Atelectrauma can be avoided if expiration is sufficiently brief: evidence from inverse modeling and oscillometry during airway pressure release ventilation.

BACKGROUND: Airway pressure release ventilation (APRV) has been shown to be protective against atelectrauma if expirations are brief. We hypothesize that this is protective because epithelial surfaces are not given enough time to come together and adhere during expiration, thereby avoiding their highly damaging forced separation during inspiration. METHODS: We investigated this hypothesis in a porcine model of ARDS induced by Tween lavage. Animals were ventilated with APRV in 4 groups based on whether inspiratory pressure was 28 or 40 cmH2O, and whether expiration was terminated when end-expiratory flow reached either 75% (a shorter expiration) or 25% (a longer expiration) of its initial peak value. A mathematical model of respiratory system mechanics that included a volume-dependent elastance term characterized by the parameter E 2 was fit to airway pressure-flow data obtained each hour for 6 h post-Tween injury during both expiration and inspiration. We also measured respiratory system impedance between 5 and 19 Hz continuously through inspiration at the same time points from which we derived a time-course for respiratory system resistance ( R rs ). RESULTS: E 2 during both expiration and inspiration was significantly different between the two longer expiration versus the two shorter expiration groups (ANOVA, p < 0.001). We found that E 2 was most depressed during inspiration in the higher-pressure group receiving the longer expiration, suggesting that E 2 reflects a balance between strain stiffening of the lung parenchyma and ongoing recruitment as lung volume increases. We also found in this group that R rs increased progressively during the first 0.5 s of inspiration and then began to decrease again as inspiration continued, which we interpret as corresponding to the point when continuing derecruitment was reversed by progressive lung inflation. CONCLUSIONS: These findings support the hypothesis that sufficiently short expiratory durations protect against atelectrauma because they do not give derecruitment enough time to manifest. This suggests a means for the personalized adjustment of mechanical ventilation.

Inconsistent Methods Used to Set Airway Pressure Release Ventilation in Acute Respiratory Distress Syndrome: A Systematic Review and Meta-Regression Analysis.

Airway pressure release ventilation (APRV) is a protective mechanical ventilation mode for patients with acute respiratory distress syndrome (ARDS) that theoretically may reduce ventilator-induced lung injury (VILI) and ARDS-related mortality. However, there is no standard method to set and adjust the APRV mode shown to be optimal. Therefore, we performed a meta-regression analysis to evaluate how the four individual APRV settings impacted the outcome in these patients. Methods: Studies investigating the use of the APRV mode for ARDS patients were searched from electronic databases. We tested individual settings, including (1) high airway pressure (PHigh); (2) low airway pressure (PLow); (3) time at high airway pressure (THigh); and (4) time at low pressure (TLow) for association with PaO2/FiO2 ratio and ICU length of stay. Results: There was no significant difference in PaO2/FiO2 ratio between the groups in any of the four settings (PHigh difference -12.0 [95% CI -100.4, 86.4]; PLow difference 54.3 [95% CI -52.6, 161.1]; TLow difference -27.19 [95% CI -127.0, 72.6]; THigh difference -51.4 [95% CI -170.3, 67.5]). There was high heterogeneity across all parameters (PhHgh I2 = 99.46%, PLow I2 = 99.16%, TLow I2 = 99.31%, THigh I2 = 99.29%). Conclusions: None of the four individual APRV settings independently were associated with differences in outcome. A holistic approach, analyzing all settings in combination, may improve APRV efficacy since it is known that small differences in ventilator settings can significantly alter mortality. Future clinical trials should set and adjust APRV based on the best current scientific evidence available.

Effects of Lung Injury and Abdominal Insufflation on Respiratory Mechanics and Lung Volume During Time-Controlled Adaptive Ventilation.

