Clinical and Biological Markers in Acute Respiratory Failure
Condition: Ventilator-Associated Pneumonia; Acute Respiratory Distress Syndrome
MeSH terms: Pneumonia; Pneumonia, Ventilator-Associated; Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Acute Lung Injury; Syndrome
Study type: Observational

Summary: 
      In a recent experimental study, the investigators showed that the growth factor Activin A is
      expressed in the lungs of rats with the acute respiratory distress syndrome (ARDS) at levels
      that are comparable with those determined in the bronchoalveolar (BAL) lavage fluid from
      patients with ARDS. In the same study, the administration of the Activin A inhibitor
      Folistatin resulted in attenuation of the histological damage of the ARDS-afflicted rat lung.

      The precise role of Activin A/Folistatin in acute respiratory failure associated with acute
      lung inflammatory pathology has not been elucidated yet. Therefore, the purpose of the
      present, observational study is to investigate the role of Activin A/Folistatin in
      respiratory failure due to ARDS and/or ventilator-associated pneumonia (VAP), also in
      relation with other biochemical markers, such as cytokines and surfactant-related proteins.
    

Detailed description: 
      Rationale Survival from the Acute Respiratory Distress (ARDS) has been associated with
      clinical (e.g. age, sepsis, and organ failure) and biological factors. The latter include
      inflammatory mediators (e.g. cytokines), factors of activation/damage of the capillary
      endothelium (e.g. von Willebrand factor) and the alveolar epithelium (e.g. intracellular
      adhesion molecule-1), and factors associated with the coagulation/fibrinolysis cascade (e.g.
      protein C). These biochemical markers have been previously associated with the duration of
      mechanical ventilation, the ARDS-induced organ dysfunction/failure, and the survival of the
      patients. A combination of biochemical and clinical markers might be useful as a prognostic
      tool in ARDS.

      In a recent experimental study, the investigators showed that the growth factor Activin A is
      expressed in the lungs of rats with ARDS at levels that are comparable with those determined
      in the bronchoalveolar (BAL) lavage fluid from patients with ARDS. In the same study, the
      administration of the Activin A inhibitor Folistatin resulted in attenuation of the
      histological damage of the ARDS-afflicted rat lung.

      The precise role of Activin A/Folistatin in acute respiratory failure associated with acute
      lung inflammatory pathology has not been elucidated yet. Therefore, the purpose of the
      present, observational study is to investigate the role of Activin A/Folistatin in
      respiratory failure due to ARDS and/or ventilator-associated pneumonia (VAP), in relation
      with the other biochemical markers.

      Methods Patients The study protocol has been approved by the Institutional Review Board of
      Evaggelismos General Hospital, Athens, Greece. A study information sheet detailing the
      associated potential risks and benefits will be provided to a first degree relative of
      eligible patients. Subsequently, following a detailed discussion of the study with the
      investigator(s), a written informed consent will be requested.

      Continuous monitoring of patients will include electrocardiographic lead II, intraarterial
      pressure [and/or cardiac index (PICCO plus, Pulsion Medical Systems, Munich, Germany) - in
      concordance with clinical indications] and peripheral oxygen saturation (SpO2). Maintenance
      of anesthesia will be achieved with intravenous midazolam or propofol and/or fentanyl or
      remifentanyl. Neuromuscular blockade (cisatracurium) will be used in concordance with recent
      recommendations, and/or as part of the treatment prescribed by the attending physicians. The
      follow-up of the patients will last for 60 days or until hospital discharge (if it occurs
      earlier than day 60 after study enrollment).

      Conventional Mechanical Ventilation (CMV) Strategy Patients eligible for the study will be
      initially on CMV ([Siemens 300C ventilator (Siemens, Berlin, Germany), with the following
      FiO2/PEEP combinations: 0.5/10-12 cm H2O, 0.6/14-16 cm H2O, 0.7/14-16 cm H2O, 0.8/14-16 cm
      H2O, 0.9/16-18 cm H2O, 1.0/20-24 cm H2O. In patients with a body mass index of > 27 kg/m2 or
      with an intra-abdominal pressure of > 15 cmH2O, the positivity of end-expiratory
      transpulmonary pressure will be confirmed with the use of an esophageal balloon catheter
      (whenever feasible). Regarding patients with PaO2/FiO2 of less than 200 mmHg, the use of a
      high PEEP is consistent with recently published data on relevant survival benefits. The tidal
      volume will be 5.5-7.5ml/kg predicted body weight with a maximum allowable plateau pressure
      of ≤32 cmH2O. The goals for tidal volume and plateau pressure will be 6.0 ml/Kg predicted
      body weight and 30 cmH2O, respectively, provided that the below-mentioned gas exchange goals
      are achievable. Respiratory rate will be adjusted so that arterial pH (pHa) will range from
      7.20 to 7.45 and the inspiratory to expiratory time (I/E) ratio will be 1:2. Oxygenation
      targets will be as follows: SaO2=90-95% or PaO2=60-80 mmHg. The target pHa will be >7.20. In
      cases of pHa of <7.20, breathing circuit deadspace will be reduced by substituting the
      routinely used catheter mount (Mallinckrodt Dar, Mirandola, Italy) with a short angular
      connector. Additional measures for pHa control may include increasing the tidal volume up to
      8.0 mL/Κg predicted body weight and the respiratory rate up to 35/min, and starting a
      continuous bicarbonate infusion or implementing extracorporeal removal of CO2.

