key: cord-0851470-k7mskn56
authors: Gutiérrez‐Zarate, Damián; Rosas‐Sánchez, Karina; Flores‐Carrillo, Juan Carlos; Medrano‐Ahumada, Salvador; Martínez‐Franco, Michel
title: Early management of critically ill patients with COVID‐19
date: 2020-10-19
journal: J Am Coll Emerg Physicians Open
DOI: 10.1002/emp2.12294
sha: ce03622fe6462100fada5f8825f0adbaa5c230c7
doc_id: 851470
cord_uid: k7mskn56

Coronavirus disease 2019 (COVID‐19) is associated with a severe acute respiratory condition requiring respiratory support and mechanical ventilation. Based on the pathophysiology and clinical course of the disease, a therapeutic approach can be adapted. Three phases have been identified, in which different strategies are recommended in a stepwise invasiveness approach. In the second or acute phase, patients are frequently admitted to the ICU for severe pneumonia and hypoxemia with evidence of a proinflammatory and hypercoagulable state. This stage is an opportunity to intervene early in the disease. Medical strategies and mechanical ventilation should be individualized to improve outcomes.

The criteria for admission to the ICU vary by hospital depending on the capacity and resources available. According to data derived from the experience in China, 6% of the cases are classified as critical and 14% as severe. 7 In reports from the Lombardy region of Italy, up to 16% of hospitalized patients have required admission to the ICU. 8 Most patients admitted to the ICU are older and have comorbidities such as hypertension, cardiovascular disease, and chronic obstructive pulmonary disease (COPD). 9 The main indication for admission is acute hypoxemic respiratory failure (70%), followed by septic shock (15%). 10 The mortality rate of critically ill patients is high and varies from 20% to >90%. 11 

According to published findings and to clinical observations of patients with COVID-19, hypotheses on the pathogenesis of SARS-CoV-2 infection have been proposed, but the exact pathogenesis is still controversial. Most experts agree that the illness can be divided in phases. [12] [13] [14] Once the virus enters the body through the mucous membranes of the upper respiratory tract, it reaches the peripheral circulation through the lungs, causing a first viremic phase. In this phase, symptoms of fever and cough predominate. The virus has a predisposition for organs that express angiotensin-converting enzyme 2 (ACE2) receptors, such as the lungs, heart, kidney, and gastrointestinal tract. 12, 14 A second, acute phase or pneumonia phase occurs between days 7 and 14 after the onset of symptoms. Here, the lymphocyte count begins to decrease because of a reduction in B lymphocytes, which can hinder the production of antibodies. This is when a second attack is produced by the activation of an uncontrolled inflammatory response. Although the concept of the cytokine storm is still controversial because of lower levels of proinflammatory cytokines compared to other acute conditions, 15 there is no doubt that the inflammatory response plays an important role in the pathogenesis of COVID-19. 16 Endothelial damage is considerable and is characteristic at this stage of the disease; it may be the principal determinant of microvascular dysfunction, inflammation, and a procoagulant state. 17, 18 This is supported by observations of significant increases in inflammatory markers such as C-reactive protein (CRP), ferritin, and proinflammatory cytokines. 19 In addition, an unusual hypercoagulable state is characterized by prolonged prothrombin time and elevated D-dimer. 12 In the third phase of the disease, if the patient's immune system is competent, in most cases the virus will be effectively suppressed, and the patient enters a recovery or convalescence phase. In certain patients, possibly more likely in those with comorbidities, the immune system cannot control the acute phase, perpetuating the inflammatory response. 12 These patients present with severe symptoms, entering a critical condition characterized by organ failures requiring mechanical ventilation and organ support, with an increased risk of mortality (reaching 50%). 1

Based on the pathogenesis of the SARS-CoV-2 virus, we suggest that the treatment for COVID-19 should be based on the phase and time of symptom onset ( Figure 1 ). The opportunity to intervene is between the first and second phases, when there is evidence of a predominantly proinflammatory and hypercoagulable state. 21

At the time of symptom onset, antiviral therapy is the potential treatment. Currently, multiple treatments with potential activity against SARS-CoV-2 are being evaluated, and some of these treatments are available for other indications.

