Update of the recommendations of the Sociedade Portuguesa de Cuidados Intensivos and the Infection and Sepsis Group for the approach to COVID-19 in Intensive Care Medicine

João João Mendes José Artur Paiva Filipe Gonzalez Paulo Mergulhão Filipe Froes Roberto Roncon João Gouveia About the authors

RESUMO

Introdução:

A Sociedade Portuguesa de Cuidados Intensivos e o Grupo de Infeção e Sépsis emitiram previamente recomendações visando à organização dos serviços de saúde e ao manejo dos doentes críticos com COVID-19. Em virtude da evolução do conhecimento, o painel de peritos voltou a se organizar para rever a atual evidência e emitir recomendações atualizadas.

Métodos:

Foi reunido um painel nacional de peritos que declararam não ter conflitos de interesse para o desenvolvimento das recomendações. Foram desenvolvidas perguntas operacionais conforme a metodologia PICO, e foi conduzida uma revisão sistemática rápida por meio da consulta de diferentes fontes bibliográficas. O painel determinou a direção e a força das recomendações com a utilização de duas rodadas de um método Delphi, conduzido seguindo princípios do sistema GRADE. Uma recomendação forte recebeu a redação “recomenda-se”, e uma recomendação fraca foi redigida como “sugere-se”.

Resultados:

Foram emitidas 48 recomendações e 30 sugestões abrangendo os seguintes tópicos: diagnóstico de infecção por SARS-CoV-2, coinfecção e superinfecção; critérios de admissão, cura e suspensão de isolamento; organização dos serviços; Equipamentos de Proteção Individual; terapêuticas de suporte respiratório e outras e terapêuticas específicas (antivirais, imunomodeladores e anticoagulação).

Conclusão:

Essas recomendações, especificamente orientadas para a realidade portuguesa, mas que podem se aplicar também aos Países Africanos de Língua Oficial Portuguesa e ao Timor-Leste, visam apoiar os profissionais de saúde no manejo de doentes críticos com COVID-19. Pretende-se que sejam constantemente revistas, de modo a refletir o avanço de nossa compreensão e o da terapêutica dessa patologia.

Descritores:
COVID-19/terapia; COVID-19/diagnóstico; Infecções por coronavírus; SARS-CoV-2; Guia de práticas clínicas como assunto

ABSTRACT

Introduction:

The Sociedade Portuguesa de Cuidados Intensivos and the Infection and Sepsis Group have previously issued health service and management recommendations for critically ill patients with COVID-19. Due to the evolution of knowledge, the panel of experts was again convened to review the current evidence and issue updated recommendations.

Methods:

A national panel of experts who declared that they had no conflicts of interest regarding the development of the recommendations was assembled. Operational questions were developed based on the PICO methodology, and a rapid systematic review was conducted by consulting different bibliographic sources. The panel determined the direction and strength of the recommendations using two Delphi rounds, conducted in accordance with the principles of the GRADE system. A strong recommendation received the wording “is recommended”, and a weak recommendation was written as “is suggested.”

Results:

A total of 48 recommendations and 30 suggestions were issued, covering the following topics: diagnosis of SARS-CoV-2 infection, coinfection and superinfection; criteria for admission, cure and suspension of isolation; organization of services; personal protective equipment; and respiratory support and other specific therapies (antivirals, immunomodulators and anticoagulation).

Conclusion:

These recommendations, specifically oriented to the Portuguese reality but that may also apply to Portuguese-speaking African countries and East Timor, aim to support health professionals in the management of critically ill patients with COVID-19. They will be continuously reviewed to reflect the progress of our understanding and the treatment of this pathology.

Keywords:
COVID-19/therapy; COVID-19/diagnosis; Coronavirus infections; SARS-CoV-2; Practice guidelines as topic

INTRODUCTION

Coronavirus 2019 (COVID-19), the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was initially reported in the city of Wuhan, in the Chinese province of Hubei, and rapidly spread throughout China, with subsequent involvement of multiple countries. The World Health Organization (WHO) classified the COVID-19 epidemic as a pandemic on March 11, 2021,(11 World Health Organization. Coronavirus disease 2019 (COVID-19) Situation report. 2020. Available from: https://www.who.int/emergencies/diseases/novel-coronavirus-2019/situation-reports
https://www.who.int/emergencies/diseases...
) when the disease had already been identified in 114 countries. In Portugal, the first cases were reported on March 2, 2021, and the first death from the disease occurred on March 16, 2021.(22 República Portuguesa. Serviço Nacional de Saúde. Direçao Geral de Saúde. Relatório de Situação. 2020. Disponível em: https://covid19.min-saude.pt/relatorio-de-situacao/
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)

In response to the COVID-19 pandemic, Sociedade Portuguesa de Cuidados Intensivos and the Infection and Sepsis Group issued recommendations aimed at organizing intensive care services as well as providing diagnosis and treatment (supportive and specific) guidance for critically ill patients with COVID-19.(33 Mendes JJ, Mergulhão P, Froes F, Paiva JA, Gouveia J. Recommendations from the Sociedade Portuguesa de Cuidados Intensivos and Infection & Sepsis Group for intensive care approach to COVID-19. Rev Bras Ter Intensiva. 2020;32(1):2-10.) Due to the evolution of knowledge, the panel of experts was again convened to review the current evidence and issue updated recommendations.

The present document is divided into two sections: (1) a review of SARS-CoV-2 virology and the clinical presentation of COVID-19 and (2) health services and management recommendations/suggestions for patients with COVID-19 in intensive care departments.

METHODS

A national panel of experts was invited by the heads of the Sociedade Portuguesa de Cuidados Intensivos and the Infection and Sepsis Group to prepare these recommendations. All panel members declared that they had no conflicts of interest regarding the development of the recommendations.

The first iteration of the Recommendations of the Sociedade Portuguesa de Cuidados Intensivos and the Infection and Sepsis Group for the approach to COVID-19 in Intensive Care Medicine was used as the basis(33 Mendes JJ, Mergulhão P, Froes F, Paiva JA, Gouveia J. Recommendations from the Sociedade Portuguesa de Cuidados Intensivos and Infection & Sepsis Group for intensive care approach to COVID-19. Rev Bras Ter Intensiva. 2020;32(1):2-10.) for the adaptation and development of these new recommendations. Communication and elaboration among the group were facilitated by electronic mail and teleconference, with the online sharing of a central document. Clinical questions were asked, emphasizing measures of potential impact on the organization of health services and the management of patients with COVID-19 in intensive care departments. For each question, operational questions were developed in accordance with the PICO methodology (participants, interventions, comparisons and outcomes),(44 Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, Schünemann HJ; GRADE Working Group. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ. 2008;336(7650):924-6.) with the population of interest being patients with COVID-19 requiring hospitalization in intensive care departments. For each clinical question, a rapid systematic review was conducted by reviewing the topics listed in the DynaMed and UptoDate databases; several bibliographic searches, with an emphasis on systematic reviews and clinical trials, in PubMed® and in the Cochrane Library used different combinations of search terms related to infection by SARS-CoV-2 and COVID-19 throughout the period encompassing the preparation of the document and review of the topics related to the norms and normative circulars of the Directorate-General for Health (DGS; available at https://www.dgs.pt/normas-orientacoes-e-informacoes/normas-e-circulares-normativas.aspx)

Finally, the panel determined the direction (positive or negative) and strength (strong or weak) of the recommendations using two Delphi rounds (self-administered questionnaire, without meetings between the participants).(55 Boulkedid R, Abdoul H, Loustau M, Sibony O, Alberti C. Using and reporting the Delphi method for selecting healthcare quality indicators: a systematic review. PLoS One. 2011;6(6):e20476.) All these procedures were conducted in accordance with the principles of the GRADE system and taking into account the following factors: quality of evidence, certainty of the balance between advantages and disadvantages, certainty or similarity in values and preferences, and implications of resources. To obtain a consensus, an average level of agreement equal to or greater than 80% was required. When the level of agreement was less than 80%, additional discussion and voting were conducted. A strong recommendation received the wording “is recommended,” and a weak recommendation was written as “is suggested.”

SARS-CoV-2

Virological characteristics

SARS-CoV-2 is a simple positive-sense RNA (ribonucleic acid) genome virus belonging to the genus Betacoronaviruses (β-CoV), whose virion has four structural proteins. The structural proteins S (spike), E (envelope) and M (membrane) create the viral envelope, and protein N (nucleus) contains the RNA genome.

There are four strains (HCoV-229E, HCoV-NL63, HCoV-OC43 and HCoV-HKU1) that circulate seasonally in the human population, most often causing low-severity respiratory infections (for example, constipation) and, rarely, viral pneumonia.(66 Tang X, Wu C, Li X, Song Y, Yao X, Wu X, et al. On the origin and continuing evolution of SARS-CoV-2. Natl Sci Rev. 2020;7(6):1012-23.) Until the emergence of SARS-CoV-2,(77 Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, Zhao X, Huang B, Shi W, Lu R, Niu P, Zhan F, Ma X, Wang D, Xu W, Wu G, Gao GF, Tan W; China Novel Coronavirus Investigating and Research Team. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med. 2020;382(8):727-33.) two other strains that caused epidemic outbreaks with zoonotic origin had been described that passed the species barrier. One of the strains is severe acute respiratory syndrome coronavirus (SARS-CoV-1), which originated from bats and was transmitted to the African civet; SARS-CoV-1 causes severe acute respiratory syndrome (SARS) in humans and circulated between 2002 and 2004. The other strain is Middle East respiratory syndrome coronavirus (MERS-CoV), which originated from bats and was transmitted to camelids; MERS-CoV causes Middle East respiratory syndrome (MERS) and has circulated since 2012.(88 Xie M, Chen Q. Insight into 2019 novel coronavirus - An updated interim review and lessons from SARS-CoV and MERS-CoV. Int J Infect Dis. 2020;94:119-24.) Both SARS-CoV-1 and MERS-CoV have a high mortality rate and may present as acute respiratory failure, requiring invasive mechanical ventilation, vasopressor support and renal replacement techniques.(88 Xie M, Chen Q. Insight into 2019 novel coronavirus - An updated interim review and lessons from SARS-CoV and MERS-CoV. Int J Infect Dis. 2020;94:119-24.) SARS-CoV-2 shares a genetic identity of 96.2% with a coronavirus circulating in natural populations of bats of the species Rhinolophus affinis (SARSr-Ra-Bat-CoV-RaTG13.9), and the pangolin has been hypothesized as the intermediate host.(66 Tang X, Wu C, Li X, Song Y, Yao X, Wu X, et al. On the origin and continuing evolution of SARS-CoV-2. Natl Sci Rev. 2020;7(6):1012-23.)

The basic number of reproductions (R0, number of new cases generated from a single confirmed case in a completely susceptible population) is an indicator of the transmissibility of infection and should be calculated in the initial phase of an epidemic (without considering the implementation of containment and delay measures). Based on the epidemic curve until March 16, 2020, in Portugal, the R0 was estimated at 2.02, with a 95% confidence interval of 1.92 to 2.11.(99 República Portuguesa. Serviço Nacional de Saúde. Instituto Nacional de Saúde Doutor Ricardo Jorge. Covid-19: curva epidémica e parâmetros de transmissibilidade. 2021. Disponível em: http://www.insa.min-saude.pt/category/areas-de-atuacao/epidemiologia/covid-19-curva-epidemica-e-parametros-de-transmissibilidade/
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) The effective reproduction number (R(t)) represents the potential effective propagation of a virus under certain conditions as a function of time and is influenced by public health interventions.(1010 Wu JT, Leung K, Leung GM. Nowcasting and forecasting the potential domestic and international spread of the 2019-nCoV outbreak originating in Wuhan, China: a modelling study. Lancet. 2020;395(10225):689-97.)

SARS-CoV-2, similar to what occurs with other viruses (especially RNA), undergoes frequent changes or mutations. The mutations detected thus far have not changed the biological properties of SARS-CoV-2 responsible for the characteristics of the disease, and the new viruses are considered variants of SARS-CoV-2, not new strains. The Centers for Disease Control and Prevention (CDC) classifies the SARS-CoV-2 variants into variants of interest (which have specific genetic markers but still no clinical/epidemiological evidence), variants of concern (for which there is clinical/epidemiological evidence of increased transmissibility, more severe disease, an increase in hospitalizations or deaths, a significant reduction in neutralization by antibodies generated during previous infection or vaccination, reduced efficacy of therapies/vaccines or failure in diagnostic detection) and variants with high consequences (for which the efficacy of preventive or therapeutic measures is significantly reduced in relation to the previously circulating variants).(1111 Abdool Karim SS, de Oliveira T. New SARS-CoV-2 Variants - Clinical, Public Health, and Vaccine Implications. N Engl J Med. 2021;384(19):1866-8.) There are no variants of high consequences yet, but three variants of concern resulting from mutations in the gene encoding structural protein S have become dominant in the countries where they have been identified and spread globally, with repercussions on the epidemiology of the disease and on vaccine efficacy. These three are variant B.1.1.7 (VOC-202012/01), or the British variant, resulting from the N501Y mutation (change from asparagine - N - to tyrosine - Y - at position 501), which increases transmissibility (between 43% and 82%)(1111 Abdool Karim SS, de Oliveira T. New SARS-CoV-2 Variants - Clinical, Public Health, and Vaccine Implications. N Engl J Med. 2021;384(19):1866-8.) and is possibly associated with higher mortality and lower effectiveness of the therapeutic use of monoclonal antibodies;(1111 Abdool Karim SS, de Oliveira T. New SARS-CoV-2 Variants - Clinical, Public Health, and Vaccine Implications. N Engl J Med. 2021;384(19):1866-8.) variant B.1.351 (501Y.V2), initially identified in South Africa, resulting from the E484K mutation (change from glutamic acid (E) to lysine (K) at position 484), which is associated with avoidance or greater difficulty in recognition of the virus by the natural immune response(1111 Abdool Karim SS, de Oliveira T. New SARS-CoV-2 Variants - Clinical, Public Health, and Vaccine Implications. N Engl J Med. 2021;384(19):1866-8.) or induced by a vaccine;(1212 Madhi SA, Baillie V, Cutland CL, Voysey M, Koen AL, Fairlie L, Padayachee SD, Dheda K, Barnabas SL, Bhorat QE, Briner C, Kwatra G, Ahmed K, Aley P, Bhikha S, Bhiman JN, Bhorat AE, du Plessis J, Esmail A, Groenewald M, Horne E, Hwa SH, Jose A, Lambe T, Laubscher M, Malahleha M, Masenya M, Masilela M, McKenzie S, Molapo K, Moultrie A, Oelofse S, Patel F, Pillay S, Rhead S, Rodel H, Rossouw L, Taoushanis C, Tegally H, Thombrayil A, van Eck S, Wibmer CK, Durham NM, Kelly EJ, Villafana TL, Gilbert S, Pollard AJ, de Oliveira T, Moore PL, Sigal A, Izu A; NGS-SA Group; Wits-VIDA COVID Group. Efficacy of the ChAdOx1 nCoV-19 Covid-19 Vaccine against the B.1.351 Variant. N Engl J Med. 2021;384(20):1885-98.) and variant P.1 (B.1.1.28.1), identified in Manaus, Brazil, which shares the mutation (and the respective risks) of variant B.1.351.(1111 Abdool Karim SS, de Oliveira T. New SARS-CoV-2 Variants - Clinical, Public Health, and Vaccine Implications. N Engl J Med. 2021;384(19):1866-8.) In Portugal, variant B.1.1.7. was identified in January 2021,(1313 European Centre for Disease Prevention and Control (ECDC). Risk Assessment: Risk related to the spread of new SARS-CoV-2 variants of concern in the EU/EEA - first update. 2021. Available from: https://www.ecdc.europa.eu/en/publications-data/covid-19-risk-assessment-spread-new-variants-concern-eueea-first-update
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) becoming dominant in the following month; the circulation of the others was still very limited.(1414 República Portuguesa. Serviço Nacional de Saúde. Instituto Nacional de Saúde Doutor Ricardo Jorge. Diversidade genética do novo coronavírus SARS-CoV-2 (COVID-19) em Portugal - Relatório de situação]. 2021. Disponível em: https://insaflu.insa.pt/covid19/relatorios/INSA_SARS_CoV_2_DIVERSIDADE_GENETICA_relatorio_situacao_2021-09-14.pdf
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)

Forms of transmission

Effective person-to-person transmission of SARS-CoV-2 was established a few weeks after the first reported cases.(1515 Chan JF, Yuan S, Kok KH, To KK, Chu H, Yang J, et al. A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster. Lancet. 2020;395(10223):514-23.) The amount of virus release from the upper airways is a determinant of transmissibility, with very high viral load values in the pharynx during the first week of symptoms, with a peak around the 4th day.(1616 He X, Lau EH, Wu P, Deng X, Wang J, Hao X, et al. Temporal dynamics in viral shedding and transmissibility of COVID-19. Nat Med. 2020;26(5):672-5.) The viral load may be elevated 2 to 3 days before the onset of symptoms, and asymptomatic individuals may also spread the virus.(1717 Gandhi M, Yokoe DS, Havlir DV. Asymptomatic Transmission, the Achilles’ Heel of Current Strategies to Control Covid-19. N Engl J Med. 2020;382(22):2158-60.)

Transmission occurs predominantly by inhalation - and possibly by contact with mucous membranes (for example, ocular and digestive) - of respiratory droplets (macro droplets, which are particles with a diameter > 5mm that, because of the effect of gravity, travel distances less than 1m) expelled in the course of interactions between people in close contact (usually less than 1m).(1818 World Health Organization (WHO). Coronavirus disease (COVID-19): how is it transmitted? 2020. Available from: https://www.who.int/news-room/q-a-detail/coronavirus-disease-covid-19-how-is-it-transmitted
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) The virus persists on inanimate surfaces for up to 72 hours,(1919 van Doremalen N, Bushmaker T, Morris DH, Holbrook MG, Gamble A, Williamson BN, et al. Aerosol and surface stability of SARS-CoV-2 as compared with SARS-CoV-1. N Engl J Med. 2020;382(16):1564-7.) but there are no convincing data supporting transmission through fomites (inanimate objects or substances capable of absorbing, retaining and transporting infectious agents) or surfaces of common use.(2020 Kampf G, Todt D, Pfaender S, Steinmann E. Persistence of coronaviruses on inanimate surfaces and their inactivation with biocidal agents. J Hosp Infect. 2020;104(3):246-51.) Airborne transmission via aerosols (microdroplets, particle diameter  5m) in the community seems to be more of an exception than the rule.(2121 Anderson EL, Turnham P, Griffin JR, Clarke CC. Consideration of the aerosol transmission for COVID-19 and public health. Risk Anal. 2020;40(5):902-7.) However, in the hospital setting (particularly in intensive care departments), airborne transmission should always be considered during the provision of potentially aerosol-generating clinical care (for example, intubation, aspiration of secretions and bronchoscopy) or prolonged contact (> 15 minutes) and/or intimate contact (e.g., placement of a central venous catheter, surgery and cardiorespiratory resuscitation maneuvers).(2222 Tran K, Cimon K, Severn M, Pessoa-Silva C, Conly J. Aerosol-generating procedures and risk of transmission of acute respiratory infections: a systematic review. CADTH Technol Overv. 2013;3(1):e3201.)

SARS-CoV-2 transmission can potentially occur through other pathways, such as fecal-oral transmission, because the presence of viral genetic material has been detected in the feces (but not in the urine) of patients, maintained for periods longer than in respiratory samples,(2323 Wu Y, Guo C, Tang L, Hong Z, Zhou J, Dong X, et al. Prolonged presence of SARS-CoV-2 viral RNA in faecal samples. Lancet Gastroenterol Hepatol. 2020;5(5):434-5.) and parenteral transmission, although the presence of viral genetic material has been rarely detected in blood products.(2424 Wang W, Xu Y, Gao R, Lu R, Han K, Wu G, et al. Detection of SARS-CoV-2 in different types of clinical specimens. JAMA. 2020;323(18):1843-4.) Although the probability of transmission through these last two pathways has not been established, the handling of feces and blood from confirmed cases must be conducted in accordance with strict safety measures.(2424 Wang W, Xu Y, Gao R, Lu R, Han K, Wu G, et al. Detection of SARS-CoV-2 in different types of clinical specimens. JAMA. 2020;323(18):1843-4.)

COVID-19

Pathophysiology

The pathophysiological processes associated with COVID-19 are summarized in figure 1 (Appendix 1). SARS-CoV-2 infection occurs after contact with a significant inoculum, and viral uptake occurs in target cells that coexpress angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2). SARS-CoV-2 interacts with the host through the structural protein S, which binds to the complementary receptor on target cells (ACE2), and TMPRSS2 is responsible for the cleavage of ACE2 and activation of S.(2525 Hoffmann M, Kleine-Weber H, Schroeder S, Kruger N, Herrler T, Erichsen S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell. 2020;181(2):271-80.e8.)

Viral replication cycles occur initially in epithelial cells of the upper respiratory tract, with subsequent extension to segments of the lower respiratory tract, likely involving an aspiration mechanism.(2626 Hou YJ, Okuda K, Edwards CE, Martinez DR, Asakura T, Dinnon KH 3rd, et al. SARS-CoV-2 reverse genetics reveals a variable infection gradient in the respiratory tract. Cell. 2020;182(2):429-46.e14.) At the alveolar-capillary level, binding to ACE2 on epithelial cells (especially type 2 alveolar epithelial cells) and endothelial cells results in direct viral cytotoxicity and innate immune response activation but also in renin-angiotensin-aldosterone system activation via the negative regulation of ACE2 expression and the consequent reduction in the generation of angiotensin 1-7 (which has vasodilator and antiinflammatory effects) and the excessive production of angiotensin 2.(2727 Miesbach W. Pathological role of angiotensin II in severe COVID-19. TH Open. 2020;4(2):e138-e44.) This increase in angiotensin 2, associated with endothelial injury and adaptive immune response activation, results in microvascular dysfunction and microthrombosis.(2828 Varga Z, Flammer AJ, Steiger P, Haberecker M, Andermatt R, Zinkernagel AS, et al. Endothelial cell infection and endotheliitis in COVID-19. Lancet. 2020;395(10234):1417-8.) These local thrombo-inflammatory phenomena can be amplified, resulting in a dysregulated inflammatory response reminiscent of cytokine release syndromes,(2929 Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ; HLH Across Speciality Collaboration, UK. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020;395(10229):1033-4.) with the production of proinflammatory cytokines, particularly interleukin (IL)-1, IL-6 and tumor necrosis factor alpha (TNF-α), often associated with coagulopathy.(3030 Connors JM, Levy JH. COVID-19 and its implications for thrombosis and anticoagulation. Blood. 2020;135(23):2033-40.)

The overlap of these pathophysiological processes translates into evolution through several stages of the disease, for example, the three-stage classification proposed by Siddiqi et al.:(3131 Siddiqi HK, Mehra MR. COVID-19 illness in native and immunosuppressed states: a clinical-therapeutic staging proposal. J Heart Lung Transplant. 2020;39(5):405-7.) stage I (early phase), viral replication; stage II (pulmonary phase), activation of the adaptive immune response, which results in reduced viral load but initiates a thrombo-inflammatory cascade capable of causing tissue injury, with predominantly pulmonary expression; and stage III (hyperinflammatory phase), dysregulated immune response, leading to cytokine storm syndrome.(3232 Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497-506.) It is extremely important to recognize that patients do not progress through all three stages and that the diagnosis of the hyperinflammatory phase implies the exclusion of bacterial overinfection.(3333 Xu X, Han M, Li T, Sun W, Wang D, Fu B, et al. Effective treatment of severe COVID-19 patients with tocilizumab. Proc Natl Acad Sci U S A. 2020;117(20):10970-5.)

Pulmonary manifestations are dependent on the stage of disease progression and result from the interaction of the referred pathophysiological mechanisms: dead space ventilation (due to microvascular dysfunction) and intrapulmonary shunt (due to increased permeability of the alveolar-capillary membrane and alveolar filling with inflammatory exudate). The relative preponderance of these various mechanisms, associated with possible forms of nonprotective ventilation or patient self-inflicted lung injury (P-SILI, intra-alveolar fluid transudation due to changes in the pressure gradient resulting from very negative intrathoracic pressure in the context of increased respiratory drive),(3434 Brochard L, Slutsky A, Pesenti A. Mechanical ventilation to minimize progression of lung injury in acute respiratory failure. Am J Respir Crit Care Med. 2017;195(4):438-42.) probably results in different phenotypes,(3535 Gattinoni L, Chiumello D, Caironi P, Busana M, Romitti F, Brazzi L, et al. COVID-19 pneumonia: different respiratory treatments for different phenotypes? Intensive Care Medicine. 2020;46(6):1099-102.,3636 Gattinoni L, Coppola S, Cressoni M, Busana M, Rossi S, Chiumello D. Covid-19 does not lead to a “typical” acute respiratory distress syndrome. Am J Respir Crit Care Med. 2020;201(10):1299-300.) with distinct anatomopathological signatures.(3737 Copin MC, Parmentier E, Duburcq T, Poissy J, Mathieu D; Lille COVID-19 ICU and Anatomopathology Group. Time to consider histologic pattern of lung injury to treat critically ill patients with COVID-19 infection. Intensive Care Med. 2020;46(6):1124-6.,3838 Dolhnikoff M, Duarte-Neto AN, de Almeida Monteiro RA, da Silva LF, de Oliveira EP, Saldiva PH, et al. Pathological evidence of pulmonary thrombotic phenomena in severe COVID-19. J Thromb Haemost. 2020;18(6):1517-9.)

