“[T]hese findings emphasize the importance of directly measuring lung aeration to understand lung disease rather than relying on measures of gas exchange alone.”

There is increasing awareness that aeration state of the lung, rather than absolute volume, is the primary determinant of ventilator-induced lung injury in neonates.  For example, atelectasis (low lung volumes with alveolar collapse) and overdistension (excessive lung volume and stretch on alveoli) are both injurious and present with similarly impaired gas exchange and lung mechanics despite diametrically opposing aeration states. Current lung protective strategies aim to maximize gas exchange while minimizing those injurious states.  To do so, clinicians need accurate bedside tools to guide respiratory support. When compared to older patients, regional and dynamic assessment of neonatal lung aeration is difficult. There are fewer validated bedside tools, many of which also deliver excessive ionizing radiation (such as chest radiography). Consequently, lung ultrasound has generated considerable interest as a tool that may address this clinical problem in neonates.

In this issue of Anesthesiology, Loi et al.  described changes in ultrasound determined global and regional aeration across 10 lung regions in a cohort of 246 infants with various causes of primary lung disease, including respiratory distress syndrome secondary to surfactant deficiency (50), evolving bronchopulmonary dysplasia (50), neonatal acute respiratory distress syndrome (80), transient tachypnea of the neonate (50), and no lung disease (16). Outcomes included a novel measure of regional aeration heterogeneity, expressed as the coefficient of variation of the lung ultrasound scores from each of the 10 lung regions. The authors then determined the differences in global lung ultrasound scores and the distribution of region-specific aeration patterns between disease groups. Not surprisingly, transient tachypnea of the neonate and evolving bronchopulmonary dysplasia had the highest global intrapatient heterogeneity (coefficient of variation, 61% and 57%, respectively), compared to term controls (1.6%).

Interpatient heterogeneity was expressed with the Gini–Simpson index. All respiratory conditions showed moderate to high interpatient heterogeneity of aeration, ranging from a Gini–Simpson heterogeneity index of 0.5 (neonatal acute respiratory distress syndrome) to 0.72 (evolving bronchopulmonary dysplasia). Again controls showed minimal heterogeneity (Gini–Simpson index, 0.3). Greater aeration heterogeneity indicates that lung regions have different volume states (such as atelectasis, overdistension, and adequate recruitment), but not necessarily which ones. Interestingly, greater aeration heterogeneity correlated with better global lung ultrasound scores and oxygenation.

To accommodate rapidly changing lung aeration states, the ideal neonatal bedside lung monitoring tool should be radiation-free, easy to learn, and repeatable. In recent years, lung ultrasound has been proven accurate in diagnosing numerous neonatal respiratory disorders, including the need for surfactant therapy and the risk of bronchopulmonary dysplasia.  Functional applications of lung ultrasound such as monitoring of lung volume during lung recruitment are also in development.  Ultrasound interacts with the reflective pleural surface and generates reproducible artifact patterns that vary with a known relationship depending on lung aeration.  These artifact patterns are then categorized and assigned aeration scores.  Most commonly, lung ultrasound images are acquired images from multiple regions of the lung that are then totaled to provide a global aeration score.  To date, neonatal lung ultrasound studies have primarily used global aeration scores. An alternative approach is to assess each regional score individually, as used in this study.  Comparing regional scores from different lung regions and between patients may provide important information regarding the regional aeration characteristics of the lung. 

In their study, Loi et al. provide the first evidence of the use of lung ultrasound to examine regional aeration heterogeneity in infants.  Here, they identified distinct patterns of regional lung aeration in infants with different respiratory pathologies. Their findings are consistent with observational studies using electrical impedance tomography, a bedside technique specifically designed to measure regional aeration patterns.  The authors also postulated that the association between greater heterogeneity and better oxygenation was due to better total lung aeration. As both interstitial lung disease and loss of aeration can produce the same ultrasound findings, an alternative explanation is that the findings are due to increased interstitial inflammatory changes that are observed with evolving lung disease in the absence of significant atelectasis.  Regardless, these findings emphasize the importance of directly measuring lung aeration to understand lung disease rather than relying on measures of gas exchange alone.

There is increasing interest in the importance of aeration heterogeneity as an independent mechanism of lung injury.  Injurious mechanisms such as volutrauma (overdistension), barotrauma (excessive energy transmission), or atelectasis (shear stress and biotrauma) are often thought of as a singular process occurring universally throughout the lung. This is overly simplistic. Due to variable gravity dependency and inconsistent expression of lung disease, lung mechanics are rarely uniform, especially during anesthesia and mechanical ventilation when the patient loses control of aeration.  When respiratory support is not optimal, or disease is severe, the resultant heterogenous aeration state allows multiple injury mechanisms to occur simultaneously within different parts of the lung. In animal studies, such highly heterogeneous states are the most injurious.  Unfortunately, the authors did not report lung injury outcomes. Thus, the moderate association between lung ultrasound heterogeneity scores and different pathologies should not be conflated to conclude lung ultrasound can be used to guide lung-protective ventilation settings.

  1. As neonatal respiratory diseases encompass a broad range of pathologic origins and clinical presentations, the high variability in regional lung aeration demonstrated in this study is not surprising.  This may have been due to methodologic limitations common to observational lung imaging studies. First, timing with relation to the disease status of each infant was not standardized. Timing has significant implications as acute lung disease creates more gravity-dependent heterogeneity than established disease, such as bronchopulmonary dysplasia, in which heterogeneity is usually driven by inflammatory changes in the lung.  Furthermore, the type of respiratory support delivered, whether it was optimized at the time of imaging, and the impact of spontaneous breathing are likely to have notable influences on lung ultrasound findings.  Detailed descriptions of respiratory phenotypes (regardless of modality) are less reliant on the overall population size, and more reliant on the population size of each lung phenotype. Replication of these findings in larger populations prospectively standardized by lung pathology and treatment is needed to determine whether lung ultrasound is suitable in the perioperative setting, especially if the goal is to target ventilation strategies to the specific respiratory diseases. Although such comprehensive longitudinal imaging studies require significant resources, given their expertise, the authors are well positioned to conduct such a study. This may also allow the true relationship between the evolution of aeration heterogeneity within specific respiratory diseases and important respiratory outcomes to be determined.

In the absence of accurate and reliable neonatal lung imaging tools, heterogenous lung aeration will likely remain an underrecognized risk factor for lung injury. The results from this paper provide evidence that lung ultrasound may address some of these knowledge gaps, but also raises important questions. When during an infant’s illness do injurious aeration states develop, and how can clinicians use this information to reduce risk? How do regional aeration characteristics evolve with time? And ultimately, how do these changes impact long-term respiratory outcomes? Answering these questions will provide clinicians with the knowledge to define neonatal lung phenotypes at the bedside and offer directed treatments that aim to avoid the injurious aeration states associated with mechanical ventilation.