Acute respiratory distress syndrome (ARDS) constitutes a cataclysmic respiratory entity described half a century ago by Ashbaugh et al.1 The Berlin consensus is the most recent ARDS definition2 and considers the syndrome based only on clinical variables (hypoxemia, presence of risk factor and bilateral infiltrate in the X-ray). This definition also mentions that diffuse alveolar damage (DAD) is the ARDS histological hallmark, but it was ruled out from the definition given the procedure to diagnose DAD was considered unfeasible in the real world.3 Despite all efforts, many pharmacological treatments currently tried out on patients with ARDS were unable to demonstrate their effectiveness.4–6 A plausible hypothesis to explain these negative results postulates that ARDS is a syndrome that can harbor several different diseases.5,7–9 Furthermore, this fact may determine that patients who carry conditions that mimic ARDS (e.g. pulmonary embolism, lung cancer or alveolar hemorrhage)9,10 are not diagnosed and thus not specifically treated. Therefore, their outcome could be more prone to deterioration.7

Currently, despite several techniques existing to study the histology in patients with diffuse parenchymal lung diseases, open lung biopsy continues to be the gold standard.11 In patients with ARDS, open lung biopsy may be indicated in two situations: (a) early in the course of an ARDS when a curable etiology is highly suspect and less invasive diagnostic procedures are inconclusive and/or toward the end of the first week of evolution in order to diagnose the fibroproliferative phase.12,13

The two primary endpoints of this study are to describe the rate of treatment change associated with the histological result and to describe the rate of side effects associated with open lung biopsy.

Authorization to report the present results was obtained from the ethics committee of the Hospital Santa Clara, Bogota, Colombia. Informed consent was obtained to perform the open lung biopsy.

During the study period 32 open lung biopsies were performed; 17 were ruled out as they did not have ARDS and 15 were considered for further analysis. Of these, 9 were discharged from the hospital and the others were pronounced dead. The reasons of death were refractory hypoxemia (patients 3 and 12), shock (patient 1 and 8) and both refractory hypoxemia and shock (patient 2 and 7).

The median age of the patient was 33 (25; 45) years old. Likewise, the median days between hospital admission and ARDS diagnosis was 5 (2; 9) days, and from the ARDS diagnosis to the open lung biopsy 3 (2; 8) days. Clinical and analytical variables of each patient are shown in Table 1 and Fig. 1.

Figure 1.

Interaction between length in ICU, severity, outcome and presence of side effect associated to open lung biopsy.

(0.1MB).

The result of the open lung biopsies allowed us to diagnose a specific histological entity in all the patients except for one that presented lung edema (Table 2). Within the group of patients with a specific histological entity, 12 presented DAD (4 as an isolated pattern and 8 associated with another entity), 1 presented Bronchiolitis Obliterans Organizing Pneumonia and 1 presented a Wegener granumolmatous with alveolar hemorrhage. The presence of DAD did not modify the risk of death (DAD 1 of 3 and non DAD 5 of 12; p=0.792).

The open lung biopsy results determined a treatment optimization in 11 patients; in most of the cases the change was related to anti-tuberculous and steroid treatment (Table 3). Limitation in the therapeutic effort or indication of a new procedure or medical interconsultation was not performed based on the open lung biopsy result.

Regarding side effects associated with open lung biopsy, no deaths but 3 airway leaks and 1 hemothorax were registered. All side effect were resolved before ICU discharge.

The main result of our study is the high rate of treatment change (0.73) associated with the pathological result of and the acceptable rate of side effects (0.25) of the open lung biopsy. These results, which are in line with reports from other authors,20–22 confirm the useful information that open lung biopsies provide in patients with ARDS of unknown etiology.