In addition to pulmonary manifestations, extrapulmonary manifestations (cardiovascular, renal, endocrinological, neurological, gastrointestinal and hepatobiliary) are also described, whose pathophysiological processes are similar to those previously described and are associated, in the early stages, with direct viral cytotoxicity (in tissues in which ACE2 and TMPRSSS2 are coexpressed, such as, myocytes, proximal renal tubular cells, podocytes, pancreatic beta cells, esophageal keratinocytes, gastrointestinal epithelial cells and cholangiocytes)(3939 Puelles VG, Lutgehetmann M, Lindenmeyer MT, Sperhake JP, Wong MN, Allweiss L, et al. Multiorgan and renal tropism of SARS-CoV-2. N Engl J Med. 2020;383(6):590-2.) and, in advanced stages, with deregulated inflammatory responses and with possible thrombo-inflammatory phenomena. Thus, for example, with regard to cardiology, myocarditis may occur (by direct cytopathic effects or inflammatory mechanisms), but the risk of acute coronary events is higher, especially in patients with previous cardiovascular disease and with higher ACE2 expression, via thrombo-inflammatory mechanisms. In the extrapulmonary environment, lymphopenia deserves special mention, occurring predominantly by direct cytotoxic action of the virus after ACE2-dependent or ACE2-independent entry,(4040 Gupta A, Madhavan MV, Sehgal K, Nair N, Mahajan S, Sehrawat TS, et al. Extrapulmonary manifestations of COVID-19. Nat Med. 2020;26(7):1017-32.) as do stomatological manifestations (namely, anosmia), which occur because nasal epithelial cells have the highest ACE2 expression in the entire respiratory tract.(4141 Sungnak W, Huang N, Bécavin C, Berg M, Queen R, Litvinukova M, Talavera-López C, Maatz H, Reichart D, Sampaziotis F, Worlock KB, Yoshida M, Barnes JL; HCA Lung Biological Network. SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes. Nat Med. 2020;26(5):681-7.) However, the distribution of these different pathophysiological mechanisms is not uniform(4242 Dorward DA, Russell CD, Um IH, Elshani M, Armstrong SD, Penrice-Randal R, et al. Tissue-specific immunopathology in fatal COVID-19. Am J Respir Crit Care Med. 2021;203(2):192-201) because direct viral cytotoxicity, as measured by the expression of SARS-CoV-2 genetic and protein material, occurs in a wide variety of sites, including the respiratory tract and various extrapulmonary sites, and thrombo-inflammatory phenomena, measured by histological activity, are more expressive in the lung and in the reticulum endothelial system.

Prolonged or long COVID-19(4343 Datta SD, Talwar A, Lee JT. A proposed framework and timeline of the spectrum of disease due to SARS-CoV-2 infection: illness beyond acute infection and public health implications. JAMA. 2020;324(22):2251-2.) occurs 4 weeks after the initial infection and continues for a period of time not yet fully defined, presenting as multiple syndromes resulting from different pathophysiological processes along the spectrum of the disease (for example, organ dysfunction resulting from acute viral infection, a persistent hyperinflammatory state and psychological and physical weakness due to disease).

CLINICAL

General presentation and pulmonary manifestations

After an incubation period (time from exposure to the onset of symptoms) of 1 to 14 days (median of 5 days), the symptomatic period begins. COVID-19 evolves through three different stages,(3131 Siddiqi HK, Mehra MR. COVID-19 illness in native and immunosuppressed states: a clinical-therapeutic staging proposal. J Heart Lung Transplant. 2020;39(5):405-7.) which are not always present (Figure 2 - Appendix 1).

Stage I (early phase), resulting from viral replication, is characterized by clinical stability with mild symptoms. In Portugal,(22 República Portuguesa. Serviço Nacional de Saúde. Direçao Geral de Saúde. Relatório de Situação. 2020. Disponível em: https://covid19.min-saude.pt/relatorio-de-situacao/
https://covid19.min-saude.pt/relatorio-d...
) the most frequent symptoms are cough and fever, usually in association with myalgia, headache and asthenia. Atypical symptoms are also described, and gastrointestinal and stomatological changes (anosmia and/or ageusia) are the most frequently reported (possibly in isolation) in retrospective studies. There is no specific analytical signature of COVID-19, but lymphopenia (lymphocyte count < 1.0 × 109/L), associated with a slight increase in C-reactive protein, transaminases and lactate dehydrogenase,(3232 Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497-506.,4444 Rodriguez-Morales AJ, Cardona-Ospina JA, Gutiérrez-Ocampo E, Villamizar-Peña R, Holguin-Rivera Y, Escalera-Antezana JP, Alvarado-Arnez LE, Bonilla-Aldana DK, Franco-Paredes C, Henao-Martinez AF, Paniz-Mondolfi A, Lagos-Grisales GJ, Ramírez-Vallejo E, Suárez JA, Zambrano LI, Villamil-Gómez WE, Balbin-Ramon GJ, Rabaan AA, Harapan H, Dhama K, Nishiura H, Kataoka H, Ahmad T, Sah R; Latin American Network of Coronavirus Disease 2019-COVID-19 Research (LANCOVID-19). Clinical, laboratory and imaging features of COVID-19: a systematic review and meta-analysis. Travel Med Infect Dis. 2020;34:101623.) is frequent during this stage. The amplitude of the analytical changes, namely, the degree of lymphopenia and elevation of D-dimer, in the early stage of the disease is associated with the probability of clinical progression to the later stages of COVID-19.(4545 Wu C, Chen X, Cai Y, Xia J, Zhou X, Xu S, et al. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China. JAMA Intern Med. 2020;180(7):934-43.) The appearance of changes on plain chest radiography is unlikely, but there are studies showing that changes in chest computed tomography (CT) may precede positivity identified via molecular biology tests.(4646 Ai T, Yang Z, Hou H, Zhan C, Chen C, Lv W, et al. Correlation of chest CT and RT-PCR testing in coronavirus disease 2019 (COVID-19) in China: a report of 1014 cases. Radiology. 2020;296(2):E32-E40.)

Stage II (pulmonary phase), resulting from adaptive immune response activation and thrombo-inflammatory activity, which result in tissue injury with predominantly pulmonary presentation, typically begins 5 to 7 days after the onset of symptoms, coinciding with the time of hospitalization.(4747 Garg S, Kim L, Whitaker M, O’Halloran A, Cummings C, Holstein R, et al. Hospitalization Rates and Characteristics of Patients Hospitalized with Laboratory-Confirmed Coronavirus Disease 2019 - COVID-NET, 14 States, March 1-30, 2020. MMWR Morb Mortal Wkly Rep. 2020;69(15):458-64.) In Portugal,(4848 Nogueira PJ, de Araujo Nobre M, Costa A, Ribeiro RM, Furtado C, Bacelar Nicolau L, et al. The role of health preconditions on COVID-19 deaths in Portugal: evidence from surveillance data of the first 20293 infection cases. J Clin Med. 2020;9(8):2368.,4949 Ricoca Peixoto V, Vieira A, Aguiar P, Sousa P, Carvalho C, Thomas DR, et al. Determinants of hospitalizations, intensive care unit admission and death among 20,293 reported cases in Portugal, March to April 2020. Euro Surveill. 2021;26(33):2001059.) similar to the rest of the world,(4444 Rodriguez-Morales AJ, Cardona-Ospina JA, Gutiérrez-Ocampo E, Villamizar-Peña R, Holguin-Rivera Y, Escalera-Antezana JP, Alvarado-Arnez LE, Bonilla-Aldana DK, Franco-Paredes C, Henao-Martinez AF, Paniz-Mondolfi A, Lagos-Grisales GJ, Ramírez-Vallejo E, Suárez JA, Zambrano LI, Villamil-Gómez WE, Balbin-Ramon GJ, Rabaan AA, Harapan H, Dhama K, Nishiura H, Kataoka H, Ahmad T, Sah R; Latin American Network of Coronavirus Disease 2019-COVID-19 Research (LANCOVID-19). Clinical, laboratory and imaging features of COVID-19: a systematic review and meta-analysis. Travel Med Infect Dis. 2020;34:101623.) these patients tend to be older (> 60 years) with more cardiovascular risk factors (hypertension, diabetes mellitus and, in particular, obesity) and comorbidities (heart disease, chronic kidney disease and neuromuscular disease). Clinical presentation is more frequently due to worsening of the respiratory condition, with cases of silent hypoxemia being described,(5050 Wilkerson RG, Adler JD, Shah NG, Brown R. Silent hypoxia: a harbinger of clinical deterioration in patients with COVID-19. Am J Emerg Med. 2020;38(10):2243.e5-2243.e6.) with an absence of dyspnea (due to normal pulmonary compliance), although with increased respiratory drive,(3535 Gattinoni L, Chiumello D, Caironi P, Busana M, Romitti F, Brazzi L, et al. COVID-19 pneumonia: different respiratory treatments for different phenotypes? Intensive Care Medicine. 2020;46(6):1099-102.,3636 Gattinoni L, Coppola S, Cressoni M, Busana M, Rossi S, Chiumello D. Covid-19 does not lead to a “typical” acute respiratory distress syndrome. Am J Respir Crit Care Med. 2020;201(10):1299-300.) typically with radiological images characterized by focal or multifocal peripheral ground-glass infiltrates with predominantly basal or, later, crazy-paving pattern, and symptomatic hypoxemia being described, with clear signs of increased respiratory effort (due to reduced pulmonary compliance), typically with radiological images characterized by a confluence of consolidations predominantly affecting the dependent areas of the lung. Progression in this stage is characterized by a gradual increase in C-reactive protein, and the first manifestations of coagulopathy associated with COVID-19 may occur, characterized by increases in D-dimer and fibrinogen.(3030 Connors JM, Levy JH. COVID-19 and its implications for thrombosis and anticoagulation. Blood. 2020;135(23):2033-40.)

Stage III (hyperinflammatory phase), resulting from dysregulated immune responses conditioning cytokine storm syndromes, usually occurs during hospitalization and is characterized, from the clinical point of view, by severe worsening of the respiratory condition (invariably with the need for ventilatory support), often associated with hemodynamic instability and multiorgan insufficiency. Although the analytical markers of the hyperinflammatory phase are nonspecific, extreme elevation of C-reactive protein associated with elevation of D-dimer and ferritin is frequent.(5151 Chen G, Wu D, Guo W, Cao Y, Huang D, Wang H, et al. Clinical and immunological features of severe and moderate coronavirus disease 2019. J Clin Invest. 2020;130(5):2620-9.,5252 Liu T, Zhang J, Yang Y, Ma H, Li Z, Zhang J, et al. The role of interleukin-6 in monitoring severe case of coronavirus disease 2019. EMBO Mol Med. 2020;12(7):e12421.) Although its diagnostic relevance is questionable, proinflammatory ILs, namely, IL-6, are also elevated.(5353 Sinha P, Matthay MA, Calfee CS. Is a “cytokine storm” relevant to COVID-19? JAMA Intern Med. 2020;180(9):1152-4.) Once again, it is extremely important to recognize that the diagnosis of the hyperinflammatory phase implies the exclusion of bacterial overinfection (for which procalcitonin may play an important role)(3333 Xu X, Han M, Li T, Sun W, Wang D, Fu B, et al. Effective treatment of severe COVID-19 patients with tocilizumab. Proc Natl Acad Sci U S A. 2020;117(20):10970-5.) because there is often a temporal coincidence between the two. In addition, patients do not progress through all three stages, and the rate of onset of respiratory failure is variable.(5454 Camporota L, Vasques F, Sanderson B, Barrett NA, Gattinoni L. Identification of pathophysiological patterns for triage and respiratory support in COVID-19. Lancet Respir Med. 2020;8(8):752-4.) Other markers (for example, troponin I and natriuretic peptide type B) may be used in conjunction with other complementary diagnostic tests (for example, echocardiography) for the diagnosis of specific organ involvement.(4040 Gupta A, Madhavan MV, Sehgal K, Nair N, Mahajan S, Sehrawat TS, et al. Extrapulmonary manifestations of COVID-19. Nat Med. 2020;26(7):1017-32.)

The rate of onset of respiratory failure(5454 Camporota L, Vasques F, Sanderson B, Barrett NA, Gattinoni L. Identification of pathophysiological patterns for triage and respiratory support in COVID-19. Lancet Respir Med. 2020;8(8):752-4.) may occur with hyperacute presentation (fulminant form, progressing in hours), indolent presentation (progressive form, progressing in days) or biphasic presentation (initially indolent form followed by clinical improvement and subsequent reaggregation). Hyperacute presentation in the first 7 days of disease progression is atypical and requires the exclusion of a previously existing disease (for example, decompensation of congestive heart failure), which has important therapeutic and prognostic implications.

Long-term COVID-19 includes pulmonary sequelae as well as extrapulmonary sequelae (cardiovascular, neurological and/or psychological), and only limited information is available regarding clinical presentation and long-term prognosis.(4343 Datta SD, Talwar A, Lee JT. A proposed framework and timeline of the spectrum of disease due to SARS-CoV-2 infection: illness beyond acute infection and public health implications. JAMA. 2020;324(22):2251-2.)

Extrapulmonary manifestations

Hematological manifestations

Patients infected with SARS-CoV-2 may present several hematological changes, and lymphopenia is a cardinal laboratory finding (in up to 90% of patients),(3232 Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497-506.,4444 Rodriguez-Morales AJ, Cardona-Ospina JA, Gutiérrez-Ocampo E, Villamizar-Peña R, Holguin-Rivera Y, Escalera-Antezana JP, Alvarado-Arnez LE, Bonilla-Aldana DK, Franco-Paredes C, Henao-Martinez AF, Paniz-Mondolfi A, Lagos-Grisales GJ, Ramírez-Vallejo E, Suárez JA, Zambrano LI, Villamil-Gómez WE, Balbin-Ramon GJ, Rabaan AA, Harapan H, Dhama K, Nishiura H, Kataoka H, Ahmad T, Sah R; Latin American Network of Coronavirus Disease 2019-COVID-19 Research (LANCOVID-19). Clinical, laboratory and imaging features of COVID-19: a systematic review and meta-analysis. Travel Med Infect Dis. 2020;34:101623.,5555 Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395(10229):1054-62.) with a reduction in CD4+ and CD8+ lymphocyte subpopulations associated with worse clinical progression.(5656 Qin C, Zhou L, Hu Z, Zhang S, Yang S, Tao Y, et al. Dysregulation of immune response in patients with coronavirus 2019 (COVID-19) in Wuhan, China. Clin Infect Dis. 2020;71(15):762-8.) Leukocytosis with neutrophilia (rarer) is also a marker of poor prognosis.(3232 Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497-506.,4444 Rodriguez-Morales AJ, Cardona-Ospina JA, Gutiérrez-Ocampo E, Villamizar-Peña R, Holguin-Rivera Y, Escalera-Antezana JP, Alvarado-Arnez LE, Bonilla-Aldana DK, Franco-Paredes C, Henao-Martinez AF, Paniz-Mondolfi A, Lagos-Grisales GJ, Ramírez-Vallejo E, Suárez JA, Zambrano LI, Villamil-Gómez WE, Balbin-Ramon GJ, Rabaan AA, Harapan H, Dhama K, Nishiura H, Kataoka H, Ahmad T, Sah R; Latin American Network of Coronavirus Disease 2019-COVID-19 Research (LANCOVID-19). Clinical, laboratory and imaging features of COVID-19: a systematic review and meta-analysis. Travel Med Infect Dis. 2020;34:101623.,5555 Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395(10229):1054-62.)

Coagulopathy associated with COVID-19, with the previously described analytical pattern, is essentially a prothrombotic dyscrasia (the hemorrhagic risk in COVID-19 is relatively low, approximately 2.7%),(5757 Helms J, Tacquard C, Severac F, Leonard-Lorant I, Ohana M, Delabranche X, Merdji H, Clere-Jehl R, Schenck M, Fagot Gandet F, Fafi-Kremer S, Castelain V, Schneider F, Grunebaum L, Anglés-Cano E, Sattler L, Mertes PM, Meziani F; CRICS TRIGGERSEP Group (Clinical Research in Intensive Care and Sepsis Trial Group for Global Evaluation and Research in Sepsis). High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study. Intensive Care Med. 2020;46(6):1089-98.) with strong variability in the incidence and distribution of events, depending on the thromboprophylaxis regimens.(5757 Helms J, Tacquard C, Severac F, Leonard-Lorant I, Ohana M, Delabranche X, Merdji H, Clere-Jehl R, Schenck M, Fagot Gandet F, Fafi-Kremer S, Castelain V, Schneider F, Grunebaum L, Anglés-Cano E, Sattler L, Mertes PM, Meziani F; CRICS TRIGGERSEP Group (Clinical Research in Intensive Care and Sepsis Trial Group for Global Evaluation and Research in Sepsis). High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study. Intensive Care Med. 2020;46(6):1089-98.,5858 Al-Ani F, Chehade S, Lazo-Langner A. Thrombosis risk associated with COVID-19 infection. A scoping review. Thromb Res. 2020;192:152-60.) COVID-19 is associated with venous thromboembolic events (cumulative incidence of deep vein thrombosis and pulmonary thromboembolism, 31.3%),(5858 Al-Ani F, Chehade S, Lazo-Langner A. Thrombosis risk associated with COVID-19 infection. A scoping review. Thromb Res. 2020;192:152-60.) even under prophylactic anticoagulation;(5757 Helms J, Tacquard C, Severac F, Leonard-Lorant I, Ohana M, Delabranche X, Merdji H, Clere-Jehl R, Schenck M, Fagot Gandet F, Fafi-Kremer S, Castelain V, Schneider F, Grunebaum L, Anglés-Cano E, Sattler L, Mertes PM, Meziani F; CRICS TRIGGERSEP Group (Clinical Research in Intensive Care and Sepsis Trial Group for Global Evaluation and Research in Sepsis). High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study. Intensive Care Med. 2020;46(6):1089-98.) arterial thrombotic events (for example, acute myocardial infarction and stroke);(5959 Bilaloglu S, Aphinyanaphongs Y, Jones S, Iturrate E, Hochman J, Berger JS. Thrombosis in hospitalized patients with COVID-19 in a New York City Health System. JAMA. 2020;324(8):799-801.) intravenous catheter thrombosis and coagulation of extracorporeal systems (for example, hemofilters in the context of the renal function replacement technique);(5757 Helms J, Tacquard C, Severac F, Leonard-Lorant I, Ohana M, Delabranche X, Merdji H, Clere-Jehl R, Schenck M, Fagot Gandet F, Fafi-Kremer S, Castelain V, Schneider F, Grunebaum L, Anglés-Cano E, Sattler L, Mertes PM, Meziani F; CRICS TRIGGERSEP Group (Clinical Research in Intensive Care and Sepsis Trial Group for Global Evaluation and Research in Sepsis). High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study. Intensive Care Med. 2020;46(6):1089-98.) and microthrombotic phenomena, which contribute to the pathophysiology of hypoxemic respiratory failure.(3838 Dolhnikoff M, Duarte-Neto AN, de Almeida Monteiro RA, da Silva LF, de Oliveira EP, Saldiva PH, et al. Pathological evidence of pulmonary thrombotic phenomena in severe COVID-19. J Thromb Haemost. 2020;18(6):1517-9.) Thrombocytopenia and increased D-dimer concentrations upon admission (and longitudinal increase during hospitalization) are associated with more severe disease and a worse prognosis.(5555 Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395(10229):1054-62.,6060 Tang N, Bai H, Chen X, Gong J, Li D, Sun Z. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost. 2020;18(5):1094-9.)

Gastrointestinal and hepatobiliary manifestations

The gastrointestinal manifestations of SARS-CoV-2 infection (anorexia, nausea/vomiting, diarrhea and abdominal pain) are frequent (up to 60% of patients) and may occur in isolation. Viral shedding in feces is frequent, and the presence of gastrointestinal manifestations is associated with longer disease duration but not with clinical severity.(6161 Mao R, Qiu Y, He JS, Tan JY, Li XH, Liang J, et al. Manifestations and prognosis of gastrointestinal and liver involvement in patients with COVID-19: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol. 2020;5(7):667-78.) Importantly, gastrointestinal bleeding is rare in the context of COVID-19, even in critically ill patients under mechanical ventilation and with coagulation disorders.(6262 Nobel YR, Phipps M, Zucker J, Lebwohl B, Wang TC, Sobieszczyk ME, et al. Gastrointestinal symptoms and coronavirus disease 2019: a case-control study from the United States. Gastroenterology. 2020;159(1):373-5.e2.) Hepatocellular lesions (with elevation of transaminases less than five times the upper limit of normal) is frequent in SARS-CoV-2 infection, and there is an association between the magnitude of liver function changes and disease severity.(6161 Mao R, Qiu Y, He JS, Tan JY, Li XH, Liang J, et al. Manifestations and prognosis of gastrointestinal and liver involvement in patients with COVID-19: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol. 2020;5(7):667-78.)

Cardiovascular manifestations

SARS-CoV-2 infection can result in direct and indirect cardiovascular injury,(4040 Gupta A, Madhavan MV, Sehgal K, Nair N, Mahajan S, Sehrawat TS, et al. Extrapulmonary manifestations of COVID-19. Nat Med. 2020;26(7):1017-32.,6363 Clerkin KJ, Fried JA, Raikhelkar J, Sayer G, Griffin JM, Masoumi A, et al. COVID-19 and cardiovascular disease. Circulation. 2020;141(20):1648-55.) i.e., ischemic cardiac injury (including type 1 acute myocardial infarction due to atherothrombotic coronary disease and precipitated by atherosclerotic plaque disruption and type 2 acute myocardial infarction due to an imbalance between oxygen supply and needs) and nonischemic (infectious myocarditis) or inflammatory injury potentially associated with ventricular dysfunction (left or global) complicated by acute heart failure or cardiogenic shock;(4040 Gupta A, Madhavan MV, Sehgal K, Nair N, Mahajan S, Sehrawat TS, et al. Extrapulmonary manifestations of COVID-19. Nat Med. 2020;26(7):1017-32.,6363 Clerkin KJ, Fried JA, Raikhelkar J, Sayer G, Griffin JM, Masoumi A, et al. COVID-19 and cardiovascular disease. Circulation. 2020;141(20):1648-55.) acute cor pulmonale, associated or not with pulmonary thromboembolism;(6464 Creel-Bulos C, Hockstein M, Amin N, Melhem S, Truong A, Sharifpour M. Acute cor pulmonale in critically ill patients with Covid-19. N Engl J Med. 2020;382(21):e70.) and dysrhythmias, including a higher prevalence of de novo atrial fibrillation and prolonged QTc since admission.(6565 Richardson S, Hirsch JS, Narasimhan M, Crawford JM, McGinn T, Davidson KW, et al. Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City Area. JAMA. 2020;323(20):2052-9. Erratum in JAMA. 2020;323(20):2098.) The frequency and magnitude of the elevation of cardiac biomarkers (for example, troponin and natriuretic peptide type B) are associated with more severe disease and a worse prognosis, especially in patients with preexisting cardiovascular disease.(6666 Shi S, Qin M, Shen B, Cai Y, Liu T, Yang F, et al. Association of cardiac injury with mortality in hospitalized patients with COVID-19 in Wuhan, China. JAMA Cardiol. 2020;5(7):802-10.)

Neurological manifestations

Mild neurological manifestations of SARS-CoV-2 infection (headache, dizziness and myalgia) are frequent (up to 50% of patients),(6767 Mao L, Jin H, Wang M, Hu Y, Chen S, He Q, et al. Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China. JAMA Neurol. 2020;77(6):683-90.) and stomatological manifestations (especially ageusia and anosmia) may occur in isolation (in up to 3% of patients).(6868 Spinato G, Fabbris C, Polesel J, Cazzador D, Borsetto D, Hopkins C, et al. Alterations in smell or taste in mildly symptomatic outpatients with SARS-CoV-2 infection. JAMA. 2020;323(20):2089-90.) Severe neurological manifestations of COVID-19 can occur by different direct and indirect mechanisms and are varied: acute stroke (in up to 6% of critically ill patients); alteration of the state of consciousness; acute inflammatory demyelinating polyneuropathy (Guillain-Barré-like syndrome); posterior reversible encephalopathy syndrome (PRES); and acute necrotizing encephalopathy, including the brainstem and basal ganglia.(4040 Gupta A, Madhavan MV, Sehgal K, Nair N, Mahajan S, Sehrawat TS, et al. Extrapulmonary manifestations of COVID-19. Nat Med. 2020;26(7):1017-32.)

