RESUMEN
RATIONALE: Mechanical power (MP) is a summary variable incorporating all causes of ventilator-induced-lung-injury (VILI). We expressed MP as the ratio between observed and normal expected values (MPratio). OBJECTIVE: To define a threshold value of MPratio leading to the development of VILI. METHODS: In a population of 82 healthy pigs, a threshold of MPratio for VILI, as assessed by histological variables and confirmed by using unsupervised cluster analysis was 4.5. The population was divided into two groups with MPratio above or below the threshold. MEASUREMENTS AND MAIN RESULTS: We measured physiological variables every six hours. At the end of the experiment, we measured lung weight and wet-to-dry ratio to quantify edema. Histological samples were analyzed for alveolar ruptures, inflammation, alveolar edema, atelectasis. An MPratio threshold of 4.5 was associated with worse injury, lung weight, wet-to-dry ratio and fluid balance (all p < 0.001). After 48 h, in the two MPratio clusters (above or below 4.5), respiratory system elastance, mean pulmonary artery pressure and physiological dead space differed by 32%, 36% and 22%, respectively (all p < 0.001), being worse in the high MPratio group. Also, the changes in driving pressure, lung elastance, pulmonary artery occlusion pressure, central venous pressure differed by 17%, 64%, 8%, 25%, respectively (all p < 0.001). LIMITATIONS: The main limitation of this study is its retrospective design. In addition, the computation for the expected MP in pigs is based on arbitrary criteria. Different values of expected MP may change the absolute value of MP ratio but will not change the concept of the existence of an injury threshold. CONCLUSIONS: The concept of MPratio is a physiological and intuitive way to quantify the risk of ventilator-induced lung injury. Our results suggest that a mechanical power ratio > 4.5 MPratio in healthy lungs subjected to 48 h of mechanical ventilation appears to be a threshold for the development of ventilator-induced lung injury, as indicated by the convergence of histological, physiological, and anatomical alterations. In humans and in lungs that are already injured, this threshold is likely to be different.
RESUMEN
Excessive tidal stretching may initiate damage or retard healing after lung injury. However, it is seldom considered whether intracycle power and ventilatory forces of lesser magnitude than those required to cross an injury threshold might stimulate or accelerate beneficial adaptive responses. Acute lung injury is a dynamic process that may exhibit phase-dependent reparative responses to mechanical stress broadly similar to physical training, body trauma or sepsis. We propose that lower stress may not always be better through all phases of ARDS; moderately high tidal airway pressures that stay below the threshold of global injury may have potential to speed healing of the injured lung.
RESUMEN
BACKGROUND: Mechanical ventilation, a lifesaving intervention in critical care, can lead to damage in the extracellular matrix (ECM), triggering inflammation and ventilator-induced lung injury (VILI), particularly in conditions such as acute respiratory distress syndrome (ARDS). This review discusses the detailed structure of the ECM in healthy and ARDS-affected lungs under mechanical ventilation, aiming to bridge the gap between experimental insights and clinical practice by offering a thorough understanding of lung ECM organization and the dynamics of its alteration during mechanical ventilation. MAIN TEXT: Focusing on the clinical implications, we explore the potential of precise interventions targeting the ECM and cellular signaling pathways to mitigate lung damage, reduce inflammation, and ultimately improve outcomes for critically ill patients. By analyzing a range of experimental studies and clinical papers, particular attention is paid to the roles of matrix metalloproteinases (MMPs), integrins, and other molecules in ECM damage and VILI. This synthesis not only sheds light on the structural changes induced by mechanical stress but also underscores the importance of cellular responses such as inflammation, fibrosis, and excessive activation of MMPs. CONCLUSIONS: This review emphasizes the significance of mechanical cues transduced by integrins and their impact on cellular behavior during ventilation, offering insights into the complex interactions between mechanical ventilation, ECM damage, and cellular signaling. By understanding these mechanisms, healthcare professionals in critical care can anticipate the consequences of mechanical ventilation and use targeted strategies to prevent or minimize ECM damage, ultimately leading to better patient management and outcomes in critical care settings.
