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.

Conclusion: 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.

Keywords: Biomarkers; Lung damage; Mechanical ventilation; Personalized early intervention.

Fig. 1

Flowchart of patients in the study. PASS: the Procalcitonin And Survival Study, a 1200-patient intensive care randomized trial [21]

Fig. 2

Surfactant protein D serum levels according to primary admission reason. a “Learning cohort”/northern sites. b “Validating cohort.” Boxes are medians and interquartile ranges. Whiskers are total range. Rhombuses are means

Fig. 3

Cumulative incidence of successful weaning from respirator within 28 days after intensive care admission and death while intubated—total cohort (“learning”/northern cohort + “validating”/southern cohort). The two upper curves are regarding “successful weaning from respirator” (vs. still intubated at day 28); the two lower curves are regarding “dead while intubated” (vs. alive at day 28). Patients extubated <48 h at death were counted as “dead while intubated.” Patients extubated and alive at day 28 and those extubated ≥48 h at death were counted as successfully weaned from ventilator. N = 758. Gray scales are 95% CI. SPD surfactant protein D. “High SPD is >525.6 ng/mL

Fig. 4

Adjusted odds ratios for the patient being “alive and without mechanical ventilation for ≥20 days within first 28 days after ICU admission.” All variables were entered in the same logistic regression model. The graph is separated to display odds ratios for both binary and continuous covariates. Cut points for SP-D and CC16 are equal to upper 15 percentile in the northern/learning cohort. Boxes and whiskers are odds ratio and 95% CIs, respectively