Renal manifestations

Acute kidney injury, resulting from glomerular and/or tubular pathology (by direct or indirect mechanisms), is a frequent complication (up to 30% of patients) of SARS-CoV-2 infection,(6969 Hirsch JS, Ng JH, Ross DW, Sharma P, Shah HH, Barnett RL, Hazzan AD, Fishbane S, Jhaveri KD; Northwell COVID-19 Research Consortium; Northwell Nephrology COVID-19 Research Consortium. Acute kidney injury in patients hospitalized with COVID-19. Kidney Int. 2020;98(1):209-18.,7070 Cheng Y, Luo R, Wang K, Zhang M, Wang Z, Dong L, et al. Kidney disease is associated with in-hospital death of patients with COVID-19. Kidney Int. 2020;97(5):829-38.) affecting up to 22% of those admitted to intensive care units.(6565 Richardson S, Hirsch JS, Narasimhan M, Crawford JM, McGinn T, Davidson KW, et al. Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City Area. JAMA. 2020;323(20):2052-9. Erratum in JAMA. 2020;323(20):2098.) Changes in urinary sediment (for example, proteinuria and hematuria) are frequent (up to 90% of patients),(7171 Cummings MJ, Baldwin MR, Abrams D, Jacobson SD, Meyer BJ, Balough EM, et al. Epidemiology, clinical course, and outcomes of critically ill adults with COVID-19 in New York City: a prospective cohort study. Lancet. 2020;395(10239):1763-70.) and the elevation of serum biomarkers of acute kidney injury (for example, creatinine) is associated with increased mortality.(7070 Cheng Y, Luo R, Wang K, Zhang M, Wang Z, Dong L, et al. Kidney disease is associated with in-hospital death of patients with COVID-19. Kidney Int. 2020;97(5):829-38.) A history of end-stage renal disease (especially patients on hemodialysis and renal transplant recipients) is associated with more severe disease and a worse prognosis.(7272 Valeri AM, Robbins-Juarez SY, Stevens JS, Ahn W, Rao MK, Radhakrishnan J, et al. Presentation and outcomes of patients with ESKD and COVID-19. J Am Soc Nephrol. 2020;31(7):1409-15.)

Endocrine manifestations

Patients hospitalized with COVID-19 often present changes in glucose metabolism, especially euglycemic ketosis and diabetic ketoacidosis in addition to hyperglycemia,(4040 Gupta A, Madhavan MV, Sehgal K, Nair N, Mahajan S, Sehrawat TS, et al. Extrapulmonary manifestations of COVID-19. Nat Med. 2020;26(7):1017-32.) and changes in thyroid function, namely, reductions in thyroid-stimulating hormone (TSH) and FT4.(7373 Chen M, Zhou W, Xu W. Thyroid function analysis in 50 patients with COVID-19: a retrospective study. Thyroid. 2021;31(1):8-11.) A history of diabetes mellitus and/or obesity is associated with more severe disease and a worse prognosis.(7474 CDC COVID-19 Response Team. Preliminary estimates of the prevalence of selected underlying health conditions among patients with coronavirus disease 2019 - United States, February 12-March 28, 2020. MMWR Morb Mortal Wkly Rep. 2020;69(13):382-6.)

Dermatological manifestations

Mild (acrocutaneous lesions (leg), maculopapular rash (urticaria) and papulovesicular rash) and greater severity (exanthema and livedo reticularis) dermatological manifestations are frequently found in patients hospitalized with COVID-19 (up to 20% of patients), either at admission or during the disease course.(7575 Recalcati S. Cutaneous manifestations in COVID-19: a first perspective. J Eur Acad Dermatol Venereol. 2020;34(5):e212-e213.)

Definitions of severity

The definitions of COVID-19 severity by the WHO(7676 World Health Organization (WHO). COVID-19 Clinical management: living guidance. 25 January 2021. Available from: file:///C:/Users/elisabete.freitas/Downloads/WHO-2019-nCoV-clinical-2021.1-eng.pdf) provide a pragmatic structure (based on clinical indicators) to define subgroups of disease severity. We used these criteria (Table 1 - Appendix 1) as aids in the evaluation, guidance and treatment of patients with COVID-19.

DIAGNOSIS OF INFECTION

Diagnosis of SARS-CoV-2 infection

It is recommended that all patients requiring hospitalization in intensive care units undergo a diagnostic test to identify SARS-CoV-2.

It is recommended that the initial diagnostic test in patients requiring hospitalization in intensive care units be a molecular nucleic acid amplification test (NAAT) using a sample from the upper respiratory tract (exudate from the nasopharynx and oropharynx collected with a swab) in the context of pneumonia, whenever possible, to the lower respiratory tract (for example, bronchial secretions collected by endotracheal aspirate).

It is suggested that when NAAT results cannot be obtained in less than 12 hours (or if NAATs are not available), a rapid antigen test should be used, and a confirmatory NAAT should be conducted as soon as possible if the rapid antigen test result is negative.

It is suggested that during hospitalization, between the third and fifth day after the initial negative test and periodically every 5 days (counted from the last test), NAATs should be used for screening.

It is recommended not to use serological tests in the acute phase.

It is recommended not to use chest CT as the first diagnostic test in patients with suspected SARS-CoV-2 infection.

The primary aims of laboratory diagnostic tests for SARS-CoV-2 are to diagnose COVID-19 and to detect asymptomatic or presymptomatic cases, limiting the spread in the hospital setting.(7777 República Portuguesa. Serviço Nacional de Saúde. Direçao Geral de Saúde. Norma 019/2020 - Estratégia nacional de testes para SARS-CoV-2. 2020. Disponível em: https://covid19.min-saude.pt/wp-content/uploads/2021/03/Norma_019_2020_act_26_02_2021.pdf
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) Molecular NAATs (reverse transcription-polymerase chain reaction (RT-PCR) and real-time RT-PCR (rRT-PCR)) are the reference methods (gold standard) for the diagnosis and screening of SARS-CoV-2 infection.(7777 República Portuguesa. Serviço Nacional de Saúde. Direçao Geral de Saúde. Norma 019/2020 - Estratégia nacional de testes para SARS-CoV-2. 2020. Disponível em: https://covid19.min-saude.pt/wp-content/uploads/2021/03/Norma_019_2020_act_26_02_2021.pdf
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)

The NAATs for the identification of SARS-CoV-2 have high specificity, and patients with a higher viral load (further into the disease course) may be more likely to have a positive test. However, in patients with suspected COVID-19 and an negative initial rRT-PCR result, repetition (conversion over days) was positive in 23% of cases (with 4% more cases identified by a third test), indicating a sensitivity < 80%.(4646 Ai T, Yang Z, Hou H, Zhan C, Chen C, Lv W, et al. Correlation of chest CT and RT-PCR testing in coronavirus disease 2019 (COVID-19) in China: a report of 1014 cases. Radiology. 2020;296(2):E32-E40.) This means that a single negative rRT-PCR test does not exclude SARS-CoV-2 infection.

Rapid antigen tests are proximity tests (point-of-care), with results available 15 to 30 minutes and an analytical sensitivity (≥ 90%) and specificity (≥ 97%) lower than those for NAATs.(7878 Crozier A, Rajan S, Buchan I, McKee M. Put to the test: use of rapid testing technologies for covid-19. BMJ. 2021;372:n208.) The only reason for their use should be in the context of the unavailability of the gold standard.

Serological tests assess the immune response to SARS-CoV-2 infection. In viral infections, the immune response lags at least 5 to 7 days from the viremia phase,(7979 Miller JM, Binnicker MJ, Campbell S, Carroll KC, Chapin KC, Gilligan PH, et al. A Guide to Utilization of the Microbiology Laboratory for Diagnosis of Infectious Diseases: 2018 Update by the Infectious Diseases Society of America and the American Society for Microbiology. Clin Infect Dis. 2018;67(6):e1-e94.,8080 Landry ML. Immunoglobulin M for acute infection: true or false? Clin Vaccine Immunol. 2016;23(7):540-5.) which is why serological tests are considered inadequate for the evaluation of SARS-CoV-2 infection in the acute phase.(8181 Heymann DL. Data sharing and outbreaks: best practice exemplified. Lancet. 2020;395(10223):469-70.)

There are radiological changes suggestive of COVID-19, and studies have shown that changes in chest CT precede NAAT positivity.(4646 Ai T, Yang Z, Hou H, Zhan C, Chen C, Lv W, et al. Correlation of chest CT and RT-PCR testing in coronavirus disease 2019 (COVID-19) in China: a report of 1014 cases. Radiology. 2020;296(2):E32-E40.) However, the widespread use of CT devices potentially increases the risk of cross-infection and should be reserved for situations that would result in changes in clinical management.(8282 American College of Radiology (ACR). ACR recommendations for the use of chest radiography and computed tomography (CT) for suspected COVID-19 infection. March 11, 2020. Available from: https://www.acr.org/Advocacy-and-Economics/ACR-Position-Statements/Recommendations-for-Chest-Radiography-and-CT-for-Suspected-COVID19-Infection
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)

Diagnosis of co-infection and superinfection

The collection of blood cultures (at least two sets of aerobic and anaerobic blood cultures) from the lower respiratory tract is recommended for the investigation of other microbiological agents and antigenuria for Legionella pneumophila and Streptococcus pneumoniae.

It is suggested to consider requesting other tests (for example, NAATs for other viruses, e.g., influenza, and other respiratory viruses, serology for atypical microorganisms, galactomannan detection) based clinical symptoms and epidemiology.

Coinfection by other microbiological agents, especially in the presence of septic shock, is possible.(8383 Bouadma L, Lescure FX, Lucet JC, Yazdanpanah Y, Timsit JF. Severe SARS-CoV-2 infections: practical considerations and management strategy for intensivists. Intensive Care Med. 2020;46(4):579-82.) Patients with suspected or confirmed SARS-CoV-2 infection should undergo testing, when appropriate, for other agents (bacteria, viruses or fungi). In the context of sepsis, the collection of blood cultures (at least two sets of aerobic and anaerobic blood cultures) and lower respiratory tract samples are indicated for the investigation of other microbiological agents and the detection of antigenuria for Legionella pneumophila and Streptococcus pneumoniae.(8383 Bouadma L, Lescure FX, Lucet JC, Yazdanpanah Y, Timsit JF. Severe SARS-CoV-2 infections: practical considerations and management strategy for intensivists. Intensive Care Med. 2020;46(4):579-82.) In an appropriate clinical-epidemiological context, the request for other microbiological tests is indicated (for example, detection by molecular biology methods for influenza virus and other respiratory viruses and serology for atypical microorganisms).(8484 Kim D, Quinn J, Pinsky B, Shah NH, Brown I. Rates of co-infection between SARS-CoV-2 and other respiratory pathogens. JAMA. 2020;323(20):2085-6.) Coinfection with Aspergillus spp. has also been described, and galactomannan assays can be considered in an appropriate clinical-epidemiological context.(8585 van Arkel AL, Rijpstra TA, Belderbos HN, van Wijngaarden P, Verweij PE, Bentvelsen RG. COVID-19-associated Pulmonary Aspergillosis. Am J Respir Crit Care Med. 2020;202(1):132-5.)

Criteria for admission to intensive care units

It is recommended that patients with severe or critical COVID-19 criteria be referred early to intensive care units.

It is recommended that admission to the intensive care unit be based on a case-by-case assessment that includes the presentation and severity of acute disease, the reversibility and favorable prognosis of acute disease, history of comorbidities, and poor functional status and frailty prior to the acute situation motivating admission.

It is recommended that whenever there is no possibility of a local response, referral and transfer of the patient should be based on the intensive care referral network so that the necessary care can be provided.

It is recommended that the decision to admit (or not) be accompanied by the development of a care plan based on a decision model shared with the patient or with his or her family; collegial methodology, ideally multiprofessional and multispecialty, coordinated by an experienced intensivist; and the use of national and international standards and guidelines.

The essential part of the decision-making process for admission to intensive care is based on expectations of individual benefits (vital and functional) and on the clinical evaluation of each patient, in his or her biopsychosocial dimension, determining adequate severity stratification and consequent decisions regarding the level of care, ensuring that there is no difference between the necessary care and care provided.(8686 Vergano M, Bertolini G, Giannini A, Gristina GR, Livigni S, Mistraletti G, et al. Clinical ethics recommendations for the allocation of intensive care treatments in exceptional, resource-limited circumstances: the Italian perspective during the COVID-19 epidemic. Crit Care. 2020;24(1):165.) Decisions of nonadmission to intensive care units should never be confused with abandonment, requiring, on the contrary, the development of a care plan of which an intensivist is an integral part.(8787 National Institute for Health and Care Excellence (NICE). COVID-19 rapid guideline: critical care in adults. NICE guideline [NG159]. March 20, 2020. Available from: https://www.nice.org.uk/guidance/ng159
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)

The lack of planning in situations of potential scarcity of resources leads to inefficiency, waste and the use of prioritization and rationing strategies that are otherwise unnecessary. The use of objective criteria favors a better decision; mitigates the anguish and individual discomfort of professionals;(77 Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, Zhao X, Huang B, Shi W, Lu R, Niu P, Zhan F, Ma X, Wang D, Xu W, Wu G, Gao GF, Tan W; China Novel Coronavirus Investigating and Research Team. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med. 2020;382(8):727-33.) and attenuates subjectivity and promotes a decision model that involves the patient, their representatives(8888 Moutel G. Anticipating the role of the intensive care unit in healthcare and life trajectories. Ann Transl Med. 2017;5(Suppl 4):S37.) and society while maintaining respect for the principle of autonomy.(8989 Dove ES, Kelly SE, Lucivero F, Machirori M, Dheensa S, Prainsack B. Beyond individualism: is there a place for relational autonomy in clinical practice and research? Clin Ethics. 2017;12(3):150-65.) The fundamental values that underlie the ethical decision-making matrix of the flow and admission of patients to intensive care units include (1) planning, which involves the development and implementation of a proactive contingency plan (developed by intensive care specialists, agreed upon by other hospital services and approved by a board of directors), with a level of interinstitutional collaboration, namely, referral and regional and interregional transfer based on an intensive care medicine referral network;(22 República Portuguesa. Serviço Nacional de Saúde. Direçao Geral de Saúde. Relatório de Situação. 2020. Disponível em: https://covid19.min-saude.pt/relatorio-de-situacao/
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) (2) maximizing benefits, considering four fundamental criteria, i.e., presentation and severity of acute disease, especially the number and severity of organ dysfunctions (for example, Sequential Organ Failure Assessment (SOFA)); the reversibility and prognosis of acute disease; a history comorbidities; and poor functional state and frailty (clinical frailty scale) prior to the acute situation motivating admission;(8787 National Institute for Health and Care Excellence (NICE). COVID-19 rapid guideline: critical care in adults. NICE guideline [NG159]. March 20, 2020. Available from: https://www.nice.org.uk/guidance/ng159
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,9090 Robert R, Kentish-Barnes N, Boyer A, Laurent A, Azoulay E, Reignier J. Ethical dilemmas due to the Covid-19 pandemic. Ann Intensive Care. 2020;10(1):84.) (3) exercising collegiality and utilizing a shared decision model, involving the elaboration of a care plan, based on a decision model shared with the patient or his or her family members that represents the patient’s values;(9191 Kon AA, Davidson JE, Morrison W, Danis M, White DB; American College of Critical Care Medicine; American Thoracic Society. Shared Decision Making in ICUs: An American College of Critical Care Medicine and American Thoracic Society Policy Statement. Crit Care Med. 2016;44(1):188-201.) collegial methodology, ideally involving multiple professionals and multiple specialties, coordinated by an experienced intensivist;(8686 Vergano M, Bertolini G, Giannini A, Gristina GR, Livigni S, Mistraletti G, et al. Clinical ethics recommendations for the allocation of intensive care treatments in exceptional, resource-limited circumstances: the Italian perspective during the COVID-19 epidemic. Crit Care. 2020;24(1):165.,9090 Robert R, Kentish-Barnes N, Boyer A, Laurent A, Azoulay E, Reignier J. Ethical dilemmas due to the Covid-19 pandemic. Ann Intensive Care. 2020;10(1):84.,9292 Christian MD, Sprung CL, King MA, Dichter JR, Kissoon N, Devereaux AV, Gomersall CD; Task Force for Mass Critical Care; Task Force for Mass Critical Care. Triage: care of the critically ill and injured during pandemics and disasters: CHEST consensus statement. Chest. 2014;146(4 Suppl):e61S-74S.) and the use of national and international standards and guidelines;(8686 Vergano M, Bertolini G, Giannini A, Gristina GR, Livigni S, Mistraletti G, et al. Clinical ethics recommendations for the allocation of intensive care treatments in exceptional, resource-limited circumstances: the Italian perspective during the COVID-19 epidemic. Crit Care. 2020;24(1):165.,9090 Robert R, Kentish-Barnes N, Boyer A, Laurent A, Azoulay E, Reignier J. Ethical dilemmas due to the Covid-19 pandemic. Ann Intensive Care. 2020;10(1):84.,9292 Christian MD, Sprung CL, King MA, Dichter JR, Kissoon N, Devereaux AV, Gomersall CD; Task Force for Mass Critical Care; Task Force for Mass Critical Care. Triage: care of the critically ill and injured during pandemics and disasters: CHEST consensus statement. Chest. 2014;146(4 Suppl):e61S-74S.) (4) imparting equity, operationalized to avoid first come, first served, which cannot be used in situations where the response must be urgent and fast and the lack of resources can be fatal;(8686 Vergano M, Bertolini G, Giannini A, Gristina GR, Livigni S, Mistraletti G, et al. Clinical ethics recommendations for the allocation of intensive care treatments in exceptional, resource-limited circumstances: the Italian perspective during the COVID-19 epidemic. Crit Care. 2020;24(1):165.) (5) providing triage and establishing duty of care, recognizing that in situations of high demand, screening decisions are essential to define the level of care, initiate organ support therapy, recognize therapeutic ceilings, suspend organ support and/or refer patients to palliative care; and (6) establishing cross-sectional resource use criteria, not allowing discrimination (positive or negative) in the criteria for resource allocation or the formulation of ethical decisions for patients with COVID-19 or other clinical conditions.

INFECTION CONTROL

Personal protective equipment

It is recommended that all health professionals involved in the provision of clinical care to patients with (or suspected of) infection by coronavirus severe acute respiratory syndrome 2 (SARS-CoV-2) use universal protection, contact protection and droplet protection. These measures include hand hygiene and the use of specific, disposable (single use) and waterproof personal protective equipment: surgical mask, eye protection, cap, smock, clean gloves (covering the cuff) and footwear protection (ideally, waterproof shoes and exclusive use in isolation areas or, optionally, waterproof shoe covers).

It is recommended that all health professionals involved in the provision of potentially aerosol-generating clinical care (for example, intubation, secretion aspiration, and bronchoscopy) or prolonged contact (> 15 minutes) and/or intimate contact (for example, placement of a central venous catheter, surgery, and cardiopulmonary resuscitation maneuvers) to patients with (or suspected of) SARS-CoV-2 infection use airway protection. These measures include hand hygiene and the use of specific, disposable (single use) and waterproof personal protective equipment: respirator with a facial filter, eye protection (with side protection), cap, smock (with cuffs that tighten or with elastics and that cover up to the middle of the leg or ankle) and apron, clean gloves (covering the cuff of the gown) and footwear protection (ideally waterproof shoes and exclusive use in isolation areas or, optionally, waterproof shoe covers).

It is suggested that full protection (waterproof, with built-in hood and neck protection) be limited to professionals with training and practical experience for this purpose.

It is suggested that an order and technique for placement (donning) and removal (doffing) of personal protective equipment be strictly adhered to (ideally using a mirror or surveillance by another health professional), ensuring proper sealing of the face mask, with additional care during the removal procedure to avoid contamination of oneself, others and the environment.

It is recommended that all health professionals involved in the provision of clinical care have training and practical experience in the procedures for donning and doffing personal protective equipment prior to contact with patients.

Regarding personal protective equipment, the recommendations of the DGS are adopted,(9393 República Portuguesa. Serviço Nacional de Saúde. Direçao Geral de Saúde. Norma 07/2020. Prevenção e Controlo de Infeção por SARS-CoV-2 (COVID-19): Equipamentos de Proteção Individual (EPI). 29/03/2020. Disponível em https://www.dgs.pt/directrizes-da-dgs/normas-e-circulares-normativas/norma-n-0072020-de-29032020-pdf.aspx
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) which are based on the guidelines issued by the WHO(9494 World Health Organization. Rational use of personal protective equipment for coronavirus disease 2019 (COVID-19). 2020.) and the European Center for Disease Prevention and Control (ECDC)(9595 European Centre for Disease Prevention and Control (ECDC). Guidance for wearing and removing personal protective equipment in healthcare settings for the care of patients with suspected or confirmed COVID-19. 28 Feb 2020. Available from https://www.ecdc.europa.eu/en/publications-data/guidance-wearing-and-removing-personal-protective-equipment-healthcare-settings
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) for the prevention and control of infections in cases of suspected or confirmed infection by SARS-CoV-2.

It is necessary to provide detailed definitions for some medical devices. Surgical masks are used to protect health professionals from exposure to agents transmitted by droplets (large respiratory particles > 0.5µm); respirators with facial filters (which include the N95 or FFP2 and FFP3 masks, depending on the American or European designation and respective filtration rate) are used to protect health professionals from exposure to transmissible agents by air (small respiratory particles, < 0.5µm) or by droplets.

The current evidence, which includes randomized and controlled studies, systematic reviews and meta-analyses of seasonal respiratory viral infections (for example, influenza) and seasonal coronavirus,(9696 Loeb M, Dafoe N, Mahony J, John M, Sarabia A, Glavin V, et al. Surgical mask vs N95 respirator for preventing influenza among health care workers: a randomized trial. JAMA. 2009;302(17):1865-71.

97 Long Y, Hu T, Liu L, Chen R, Guo Q, Yang L, et al. Effectiveness of N95 respirators versus surgical masks against influenza: A systematic review and meta-analysis. J Evid Based Med. 2020;13(2):93-101.
-9898 Alhazzani W, Moller MH, Arabi YM, Loeb M, Gong MN, Fan E, et al. Surviving Sepsis Campaign: guidelines on the management of critically ill adults with Coronavirus Disease 2019 (COVID-19). Intensive Care Med. 2020;46(5):854-87.) notes the absence of additional benefits from the use of respirators with facial filters (in relation to masks) by health professionals involved in the provision of nonaerosol-generating clinical care. Regardless of the type of equipment, there is evidence that ensuring a good fit of the mask to the face is an effective way to optimize effectiveness.(9999 Brooks JT, Beezhold DH, Noti JD, Coyle JP, Derk RC, Blachere FM, et al. Maximizing fit for cloth and medical procedure masks to improve performance and reduce SARS-CoV-2 transmission and exposure, 2021. MMWR Morb Mortal Wkly Rep. 2021;70(7):254-7.)

Organization of services

It is recommended that the management of all level 2 (intermediate) and 3 (intensive) patients in the hospital (regardless of the service in which they are located) be performed by intensive care unit specialists in strict coordination with the Clinical Management, Directorate-General of Health and Ministry of Health.

It is recommended that in hospitals where there is more than one intensive care unit, a cohort area of confirmed critical cases of COVID-19 be created and a cohort area of suspected critically ill patients (for transient hospitalization) be considered, namely, establishing criteria for activation.

Isolation in a single room with negative pressure, a shower, private bathroom and adequate ventilation system, with capacity for at least 6-12 air changes/hour, is recommended. Once these resources are exhausted, it is recommended that patients be isolated in a single room with a ventilation system capable of at least 6-12 air changes/hour. When individual isolation rooms are not available, isolation in a cohort is recommended, respecting a minimum distance greater than 1 m between patients.

The delimitation of risk areas and predefined routes for professionals, patients and waste is recommended.

It is recommended to restrict visitations to all patients and limit the number of professionals in contact with patients (ideally with dedicated professionals), with the implementation of alternative, remote ways of communication between patients and families and between clinical teams, patients and families, regardless of the place of isolation.

Intensive care beds represent a scarce good, and very few exist in individual rooms with negative pressure.(100100 Rhodes A, Ferdinande P, Flaatten H, Guidet B, Metnitz PG, Moreno RP. The variability of critical care bed numbers in Europe. Intensive Care Med. 2012;38(10):1647-53.) In this context, it is especially necessary to have a full understanding of the organization and structure of intensive care units to ensure responsiveness and minimize the risk of nosocomial transmission of SARS-CoV-2.