Asunto(s)
Matriz Extracelular , Pulmón , Respiración Artificial , Síndrome de Dificultad Respiratoria , Humanos , Matriz Extracelular/metabolismo , Síndrome de Dificultad Respiratoria/terapia , Síndrome de Dificultad Respiratoria/fisiopatología , Respiración Artificial/efectos adversos , Respiración Artificial/métodos , Pulmón/fisiopatología , Pulmón/metabolismo , Lesión Pulmonar Inducida por Ventilación Mecánica/fisiopatología , Lesión Pulmonar Inducida por Ventilación Mecánica/prevención & control , Metaloproteinasas de la Matriz/metabolismo , AnimalesRESUMEN
Acute respiratory distress syndrome (ARDS) is a well-defined clinical entity characterized by the acute onset of diffuse pulmonary injury and hypoxemia not explained by fluid overload. The COVID-19 pandemic brought about an unprecedented volume of patients with ARDS and challenged our understanding and clinical approach to treatment of this clinical syndrome. Unique to COVID-19 ARDS is the disruption and dysregulation of the pulmonary vascular compartment caused by the SARS-CoV-2 virus, which is a significant cause of hypoxemia in these patients. As a result, gas exchange does not necessarily correlate with respiratory system compliance and mechanics in COVID-19 ARDS as it does with other etiologies. The purpose of this review is to relate the mechanics of COVID-19 ARDS to its underlying pathophysiologic mechanisms and outline the lessons we have learned in the management of this clinic syndrome.
RESUMEN
Clinicians currently monitor pressure and volume at the airway opening, assuming that these observations relate closely to stresses and strains at the micro level. Indeed, this assumption forms the basis of current approaches to lung protective ventilation. Nonetheless, although the airway pressure applied under static conditions may be the same everywhere in healthy lungs, the stresses within a mechanically non-uniform ARDS lung are not. Estimating actual tissue stresses and strains that occur in a mechanically non-uniform environment must account for factors beyond the measurements from the ventilator circuit of airway pressures, tidal volume, and total mechanical power. A first conceptual step for the clinician to better define the VILI hazard requires consideration of lung unit tension, stress focusing, and intracycle power concentration. With reasonable approximations, better understanding of the value and limitations of presently used general guidelines for lung protection may eventually be developed from clinical inputs measured by the caregiver. The primary purpose of the present thought exercise is to extend our published model of a uniform, spherical lung unit to characterize the amplifications of stress (tension) and strain (area change) that occur under static conditions at interface boundaries between a sphere's surface segments having differing compliances. Together with measurable ventilating power, these are incorporated into our perspective of VILI risk. This conceptual exercise brings to light how variables that are seldom considered by the clinician but are both recognizable and measurable might help gauge the hazard for VILI of applied pressure and power.
Asunto(s)
Alveolos Pulmonares , Humanos , Modelos Biológicos , Alveolos Pulmonares/fisiología , Alveolos Pulmonares/fisiopatología , Respiración Artificial/métodos , Respiración Artificial/efectos adversos , Síndrome de Dificultad Respiratoria/fisiopatología , Síndrome de Dificultad Respiratoria/terapia , Estrés MecánicoRESUMEN
PURPOSE OF REVIEW: Describe the rationale for concern and accumulating pathophysiologic evidence regarding the adverse effects of high-level positive end expiratory pressure (PEEP) on excessive mechanical stress and ventilator-induced lung injury (VILI). RECENT FINDINGS: Although the inclusion of PEEP in numerical estimates of mechanical power may be theoretically debated, its potential to increase stress, strain, and mean airway pressure are not. Recent laboratory data in a variety of animal models demonstrate that higher levels of PEEP coupled with additional fluids needed to offset its impediment of hemodynamic function are associated with increased VILI. Moreover, counteracting end-tidal hyperinflation by external chest wall pressure may paradoxically improve respiratory mechanics, indicating that lower PEEP helps protect the small 'baby lung' of advanced acute respiratory distress syndrome (ARDS). SUMMARY: The potentially adverse effects of PEEP on VILI can be considered in three broad categories. First, the contribution of PEEP to total mechanical energy expressed through mechanical power, raised mean airway pressure, and end-tidal hyperinflation; second, the hemodynamic consequences of altered cardiac loading, heightened pulmonary vascular stress and total lung water; and third, the ventilatory consequences of compromised carbon dioxide eliminating efficiency. Minimizing ventilation demands, optimized body positioning and care to avoid unnecessary PEEP are central to lung protection in all stages of ARDS.