Remdesivir is a nucleotide analog with in vitro activity against SARS-CoV-2. 22 days for placebo, P < 0.001) and association with a trend toward lower mortality but without statistical significance (8% vs 11.6% on placebo, P = 0.059). 23

These drugs inhibit SARS-CoV-2 in vitro, and it seems that hydroxychloroquine has greater antiviral activity. 24 

These are enhanced protease inhibitors used for antiretroviral treatment against HIV and with demonstrated in vitro activity against MERS-CoV. 28 The results of a randomized study of 199 patients with COVID-19 showed no decrease in time to clinical improvement or mortality. 29

Favipiravir is an RNA polymerase inhibitor used in Asia against influenza, but little evidence is currently available on its efficacy. Interferon beta has demonstrated evidence of in vitro activity against MERS-CoV. 30 

In this phase, the virus activates a proinflammatory response that is associated with disease severity. 32 Patients are frequently admitted to the ICU for severe pneumonia and hypoxemia in this phase. Modulating the immune response is proposed as a therapeutic approach. 33,34

A hypercoagulable state has been described in critically ill patients with COVID-19, 20 and the rate of pulmonary microembolism is probably higher than that reported because of the difficulty of performing imaging studies in severely ill patients. 35 Tang et al described alterations in coagulation markers, especially D-dimer, that were associated with higher mortality in hospitalized patients. 36 In a prospective cohort study, Helms et al reported a rate of thrombotic complications of 16.7% in patients with COVID-19 and acute respiratory distress syndrome (ARDS), mainly due to pulmonary embolism. 37 Low-molecular-weight heparin (LMWH) has been associated with decreased mortality in COVID-19 patients with a sepsis-induced coagulopathy score >4 and D-dimer >6 times the normal value. 38 

Steroids decrease systemic and pulmonary inflammation, but they also inhibit the immune response and, in the context of viral pneumonia, might delay viral elimination. 41 

Immune response-modulating drugs have been considered as potential treatment strategies in COVID-19.

Tocilizumab is a monoclonal antibody that binds and blocks the IL-6 receptor. 51 It is commonly used in autoimmune diseases such as rheumatoid arthritis and juvenile idiopathic arthritis. In severe forms of COVID-19, the exaggerated immune response leads to severe respiratory failure; in these cases, inhibition of IL-6 could decrease the response in the acute phase. Evidence of the efficacy of tocilizumab is low because of poor study designs and lack of clinical trials, but clinical experience in China seems to support its use. 52 A case-control study in France suggests that tocilizumab can reduce the rate of ICU admissions and mortality in patients with severe SARS-CoV-2 pneumonia. 53 In small retrospective studies, improvement in biochemical parameters of inflammation and in oxygenation have been observed, with a reduction in ventilatory support. 54, 55 In a prospective study in patients with severe COVID-19 and ARDS taking tocilizumab, respiratory parameters improved. 56 In the setting of rheumatoid arthritis, the standard recommended dose of tocilizumab is a first dose of 4-8 mg/kg (maximum dose of 800 mg). 51 The considerations for the use of tocilizumab are patients diagnosed with severe to critical COVID-19 and high blood IL-6. 52

Baricitinib is a Janus kinase inhibitor that has anti-inflammatory effects by inhibiting the release of cytokines. It is approved for use in rheumatoid arthritis. In addition, baricitinib seems to have an antivi- standard therapy (ritonavir-lopinavir plus hydroxychloroquine). 58 The greatest concern with baricitinib is the increased risk of reactivation of latent infections such as tuberculosis and hepatitis B. 

The most frequent complication of COVID-19 is acute hypoxemic respiratory failure. The mechanisms of hypoxemia are diverse and include pulmonary edema, vascular microthrombosis, and impaired ventilation/perfusion (V/Q). The recommended objective is to maintain oxygen saturation at 92%-96%. 43 It is possible that in most patients it is only necessary to use supplemental oxygen at low flows (nasal cannula, simple mask, or mask with reservoir). The challenge is patients with rapid and progressive deterioration in whom the choice of strategies such as a high-flow nasal cannula (HFNC), noninvasive mechanical ventilation (NIMV), and early intubation is controversial.