After utilizing all individual rooms with negative pressure, the following strategy should be applied: create COVID-19 and non-COVID-19 cohorts, and within the COVID-19 cohorts, create two subcohorts, i.e., critical suspected COVID-19 cases and critical confirmed COVID-19 cases.(101101 Paiva JA, Almeida-Sousa JP, Araújo R, Bento L, Branco M, Câmara M, Catorze N, Gomes R, Martins AP, Mergulhão P, Nunez D, Gouveia J; Task Force Medicina Intensiva da DGS para COVID-19. Linhas orientadoras dos planos de contingência dos Serviços e da Rede de Medicina Intensiva para o doente COVID-19 crítico. 2020. Disponível em https://www.spci.pt/media/covid-19/Task-Force-Medicina-Intensiva-COVID19-final-v4.pdf
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) The benefits resulting from the concentration of experience and resources provided to COVID-19 cohorts should be tempered by detailed attention to the logistical and organizational/structural aspects of these spaces, with simulation training playing an important role in the preparation of the teams, ensuring proficiency in different procedures related to intensive medicine and infection control.(102102 Wax RS, Christian MD. Practical recommendations for critical care and anesthesiology teams caring for novel coronavirus (2019-nCoV) patients. Can J Anaesth. 2020;67(5):568-76.)

From the outset, clear delimitation of risk areas is necessary.(103103 Vargas M, De Marco G, De Simone S, Servillo G. Logistic and organizational aspects of a dedicated intensive care unit for COVID-19 patients. Crit Care. 2020;24(1):237.) Areas of basal risk (clean or green areas) are areas where circulation occurs in accordance with the rules of the rest of the hospital and where all support services should be moved (for example, information systems for clinical practice, pharmacy and storage spaces). Intermediate-risk areas (gray areas) are transition zones between basal risk areas and high-risk areas, and high-risk areas (red areas) are areas where direct care is provided to patients, requiring the use of appropriate personal protective equipment and where the possibility of placing the entire space under pressure should be evaluated (maximizing the number of air recirculations).

The transition between these different areas should be made through predefined routes for professionals, patients and waste. In the specific areas accessed by professionals, zones (ideally equipped with mirrors) should be created for the donning and doffing of personal protective equipment, with proximity to bathing areas. Waste corridors must be separate from all other walkways, in compliance with the appropriate guidelines (accommodation, cleaning and transportation of properly identified containers).

The implementation of alternative, remote ways of communication between patients and families and between treatment teams, patients and families has benefits for patients and families and increases the quality of care.(104104 Rose L, Yu L, Casey J, Cook A, Metaxa V, Pattison N, et al. Communication and virtual visiting for families of patients in intensive care during COVID-19: A UK National Survey. Ann Am Thorac Soc. 2021 Feb 22. doi: 10.1513/AnnalsATS.202012-1500OC.
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)

SUPPORTIVE THERAPY

Oxygen therapy, respiratory support and adjuvant therapies

The indications for oxygen therapy and respiratory support for respiratory failure in the context of COVID-19 are summarized in figure 3 (Appendix 1).

In patients with COVID-19, it is recommended to administer conventional oxygen therapy (through a nasal cannula or a Venturi mask) if peripheral oxygen saturation (SpO2) < 90%, with the goal of an SpO2 between 92% and 96%.

When using nasal cannulae, it is suggested to place a surgical mask over the oxygen supply device. When using a Venturi mask, a device that incorporates a filtering medium in the exhalation ports or, optionally, the placement of a surgical mask under the oxygen supply device is suggested.

Conventional oxygen therapy should be administered if peripheral oxygen saturation (SpO2) is less than 90%, with the goal of an SpO2 between 92% and 96%, through a nasal cannula or Venturi mask.(7676 World Health Organization (WHO). COVID-19 Clinical management: living guidance. 25 January 2021. Available from: file:///C:/Users/elisabete.freitas/Downloads/WHO-2019-nCoV-clinical-2021.1-eng.pdf) There are no specific data on COVID-19, but in critically ill patients, hypoxemia,(105105 van den Boom W, Hoy M, Sankaran J, Liu M, Chahed H, Feng M, et al. The search for optimal oxygen saturation targets in critically ill patients: observational data from large ICU databases. Chest. 2020;157(3):566-73.) as a liberal oxygen therapy strategy,(106106 Chu DK, Kim LH, Young PJ, Zamiri N, Almenawer SA, Jaeschke R, et al. Mortality and morbidity in acutely ill adults treated with liberal versus conservative oxygen therapy (IOTA): a systematic review and meta-analysis. Lancet. 2018;391(10131):1693-705.) is associated with worse outcomes (including mortality); therefore, an SpO2 between 92% and 96% is considered reasonable.(7676 World Health Organization (WHO). COVID-19 Clinical management: living guidance. 25 January 2021. Available from: file:///C:/Users/elisabete.freitas/Downloads/WHO-2019-nCoV-clinical-2021.1-eng.pdf,9898 Alhazzani W, Moller MH, Arabi YM, Loeb M, Gong MN, Fan E, et al. Surviving Sepsis Campaign: guidelines on the management of critically ill adults with Coronavirus Disease 2019 (COVID-19). Intensive Care Med. 2020;46(5):854-87.) To reduce the risk of aerosolization, a surgical mask can be placed over the nasal cannula, or, in the case of using a Venturi mask, choose a device that incorporates a filtering medium in the exhalation ports (for example, Intersurgical FiltaMask™),(107107 Winck JC, Scala R. Non-invasive respiratory support paths in hospitalized patients with COVID-19: proposal of an algorithm. Pulmonology. 2021;27(4):305-12.) or optionally, place a surgical mask under the oxygen supply device.(108108 Binks AC, Parkinson SM, Sabbouh V. Oxygen: under or over a surgical facemask for COVID-19 patients? Anaesthesia. 2020;75(12):1691-2.) No humidification is required for oxygen flows < 4L/minute,(109109 Mermilliod G, Hansen P, Salemi C. Prolonged, multipatient use of oxygen humidifier bottles. Infect Control Hosp Epidemiol. 1994;15(2):70-1.) and the use of bubble humidifiers with oxygen flow ≥ 5L/minute potentially produces aerosols with a risk of microorganism transmission.(110110 Rhame FS, Streifel A, McComb C, Boyle M. Bubbling humidifiers produce microaerosols which can carry bacteria. Infect Control. 1986;7(8):403-7.)

It is suggested, in patients with COVID-19, in the failure of conventional oxygen therapy (peripheral oxygen saturation-SpO2 < 92% with fraction of inspired oxygen (FiO2) > 0.6, increased respiratory work and/or respiratory rate ≥ 30 cpm) consider, in the absence of criteria for endotracheal intubation, a trial of non-invasive ventilatory therapies (high-flow nasal cannulae (HFNC) or noninvasive mechanical ventilation (NIV)) provided that (1) professionals use contact, droplet and airway precautions (ideally in rooms or areas with negative pressure) and strategies aimed at minimizing aerosol production are used; (2) a protocol suitable for respiratory failure is established and implemented; (3) the technique is initiated in a highly monitored environment to avoid delays in endotracheal intubation in the event of failure of response; and (4) failure criteria are established and respected.

When failure of conventional oxygen therapy (SpO2 < 92% with FiO2 > 0.6, increased respiratory work and/or respiratory rate ≥ 30 cpm) should be considered, in the absence of criteria for endotracheal intubation, noninvasive ventilatory therapies (HFNC or NIV) should be attempted.

The use of HFNC and NIV in respiratory failure due to COVID-19 was initially disputed due to a concern associated with the potential creation and propulsion of droplets and/or aerosols, with a risk of in-hospital transmission, particularly to health professionals.(111111 Cheung JC, Ho LT, Cheng JV, Cham EY, Lam KN. Staff safety during emergency airway management for COVID-19 in Hong Kong. Lancet Respir Med. 2020;8(4):e19.) Regarding HFNC, the best evidence demonstrates that the risk of aerosol generation is low (not higher than conventional oxygen therapy) when HFNC is correctly applied (with adapted nasal cannulae).(112112 Hui DS, Chow BK, Lo T, Tsang OT, Ko FW, Ng SS, et al. Exhaled air dispersion during high-flow nasal cannula therapy versus CPAP via different masks. Eur Respir J. 2019;53(4):1802339.,113113 Leonard S, Volakis LI, DeBellis R, Kahlon A, Mayar S, Dungan II GC. Transmission Assessment Report: High Velocity Nasal Insufflation (HVNI) Therapy Application in Management of COVID-19. VAPOTHERM, 2020. Available from: https://content.vapotherm.com/hubfs/COVID-19%20Transmission%20Assessment%20Report.pdf
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) NIV was systematically associated with an increased risk of aerosol generation,(2222 Tran K, Cimon K, Severn M, Pessoa-Silva C, Conly J. Aerosol-generating procedures and risk of transmission of acute respiratory infections: a systematic review. CADTH Technol Overv. 2013;3(1):e3201.,111111 Cheung JC, Ho LT, Cheng JV, Cham EY, Lam KN. Staff safety during emergency airway management for COVID-19 in Hong Kong. Lancet Respir Med. 2020;8(4):e19.) especially when using ventilated and/or poorly sealed oronasal masks combined with single-circuit ventilators. These techniques should ideally be performed in negative pressure rooms (with at least six air changes per hour) or in rooms equipped with HEPA (high efficiency particulate air) filters or, in the absence of these conditions, in rooms with natural ventilation with an air flow of at least 160 L/second per patient.(114114 Raoof S, Nava S, Carpati C, Hill NS. High flow, non-invasive ventilation and awake (non-intubation) proning in covid-19 patients with respiratory failure. Chest. 2020;158(5):1992-2002.) HFNC and NIV should not be excluded based only on the risk of in-hospital transmission, especially if professionals use contact, droplet and airway precautions. In addition to the classic criteria for invasive mechanical ventilation (respiratory or cardiocirculatory arrest, hemodynamic instability and altered state of consciousness), the choice of a ventilatory therapy trial is justified as long as a protocol suitable for respiratory failure is established and implemented; the technique is initiated in an environment of high monitoring, avoiding delays in endotracheal intubation in case of failure of response; and failure criteria are established and respected. Respecting these criteria, in hypoxemic acute respiratory failure in the context of COVID-19, a late invasive mechanical ventilation strategy (compared to an early strategy) has not been associated with increased mortality or other relevant outcomes,(115115 Siempos II, Xourgia E, Ntaidou TK, Zervakis D, Magira EE, Kotanidou A, et al. Effect of early vs. delayed or no intubation on clinical outcomes of patients with COVID-19: an observational study. Front Med (Lausanne). 2020;7:614152.

116 Lee YH, Choi KJ, Choi SH, Lee SY, Kim KC, Kim EJ, et al. Clinical significance of timing of intubation in critically ill patients with COVID-19: a multi-center retrospective study. J Clin Med. 2020;9(9):2847.
-117117 Papoutsi E, Giannakoulis VG, Xourgia E, Routsi C, Kotanidou A, Siempos II. Effect of timing of intubation on clinical outcomes of critically ill patients with COVID-19: a systematic review and meta-analysis of non-randomized cohort studies. Crit Care. 2021;25(1):121.) and in some series, it was also associated with a reduction in mortality.(118118 Dupuis C, Bouadma L, de Montmollin E, Goldgran-Toledano D, Schwebel C, Reignier J, et al. Association between early invasive mechanical ventilation and day-60 mortality in acute hypoxemic respiratory failure related to coronavirus disease-2019 pneumonia. Crit Care Explor. 2021;3(1):e0329.)

It is suggested that the choice between noninvasive ventilatory therapies (HFNC and NIV)) is based on weigh individual risks and benefits as well as on the availability of equipment/interfaces and local experience of the staff.

Aside from carbon dioxide retention (partial pressure of carbon dioxide (PaCO2) > 45mmHg in the context of acute respiratory failure), there is currently no evidence of superiority between HFNC and NIV for respiratory failure due to COVID-19. Thus, until defining clear phenotypes of respiratory failure associated with COVID-19, the decision should be based on weighing individual risks and benefits (for example, the use of HFNC may allow for more comfort, while the use of NIV may be more beneficial in patients with an obese biotype and/or evidence of alveolar collapse on chest imaging because it allows alveolar recruitment)(107107 Winck JC, Scala R. Non-invasive respiratory support paths in hospitalized patients with COVID-19: proposal of an algorithm. Pulmonology. 2021;27(4):305-12.) and on the availability of equipment/interfaces and experience of the staff.

It is suggested that if a decision to use high-flow oxygen therapy via nasal cannula is made (1) a surgical mask should be placed over the nasal cannulae; (2) nasal cannulas should be adapted to the size of the nostrils, with a flow rate of 50 - 60L/minute and FiO2 titrated for SpO2 between 92% and 96%; (3) the ROX index should be evaluated at 2, 6 and 12 hours, with maintenance of support if ≥ 4.88, in the absence of criteria for endotracheal intubation; and (4) in case of failure, treatment should be optimized, considering increased support up to 60L/minute in a prone position, a transition to NIV or endotracheal intubation (and invasive ventilatory support).

The application of HFNC therapy uses nasal cannulas (which should occupy ≥ 50% of the size of the nostrils), starting with flows of 20 - 30L/minute, which can be increased (at levels of 10L/minute in short intervals) up to 50 - 60L/minute,(107107 Winck JC, Scala R. Non-invasive respiratory support paths in hospitalized patients with COVID-19: proposal of an algorithm. Pulmonology. 2021;27(4):305-12.) to provide an average positive end-expiratory pressure (PEEP) of 5 - 6cmH2O (with mouth closed). The temperature (initially 37°C) is titrated based on the patient’s preferences and secretion characteristics, and FiO2 is titrated for SpO2 between 92% and 96%. HFNC therapy can be performed using dedicated systems with turbines (connected to an oxygen source) and conventional fans with active humidification systems, in addition to flow meters (high flow rate, connected to an air and oxygen source) and mixers combined with the active humidification system.

The risk of aerosolization is reduced when a surgical mask is placed over the nasal cannula.(113113 Leonard S, Volakis LI, DeBellis R, Kahlon A, Mayar S, Dungan II GC. Transmission Assessment Report: High Velocity Nasal Insufflation (HVNI) Therapy Application in Management of COVID-19. VAPOTHERM, 2020. Available from: https://content.vapotherm.com/hubfs/COVID-19%20Transmission%20Assessment%20Report.pdf
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HFNC therapy, in the context of hypoxemic acute respiratory failure, has shown improved results,(119119 Frat JP, Thille AW, Mercat A, Girault C, Ragot S, Perbet S, Prat G, Boulain T, Morawiec E, Cottereau A, Devaquet J, Nseir S, Razazi K, Mira JP, Argaud L, Chakarian JC, Ricard JD, Wittebole X, Chevalier S, Herbland A, Fartoukh M, Constantin JM, Tonnelier JM, Pierrot M, Mathonnet A, Béduneau G, Delétage-Métreau C, Richard JC, Brochard L, Robert R; FLORALI Study Group; REVA Network. High-flow oxygen through nasal cannula in acute hypoxemic respiratory failure. N Engl J Med. 2015;372(23):2185-96.

120 Rochwerg B, Granton D, Wang DX, Helviz Y, Einav S, Frat JP, et al. High flow nasal cannula compared with conventional oxygen therapy for acute hypoxemic respiratory failure: a systematic review and meta-analysis. Intensive Care Med. 2019;45(5):563-72.
-121121 Ferreyro BL, Angriman F, Munshi L, Del Sorbo L, Ferguson ND, Rochwerg B, et al. Association of noninvasive oxygenation strategies with all-cause mortality in adults with acute hypoxemic respiratory failure: a systematic review and meta-analysis. JAMA. 2020;324(1):57-67.) and there is evidence of its efficacy in patients with COVID-19,(122122 Rochwerg B, Solo K, Darzi A, Chen G, Khamis AM; COVID-19 Systematic Urgent Review Group Effort (SURGE) Study Authors, et al. Update alert: ventilation techniques and risk for transmission of coronavirus disease, including COVID-19. Ann Intern Med. 2020;173(6):W122.) with a higher success rate when the initial PaO2/FiO2 ratio is > 200mmHg.(123123 Wang K, Zhao W, Li J, Shu W, Duan J. The experience of high-flow nasal cannula in hospitalized patients with 2019 novel coronavirus-infected pneumonia in two hospitals of Chongqing, China. Ann Intensive Care. 2020;10(1):37.) This evidence led the panel of experts of the Surviving Sepsis Campaign to recommend HFNC as the primary noninvasive ventilatory therapy.(9898 Alhazzani W, Moller MH, Arabi YM, Loeb M, Gong MN, Fan E, et al. Surviving Sepsis Campaign: guidelines on the management of critically ill adults with Coronavirus Disease 2019 (COVID-19). Intensive Care Med. 2020;46(5):854-87.)

There are validated scores for hypoxemic respiratory failure (ROX index and SpO2/FiO2/respiratory rate)(124124 Roca O, Caralt B, Messika J, Samper M, Sztrymf B, Hernández G, et al. An index combining respiratory rate and oxygenation to predict outcome of nasal high-flow therapy. Am J Respir Crit Care Med. 2019;199(11):1368-76.) that have been validated for COVID-19.(125125 Noeman-Ahmed Y, Gokaraju S, Powrie DJ, Amran DA, El Sayed I, Roshdy A. Predictors of CPAP outcome in hospitalized COVID-19 patients. Respirology. 2020;25(12):1316-9.

126 Burns GP, Lane ND, Tedd HM, Deutsch E, Douglas F, West SD, et al. Improved survival following ward-based non-invasive pressure support for severe hypoxia in a cohort of frail patients with COVID-19: retrospective analysis from a UK teaching hospital. BMJ Open Respir Res. 2020;7(1):e000621.
-127127 Calligaro GL, Lalla U, Audley G, Gina P, Miller MG, Mendelson M, et al. The utility of high-flow nasal oxygen for severe COVID-19 pneumonia in a resource-constrained setting: a multi-centre prospective observational study. EClinicalMedicine. 2020;28:100570.) Although the failure criteria are slightly different for COVID-19, the ROX index should be evaluated at 2, 6 and 12 hours, maintaining the therapy if ≥ 4.88 in the absence of criteria for endotracheal intubation. Lower values should be considered potential failure and should lead to therapy optimization, considering increased support up to 60 L/minute in the prone position, a transition to NIV or endotracheal intubation (and invasive ventilatory support).

It is suggested that if noninvasive mechanical ventilation is initiated, (1) interfaces with maximum sealing should be used, as well as specific ventilators and ventilatory circuits with antibacterial/antiviral filters; (2) ideally, non-invasive ventilation (NIV) helmets or, optionally, face masks (or oronasal) capable of specific configurations for continuous positive airway pressure (CPAP; up to a maximum of 12 - 14cmH2O) or bilevel positive airway pressure (BPAP; with support pressure to maintain tidal volume between 6 and 8mL/kg), FiO2 titrated to SpO2 between 92% and 96% should be used; (3) PaO2/FiO2 should be evaluated at 1 hour with maintenance of support and improvement (ΔPaO2/FiO2) ≥ 30%, in the absence of criteria for endotracheal intubation; and (4) in case of failure, therapy should be optimized, considering increased support in a prone position, eventual transition to HFNC therapy in a prone position or endotracheal intubation (and invasive ventilatory support).

The application of NIV involves the administration of CPAP/PEEP with initial continuous pressures of 8 - 10cmH2O to a maximum of 12 - 14cmH2O (with the need to compensate the resistance imposed via the use of a heat and moisture exchange filter (HMEF) and antibacterial/antiviral filters), using multiple interfaces and ventilation systems that provide FiO2 of 0.8 - 1.0.(107107 Winck JC, Scala R. Non-invasive respiratory support paths in hospitalized patients with COVID-19: proposal of an algorithm. Pulmonology. 2021;27(4):305-12.) The association of positive pressure during the inspiratory phase (IPAP) greater than that applied during the expiratory phase (EPAP) provides complete ventilatory support, i.e., bilevel positive airway pressure (BPAP). The pressure support corresponds to the difference between the IPAP and EPAP (often called DP) and should be adjusted to maintain a tidal volume between 6 and 8mL/kg.(107107 Winck JC, Scala R. Non-invasive respiratory support paths in hospitalized patients with COVID-19: proposal of an algorithm. Pulmonology. 2021;27(4):305-12.)

The risk of aerosolization can be minimized using helmets or interfaces with maximum sealing, as well as ventilators and ventilatory circuits with antibacterial/antiviral filters.(128128 Hui DS, Chow BK, Lo T, Ng SS, Ko FW, Gin T, et al. Exhaled air dispersion during noninvasive ventilation via helmets and a total facemask. Chest. 2015;147(5):1336-43.)

NIV can be applied via different interfaces: ideally, VNI helmets with air cushions, or, optionally, face masks (or oronasal masks) not ventilated (without intentional leakage and without an anti-asphyxia valve). When applying the helmet-type interface, the specific configurations used should be different from those for facial (or oronasal) masks, with an increase in pressures (IPAP/EPAP) by 50% as well as an increase in the pressurization rate.(129129 Vargas F, Thille A, Lyazidi A, Campo FR, Brochard L. Helmet with specific settings versus facemask for noninvasive ventilation. Crit Care Med. 2009;37(6):1921-8.) These interfaces connect to dual circuit systems in dedicated ventilators or conventional intensive care ventilators, to single circuits with passive exhalation valves incorporated in the circuit or added to the circuit (for example, whisper swivel or plateau valves), or to active exhalation valves (connected to the pressure line and the flow line). The environment should be protected by HMEFs and antibacterial/antiviral filters in double HMEF circuits, placed between the interface and Y, by an antibacterial/antiviral filter, placed in the connection between the expiratory branch and the ventilator, and by single HMEF circuits, placed between the interface and the ventilator interface and the exhalation valve and antibacterial/antiviral filter, placed between the circuit and the ventilator. Another option is CPAP/PEEP administration with high FiO2 and flow meters (high flow rate, connected to the oxygen source), connected by means of a flow acceleration valve to an interface (oronasal mask; for example, CPAP Boussignac) or a helmet with adjustable PEEP valve in the expiratory branch. Similar to what occurs with NIV circuits, the environment must also be protected by the interposition of HMEFs and antibacterial/antiviral filters placed between the flow acceleration valve and the oronasal mask or in the expiratory branch of the helmet before the PEEP valve.

NIV is indicated in the acute exacerbation of chronic hypercapnic respiratory failure (for example, pulmonary obstruction, obstructive sleep apnea and obesity-hypoventilation syndrome),(130130 Osadnik CR, Tee VS, Carson-Chahhoud KV, Picot J, Wedzicha JA, Smith BJ. Non-invasive ventilation for the management of acute hypercapnic respiratory failure due to exacerbation of chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2017;7(7):CD004104.) in which the use of BPAP is promoted, and hypoxemic acute respiratory failure associated with acute cardiogenic lung edema,(131131 Vital FM, Ladeira MT, Atallah AN. Non-invasive positive pressure ventilation (CPAP or bilevel NPPV) for cardiogenic pulmonary oedema. Cochrane Database Syst Rev. 2013;(5):CD005351.) in which the use of CPAP/PEEP is promoted. In hypoxemic acute respiratory failure, the evidence suggests that the use of NIV with a helmet (but not with a face mask) produces better results (reduction in the risk of endotracheal intubation and mortality benefits) than HFNC,(121121 Ferreyro BL, Angriman F, Munshi L, Del Sorbo L, Ferguson ND, Rochwerg B, et al. Association of noninvasive oxygenation strategies with all-cause mortality in adults with acute hypoxemic respiratory failure: a systematic review and meta-analysis. JAMA. 2020;324(1):57-67.) and for COVID-19, there are data that NIV using a helmet, compared to HFNC, reduces the risk of intubation.(132132 Grieco DL, Menga LS, Cesarano M, Rosà T, Spadaro S, Bitondo MM, Montomoli J, Falò G, Tonetti T, Cutuli SL, Pintaudi G, Tanzarella ES, Piervincenzi E, Bongiovanni F, Dell’Anna AM, Delle Cese L, Berardi C, Carelli S, Bocci MG, Montini L, Bello G, Natalini D, De Pascale G, Velardo M, Volta CA, Ranieri VM, Conti G, Maggiore SM, Antonelli M; COVID-ICU Gemelli Study Group. Effect of Helmet Noninvasive Ventilation vs High-Flow Nasal Oxygen on Days Free of Respiratory Support in Patients With COVID-19 and Moderate to Severe Hypoxemic Respiratory Failure: The HENIVOT Randomized Clinical Trial. JAMA. 2021;325(17):1731-43.) These data come mainly from Italian groups who have substantial experience in the use of NIV with a helmet (which has a long learning curve) and cannot be generalized to low-volume centers.

