Bursting at the Seams: Barotrauma in Coronavirus Disease 2019 Acute Respiratory Distress Syndrome Patients.

“Building an airplane as we are flying it.” This is the sentiment often used to describe the plight of the scientific community after the onset of the 2020 coronavirus disease 2019 (COVID-19) global pandemic. Patients stricken with respiratory symptoms began to overwhelm hospitals, with little lead time for clinicians or scientists to delineate the disease course or treatment. Colleagues in China and Italy, living in the early epicenters of the pandemic, described a respiratory failure condition that bore similarities to acute respiratory distress syndrome (ARDS). As time progressed, however, multiple centers began to cite key differences between COVID-19 ARDS and “classical” ARDS, both clinically and pathophysiologically (1). Differences included the time of onset to ARDS, differences in lung compliance, and steroid responsiveness (1, 2).

In this issue of Critical Care Medicine, Belletti et al (3) bring to the forefront a phenomenon that may be another distinguishing consequence of COVID-19 ARDS, an increased rate of barotrauma in adult patients undergoing invasive mechanical ventilation. Defining barotrauma as the development of pneumothorax or pneumomediastinum, the authors performed a systematic review of the current literature and conclude that there may be an increased occurrence rate of barotrauma in COVID-19 patients. The pathophysiologic mechanism has yet to be elucidated, however, its implications could change the approach to mechanical ventilation in COVID-19 patients.

Belletti et al (3) performed their systematic review in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines and followed Cochrane Collaboration recommendations. A total of 13 studies met the authors’ inclusion criteria: studies investigating adult patients with COVID-19 ARDS requiring mechanical ventilation, which had reported data on the rate and outcome of barotrauma. These studies encompassed data from 1,814 mechanically ventilated COVID-19 patients and 493 mechanically ventilated non-COVID-19 (control) patients. All 13 studies were observational (one was multicenter) and most studies were conducted in the United States. The primary outcome was the number of patients with at least one barotrauma event, defined as development of pneumothorax or pneumomediastinum. Secondary outcomes were all-cause follow-up mortality and predictors of barotrauma. The authors found a total of 266 of 1,814 patients with COVID-19 ARDS, or 14.7% who had at least one barotrauma event. On pooled analysis, the rate of barotrauma was 16.1% (95% CI, 11.8–20.4%). Three of the 13 studies included non-COVID-19 ARDS (control) patients in whom barotrauma occurred in 31 of 493 patients or 6.3%, with a pooled rate of 5.7% (95% CI, –2.1% to 13.5%) (3). Although the control group was small in number, the authors note that the 6% rate of barotrauma in non-COVID-19 ARDS patients is consistent with a previous prospective multicenter study (4).

The secondary outcome of pooled mortality in COVID-19 and non-COVID-19 ARDS patients with and without barotrauma was also reported. An international, multicenter, prospective study prior to both this systematic review and the pandemic cited a mortality rate of 46.1% in non-COVID-19 patients with severe ARDS (5). Grasselli et al (6) reported a mortality rate of 48.7% in COVID-19 ARDS patients, not stratified for barotrauma. In the current study by Belletti et al (3), the mortality rate in ventilated COVID-19 patients who developed barotrauma was 61.6% (95% CI, 50.2–73%) and 49.5% in COVID-19 patients without a barotrauma event. Finally, only one of the 13 studies reported a 10% mortality rate in non-COVID ARDS patients who developed barotrauma (3). The implications of such a small cohort is admittedly limited.

The authors also analyzed separately the development of pneumothorax or pneumomediastinum in the COVID-19 patients and cite pooled rates of 10.7% and 11.2%, respectively (3). This contrasts to the reported combined rate of barotrauma in non-COVID ARDS patients ranging from 3% to 10% (4). Limited specific data on pneumothorax or pneumomediastinum was available on control (non-COVID-19 ARDS) patients. The majority of COVID-19 patients who developed pneumothorax underwent chest tube drainage; however, the study could be strengthened with more detail regarding the treatment strategies for the barotrauma events in a larger proportion of patients. Indeed, absence of appropriate management of pneumothorax or pneumomediastinum could impact ultimate outcomes such as mortality. Standardized treatment approaches could also limit any confounding factors between groups related to pneumothorax/pneumomediastinum management.