BACKGROUD: Lung volume measurements are important for monitoring functional aeration and recruitment and may help guide adjustments in ventilator settings. The expiratory phase of airway pressure release ventilation (APRV) may provide physiologic information about lung volume based on the expiratory flow-time slope, angle, and time to approach a no-flow state (expiratory time [TE]). We hypothesized that expiratory flow would correlate with estimated lung volume (ELV) as measured using a modified nitrogen washout/washin technique in a large-animal lung injury model. METHODS: Eight pigs (35.2 ± 1.0 kg) were mechanically ventilated using an Engström Carescape R860 on the APRV mode. All settings were held constant except the expiratory duration, which was adjusted based on the expiratory flow curve. Abdominal pressure was increased to 15 mm Hg in normal and injured lungs to replicate a combination of pulmonary and extrapulmonary lung injury. ELV was estimated using the Carescape FRC INview tool. The expiratory flow-time slope and TE were measured from the expiratory flow profile. RESULTS: Lung elastance increased with induced lung injury from 29.3 ± 7.3 cm H2O/L to 39.9 ± 15.1cm H2O/L, and chest wall elastance increased with increasing intra-abdominal pressures (IAPs) from 15.3 ± 4.1 cm H2O/L to 25.7 ± 10.0 cm H2O/L in the normal lung and 15.8 ± 6.0 cm H2O/L to 33.0 ± 6.2 cm H2O/L in the injured lung (P = .39). ELV decreased from 1.90 ± 0.83 L in the injured lung to 0.67 ± 0.10 L by increasing IAP to 15 mm Hg. This had a significant correlation with a TE decrease from 2.3 ± 0.8 s to 1.0 ± 0.1 s in the injured group with increasing insufflation pressures (ρ = 0.95) and with the expiratory flow-time slope, which increased from 0.29 ± 0.06 L/s2 to 0.63 ± 0.05 L/s2 (ρ = 0.78). CONCLUSIONS: Changes in ELV over time, and the TE and flow-time slope, could be used to demonstrate evolving lung injury during APRV. Using the slope to infer changes in functional lung volume represents a unique, reproducible, real-time, bedside technique that does not interrupt ventilation and may be used for clinical interpretation.

Time-Controlled Adaptive Ventilation (TCAV): a personalized strategy for lung protection.

Acute respiratory distress syndrome (ARDS) alters the dynamics of lung inflation during mechanical ventilation. Repetitive alveolar collapse and expansion (RACE) predisposes the lung to ventilator-induced lung injury (VILI). Two broad approaches are currently used to minimize VILI: (1) low tidal volume (LVT) with low-moderate positive end-expiratory pressure (PEEP); and (2) open lung approach (OLA). The LVT approach attempts to protect already open lung tissue from overdistension, while simultaneously resting collapsed tissue by excluding it from the cycle of mechanical ventilation. By contrast, the OLA attempts to reinflate potentially recruitable lung, usually over a period of seconds to minutes using higher PEEP used to prevent progressive loss of end-expiratory lung volume (EELV) and RACE. However, even with these protective strategies, clinical studies have shown that ARDS-related mortality remains unacceptably high with a scarcity of effective interventions over the last two decades. One of the main limitations these varied interventions demonstrate to benefit is the observed clinical and pathologic heterogeneity in ARDS. We have developed an alternative ventilation strategy known as the Time Controlled Adaptive Ventilation (TCAV) method of applying the Airway Pressure Release Ventilation (APRV) mode, which takes advantage of the heterogeneous time- and pressure-dependent collapse and reopening of lung units. The TCAV method is a closed-loop system where the expiratory duration personalizes VT and EELV. Personalization of TCAV is informed and tuned with changes in respiratory system compliance (CRS) measured by the slope of the expiratory flow curve during passive exhalation. Two potentially beneficial features of TCAV are: (i) the expiratory duration is personalized to a given patient's lung physiology, which promotes alveolar stabilization by halting the progressive collapse of alveoli, thereby minimizing the time for the reopened lung to collapse again in the next expiration, and (ii) an extended inspiratory phase at a fixed inflation pressure after alveolar stabilization gradually reopens a small amount of tissue with each breath. Subsequently, densely collapsed regions are slowly ratcheted open over a period of hours, or even days. Thus, TCAV has the potential to minimize VILI, reducing ARDS-related morbidity and mortality.

The use of protective mechanical ventilation during extracorporeal membrane oxygenation for the treatment of acute respiratory failure.