Although there is a validated score to evaluate hypoxemic respiratory failure in NIV, the HACOR index,(133133 Duan J, Han X, Bai L, Zhou L, Huang S. Assessment of heart rate, acidosis, consciousness, oxygenation, and respiratory rate to predict noninvasive ventilation failure in hypoxemic patients. Intensive Care Med. 2017;43(2):192-9.) it has not yet been validated in the specific context of COVID-19. Maintenance of support is suggested if PaO2/FiO2 improves ≥ 30% afer 1 hour compared to PaO2/FiO2 prior to the onset of NIV (which indicates pulmonary recruitability),(134134 Aliberti S, Radovanovic D, Billi F, Sotgiu G, Costanzo M, Pilocane T, et al. Helmet CPAP treatment in patients with COVID-19 pneumonia: a multicentre cohort study. Eur Respir J. 2020;56(4):2001935.) in the absence of criteria for endotracheal intubation. Lower values should be considered potential failure and should lead to therapy optimization, considering increased support in a prone position, eventual transition to NIV in a prone position or endotracheal intubation (and invasive ventilatory support). Additionally, an expired tidal volume > 8 mL/kg of ideal weight is a predictor of NIV failure(135135 Carteaux G, Millán-Guilarte T, De Prost N, Razazi K, Abid S, Thille AW, et al. Failure of noninvasive ventilation for de novo acute hypoxemic respiratory failure: role of tidal volume. Crit Care Med. 2016;44(2):282-90.) and should lead to the consideration of endotracheal intubation (and invasive ventilatory support) because it is associated with changes in the pressure gradient, potentially resulting in P-SILI.(3434 Brochard L, Slutsky A, Pesenti A. Mechanical ventilation to minimize progression of lung injury in acute respiratory failure. Am J Respir Crit Care Med. 2017;195(4):438-42.) In patients with NIV, rotation of noninvasive ventilatory strategies should be considered, with periods of up to 1 hour of HFNC therapy, allowing oral feeding and rest.(107107 Winck JC, Scala R. Non-invasive respiratory support paths in hospitalized patients with COVID-19: proposal of an algorithm. Pulmonology. 2021;27(4):305-12.)

A structured prone protocol (when awake) is suggested for all patients under HFNC therapy or NIV able to comply with orders, as long as clinically tolerated.

A prone position (ventral decubitus, when awake) may, in combination with NIV or HFNC therapy, increase comfort and improve PaO2/FiO2 by up to 35mmHg,(136136 Ding L, Wang L, Ma W, He H. Efficacy and safety of early prone positioning combined with HFNC or NIV in moderate to severe ARDS: a multi-center prospective cohort study. Crit Care. 2020;24(1):28.) a benefit already demonstrated in patients with COVID-19.(137137 Sun Q, Qiu H, Huang M, Yang Y. Lower mortality of COVID-19 by early recognition and intervention: experience from Jiangsu Province. Ann Intensive Care. 2020;10(1):33.,138138 Caputo ND, Strayer RJ, Levitan R. Early self-proning in awake, non-intubated patients in the emergency department: a single ED’s experience during the COVID-19 pandemic. Acad Emerg Med. 2020;27(5):375-8.) An increasing number of observational studies (not randomized controlled studies) describe the safety and clinical benefits (reduction in dyspnea and respiratory work, but with no benefit in mortality or reduction in intubation rate) of prolonged periods (> 16 hours per day) of HFNC therapy in a prone position for hypoxemic respiratory failure due to COVID-19, especially with PaO2/FiO2 < 300.(139139 Weatherald J, Solverson K, Zuege DJ, Loroff N, Fiest KM, Parhar KK. Awake prone positioning for COVID-19 hypoxemic respiratory failure: a rapid review. J Crit Care. 2021;61:63-70.) There is no clear protocol for the use of the prone position; however, at least twice a day for periods longer than 30 minutes, until the patient shows fatigue/intolerance, is recommended.(136136 Ding L, Wang L, Ma W, He H. Efficacy and safety of early prone positioning combined with HFNC or NIV in moderate to severe ARDS: a multi-center prospective cohort study. Crit Care. 2020;24(1):28.) The protocol (including the provision of an information leaflet), with the establishment of a long-term strategy (for example, variation in position between ventral decubitus, right lateral decubitus, left lateral decubitus and Fowler decubitus, every 2 hours) associated with positioning adjuvants, may be useful for improving therapeutic adherence.(114114 Raoof S, Nava S, Carpati C, Hill NS. High flow, non-invasive ventilation and awake (non-intubation) proning in covid-19 patients with respiratory failure. Chest. 2020;158(5):1992-2002.)

A structured protocol for weaning from noninvasive ventilatory therapy is suggested.

If clinical and blood gas stability is maintained in NIV and/or HFNC therapy, the weaning process from NIV therapy should be initiated. For HFNC therapy, the flow rate should be initially maintained, with a progressive reduction in FiO2 of 0.40 until reaching the target SpO2.(140140 Blez D, Soulier A, Bonnet F, Gayat E, Garnier M. Monitoring of high-flow nasal cannula for SARS-CoV-2 severe pneumonia: less is more, better look at respiratory rate. Intensive Care Med. 2020;46(11):2094-5.) A subsequent weaning protocol has not yet been established, but reducing the output by 10 L/minute to 20L/minute (with maintenance of FiO2) is recommended, after which the reduction in FiO2 can begins until complete autonomization.(107107 Winck JC, Scala R. Non-invasive respiratory support paths in hospitalized patients with COVID-19: proposal of an algorithm. Pulmonology. 2021;27(4):305-12.) For NIV with a face mask, there is no formal approach to ventilatory weaning. Typically, when withdrawing the interface (for example, for oral feeding), the patient’s tolerance is evaluated. If there are no signs of respiratory distress or worsening of SpO2 during this period, NIV can be discontinued. In patients in whom the primary cause has been resolved but who do not tolerate the suspension of NIV, weaning should occur over the course of periods; that is, the clinician should reduce the time to progressively decrease NIV, preferentially maintaining ventilation during sleep. For NIV with a helmet, a spontaneous breathing test (ERT) should be performed if the patient does not show signs of respiratory distress and maintains target a SpO2 with FiO2 < 0.5 and PEEP ≤ 6cmH2O. At least 24 hours with FiO2 ≤ 0.4 (by Venturi mask or HFNC) and PaO2/FiO2 > 250 is considered successful weaning.(107107 Winck JC, Scala R. Non-invasive respiratory support paths in hospitalized patients with COVID-19: proposal of an algorithm. Pulmonology. 2021;27(4):305-12.,134134 Aliberti S, Radovanovic D, Billi F, Sotgiu G, Costanzo M, Pilocane T, et al. Helmet CPAP treatment in patients with COVID-19 pneumonia: a multicentre cohort study. Eur Respir J. 2020;56(4):2001935.)

It is suggested that the decision of endotracheal intubation be based on a composite evaluation of the oxygenation state (as assessed by the ROX index and/or PaO2/FiO2) and ventilation (respiratory acidosis with pH < 7.30) but also on the respiratory effort perceived by the patient.

We suggest a structured protocol for endotracheal intubation, performed by an experienced operator, using contact, droplet and airway precautions (ideally in a negative pressure room).

The need for endotracheal intubation and invasive ventilatory support should be based on the clinical gestalt of an experienced intensivist,(141141 Cable C, Bell D, Gallo de Moraes A, Kaul V. Timing of intubation in patients with COVID-19. Chest NetWorks. 2021. Available from: https://www.chestnet.org/topic-collections/covid-19/covid-in-focus/timing-of-intubation-in-patients-with-covid-19
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) encompassing not only the state of oxygenation (as assessed by the ROX index and/or PaO2/FiO2) and ventilation (respiratory acidosis with pH < 7.30) but also an evaluation of respiratory effort perceived by the patient (dyspnea or intolerable discomfort) and other factors (for example, unmanageable volume of bronchial secretions). The gold standard for the evaluation of increased respiratory effort is the assessment of the electrical activity of the diaphragm using surface electrodes or esophageal catheters, followed by a quantitative evaluation of inspiratory effort (esophageal pressure), which is neither widely available nor compatible with use at the bedside outside a study environment.(142142 Vaporidi K, Akoumianaki E, Telias I, Goligher EC, Brochard L, Georgopoulos D. Respiratory drive in critically ill patients. Pathophysiology and clinical implications. Am J Respir Crit Care Med. 2020;201(1):20-32.) The evaluation of respiratory effort should be based on an objective examination, e.g., the presence of a rapid breathing pattern (respiratory rate ≥ 30 cpm), thoracoabdominal breathing, accessory respiratory muscle use, including palpation of the sternocleidomastoids, and thoracoabdominal breathing,(142142 Vaporidi K, Akoumianaki E, Telias I, Goligher EC, Brochard L, Georgopoulos D. Respiratory drive in critically ill patients. Pathophysiology and clinical implications. Am J Respir Crit Care Med. 2020;201(1):20-32.) and, eventually, ultrasound evaluation of the diaphragm, namely, evaluation of the diaphragmatic thickening fraction.(143143 Vivier E, Mekontso Dessap A, Dimassi S, Vargas F, Lyazidi A, Thille AW, et al. Diaphragm ultrasonography to estimate the work of breathing during non-invasive ventilation. Intensive Care Med. 2012;38(5):796-803.)

When an endotracheal intubation decision is made (procedure with a high risk of aerosol generation),(2222 Tran K, Cimon K, Severn M, Pessoa-Silva C, Conly J. Aerosol-generating procedures and risk of transmission of acute respiratory infections: a systematic review. CADTH Technol Overv. 2013;3(1):e3201.,111111 Cheung JC, Ho LT, Cheng JV, Cham EY, Lam KN. Staff safety during emergency airway management for COVID-19 in Hong Kong. Lancet Respir Med. 2020;8(4):e19.) all strategies that minimize the risk of transmission to health professionals should be used.(144144 Peng PW, Ho PL, Hota SS. Outbreak of a new coronavirus: what anaesthetists should know. Br J Anaesth. 2020;124(5):497-501.) The procedure should be performed by an experienced operator (the operator with the highest probability of intubation on the first attempt) with contact, droplet and airway precautions (ideally in a negative pressure room) and using a systematized protocol,(144144 Peng PW, Ho PL, Hota SS. Outbreak of a new coronavirus: what anaesthetists should know. Br J Anaesth. 2020;124(5):497-501.) as systematized in table 2 (Appendix 1).

It is suggested that after intubation and invasive ventilatory support, the following be used: (1) a classic ventilation strategy based on the ARDS Network protocol (tidal volume of 4 - 6mL/kg of ideal body weight with an upper limit plateau pressure < 30cmH2O) with minimum respiratory rate for pH > 7.30 associated with a driving pressure < 15cmH2O; (2) ventral decubitus for minimum periods of 16 hours if PaO2/FiO2 < 150mmHg; (3) neuromuscular blockers for ≤ 48 hours if PaO2/FiO2 < 150mmHg or severe dyssynchrony or elevated respiratory drive not controlled by optimized analgesics; and (4) in mild ARDS (PaO2/FiO2 between 200 - 300mmHg), the use of low PEEP, and in moderate to severe ARDS (PaO2/FiO2 < 200mmHg), application of high PEEP only after an evaluation of recruitment potential.

Once invasive ventilatory support is initiated, a protective ventilation strategy associated with adjuvant therapies, both personalized, should be used, guided by clinical, imaging and ventilatory mechanics parameters. The recommendations made are based on international recommendations(145145 Papazian L, Aubron C, Brochard L, Chiche JD, Combes A, Dreyfuss D, et al. Formal guidelines: management of acute respiratory distress syndrome. Ann Intensive Care. 2019;9(1):69.) for typical ARDS (not associated with COVID-19), which systematically reduces morbidity and mortality in this population: a classic ventilation strategy based on the ARDS Network protocol (tidal volume of 4 - 6mL/kg of ideal body weight with a limit higher for plateau pressures < 30cmH2O) with a minimum respiratory rate at pH > 7.30(146146 Acute Respiratory Distress Syndrome Network, Brower RG, Matthay MA, Morris A, Schoenfeld D, Thompson BT, et al. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med. 2000;342(18):1301-8.,147147 Walkey AJ, Goligher EC, Del Sorbo L, Hodgson CL, Adhikari NK, Wunsch H, et al. Low tidal volume versus non-volume-limited strategies for patients with acute respiratory distress syndrome. A systematic review and meta-analysis. Ann Am Thorac Soc. 2017;14(Suppl 4):S271-9.) associated with a driving pressure < 15cmH2O;(148148 Amato MB, Meade MO, Slutsky AS, Brochard L, Costa EL, Schoenfeld DA, et al. Driving pressure and survival in the acute respiratory distress syndrome. N Engl J Med. 2015;372(8):747-55.) and decubitus for minimum periods of 16 hours if PaO2/FiO2 < 150mmHg(149149 Guérin C, Reignier J, Richard JC, Beuret P, Gacouin A, Boulain T, Mercier E, Badet M, Mercat A, Baudin O, Clavel M, Chatellier D, Jaber S, Rosselli S, Mancebo J, Sirodot M, Hilbert G, Bengler C, Richecoeur J, Gainnier M, Bayle F, Bourdin G, Leray V, Girard R, Baboi L, Ayzac L; PROSEVA Study Group. Prone positioning in severe acute respiratory distress syndrome. N Engl J Med. 2013;368(23):2159-68.) and neuromuscular blockers for ≤ 48 hours if PaO2/FiO2 < 150mmHg,(150150 Papazian L, Forel JM, Gacouin A, Penot-Ragon C, Perrin G, Loundou A, Jaber S, Arnal JM, Perez D, Seghboyan JM, Constantin JM, Courant P, Lefrant JY, Guérin C, Prat G, Morange S, Roch A; ACURASYS Study Investigators. Neuromuscular blockers in early acute respiratory distress syndrome. N Engl J Med. 2010;363(12):1107-16.) or severe dyssynchrony or elevated respiratory drive not controlled by optimized analgosedation.(3535 Gattinoni L, Chiumello D, Caironi P, Busana M, Romitti F, Brazzi L, et al. COVID-19 pneumonia: different respiratory treatments for different phenotypes? Intensive Care Medicine. 2020;46(6):1099-102.) Respiratory drive can be monitored using P 0.1 (airway occlusion pressure, i.e., pressure generated in the airways during the first 100 milliseconds of an inspiratory effort against an occluded airway), considering a cutoff value > 3.5cmH2O for increased respiratory drive.(142142 Vaporidi K, Akoumianaki E, Telias I, Goligher EC, Brochard L, Georgopoulos D. Respiratory drive in critically ill patients. Pathophysiology and clinical implications. Am J Respir Crit Care Med. 2020;201(1):20-32.,151151 Jonkman AH, de Vries HJ, Heunks LM. Physiology of the respiratory drive in ICU patients: implications for diagnosis and treatment. Crit Care. 2020;24(1):104.) Regarding the PEEP strategy, for mild ARDS (PaO2/FiO2 between 200 - 300mmHg), the use of a low PEEP without recruitment maneuvers should be considered because there is no clear evidence of benefits (and potential risks) of using a high PEEP strategy (associated or not with recruitment maneuvers),(152152 Brower RG, Lanken PN, MacIntyre N, Matthay MA, Morris A, Ancukiewicz M, Schoenfeld D, Thompson BT; National Heart, Lung, and Blood Institute ARDS Clinical Trials Network. Higher versus lower positive end-expiratory pressures in patients with the acute respiratory distress syndrome. N Engl J Med. 2004;351(4):327-36.

153 Meade MO, Cook DJ, Guyatt GH, Slutsky AS, Arabi YM, Cooper DJ, Davies AR, Hand LE, Zhou Q, Thabane L, Austin P, Lapinsky S, Baxter A, Russell J, Skrobik Y, Ronco JJ, Stewart TE; Lung Open Ventilation Study Investigators. Ventilation strategy using low tidal volumes, recruitment maneuvers, and high positive end-expiratory pressure for acute lung injury and acute respiratory distress syndrome: a randomized controlled trial. JAMA. 2008;299(6):637-45.

154 Mercat A, Richard JC, Vielle B, Jaber S, Osman D, Diehl JL, Lefrant JY, Prat G, Richecoeur J, Nieszkowska A, Gervais C, Baudot J, Bouadma L, Brochard L; Expiratory Pressure (Express) Study Group. Positive end-expiratory pressure setting in adults with acute lung injury and acute respiratory distress syndrome: a randomized controlled trial. JAMA. 2008;299(6):646-55.
-155155 Writing Group for the Alveolar Recruitment for Acute Respiratory Distress Syndrome Trial (ART) Investigators, Cavalcanti AB, Suzumura EA, Laranjeira LN, Paisani DM, Damiani LP, et al. 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. JAMA. 2017;318(14):1335-45.) which does not exclude the use of low-risk recruitment maneuvers (for example, CPAP 40/40) after derecruitment maneuvers (aspiration and disconnection). Furthermore, in moderate to severe ARDS (PaO2/FiO2 < 200mmHg), the ideal PEEP level depends on the ARDS phenotype, which can be assessed by means of recruitment potential based on chest imaging(156156 Ball L, Robba C, Maiello L, Herrmann J, Gerard SE, Xin Y, Battaglini D, Brunetti I, Minetti G, Seitun S, Vena A, Giacobbe DR, Bassetti M, Rocco PR, Cereda M, Castellan L, Patroniti N, Pelosi P; GECOVID (GEnoa COVID-19) group. Computed tomography assessment of PEEP-induced alveolar recruitment in patients with severe COVID-19 pneumonia. Crit Care. 2021;25(1):81.) or on pulmonary mechanics, reserving high PEEP for cases of potential pulmonary recruitment. Recruitment potential can be measured via ventilatory mechanics (for example, recruitment/inflation ratio)(157157 Chen L, Del Sorbo L, Grieco DL, Junhasavasdikul D, Rittayamai N, Soliman I, et al. Potential for lung recruitment estimated by the recruitment-to-inflation ratio in acute respiratory distress syndrome. A clinical trial. Am J Respir Crit Care Med. 2020;201(2):178-87.) followed by the best PEEP trial strategy, based on an approach validated using available resources; if several techniques are available, the best adapted to the characteristics of the patient should be used, e.g., high PEEP based on the ARDS Network protocol; an approach to improve static compliance or driving pressure; a maximum recruitment maneuver followed by PEEP for optimal SpO2 or better static compliance; incremental PEEP to achieve a plateau pressure below 30cmH2O; or transpulmonary pressure calculated by esophageal manometry.(145145 Papazian L, Aubron C, Brochard L, Chiche JD, Combes A, Dreyfuss D, et al. Formal guidelines: management of acute respiratory distress syndrome. Ann Intensive Care. 2019;9(1):69.)

It is recommended that routine use of inhaled nitric oxide is not used.

The use of inhaled nitric oxide in typical ARDS results in a transient improvement in oxygenation but has no significant effect on mortality and is associated with an increased risk of acute kidney injury.(158158 Gebistorf F, Karam O, Wetterslev J, Afshari A. Inhaled nitric oxide for acute respiratory distress syndrome (ARDS) in children and adults. Cochrane Database Syst Rev. 2016;2016(6):CD002787.) Thus, inhaled nitric oxide therapy should not be used routinely; however, the recommendation does not rule out its use as a rescue therapy (i.e., ARDS is associated with refractory hypoxemia), especially if associated with right ventricular dysfunction.(159159 Longobardo A, Montanari C, Shulman R, Benhalim S, Singer M, Arulkumaran N. Inhaled nitric oxide minimally improves oxygenation in COVID-19 related acute respiratory distress syndrome. Br J Anaesth. 2021;126(1):e44-6.)

A structured protocol for weaning and extubation of invasive ventilatory support is suggested.

Regarding ventilatory weaning, the need for reintubation associated with progression to the hyperinflammatory stage with a high risk of postextubation respiratory failure have been described (PaO2/FiO2 > 150mmHg with ≤ 6cmH2O with cardiocirculatory stability and an adequate state of consciousness).(160160 Podcast Sociedade Portuguesa de Cuidados Intensivos (SPCI). Webninar COVID-19 - 23 Março 2020. Learning with the Italian experience. Com o Dr. Tommaso Mauri, Professor José Artur Paiva, Dr. João Gouveia e Dr. Filipe Froes. Available from: https://www.spci.pt/webinar-covid19-23-marco-2020
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) The ERT must be performed at support pressure using a closed circuit (for example, support pressure of 7cmH2O for 30 to 120 minutes) and not in a T-tube, which not only minimizes the risk of aerosolization but is also associated with a higher extubation success rate and reduced hospital mortality.(161161 Subirà C, Hernández G, Vázquez A, Rodríguez-García R, González-Castro A, García C, et al. Effect of pressure support vs T-piece ventilation strategies during spontaneous breathing trials on successful extubation among patients receiving mechanical ventilation: a randomized clinical Trial. JAMA. 2019;321(22):2175-82.) If tolerance is demonstrated, as assessed by objective and subjective criteria, extubation should be considered.(162162 MacIntyre NR, Cook DJ, Ely EW Jr, Epstein SK, Fink JB, Heffner JE, Hess D, Hubmayer RD, Scheinhorn DJ; American College of Chest Physicians; American Association for Respiratory Care; American College of Critical Care Medicine. Evidence-based guidelines for weaning and discontinuing ventilatory support: a collective task force facilitated by the American College of Chest Physicians; the American Association for Respiratory Care; and the American College of Critical Care Medicine. Chest. 2001;120(6 Suppl):375S-95S.)

The extubation procedure, because it is often associated with coughing, is a potentially aerosol-generating procedure, and all strategies that minimize the risk of transmission to health professionals (if extubation occurs during the infectious period of the disease) should be maintained. The procedure should be performed ideally by two operators, with contact, droplet and airway precautions (ideally in a negative pressure room) and using a systematized protocol, as shown in table 3 (Appendix 1).

If ERT failure occurs, the patient should be connected to a ventilatory mode that provides comfort and adequate gas exchange, identifying and optimizing potential causes of failure.(162162 MacIntyre NR, Cook DJ, Ely EW Jr, Epstein SK, Fink JB, Heffner JE, Hess D, Hubmayer RD, Scheinhorn DJ; American College of Chest Physicians; American Association for Respiratory Care; American College of Critical Care Medicine. Evidence-based guidelines for weaning and discontinuing ventilatory support: a collective task force facilitated by the American College of Chest Physicians; the American Association for Respiratory Care; and the American College of Critical Care Medicine. Chest. 2001;120(6 Suppl):375S-95S.) In difficult weaning occurs (failure of multiple spontaneous breathing tests), two weaning strategies, successfully studied in randomized clinical trials, are possible: increased ERT time or progressive reduction in support pressure.(162162 MacIntyre NR, Cook DJ, Ely EW Jr, Epstein SK, Fink JB, Heffner JE, Hess D, Hubmayer RD, Scheinhorn DJ; American College of Chest Physicians; American Association for Respiratory Care; American College of Critical Care Medicine. Evidence-based guidelines for weaning and discontinuing ventilatory support: a collective task force facilitated by the American College of Chest Physicians; the American Association for Respiratory Care; and the American College of Critical Care Medicine. Chest. 2001;120(6 Suppl):375S-95S.)

It is suggested to consider tracheotomy from the 10th day of mechanical ventilation.

Tracheotomy, similar to the approach for respiratory failure not associated with COVID-19, should be considered from the 10th day of mechanical ventilation.(163163 Rosano A, Martinelli E, Fusina F, Albani F, Caserta R, Morandi A, et al. Early percutaneous tracheostomy in coronavirus disease 2019: association with hospital mortality and factors associated with removal of tracheostomy tube at ICU discharge. A cohort study on 121 patients. Crit Care Med. 2021;49(2):261-70.) The procedure can generate aerosols; therefore, all strategies that minimize the risk of transmission to health professionals (if the procedure occurs during the infectious period) should be maintained. The procedure (percutaneous or surgical) should be performed, ideally, by two operators using contact, droplet and airway precautions (ideally in a negative pressure room) and using a systematized protocol.(164164 Sociedade Portuguesa de Otorrinolaringologia e Cirurgia da Cabeça e Pescoço (SPORL-CCP), Colégio da Especialidade de Otorrinolaringologia da Ordem dos Médicos. Recomendações para a realização de traqueotomia em doente com COVID-19. 24 de março de 2020. Disponível em: https://www.sporl.pt/traqueotomia
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Bronchofibroscopy and inhalation therapy

It is suggested to reserve bronchofibroscopy for urgent situations (for example, atelectasis with ventilatory impairment and critical obstruction of the central airway) or when the examination results may lead to a significant modification in the therapeutic strategy (for example, suspicion of coinfection or superinfection). It is suggested that if a decision is made to perform bronchofibroscopy, the technique should be performed by the most experienced operator, and airway precautions should be used (with, ideally, the procedure occurring in a negative pressure room). Disposable video bronchoscopes and the operator to the rear of the patient’s head are suggested.

