It is time to update the ARDS definition: It starts with COVID-19-induced respiratory failure.

Coronavirus disease 2019 (COVID-19) may rapidly worsen respiratory failure, thereby leading to death. COVID-19-induced respiratory failure exhibits some atypical characteristics, silent hypoxemia, and high lung compliance. Some histopathological changes associated with COVID-19-induced respiratory failure differ from those of classic acute respiratory distress syndrome (ARDS). However, compared with classical ARDS, COVID-19-induced respiratory failure has a similar timing of onset, clinical syndromes, radiological profile, and mortality rate in the intensive care unit (ICU). Respiratory failure induced by COVID-19 is a type of ARDS and is currently underdiagnosed. This condition stretches the definition of classic ARDS; therefore, an updated definition is warranted.

COVID-19 Demonstrates That Inflammation Is a Hyperviscous State.

Many of the complications of severe coronavirus disease-2019 (COVID-19) are caused by blood hyperviscosity driven by marked hyperfibrinogenemia. This results in a distinctive hyperviscosity syndrome which affects areas of high and low shear. A change in blood viscosity causes a threefold inverse change in blood flow, which increases the risk of thrombosis in both arteries and veins despite prophylactic anticoagulation. Increased blood viscosity decreases perfusion of all tissues, including the lungs, heart, and brain. Decreased perfusion of the lungs causes global ventilation-perfusion mismatch which results in silent hypoxemia and decreased efficacy of positive pressure ventilation in treating pulmonary failure in COVID-19. Increased blood viscosity causes a mismatch in oxygen supply and demand in the heart, resulting in myocarditis and ventricular diastolic dysfunction. Decreased perfusion of the brain causes demyelination because of a sublethal cell injury to oligodendrocytes. Hyperviscosity can cause stasis in capillaries, which can cause endothelial necrosis. This can lead to the rarefaction of capillary beds, which is noted in "long-COVID." The genome of the virus which causes COVID-19, severe acute respiratory syndrome coronavirus 2, contains an extraordinarily high number of the oligonucleotide virulence factor 5'-purine-uridine-uridine-purine-uridine-3', which binds to toll-like receptor 8, hyperactivating innate immunity. This can lead to a marked elevation in fibrinogen levels and an increased prevalence of neutrophil extracellular traps in pulmonary failure, as seen in COVID-19 patients.

Silent Hypoxemia in the Emergency Department: A Retrospective Cohort of Two Clinical Phenotypes in Critical COVID-19.

INTRODUCTION: Understanding hypoxemia, with and without the clinical signs of acute respiratory failure (ARF) in COVID-19, is key for management. Hence, from a population of critical patients admitted to the emergency department (ED), we aimed to study silent hypoxemia (Phenotype I) in comparison to symptomatic hypoxemia with clinical signs of ARF (Phenotype II). METHODS: This multicenter study was conducted between 1 March and 30 April 2020. Adult patients who were presented to the EDs of nine Great-Eastern French hospitals for confirmed severe or critical COVID-19, who were then directly admitted to the intensive care unit (ICU), were retrospectively included. RESULTS: A total of 423 critical COVID-19 patients were included, out of whom 56.1% presented symptomatic hypoxemia with clinical signs of ARF, whereas 43.9% presented silent hypoxemia. Patients with clinical phenotype II were primarily intubated, initially, in the ED (46%, p < 0.001), whereas those with silent hypoxemia (56.5%, p < 0.001) were primarily intubated in the ICU. Initial univariate analysis revealed higher ICU mortality (29.2% versus 18.8%, p < 0.014) and in-hospital mortality (32.5% versus 18.8%, p < 0.002) in phenotype II. However, multivariate analysis showed no significant differences between the two phenotypes regarding mortality and hospital or ICU length of stay. CONCLUSIONS: Silent hypoxemia is explained by various mechanisms, most physiological and unspecific to COVID-19. Survival was found to be comparable in both phenotypes, with decreased survival in favor of Phenotype II. However, the spectrum of silent to symptomatic hypoxemia appears to include a continuum of disease progression, which can brutally evolve into fatal ARF.

