“…ARDS is the epilog of inflammatory dissemination, which sometimes starts in localized lung regions…”
“…the trajectory of ARDS may be determined by events occurring well before pulmonary dysfunction is obvious.”
CLINICIANS diagnose acute respiratory distress syndrome (ARDS) using consensus criteria such as the Berlin definition,1 which primarily rely on blood oxygen levels and on chest radiography to identify inflammatory lung injury. Patients who meet these criteria may benefit from low-stretch ventilation,2 prone positioning,3 muscle paralysis,4 and perhaps lung recruitment.5 Because ARDS is often underdiagnosed,6 improving its recognition and the application of evidence-based treatment should improve outcomes. Investigators, encouraged by funding agencies, are conducting research on early preemptive strategies capable of reducing ARDS incidence.7 However, there is no accepted standard for ARDS: autopsy studies show that consensus definitions have limited specificity (around 50%) when tested against histologically proven injury.8,9 This is obviously problematic when the goal is to contain lung inflammation: early therapy will have uncertain success until better markers of injury progression are available. Clinically diagnosed ARDS is the epilog of inflammatory dissemination, which sometimes starts in localized lung regions.10 We know little about this evolution. But the imaging study by Wellman et al.11 published in this issue of Anesthesiology provides some insight into the early stages of lung injury.
The authors studied sheep receiving a lipopolysaccharide infusion (a model of septic lung injury) while ventilated for 20 h. Positron emission tomography (PET) was performed at baseline and at 6 and 20 h of ventilation while lung injury progressed. By measuring distribution and cell uptake of 2-deoxy-2-[(18)F]fluoro-d-glucose—a radioactive, nonmetabolized analog of glucose—the authors measured regional metabolic activity (assumed to reflect acute inflammation) and abundance of neutrophils in pulmonary tissue. Spatially matched measurements of aeration, ventilation, and perfusion were also obtained. In a similar model, the same group previously showed that 2-deoxy-2-[(18)F]fluoro-d-glucose PET detected regional inflammatory responses to lipopolysaccharide and ventilator-induced lung stretch.12
The long duration of the experiments and the large animal model used created fairly realistic conditions and thus meaningful results: a major improvement over the majority of experimental studies in this field, which use small animals and shorter time scales (few hours). But the work by Wellman et al.11 is remarkable also for other reasons. First, thanks to the study design, the authors were able to capture a time frame when regional inflammation was detectable but severe hypoxemia and loss of aeration (which essentially define clinical ARDS) were not. This result suggests that the trajectory of ARDS may be determined by events occurring well before pulmonary dysfunction is obvious. If this very early stage is detected, intervention may have more chances of success than anything attempted in established ARDS. Second, the earliest metabolic changes were visible in the dependent (dorsal) regions of the lungs where aeration was reduced. Later on, metabolic activity also increased in the nondependent (ventral) lung, which was more inflated. With microarray methodology, the authors showed differential gene activation in dependent versus nondependent tissue, supporting regional differences of injury mechanisms.
Early inflammation in the dorsal lung suggests that injury may originate here. There are various potential explanations for this finding, with dorsal preponderance of blood flow13,14 and unstable atelectasis (“atelectrauma”) being high on the list.15 In addition, specific ventilation was also consistently higher in dorsal (poorly aerated) versus ventral lung regions (fig. 3C in the main text of the article11 ). Specific ventilation is a measurement of alveolar gas turnover that is indirectly related to regional stretch induced by the ventilator.16 It does not necessarily coincide with pulmonary aeration: studies have shown that lung tissue with reduced, but not abolished, gas content may be hyperventilated.17,18 High specific ventilation could be a marker of gas maldistribution and of local augmentation of lung stretch.
Several mechanisms of ventilator-induced injury are relatively well understood in established ARDS, when tidal volume is concentrated in a small fraction of viable but hyperinflated “baby lung,” causing alveolar epithelial damage in these regions.19 Yet, the processes through which ventilation might cause harm in minimally diseased or in healthy lungs (e.g., during surgical anesthesia20 ) remain uncertain. The results of the study by Wellman et al.11 support a model wherein local events may trigger injury in poorly inflated lung regions when inflammation is still mild and before macroscopic hyperinflation of the “baby lung.” Systemic inflammation likely potentiates the harmful effects of mechanical ventilation, but it might not be obligatory: a previous study by the same group showed increased dorsal metabolic activity during prolonged ventilation in healthy animals.21 Nevertheless, the current study suggests important links among regional lung mechanics, metabolic activity, and gene expression, which may explain how mechanical ventilation injures patients before they have the functional and morphologic characteristics of ARDS.
It is unlikely that PET will be used on a broad clinical scale for the identification of patients at risk of ARDS. It is more plausible that targeted microarray methodology, enabled by studies such as the study by Wellman et al.,11 will yield more precise biomarkers of lung inflammation and, at some point, more personalized care. In the meantime, clinicians will have to deal with ambiguous selection criteria and inherently uncertain decision-making. But studies like this are valuable not only in their application of innovative techniques, but also in their unearthing of novel information that itself may increase the success of efforts to preempt ARDS development. If the dorsal lung is vulnerable in the early stages of lung injury, strategies could be designed to improve the alveolar microenvironment (e.g., with patient positioning) or to deliver therapeutics in a more targeted manner—approaches that could be more effective than simply using canonic low-stretch ventilation, which did not prevent inflammation from evolving to severe injury in the authors’ study. All of us interested in the prevention of ARDS should take note here: our best weapon against ARDS may not be completely protective in the earliest stages of lung injury.
The authors are not supported by, nor maintain any financial interest in, any commercial activity that may be associated with the topic of this article.