Bronchofibroscopy is associated with a risk of aerosol generation.(2222 Tran K, Cimon K, Severn M, Pessoa-Silva C, Conly J. Aerosol-generating procedures and risk of transmission of acute respiratory infections: a systematic review. CADTH Technol Overv. 2013;3(1):e3201.) The indications for use should be selective and always well analyzed, using all strategies that minimize the risk of transmission to health professionals.(8383 Bouadma L, Lescure FX, Lucet JC, Yazdanpanah Y, Timsit JF. Severe SARS-CoV-2 infections: practical considerations and management strategy for intensivists. Intensive Care Med. 2020;46(4):579-82.) The recommendations contained in the “Position document of the Portuguese Society of Pulmonology for the performance of bronchoscopies during the COVID-19 outbreak” should be followed.(165165 Sociedade Portuguesa de Pneumologia. Comissão de Técnicas Endoscópicas. Documento de posição da Sociedade Portuguesa de Pneumologia para a realização de broncoscopias durante o surto de COVID-19. 2020. Disponível em: https://www.sppneumologia.pt/uploads/subcanais2_conteudos_ficheiros/posicao-da-spp-para-a-realizacao-de-broncoscopias-durante-a-pandemia-do-coronavirus-(2).pdf
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It is suggested that when the administration of inhalation therapy is clinically indicated, pneumatic, ultrasonic or oscillatory membrane nebulization systems should not be used.

The administration of inhalation therapy using pneumatic, ultrasonic or oscillatory membrane nebulization systems is associated with a risk of aerosol generation,(2222 Tran K, Cimon K, Severn M, Pessoa-Silva C, Conly J. Aerosol-generating procedures and risk of transmission of acute respiratory infections: a systematic review. CADTH Technol Overv. 2013;3(1):e3201.) and all strategies that minimize the risk of transmission to health professionals should be used.(8383 Bouadma L, Lescure FX, Lucet JC, Yazdanpanah Y, Timsit JF. Severe SARS-CoV-2 infections: practical considerations and management strategy for intensivists. Intensive Care Med. 2020;46(4):579-82.,166166 Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention (2020 update). Available from: https://webmed.irkutsk.ru/doc/pdf/ginareport.pdf
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Extracorporeal life support

It is recommended that critically ill patients with respiratory failure associated with COVID-19 be referred for extracorporeal respiratory support after optimized invasive mechanical ventilation and associated adjuvant strategies fail. It is recommended that critically ill patients with cardiogenic shock associated with COVID-19 be referred for extracorporeal cardiorespiratory support when conventional therapy fails.

It is recommended that the referral of critically ill patients with respiratory failure and/or cardiogenic shock associated with COVID-19 and indications for extracorporeal life support be restricted to reference centers recognized by the Ministry of Health and the General Directorate of Health.

It is recommended that the interhospital transfer of critically ill patients with respiratory failure and/or cardiogenic shock associated with COVID-19 and indications for extracorporeal life support occur within the reference center and be conducted, whenever possible, by an in loco dedicated rescue team.

Extracorporeal life support (ECLS), also known as extracorporeal membrane oxygenation (ECMO), is a form of extracorporeal support in which blood is drained by an external pump to a gas exchange membrane (fed by a constant flow of controlled gas via a flow meter equipped with a mixer) and then returned to systemic circulation. There are different forms of ECLS, depending on the blood flow and the cannulation site. High-flow systems, which are of interest in this context, use large-caliber cannulae (18 - 31 F) to drain blood at high flow rates (3.0 to 8.0L/minute) from the venous system and return it to the venous system (veno-venous ECLS, or VV ECLS, which provides respiratory support) or to a large artery (veno-arterial ECLS, or VA ECLS, which provides cardiorespiratory support). Other configurations are also possible, such as veno-arteriovenous (V-AV) ECLS and left ventricular decompression measures (for example, microaxial pumps), which have specific indications.(167167 Rajagopal K, Keller SP, Akkanti B, Bime C, Loyalka P, Cheema FH, et al. Advanced Pulmonary and Cardiac Support of COVID-19 Patients: Emerging Recommendations from ASAIO-A “Living Working Document”. ASAIO J. 2020;66(6):588-98.)

The first reports on the use of ECLS in the treatment of patients with severe COVID-19 from China associated the technique with a mortality rate higher than 70%,(168168 Zeng Y, Cai Z, Xianyu Y, Yang BX, Song T, Yan Q. Prognosis when using extracorporeal membrane oxygenation (ECMO) for critically ill COVID-19 patients in China: a retrospective case series. Crit Care. 2020;24(1):148.) questioning its usefulness, in particular in a pandemic context, in which the optimization of available resources is particularly relevant.(169169 Ramanathan K, Antognini D, Combes A, Paden M, Zakhary B, Ogino M, et al. Planning and provision of ECMO services for severe ARDS during the COVID-19 pandemic and other outbreaks of emerging infectious diseases. Lancet Respir Med. 2020;8(5):518-26.) Additionally, a hypothesis was proposed, according to which ECLS could worsen the prognosis of patients with severe COVID-19 by worsening lymphopenia and exacerbating the inflammatory response resulting from the use of an extracorporeal circuit.(170170 Henry BM. COVID-19, ECMO, and lymphopenia: a word of caution. Lancet Respir Med. 2020;8(4):e24.) The European Chapter of the Extracorporeal Life Support Organization (Euro-ELSO) conducted a summary report with weekly updates of COVID-19 cases involving ECLS in Europe that did not confirm these concerns.(171171 EuroELSO. Coronavirus. Survey on ECMO use. Available from: https://www.euroelso.net/covid-19/covid-19-survey/
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For respiratory failure associated with COVID-19, the type of support to be instituted should be, with particular exceptions, VV ECLS. This modality allows extracorporeal hematosis (oxygenation and removal of carbon dioxide) and has been used in cases of severe respiratory failure refractory to conventional treatment.(172172 Abrams D, Brodie D. Extracorporeal Membrane Oxygenation for Adult Respiratory Failure: 2017 Update. Chest. 2017;152(3):639-49.) The different configurations (femoro-jugular, jugulo-femoral and femoro-femoral) should be used based on the experience of the reference center and based on the specificities of each patient (for example, presence of deep vein thrombosis and morbid obesity). The use of a single cannula for VV ECLS (for example, cannula), which is not contraindicated, is also not recommended due to the frequent need for high flow in the extracorporeal circuit.(167167 Rajagopal K, Keller SP, Akkanti B, Bime C, Loyalka P, Cheema FH, et al. Advanced Pulmonary and Cardiac Support of COVID-19 Patients: Emerging Recommendations from ASAIO-A “Living Working Document”. ASAIO J. 2020;66(6):588-98.)

The indications, as well as contraindications, for referral of critically ill patients with respiratory failure associated with COVID-19 for extracorporeal respiratory support are summarized in table 4 (Appendix 1). In the therapeutic approach, ECLS should only be considered after the failure of optimized invasive mechanical ventilation and associated adjuvant strategies, such as ventral decubitus, neuromuscular block and individualization of ventilatory parameters guided by transpulmonary pressure. The clinical suspicions of pulmonary thromboembolism or patent foramen ovale with a right-to-left shunt should be investigated by means of appropriate imaging tests prior to referral to ECLS.(173173 Badulak J, Antonini MV, Stead CM, Shekerdemian L, Raman L, Paden ML, Agerstrand C, Bartlett RH, Barrett N, Combes A, Lorusso R, Mueller T, Ogino MT, Peek G, Pellegrino V, Rabie AA, Salazar L, Schmidt M, Shekar K, MacLaren G, Brodie D; ELSO COVID-19 Working Group Members. Extracorporeal Membrane Oxygenation for COVID-19: Updated 2021 Guidelines from the Extracorporeal Life Support Organization. ASAIO J. 2021;67(5):485-95,174174 Camporota L, Meadows C, Ledot S, Scott I, Harvey C, Garcia M, Vuylsteke A; NHS England ECMO Service. Consensus on the referral and admission of patients with severe respiratory failure to the NHS ECMO service. Lancet Respir Med. 2021;9(2):e16-7.)

Right ventricular assistance associated with VV ECLS through cannulation of the pulmonary trunk can be considered in the presence of right ventricular dysfunction (after exclusion of pulmonary thromboembolism), and conversion to V-AV ECLS should be considered in the presence of shock associated with severe acute cor pulmonale.(167167 Rajagopal K, Keller SP, Akkanti B, Bime C, Loyalka P, Cheema FH, et al. Advanced Pulmonary and Cardiac Support of COVID-19 Patients: Emerging Recommendations from ASAIO-A “Living Working Document”. ASAIO J. 2020;66(6):588-98.)

In cardiogenic shock associated with COVID-19, the support modality instituted should be VA ECLS, which allows complete cardiorespiratory support and has been used, based on observational cohorts, in the context of cardiogenic shock (of different etiologies) refractory to conventional treatment.(167167 Rajagopal K, Keller SP, Akkanti B, Bime C, Loyalka P, Cheema FH, et al. Advanced Pulmonary and Cardiac Support of COVID-19 Patients: Emerging Recommendations from ASAIO-A “Living Working Document”. ASAIO J. 2020;66(6):588-98.) A clinical aspect that has received increasing attention and may be relevant in the use of VA ECLS in severe COVID-19 is the description of different forms of cardiac involvement in this disease due to right ventricular dysfunction(175175 Lazzeri C, Bonizzoli M, Batacchi S, Cianchi G, Franci A, Fulceri GE, et al. Cardiac involvment in COVID-19-related acute respiratory distress syndrome. Am J Cardiol. 2020;132:147-9.) consequent to pulmonary hypertension associated with ARDS(175175 Lazzeri C, Bonizzoli M, Batacchi S, Cianchi G, Franci A, Fulceri GE, et al. Cardiac involvment in COVID-19-related acute respiratory distress syndrome. Am J Cardiol. 2020;132:147-9.) and acute myocarditis caused by acute SARS-CoV-2 infection.(176176 Doyen D, Moceri P, Ducreux D, Dellamonica J. Myocarditis in a patient with COVID-19: a cause of raised troponin and ECG changes. Lancet. 2020;395(10235):1516.) In these cases, the emergent use of VA ECLS may constitute a therapeutic option as a bridge to recovery in cases of hemodynamic collapse.(177177 Salamanca J, Díez-Villanueva P, Martínez P, Cecconi A, González de Marcos B, Reyes G, et al. COVID-19 “Fulminant Myocarditis” successfully treated with temporary mechanical circulatory support. JACC Cardiovasc Imaging. 2020;13(11):2457-9.) Due to the frequent incidence of lower limb ischemia associated with arterial cannulation, the use of a return cannula with a lumen ≤ 17 F associated with anterograde reperfusion of the homolateral superficial femoral artery (with continuous monitoring of the oxygenation of the extremities of the lower limbs) is recommended. For differential hypoxia refractory to initial interventions, i.e., reduction in output, reduction in afterload and increase in inotropism, the conversion to V-AV ECLS or VV ECLS should be considered, based on native cardiac function.(167167 Rajagopal K, Keller SP, Akkanti B, Bime C, Loyalka P, Cheema FH, et al. Advanced Pulmonary and Cardiac Support of COVID-19 Patients: Emerging Recommendations from ASAIO-A “Living Working Document”. ASAIO J. 2020;66(6):588-98.) The use of left ventricular decompression measures (for example, percutaneous pulmonary artery venting) and the combination of microaxial pumps (for example, Impella™ in a configuration called ECMPELLA) should be individualized based on the hemodynamic profile.(167167 Rajagopal K, Keller SP, Akkanti B, Bime C, Loyalka P, Cheema FH, et al. Advanced Pulmonary and Cardiac Support of COVID-19 Patients: Emerging Recommendations from ASAIO-A “Living Working Document”. ASAIO J. 2020;66(6):588-98.)

The indications, as well as contraindications, for referral of critically ill patients with cardiogenic shock associated with COVID-19 for extracorporeal cardiorespiratory support are summarized in table 5 (Appendix 1). In the therapeutic approach, ECLS should only be considered when conventional therapy fails. Prior to referral, echocardiography should be performed to assess cardiac structure and function, including biventricular function and vascular filling.

As COVID-19 is a very recent disease and ECLS is an organ support therapy used only in extremely severe cases, experience with the use of this technique in this particular context is limited and preliminary. The use of ECLS therapy should always be considered taking into account the available resources resulting from the pandemic context and the potential benefits of the support relative to the associated risks.(174174 Camporota L, Meadows C, Ledot S, Scott I, Harvey C, Garcia M, Vuylsteke A; NHS England ECMO Service. Consensus on the referral and admission of patients with severe respiratory failure to the NHS ECMO service. Lancet Respir Med. 2021;9(2):e16-7.)

Technological advances have made it possible to achieve excellent clinical results with ECLS in several centers worldwide, but international guidelines recommend its use in specialized centers because there is a direct correlation between the volume of ECLS cases and hospital survival.(178178 Barbaro RP, Odetola FO, Kidwell KM, Paden ML, Bartlett RH, Davis MM, et al. Association of hospital-level volume of extracorporeal membrane oxygenation cases and mortality. Analysis of the extracorporeal life support organization registry. Am J Respir Crit Care Med. 2015;191(8):894-901.) In Portugal, there are reference centers recognized by the Ministry of Health and the DGS, and interhospital transfer should be preceded whenever possible by the on-site implementation of ECLS by a dedicated rescue team to minimize the risk of clinical deterioration associated with transport.(174174 Camporota L, Meadows C, Ledot S, Scott I, Harvey C, Garcia M, Vuylsteke A; NHS England ECMO Service. Consensus on the referral and admission of patients with severe respiratory failure to the NHS ECMO service. Lancet Respir Med. 2021;9(2):e16-7.)

Other organ support

A conservative fluid therapy strategy is recommended for critically ill patients with COVID-19, especially in the absence of shock. It is recommended that septic shock in critically ill patients with COVID-19 be treated based on the clinical guidelines applicable to patients with septic shock not associated with COVID-19. It is recommended that nonpulmonary organ dysfunction in critically ill patients with COVID-19 be managed based on the clinical guidelines applicable to non-COVID-19 patients.

There is no direct evidence (e.g., based on specific studies) for an ideal hemodynamic support strategy for COVID-19, but it is recognized that the presence of shock, operationally defined as the need for vasopressors for mean arterial pressure (MAP) ≥ 65mmHg and lactate > 2mmol/L, in the absence of hypovolemia,(179179 Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315(8):801-10.) in the context of SARS-CoV-2 infection is reduced (< 5%), even in intensive care patients.(180180 Wu Z, McGoogan JM. Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72314 Cases From the Chinese Center for Disease Control and Prevention. JAMA. 2020;323(13):1239-42.) This fact, associated with the high risk of death from hypoxemic respiratory failure,(181181 Yang X, Yu Y, Xu J, Shu H, Xia J, Liu H, et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med. 2020;8(5):475-81.) potentially aggravated by the administration of fluids,(182182 Malbrain ML, Van Regenmortel N, Saugel B, De Tavernier B, Van Gaal PJ, Joannes-Boyau O, et al. Principles of fluid management and stewardship in septic shock: it is time to consider the four D’s and the four phases of fluid therapy. Ann Intensive Care. 2018;8(1):66.) supports the use of a conservative fluid therapy strategy, especially in the absence of tissue hypoperfusion.

In the presence of hypotension with tissue hypoperfusion, evaluated by clinical perfusion parameters (for example, capillary reperfusion time and skin temperature) and analytical parameters (for example, serum lactate), the approach is similar to that for hypotension associated with sepsis in the non-COVID-19 context.(183183 Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Crit Care Med. 2017;45(3):486-552.) The administration of repeated boluses begins(9898 Alhazzani W, Moller MH, Arabi YM, Loeb M, Gong MN, Fan E, et al. Surviving Sepsis Campaign: guidelines on the management of critically ill adults with Coronavirus Disease 2019 (COVID-19). Intensive Care Med. 2020;46(5):854-87.) with 250 to 500cc crystalloid, ideally, balanced solutions, such as lactated Ringer’s solution or Plasma-Lyte®,(184184 Brown RM, Wang L, Coston TD, Krishnan NI, Casey JD, Wanderer JP, et al. Balanced crystalloids versus saline in sepsis. A secondary analysis of the SMART clinical trial. Am J Respir Crit Care Med. 2019;200(12):1487-95.) avoiding synthetic colloids (starches, dextrans and gelatins), which are not cost effective.(185185 Lewis SR, Pritchard MW, Evans DJ, Butler AR, Alderson P, Smith AF, et al. Colloids versus crystalloids for fluid resuscitation in critically ill people. Cochrane Database Syst Rev. 2018;8(8):CD000567.) Albumin (20%) is as safe and effective as crystalloids but has a higher cost(9898 Alhazzani W, Moller MH, Arabi YM, Loeb M, Gong MN, Fan E, et al. Surviving Sepsis Campaign: guidelines on the management of critically ill adults with Coronavirus Disease 2019 (COVID-19). Intensive Care Med. 2020;46(5):854-87.,185185 Lewis SR, Pritchard MW, Evans DJ, Butler AR, Alderson P, Smith AF, et al. Colloids versus crystalloids for fluid resuscitation in critically ill people. Cochrane Database Syst Rev. 2018;8(8):CD000567.) and should be reserved for very particular situations, such as hypoalbuminemic and hyponcotic septic patients with associated ARDS. In an intensive care setting, an echocardiogram should be performed as soon as possible, allowing a better characterization of the hemodynamic changes due to shock and facilitating the selection of the best therapeutic options, in addition to establishing a strategy for the evaluation of dynamic parameters of fluid response and guiding fluid therapy, such as variations in systolic volume, variations in pulse pressure and changes in systolic volume with a fluid challenge or, ideally, with passive elevation of the legs.(186186 Bednarczyk JM, Fridfinnson JA, Kumar A, Blanchard L, Rabbani R, Bell D, et al. Incorporating dynamic assessment of fluid responsiveness into goal-directed therapy: a systematic review and meta-analysis. Crit Care Med. 2017;45(9):1538-45.,187187 Bentzer P, Griesdale DE, Boyd J, MacLean K, Sirounis D, Ayas NT. Will this hemodynamically unstable patient respond to a bolus of intravenous fluids? JAMA. 2016;316(12):1298-309.) This last test is performed by measuring cardiac output (by means of echocardiographic, minimally invasive or invasive methods) with the patient in a semidorsal position (head elevated 45°), positioning the patient in dorsal decubitus, with passive elevation of the patient’s lower limbs (at 45°), repeating the cardiac output measurement. This maneuver mobilizes approximately 150 - 300cc of blood from the lower body to the central circulation, resulting in an increase in preload (reversible in less than 30 seconds) and representing an increase of > 12% in cardiac output and the ability to respond to fluids.(187187 Bentzer P, Griesdale DE, Boyd J, MacLean K, Sirounis D, Ayas NT. Will this hemodynamically unstable patient respond to a bolus of intravenous fluids? JAMA. 2016;316(12):1298-309.)

Early vasopressor perfusion may be considered for patients with severe hypotension (MAP < 50mmHg) or without tension response to the first bolus of fluid.(188188 Gamper G, Havel C, Arrich J, Losert H, Pace NL, Müllner M, et al. Vasopressors for hypotensive shock. Cochrane Database Syst Rev. 2016;2(2):CD003709.) Norepinephrine is the vasopressor of choice (which can be administered peripherally in an initial phase) and should be started at 0.5µg/minute and titrated up to 15µg/minute. Dopamine is associated with a higher incidence of arrhythmic events and mortality and should be avoided.(188188 Gamper G, Havel C, Arrich J, Losert H, Pace NL, Müllner M, et al. Vasopressors for hypotensive shock. Cochrane Database Syst Rev. 2016;2(2):CD003709.) MAP ≥ 65mmHg is considered sufficient for most patients, but patients with a history of hypertension may benefit (reduced incidence of acute kidney injury) from higher values (MAP 75 - 85mmHg) but with a higher risk of dysrhythmias.(189189 Asfar P, Meziani F, Hamel JF, Grelon F, Megarbane B, Anguel N, Mira JP, Dequin PF, Gergaud S, Weiss N, Legay F, Le Tulzo Y, Conrad M, Robert R, Gonzalez F, Guitton C, Tamion F, Tonnelier JM, Guezennec P, Van Der Linden T, Vieillard-Baron A, Mariotte E, Pradel G, Lesieur O, Ricard JD, Hervé F, du Cheyron D, Guerin C, Mercat A, Teboul JL, Radermacher P; SEPSISPAM Investigators. High versus low blood-pressure target in patients with septic shock. N Engl J Med. 2014;370(17):1583-93.) If the echocardiographic evaluation indicates changes in cardiac function associated with low/inadequate cardiac output, an inotropic agent should be administered, of which dobutamine (up to 20µg/kg/minute) is the first option.(9898 Alhazzani W, Moller MH, Arabi YM, Loeb M, Gong MN, Fan E, et al. Surviving Sepsis Campaign: guidelines on the management of critically ill adults with Coronavirus Disease 2019 (COVID-19). Intensive Care Med. 2020;46(5):854-87.,190190 Moller MH, Granholm A, Junttila E, Haney M, Oscarsson-Tibblin A, Haavind A, et al. Scandinavian SSAI clinical practice guideline on choice of inotropic agent for patients with acute circulatory failure. Acta Anaesthesiol Scand. 2018;62(4):420-50.) If there is an additional need to increase blood pressure, the combination or potential replacement of noradrenaline with adrenaline should be considered.(188188 Gamper G, Havel C, Arrich J, Losert H, Pace NL, Müllner M, et al. Vasopressors for hypotensive shock. Cochrane Database Syst Rev. 2016;2(2):CD003709.)

The use of low doses of hydrocortisone intravenously (ideally, 200 mg per day in continuous infusion or, optionally, in a 50mg bolus every 6 hours) should be considered exclusively for patients with septic shock without response to vasopressors(191191 Rygard SL, Butler E, Granholm A, Moller MH, Cohen J, Finfer S, et al. Low-dose corticosteroids for adult patients with septic shock: a systematic review with meta-analysis and trial sequential analysis. Intensive Care Med. 2018;44(7):1003-16.) (operational definition, need for noradrenaline > 0.25µg/kg/minute or adrenaline > 0.25µg/kg/minute to maintain MAP within the target values). The duration of corticosteroid therapy instituted in the context of hemodynamic instability is a clinical decision that should be weighed with the need for corticosteroid therapy for other reasons in the context of COVID-19 respiratory failure.(9898 Alhazzani W, Moller MH, Arabi YM, Loeb M, Gong MN, Fan E, et al. Surviving Sepsis Campaign: guidelines on the management of critically ill adults with Coronavirus Disease 2019 (COVID-19). Intensive Care Med. 2020;46(5):854-87.)

The therapeutic targets of fluid administration, associated or not with noradrenaline perfusion, are the restoration of perfusion pressure and improvements in tissue hypoperfusion, which can be evaluated by clinical signs(192192 Hernández G, Ospina-Tascón GA, Damiani LP, Estenssoro E, Dubin A, Hurtado J, et al. Effect of a resuscitation strategy targeting peripheral perfusion status vs serum lactate levels on 28-day mortality among patients with septic shock: the ANDROMEDA-SHOCK randomized clinical trial. JAMA. 2019;321(7):654-64.) and/or biochemical tests. The normalization of lactate (or an improvement ≥ 20%, every 2 hours, in the first 8 hours) is an appropriate therapeutic target.(193193 Pan J, Peng M, Liao C, Hu X, Wang A, Li X. Relative efficacy and safety of early lactate clearance-guided therapy resuscitation in patients with sepsis: a meta-analysis. Medicine (Baltimore). 2019;98(8):e14453.) The use of adrenaline results in the production of aerobic lactate (through the stimulation of beta 2 adrenergic receptors in skeletal muscle), preventing the use of lactate washout to guide resuscitation.(188188 Gamper G, Havel C, Arrich J, Losert H, Pace NL, Müllner M, et al. Vasopressors for hypotensive shock. Cochrane Database Syst Rev. 2016;2(2):CD003709.)

There is no direct evidence for an ideal strategy for other forms of organ support in COVID-19, but renal support techniques deserve special reference in the context of acute kidney injury associated with COVID-19. Before initiating renal support techniques, the reversible factors of acute kidney injury (especially prenatal causes) should be corrected,(194194 Khwaja A. KDIGO clinical practice guidelines for acute kidney injury. Nephron Clin Pract. 2012;120(4):c179-84.) and exposure to risk factors should always be avoided (for example, administration of intravenous contrast to perform imaging tests).(194194 Khwaja A. KDIGO clinical practice guidelines for acute kidney injury. Nephron Clin Pract. 2012;120(4):c179-84.)