Determinants of Increased Effort of Breathing in Non-Intubated Critical COVID-19 Patients.

Background and objectives: Acute respiratory distress syndrome (ARDS) is the most common complication occurring in COVID-19 patients admitted to the ICU. Given the increased respiratory work of these patients, it is necessary to evaluate their actual breathing efforts. The aim of this study is to report the incidence and determinants of increased effort of breathing (EOB) in critical COVID-19 patients. Materials and Methods: This was a retrospective study of COVID-19 patients admitted to the ICU during the year of 2020. Respiratory rate (RR) was chosen as an indicator of EOB. The cut-off value was set at more than 20 breaths per minute. ROC-AUC analysis was performed to identify the accuracy of the PaO2 and PaCO2 to determine increased EOB. Furthermore, multivariate regression analysis was performed to reveal the determinants of increased EOB. Results: 213 patients were included in the study. Mean RR in the population was 24.20 ± 6.28. 138 (64.8%) of the patients had increased EOB. The ROC-AUC analysis revealed the PaO2 (0.656 (CI 95%: 0.579-0.734, p < 0.001) as more accurate predictor of EOB than PaCO2 (0.584 (CI 95%: 0.505-0.662, p = 0.043). In the final multivariate model, the SpO2 (exp(B) = 0.922, CI 95%: 0.874-0.97 p = 0.033), PaO2/FiO2 ratio (exp(B) = 0.996, CI 95%: 0.922-1.000, p = 0.003) and PaO2 (exp(B) = 0.989 CI 95%: 0.982-0.996 p = 0.003) prevailed as independent predictors of increased EOB. Conclusions: To conclude, PaO2 was revealed as a more accurate predictor of increased EOB than PaCO2. Further investigation revealed the independent determinants of EOB: blood oxygen saturation, PaO2 and PaO2/FiO2 ratio.

Prevalence, Presentation and Outcomes of Silent Hypoxemia in COVID-19.

Dyspnea is reported in a minority of patients affected by coronavirus disease 2019 (COVID-19). Even patients with pneumonia can present hypoxemia without any respiratory distress, a phenomenon known as "silent" or "happy hypoxemia". During the current pandemic there were only a few studies conducted on this subject and these were quite heterogeneous. Therefore, the prevalence of "silent hypoxemia" varied substantially. While studies did not show a clear tendency of "silent hypoxemia" to poorer outcomes compared to hypoxemia presenting with dyspnea, several showed that patients with "silent hypoxemia" are not protected from poor outcomes either. There is a need for a uniform definition of "silent hypoxemia", in order to better guide clinicians and investigators. More studies are needed to shed light on the mechanisms of "silent hypoxemia", as well as its presentation and influence in the disease's progression and outcomes, so as to better assist physicians in the care of COVID-19 patients.

Characteristics and predictors for silent hypoxemia in a cohort of hospitalized COVID-19 patients.

BACKGROUND: An intriguing feature recently unveiled in some COVID-19 patients is the "silent hypoxemia" phenomenon, which refers to the discrepancy of subjective well-being sensation while suffering hypoxia, manifested as the absence of dyspnea. OBJECTIVE: To describe the clinical characteristics and predictors of silent hypoxemia in hospitalized COVID-19 patients. METHODS: We conducted a prospective cohort study including consecutive hospitalized adult (≥ 18 years) patients with confirmed COVID-19 presenting to the emergency department with oxygen saturation (SpO2) ≤ 80% on room air from March 15 to June 30, 2020. We analyzed the characteristics, disease severity, and in-hospital outcomes of patients presenting with dyspnea and those without dyspnea (silent hypoxemia). RESULTS: We studied 470 cases (64.4% men; median age 55 years, interquartile range 46-64). There were 447 (95.1%) patients with dyspnea and 23 (4.9%) with silent hypoxemia. The demographic and clinical characteristics, comorbidities, laboratory and imaging findings, disease severity, and outcomes were similar between groups. Higher breathing and heart rates correlated significantly with lower SpO2 in patients with dyspnea but not in those with silent hypoxemia. Independent predictors of silent hypoxemia were the presence of new-onset headache (OR 2.919, 95% CI 1.101-7.742; P = 0.031) and presenting to the emergency department within the first eight days after symptoms onset (OR 3.183, 95% CI 1.024-9.89; P = 0.045). CONCLUSIONS: Patients with silent hypoxemia sought medical attention earlier and had new-onset headache more often. They were also likely to display lower hemodynamic compensatory responses to hypoxemia, which may underestimate the disease severity.