Acute respiratory failure (ARF) strikes an estimated two million people in the United States each year, with care exceeding US$50 billion. The hallmark of ARF is a heterogeneous injury, with normal tissue intermingled with a large volume of low compliance and collapsed tissue. Mechanical ventilation is necessary to oxygenate and ventilate patients with ARF, but if set inappropriately, it can cause an unintended ventilator-induced lung injury (VILI). The mechanism of VILI is believed to be overdistension of the remaining normal tissue known as the 'baby' lung, causing volutrauma, repetitive collapse and reopening of lung tissue with each breath, causing atelectrauma, and inflammation secondary to this mechanical damage, causing biotrauma. To avoid VILI, extracorporeal membrane oxygenation (ECMO) can temporally replace the pulmonary function of gas exchange without requiring high tidal volumes (VT) or airway pressures. In theory, the lower VT and airway pressure will minimize all three VILI mechanisms, allowing the lung to 'rest' and heal in the collapsed state. The optimal method of mechanical ventilation for the patient on ECMO is unknown. The ARDSNetwork Acute Respiratory Management Approach (ARMA) is a Rest Lung Approach (RLA) that attempts to reduce the excessive stress and strain on the remaining normal lung tissue and buys time for the lung to heal in the collapsed state. Theoretically, excessive tissue stress and strain can also be avoided if the lung is fully open, as long as the alveolar re-collapse is prevented during expiration, an approach known as the Open Lung Approach (OLA). A third lung-protective strategy is the Stabilize Lung Approach (SLA), in which the lung is initially stabilized and gradually reopened over time. This review will analyze the physiologic efficacy and pathophysiologic potential of the above lung-protective approaches.

Airway pressure release ventilation for lung protection in acute respiratory distress syndrome: an alternative way to recruit the lungs.

PURPOSE OF REVIEW: Airway pressure release ventilation (APRV) is a modality of ventilation in which high inspiratory continuous positive airway pressure (CPAP) alternates with brief releases. In this review, we will discuss the rationale for APRV as a lung protective strategy and then provide a practical introduction to initiating APRV using the time-controlled adaptive ventilation (TCAV) method. RECENT FINDINGS: APRV using the TCAV method uses an extended inspiratory time and brief expiratory release to first stabilize and then gradually recruit collapsed lung (over hours/days), by progressively 'ratcheting' open a small volume of collapsed tissue with each breath. The brief expiratory release acts as a 'brake' preventing newly recruited units from re-collapsing, reversing the main drivers of ventilator-induced lung injury (VILI). The precise timing of each release is based on analysis of expiratory flow and is set to achieve termination of expiratory flow at 75% of the peak expiratory flow. Optimization of the release time reflects the changes in elastance and, therefore, is personalized (i.e. conforms to individual patient pathophysiology), and adaptive (i.e. responds to changes in elastance over time). SUMMARY: APRV using the TCAV method is a paradigm shift in protective lung ventilation, which primarily aims to stabilize the lung and gradually reopen collapsed tissue to achieve lung homogeneity eliminating the main mechanistic drivers of VILI.

Sustained vs. Intratidal Recruitment in the Injured Lung During Airway Pressure Release Ventilation: A Computational Modeling Perspective.

INTRODUCTION: During mechanical ventilation, cyclic recruitment and derecruitment (R/D) of alveoli result in focal points of heterogeneous stress throughout the lung. In the acutely injured lung, the rates at which alveoli can be recruited or derecruited may also be altered, requiring longer times at higher pressure levels to be recruited during inspiration, but shorter times at lower pressure levels to minimize collapse during exhalation. In this study, we used a computational model to simulate the effects of airway pressure release ventilation (APRV) on acinar recruitment, with varying inspiratory pressure levels and durations of exhalation. MATERIALS AND METHODS: The computational model consisted of a ventilator pressure source, a distensible breathing circuit, an endotracheal tube, and a porcine lung consisting of recruited and derecruited zones, as well as a transitional zone capable of intratidal R/D. Lung injury was simulated by modifying each acinus with an inflation-dependent surface tension. APRV was simulated for an inhalation duration (Thigh) of 4.0 seconds, inspiratory pressures (Phigh) of 28 and 40 cmH2O, and exhalation durations (Tlow) ranging from 0.2 to 1.5 seconds. RESULTS: Both sustained acinar recruitment and intratidal R/D within the subtree were consistently higher for Phigh of 40 cmH2O vs. 28 cmH2O, regardless of Tlow. Increasing Tlow was associated with decreasing sustained acinar recruitment, but increasing intratidal R/D, within the subtree. Increasing Tlow was associated with decreasing elastance of both the total respiratory system and transitional subtree of the model. CONCLUSIONS: Our computational model demonstrates the confounding effects of cyclic R/D, sustained recruitment, and parenchymal strain stiffening on estimates of total lung elastance during APRV. Increasing inspiratory pressures leads to not only more sustained recruitment of unstable acini but also more intratidal R/D. Our model indicates that higher inspiratory pressures should be used in conjunction with shorter exhalation times, to avoid increasing intratidal R/D.