Asunto(s)
Síndrome de Dificultad Respiratoria , Lesión Pulmonar Inducida por Ventilación Mecánica , Animales , Humanos , Volumen de Ventilación Pulmonar/fisiología , Respiración con Presión Positiva/efectos adversos , Pulmón , Lesión Pulmonar Inducida por Ventilación Mecánica/prevención & controlRESUMEN
The effort to minimize VILI risk must be multi-pronged. The need to adequately ventilate, a key determinant of hazardous power, is reduced by judicious permissive hypercapnia, reduction of innate oxygen demand, and by prone body positioning that promotes both efficient pulmonary gas exchange and homogenous distributions of local stress. Modifiable ventilator-related determinants of lung protection include reductions of tidal volume, plateau pressure, driving pressure, PEEP, inspiratory flow amplitude and profile (using longer inspiration to expiration ratios), and ventilation frequency. Underappreciated conditional cofactors of importance to modulate the impact of local specific power may include lower vascular pressures and blood flows. Employed together, these measures modulate ventilation power with the intent to avoid VILI while achieving clinically acceptable targets for pulmonary gas exchange.
RESUMEN
Although the stretch that generates ventilator-induced lung injury (VILI) occurs within the peripheral tissue that encloses the alveolar space, airway pressures and volumes monitor the gas within the interior core of the lung unit, not its cellular enclosure. Measured pressures (plateau pressure, positive end-expiratory pressure, and driving pressure) and tidal volumes paint a highly relevant but incomplete picture of forces that act on the lung tissues themselves. Convenient and clinically useful measures of the airspace, such as pressure and volume, neglect the partitioning of tidal elastic energy into the increments of tension and surface area that constitute actual stress and strain at the alveolar margins. More sharply focused determinants of VILI require estimates of absolute alveolar dimension and morphology and the lung's unstressed volume at rest. We present a highly simplified but informative mathematical model that translates the radial energy of pressure and volume of the airspace into its surface energy components. In doing so it elaborates conceptual relationships that highlight the forces tending to cause end-tidal hyperinflation of aerated units within the 'baby lung' of acute respiratory distress syndrome (ARDS).
Asunto(s)
Síndrome de Dificultad Respiratoria , Lesión Pulmonar Inducida por Ventilación Mecánica , Humanos , Pulmón , Respiración con Presión Positiva/métodos , Volumen de Ventilación Pulmonar , Síndrome de Dificultad Respiratoria/complicaciones , Lesión Pulmonar Inducida por Ventilación Mecánica/etiología , Respiración Artificial/métodosRESUMEN
Nutritional support for acute respiratory distress syndrome (ARDS) patients shares metabolic notions common to other critically ill conditions. Nevertheless, it generates specific concern regarding the primary limitation of oxygen supply and the complications of carbon dioxide elimination, as well as the significant metabolic alterations due to the body's response to illness. In the present narrative review, after briefly summarizing the pathophysiology of critical illness stress response and patients' metabolic requirements, we focus on describing the characteristics of metabolic and artificial nutrition in patients with acute respiratory failure. In patients with ARDS, several aspects of metabolism assume special importance. The physiological effects of substrate metabolism are described for this setting, particularly regarding energy consumption, diet-induced thermogenesis, and the price of their clearance, transformation, and storage. Moreover, we review the possible direct effects of macronutrients on lung tissue viability during ARDS. Finally, we summarize the noteworthy characteristics of metabolic control in critically ill patients with ARDS and offer a suggestion as to the ideal methods of metabolic support for this problem.
RESUMEN
At the bedside, assessing the risk of ventilator-induced lung injury (VILI) requires parameters readily measured by the clinician. For this purpose, driving pressure (DP) and end-inspiratory static 'plateau' pressure ([Formula: see text]) of the tidal cycle are unquestionably useful but lack key information relating to associated volume changes and cumulative strain. 'Mechanical power', a clinical term which incorporates all dissipated ('non-elastic') and conserved ('elastic') energy components of inflation, has drawn considerable interest as a comprehensive 'umbrella' variable that accounts for the influence of ventilating frequency per minute as well as the energy cost per tidal cycle. Yet, like the raw values of DP and [Formula: see text], the absolute levels of energy and power by themselves may not carry sufficiently precise information to guide safe ventilatory practice. In previous work we introduced the concept of 'damaging energy per cycle'. Here we describe how-if only in concept-the bedside clinician might gauge the theoretical hazard of delivered energy using easily observed static circuit pressures ([Formula: see text] and positive end expiratory pressure) and an estimate of the maximally tolerated (threshold) non-dissipated ('elastic') airway pressure that reflects the pressure component applied to the alveolar tissues. Because its core inputs are already in use and familiar in daily practice, the simplified mathematical model we propose here for damaging energy and power may promote deeper comprehension of the key factors in play to improve lung protective ventilation.