The indications are similar to those for non-COVID-19 critically ill patients, and outside conventional indications (severe metabolic acidemia, pH < 7.1; electrolyte changes, especially kalemia > 6.5mEq/L associated with electrocardiographic changes; drug poisoning/life-threatening dialysable toxins; overload, refractory water overload, and uremia, such as, pericarditis or encephalopathy), a delayed initiation strategy for renal support should be favored.(195195 STARRT-AKI Investigators; Canadian Critical Care Trials Group; Australian and New Zealand Intensive Care Society Clinical Trials Group; United Kingdom Critical Care Research Group; Canadian Nephrology Trials Network; Irish Critical Care Trials Group, Bagshaw SM, Wald R, Adhikari NK, Bellomo R, da Costa BR, Dreyfuss D, et al. Timing of initiation of renal-replacement therapy in acute kidney injury. N Engl J Med. 2020;383(3):240-51.) In particular, sodium bicarbonate is known to be safe to administer (in a controlled manner) to patients with metabolic acidemia, especially of uremic etiology.(196196 Jaber S, Paugam C, Futier E, Lefrant JY, Lasocki S, Lescot T, Pottecher J, Demoule A, Ferrandière M, Asehnoune K, Dellamonica J, Velly L, Abback PS, de Jong A, Brunot V, Belafia F, Roquilly A, Chanques G, Muller L, Constantin JM, Bertet H, Klouche K, Molinari N, Jung B; BICAR-ICU Study Group. Sodium bicarbonate therapy for patients with severe metabolic acidaemia in the intensive care unit (BICAR-ICU): a multicentre, open-label, randomised controlled, phase 3 trial. Lancet. 2018;392(10141):31-40.)

Multiple renal support techniques are available, including intermittent hemodialysis (HDI), continuous renal replacement therapies (CRRTs) and hybrid therapies, also known as prolonged intermittent renal replacement therapies (PIRRTs), such as sustained low-efficiency dialysis (SLED) dialysis. There are no studies that demonstrate the practical superiority of any of the modalities, and recommendations are motivated by the need to optimize patient therapy and minimize the risk of transmission to health professionals. Thus, CRRTs are considered the preferred modality because they allow the optimization of drug dosage and the flow of dialysate to waste bags (not to the hospital sewage system) and minimize interactions with the nursing team.(197197 Raza A, Estepa A, Chan V, Jafar MS. Acute renal failure in critically ill COVID-19 patients with a focus on the role of renal replacement therapy: a review of what we know so far. Cureus. 2020;12(6):e8429.) However, in situations where equipment isis a limiting factor, hybrid or intermittent techniques, which allow the maximization of resources, should be performed.

Coinfection, superinfection and antimicrobials

In critically ill patients with suspected severe pneumonia combined with seasonal influenza, it is recommended to start antibiotic therapy for influenza and reassess the clinical picture after obtaining cultural and laboratory results.

In critically ill patients with suspected severe pneumonia combined with seasonal influenza, it is recommended to start antibiotic therapy for influenza and reassess the clinical picture after obtaining cultural and laboratory results.

In critically ill patients with COVID-19, in the presence of septic shock, it is recommended to administer antibiotic therapy until obtaining cultural results that allow the affirmation or exclusion of the coexistence of bacterial infection.

It is recommended to reassess decisions regarding antibiotic therapy initiated at admission up to 72 hours, depending on the microbiological results available, the clinical evolution and inflammatory biomarkers (namely, procalcitonin).

For critically ill patients with COVID-19, it is recommended to maintain a high index of suspicion for nosocomial infection (namely, ventilator-associated pneumonia).

In critical patients with COVID-19 without a microbiological diagnosis or with unfavorable progression under appropriate antibiotic therapy, it is suggested to consider invasive pulmonary aspergillosis associated with COVID-19.

It is important to distinguish between coinfection, i.e., infection present at admission, and overinfection, i.e., infection that appears more than 48 hours after admission.

In the context of COVID-19, coinfection by other agents, even in critically ill patients, is infrequent.(198198 Russell CD, Fairfield CJ, Drake TM, Turtle L, Seaton RA, Wootton DG, Sigfrid L, Harrison EM, Docherty AB, de Silva TI, Egan C, Pius R, Hardwick HE, Merson L, Girvan M, Dunning J, Nguyen-Van-Tam JS, Openshaw PJM, Baillie JK, Semple MG, Ho A; ISARIC4C investigator. Co-infections, secondary infections, and antimicrobial use in patients hospitalised patients with COVID-19 during the first pandemic wave the ISARIC WHO CCP-UK study: a prospective, multicentre cohort study. Lancet Microbe. 2021;2(8):e354-65.,199199 Llitjos JF, Bredin S, Lascarrou JB, Soumagne T, Cojocaru M, Leclerc M, et al. Increased susceptibility to intensive care unit-acquired pneumonia in severe COVID-19 patients: a multicentre retrospective cohort study. Ann Intensive Care. 2021;11(1):20.) However, coinfection is difficult to exclude quickly, and the delay in the institution of appropriate antibiotic therapy in septic shock may be associated with increased mortality. A more liberal antibiotic therapy strategy is recommended and should be reviewed as a function of the microbiological findings, clinical evolution and inflammatory markers (namely, procalcitonin).(200200 Peters C, Williams K, Un EA, Little L, Saad A, Lendrum K, et al. Use of procalcitonin for antibiotic stewardship in patients with COVID-19: a quality improvement project in a district general hospital. Clin Med (Lond). 2021;21(1):e71-6.,201201 Williams EJ, Mair L, de Silva TI, Green DJ, House P, Cawthron K, et al. Evaluation of procalcitonin as a contribution to antimicrobial stewardship in SARS-CoV-2 infection: a retrospective cohort study. J Hosp Infect. 2021;110:103-7.)

In the context of critical COVID-19, nosocomial overinfection by other agents, particularly ventilator-associated pneumonia, is frequent.(202202 Rouzé A, Martin-Loeches I, Povoa P, Makris D, Artigas A, Bouchereau M, Lambiotte F, Metzelard M, Cuchet P, Boulle Geronimi C, Labruyere M, Tamion F, Nyunga M, Luyt CE, Labreuche J, Pouly O, Bardin J, Saade A, Asfar P, Baudel JL, Beurton A, Garot D, Ioannidou I, Kreitmann L, Llitjos JF, Magira E, Mégarbane B, Meguerditchian D, Moglia E, Mekontso-Dessap A, Reignier J, Turpin M, Pierre A, Plantefeve G, Vinsonneau C, Floch PE, Weiss N, Ceccato A, Torres A, Duhamel A, Nseir S; coVAPid study Group. Relationship between SARS-CoV-2 infection and the incidence of ventilator-associated lower respiratory tract infections: a European multicenter cohort study. Intensive Care Med. 2021;47(2):188-98.,203203 Blonz G, Kouatchet A, Chudeau N, Pontis E, Lorber J, Lemeur A, et al. Epidemiology and microbiology of ventilator-associated pneumonia in COVID-19 patients: a multicenter retrospective study in 188 patients in an un-inundated French region. Crit Care. 2021;25(1):72.) The etiological agents do not seem to differ significantly when compared to those observed in other populations, with a predominance of gram-negative bacteria (Enterobacteria and nonfermenters), with gram-positive bacteria present in 10% to 30% of cases.(202202 Rouzé A, Martin-Loeches I, Povoa P, Makris D, Artigas A, Bouchereau M, Lambiotte F, Metzelard M, Cuchet P, Boulle Geronimi C, Labruyere M, Tamion F, Nyunga M, Luyt CE, Labreuche J, Pouly O, Bardin J, Saade A, Asfar P, Baudel JL, Beurton A, Garot D, Ioannidou I, Kreitmann L, Llitjos JF, Magira E, Mégarbane B, Meguerditchian D, Moglia E, Mekontso-Dessap A, Reignier J, Turpin M, Pierre A, Plantefeve G, Vinsonneau C, Floch PE, Weiss N, Ceccato A, Torres A, Duhamel A, Nseir S; coVAPid study Group. Relationship between SARS-CoV-2 infection and the incidence of ventilator-associated lower respiratory tract infections: a European multicenter cohort study. Intensive Care Med. 2021;47(2):188-98.,203203 Blonz G, Kouatchet A, Chudeau N, Pontis E, Lorber J, Lemeur A, et al. Epidemiology and microbiology of ventilator-associated pneumonia in COVID-19 patients: a multicenter retrospective study in 188 patients in an un-inundated French region. Crit Care. 2021;25(1):72.) In immunocompromised patients with chronic obstructive pulmonary disease or unfavorable evolution, despite adequate antibiotic therapy, pulmonary aspergillosis associated with COVID-19 should be considered.(204204 Wang J, Yang Q, Zhang P, Sheng J, Zhou J, Qu T. Clinical characteristics of invasive pulmonary aspergillosis in patients with COVID-19 in Zhejiang, China: a retrospective case series. Crit Care. 2020;24(1):299.,205205 Bartoletti M, Pascale R, Cricca M, Rinaldi M, Maccaro A, Bussini L, Fornaro G, Tonetti T, Pizzilli G, Francalanci E, Giuntoli L, Rubin A, Moroni A, Ambretti S, Trapani F, Vatamanu O, Ranieri VM, Castelli A, Baiocchi M, Lewis R, Giannella M, Viale P; PREDICO study group. Epidemiology of invasive pulmonary aspergillosis among COVID-19 intubated patients: a prospective study. Clin Infect Dis. 2020:ciaa1065.)

SPECIFIC THERAPY

Antiviral drugs

Remdesivir

In critically ill patients infected with SARS-CoV-2 who require a noninvasive ventilatory strategy (NIV or HFNC therapy), invasive ventilatory support, extracorporeal respiratory support or vasopressors are recommended; remdesivir is not recommended.

In critical patients infected with SARS-CoV-2 who require conventional oxygen therapy, it is suggested to consider the use of remdesivir in the first 72 hours after the first positive SARS-CoV-2 test.

It is suggested that in patients infected with SARS-CoV-2 previously treated with remdesivir with clinical deterioration, requiring escalation of ventilatory support and corticosteroid therapy, remdesivir should be maintained until the completion of the therapeutic course.

Remdesivir is an analog of adenosine that targets RNA-dependent RNA polymerase and was initially developed for the treatment of Ebola and Marburg viruses; however, it has been shown to have a spectrum of activity against other viruses.(206206 Lo MK, Jordan R, Arvey A, Sudhamsu J, Shrivastava-Ranjan P, Hotard AL, et al. GS-5734 and its parent nucleoside analog inhibit Filo-, Pneumo-, and Paramyxoviruses. Sci Rep. 2017;7:43395.) Remdesivir demonstrated in vitro efficacy in the inhibition of SARS-CoV-2, MERS-CoV and SARS-CoV-1,(207207 Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020;30(3):269-71.) and in animal models infected with SARS-CoV-2, it demonstrated therapeutic activity (ability to reduce viral loads, pulmonary pathological changes and progression of clinical disease) when started early.(208208 Williamson BN, Feldmann F, Schwarz B, Meade-White K, Porter DP, Schulz J, et al. Clinical benefit of remdesivir in rhesus macaques infected with SARS-CoV-2. Nature. 2020;585(7824):273-6.)

The dose studied for the treatment of SARS-CoV-2 infection is 200mg on day 1, followed by 100 mg per day, administered intravenously (in 30 to 60 minutes), for up to 10 days. The most frequent adverse effects are gastrointestinal symptoms (nausea and vomiting), injection site reactions (phlebitis) and an increase in transaminases.

In ACTT-1 (Adaptive COVID-19 Treatment Trial), a multinational controlled and randomized study that randomized patients in the first 72 hours after a positive SARS-CoV-2 test for treatment with remdesivir or placebo, remdesivir was associated with a shorter recovery time (7 days versus 9 days) in a subgroup of patients who also received conventional oxygen therapy, at the time of randomization, with reduced progression (17% versus 24%) to noninvasive ventilation strategy (VIV or HFNC), invasive ventilatory support or extracorporeal respiratory support.(209209 Beigel JH, Tomashek KM, Dodd LE, Mehta AK, Zingman BS, Kalil AC, Hohmann E, Chu HY, Luetkemeyer A, Kline S, Lopez de Castilla D, Finberg RW, Dierberg K, Tapson V, Hsieh L, Patterson TF, Paredes R, Sweeney DA, Short WR, Touloumi G, Lye DC, Ohmagari N, Oh MD, Ruiz-Palacios GM, Benfield T, Fätkenheuer G, Kortepeter MG, Atmar RL, Creech CB, Lundgren J, Babiker AG, Pett S, Neaton JD, Burgess TH, Bonnett T, Green M, Makowski M, Osinusi A, Nayak S, Lane HC; ACTT-1 Study Group Members. Remdesivir for the treatment of Covid-19 - Final report. N Engl J Med. 2020;383(19):1813-26.) The SIMPLE study compared 5 and 10 days of remdesivir treatment in patients with SARS-CoV-2 pneumonia without the need for mechanical ventilation, showing overlap between the two groups, i.e., in nonventilated patients, a 5-day therapeutic course with remdesivir is possible (no differences in mortality or adverse effects).(210210 Goldman JD, Lye DC, Hui DS, Marks KM, Bruno R, Montejano R, Spinner CD, Galli M, Ahn MY, Nahass RG, Chen YS, SenGupta D, Hyland RH, Osinusi AO, Cao H, Blair C, Wei X, Gaggar A, Brainard DM, Towner WJ, Muñoz J, Mullane KM, Marty FM, Tashima KT, Diaz G, Subramanian A; GS-US-540-5773 Investigators. Remdesivir for 5 or 10 days in patients with severe Covid-19. N Engl J Med. 2020;383(19):1827-37.)

In the SOLIDARITY trial, there was a trend toward higher mortality in critically ill patients infected with SARS-CoV-2 treated with remdesivir requiring invasive ventilatory support.(211211 WHO Solidarity Trial Consortium, Pan H, Peto R, Henao-Restrepo AM, Preziosi MP, Sathiyamoorthy V, et al. Repurposed Antiviral Drugs for Covid-19 - Interim WHO Solidarity Trial Results. N Engl J Med. 2021;384(6):497-511.) A meta-analysis of multiple studies(209209 Beigel JH, Tomashek KM, Dodd LE, Mehta AK, Zingman BS, Kalil AC, Hohmann E, Chu HY, Luetkemeyer A, Kline S, Lopez de Castilla D, Finberg RW, Dierberg K, Tapson V, Hsieh L, Patterson TF, Paredes R, Sweeney DA, Short WR, Touloumi G, Lye DC, Ohmagari N, Oh MD, Ruiz-Palacios GM, Benfield T, Fätkenheuer G, Kortepeter MG, Atmar RL, Creech CB, Lundgren J, Babiker AG, Pett S, Neaton JD, Burgess TH, Bonnett T, Green M, Makowski M, Osinusi A, Nayak S, Lane HC; ACTT-1 Study Group Members. Remdesivir for the treatment of Covid-19 - Final report. N Engl J Med. 2020;383(19):1813-26.

210 Goldman JD, Lye DC, Hui DS, Marks KM, Bruno R, Montejano R, Spinner CD, Galli M, Ahn MY, Nahass RG, Chen YS, SenGupta D, Hyland RH, Osinusi AO, Cao H, Blair C, Wei X, Gaggar A, Brainard DM, Towner WJ, Muñoz J, Mullane KM, Marty FM, Tashima KT, Diaz G, Subramanian A; GS-US-540-5773 Investigators. Remdesivir for 5 or 10 days in patients with severe Covid-19. N Engl J Med. 2020;383(19):1827-37.

211 WHO Solidarity Trial Consortium, Pan H, Peto R, Henao-Restrepo AM, Preziosi MP, Sathiyamoorthy V, et al. Repurposed Antiviral Drugs for Covid-19 - Interim WHO Solidarity Trial Results. N Engl J Med. 2021;384(6):497-511.
-212212 Wang Y, Zhang D, Du G, Du R, Zhao J, Jin Y, et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet. 2020;395(10236):1569-78.) published together with the SOLIDARITY results(211211 WHO Solidarity Trial Consortium, Pan H, Peto R, Henao-Restrepo AM, Preziosi MP, Sathiyamoorthy V, et al. Repurposed Antiviral Drugs for Covid-19 - Interim WHO Solidarity Trial Results. N Engl J Med. 2021;384(6):497-511.) does not allow us to conclude that remdesivir provides significant benefits. In contrast, a meta-analysis published together with a review of the guidelines of the Surviving Sepsis Campaign(213213 Alhazzani W, Evans L, Alshamsi F, Moller MH, Ostermann M, Prescott HC, et al. Surviving Sepsis Campaign Guidelines on the Management of Adults With Coronavirus Disease 2019 (COVID-19) in the ICU: First Update. Crit Care Med. 2021;49(3):e219-34.) suggests that remdesivir may reduce the recovery time and severe adverse events (compared to standard therapy).

The Food and Drug Administration (FDA) and European Medicines Agency (EMA) approved remdesivir for patients with SARS-CoV-2 pneumonia who require supplemental oxygen therapy. However, discordant results have led the WHO to report an absence of clinical benefits with remdesivir(7676 World Health Organization (WHO). COVID-19 Clinical management: living guidance. 25 January 2021. Available from: file:///C:/Users/elisabete.freitas/Downloads/WHO-2019-nCoV-clinical-2021.1-eng.pdf), while the Surviving Sepsis Campaign recommends its use in critically ill patients who do not require invasive ventilatory support.(213213 Alhazzani W, Evans L, Alshamsi F, Moller MH, Ostermann M, Prescott HC, et al. Surviving Sepsis Campaign Guidelines on the Management of Adults With Coronavirus Disease 2019 (COVID-19) in the ICU: First Update. Crit Care Med. 2021;49(3):e219-34.)

Considering the moderate quality evidence of clinical benefits (reduction in disease duration combined with fewer adverse events) and the potential reduction in viral clearance resulting from the use of corticosteroids, remdesivir can be considered in the first 72 hours after the first positive test for SARS-CoV-2 (inclusion criteria in ACTT-1) for patients receiving conventional oxygen therapy but not a noninvasive ventilation strategy (NIV or HFNC) or invasive ventilatory support.

The combination of an antiviral with corticosteroid therapy for some viral infections can prevent a reduction in viral clearance resulting from the use of corticosteroids.(214214 Arabi YM, Mandourah Y, Al-Hameed F, Sindi AA, Almekhlafi GA, Hussein MA, Jose J, Pinto R, Al-Omari A, Kharaba A, Almotairi A, Al Khatib K, Alraddadi B, Shalhoub S, Abdulmomen A, Qushmaq I, Mady A, Solaiman O, Al-Aithan AM, Al-Raddadi R, Ragab A, Balkhy HH, Al Harthy A, Deeb AM, Al Mutairi H, Al-Dawood A, Merson L, Hayden FG, Fowler RA; Saudi Critical Care Trial Group. Corticosteroid Therapy for Critically Ill Patients with Middle East Respiratory Syndrome. Am J Respir Crit Care Med. 2018;197(6):757-67.) For SARS-CoV-2, there are divergent observational studies on the effect of corticosteroids on viral clearance;(215215 Spagnuolo V, Guffanti M, Galli L, Poli A, Querini PR, Ripa M, et al. Viral clearance after early corticosteroid treatment in patients with moderate or severe covid-19. Sci Rep. 2020;10(1):21291.,216216 Li Q, Li W, Jin Y, Xu W, Huang C, Li L, et al. Efficacy Evaluation of early, low-dose, short-term corticosteroids in adults hospitalized with non-severe COVID-19 pneumonia: a retrospective cohort study. Infect Dis Ther. 2020;9(4):823-36.) as such, specific studies are needed on this issue. Thus, if remdesivir has already been previously prescribed (respecting previous indications), it is suggested to complete the therapeutic course.

Other

In critically ill patients infected with SARS-CoV-2, the nonroutine use of other antivirals outside the scope of clinical use protocols or clinical trials is recommended.

Lopinavir/ritonavir is a combination of protease inhibitors used in the treatment of human immunodeficiency virus (HIV) infection; lopinavir has antiretroviral action, and ritonavir (in low dose, acts as a CYP3A inhibitor) serves as a booster of the former. Evidence from multiple randomized clinical trials, including data from the RECOVERY (Randomized Evaluation of COVID-19 Therapy) and SOLIDARITY trials, indicates that lopinavir-ritonavir is not more effective than the standard therapy for the treatment of patients with mild to severe COVID-19.(211211 WHO Solidarity Trial Consortium, Pan H, Peto R, Henao-Restrepo AM, Preziosi MP, Sathiyamoorthy V, et al. Repurposed Antiviral Drugs for Covid-19 - Interim WHO Solidarity Trial Results. N Engl J Med. 2021;384(6):497-511.,217217 Cao B, Wang Y, Wen D, Liu W, Wang J, Fan G, et al. A trial of lopinavir-ritonavir in adults hospitalized with severe Covid-19. N Engl J Med. 2020;382(19):1787-99.

218 Magagnoli J, Narendran S, Pereira F, Cummings TH, Hardin JW, Sutton SS, et al. Outcomes of hydroxychloroquine usage in United States veterans hospitalized with COVID-19. Med (N Y). 2020;1(1):114-27.e3.
-219219 RECOVERY Collaborative Group. Lopinavir-ritonavir in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. Lancet. 2020;396(10259):1345-52.) Additionally, the lopinavir/ritonavir arm of the SOLIDARITY trial was discontinued due to an unfavorable adverse effects profile (in particular, gastrointestinal effects).(217217 Cao B, Wang Y, Wen D, Liu W, Wang J, Fan G, et al. A trial of lopinavir-ritonavir in adults hospitalized with severe Covid-19. N Engl J Med. 2020;382(19):1787-99.)

Darunavir, in combination with ritonavir or cobicistat, has a mechanism of action that overlaps that of lopinavir/ritonavir, but the available evidence does not support its use in patients infected with SARS-CoV-2 because of the lack of clinical benefits and possible association with adverse events.(220220 Chen J, Xia L, Liu L, Xu Q, Ling Y, Huang D, et al. Antiviral activity and safety of darunavir/cobicistat for the treatment of COVID-19. Open Forum Infect Dis. 2020;7(7):ofaa241.)

Favipiravir is a broad-spectrum antiviral that targets RNA-dependent RNA polymerase; large-scale production was limited because it has a teratogenic effect.(221221 Hayden FG, Shindo N. Influenza virus polymerase inhibitors in clinical development. Curr Opin Infect Dis. 2019;32(2):176-86.) Evidence from multiple randomized clinical trials does not support its use in patients infected with SARS-CoV-2 infection because of the lack of clinical benefits associated with a not fully characterized safety profile.(222222 Udwadia ZF, Singh P, Barkate H, Patil S, Rangwala S, Pendse A, et al. Efficacy and safety of favipiravir, an oral RNA-dependent RNA polymerase inhibitor, in mild-to-moderate COVID-19: a randomized, comparative, open-label, multicenter, phase 3 clinical trial. Int J Infect Dis. 2021;103:62-71.

223 Ivashchenko AA, Dmitriev KA, Vostokova NV, Azarova VN, Blinow AA, Egorova AN, et al. AVIFAVIR for Treatment of Patients with Moderate COVID-19: Interim Results of a Phase II/III Multicenter Randomized Clinical Trial. Clin Infect Dis. 2021;73(3):531-4.
-224224 Lou Y, Liu L, Yao H, Hu X, Su J, Xu K, et al. Clinical outcomes and plasma concentrations of baloxavir marboxil and favipiravir in COVID-19 patients: an exploratory randomized, controlled trial. Eur J Pharm Sci. 2021;157:105631.)

Ribavirin was tested together with lopinavir/ritonavir in patients with SARS-CoV-1,(225225 Chu CM, Cheng VC, Hung IF, Wong MM, Chan KH, Chan KS, Kao RY, Poon LL, Wong CL, Guan Y, Peiris JS, Yuen KY; HKU/UCH SARS Study Group. Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings. Thorax. 2004;59(3):252-6.,226226 Chan KS, Lai ST, Chu CM, Tsui E, Tam CY, Wong MM, et al. Treatment of severe acute respiratory syndrome with lopinavir/ritonavir: a multicentre retrospective matched cohort study. Hong Kong Med J. 2003;9(6):399-406.) but the doses required for optimization of antiviral activity exceed the toxicity limit.

Regarding other antivirals that act on influenza viruses (oseltamivir, umifenovir and baloxavir), there is no evidence available to support their use in patient with COVID-19.(224224 Lou Y, Liu L, Yao H, Hu X, Su J, Xu K, et al. Clinical outcomes and plasma concentrations of baloxavir marboxil and favipiravir in COVID-19 patients: an exploratory randomized, controlled trial. Eur J Pharm Sci. 2021;157:105631.)