Ratchet recruitment in the acute respiratory distress syndrome: lessons from the newborn cry.

Patients with acute respiratory distress syndrome (ARDS) have few treatment options other than supportive mechanical ventilation. The mortality associated with ARDS remains unacceptably high, and mechanical ventilation itself has the potential to increase mortality further by unintended ventilator-induced lung injury (VILI). Thus, there is motivation to improve management of ventilation in patients with ARDS. The immediate goal of mechanical ventilation in ARDS should be to prevent atelectrauma resulting from repetitive alveolar collapse and reopening. However, a long-term goal should be to re-open collapsed and edematous regions of the lung and reduce regions of high mechanical stress that lead to regional volutrauma. In this paper, we consider the proposed strategy used by the full-term newborn to open the fluid-filled lung during the initial breaths of life, by ratcheting tissues opened over a series of initial breaths with brief expirations. The newborn's cry after birth shares key similarities with the Airway Pressure Release Ventilation (APRV) modality, in which the expiratory duration is sufficiently short to minimize end-expiratory derecruitment. Using a simple computational model of the injured lung, we demonstrate that APRV can slowly open even the most recalcitrant alveoli with extended periods of high inspiratory pressure, while reducing alveolar re-collapse with brief expirations. These processes together comprise a ratchet mechanism by which the lung is progressively recruited, similar to the manner in which the newborn lung is aerated during a series of cries, albeit over longer time scales.

First Stabilize and then Gradually Recruit: A Paradigm Shift in Protective Mechanical Ventilation for Acute Lung Injury.

Acute respiratory distress syndrome (ARDS) is associated with a heterogeneous pattern of injury throughout the lung parenchyma that alters regional alveolar opening and collapse time constants. Such heterogeneity leads to atelectasis and repetitive alveolar collapse and expansion (RACE). The net effect is a progressive loss of lung volume with secondary ventilator-induced lung injury (VILI). Previous concepts of ARDS pathophysiology envisioned a two-compartment system: a small amount of normally aerated lung tissue in the non-dependent regions (termed "baby lung"); and a collapsed and edematous tissue in dependent regions. Based on such compartmentalization, two protective ventilation strategies have been developed: (1) a "protective lung approach" (PLA), designed to reduce overdistension in the remaining aerated compartment using a low tidal volume; and (2) an "open lung approach" (OLA), which first attempts to open the collapsed lung tissue over a short time frame (seconds or minutes) with an initial recruitment maneuver, and then stabilize newly recruited tissue using titrated positive end-expiratory pressure (PEEP). A more recent understanding of ARDS pathophysiology identifies regional alveolar instability and collapse (i.e., hidden micro-atelectasis) in both lung compartments as a primary VILI mechanism. Based on this understanding, we propose an alternative strategy to ventilating the injured lung, which we term a "stabilize lung approach" (SLA). The SLA is designed to immediately stabilize the lung and reduce RACE while gradually reopening collapsed tissue over hours or days. At the core of SLA is time-controlled adaptive ventilation (TCAV), a method to adjust the parameters of the airway pressure release ventilation (APRV) modality. Since the acutely injured lung at any given airway pressure requires more time for alveolar recruitment and less time for alveolar collapse, SLA adjusts inspiratory and expiratory durations and inflation pressure levels. The TCAV method SLA reverses the open first and stabilize second OLA method by: (i) immediately stabilizing lung tissue using a very brief exhalation time (≤0.5 s), so that alveoli simply do not have sufficient time to collapse. The exhalation duration is personalized and adaptive to individual respiratory mechanical properties (i.e., elastic recoil); and (ii) gradually recruiting collapsed lung tissue using an inflate and brake ratchet combined with an extended inspiratory duration (4-6 s) method. Translational animal studies, clinical statistical analysis, and case reports support the use of TCAV as an efficacious lung protective strategy.