Asunto(s)
Síndrome de Dificultad Respiratoria , Lesión Pulmonar Inducida por Ventilación Mecánica , Humanos , Volumen de Ventilación Pulmonar , Síndrome de Dificultad Respiratoria/complicaciones , Respiración Artificial/efectos adversos , Lesión Pulmonar Inducida por Ventilación Mecánica/etiología , Lesión Pulmonar Inducida por Ventilación Mecánica/prevención & control , Modelos TeóricosRESUMEN
Rationale: In the EOLIA (ECMO to Rescue Lung Injury in Severe ARDS) trial, oxygenation was similar between intervention and conventional groups, whereas [Formula: see text]e was reduced in the intervention group. Comparable reductions in ventilation intensity are theoretically possible with low-flow extracorporeal CO2 removal (ECCO2R), provided oxygenation remains acceptable. Objectives: To compare the effects of ECCO2R and extracorporeal membrane oxygenation (ECMO) on gas exchange, respiratory mechanics, and hemodynamics in animal models of pulmonary (intratracheal hydrochloric acid) and extrapulmonary (intravenous oleic acid) lung injury. Methods: Twenty-four pigs with moderate to severe hypoxemia (PaO2:FiO2 ⩽ 150 mm Hg) were randomized to ECMO (blood flow 50-60 ml/kg/min), ECCO2R (0.4 L/min), or mechanical ventilation alone. Measurements and Main Results: [Formula: see text]o2, [Formula: see text]co2, gas exchange, hemodynamics, and respiratory mechanics were measured and are presented as 24-hour averages. Oleic acid versus hydrochloric acid showed higher extravascular lung water (1,424 ± 419 vs. 574 ± 195 ml; P < 0.001), worse oxygenation (PaO2:FiO2 = 125 ± 14 vs. 151 ± 11 mm Hg; P < 0.001), but better respiratory mechanics (plateau pressure 27 ± 4 vs. 30 ± 3 cm H2O; P = 0.017). Both models led to acute severe pulmonary hypertension. In both models, ECMO (3.7 ± 0.5 L/min), compared with ECCO2R (0.4 L/min), increased mixed venous oxygen saturation and oxygenation, and improved hemodynamics (cardiac output = 6.0 ± 1.4 vs. 5.2 ± 1.4 L/min; P = 0.003). [Formula: see text]o2 and [Formula: see text]co2, irrespective of lung injury model, were lower during ECMO, resulting in lower PaCO2 and [Formula: see text]e but worse respiratory elastance compared with ECCO2R (64 ± 27 vs. 40 ± 8 cm H2O/L; P < 0.001). Conclusions: ECMO was associated with better oxygenation, lower [Formula: see text]o2, and better hemodynamics. ECCO2R may offer a potential alternative to ECMO, but there are concerns regarding its effects on hemodynamics and pulmonary hypertension.