HFNC have been effective in hypoxemic respiratory failure, reducing the need for intubation and mortality compared to NIMV. 59 In patients with COVID-19, the HFNC failure rate was 41% to >60% among patients with PaO 2 /FiO 2 <200 mmHg, 60 which is a higher rate than in patients with non-COVID hypoxemic respiratory failure (failure rate of 40% and 35% in patients with PaO 2 /FiO 2 below 200 mmHg). 59 Some case series indicate a sustained improvement in oxygenation when combining HFNC and prone positioning in awake patients with COVID-19. 61 There is less evidence for NIMV in hypoxemic respiratory failure, and it is probably reserved for patients with a history of COPD, respiratory failure with hypercapnia, and/or cardiogenic pulmonary edema. There is a risk of aerosolization with either of the 2 devices; and,

if used, health personnel should wear the optimal personal protective equipment, and negative pressure isolation rooms should be available at the hospital. 62

The decision to intubate a patient is difficult, even more so in extreme situations such as this pandemic, where resources such as ventilators are limited. An apparently frequent form of presentation called "silent hypoxemia" is described in patients with COVID-19, characterized by low arterial oxygen content in the absence of respiratory symptoms. This phenomenon is poorly documented in the literature and is based on physiological concepts described elegantly by

Dr. Martin Tobin. 63 Intubation and initiation of mechanical ventilation should be considered part of the treatment and not as rescue therapies in patients with progressive deterioration. Delaying intubation until the late phases, when the inflammatory response is exacerbated with multiple-organ failure, probably explains the high mortality reported worldwide. When the respiratory drive is not reduced after the administration of supplemental oxygen or with non-invasive support, respiratory efforts in spontaneous ventilation increase the stress on the tissue and increase capillary leakage, causing patient self-induced lung injury. 64, 65 As suggested in some observational studies when the patient is on mechanical ventilation, there are no changes in lung compliance over time and the patient also presents with higher respiratory drive that predicts relapse of respiratory failure with higher need for neuromuscular blockers. Thus, self-inflicted lung injury during spontaneous ventilation is one of the main determinants for deterioration. [66] [67] [68] The indication for early intubation from the Chinese Society of Anesthesiology is respiratory failure (tachypnea ≥ 30 per minute, low oxygenation with PaO 2 /FiO 2 <150 mmHg) that does not improve after 2 hours of therapy with high-flow oxygen or noninvasive ventilation. 69 Other expert authors recommend intubation in patients with high respiratory drive and at high risk of patient self-inflicted lung injury. 70 This allows the equipment to be prepared for the procedure, the medical staff to have the appropriate protective equipment, the most experienced operator to be recruited, bag-mask ventilation to be preferably avoided, a rapid induction sequence to be applied, and video laryngoscopy to be used. It also prevents progressive lung damage ("ventilator-induced lung injury [VILI] vortex") and unnecessary exposure of personnel to viral transmission. 71

COVID-19 pneumonia seems to have special characteristics that make it different from classic ARDS, as described by Gattinoni et al. 72 Using computed tomography (CT) imaging, it has been possible to characterize COVID-19 ARDS (CARDS) as a continuum on which the initial phase presents with low elastance (high compliance) with low lung weight and low oxygenation. In this "Type L" disease, lung damage is mainly interstitial, and on CT it appears as a ground-glass pattern. Patients may present with "silent hypoxemia" without presenting deterioration, but for various reasons they may progress to a characteristic type of ARDS. "Type H" CARDS, with high elastance (low compliance), appears on CT as consolidations, and the lung weight is high. These types of CARDS are the extremes of a continuous spectrum of lung disease caused by the virus. It is also important to consider endothelial damage, pulmonary vasculature dysregulation, and the hypercoagulability state that produces micro-and macrothrombosis, leading to alterations in ventilation-perfusion, which are also determinants of the mechanical ventilation strategies. 73 The objectives of ventilation are to minimize VILI and to reduce and It is important to avoid alveolar recruitment strategies since they have been associated with increased mortality in patients with ARDS, and low recruitment potential has been observed in CARDS. 77, 78 Using the prone position in PaO 2 /FiO 2 ≤ 150 mmHg for at least 16 hours redistributes pulmonary blood flow and is the safest form of pulmonary recruitment to open areas of collapse in dependent lung regions. 79 The use of continuous prone positioning for >24 hours is safe and is probably more beneficial in these patients for reducing procedures needed because of changes in position. 80 Mechanical ventilation in CARDS is complex, and owing to the heterogeneity of the pulmonary pathology, pulmonary protection strategies should be individualized to improve outcomes ( Figure 2 ).