Ventilator-Induced Lung Injury as a Dynamic Balance Between Epithelial Cell Damage and Recovery.

Acute respiratory distress syndrome (ARDS) has a high mortality rate that is due in part to ventilator-induced lung injury (VILI). Nevertheless, the majority of patients eventually recover, which means that their innate reparative capacities eventually prevail. Since there are currently no medical therapies for ARDS, minimizing its mortality thus amounts to achieving an optimal balance between spontaneous tissue repair versus the generation of VILI. In order to understand this balance better, we developed a mathematical model of the onset and recovery of VILI that incorporates two hypotheses: (1) a novel multi-hit hypothesis of epithelial barrier failure, and (2) a previously articulated rich-get-richer hypothesis of the interaction between atelectrauma and volutrauma. Together, these concepts explain why VILI appears in a normal lung only after an initial latent period of injurious mechanical ventilation. In addition, they provide a mechanistic explanation for the observed synergy between atelectrauma and volutrauma. The model recapitulates the key features of previously published in vitro measurements of barrier function in an epithelial monolayer and in vivo measurements of lung function in mice subjected to injurious mechanical ventilation. This provides a framework for understanding the dynamic balance between factors responsible for the generation of and recovery from VILI.

Protective ventilation in a pig model of acute lung injury: timing is as important as pressure.

Ventilator-induced lung injury (VILI) is a significant risk for patients with acute respiratory distress syndrome (ARDS). Management of the patient with ARDS is currently dominated by the use of low tidal volume mechanical ventilation, the presumption being that this mitigates overdistension (OD) injury to the remaining normal lung tissue. Evidence exists, however, that it may be more important to avoid cyclic recruitment and derecruitment (RD) of lung units, although the relative roles of OD and RD in VILI remain unclear. Forty pigs had a heterogeneous lung injury induced by Tween instillation and were randomized into four groups (n = 10 each) with higher (↑) or lower (↓) levels of OD and/or RD imposed using airway pressure release ventilation (APRV). OD was increased by setting inspiratory airway pressure to 40 cmH2O and lessened with 28 cmH2O. RD was attenuated using a short duration of expiration (∼0.45 s) and increased with a longer duration (∼1.0 s). All groups developed mild ARDS following injury. RD ↑ OD↑ caused the greatest degree of lung injury as determined by [Formula: see text]/[Formula: see text] ratio (226.1 ± 41.4 mmHg). RD ↑ OD↓ ([Formula: see text]/[Formula: see text]= 333.9 ± 33.1 mmHg) and RD ↓ OD↑ ([Formula: see text]/[Formula: see text] = 377.4 ± 43.2 mmHg) were both moderately injurious, whereas RD ↓ OD↓ ([Formula: see text]/[Formula: see text] = 472.3 ± 22.2 mmHg; P < 0.05) was least injurious. Both tidal volume and driving pressure were essentially identical in the RD ↑ OD↓ and RD ↓ OD↑ groups. We, therefore, conclude that considerations of expiratory time may be at least as important as pressure for safely ventilating the injured lung.NEW & NOTEWORTHY In a large animal model of ARDS, recruitment/derecruitment caused greater VILI than overdistension, whereas both mechanisms together caused severe lung damage. These findings suggest that eliminating cyclic recruitment and derecruitment during mechanical ventilation should be a preeminent management goal for the patient with ARDS. The airway pressure release ventilation (APRV) mode of mechanical ventilation can achieve this if delivered with an expiratory duration (TLow) that is brief enough to prevent derecruitment at end expiration.

Myths and Misconceptions of Airway Pressure Release Ventilation: Getting Past the Noise and on to the Signal.

