title: Prediction of non-recovery from ventilator-demanding acute respiratory failure, ARDS and death using lung damage biomarkers: data from a 1200-patient critical care randomized trial.
abstract: BACKGROUND
  It is unclear whether biomarkers of alveolar damage (surfactant protein D, SPD) or conductive airway damage (club cell secretory protein 16, CC16) measured early after intensive care admittance are associated with one-month clinical respiratory prognosis. If patients who do not recover respiratory function within one month can be identified early, future experimental lung interventions can be aimed toward this high-risk group. We aimed to determine, in a heterogenous critically ill population, whether baseline profound alveolar damage or conductive airway damage has clinical respiratory impact one month after intensive care admittance.
  
  
  METHODS
  Biobank study of biomarkers of alveolar and conductive airway damage in intensive care patients was conducted. This was a sub-study of 758 intubated patients from a 1200-patient randomized trial. We split the cohort into a "learning cohort" and "validating cohort" based on geographical criteria: northern sites (learning) and southern sites (validating).
  
  
  RESULTS
  Baseline SPD above the 85th percentile in the "learning cohort" predicted low chance of successful weaning from ventilator within 28 days (adjusted hazard ratio 0.6 [95% CI 0.4-0.9], p = 0.005); this was confirmed in the validating cohort. CC16 did not predict the endpoint. The absolute risk of not being successfully weaned within the first month was 48/106 (45.3%) vs. 175/652 (26.8%), p < 0.0001 (high SPD vs. low SPD). The chance of being "alive and without ventilator ≥20 days within the first month" was lower among patients with high SPD (adjusted OR 0.2 [95% CI 0.2-0.4], p < 0.0001), confirmed in the validating cohort, and the risk of ARDS was higher among patients with high SPD (adjusted OR 3.4 [95% CI 1.0-11.4], p = 0.04)-also confirmed in the validating cohort.
  
  
  CONCLUSIONS
  Early profound alveolar damage in intubated patients can be identified by SPD blood measurement at intensive care admission, and high SPD level is a strong independent predictor that the patient suffers from ARDS and will not recover independent respiratory function within one month. This knowledge can be used to improve diagnostic and prognostic models and to identify the patients who most likely will benefit from experimental interventions aiming to preserve alveolar tissue and therefore respiratory function. Trial registration This is a sub-study to the Procalcitonin And Survival Study (PASS), Clinicaltrials.gov ID: NCT00271752, first registered January 1, 2006.
authors.affiliation: CHIP/Department of Infectious Diseases, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, Copenhagen Ø, Denmark. jens.ulrik.jensen@regionh.dk.|Department of Clinical Microbiology, Copenhagen University Hospital, Hvidovre, Denmark. jens.ulrik.jensen@regionh.dk.
authors.forename: Jens-Ulrik S
authors.identifier: http://orcid.org/0000-0003-4036-0521
authors.initials: JS
authors.lastname: Jensen
authors.affiliation: CHIP/Department of Infectious Diseases, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, Copenhagen Ø, Denmark.|Department of Anesthesia and Intensive Care, Copenhagen University Hospital, Hillerød, Denmark.
authors.forename: Theis S
authors.initials: TS
authors.lastname: Itenov
authors.affiliation: Department of Anesthesia and Intensive Care, Bispebjerg Hospital, Copenhagen University Hospital, Copenhagen, Denmark.|Department of Anesthesia and Intensive Care, Copenhagen University Hospital, Gentofte, Denmark.
authors.forename: Katrin M
authors.initials: KM
authors.lastname: Thormar
authors.affiliation: Department of Anesthesia and Intensive Care, Copenhagen University Hospital, Hillerød, Denmark.|Department of Anesthesia and Intensive Care, Copenhagen University Hospital, Glostrup, Denmark.
authors.forename: Lars
authors.initials: L
authors.lastname: Hein
authors.affiliation: Department of Anesthesia and Intensive Care, Copenhagen University Hospital, Gentofte, Denmark.|Department of Anesthesia and Intensive Care, Copenhagen University Hospital, Glostrup, Denmark.
authors.forename: Thomas T
authors.initials: TT
authors.lastname: Mohr
authors.affiliation: Department of Anesthesia and Intensive Care, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Mads H
authors.initials: MH
authors.lastname: Andersen
authors.affiliation: Department of Anesthesia and Intensive Care, Copenhagen University Hospital, Hvidovre, Denmark.
authors.forename: Jesper
authors.initials: J
authors.lastname: Løken
authors.affiliation: Department of Anesthesia and Intensive Care, Copenhagen University Hospital, Herlev, Denmark.
authors.forename: Hamid
authors.initials: H
authors.lastname: Tousi
authors.affiliation: Department of Clinical Microbiology, Copenhagen University Hospital, Hvidovre, Denmark.
authors.forename: Bettina
authors.initials: B
authors.lastname: Lundgren
authors.affiliation: Department of Anesthesia and Intensive Care, Copenhagen University Hospital, Glostrup, Denmark.
authors.forename: Hans Christian
authors.initials: HC
authors.lastname: Boesen
authors.affiliation: CHIP/Department of Infectious Diseases, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, Copenhagen Ø, Denmark.
authors.forename: Maria E
authors.initials: ME
authors.lastname: Johansen
authors.affiliation: Centre for Thrombosis and Hemostasis, Rigshospitalet, Copenhagen University Hospital, Copenhagen Ø, Denmark.
authors.forename: Sisse R
authors.initials: SR
authors.lastname: Ostrowski
authors.affiliation: Centre for Thrombosis and Hemostasis, Rigshospitalet, Copenhagen University Hospital, Copenhagen Ø, Denmark.
authors.forename: Pär I
authors.initials: PI
authors.lastname: Johansson
authors.affiliation: CHIP/Department of Infectious Diseases, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, Copenhagen Ø, Denmark.
authors.forename: Jesper
authors.initials: J
authors.lastname: Grarup
authors.affiliation: Centre for Respiratory Medicine and Allergy, University South Manchester Hospital NHS Foundation Trust and University of Manchester, Manchester, UK.
authors.forename: Jørgen
authors.initials: J
authors.lastname: Vestbo
authors.affiliation: CHIP/Department of Infectious Diseases, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, Copenhagen Ø, Denmark.
authors.forename: Jens D
authors.initials: JD
authors.lastname: Lundgren
keywords: Biomarkers; Lung damage; Mechanical ventilation; Personalized early intervention