With the rapid increase in the number of COVID-19 cases, health services are being overburdened to provide adequate care. 5, 6 This has had an important impact on the proportion of deaths among critically ill patients. Therefore, each ICU must adapt and create care protocols for critically ill patients with COVID-19 according to its own needs and resources. 81 There is a rapidly expanding knowledge regarding COVID-19 treatment. To date, the current clinical evidence supports the use of remdesivir as an antiviral; it should be started in the viremic phase, preferred for patients hospitalized and receiving oxygen to prevent further deterioration. In severe and critical cases, it is recommended to start low corticosteroid dose and LMWH as early as possible to limit the acute phase. Other immunomodulatory agents like tocilizumab or baricitinib have limited evidence to recommended systematic use when managing respiratory failure is essential to monitor hypoxemia and the patient's respiratory effort and not delaying intubation. The cornerstone of care remains supportive and high-quality intensive care.

It is important to keep in mind that the mechanisms of SARS-CoV-2 viral injury are time dependent. Therefore, early and systematic interventions could be the key to decreasing the proportion of patients with severe COVID-19 who need mechanical ventilation and individualizing mechanical ventilation strategies in critically ill patients could decrease mortality.

Damián Gutiérrez-Zarate MD https://orcid.org/0000-0001-9353-4754

Vital surveillances: the epidemiological characteristics of an outbreak of 2019 novel coronavirus diseases (COVID-19)-China

Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases from the Chinese center for disease control and prevention

Estimate of the basic reproduction number for COVID-19: a systematic review and meta-analysis

Comparison of hospitalized patients with ARDS caused by COVID-19 and H1N1

Hospital surge capacity in a tertiary emergency referral center during the COVID-19 outbreak in Italy

Critical care surge capacity to respond to the COVID-19 pandemic in Italy: a rapid and affordable solution in the novara hospital

WHO-China Joint Mission. Report of the WHO-China Joint Mission on Coronavirus Disease

Critical care utilization for the COVID-19 outbreak in Lombardy, Italy: early experience and forecast during an emergency response

Predictive symptoms and comorbidities for severe COVID-19 and intensive care unit admission: a systematic review and meta-analysis

Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study

Intensive care management of coronavirus disease 2019 (COVID-19): challenges and recommendations

COVID-19: towards understanding of pathogenesis

Pathogenesis of COVID-19 from a cell biology perspective

Respiratory virus infections: understanding COVID-19

Cytokine levels in critically Ill patients with COVID-19 and other conditions

COVID-19: consider cytokine storm syndromes and immunosuppression

Endothelial cell infection and endotheliitis in COVID-19

Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19

Dysregulation of immune response in patients with COVID-19 in Wuhan, China

Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in

COVID-19 illness in native and immunosuppressed states: a clinical-therapeutic staging proposal

Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro

Remdesivir for the treatment of Covid-19 -preliminary report

In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)

Observational study of hydroxychloroquine in hospitalized patients with covid-19

Hydroxychloroquine with or without Azithromycin in Mild-to-Moderate Covid-19 [published online ahead of print

Hydroxychloroquine or chloroquine for treatment or prophylaxis of COVID-19: a living systematic review

Screening of an FDAapproved compound library identifies four small-molecule inhibitors of Middle East respiratory syndrome coronavirus replication in cell culture

A trial of lopinavir-ritonavir in adults hospitalized with severe covid-19

Broad-spectrum antivirals for the emerging middle east respiratory syndrome coronavirus

Triple combination of interferon beta-1b, lopinavir-ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, phase 2 trial

Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan

A living WHO guideline on drugs for covid-19

Management of critically ill patients with COVID-19 in ICU: statement from front-line intensive care experts in Wuhan

