Postoperative pain usually lasts considerably longer than the duration of plain bupivacaine HCl when used for single-injection peripheral nerve blocks, even with unapproved additives such as epinephrine, clonidine, and steroids. A formulation of bupivacaine HCl within liposomes (Exparel, Pacira BioSciences, USA) is approved by the U.S. Food and Drug Administration (Silver Spring, Maryland) for use in interscalene, adductor canal, transversus abdominis plane, and popliteal–sciatic nerve blocks. Pacira proposes that liposomal bupivacaine lasts 48 to 72 h, which far exceeds the duration of plain bupivacaine (usually less than 24 h). However, the extent to which liposomal bupivacaine prolongs analgesia remains controversial.  A trial by Chan et al. in this issue of Anesthesiology helps us understand this potentially transformative local anesthetic. 

Chan et al. evaluated 80 patients having distal radial fracture fixation with a supraclavicular brachial plexus block who were randomized to bupivacaine hydrochloride (20 ml of 0.5%) or a combination of bupivacaine hydrochloride (10 ml of 0.5%) and liposomal bupivacaine (10 ml of 1.3%).  The primary outcome was weighted area under the pain-at-rest curve (AUC) during the initial 48 postoperative hours. As defined by the authors, weighted AUC is AUC divided by the monitoring period, which is generally referred to as time-weighted average. Addition of liposomal bupivacaine improved weighted AUC compared with standard bupivacaine: 0.6 versus 1.4 points (P < 0.001). This result raises two fundamental questions. The first is whether weighted AUC adequately characterizes the temporal nature of pain. And the second is whether the improvement was clinically meaningful.

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.

In this month’s issue of Anesthesiology, Corlette et al. present a review aiming to analyze published electroencephalography (EEG) profiles in anesthetized neonates. This article comes from a team renowned not only for their expertise in pediatric and neonatal anesthesia and their focused work on EEG monitoring in young children but also for their considerations on consciousness and its abolition in anesthetized neonates.

The authors found only nine observational studies describing the evolution of EEG in anesthetized neonates, reflecting the complexity and rarity of research in this field. Despite the weaknesses of most publications analyzed, a characteristic profile marked by the alternation of high- and low-amplitude EEG activity segments, termed discontinuity, was identified. This discontinuity pattern is characteristic of the EEG of the immature brain, and the authors discuss its presence in anesthetized full-term neonates and modulatory factors such as hypothermia or sevoflurane concentration. Several pathophysiological hypotheses are raised, and the diagnostic ambiguity with burst suppression tracings is analyzed.

EEG analysis enables visualization of the pharmacodynamic effects of γ-aminobutyric acid–mediated (GABAergic) anesthetic agents on the cerebral cortex. The complexity of interpreting EEG changes in anesthetized neonates is due to the need to consider both the particularities of the EEG trace in the neonate, whose cerebral cortex is still maturing, and the possible pharmacodynamic specificities of anesthetic agents on this immature brain.

Conventional EEG, obtained by electrodes on the scalp, captures a low-amplitude electrical signal representing the summation of the electrical potentials of cortical neurons, organized in columns. In awake adults, there is rich, desynchronized spontaneous activity, typically resulting in a low-amplitude EEG with rapid oscillations, dominated by alpha and beta types. GABAergic anesthetic agents induce dose-dependent neuronal inhibition, electrically translated by synchronization of neuronal discharges leading to characteristic profiles on the cortical EEG. These profiles show a dose-dependent slowing and increase in the amplitude of the slow oscillations, up to the occurrence of burst suppression and possible isoelectric tracing. Functionally, the adult brain is characterized by rich and complex neuronal activity, organized into networks with thalamo-cortical and cortico-cortical connections, involved in consciousness and reactivity to ascending stimuli. EEG tracings recorded in anesthetized children greater than 1 yr old are close to those observed in adults, differing mainly in oscillation amplitude changes. 

Conversely, in neonates, cerebral immaturity is associated with a distinctive and evolving EEG pattern in the first months of life. The dynamic processes of cerebral maturation result in changes in cortical neuron activity and hence in the EEG patterns.  Cerebral maturation begins in utero and continues rapidly through the first 3 months of life and then more slowly into adolescence. This postnatal maturation involves the continuation of several processes initiated in utero, such as intrinsic subcortical brain activity, white matter myelination, increase in cortical grey matter and dendritic growth of cortical pyramidal neurons, and synaptogenesis. These processes lead to the organization and progressive development of thalamocortical and corticocortical neuronal connections. Pharmacologically, γ-aminobutyric acid initially has an excitatory function, which changes to an inhibitory function during the third trimester of pregnancy.

