Can Biomarkers Correctly Predict Ventilator-associated Pneumonia in Patients Treated With Targeted Temperature Management After Cardiac Arrest? An Exploratory Study of the Multicenter Randomized Antibiotic (ANTHARTIC) Study

Abstract

Importance: Ventilator-associated pneumonia (VAP) frequently occurs in patients with cardiac arrest. Diagnosis of VAP after cardiac arrest remains challenging, while the use of current biomarkers such as C-reactive protein (CRP) or procalcitonin (PCT) is debated.

Objectives: To evaluate biomarkers' impact in helping VAP diagnosis after cardiac arrest.

Design setting and participants: This is a prospective ancillary study of the randomized, multicenter, double-blind placebo-controlled ANtibiotherapy during Therapeutic HypothermiA to pRevenT Infectious Complications (ANTHARTIC) trial evaluating the impact of antibiotic prophylaxis to prevent VAP in out-of-hospital patients with cardiac arrest secondary to shockable rhythm and treated with therapeutic hypothermia. An adjudication committee blindly evaluated VAP according to predefined clinical, radiologic, and microbiological criteria. All patients with available biomarker(s), sample(s), and consent approval were included.

Main outcomes and measures: The main endpoint was to evaluate the ability of biomarkers to correctly diagnose and predict VAP within 48 hours after sampling. The secondary endpoint was to study the combination of two biomarkers in discriminating VAP. Blood samples were collected at baseline on day 3. Routine and exploratory panel of inflammatory biomarkers measurements were blindly performed. Analyses were adjusted on the randomization group.

Results: Among 161 patients of the ANTHARTIC trial with available biological sample(s), patients with VAP (n = 33) had higher body mass index and Acute Physiology and Chronic Health Evaluation II score, more unwitnessed cardiac arrest, more catecholamines, and experienced more prolonged therapeutic hypothermia duration than patients without VAP (n = 121). In univariate analyses, biomarkers significantly associated with VAP and showing an area under the curve (AUC) greater than 0.70 were CRP (AUC = 0.76), interleukin (IL) 17A and 17C (IL17C) (0.74), macrophage colony-stimulating factor 1 (0.73), PCT (0.72), and vascular endothelial growth factor A (VEGF-A) (0.71). Multivariate analysis combining novel biomarkers revealed several pairs with p value of less than 0.001 and odds ratio greater than 1: VEGF-A + IL12 subunit beta (IL12B), Fms-related tyrosine kinase 3 ligands (Flt3L) + C-C chemokine 20 (CCL20), Flt3L + IL17A, Flt3L + IL6, STAM-binding protein (STAMBP) + CCL20, STAMBP + IL6, CCL20 + 4EBP1, CCL20 + caspase-8 (CASP8), IL6 + 4EBP1, and IL6 + CASP8. Best AUCs were observed for CRP + IL6 (0.79), CRP + CCL20 (0.78), CRP + IL17A, and CRP + IL17C.

Conclusions and relevance: Our exploratory study shows that specific biomarkers, especially CRP combined with IL6, could help to better diagnose or predict early VAP occurrence in cardiac arrest patients.

Keywords: C-reactive protein/procalcitonin; biomarker; cardiac arrest; chemokine/interleukin; ventilator-assisted pneumonia.

Figure 1.

Flowchart. ATB = antibiotic, D = day after inclusion, pts = patients, VAP = ventilator-associated pneumonia occurring within 2 days after sampling (green group), VAP-0 = no ventilator-associated pneumonia diagnosed within 2 days after sampling (yellow group), wo = without. *: one patient, with only one blood sample available at baseline (D0) but not at D3, did not experience VAP at D1-D2 but VAP occurred at D3-D4.

Figure 2.

Association between “routine” biomarkers and ventilator-associated pneumonia occurrence adjusted on randomization group. A, C-reactive protein (CRP). B, Procalcitonin (PCT). See also eTable S2 (http://links.lww.com/CCX/B358) for corresponding values. CRP and PCT are expressed as logarithmic values. D0 = sampling at baseline, D3 = sampling at D3 after inclusion. VAP = ventilator-associated pneumonia within 2 days after sampling (gray box plots).

Figure 3.

Best areas under the curve for significant combinations of two biomarkers, including C-reactive protein (CRP) and adjusted on group randomization, to predict ventilator-associated pneumonia (VAP) within 2 days after sampling. A, CRP and interleukin (IL)17A. B, CRP and IL6. C, CRP and IL17C. D, CRP and C–C chemokine 20 (CCL20). ROC = receiver operating characteristic.