Lung Biopsy in patients with Acute Respiratory Distress Syndrome Supported on Extracorporeal Membrane Oxygenation: A Two-year Experience

Veno-venous extracorporeal membrane oxygenation (VV-ECMO) is an increasingly utilized rescue therapy for patients with acute respiratory distress syndrome (ARDS).¹ Guidelines recommend lung biopsy if a diagnosis is not established within the first week of ECMO therapy although there is minimal data to support the safety or utility of this recommendation.² While the role of lung biopsy in neonatal and pediatric patients on VV-ECMO is well described,³ reports in adults are prohibitively small.⁴ Indeed, the largest study reflective of current practice describes lung biopsy in 2 patients with ARDS.⁵ We report our experience with adults with ARDS undergoing lung biopsy while on VV-ECMO.

We reviewed consecutive adults placed on VV-ECMO at our medical center between January 1, 2016 and December 31, 2017. Patients who remained hospitalized during their index admission at the time of review were excluded. Of 50 total patients, 9 met the Berlin Definition for severe ARDS and underwent a lung biopsy while on VV-ECMO.⁶ One patient underwent two separate biopsy procedures. Patient characteristics are summarized in Table 1. The median age was 49.5 years (range 19–78) and the median number of days on ECMO prior to biopsy was 14.3 (range 1–50). At our center, we do not routinely use therapeutic anticoagulation unless indicated for another diagnosis. Accordingly, 5 (50%) of our patients were not on systemic anticoagulation at the time of biopsy. Transbronchial biopsy with cup forceps was the most common biopsy technique (4, 40%) followed by transbronchial cryobiopsy (2, 20%). Diffuse alveolar damage (DAD) was the most common pathology identified (7, 70%). In 2 cases, pathology results led to a direct change in management. Patients received a mean of 3.4 units of packed red blood cells over the 3 days following biopsy (range 0–8). One patient experienced clinically significant hemoptysis following a transbronchial biopsy with forceps. No patients experienced a hemothorax or pneumothorax in the 24 hours following the procedure.

Table 1.

Patient and biopsy characteristics

Age	Sex	History	Days on ECMO prior to biopsy	Systemic anticoagulation prior to biopsy	Procedure	Pathology	Impact on Management	Transfusions during the 5 days prior to biopsy (units)	Transfusions during the 3 days following biopsy (units)	New PTX following procedure	Survival to hospital discharge
26	F	DAH without known autoimmune disease	2	No	VATS	DAD without capillaritis	Cytotoxic therapy withheld	2	3	No	No
66	M	ARDS following HSCT	23	Yes	Tbbx with cup forceps	Organizing pneumonia	None (Continued on steroids)	3	1	No	No
66	F	ARDS, concern for rapidly progressive ILD	1	No	Cryobiopsy	DAD	None	2	4	No	No
78	M	ARDS with CMV viremia	10	No	Tbbx with cup forceps	DAD, no CMV seen	None	3	0	No	No
32*	F	Lung transplant recipient with ARDS and CMV viremia	20	No	Tbbx with cup forceps	DAD, no acute rejection, + CMV inclusions	Immunosuppressive medication reduced, continued on antiviral therapy	3	1	No	No
32*	F	Lung transplant recipient with ARDS and CMV viremia	50	Yes	Tbbx with cup forceps	Scant lung parenchyma with chronic inflammation. No CMV	None	4	6	No	No
43	F	ARDS & Influenza A (H1N1)	10	Yes	Wedge resection during emergent thoracotomy for hemothorax	DAD, negative infectious stains	None	11	3	No	Yes
56	F	ARDS and Influenza A	3	Yes	Cryobiopsy	DAD and organizing pneumonia	None (Continued on steroids)	3	0	No	Yes
19	F	ARDS & disseminated adenovirus	11	Yes	Mini-thoracotomy	DAD and organizing pneumonia, necrotizing candida lusitaniae pneumonia	None (Continued on micafungin)	5	8	No	No
62	M	ARDS	13	No	Wedge resection during exploratory thoracotomy for intrathoracic hematoma evacuation	Chronic inflammation with areas of organization	None	13	8	No	No

Abbreviations: ARDS, acute respiratory distress syndrome; CMV, cytomegalovirus; DAD, diffuse alveolar damage; DAH, diffuse alveolar hemorrhage; ECMO, extracorporeal membrane oxygenation; HSCT, hematopoietic stem cell transplant; ILD, interstitial lung disease; F, female; M, male; Pt, patient; PTX, pneumothorax; Tbbx, transbronchial biopsy; VATS, video-assisted thoracoscopic surgery

^*Patient underwent two separate lung biopsy procedures

Our results have several important implications. We are the first to describe the use of transbronchial cryobiopsy for patients on ECMO. This technique may be a useful alternative to open lung biopsy in critically ill patients. Second, we found that even within a single institution, the decision to pursue lung biopsy and the sampling technique used is variable. In our cohort, patients who required an operative procedure for another indication had a surgical lung biopsy performed. There were no other identifiable patient characteristics that determined procedure selection. We presume that our experience is not unique and reflective of a lack of data to guide best practice. The high mortality of patients who underwent biopsy compared to all patients placed on VV-ECMO during the study period (78% vs 54% respectively) and median number of days on ECMO prior to biopsy (14.3) suggest that biopsy was pursued predominantly in severely ill patients who were difficult to liberate from ECMO.

Third, acknowledging the limitations of our sample size and selection bias, our experience suggests that lung biopsy is feasible and in general safe for patients with ARDS on VV-ECMO. Our group and others have described the use of therapeutic anticoagulation-free VV-ECMO.⁷ This technical advance is important as hemorrhage is one of the most common complications of lung biopsy. Avoiding anticoagulation may decrease the procedural risk of lung biopsy for patients on VV-ECMO. Fourth, DAD was the histopathologic diagnosis in 70% of biopsy specimens. To our knowledge, this is the first description of the correlation between the Berlin Definition of ARDS and the presence of DAD on histopathologic examination of lung biopsy specimens for patients on VV-ECMO. This rate is higher than what has been reported in studies of open lung biopsy in non-resolving ARDS for patients not on ECMO⁸ and in autopsy series.⁹ As the presence of DAD has been associated with poor outcomes for patients with ARDS, the frequent identification of DAD in our study may be a reflection of our cohort’s severity of illness.¹⁰

Finally, while biopsy results infrequently changed management, they were helpful in excluding causes of respiratory failure that were potentially rapidly responsive to targeted therapy (e.g., organizing pneumonia, infection, acute rejection) - information that was useful in all cases when discussing expectations and prognosis with families. We wonder whether the established recommendation to pursue lung biopsy in ARDS only when there is a high likelihood of a “contributive result” might require reframing in patients who do not experience clinical improvement after several weeks on ECMO.¹¹ The use of lung biopsy to guide prognosis in critically ill children on ECMO is well-described.³ Perhaps in adults, documenting extensive fibrosis might inform decision making and goals of care discussions for ECMO-dependent patients.