Syncope and silent hypoxemia in COVID-19: Implications for the autonomic field.

Coronavirus-19 (COVID-19), the infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, has wreaked havoc across the globe since its emergence in December 2019. Reports of patients presenting with syncope and pre-syncope, as well as hypoxemia without symptoms of dyspnea ("silent hypoxemia"), have led researchers to speculate whether SARS-CoV-2 can alter autonomic nervous system function. As viral infections are commonly reported triggers of altered autonomic control, we must consider whether SARS-CoV-2 can also interfere with autonomic activity, at least in some patients. As we are still in the early stages of understanding COVID-19, we still do not know whether syncope and silent hypoxemia are more strongly associated with COVID-19 compared to any other viral infections that severely compromise gas exchange. Therefore, in this perspective we discuss these two intriguing clinical presentations, as they relate to autonomic nervous system function. In our discussion, we will explore COVID-specific, as well as non-COVID specific mechanisms that may affect autonomic activity and potential therapeutic targets. As we move forward in our understanding of COVID-19, well-designed prospective studies with appropriate control and comparator groups will be necessary to identify potential unique effects of COVID-19 on autonomic function.

[Pulse oximetry: Role in the COVID-19 patient at home]. / Pulsioximetría: papel en el paciente COVID-19 domiciliario.

COVID-19 behaves like a heterogeneous disease. Some patients may develop dyspnea-free hypoxemia during its evolution (silent hypoxemia). Pulse oximetry plays a crucial role in detecting hypoxemia in these patients, especially when they remain at home. Patients with SpO2 levels ≤ 92% or desaturations ≥ 3% after exercise test require hospital admission. Progressive saturation declines reaching SpO2 levels < 96% require strict clinical assessment (radiological study, blood test) for which it will be sent to a health center.

Early stage nonclinical pulmonary disorder in COVID-19 may present asymptomatic and fuel the contagion.

Evidence shows that pulmonary problems in coronavirus disease 2019 (COVID-19) may set off from vascular injury that progresses to physiological disturbances through a compromised gas exchange, following an infection with the severe acute respiratory syndrome coronavirus 2. In this process, inefficient gas exchange in the alveolar could precipitate silent nonclinical hypoxemia. Unfortunately, patients with "silent hypoxemia" do not necessarily experience any breathing difficulty (dyspnea) at the early stage of COVID-19 while the disease progresses. As a result, several asymptomatic, presymptomatic and patients with mild symptoms may escape quarantine measure and thus continue to spread the virus through contacts. Therefore, early diagnosis of "silent hypoxemia", which attracts no clinical warnings, could be an important diagnostic measure to prevent acute respiratory distress syndrome from the risk of pulmonary failure among the presymptomatic and as a screening tool in the asymptomatic who are hitherto potential spreaders of the virus.

The Pathophysiology and Dangers of Silent Hypoxemia in COVID-19 Lung Injury.