      PEEP/FiO2 Algorithm

        1. Recruitment Maneuver (RM) - Continuous positive airway pressure of up to 45 cmH2O for 40
           s at an FiO2 of 1.0 plus subsequent PEEP, FiO2 titration so that SaO2=90-95%, or
           PaO2=60-80 (An additional RM may be administered at 5 and 10 hours after the original
           RM)

        2. FiO2 reduction will always precede PEEP reduction.

        3. Weaning from CMV will be initiated when target gas-exchange is achievable at an FiO2 of
           0.5 and a PEEP of less 8 cmH2O..

        4. RMs may be administered during the first 5 days of study enrollment.

      Rescue oxygenation Rescue oxygenation methodology may include high frequency oscillation
      (HFO) with/without tracheal gas insufflation (TGI), prone positioning, inhaled nitric oxide,
      and extracorporeal membrane oxygenation. The duration of the rescue oxygenation session will
      be at least 10 hours with allowance for an unlimited extension if PaO2<60 mmHg. Rescue
      initiation criterion: PaO2<60 mmHg for more than 30 min at FiO2=1.0, in the absence of any
      reversible cardio-respiratory pathology and/or ventilator malfunction.

      Bronchoscopies Bronchoalveolar lavage (BAL) BAL of ≤100 mL will be performed on day 1 and 5
      post-enrollment. Patients will be eligible for BAL if their PaO2/FiO2 has exceeded 100 mmHg
      for more than 12 hours and they are intubated with an orotracheal tube with an internal
      diameter of ≥8.5 mm, or a tracheostomy tube. An (additional) RM will be performed after the
      fiberoptic bronchoscopic procedure. BAL fluid samples will be used for microbiological
      cultures, cell count, and the determination of biological markers. On the days of the
      bronchoscopic procedures, the remainder of blood samples used for routine laboratory tests,
      will be used for the determination of the concentrations of biological markers in the
      peripheral blood.

      BAL fluid studies The initial, 20-mL portion of the BAL fluid aspirate (which corresponds to
      the bronchial sample) will be sent for microbiological cultures, and the rest will be stored
      in ice-cold tubes. Subsequently, the BAL fluid will be filtered through sterile gauze and
      centrifuged at 500 g for 15 min at 4 degrees Celcius. The supernatant will be used for the
      determination of the concentrations of Activin A, inflammatory markers, and
      surfactant-related proteins. The sediment will be used for total cell count, determination of
      cell type, and estimation of cell viability on a Neubauer plate. Both the supernatant and
      sediment will be stored at -70 degrees Celcius.

      BAL cell studies These studies will be conducted in a centrifuged, hematoxylin-eosine stained
      preparation with a cell count of at least 300 for cell type determination.

      POTENTIAL, PROTOCOL-RELATED RISKS AND THEIR PREVENTION Potential risks: Hypoxemia,
      Hypercapnia, Hemorrhage, Arrhythmias, Barotrauma. Preventive measures: Pre-oxygenation and
      titration of sedation. ContinUous monitoring of cardio-respiratory parameters during
      bronchoscopy. Bronchoscopy by an experienced endoscopist, in the presence of an experienced
      operator of the conventional ventilator. Use of maximal internal diameter tracheal tube, in
      conjunction with a minimal outer diameter bronchoscope. Potential benefits: BAL culture for
      reliable identification of pathogens, with consequent use of a targeted antibiotic treatment
      and avoidance of unnecessarily broad antibiotic regimens. The second BAL sample will enable
      the confirmation of the effectiveness of the antibiotic treatment through the documentation
      of the reduction in the concentrations of the colony forming units of the pathogens.

      Since the investigational interventions of the present study protocol are close to the
      departmenal, common clinical practice, the investigators applied for the characterization of
      the present study protocol as "observational".

      Patient follow-up Days 1-10 post-enrollment: Recording of detailed data on respiratory
      mechanics, gas-exchange, hemodynamics, results of laboratory testing, and medical treatment.
      Days 1-60 post-enrollment: Recording of organ failures and clinical course complications. The
      final clinical outcome, i.e. survival to hospital discharge, will also be documented.

      Statistical Analysis The normality of the distributions of the values of the biological
      markers will be tested with the Kolmogorov Smirnov test. Logistic regression models including
      the biological markers as explanatory variables will be used to identify their potential
      effect on clinical outcomes. In addition, receiver operating characteristic curves will be
      constructed, in order to assess the prognostic value of the biological markers with respect
      to clinical outcomes. Based on prior data, the investigators estimate that complete data from
      a minimum of 50 patients will be needed for study completion.

      The current protocol constitutes part of the protocol of concurrently terminated NCT01478802
    

Intervention name(s): Bronchoscopy for the sampling of bronchoalveolar lavage (BAL) fluid
Intervention type(s): Other
Intervention MeSH terms: Dimercaprol
Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Intensive care unit patients with acute respiratory failure due to ventilator-associated
        pneumonia or the acute respiratory distress syndrome.
      
Biospecimen description: 
      Bronchoalveolar Lavage Fluid
    
Keywords: Pneumonia, Ventilator-Associated; Respiratory Distress Syndrome, Adult; Pulmonary Surfactant-Associated Proteins; activin A