Proteomic Profiling to Reveal Novel Prognostic Markers for Neurological Outcome Following Resuscitation
Condition: Cardiac Arrest With Successful Resuscitation
MeSH terms: Heart Arrest
Study type: Observational [Patient Registry]

Summary: 
      Background: Cardiac arrest is a life-threatening event. Intensivists are challenged with an
      increasing number of patients with uncertain neurological outcome following cardiopulmonary
      resuscitation (CPR). The prognostic value of current biomarkers for neurophysiologic
      long-term outcome is limited.

      Hypothesis: We hypothesize that specific brain-derived tissue leakage proteins can be
      identified to reveal novel, more reliable prognostic biomarkers for good neurological
      outcome.

      Methods: This translational study (n=100) is a combination of a prospective basic science
      study intended to reduce the number of potential plasma biomarker candidates by proteomic
      shotgun analyses in brain tissue autopsy samples and plasma samples from resuscitated
      patients (n=10) and a prospective clinical validation study in a large study population
      (n=90) by high-throughput analyses. Selection of proteomic markers and signature estimation
      will be performed to discriminate patients with good and poor outcome.

      Clinical perspective: A structured proteomic analysis approach might identify the best marker
      out of all proteins liberated during cellular damage.
    

Detailed description: 
      Background: Cardiac arrest is a life-threatening event. Intensivists are challenged with an
      increasing number of patients with uncertain neurological outcome following cardiopulmonary
      resuscitation (CPR). The prognostic value of current biomarkers for neurophysiologic
      long-term outcome is limited. Therefore, identification of novel plasma markers with higher
      predictive value for neurophysiological recovery is critical for patient management after
      CPR.

      Hypothesis: We hypothesize that specific brain-derived tissue leakage proteins can be
      identified to reveal novel, more reliable prognostic biomarkers for good neurological
      outcome.

      Methods: This translational study (n=100) is a combination of a prospective basic science
      study intended to reduce the number of potential plasma biomarker candidates by proteomic
      shotgun analyses in brain tissue autopsy samples and plasma samples from resuscitated
      patients (n=10) and a prospective clinical validation study in a large study population
      (n=90) by high-throughput analyses. Samples will be analyzed by proteomic shotgun analyses
      using the Q-Exactive quadrupole-orbitrap mass spectrometer (MS). MS/MS data will be
      interpreted by the MaxQuant and Perseus Software. In order to identify brain-derived proteins
      within plasma, the plasma proteome of 10 resuscitated patients will be compared to the
      proteomic profile of brain tissue. This will reduce the number of potential plasma biomarker
      candidates associated with neurologic outcome. The prospective validation in plasma samples
      will be performed by a targeted proteomics approach using selected reaction monitoring (SRM)
      on a triple quadrupole ion MS. Neurological outcome will be assessed by the five-point scale
      (death, persistent vegetative state, severe disability, moderate disability, and good
      recovery) according to the cerebral performance categories (CPC). A CPC sore of <3 is
      considered a good neurological outcome. Selection of proteomic markers and signature
      estimation will be performed by L1 regularized logistic regression, where the tuning
      parameter will be optimized by cross-validated model performance. The signature's ability to
      discriminate patients with good and poor outcome will be described by ROC analysis.

      Clinical perspective: An accurate predictor of neurological outcome following CPR is of
      utmost clinical importance. However, previous studies focused on a very limited array of
      biomarkers. Therefore, a structured proteomic analysis approach might identify the best
      marker out of all proteins liberated during cellular damage.
    

Observational model: Cohort
Time perspective: Prospective
Sampling method: Probability Sample
Study population: 
        Resuscitated patients
      
Biospecimen description: 
      Plasma samples stored at -80°C
    
Keywords: Prognosis; Neurological outcome; Resuscitation; Biomarker