key: cord-0914314-o4ofqk5e
authors: Maron, Bradley A.; Gladwin, Mark T.; Bonnet, Sebastien; De Jesus Perez, Vinicio; Perman, Sarah M.; Yu, Paul B.; Ichinose, Fumito
title: Perspectives on Cardiopulmonary Critical Care for Patients With COVID‐19: From Members of the American Heart Association Council on Cardiopulmonary, Critical Care, Perioperative and Resuscitation
date: 2020-07-16
journal: J Am Heart Assoc
DOI: 10.1161/jaha.120.017111
sha: 7e383f7f30ac8502adc5329a73ecad630071b38c
doc_id: 914314
cord_uid: o4ofqk5e

The coronavirus disease 2019 (COVID-19) pandemic, caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), marks a global event that will permanently reshape implementation of intensive care medicine. As of June 4, 2020, there are 6,606,455 reported cases of COVID-19 including 388,556 fatalities spanning 215 countries and territories, although epidemiological data remain incomplete. Early autopsy reports emphasize proximal airway and distal airspace involvement, including alveolar epithelial inflammation and capillary thickening.

and polymerase chain reaction-based testing, or who test positive for SARS-CoV-2 should be maintained in single-occupancy rooms with closed doors and under droplet contact precautions. If PPE resources are available, these patients can be managed with more rigorous aerosol transmission precautions in negative pressure isolation. The ideal management approach to confirmed COVID-19 cases is placement in specialized cohort units, which allows providers to maintain higher levels of protection for aerosol transmission using a PPE set that includes a fitted respirator mask (N95, FFP2) or a powered air-purifying respirator, gloves, gown, and eye protection (face shield or safety goggles). It is important to recognize that the techniques for doffing are as important as donning, since the PPE exterior may be contaminated (see https://www.cdc.gov/vhf/ ebola/ hcp/ppe-train ing/n95re spira tor_gown/donni ng_01.html). Unconventional but effective alternative methods to protect providers during intubation, such as using an aerosol box, have also been used when standard PPE availability is limited. 2 

The cumulative incidence of out-of-hospital cardiac arrest has increased notably by approximately 60% during the pandemic in one Italian series, with 77% attributable to COVID-19. 3 Cardiopulmonary resuscitation during COVID-19 continues to focus on the provision of quality compressions, potentially with mechanical devices to limit resuscitation team size, and early first-pass success during intubation via video laryngoscopy. Standard advanced cardiac life support algorithms remain; however, guidelines have been updated to account for ensuring adequate PPE, minimizing the size of resuscitative teams, and providing strategies for prompt resuscitative measures in unique situations such as the proned patient or the patient with refractory hypoxemia. Because chest compression is considered to be an aerosolgenerating procedure, recommendations have been made to decrease the number of cardiopulmonary resuscitation providers to minimize exposure and conserve PPE. Given the lack of data regarding outcomes for patients who suffer cardiac arrest after COVID-19 infection, early advanced care planning is necessary to establish appropriate goals of care. The decision regarding the appropriateness of beginning or continuing a resuscitation should be addressed by the medical team. 4 Various scoring methods are available to prioritize scarce critical care services, but any decision to limit care should be made in advance of rapid clinical deterioration. This is important, as a subset of patients with COVID-19 present with mild hypoxia but quickly develop acute hypoxemic respiratory failure associated with the development of bilateral lung infiltrates. It is reasonable to offer supplemental oxygen via high-flow nasal cannula or noninvasive positive pressure ventilation in patients with mild hypoxemia; however, early intubation and mechanical ventilation may be necessary, as respiratory condition may worsen rapidly. In New York City, more than 30% of patients with COVID-19 who received invasive mechanical ventilation did not need supplemental oxygen during the first 3 hours after presenting to the emergency department. 5 Of the 393 patients with COVID-19 admitted to 2 New York City hospitals, 130 patients (33.1%) developed severe respiratory failure requiring mechanical ventilation. It is important to note that the field is evolving continuously, and approaches to limit intubation and mechanical ventilation are being considered. Many centers have adapted a strategy of earlier prone positioning in non-mechanically ventilated patients compared with usual care and, similarly, a low threshold to use high-flow oxygen and noninvasive ventilation with appropriate aerosol-transmission precautions.