Asunto(s)
Lesión Pulmonar Aguda , Hipertensión Pulmonar , Animales , Dióxido de Carbono , Ácido Clorhídrico , Ácido Oléico , Respiración Artificial/métodos , PorcinosRESUMEN
BACKGROUND: Gradually changing respiratory rate (RR) during time to reduce ventilation-induced lung injury has not been investigated. The authors hypothesized that gradual, compared with abrupt, increments in RR would mitigate ventilation-induced lung injury and that recruitment maneuver before abruptly increasing RR may prevent injurious biologic impact. METHODS: Twenty-four hours after intratracheal administration of Escherichia coli lipopolysaccharide, 49 male Wistar rats were anesthetized and mechanically ventilated (tidal volume, 6 ml/kg; positive end-expiratory pressure, 3 cm H2O) with RR increase patterns as follows (n = 7 per group): (1) control 1, RR = 70 breaths/min for 2 h; (2) and (3) abrupt increases of RR for 1 and 2 h, respectively, both for 2 h; (4) shorter RR adaptation, gradually increasing RR (from 70 to 130 breaths/min during 30 min); (5) longer RR adaptation, more gradual increase in RR (from 70 to 130 breaths/min during 60 min), both for 2 h; (6) control 2, abrupt increase of RR maintained for 1 h; and (7) control 3, recruitment maneuver (continuous positive airway pressure, 30 cm H2O for 30 s) followed by control-2 protocol. RESULTS: At the end of 1 h of mechanical ventilation, cumulative diffuse alveolar damage scores were lower in shorter (11.0 [8.0 to 12.0]) and longer (13.0 [11.0 to 14.0]) RR adaptation groups than in animals with abrupt increase of RR for 1 h (25.0 [22.0 to 26.0], P = 0.035 and P = 0.048, respectively) and 2 h (35.0 [32.0 to 39.0], P = 0.003 and P = 0.040, respectively); mechanical power and lung heterogeneity were lower, and alveolar integrity was higher, in the longer RR adaptation group compared with abruptly adjusted groups; markers of lung inflammation (interleukin-6), epithelial (club cell secretory protein [CC-16]) and endothelial cell damage (vascular cell adhesion molecule 1 [VCAM-1]) were higher in both abrupt groups, but not in either RR adaptation group, compared with controls. Recruitment maneuver prevented the increase in VCAM-1 and CC-16 gene expressions in the abruptly increased RR groups. CONCLUSIONS: In mild experimental acute respiratory distress syndrome in rats, gradually increasing RR, compared with abruptly doing so, can mitigate the development of ventilation-induced lung injury. In addition, recruitment maneuver prevented the injurious biologic impact of abrupt increases in RR.
Asunto(s)
Productos Biológicos , Lesión Pulmonar , Síndrome de Dificultad Respiratoria , Ratas , Masculino , Animales , Ratas Wistar , Frecuencia Respiratoria , Molécula 1 de Adhesión Celular Vascular , Síndrome de Dificultad Respiratoria/prevención & control , Presión de las Vías Aéreas Positiva ContínuaRESUMEN
BACKGROUND: Ventilatory ratio (VR) has been proposed as an alternative approach to estimate physiological dead space. However, the absolute value of VR, at constant dead space, might be affected by venous admixture and CO2 volume expired per minute (VCO2). METHODS: This was a retrospective, observational study of mechanically ventilated patients with acute respiratory distress syndrome (ARDS) in the UK and Italy. Venous admixture was either directly measured or estimated using the surrogate measure PaO2/FiO2 ratio. VCO2 was estimated through the resting energy expenditure derived from the Harris-Benedict formula. RESULTS: A total of 641 mechanically ventilated patients with mild (n=65), moderate (n=363), or severe (n=213) ARDS were studied. Venous admixture was measured (n=153 patients) or estimated using the PaO2/FiO2 ratio (n=448). The VR increased exponentially as a function of the dead space, and the absolute values of this relationship were a function of VCO2. At a physiological dead space of 0.6, VR was 1.1, 1.4, and 1.7 in patients with VCO2 equal to 200, 250, and 300, respectively. VR was independently associated with mortality (odds ratio [OR]=2.5; 95% confidence interval [CI], 1.8-3.5), but was not associated when adjusted for VD/VTphys, VCO2, PaO2/FiO2 (ORadj=1.2; 95% CI, 0.7-2.1). These three variables remained independent predictors of ICU mortality (VD/VTphys [ORadj=17.9; 95% CI, 1.8-185; P<0.05]; VCO2 [ORadj=0.99; 95% CI, 0.99-1.00; P<0.001]; and PaO2/FiO2 (ORadj=0.99; 95% CI, 0.99-1.00; P<0.001]). CONCLUSIONS: VR is a useful aggregate variable associated with outcome, but variables not associated with ventilation (VCO2 and venous admixture) strongly contribute to the high values of VR seen in patients with severe illness.