In the pursuit of science, competitive ideas and debate are necessary means to attain knowledge and expose our ignorance. To quote Murray Gell-Mann (1969 Nobel Prize laureate in Physics): "Scientific orthodoxy kills truth". In mechanical ventilation, the goal is to provide the best approach to support patients with respiratory failure until the underlying disease resolves, while minimizing iatrogenic damage. This compromise characterizes the philosophy behind the concept of "lung protective" ventilation. Unfortunately, inadequacies of the current conceptual model-that focuses exclusively on a nominal value of low tidal volume and promotes shrinking of the "baby lung" - is reflected in the high mortality rate of patients with moderate and severe acute respiratory distress syndrome. These data call for exploration and investigation of competitive models evaluated thoroughly through a scientific process. Airway Pressure Release Ventilation (APRV) is one of the most studied yet controversial modes of mechanical ventilation that shows promise in experimental and clinical data. Over the last 3 decades APRV has evolved from a rescue strategy to a preemptive lung injury prevention approach with potential to stabilize the lung and restore alveolar homogeneity. However, several obstacles have so far impeded the evaluation of APRV's clinical efficacy in large, randomized trials. For instance, there is no universally accepted standardized method of setting APRV and thus, it is not established whether its effects on clinical outcomes are due to the ventilator mode per se or the method applied. In addition, one distinctive issue that hinders proper scientific evaluation of APRV is the ubiquitous presence of myths and misconceptions repeatedly presented in the literature. In this review we discuss some of these misleading notions and present data to advance scientific discourse around the uses and misuses of APRV in the current literature.

Assessment of Heterogeneity in Lung Structure and Function During Mechanical Ventilation: A Review of Methodologies.

The mammalian lung is characterized by heterogeneity in both its structure and function, by incorporating an asymmetric branching airway tree optimized for maintenance of efficient ventilation, perfusion, and gas exchange. Despite potential benefits of naturally occurring heterogeneity in the lungs, there may also be detrimental effects arising from pathologic processes, which may result in deficiencies in gas transport and exchange. Regardless of etiology, pathologic heterogeneity results in the maldistribution of regional ventilation and perfusion, impairments in gas exchange, and increased work of breathing. In extreme situations, heterogeneity may result in respiratory failure, necessitating support with a mechanical ventilator. This review will present a summary of measurement techniques for assessing and quantifying heterogeneity in respiratory system structure and function during mechanical ventilation. These methods have been grouped according to four broad categories: (1) inverse modeling of heterogeneous mechanical function; (2) capnography and washout techniques to measure heterogeneity of gas transport; (3) measurements of heterogeneous deformation on the surface of the lung; and finally (4) imaging techniques used to observe spatially-distributed ventilation or regional deformation. Each technique varies with regard to spatial and temporal resolution, degrees of invasiveness, risks posed to patients, as well as suitability for clinical implementation. Nonetheless, each technique provides a unique perspective on the manifestations and consequences of mechanical heterogeneity in the diseased lung.

Electric Cell-Substrate Impedance Sensing (ECIS) as a Platform for Evaluating Barrier-Function Susceptibility and Damage from Pulmonary Atelectrauma.

Biophysical insults that either reduce barrier function (COVID-19, smoke inhalation, aspiration, and inflammation) or increase mechanical stress (surfactant dysfunction) make the lung more susceptible to atelectrauma. We investigate the susceptibility and time-dependent disruption of barrier function associated with pulmonary atelectrauma of epithelial cells that occurs in acute respiratory distress syndrome (ARDS) and ventilator-induced lung injury (VILI). This in vitro study was performed using Electric Cell-substrate Impedance Sensing (ECIS) as a noninvasive evaluating technique for repetitive stress stimulus/response on monolayers of the human lung epithelial cell line NCI-H441. Atelectrauma was mimicked through recruitment/derecruitment (RD) of a semi-infinite air bubble to the fluid-occluded micro-channel. We show that a confluent monolayer with a high level of barrier function is nearly impervious to atelectrauma for hundreds of RD events. Nevertheless, barrier function is eventually diminished, and after a critical number of RD insults, the monolayer disintegrates exponentially. Confluent layers with lower initial barrier function are less resilient. These results indicate that the first line of defense from atelectrauma resides with intercellular binding. After disruption, the epithelial layer community protection is diminished and atelectrauma ensues. ECIS may provide a platform for identifying damaging stimuli, ventilation scenarios, or pharmaceuticals that can reduce susceptibility or enhance barrier-function recovery.