Given the risk of viral transmission via aerosolization, advanced PPE such as an N95 mask/face shield or powered air-purifying respirator should be used in a negative pressure room when administering high-flow oxygen, noninvasive ventilation, or performing endotracheal intubation. The Surviving Sepsis Campaign Guidelines for the Management of Critically Ill COVID-19 Patients 6 recommends intubation using video-guided laryngoscopy to decrease the risk of aerosol exposure by maintaining distance from the patient's mouth. Furthermore, it is recommended that a designated team of specialists with expertise in endotracheal intubation be responsible for handling intubations to minimize the time and attempts required to secure the airway.

Controversy persists regarding the optimal timing of intubation in COVID-19, in part because of the heterogeneous cardiopulmonary clinical spectrum associated with this disease and data lacking from gold-standard randomized trials. Some clues on lung subphenotypes have emerged; for example, findings from one retrospective analysis of 70 suspected patients with COVID-19 admitted to the ICU showed that estimated lung weight does not correlate with lung compliance in this population. 7 Others have shown static compliance in COVID similar to observations in non-COVID-19 patients with similar respiratory clinical phenotype. 8 Overall, there remains a pressing need for point-of-care tools to predict respiratory failure in patients with COVID-19.

We recommend adhering to long-standing and proven principles of ARDS management, particularly relative to mechanical ventilation: (1) titrate FiO 2 to a goal oxyhemoglobin saturation of 92% to 96%, (2) low tidal volume ventilation (4-6 mL/kg of predicted body weight) with positive end-expiratory pressure (PEEP) >10 cm H 2 O while maintaining plateau pressure <30 cm H 2 O, and (3) conservative fluid management if vasopressors are not required. 1 Different strategies to titrate PEEP have been implimented in clinical practice, such as using low and high ARDSnet PEEP tables for body mass index <40 kg/m 2 versus >40 kg/ m 2 , respectively, 9 titrating to static compliance, or using pressure-volume loop contour to guide decision making, mindful that atypical pressure-volume loops/ compliance curves have been observed anecdotally in patients with COVID-19. Personalized approaches to determining PEEP are likely to hinge on better characterizing the relationship between focal and nonfocal ARDS relative to lung compliance (recruitability). 10 The exact ventilator mode (ie, pressure-limited versus volume-cycled assist-control) is less important provided that a sufficient inspiratory:expiratory ratio and appropriate lung-protective low tidal volume are achieved.

These collective metrics are important for increasing mean arterial pressure across both inspiration and expiration that may improve oxygenation and prevent lung injury, respectively. In patients with persistent hypoxemia unresponsive to low tidal volume ventilation and appropriate PEEP, a trial of prone ventilation and inhaled pulmonary vasodilators (eg, inhaled nitric oxide) could be considered. Refractory hypoxemia may warrant venovenous extracorporeal membrane oxygenation as a bridge to recovery.

For patients with septic shock (ie, hemodynamic collapse attributable to COVID-19 or associated superinfection), we recommend a conservative fluid resuscitation strategy with crystalloids to prevent exacerbating lung edema, and inotropic support as indicated. Use of vasopressors should be considered if patients fail to maintain mean arterial pressure >60 mm Hg. For patients with refractory shock, a trial of low-dose corticosteroids (hydrocortisone 200 mg daily, often supplemented with oral fludrocortisone) may also improve central and peripheral blood pressure. Treatment with dexamethasone may be considered in patients with the appropriate indications. Managing the respiratory status of patients with septic shock in COVID-19 may be complicated by nosocomial ventilator-associated pneumonia (aerobic gram-negative rods and Staphylococcus aureus) and the fact that approximately 13% of patients use renal replacement therapy. 5 Several reports have shown some efficacy for use of systemic corticosteroids or experimental therapies such as convalescent plasma, favipiravir, inhaled nitric oxide, or tocilizumab in patients with COVID-19. 11 One recently reported randomized double-blind, clinical trial showed that remdesivir for 10 days shortened the recovery time in hospitalized COVID-19 patients with lower respiratory tract infection compared to placebo. 12 A number of clinical trials are under way to determine the efficacy of these potential treatments for COVID-19. A list of ongoing clinical trials in COVID-19-ARDS is provided in Table 1 . Based on the results of a clinical trial that showed remdesivir shortened the time to recovery in some patients, the US Food and Drug Administration issued an emergency use authorization for remdesivir for the treatment of suspected or laboratory-confirmed COVID-19 in adults and children hospitalized with severe disease. 13 However, given the lack of definite evidence and the potential complications associated with these medications, we recommend against their routine use at the time of this writing. Nonetheless, physicians should consider enrolling patients in ongoing clinical trials if this is an available option.