Asunto(s)
Síndrome de Dificultad Respiratoria , Humanos , Estudios Retrospectivos , Síndrome de Dificultad Respiratoria/terapia , Respiración , Italia , Espacio Muerto Respiratorio , Respiración ArtificialRESUMEN
Clinicians monitor mechanical ventilatory support using airway pressures-primarily the plateau and driving pressure, which are considered by many to determine the safety of the applied tidal volume. These airway pressures are influenced not only by the ventilator prescription, but also by the mechanical properties of the respiratory system, which consists of the series-coupled lung and chest wall. Actively limiting chest wall expansion through external compression of the rib cage or abdomen is seldom performed in the ICU. Recent literature describing the respiratory mechanics of patients with late-stage, unresolving, ARDS, however, has raised awareness of the potential diagnostic (and perhaps therapeutic) value of this unfamiliar and somewhat counterintuitive practice. In these patients, interventions that reduce resting lung volume, such as loading the chest wall through application of external weights or manual pressure, or placing the torso in a more horizontal position, have unexpectedly improved tidal compliance of the lung and integrated respiratory system by reducing previously undetected end-tidal hyperinflation. In this interpretive review, we first describe underappreciated lung and chest wall interactions that are clinically relevant to both normal individuals and to the acutely ill who receive ventilatory support. We then apply these physiologic principles, in addition to published clinical observation, to illustrate the utility of chest wall modification for the purposes of detecting end-tidal hyperinflation in everyday practice.
RESUMEN
The amount of energy delivered to the respiratory system is recognized as a cause of ventilator-induced lung injury (VILI). How energy dissipation within the lung parenchyma causes damage is still a matter of debate. Expiratory flow control has been proposed as a strategy to reduce the energy dissipated into the respiratory system during expiration and, possibly, VILI. We studied 22 healthy pigs (29 ± 2 kg), which were randomized into a control (n = 11) and a valve group (n = 11), where the expiratory flow was controlled through a variable resistor. Both groups were ventilated with the same tidal volume, positive end-expiratory pressure (PEEP), and inspiratory flow. Electric impedance tomography was continuously acquired. At completion, lung weight, wet-to-dry ratios, and histology were evaluated. The total mechanical power was similar in the control and valve groups (8.54 ± 0.83 J·min-1 and 8.42 ± 0.54 J·min-1, respectively, P = 0.552). The total energy dissipated within the whole system (circuit + respiratory system) was remarkably different (4.34 ± 0.66 vs. 2.62 ± 0.31 J/min, P < 0.001). However, most of this energy was dissipated across the endotracheal tube (2.87 ± 0.3 vs. 1.88 ± 0.2 J/min, P < 0.001). The amount dissipated into the respiratory system averaged 1.45 ± 0.5 in controls versus 0.73 ± 0.16 J·min-1 in the valve group, P < 0.001. Although respiratory mechanics, gas exchange, hemodynamics, wet-to-dry ratios, and histology were similar in the two groups, the decrease of end-expiratory lung impedance was significantly greater in the control group (P = 0.02). We conclude that with our experimental conditions, the reduction of energy dissipated in the respiratory system did not lead to appreciable differences in VILI.NEW & NOTEWORTHY Energy dissipation within the respiratory system is a factor promoting ventilator-induced lung injury (VILI). In this animal study, we modulated the expiratory flow, reducing the energy dissipated in the system. However, this reduction happened mostly across the endotracheal tube, and only partly in the respiratory system. Therefore, in healthy lungs, the advantage in energy dissipation does not reduce VILI, but the advantages might be more relevant in diseased lungs under injurious ventilation.
Asunto(s)
Lesión Pulmonar , Lesión Pulmonar Inducida por Ventilación Mecánica , Animales , Porcinos , Lesión Pulmonar Inducida por Ventilación Mecánica/etiología , Volumen de Ventilación Pulmonar , Respiración con Presión Positiva/métodos , Mecánica Respiratoria , Espiración , Respiración Artificial/efectos adversos , Respiración Artificial/métodos , PulmónRESUMEN
Acute respiratory distress syndrome (ARDS) is a heterogeneous syndrome historically characterized by the presence of severe hypoxemia, high-permeability pulmonary edema manifesting as diffuse alveolar infiltrate on chest radiograph, and reduced compliance of the integrated respiratory system as a result of widespread compressive atelectasis and fluid-filled alveoli. Coronavirus disease 19 (COVID-19)-associated ARDS (C-ARDS) is a novel etiology caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that may present with distinct clinical features as a result of the viral pathobiology unique to SARS-CoV-2. In particular, severe injury to the pulmonary vascular endothelium, accompanied by the presence of diffuse microthrombi in the pulmonary microcirculation, can lead to a clinical presentation in which the severity of impaired gas exchange becomes uncoupled from lung capacity and respiratory mechanics. The purpose of this review is to highlight the key mechanistic features of C-ARDS and to discuss the implications these features have on its treatment. In some patients with C-ARDS, rigid adherence to guidelines derived from clinical trials in the pre-COVID era may not be appropriate.