The strengths of this review include consistencies with prior studies in both the incidence rates and mortality rates of patients with COVID-19 ARDS without barotrauma (3, 5, 6). Earlier studies also showed a higher mortality rate in COVID-19 ARDS when compared with non-COVID ARDS. This could suggest increased disease severity of COVID-19 compared with other etiologies of ARDS. Thus, the authors’ finding of a higher rate of barotrauma and associated mortality in COVID-19 ARDS patients appears consistent. However, as the sentiment of “building a plane as we are flying it” captures, the unique situation of the pandemic introduces many confounding factors. Could the increase in rate of an adverse event such as barotrauma and increased mortality speak to other confounders unique to the pandemic: over-burdened hospitals, limited trained providers, and a nonstandardized ventilator strategy?

As the authors acknowledge, the study had several important limitations including the relatively small number of patients in several studies, the heterogeneity of data, and lack of a control group in 10 of the 13 included studies. Another limitation is the paucity of data regarding the ventilator settings at the time of occurrence of barotrauma. Only five studies reviewed reported ventilator settings at the time of barotrauma event, and only three reported baseline ventilator settings for both patients who developed barotrauma, and for patients who did not (3). Of the three studies that had data on a control group of patients, they found no significant difference in ventilator settings between groups (3). The authors suggest a possible increase in lung frailty secondary to COVID-19, predisposing these patients to barotrauma, but this remains a point of debate (7–10). While this possibility cannot be ruled out, standardized ventilator settings across studied groups are needed to exclude the possibility of ventilator-induced barotrauma as the primary mechanism behind the phenomena that the authors report.

Of particular interest in this review is the highlighting of the utility of the “Macklin sign,” or the appearance of air dissecting along the bronchovascular bundles on CT scan (11–15). This was initially described as the “Macklin effect” by Canadian pulmonologists Dr. Charles Macklin and Dr. Madge Macklin (12) in 1944. In animal experiments in which they over-distended a distal lower lobe of a cat lung, they observed air dissecting from over-distended alveoli traveling a path of least resistance to the hilum (11, 12). It has since been used to name the radiographic appearance of peribronchovascular emphysema on CT scan and has been reported to occur spontaneously and secondary to traumatic chest injuries (13, 14). Recently, case reports have described this radiographic sign in nonventilated COVID-19 patients (15). Belletti et al (3) suggest that this radiographic sign could be an early indicator of barotrauma in COVID-19 ARDS patients and could alert clinicians of an impending barotrauma event such as pneumothorax and pneumomediastinum up to 12 days in advance. The authors note that the clinical utility of the Macklin sign still needs confirmatory studies for this patient population; however, it holds promise as a possible tool to identify and risk stratify patients who may develop clinically significant barotrauma.

As we continue to understand more about the pathophysiology of COVID-19 ARDS, we commend the authors for highlighting a feature of severe COVID-19 respiratory disease that could impact how we mechanically ventilate these patients. Their systematic review suggests an increased rate of barotrauma events in this subset of patients, in addition to a higher mortality rate. Considering these findings, they recommend the early and proactive employment of lung-protective ventilation strategies and early consideration of tools such as extracorporeal membrane oxygenation to mitigate the detrimental effects of positive pressure on the lungs (3).

While further studies are needed to elucidate these findings in a standardized fashion, the authors aptly raise awareness to the risk of barotrauma in COVID-19 ARDS patients. They also highlight the Macklin effect, a radiographic finding that may be clinically useful to risk stratify patients. As we simultaneously learn about and treat this novel virus, we depend on invaluable reviews such as these to synthesize and summarize the existing literature, sharpen our clinical judgment and enhance our diagnostic armamentarium, while paving the way for essential future studies to be conducted.

Is barotrauma unique to the pathophysiology of COVID-19 ARDS? Or is it a marker of severe disease, apparent due to the current high rates of ARDS, nonstandardization of ventilator management during the pandemic, and the necessary utilization of healthcare providers who do not otherwise manage ventilators? As we continue to “build” the safest aircraft while we fly within it, we must maintain a healthy sense of clinical skepticism and humility with data that are presented to us. We commend the authors for their analysis of barotrauma as a potential marker of severe COVID-19 disease.