Pulmonary post-mortem findings in a series of COVID-19 cases from northern Italy: a two-centre descriptive study

Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia

High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study

Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy

Association of treatment dose anticoagulation with in-hospital survival among hospitalized patients with COVID-19

Recomendaciones sobre el tratamiento antitrombótico durante la pandemia COVID-19

Prolonged viral shedding in pandemic influenza A(H1N1): clinical significance and viral load analysis in hospitalized patients

The effect of corticosteroid treatment on patients with coronavirus infection: a systematic review and meta-analysis

Surviving sepsis campaign: guidelines on the management of critically ill adults with coronavirus disease 2019 (COVID-19)

Low-dose corticosteroid therapy does not delay viral clearance in patients with COVID-19

Early, low-dose and short-term application of corticosteroid treatment in patients with severe COVID-19 pneumonia: single-center experience from Wuhan

Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China

Dexamethasone in hospitalized patients with Covid-19 -preliminary report

Effect of hydrocortisone on 21-day mortality or respiratory support among critically Ill patients with COVID-19: a randomized clinical trial

Targeted Steroids for ARDS Due to COVID-19 Pneumonia: A Pilot Randomized Clinical Trial (NCT04360876)

Steroid Dosing by bioMARker Guided Titration in Critically Ill Patients With Pneumonia (SMART) (NCT03852537)

Tocilizumab: a review in rheumatoid arthritis

Management and treatment of COVID-19: the chinese experience

Tocilizumab therapy reduced intensive care unit admissions and/or mortality in COVID-19 patients

Effective treatment of severe COVID-19 patients with tocilizumab

Tocilizumab for the treatment of severe COVID-19

Tocilizumab for the treatment of severe COVID-19 pneumonia with hyperinflammatory syndrome and acute respiratory failure: a single center study of 100 patients in Brescia

Baricitinib as potential treatment for 2019-nCoV acute respiratory disease

Baricitinib therapy in COVID-19: a pilot study on safety and clinical impact

High-flow oxygen through nasal cannula in acute hypoxemic respiratory failure

The experience of high-flow nasal cannula in hospitalized patients with 2019 novel coronavirus-infected pneumonia in two hospitals of Chongqing

Early awake prone position combined with high-flow nasal oxygen therapy in severe COVID-19: a case series

Respiratory support for patients with COVID-19 infection

Basing respiratory management of coronavirus on physiological principles

Mechanical ventilation to minimize progression of lung injury in acute respiratory failure

Respiratory drive in the acute respiratory distress syndrome: pathophysiology, monitoring, and therapeutic interventions

Impact of initial respiratory compliance in ventilated patients with acute respiratory distress syndrome related to COVID-19

Clinical features, ventilatory management, and outcome of ARDS caused by COVID-19 are similar to other causes of ARDS

High respiratory drive and excessive respiratory efforts predict relapse of respiratory failure in critically Ill Patients with COVID-19

Expert recommendations for tracheal intubation in critically ill patients with noval coronavirus disease 2019

COVID-19-associated acute respiratory distress syndrome: is a different approach to management warranted?

Time course of evolving ventilator-induced lung injury: the "shrinking baby lung

COVID-19 pneumonia: different respiratory treatments for different phenotypes?

Dealing with the CARDS of COVID-19

An official american thoracic society/european society of intensive care medicine/society of critical care medicine clinical practice guideline: mechanical ventilation in adult patients with acute respiratory distress syndrome

Individualized PEEP setting in subjects with ARDS: a randomized controlled pilot study

Potential for lung recruitment and ventilation-perfusion mismatch in patients with the acute respiratory distress syndrome from coronavirus disease 2019

Effect of lung recruitment and titrated positive end-expiratory pressure (PEEP) vs low PEEP on mortality in patients with acute respiratory distress syndrome: a randomized clinical trial

Lung recruitability in COVID-19-associated acute respiratory distress syndrome: a single-center observational study

Prone positioning in severe acute respiratory distress syndrome

Prolonged prone position ventilation for SARS-CoV-2 patients is feasible and effective

Managing ICU surge during the COVID-19 crisis: rapid guidelines