A major challenge during epidemic disease "surge" is the potential for limited ventilators to meet demand. Scoring systems have been developed based on experience from the H1N1 epidemic and have recently been updated and published. 14 These simple scoring systems use the Sequential Organ Failure Assessment tool 15 and other widely available models to establish long-term probability of survival to generate a numerical score, which can be used to prioritize rare resources and limit subjective and possibly biased assessments. Many states are considering legislation to limit liability for providers shouldered with these tragic decisions.

An increase in circulating markers of myocardial injury is reported in 7.2% to 27.8% of patients with COVID-19 and correlates positively with disease severity including need for mechanical ventilation and biochemical measures of heart failure (eg, N-terminal pro-B-type natriuretic peptide). 16, 17 Elevated cardiac troponin-T was associated with an 11.7-fold increase in mortality risk in one series, 18 is predictive of malignant arrhythmias, and increased more frequently in patients with COVID-19 with existing ischemic heart disease, hypertension, or cardiomyopathy. 19, 20 Furthermore, a meta-analysis (N=341 patients) showed that a standardized mean difference in cardiac troponin-I of 25.6 ng/L corresponded to an increase in ICU admission, ARDS, or mortality. 21 Serial measurements are helpful in determining clinical risk and prognosis, although standardized guidelines are lacking at present. Type 2 myocardial infarction from decreased oxygenation and hemodynamic stress accompanying ARDS in COVID-19 has been reported 22 ; myocarditis attributable to cytokine storm and associated T-helper 1 and 2 cell response such as that seen previously with SARS-CoV infection; or myocarditis attributable to either direct involvement or infection of myocardial tissues by SARS-CoV-2. Some of the same factors driving type 2 myocardial infarction may also increase risk of true acute coronary syndromes in patients with COVID-19, the management of which is challenging because of concern about contagion and provider safety, and ECG mimicry of infarct attributable to myopericarditis. 23 Recently proposed guidelines suggest that computed tomographic coronary angiography may permit expedited evaluation for both acute coronary syndrome and myocarditis because of limited availability of cardiac magnetic resonance imaging and exposure risk of catheterization laboratory staff with coronary angiography. 24 In some settings, routine thrombolytic therapy is proposed if access to percutaneous coronary intervention is limited or problematic. 25 A clinical trial assessing early prophylactic medical management of acute coronary syndrome using dual antiplatelet therapy, atorvastatin 40 mg, and low-dose rivaroxaban (2.5 mg daily) in hospitalized patients with COVID-19 is ongoing (NCT04333407).

Systemic hypotension is common in COVID-19 (≈50%), although data profiling cardiac dysfunction in hemodynamically unstable patients are lacking or mixed. In one series of 24 critically ill patients including 82% with shock, echocardiographic left ventricular wall motion abnormalities were not observed. 26 High-quality echocardiographic data are limited by prone positioning of some ICU patients as well as protocols to protect sonographers, suggesting potential value for point-of-care ultrasound (NCT04339998). In exceptional cases, persistent cardiogenic shock has necessitated the use of biventricular mechanical circulatory support. Highdose intravenous immune globulin and high-dose corticosteroids were reported to reverse COVID-19 myocarditis in one case 27 ; however, high-dose corticosteroids are not routinely advised because of prolonged viremia and increased mortality observed with treatment in SARS-CoV-1. Colchicine to prevent myocarditis, cytokine storm, mechanical ventilation, or mortality is being tested currently (NCT04355143, NCT04326790, NCT04350320, NCT04375202, NCT04328480, NCT04360980, and NCT04322682).

