The novel coronavirus disease 2019 (COVID-19) outbreak, caused by the severe acute respiratory syndrome coronavirus 2 is considered the biggest medical challenge in decades, affecting over 3 million individuals worldwide, with over 75,000 deaths reported in the United States alone.¹ Although COVID-19 has a specific tropism for the lung, causing severe pneumonia and acute respiratory distress syndrome (ARDS) in severe cases, multiorgan involvement is also common, including the cardiovascular system.² As such, a review of key concepts of ARDS physiology, diagnostics, and therapeutics is important, including data on epidemiology of the disease, its effects on the cardiovascular system, and prognosis.

1. Definition. Acute hypoxemic respiratory failure in the presence of diffuse lung opacities with impairment in gas exchange is the hallmark presentation of ARDS. The Berlin definition is used to clinically define ARDS and includes 1) onset within 7 days of a known insult, most commonly pneumonia or sepsis, 2) presence of diffuse lung opacities in chest imaging, and 3) evidence of hypoxemia as defined by a ratio of partial pressure of arterial oxygen to fraction of inspired oxygen (PaO₂/FiO₂) ≤300 mmHg, at a minimum positive end-expiratory pressure (PEEP) of 5 cmH₂0.³ Because the lung opacities represent non-cardiogenic pulmonary edema, prior definitions of ARDS excluded patients with heart failure or volume overload. However, up to a third of patients with ARDS can also have any of these conditions.⁴
2. Low tidal volume ventilation. Treatment of ARDS includes identification and control of the primary insult, such as proper antimicrobial therapy and source control in cases of sepsis or pneumonia.⁴ Additional supportive therapy is aimed to restore physiologic equilibrium, improving oxygenation and pulmonary compliance while minimizing ventilator-induced lung injury.⁴ Lung-protective ventilation is a key component of ARDS treatment. Given the heterogeneous lung involvement, normal tidal volumes that are considered safe for the uninjured lung can cause alveolar overdistention in other regions, triggering additional injury and inflammation, which is a process known as volutrauma. Based on the landmark ARDSNet (Acute Respiratory Distress Syndrome Clinical Network) trial that showed a lower mortality (31% vs. 39.8%; p = 0.007) in patients who received lower tidal volumes,⁵ the current approach is to limit tidal volumes to ≤6 mL per kg of ideal body weight and keep a plateau airway pressure ≤30 cmH₂0.⁶
3. PEEP. In addition to volutrauma, the repetitive opening and closing of the alveolar units can further amplify regional strain, epithelial injury, and inflammation, which is a process known as atelectrauma⁴ that can be minimized by the addition of PEEP. Although it was suggested that higher levels of PEEP were associated with improved survival rates in patients with severe ARDS,⁶ a randomized clinical trial evaluating the effects of recruitment maneuvers and high PEEP in comparison to a low-PEEP strategy showed a higher mortality in the high-PEEP group.⁷ The risk of pneumothorax and barotrauma was also higher in the high-PEEP group. Although the best method to set PEEP remains uncertain,⁶ a commonly used strategy implies adjusting PEEP to minimize the driving pressure (difference between plateau pressure and PEEP). In fact, driving pressure has been shown to be the ventilatory variable with the strongest association with survival.⁸
4. The 3 Ps: prone, paralyze and prune. In cases of moderate to severe ARDS (PaO₂/FiO₂ <120 mmHg), ventilation in the prone position has been shown to be associated with increased survival.⁹ The use of neuromuscular blockade is recommended to minimize patient-ventilator dyssynchrony and risk of ventilator-induced injury, although an association with improved clinical outcomes was not seen in a recent clinical trial.¹⁰ A conservative fluid-management strategy is recommended, which has been shown to improve markers of lung function and shorten the duration of mechanical ventilation.¹¹
5. Refractory hypoxia. Despite supportive care, about 20% of patients with severe ARDS have refractory hypoxia (defined as a PaO₂ <60 mmHg while on a FiO₂ of 1.0), which is associated with increased mortality.¹² Adjuvant or rescue therapies in this subset of patients include the use of extracorporeal membrane oxygenation (ECMO)¹³ and the use of pulmonary vasodilators such as inhaled nitric oxide.¹⁴ A recent study comparing extracorporeal membrane oxygenation versus conventional therapy in patients with very severe ARDS was stopped early because the interim analysis showed no significant within-group 60-day mortality difference (35% vs. 46%; p = 0.09).¹³
6. Right ventricular (RV) dysfunction and ARDS. RV dysfunction can be encountered in 22-50% patients with ARDS. It is an important determinant of survival and is thought to be related to hypoxic pulmonary vasoconstriction and positive pressure ventilation, among other mechanisms.¹⁵ Therapeutic strategies include the use of pulmonary vasodilators and low-stress mechanical ventilation and prone positioning, so-called "RV-protective" ventilation.¹⁶
7. Clinical features of ARDS in COVID-19. Most patients with COVID-19 pneumonia fulfill the Berlin definition of ARDS.¹⁷ The mean PaO₂/FiO₂ was 249.6 ± 106.1 in a prospective cohort of patients from Wuhan, China.¹⁸ Although it has been suggested that patients with COVID-19 could have a different phenotype of ARDS with higher lung compliance, lower lung weight, and dissociation between the severity of hypoxemia with relative preservation of lung mechanics,¹⁹ a recent study showed minimal correlation between lung weight and compliance of the respiratory system,¹⁷ arguing against a major significance of this atypical ARDS phenotype. A study in 5,700 patients with COVID-19 hospitalized in the New York City area showed that the most common comorbidities of severe cases were essential hypertension (56.6%), obesity (41.7%), and diabetes mellitus (33.8%). Over 25% of patients required supplemental oxygen during the hospital stay, 14.2% of patients required an admission to an intensive care unit, and 12.2% required mechanical ventilation. Of 1,151 patients who required mechanical ventilation, 282 (24.5%) had died at the time of the report, with higher mortality rates in older populations.²⁰
8. More than a flu. A study comparing ARDS due to COVID-19 and H1N1 influenza showed that patients with COVID-19 were older and had higher incidence of cardiovascular disease, septic shock on presentation, lymphopenia, and presence of ground-glass opacities. Of interest, the PaO₂/FiO₂ ratios were higher in patients with H1N1. There were no significant differences in mortality rates between the 2 infections.²¹ As of early May 2020, over 75,000 deaths due to COVID-19 have been reported in the United States, which is similar to the estimated number of seasonal deaths reported annually. However, it should be remembered that fatalities related to these infections are reported in different fashions. Influenza mortality is presented as an estimate rather than absolute count, and COVID-19 fatalities are presented as raw counts. In fact, a comparison of weekly death rates suggested that the number of COVID-19 deaths was 9.5-fold to 44.1-fold greater than the count of influenza deaths.²²
9. Prognosis. The survival rate for patients with COVID-19 with ARDS is approximately 25%.²³ Factors associated with increased mortality in patients with COVID-19 pneumonia included age ≥65 years, presence of cardiovascular or cerebrovascular disease, lymphopenia, and elevation in troponin I levels.¹⁸ Despite major progress in the care of patients with ARDS, survivors are at high risk for cognitive decline, depression, post-traumatic stress disorder, and physical deconditioning.²⁴
10. The cardiovascular system and COVID-19. The cardiovascular involvement in cases of severe COVID-19 includes myocardial injury, ischemia, heart failure, and cardiac arrhythmias, as well as potential cardiac toxicity associated with some of the antimicrobials tested such as hydroxychloroquine and azithromycin.² Data from the New York City area showed >20% of patients had elevations in troponin levels. Brain natriuretic peptide levels were also elevated in most patients, with a median of 385.5 pg/mL (interquartile range 106-1996.8).²⁰ An echocardiographic study using speckle tracking in patients with COVID-19 described a lower survival rate in patients with decreased RV longitudinal strain. Patients in the lowest RV longitudinal strain tertile had higher inflammatory markers, higher incidence of ARDS, and increased mortality.²⁵