The ongoing coronavirus disease (COVID-19) pandemic has been unprecedented on many levels, not least of which are the challenges in understanding the pathophysiology of these new critically ill patients. One widely reported phenomenon is that of a profoundly hypoxemic patient with minimal to no dyspnea out of proportion to the extent of radiographic abnormality and change in lung compliance. This apparently unique presentation, sometimes called "happy hypoxemia or hypoxia" but better described as "silent hypoxemia," has led to the speculation of underlying pathophysiological differences between COVID-19 lung injury and acute respiratory distress syndrome (ARDS) from other causes. We explore three proposed distinctive features of COVID-19 that likely bear on the genesis of silent hypoxemia, including differences in lung compliance, pulmonary vascular responses to hypoxia, and nervous system sensing and response to hypoxemia. In the context of known principles of respiratory physiology and neurobiology, we discuss whether these particular findings are due to direct viral effects or, equally plausible, are within the spectrum of typical ARDS pathophysiology and the wide range of hypoxic ventilatory and pulmonary vascular responses and dyspnea perception in healthy people. Comparisons between lung injury patterns in COVID-19 and other causes of ARDS are clouded by the extent and severity of this pandemic, which may underlie the description of "new" phenotypes, although our ability to confirm these phenotypes by more invasive and longitudinal studies is limited. However, given the uncertainty about anything unique in the pathophysiology of COVID-19 lung injury, there are no compelling pathophysiological reasons at present to support a therapeutic approach for these patients that is different from the proven standards of care in ARDS.

Possible silent hypoxemia in a COVID-19 patient: A case report.

INTRODUCTION: It has been hypothesized that silent hypoxemia is the cause of rapid progressive respiratory failure with severe hypoxia that occurs in some COVID-19 patients without warning. PRESENTATION OF CASE: A 60-year-old male presented cough without any breathing difficulty. Vital signs showed blood pressure 130/75 mmHg, pulse 84x/minute, respiratory rate (RR) 21x/minute, body temperature 36.5C, and oxygen saturation (SpO2) 75% on room air. RT-PCR for COVID-19 were positive. On third day, he complained of worsening of breath shortness, but his RR was still normal (22x/minute) with SpO2 of 98% on 3 L/minute oxygen via nasal cannula. On fifth day, he experienced severe shortness of breath with RR 38x/minute. He was then intubated using a synchronized intermittent mandatory ventilation. Blood gas analysis showed pH 7.54, PaO2 58.9 mmHg, PaCO2 31.1 mmHg, HCO3 26.9mEq/L, SaO2 94.7%, FiO2 30%, and P/F ratio 196 mmHg. On eighth day, his condition deteriorated with blood pressure 80/40 mmHg with norepinephrine support, pulse 109x/minute, and SpO2 72% with ventilator. He experienced cardiac arrest and underwent basic life support, then resumed strained breathing with return of spontaneous circulation. Blood gas analysis showed pH 7.07, PaO2 58.1 mmHg, PaCO2 108.9 mmHg, HCO3 32.1mEq/L, SaO2 78.7%, FiO2 90%, and P/F ratio 65 mmHg. Three hours later, he suffered cardiac arrest again and eventually died. DISCUSSION: Possible mechanisms of silent hypoxemia are V/Q mismatch, intrapulmonary shunting, and intravascular microthrombi. CONCLUSIONS: Silent hypoxemia might be considered as an early sign of deterioration of COVID-19 patients, thus, physician may be able to intervene early and decrease its morbidity and mortality.

Coping with hypoxemia: Could erythropoietin (EPO) be an adjuvant treatment of COVID-19?

A very recent epidemiological study provides preliminary evidence that living in habitats located at 2500 m above sea level (masl) might protect from the development of severe respiratory symptoms following infection with the novel SARS-CoV-2 virus. This epidemiological finding raises the question of whether physiological mechanisms underlying the acclimatization to high altitude identifies therapeutic targets for the effective treatment of severe acute respiratory syndrome pivotal to the reduction of global mortality during the COVID-19 pandemic. This article compares the symptoms of acute mountain sickness (AMS) with those of SARS-CoV-2 infection and explores overlapping patho-physiological mechanisms of the respiratory system including impaired oxygen transport, pulmonary gas exchange and brainstem circuits controlling respiration. In this context, we also discuss the potential impact of SARS-CoV-2 infection on oxygen sensing in the carotid body. Finally, since erythropoietin (EPO) is an effective prophylactic treatment for AMS, this article reviews the potential benefits of implementing FDA-approved erythropoietin-based (EPO) drug therapies to counteract a variety of acute respiratory and non-respiratory (e.g. excessive inflammation of vascular beds) symptoms of SARS-CoV-2 infection.