Acute respiratory distress syndrome phenotypes with distinct clinical outcomes in PHARLAP trial cohort

Background: The Permissive Hypercapnia, Alveolar Recruitment and Low Airway Pressure (PHARLAP) randomised controlled trial compared an open lung ventilation strategy with control ventilation, and found that open lung ventilation did not reduce the number of ventilatorfree days (VFDs) or mortality in patients with moderate-to-severe acute respiratory distress syndrome (ARDS). Parsimonious models can identify distinct phenotypes of ARDS (hypo-inflammatory and hyperinflammatory) which are associated with different outcomes and treatment responses. Objective: To test the hypothesis that a parsimonious model would identify patients with distinctly different clinical outcomes in the PHARLAP study. Design, setting and participants: Blood and lung lavage samples were collected in a subset of PHARLAP patients who were recruited in Australian and New Zealand centres. A previously validated parsimonious model (interleukin-8, soluble tumour necrosis factor receptor-1 and bicarbonate) was used to classify patients with blood samples into hypo-inflammatory and hyperinflammatory groups. Generalised linear modelling was used to examine the interaction between inflammatory phenotype and treatment group (intervention or control). Main outcome measure: The primary outcome was number of VFDs at Day 28. Results: Data for the parsimonious model were available for 56 of 115 patients (49%). Within this subset, 38 patients (68%) and 18 patients (32%) were classified as having hypo-inflammatory and hyperinflammatory phenotypes, respectively. Patients with the hypoinflammatory phenotype had more VFDs at Day 28 when compared with those with the hyperinflammatory phenotype (median [IQR], 19.5 [11-24] versus 8 [0-21]; P = 0.03). Patients with the hyperinflammatory phenotype had numerically fewer VFDs when managed with an open lung strategy than when managed with control “protective” ventilation (median [IQR], 0 [0-19] versus 16 [8-22]). Conclusion: In the PHARLAP trial, ARDS patients classified as having a hyperinflammatory phenotype, with a parsimonious three-variable model, had fewer VFDs at Day 28 compared with patients classified as having a hypo-inflammatory phenotype. Future clinical studies of ventilatory strategies should consider incorporating distinct ARDS phenotypes into their trial design. endothelial and inflammatory markers with serial measurements of lung lavage samples and serum. Although the lack of observed clinical benefit in the PHARLAP study may reflect no difference between groups, or inadequate power to detect a difference, we hypothesised that differences in phenotypic responses could have contributed to this result. To date, the biomarker characteristics of the two phenotypes have only been studied in plasma. The differences in the biomarker signatures of the phenotypes in the lung compartment are unknown. We hypothesized that inflammatory burden in bronchoalveolar lavage (BAL) samples would reflect that observed in plasma. To test this, we used serum and BAL samples from the pre-planned PHARLAP substudy cohort to define hypo-inflammatory and hyperinflammatory phenotypes and examine outcomes.