Predictors of diffuse alveolar damage in patients with acute respiratory distress syndrome: a retrospective analysis of clinical autopsies

Abstract

Background: Although diffuse alveolar damage (DAD) is considered the typical histological pattern of acute respiratory distress syndrome (ARDS), only half of patients exhibit this morphological hallmark. Patients with DAD may have higher mortality than those without DAD. Therefore, we aimed to identify the factors associated with DAD in patients with ARDS.

Methods: We analyzed autopsy samples of 356 patients who had ARDS at the time of death. DAD was assessed by two pathologists, and ARDS criteria were evaluated by two intensivists. Criteria for severe ARDS included the degree of hypoxemia and the ancillary variables of the current Berlin definition assessed within 48 h before death: radiographic severity, high positive end-expiratory pressure (PEEP) level, and physiological variables (i.e., altered respiratory system compliance and large anatomic dead space).

Results: After multivariable analysis, high PEEP levels, physiological variables, and opacities involving only three quadrants on chest radiographs were not associated with DAD. The four markers independently associated with DAD were (1) duration of evolution (OR 3.29 [1.95-5.55] for patients with ARDS ≥ 3 days, p < 0.001), (2) degree of hypoxemia (OR 3.92 [1.48-10.3] for moderate ARDS and 6.18 [2.34-16.3] for severe ARDS, p < 0.01 for both), (3) increased dynamic driving pressure (OR 1.06 [1.04-1.09], p = 0.007), and (4) radiographic severity (OR 2.91 [1.47-5.75] for patients with diffuse opacities involving the four quadrants, p = 0.002). DAD was found in two-thirds of patients with a ratio of partial pressure of arterial oxygen to fraction of inspired oxygen ≤ 100 mmHg and opacities involving the four quadrants.

Conclusions: In addition to severe hypoxemia, diffuse opacities involving the four quadrants were a strong marker of DAD.

Keywords: Acute respiratory distress syndrome; Diffuse alveolar damage; Intensive care unit; Mechanical ventilation.

Fig. 1

Bar graph showing the proportion of patients with diffuse alveolar damage (DAD) according to radiologic severity (extent of opacities on chest radiographs) in mild, moderate, and severe acute respiratory distress syndrome (ARDS). All in all, DAD was significantly more frequent in patients with extensive infiltrates involving the four quadrants than in the others: 101 (59%) of 171 patients with four quadrants vs. 58 (31%) of 185 patients with two or three quadrants (p < 0.001)

Fig. 2

Bar graph showing the proportion of patients with diffuse alveolar damage (DAD) according to characteristics of the patients and criteria for severity of acute respiratory distress syndrome (ARDS). After multivariate analysis, the four variables independently associated with DAD (indicated by black bars) were duration of evolution of ARDS (≥3 days), severity of hypoxemia, increased dynamic driving pressure, and radiologic severity with diffuse opacities involving the four quadrants. C _RS Respiratory system compliance, PaO ₂ /FiO ₂ Ratio of partial pressure of arterial oxygen to fraction of inspired oxygen, PEEP Positive end-expiratory pressure, VE _CORR Corrected expired volume per minute

Fig. 3

Bar graph showing temporal changes of tidal volume (gray bars) in patients with moderate or severe acute respiratory distress syndrome and the proportion of patients with diffuse alveolar damage (DAD) at autopsy examination (black bars) between the first decade at left (1991–1999) and the second decade at right (2000–2010) (i.e., before and after the era of reduction in tidal volumes). From 2000, tidal volumes were significantly reduced (from 699 ± 148 ml to 543 ± 106 ml, p < 0.0001), and this reduction was associated with a parallel reduction in the proportion of patients with DAD (from 56% to 44%, p = 0.03), suggesting that low tidal volumes may attenuate DAD. *p < 0.05, **p < 0.01