Electroencephalographically, the premature brain is characterized by low and discontinuous activity, with the emergence of slow and large oscillations (delta) that increase with brain maturation, whereas the periods of discontinuity decrease.  In the full-term neonate, the EEG is mainly characterized by slow delta and theta oscillations. The discontinuity periods have almost disappeared, and when they persist transiently, they alternate with periods of slow activity (delta and theta). EEG evolves in the first months of life with an overall acceleration of oscillations, resulting in an increased dominant frequency and decreased amplitude, reflecting the complexification of neuronal electrical activity with cortical connection development.  Simply put, it could be proposed that there is a parallel evolution of neuronal organization, connection development, and EEG tracing complexity.

In this review, the authors discuss the presence and origin of discontinuity episodes (less than 25 µV) observed in EEG of full-term neonates anesthetized with sevoflurane. As previously seen, the term of discontinuity comes from the EEG in premature infants, reflecting limited neuronal activity due to immaturity. In full-term neonates anesthetized with sevoflurane, the presence of these discontinuous episodes could reflect dose-dependent GABAergic neural inhibition of physiologically already slow and easily depressible EEG. Similarly, hypothermia, associated with reduced cellular metabolism, could enhance neuronal inhibition, leading to a slowing of the EEG up to burst suppression. Burst suppression patterns are described in children and in adults as low-amplitude periods (less than 5 µV) possibly resulting from a decrease of the cerebral metabolic rate coupled with stabilization by adenosine triphosphate-gated potassium channels. 

In neonates, there is some ambiguity surrounding the description of these EEG segments of low activity, which can be considered either as true suppressions  or as the premise of suppressive segments or, as in this review, an EEG pattern close to suppression but specific to anesthetized neonates. The most interesting aspect of these EEG descriptions in anesthetized neonates is the almost systematic presence of these episodes of cortical inhibition at low doses of anesthetic, which in older children are associated with more classic EEG changes close to those observed in adults. Given the low complexity of interneuronal connections in the neonatal cortex, it may be hypothesized that inhibitory GABAergic action leads rapidly, at low doses of anesthetic, to a clear drop in cortical cerebral electrical activity.

Whether this cortical inhibition reflects the depth of the hypnotic component of anesthesia depends on the definition of hypnosis and the brain structures involved—isolated cerebral cortex, which is unlikely, or cortex and subcortex, which is more likely. Subcortical activity in anesthetized neonates is probably less easily inhibited than cortical activity. Indeed, the minimum alveolar concentration of sevoflurane (motor response to nociceptive simulation) is higher in young infants than in older children, whereas inhibition of EEG activity occurs at lower doses of sevoflurane.  Clinically, it is not uncommon to observe a hemodynamic or motor response to nociceptive stimuli in neonates, even with an isoelectric EEG. This suggests greater cortical sensitivity to GABAergic anesthetic effects compared to subcortical regions.

In the context of concerns about potential neurotoxicity of anesthetic agents on the developing brain, the question of target EEG effects arises. If the goal in neonate is, as in adults, to limit the hypnotic dose to avoid or minimize total cortical neuronal inhibition expressed as discontinuities or burst suppression episodes, then one risks subcortical structure reactivity during nociceptive stimulation, possibly causing adrenergic stimulation with stress hormone release or implicit memory trace formation facilitated by amygdala activation. Implicit memory, responsible for fear conditioning in animals, is present and stable from the first months of life, unlike explicit memory, which seems to emerge alongside language acquisition. Thus, the target of inhibiting subcortical reactivity in anesthetized neonates without overdosing the cerebral cortex seems to be crucial, possibly achievable through central analgesics such as opioids.

Beyond the challenges of interpreting EEG data from analyzed studies, owing to the variety of anesthetic agents used, from thiopental to sevoflurane, halothane, and propofol boluses, the main limitation of this review might be the lack of data and discussion on the hemodynamic state of anesthetized neonates. Neuronal metabolic activity and thus EEG patterns are highly dependent on cerebral blood flow, which is itself conditioned by blood pressure, especially below the autoregulation threshold. The studies of Rhondali et al.  have highlighted the vulnerability of young infants anesthetized with sevoflurane, particularly neonates, in terms of cerebral blood flow reduction, potentially occurring with a 20% decrease in mean arterial pressure. This hemodynamic approach to the effects of anesthesia on the EEG could be integrated into the overall reasoning of target effects of anesthesia in neonates, drawing inspiration from the triple (or double) low concept described in adults.