Given the dual role of membrane angiotensin-converting enzyme (ACE)-2 serving as the entry protein for SARS-CoV-2 and preserving endothelial barrier function in acute lung injury, there is uncertainty about whether ACE inhibitor or angiotensin receptor blocker medications, which may increase ACE-2 expression, should be continued, discontinued, or initiated in acute COVID-19 illness. Clinical data are mixed, with reports of increased mortality with inpatient use of an ACE inhibitor in one series 18 and decreased mortality with an ACE inhibitor or angiotensin receptor blocker in another, 28 both retrospective studies with multiple confounders. In one recent cross-sectional observational study involving 12 594 patients, the use of ACE inhibitors or angiotensin-receptor blockers was not associated with COVID-19 test positivity. 29 Current guidelines reflect equipoise with respect to initiating or discontinuing these medications, acknowledging that hypotension or shock may dictate practice. Several trials proposing randomization to cessation or initiation of these medications have been announced (NCT04338009, NCT04353596, NCT04351581, NCT04330300, NCT04338009, NCT04340557, NCT04345406, NCT04335786, NCT04364893). A list of pivotal clinical trials in COVID-19 is provided in Table 2 . 

It is recognized increasingly that a subset of patients with COVID-19 demonstrate severe hypoxemia despite near normal lung mechanics. Recent data from dualenergy computed tomographic imaging show striking perfusion defects attributed to morphologic abnormalities in pulmonary arteries, 30 providing an anatomic correlate to impaired hypoxic pulmonary vasoconstriction suspected clinically. 31 Attenuated hypoxic pulmonary vasoconstriction is suspected to cause intrapulmonary shunting, leading to a severe reduction in the pulmonary venous oxygenation, poor oxygen delivery, and organ dysfunction.

Akin to the 2004 SARS-CoV-1, pulmonary hypertension has been reported in patients with COVID-19, possibly via in situ microthrombosis, gross thrombosis, or luminal embolism. 32 This could explain an inverse correlation between plasma d-dimer concentration and clinical outcomes and the potential beneficial effects of anticoagulant therapies suggested by preliminary data sets, 33 as well as data from one autopsy series reporting deep vein thrombosis in 7 of 12 (58%) patients. 32 The wider implications of pulmonary hypertension on right ventricular function includes cor pulmonale in a subset of ICU patients, although the prevalence of end-stage right heart failure across COVID-19 cohorts is not clear. 34 Nonetheless, thrombolytic agents should not be considered for routine management of patients with COVID-19 outside of clinical trials, and data profiling pulmonary vascular involvement in this syndrome remains forthcoming.

Critical research is needed to clarify the totality of factors underlying hypoxemia in COVID-19, role of inhaled vasodilators, implementation of computed tomographic imaging for disease staging, and timing and appropriateness of noninvasive ventilation. This is particularly important because of wide-ranging clinical practice patterns that dominate management currently. Because COVID-19 is a rapidly evolving crisis with no end in sight at the time of this writing, we anticipate reporting further updates on our effort in critical care and cardiopulmonary medicine in the near future. 

This work is dedicated to the growing worldwide population of patients with COVID-19.

Dr Ichinose is a consultant of Nihon Kohden Innovation Center. Dr Gladwin is a co-inventor of patents and patent applications directed to the use of recombinant neuroglobin and heme-based molecules as antidotes for CO poisoning, which have been licensed by Globin Solutions, Inc. Dr Gladwin is also co-inventor on patents directed to the use of nitrite salts in cardiovascular diseases. Dr Gladwin is a principal-investigator in a research collaboration with Bayer Pharmaceuticals to evaluate riociguate as a treatment for patients with sickle cell disease. Dr Maron reports being a consultant for Actelion, and co-inventor on the following patents or patent application that are related to pulmonary hypertension (U.S. Patent #9,605,047; PCT/US2015/029672; Provisional ID: #62475955; Provisional ID: #24624; Provisional ID: #24622). Dr Yu is a co-founder of Keros Therapeutics, which develops therapeutics for hematological and musculoskeletal diseases which target TGF-ß signaling pathways. Dr Yu is compensated for work on the company's SAB and owns equity in the publicly traded company. Dr Yu's interests were reviewed and are managed by Brigham and Women's Hospital and Partners HealthCare in accordance with their conflict of interest policies.

Dr Gladwin receives research support from NIH grants 5R01HL098032, 2R01HL125886, and 5P01HL103455. Dr Ichinose receives research support from R01NS112373 and R21NS116671 and National Science Foundation grant 1557879. Dr de Jesus Perez receives research supported from NIH R01 HL134776 and R01 HL139664. Dr Perman is supported by NIH/NHLBI K23HL138164, and R03HL14836. Dr Maron is supported by NIH: R01HL139613-01, R01HL153502, U54HL119145, R21HL145420; Cardiovascular Medical Research Education Foundation, and McKenzie Family Charitable Trust, and Boston Biomedical Innovations Center.

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