Acetylsalicylic Acid Compared with Enoxaparin for the Prevention of Thrombosis and Mechanical Ventilation in COVID-19 Patients: A Retrospective Cohort Study.

BACKGROUND AND OBJECTIVE: Low-dose acetylsalicylic acid (ASA, aspirin) is a well-known and frequently studied drug for primary and secondary prevention of disease due to its anti-inflammatory and coagulopathic effects. COVID-19 complications are attributed to the role of thrombo-inflammation. Studies regarding the use of low-dose ASA in COVID-19 are limited. For this reason, we propose that the use of low-dose ASA may have protective effects in COVID-19-related thromboembolism and lung injury. This study was conducted to assess the efficacy of low-dose ASA compared with enoxaparin, an anticoagulant, for the prevention of thrombosis and mechanical ventilation. METHODS: We conducted a retrospective cohort study on COVID-19-confirmed hospitalized patients at the Mansoura University Quarantine Hospital, outpatients, and home-isolated patients from September to December 2020 in Mansoura governorate, Egypt. Binary logistic regression analysis was used to assess the effect of ASA compared with enoxaparin on thromboembolism, and mechanical ventilation needs. RESULTS: This study included 225 COVID-19 patients. Use of ASA-only (81-162 mg orally daily) was significantly associated with reduced thromboembolism (OR 0.163, p = 0.020), but both low-dose ASA and enoxaparin, and enoxaparin-only (0.5 mg/kg subcutaneously (SC) daily as prophylactic dose or 1 mg/kg SC every 12 hours as therapeutic dose) were more protective (odds ratio [OR] 0.010, OR 0.071, respectively, p < 0.001). Neither ASA-only nor enoxaparin-only were associated with a reduction in mechanical ventilation needs. Concomitant use of low-dose ASA and enoxaparin was associated with reduced mechanical ventilation (OR 0.032, 95% CI 0.004-0.226, p = 0.001). CONCLUSIONS: Low-dose ASA-only use may reduce the incidence of COVID-19-associated thromboembolism, but the reduction may be less than that of enoxaparin-only, and both ASA and enoxaparin. Concomitant use of ASA and enoxaparin demonstrates promising results with regard to the reduction of thrombotic events, and mechanical ventilation needs.

Rationales and uncertainties for aspirin use in COVID-19: a narrative review.

OBJECTIVES: To review the pathophysiology of COVID-19 disease, potential aspirin targets on this pathogenesis and the potential role of aspirin in patients with COVID-19. DESIGN: Narrative review. SETTING: The online databases PubMed, OVID Medline and Cochrane Library were searched using relevant headlines from 1 January 2016 to 1 January 2021. International guidelines from relevant societies, journals and forums were also assessed for relevance. PARTICIPANTS: Not applicable. RESULTS: A review of the selected literature revealed that clinical deterioration in COVID-19 is attributed to the interplay between endothelial dysfunction, coagulopathy and dysregulated inflammation. Aspirin has anti-inflammatory effects, antiplatelet aggregation, anticoagulant properties as well as pleiotropic effects on endothelial function. During the COVID-19 pandemic, low-dose aspirin is used effectively in secondary prevention of atherosclerotic cardiovascular disease, prevention of venous thromboembolism after total hip or knee replacement, prevention of pre-eclampsia and postdischarge treatment for multisystem inflammatory syndrome in children. Prehospital low-dose aspirin therapy may reduce the risk of intensive care unit admission and mechanical ventilation in hospitalised patients with COVID-19, whereas aspirin association with mortality is still debatable. CONCLUSION: The authors recommend a low-dose aspirin regimen for primary prevention of arterial thromboembolism in patients aged 40-70 years who are at high atherosclerotic cardiovascular disease risk, or an intermediate risk with a risk-enhancer and have a low risk of bleeding. Aspirin's protective roles in COVID-19 associated with acute lung injury, vascular thrombosis without previous cardiovascular disease and mortality need further randomised controlled trials to establish causal conclusions.