Identification of novel sub-phenotypes of severe ARDS requiring ECMO using latent class analysis

Abstract

Background: Sub-phenotyping of acute respiratory distress syndrome (ARDS) could be useful for evaluating the severity of ARDS or predicting its responsiveness to given therapeutic strategies, but no studies have yet investigated the heterogeneity of patients with severe ARDS requiring veno-venous extracorporeal membrane oxygenation (V-V ECMO).

Methods: We conducted this retrospective multicenter observational study in adult patients with severe ARDS treated by V-V ECMO. We performed latent class analysis (LCA) for identifying sub-phenotypes of severe ARDS based on the radiological and clinical findings at the start of ECMO support. Multivariate Cox regression analysis was conducted to investigate the differences in mortality and association between the PEEP setting of ≥ 10 cmH₂O and mortality by the sub-phenotypes.

Results: We identified three sub-phenotypes from analysis of the data of a total of 544 patients with severe ARDS treated by V-V ECMO, as follows: Dry type (n = 185; 34%); Wet type (n = 169; 31%); and Fibrotic type (n = 190; 35%). The 90-days in-hospital mortality risk was higher in the patients with the Fibrotic type than in those with the Dry type (adjusted hazard ratio [95% confidence interval] 1.75 [1.10-2.79], p = 0.019) or the Wet type (1.50 [1.02-2.23], p = 0.042). The PEEP setting of ≥ 10 cmH₂O during the first 3 days of ECMO decreased the 90-days in-hospital mortality risk only in patients with the Wet type, and not in those with the Dry or Fibrotic type. A significant interaction effect was observed between the Wet type and the PEEP setting of ≥ 10 cmH₂O in relation to the 90-day in-hospital mortality (p_interaction = 0.036).

Conclusions: The three sub-phenotypes showed different mortality rates and different relationships between higher PEEP settings in the early phase of V-V ECMO and patient outcomes. Our data suggest that we may need to change our management approach to patients with severe ARDS during V-V ECMO according to their clinical sub-phenotype.

Keywords: Computed tomography; In-hospital mortality; Latent class analysis; Severe acute respiratory distress syndrome; Veno-venous extracorporeal membrane oxygenation.

Fig. 1

Differences among the three sub-phenotypes in the categorized variables used for latent class analysis. The proportions of each categorized variable used for the latent class analysis among three sub-phenotypes are shown. Abbreviations: l-r, left–right; d-v, dorso-ventral; CTR, cardiothoracic ratio; RU, right upper lobe; RM, right middle lobe; RL, right lower lobe; LU, left upper lobe; LL, left lower lobe; PA, pulmonary artery size; RA / LA, right atrium / left atrium ratio; IVC, inferior vena cava; WBC, white blood cell; CRP, C-reactive protein; APTT, activated partial thromboplastin time; BUN, blood urea nitrogen; Bil, bilirubin; TP, total protein; Alb, albumin; Hb, hemoglobin; BMI, body mass index

Fig. 2

Differences in the outcomes among the three sub-phenotypes. The 90-day in-hospital mortality (A) and veno-venous extracorporeal membrane oxygenation (V-V ECMO) liberation ratio (B) were compared among the three sub-phenotypes using the log-rank test. Four patients were excluded because they had missing values about the time of ECMO liberation

Fig. 3

Differences in the effect of high positive end-expiratory pressure values after the start of V-V ECMO support among the three sub-phenotypes. The 90-day in-hospital mortality was compared between patients who received PEEP ≥ 10 cmH₂O and < 10 cmH₂O after the start of veno-venous extracorporeal membrane oxygenation (V-V ECMO) in each sub-phenotype using the log-rank test. Three patients in the Dry type were excluded because of missing PEEP values. Abbreviations: PEEP, positive end-expiratory pressure

Fig. 4

Three-axis schema to explain the differences among the three sub-phenotypes. Based on the multi-dimensional scaling according to the top 15 important variables (see sFig. 6B), we assumed that the differences among the three types could be explained by their positions along three axes: inflammatory response, intensity of opacities, and presence/absence of fibrotic changes. Namely, the Dry type may share the characteristics of the hypo-inflammatory type and tends to show a GGO pattern on the chest CT. The Wet type may share the characteristics of the hyper-inflammatory type and tends to show a pure consolidation pattern on the chest CT. The Fibrotic type tends to show a GGO pattern with fibrotic changes on the chest CT