Protective Ventilatory Strategy in Severe Acute Brain Injury (PROLABI)

This study is currently recruiting participants. (see Contacts and Locations)
Verified January 2014 by University of Turin, Italy
Sponsor:
Information provided by (Responsible Party):
Luciana Mascia, University of Turin, Italy
ClinicalTrials.gov Identifier:
NCT01690819
First received: September 12, 2012
Last updated: January 10, 2014
Last verified: January 2014
  Purpose

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 Intervention Phase
Injuries, Acute Brain
Procedure: Conventional Ventilatory Strategy
Procedure: Protective Ventilatory Strategy
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Protective Ventilatory Strategy in Severe Acute Brain Injury: Randomized Multi-center Controlled Trial

Resource links provided by NLM:


Further study details as provided by University of Turin, Italy:

Primary Outcome Measures:
  • proportion of event free survival [ Time Frame: 28 days ] [ Designated as safety issue: No ]

    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:
  • Number of ventilator free days at 28 days [ Time Frame: 28 days ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • Incidence of ventilator associated pneumonia (VAP) [ Time Frame: 28 days ] [ Designated as safety issue: No ]
  • Cumulative SOFA free score from the randomization to day 28 [ Time Frame: 28 days ] [ Designated as safety issue: No ]
  • Concentrations of plasma inflammatory cytokines [ Time Frame: 7 days ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • Glasgow Outcome Scale extended (GOSe) at 6 months [ Time Frame: at 6 months ] [ Designated as safety issue: No ]
  • Mortality at day 28 after randomization [ Time Frame: 28 days ] [ Designated as safety issue: No ]
  • LOS in ICU [ Time Frame: 20 days (average time) ] [ Designated as safety issue: No ]
    length of stay in intensive care unit

  • Hospital length of stay (HLOS) [ Time Frame: 30 days (average time) ] [ Designated as safety issue: No ]
    length of stay in hospital


Estimated Enrollment: 524
Study Start Date: October 2013
Estimated Study Completion Date: March 2016
Estimated Primary Completion Date: October 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01690819

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

Locations
Italy
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
Investigators
Principal Investigator: Luciana Mascia, MD, PhD University of Turin
  More Information

Additional Information:
No publications provided

Responsible Party: Luciana Mascia, MD, PhD, University of Turin, Italy
ClinicalTrials.gov Identifier: NCT01690819     History of Changes
Other Study ID Numbers: PROLABI
Study First Received: September 12, 2012
Last Updated: January 10, 2014
Health Authority: Italy: Ministry of Health

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

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

ClinicalTrials.gov processed this record on September 29, 2014