With the ongoing COVID-19 pandemic and the increasing number of ARDS cases, it is important to remember key concepts of the disease process and therapeutic implications. Therapy for ARDS is mostly supportive care, and there are currently no specific pharmacologic therapies against COVID-19. As such, prevention of the disease, proper hygiene, respiratory etiquette, and social distancing are the most important components of our daily fight against this infection.

References

1. COVID-19 Dashboard by the Center for Systems Science and Engineering (CSSE) at Johns Hopkins University (JHU). 2020. Available at:  https://gisanddata.maps.arcgis.com/apps/opsdashboard/index.html#/bda7594740fd40299423467b48e9ecf6. Accessed May 7, 2020.
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Clinical Topics: COVID-19 Hub, Diabetes and Cardiometabolic Disease, Heart Failure and Cardiomyopathies, Prevention, Pulmonary Hypertension and Venous Thromboembolism, Vascular Medicine, Novel Agents, Statins, Heart Failure and Cardiac Biomarkers, Pulmonary Hypertension, Hypertension

Keywords: Hypertension, Pulmonary, COVID-19, Coronavirus, Coronavirus Infections, severe acute respiratory syndrome coronavirus 2, Pandemics, Respiratory Distress Syndrome, Azithromycin, Extracorporeal Membrane Oxygenation, Troponin I, Survival Rate, Nitric Oxide, Ideal Body Weight, Hydroxychloroquine, Influenza A Virus, H1N1 Subtype, Natriuretic Peptide, Brain, Shock, Septic, Respiration, Artificial

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