The treatment was changed in roughly 3 of 4 patients based on the open lung biopsy results. The most frequent intervention was to discontinue antimicrobial (antibiotics 3/14; antituberculosis 5/10; antifungal 4/6 and antiviral 1/3) or steroid (5/10) treatment. In only one of the cases the antibiotics were changed, and in 3 of the cases steroid therapy was started after the open lung biopsy results. This is highly relevant because this means that without the information provided by the open lung biopsy, most of the patients would be exposed to an unnecessary risk sourced from the side effects of each drug. In addition, it is well known that drugs can exert their benefit only if the population in which they are tested present their target.29 Most of the preclinical ARDS models used for discovering and testing new drugs exhibit the DAD pattern,30 but only half of ARDS patients present DAD.20,31 This low clinical and pathological correlation may be responsible for the lack of effective pharmacological treatments in ARDS patients.6,15 In our cohort, we found that ARDS with DAD constituted 0.80 of the population, which was a higher proportion than what was reported in a recent meta-analysis (meta proportion of DAD 0.48, 95CI, 0.42–0.53).20 We speculate that this difference could be related to the fact that we only use this procedure in cases of completely unknown ARDS, after the patient has been evaluated by a multidisciplinary team and has undergone an exhaustive work-up diagnosis. Given the small sample, we could not exclude that this discrepancy was explained coincidently. On the other hand, diagnosing pathological patterns different from DAD is also relevant because most of them constitute entities with specific treatments and outcomes.10,20,7–28 For example, patient 15 had a high clinical suspicion of bilateral pulmonary pneumonia but the pathology analysis found alveolar edema, which could be associated with a better outcome. On the contrary, the unexpected discovery of lung cancer in patient 1 undoubtedly darkens her outcome.

In reference to procedure safety, we found that roughly 0.25 of patients presented one side effect but none of these complications resulted in death (the cause of death in the two patients with an air leak was refractory hypoxemia with shock; the other death was from refractory hypoxemia). This proportion is similar to that observed in a recent meta-analysis (metaproprotion 0.23, 95CI 0.16; 0.31).23 Furthermore, the main complication (air leak) in our cohort was also the most frequent complication in the meta-analysis mentioned before.23 This result should be considered cautiously because it is clear that open lung biopsy is an invasive and complex procedure associated with severe side effects.

Another important feature of our study is the fact that all open lung biopsies were performed by a senior thoracic surgeon at bedside without transferring the patient to the operating theater. Similar to the cohort reported on by Charbonney et al.,24 this procedure was not associated with any side effect and could avoid some risks associated with patients’ transference such as transitory disconnection of mechanical ventilation, mobilization in an unstable condition or intravenous access loss.25,26

This study has several limitations, firstly it is a retrospective study that includes a wide period of time (seven years) during which several treatments have changed. Indeed, some clinical parameters that we currently recognize as relevant (e.g. driving pressure, plateau pressure or prone position) were not recorded. This limitation, which is also shared by similar studies (Guerin et al.21: 1998–2013; Kao et al.22: 1999–2014 and Charbonney et al.24: 1993–2005), reflects the difficulty for conducting this type of study. Secondly, it has been carried out in a single center. Thirdly, there is an evident selection bias (e.g. non-resolving ARDS, different time lapsed between ARDS diagnosis and open lung biopsy, non-consecutive patients, etc.). Finally, the size of the cohort is relatively small.

This study also presents several strengths: (a) the review of the lung samples was double blind and (b) all the patients were evaluated by an interdisciplinary group of physicians with well demonstrated experience in ARDS.

To conclude, the information provided from the pathological result of the open lung biopsy performed at bedside in ARDS patients with unknown etiology could be relevant as it may optimize the treatment and outcome. Likewise, this invasive procedure seems to be associated with an acceptable risk. However, a natural question for future studies might be “Are side effects of treatment and procedures that are empirically applied to ARDS patients worse or more dangerous than side effects of open lung biopsy?”

Review concept, design and writing the manuscript: GO, MG, DM, PC

On behalf of all authors, the corresponding author declares that we have no conflicts of interest.