Beating the Clock in Ventilator-induced Lung Injury

Circadian clocks organize behavior and physiology to an approximately 24-hour rhythm, facilitating adaptation to the environmental cycle of day and night. Mounting evidence links abnormal circadian alignment of behaviors like eating, sleeping, and light exposure to adverse health outcomes (1, 2). Critical illness, and possibly the intensive care environment itself, disrupts the endogenous circadian clock and may drive pathophysiological responses (3). For example, concentrations of melatonin, its precursors and metabolites, temperature, blood pressure, and the cellular transcriptome oscillate in grossly abnormal circadian patterns in critically ill patients (4, 5).

Autonomous molecular clocks present in every cell are synchronized in vivo by systemic signals, including autonomic innervation and hormone fluctuations that are coordinated by a master clock in the hypothalamic suprachiasmatic nuclei (6, 7). Clock-mediated differences in cellular function, created by oscillations in gene expression, might make the tissue more vulnerable to physiologic insult depending on the time of day. In the lung, inflammation is circadian, as has been noted in asthma and circadian variation in myeloid cell trafficking (8, 9). The relevant question for intensivists interested in translating physiologic insights into patient care is whether common intensive care interventions affect the body differently according to the time of day.

In this issue of the Journal, Felten and colleagues (pp. 1464–1474) tested the hypothesis that ventilator-induced lung injury (VILI) is a clock-dependent phenomenon. Investigators entrained mice in a 12 hour:12 hour light:dark cycle. Rodents are typically nocturnal mammals, as compared with diurnal humans, although strain-specific patterns are not always restricted to the dark (i.e., active phase). Once entrained, mice were subjected to varying degrees of injurious mechanical ventilation at either the beginning of the rest (dawn) or the active phase (dusk) of the circadian rhythm (10). They observed greater lung injury from exposures occurring during the rest phase of the circadian cycle. The differential harm was observed histologically in neutrophil recruitment, barrier permeability, inflammatory cytokine production, and hyaline membrane structure. Most importantly, there were measurable functional differences in lung compliance, inspiratory capacity, and lung permeability, resulting in more impaired oxygenation. Several steps were taken to sequentially confirm the pathogenesis of these time-dependent effects, including experiments in a clock gene (BMAL-1) knockout model, in which previously seen myeloid cell-specific diurnal variation in VILI was abated, making mice less susceptible to VILI-induced pathology (10).

The results of this study are both intriguing and exciting as they confirm that the degree of induced lung injury, and perhaps subsequent morbidity, is circadian-dependent. How might this influence intensive care? Chronotherapy, the intentional timing of treatments to maximize benefits and minimize adverse effects, has already become established in other fields. One of the most well-known applications is the timing of statin therapy, for which numerous studies have consistently demonstrated greater benefit with evening dosing (11). Tumorigenesis is also circadian, and chronochemotherapy has attracted substantial interest (12).

Embracing circadian supportive practices such as how we feed patients (e.g., daytime bolus feeding), care patterns (e.g., clustering of activities to daytime hours), and day–night cycle sensitive building design (e.g., natural light exposure) may have a significant impact on patient outcomes (13). Although the timing of some aspects of ICU care cannot be controlled (e.g., need to intubate or unplanned admission), others can be (e.g., when to complete a bronchoalveolar lavage or take a patient back to surgery). Studies such as the present work by Felton and colleagues are important because they identify candidate mechanisms that are clinically important and exhibit a rhythmic risk profile.

VILI is a major complication of intensive care, and some pathways that mediate VILI are affected by clock gene agonists such as REV-ERB agonists, for example, the NLRP3 inflammasome. Targeting REV-ERB may abate activation of the inflammasome, thereby mitigating VILI (14). In a rat model, the REV-ERB agonist SR9009 rescued many of the deleterious changes induced by high tidal ventilation (15). Although there are no longitudinal studies of circadian rhythm throughout an ICU stay, it is possible that encouraging cell clock renormalization can improve recovery. Given the importance of circadian-organized physiology, the future practice of critical care may eventually entail a bundle of clock-entraining interventions together with judicious timing of discrete invasive procedures and other care to optimize outcomes.