ABC | Volume 114, Nº5, May 2020

Review Article Costa et al. The heart and COVID-19 Arq Bras Cardiol. 2020; 114(5):805-816 The initial assessment of patients with COVID-19 should include: ECG, arterial blood gas analysis with lactate level, d-dimer, complete blood count, kidney and liver function tests, clotting factors, troponin, creatine phosphokinase, ferritin, LDH, IL-6 and electrolytes (sodium, magnesium, potassium, and calcium). Chest radiography should be performed and chest computed tomography (CT) considered in some cases. Computed tomography evidences abnormalities in 85% of the patients, and 75% of them show bilateral pulmonary involvement, commonly characterized as ground-glass opacifications and subpleural and peripheral consolidations. 41 Those with indication for hospitalization should undergo echocardiography in the emergency department or within the first hours from hospital admission. The clinical course of COVID-19 is variable and potentially severe, because 3.4% of the patients progress to ARDS, 32 a proportion that increases in the cohorts of those hospitalized with the disease (19.6%) and among those with myocardial injury (58.5%). 9,11 Acute respiratory distress syndrome is defined based on the Berlin criteria: acute onset of pulmonary damage, bilateral pulmonary opacities on chest radiography, and pulmonary edema. The ARDS Berlin Definition stratifies the severity of pulmonary damage based on the relation between partial pressure of arterial oxygen (PaO 2 ) and fraction of inspired oxygen (FiO 2 ), acquired in a positive-end expiratory pressure (PEEP) or continuous positive airway pressure (CPAP) ≥ 5 cm H 2 O. The ARDS is considered severe when PaO 2 / FiO 2 is <100. 42 Mechanical ventilation is recommended in the presence of hypoxemia despite oxygen supply. Protective mechanical ventilation strategies should be used, with tidal volume of 6 mL/kg, plateau pressure < 30 cm H 2 O, and PEEP adjusted according to FiO 2 . Patients usually have good pulmonary compliance despite severe hypoxemia. For patients with ARDS and PaO 2 /FiO 2 ≤ 150, prone position should be considered, and, in case of significant patient-ventilator dyssynchrony, neuromuscular block can be performed. 43 Hemodynamic monitoring should be cogitated in all ICU patients with signs of shock. Minimally invasive hemodynamic monitoring and continuous cardiac output monitoring should be considered in association with dynamic echocardiography and analysis of tissue hypoperfusion markers, such as clinical parameters, arterial lactate levels, deltaPCO 2 , and base excess. In the presence of shock, norepinephrine is the drug of choice, and the addition of vasopressin is recommended if increasing doses of noradrenaline are necessary for hemodynamic optimization. 44 If cardiac dysfunction occurs, dobutamine should be added. 44 Norepinephrine should be immediately initiated, even in a peripheral access, preventing prolonged hypotension, which yields high mortality. Extracorporeal membrane oxygenation (ECMO) might be necessary for patients with acute respiratory failure refractory to initial measures. 45,46 At first, venovenous ECMO is indicated for recovery of pulmonary function. 46,47 When associated with significant cardiovascular impairment in patients with severe ventricular dysfunction and/or cardiogenic shock, venoarterial ECMO might be considered. 48 ECMO should be initiated before the installation of failure of multiple organs. 49 Specific treatment. At the present time, the treatment of critically ill patients is based on supportive measures for organic dysfunctions. Since the beginning of the pandemic, an effective antiviral treatment for COVID-19 has been sought. In China and Italy, in severe cases and in an individualized manner depending on the institution, drugs like chloroquine (CQ) or HCQ, lopinavir/ritonavir, remdesivir and favipiravir have been used. Remdesivir and favipiravir are broad-spectrum antiviral agents, whose efficacy and safety for the management of patients with COVID-19 are being assessed in randomized clinical trials. 50 A recent randomized and controlled study has shown that the lopinavir/ritonavir combination, used in the management of HIV infection, is ineffective against the SARS-CoV-2 infection. 50 Chloroquine diphosphate and HCQ sulfate are well-known useful drugs to treat malaria and autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus. In experimental studies, CQ and HCQ have shown to act against SARS-CoV-2, by interfering with ACE2 glycosylation, thus reducing the efficiency of the binding between ACE2 of host cells and the coronavirus surface protein. In addition, those drugs act by increasing the pH of endosomes and lysosomes, thus preventing virus/host cell fusion and subsequent viral replication. Moreover, HCQ prevents the presentation of viral antigens to T cells and inhibits the transcription of proinflammatory genes, hindering the release of cytokines. Thus, in experimental studies, CQ and HCQ have prevented viral entry into the cell and replication, as well as attenuated the inflammatory response. In China, a study has shown that CQwas linked to a higher percentage of clinical and virological cure, being then adopted for the treatment of COVID-19 in that country. A small study has reported that HCQ, regardless of combination with azithromycin, reduced the SARS-CoV-2 RNA detection on respiratory tract swab samples, but that study has not assessed clinical outcomes. 51-53 The major side effects of CQ and HCQ are gastrointestinal intolerance (nauseas and vomit) and, in the long-term use, retinopathy, maculopathy and cardiomyopathy. Other common side effects of those drugs are total atrioventricular block, bundle-branch block, cardiac arrhythmias, hypotension, torsades de pointes , T-wave inversion, ventricular fibrillation, and ventricular tachycardia, which are even more frequent with their prolonged use and in the presence of liver and kidney dysfunction. On March 10, 2020, the Journal of Critical Care has published a systematic review on the efficacy and safety of CQ for the treatment of COVID-19, including one narrative letter, expert consensus paper, one editorial, one in-vitro study, two national guideline documents, and the description of 23 ongoing clinical trials in China. 54 On March 21, 2020, the president of the United States urged the FDA to quickly approve CQ and HCQ for the treatment of COVID-19. However, the FDA currently recommends the compassionate drug use until scientific evidence on the efficacy of CQ, HCQ and azithromycin for the treatment of COVID-19 is available. On March 23, 2020, two studies conducted in Brazil were approved by the Brazilian Committee on Ethics in Research (CONEP): a) a phase IIb study to assess the efficacy and safety of CQ diphosphate in the treatment of patients hospitalized with SARS-CoV-2: a double-blind, randomized, clinical 811