocerebral Trauma
Trauma, Nervous System