Chloroquine and its metabolite, hydroxychloroquine, are used as antimalarials and immunomodulators (for example, in systemic lupus erythematosus). Hydroxychloroquine and chloroquine demonstrated in vitro efficacy in the inhibition of SARS-CoV-1 and SARS-CoV-2.(207207 Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020;30(3):269-71.,227227 Yao X, Ye F, Zhang M, Cui C, Huang B, Niu P, et al. 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). Clin Infect Dis. 2020;71(15):732-9.) Initial studies on SARS-CoV-2 infection, demonstrating apparent efficacy (reduction in viral shedding time and duration of symptoms as well as an attenuation of clinical and imaging manifestations) and a good safety profile,(228228 Gao J, Tian Z, Yang X. Breakthrough: chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. Biosci Trends. 2020;14(1):72-3.,229229 Gautret P, Lagier JC, Parola P, Hoang VT, Meddeb L, Mailhe M, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents. 2020;56(1):105949.) led to an official declaration of hydroxychloroquine as a therapeutic agent for COVID-19 in China.(230230 Multicenter Collaboration Group of Department of Science and Technology of Guangdong Province and Health Commission of Guangdong Province for chloroquine in the treatment of novel coronavirus pneumonia. [Expert consensus on chloroquine phosphate for the treatment of novel coronavirus pneumonia]. Zhonghua Jie He He Hu Xi Za Zhi. 2020;43(3):185-8. Chinese.) However, evidence from multiple randomized and controlled studies, including the RECOVERY trial, showed no benefits (duration of mechanical ventilation or mortality) of antimalarials with or without azithromycin.(211211 WHO Solidarity Trial Consortium, Pan H, Peto R, Henao-Restrepo AM, Preziosi MP, Sathiyamoorthy V, et al. Repurposed Antiviral Drugs for Covid-19 - Interim WHO Solidarity Trial Results. N Engl J Med. 2021;384(6):497-511.,231231 Self WH, Semler MW, Leither LM, Casey JD, Angus DC, Brower RG, et al. Effect of Hydroxychloroquine on clinical status at 14 days in hospitalized patients with COVID-19: a randomized clinical trial. JAMA. 2020;324(21):2165-76.

232 RECOVERY Collaborative Group, Horby P, Mafham M, Linsell L, Bell JL, Staplin N, et al. Effect of hydroxychloroquine in hospitalized patients with Covid-19. N Engl J Med. 2020;383(21):2030-40.

233 Ulrich RJ, Troxel AB, Carmody E, Eapen J, Backer M, DeHovitz JA, et al. Treating COVID-19 with hydroxychloroquine (TEACH): a multicenter, double-blind randomized controlled trial in hospitalized patients. Open Forum Infect Dis. 2020;7(10):ofaa446.

234 Lyngbakken MN, Berdal JE, Eskesen A, Kvale D, Olsen IC, Rueegg CS, et al. A pragmatic randomized controlled trial reports lack of efficacy of hydroxychloroquine on coronavirus disease 2019 viral kinetics. Nat Commun. 2020;11(1):5284.

235 Abd-Elsalam S, Esmail ES, Khalaf M, Abdo EF, Medhat MA, Abd El Ghafar MS, et al. Hydroxychloroquine in the treatment of COVID-19: a multicenter randomized controlled study. Am J Trop Med Hyg. 2020;103(4):1635-9.

236 Tang W, Cao Z, Han M, Wang Z, Chen J, Sun W, et al. Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial. BMJ. 2020;369:m1849.

237 Chen L, Zhang ZY, Fu JG, Feng ZP, Zhang SZ, Han QY, et al. Efficacy and safety of chloroquine or hydroxychloroquine in moderate type of COVID-19: a prospective open-label randomized controlled study. medRxiv. 2020:2020.06.19.20136093.

238 Chen Z, Hu J, Zhang Z, Jiang S, Han S, Yan D, et al. Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial. medRxiv. 2020:2020.03.22.20040758.

239 Chen J, Liu D, Liu L, Liu P, Xu Q, Xia L, et al. [A pilot study of hydroxychloroquine in treatment of patients with moderate COVID-19]. Zhejiang Da Xue Xue Bao Yi Xue Ban. 2020;49(2):215-9. Chinese.

240 Chen CP, Lin YC, Chen TC, Tseng TY, Wong HL, Kuo CY, Lin WP, Huang SR, Wang WY, Liao JH, Liao CS, Hung YP, Lin TH, Chang TY, Hsiao CF, Huang YW, Chung WS, Cheng CY, Cheng SH; Taiwan HCQ Study Group. A multicenter, randomized, open-label, controlled trial to evaluate the efficacy and tolerability of hydroxychloroquine and a retrospective study in adult patients with mild to moderate coronavirus disease 2019 (COVID-19). PLoS One. 2020;15(12):e0242763.

241 Dubée V, Roy PM, Vielle B, Parot-Schinkel E, Blanchet O, Darsonval A, et al. Hydroxychloroquine in mild-to-moderate coronavirus disease 2019: a placebo-controlled double blind trial. Clin Microbiol Infect. 2021;27(8):1124-30.

242 Cavalcanti AB, Zampieri FG, Rosa RG, Azevedo LC, Veiga VC, Avezum A, Damiani LP, Marcadenti A, Kawano-Dourado L, Lisboa T, Junqueira DL, de Barros E Silva PG, Tramujas L, Abreu-Silva EO, Laranjeira LN, Soares AT, Echenique LS, Pereira AJ, Freitas FG, Gebara OC, Dantas VC, Furtado RH, Milan EP, Golin NA, Cardoso FF, Maia IS, Hoffmann Filho CR, Kormann AP, Amazonas RB, Bocchi de Oliveira MF, Serpa-Neto A, Falavigna M, Lopes RD, Machado FR, Berwanger O; Coalition Covid-19 Brazil I Investigators. Hydroxychloroquine with or without azithromycin in mild-to-moderate Covid-19. N Engl J Med. 2020;383(21):2041-52.

243 Skipper CP, Pastick KA, Engen NW, Bangdiwala AS, Abassi M, Lofgren SM, et al. Hydroxychloroquine in nonhospitalized adults with early COVID-19 : a randomized trial. Ann Intern Med. 2020;173(8):623-31.
-244244 Mitja O, Corbacho-Monné M, Ubals M, Tebe C, Peñafiel J, Tobias A, Ballana E, Alemany A, Riera-Martí N, Pérez CA, Suñer C, Laporte P, Admella P, Mitjà J, Clua M, Bertran L, Sarquella M, Gavilán S, Ara J, Argimon JM, Casabona J, Cuatrecasas G, Cañadas P, Elizalde-Torrent A, Fabregat R, Farré M, Forcada A, Flores-Mateo G, Muntada E, Nadal N, Narejos S, Gil-Ortega AN, Prat N, Puig J, Quiñones C, Reyes-Ureña J, Ramírez-Viaplana F, Ruiz L, Riveira-Muñoz E, Sierra A, Velasco C, Vivanco-Hidalgo RM, Sentís A, G-Beiras C, Clotet B, Vall-Mayans M; BCN PEP-CoV-2 RESEARCH GROUP. Hydroxychloroquine for early treatment of adults with mild Covid-19: a randomized-controlled trial. Clin Infect Dis. 2020:ciaa1009.) The lack of clinical efficacy associated with the potential risk of cardiac complications (dysrhythmias, most frequently associated with QTc prolongation) led to the discontinuation by the WHO of the hydroxychloroquine arm of SOLIDARITY.(211211 WHO Solidarity Trial Consortium, Pan H, Peto R, Henao-Restrepo AM, Preziosi MP, Sathiyamoorthy V, et al. Repurposed Antiviral Drugs for Covid-19 - Interim WHO Solidarity Trial Results. N Engl J Med. 2021;384(6):497-511.) A recent meta-analysis associated the use of these drugs in the context of COVID-19 with increased mortality.(245245 Axfors C, Schmitt AM, Janiaud P, Van’t Hooft J, Abd-Elsalam S, Abdo EF, et al. Mortality outcomes with hydroxychloroquine and chloroquine in COVID-19 from an international collaborative meta-analysis of randomized trials. Nat Commun. 2021;12(1):2349.) In Portugal, INFARMED and DGS recommended the suspension of the use of hydroxychloroquine/chloroquine in patients infected with SARS-CoV-2.(246246 República Portuguesa. Serviço Nacional de Saúde. Direção Geral da Saúde. Infarmed. Comunicado de imprensa. Infarmed e DGS recomendam suspensão do uso de hidroxicloroquina em doentes com COVID-19. 28 maio 2020. Disponível em https://www.infarmed.pt/web/infarmed/infarmed/-/journal_content/56/15786/3701591
https://www.infarmed.pt/web/infarmed/inf...
)

Ivermectin is a semisynthetic drug used as an anthelmintic agent. The drug showed in vitro efficacy in the inhibition of SARS-CoV-2.(247247 Caly L, Druce JD, Catton MG, Jans DA, Wagstaff KM. The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antiviral Res. 2020;178:104787.) The evidence available for its clinical use in SARS-CoV-2 infection comes from a meta-analysis of trials with important methodological limitations(248248 Hill A, Abdulamir A, Ahmed S, Asghar A, Babalola OE, Basri R, et al. Meta-analysis of randomized trials of ivermectin to treat SARS-CoV-2 infection. Research Square (preprint). 2021;doi: 10.21202/rs.3.rs-148845/v1.
https://doi.org/10.21202/rs.3.rs-148845/...
) and a randomized controlled trial that indicated no benefit for its use.(249249 López-Medina E, López P, Hurtado IC, Dávalos DM, Ramirez O, Martínez E, et al. Effect of ivermectin on time to resolution of symptoms among adults with mild COVID-19: a randomized clinical trial. JAMA. 2021;325(14):1426-35.)

IMMUNOMODULATORS

Corticosteroids and interleukin-6 receptor inhibitors

It is recommended that patients with COVID-19 who do not require oxygen therapy or ventilatory support should not be treated with corticosteroids unless indicated for other reasons (for example, previous therapy, acute asthma, exacerbation of chronic obstructive pulmonary disease or septic shock without response to vasopressors).

It is recommended that patients with COVID-19 who require oxygen therapy or ventilatory support (invasive mechanical ventilation, noninvasive mechanical ventilation or high-flow oxygen therapy by nasal cannula with a flow greater than 30 L/minute and FiO2 > 0.40) and are beyond 7 days since the onset of symptoms should be treated with dexamethasone 6 mg per day intravenously or enterically for up to 10 days.

It is suggested that for previous indications, if dexamethasone is not available, hydrocortisone (50 mg every 6 hours, intravenously), methylprednisolone (32mg daily, intravenously) or prednisolone (40 mg daily, intravenously or enterally) should be administered.

It is suggested that patients with COVID-19 with C-reactive protein ≥ 7.5mg/dL, ventilatory support (invasive mechanical ventilation, noninvasive mechanical ventilation or high-flow oxygen therapy by nasal cannula with a flow greater than 30L/minute and FiO2 > 0.40) and clinical deterioration (escalation of ventilatory support and/or worsening of PaO2/FiO2), despite corticosteroid therapy, should be treated with 8mg/kg tocilizumab (up to a maximum of 800mg) intravenously (taken only) in the first 24 hours after the start of support (must be < 14 days of hospitalization), once contraindications and other causes of deterioration of respiratory failure are excluded (for example, bacterial infection, pulmonary thromboembolism, and heart failure).

It is suggested that in for previous indications, if tocilizumab is not available, sarilumab (400mg) should be administered intravenously (single dose).

It is suggested that patients with COVID-19 receiving ventilatory support (invasive mechanical ventilation, noninvasive mechanical ventilation or high-flow oxygen therapy by nasal cannula with a flow greater than 30 L/minute and FiO2 > 0.40) with moderate to severe ARDS (PaO2/FiO2 < 200) and contraindications for tocilizumab should be considered for other corticotherapy protocols.

The current view on the use of corticosteroid therapy and other immunomodulators in critically ill patients with COVID-19 is summarized in figure 4 (Appendix 1).

Corticosteroids have antiinflammatory and antifibrotic properties that potentially accelerate the resolution of pulmonary and systemic inflammatory manifestations.(250250 Villar J, Ferrando C, Martínez D, Ambrós A, Muñoz T, Soler JA, Aguilar G, Alba F, González-Higueras E, Conesa LA, Martín-Rodríguez C, Díaz-Domínguez FJ, Serna-Grande P, Rivas R, Ferreres J, Belda J, Capilla L, Tallet A, Añón JM, Fernández RL, González-Martín JM; dexamethasone in ARDS network. Dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial. Lancet Respir Med. 2020;8(3):267-76.) This effect is beneficial in some patients with pulmonary infections (for example, pneumonia to Pneumocystis jirovecii)(251251 Bozzette SA, Sattler FR, Chiu J, Wu AW, Gluckstein D, Kemper C, et al. A controlled trial of early adjunctive treatment with corticosteroids for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. California Collaborative Treatment Group. N Engl J Med. 1990;323(21):1451-7.) but deleterious or neutral in others (for example, flu).(252252 Rodrigo C, Leonardi-Bee J, Nguyen-Van-Tam J, Lim WS. Corticosteroids as adjunctive therapy in the treatment of influenza. Cochrane Database Syst Rev. 2016;3:CD010406.) There is indirect evidence(250250 Villar J, Ferrando C, Martínez D, Ambrós A, Muñoz T, Soler JA, Aguilar G, Alba F, González-Higueras E, Conesa LA, Martín-Rodríguez C, Díaz-Domínguez FJ, Serna-Grande P, Rivas R, Ferreres J, Belda J, Capilla L, Tallet A, Añón JM, Fernández RL, González-Martín JM; dexamethasone in ARDS network. Dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial. Lancet Respir Med. 2020;8(3):267-76.,253253 Lewis SR, Pritchard MW, Thomas CM, Smith AF. Pharmacological agents for adults with acute respiratory distress syndrome. Cochrane Database Syst Rev. 2019;7(7):CD004477.) of the benefits (mortality and duration of mechanical ventilation) of corticosteroids in patients with ARDS (unrelated to COVID-19). A recent systematic review suggests - with a very low level of evidence - that corticosteroids can reduce mortality at 3 months and increase ventilation-free days; however, there is no evidence of an effect on mortality beyond 3 months.(253253 Lewis SR, Pritchard MW, Thomas CM, Smith AF. Pharmacological agents for adults with acute respiratory distress syndrome. Cochrane Database Syst Rev. 2019;7(7):CD004477.)

Initial studies pointing to prolonged viral shedding in patients infected with SARS-CoV-1 and MERS-CoV(214214 Arabi YM, Mandourah Y, Al-Hameed F, Sindi AA, Almekhlafi GA, Hussein MA, Jose J, Pinto R, Al-Omari A, Kharaba A, Almotairi A, Al Khatib K, Alraddadi B, Shalhoub S, Abdulmomen A, Qushmaq I, Mady A, Solaiman O, Al-Aithan AM, Al-Raddadi R, Ragab A, Balkhy HH, Al Harthy A, Deeb AM, Al Mutairi H, Al-Dawood A, Merson L, Hayden FG, Fowler RA; Saudi Critical Care Trial Group. Corticosteroid Therapy for Critically Ill Patients with Middle East Respiratory Syndrome. Am J Respir Crit Care Med. 2018;197(6):757-67.,254254 Russell CD, Millar JE, Baillie JK. Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury. Lancet. 2020;395(10223):473-5.) were questioned after the publication of several studies demonstrating that corticotherapy not only does not delay viral clearance(255255 Fang X, Mei Q, Yang T, Li L, Wang Y, Tong F, et al. Low-dose corticosteroid therapy does not delay viral clearance in patients with COVID-19. J Infect. 2020;81(1):147-78.) but is also associated with improved clinical outcomes in patients with epidemic coronavirus infections, including SARS-CoV-2(4545 Wu C, Chen X, Cai Y, Xia J, Zhou X, Xu S, et al. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China. JAMA Intern Med. 2020;180(7):934-43.,256256 Wang Y, Jiang W, He Q, Wang C, Liu B, Zhou P, et al. Early, low-dose and short-term application of corticosteroid treatment in patients with severe COVID-19 pneumonia: single-center experience from Wuhan, China. medRxiv. 2020:2020.03.06.20032342.,257257 Lee KH, Yoon S, Jeong GH, Kim JY, Han YJ, Hong SH, et al. Efficacy of corticosteroids in patients with SARS, MERS and COVID-19: a systematic review and meta-analysis. J Clin Med. 2020;9(8):2392.) SARS-CoV-2 seems to have an earlier peak of viral replication than other viruses that cause respiratory disease, namely, SARS-CoV-1.(255255 Fang X, Mei Q, Yang T, Li L, Wang Y, Tong F, et al. Low-dose corticosteroid therapy does not delay viral clearance in patients with COVID-19. J Infect. 2020;81(1):147-78.)

In patients with COVID-19, the results of the corticosteroid arm of the RECOVERY trial indicate that, compared to placebo, the administration of dexamethasone (6mg per day, intravenously or enterically, for up to 10 days) improved mortality at 28 days in a subgroup of patients who required oxygen therapy, ventilatory support or extracorporeal support.(258258 RECOVERY Collaborative Group, Horby P, Lim WS, Emberson JR, Mafham M, Bell JL, et al. Dexamethasone in hospitalized patients with Covid-19. N Engl J Med. 2021;384(8):693-704.) In this study, the benefit was more evident in patients treated seven or more days after the onset of symptoms. In addition, a trend towards an increase in mortality was observed in patients who did not require oxygen therapy or other forms of support who received corticosteroids. These two observations support the approach that corticosteroids are indicated only when the disease is in the hyperinflammatory phase; before that, its use - unless indicated for other reasons, such as previous therapy, acute asthma, exacerbation of lung disease, obstructive or septic shock, and septic shock without response to vasopressors (operational definition, noradrenaline > 0.25µg/kg/minute or adrenaline > 0.25µg/kg/minute to maintain MAP within the target values - is potentially deleterious.

The use of dexamethasone has advantages over other corticosteroids in patients with COVID-19. It has a long half-life (up to 48 hours), allowing self-weaning; low mineralocorticoid activity, which limits hypernatremia and water retention; and good penetration into the lungs and central nervous system.(250250 Villar J, Ferrando C, Martínez D, Ambrós A, Muñoz T, Soler JA, Aguilar G, Alba F, González-Higueras E, Conesa LA, Martín-Rodríguez C, Díaz-Domínguez FJ, Serna-Grande P, Rivas R, Ferreres J, Belda J, Capilla L, Tallet A, Añón JM, Fernández RL, González-Martín JM; dexamethasone in ARDS network. Dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial. Lancet Respir Med. 2020;8(3):267-76.) Other corticosteroids, in various formulations and doses and for variable durations, were tested in patients with COVID-19 in several smaller randomized controlled studies.(259259 Jeronimo CM, Farias ME, Val FF, Sampaio VS, Alexandre MA, Melo GC, Safe IP, Borba MG, Netto RL, Maciel AB, Neto JR, Oliveira LB, Figueiredo EF, Oliveira Dinelly KM, de Almeida Rodrigues MG, Brito M, Mourão MP, Pivoto João GA, Hajjar LA, Bassat Q, Romero GA, Naveca FG, Vasconcelos HL, de Araújo Tavares M, Brito-Sousa JD, Costa FT, Nogueira ML, Baía-da-Silva DC, Xavier MS, Monteiro WM, Lacerda MV; Metcovid Team. Methylprednisolone as adjunctive therapy for patients hospitalized with coronavirus 2019 (COVID-19; Metcovid): a randomised, double-blind, phase IIb, placebo-controlled trial. Clin Infect Dis. 2021;72(9):e373-81.

260 Tomazini BM, Maia IS, Cavalcanti AB, Berwanger O, Rosa RG, Veiga VC, Avezum A, Lopes RD, Bueno FR, Silva MV, Baldassare FP, Costa EL, Moura RA, Honorato MO, Costa AN, Damiani LP, Lisboa T, Kawano-Dourado L, Zampieri FG, Olivato GB, Righy C, Amendola CP, Roepke RM, Freitas DH, Forte DN, Freitas FG, Fernandes CC, Melro LM, Junior GF, Morais DC, Zung S, Machado FR, Azevedo LC; COALITION COVID-19 Brazil III Investigators. Effect of dexamethasone on days alive and ventilator-free in patients with moderate or severe acute respiratory distress syndrome and COVID-19: the CoDEX randomized clinical trial. JAMA. 2020;324(13):1307-16.

261 Dequin PF, Heming N, Meziani F, Planteféve G, Voiriot G, Badié J, François B, Aubron C, Ricard JD, Ehrmann S, Jouan Y, Guillon A, Leclerc M, Coffre C, Bourgoin H, Lengellé C, Caille-Fénérol C, Tavernier E, Zohar S, Giraudeau B, Annane D, Le Gouge A; CAPE COVID Trial Group and the CRICS-TriGGERSep Network. Effect of hydrocortisone on 21-day mortality or respiratory support among critically ill patients with COVID-19: a randomized clinical trial. JAMA. 2020;324(13):1298-306.

262 Angus DC, Derde L, Al-Beidh F, Annane D, Arabi Y, Beane A, et al. Effect of hydrocortisone on mortality and organ support in patients with severe COVID-19: the REMAP-CAP COVID-19 corticosteroid domain randomized clinical trial. JAMA. 2020;324(13):1317-29.
-263263 WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group, Sterne JA, Murthy S, Diaz JV, Slutsky AS, Villar J, et al. Association between administration of systemic corticosteroids and mortality among critically ill patients with COVID-19: a meta-analysis. JAMA. 2020;324(13):1330-41.) Many of these studies were discontinued early due to insufficient recruitment after the results of the RECOVERY trial were made available. Given that the sample size of many of these trials was insufficient to evaluate efficacy, the evidence to support the use of other corticosteroids is not as robust as that existing for dexamethasone.(263263 WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group, Sterne JA, Murthy S, Diaz JV, Slutsky AS, Villar J, et al. Association between administration of systemic corticosteroids and mortality among critically ill patients with COVID-19: a meta-analysis. JAMA. 2020;324(13):1330-41.)

Tocilizumab is a recombinant humanized monoclonal antibody that blocks the IL-6 receptor and is used in the treatment of rheumatoid arthritis and cytokine release syndrome after therapy with T lymphocytes.(264264 Cortegiani A, Ippolito M, Greco M, Granone V, Protti A, Gregoretti C, et al. Rationale and evidence on the use of tocilizumab in COVID-19: a systematic review. Pulmonology. 2021;27(1):52-66.) Initial studies with tocilizumab did not demonstrate efficacy(265265 Salvarani C, Dolci G, Massari M, Merlo DF, Cavuto S, Savoldi L, Bruzzi P, Boni F, Braglia L, Turrà C, Ballerini PF, Sciascia R, Zammarchi L, Para O, Scotton PG, Inojosa WO, Ravagnani V, Salerno ND, Sainaghi PP, Brignone A, Codeluppi M, Teopompi E, Milesi M, Bertomoro P, Claudio N, Salio M, Falcone M, Cenderello G, Donghi L, Del Bono V, Colombelli PL, Angheben A, Passaro A, Secondo G, Pascale R, Piazza I, Facciolongo N, Costantini M; RCT-TCZ-COVID-19 Study Group. Effect of tocilizumab vs standard care on clinical worsening in patients hospitalized with COVID-19 pneumonia: a randomized clinical trial. JAMA Intern Med. 2021;181(1):24-31.,266266 Stone JH, Frigault MJ, Serling-Boyd NJ, Fernandes AD, Harvey L, Foulkes AS, Horick NK, Healy BC, Shah R, Bensaci AM, Woolley AE, Nikiforow S, Lin N, Sagar M, Schrager H, Huckins DS, Axelrod M, Pincus MD, Fleisher J, Sacks CA, Dougan M, North CM, Halvorsen YD, Thurber TK, Dagher Z, Scherer A, Wallwork RS, Kim AY, Schoenfeld S, Sen P, Neilan TG, Perugino CA, Unizony SH, Collier DS, Matza MA, Yinh JM, Bowman KA, Meyerowitz E, Zafar A, Drobni ZD, Bolster MB, Kohler M, D’Silva KM, Dau J, Lockwood MM, Cubbison C, Weber BN, Mansour MK; BACC Bay Tocilizumab Trial Investigators. Efficacy of tocilizumab in patients hospitalized with Covid-19. N Engl J Med. 2020;383(24):2333-44.) but were limited by low statistical power associated with heterogeneous study populations, with varying degrees of disease severity and, in particular, low use of corticosteroids (4% to 10%). In all these studies, the use of tocilizumab was considered safe, and although neutropenia occurred, there was not an increase in the rate of infection with clinical expression. Subsequent studies have demonstrated safety and efficacy. The COVACTA (A Study to Evaluate the Safety and Efficacy of Tocilizumab in Patients with Severe COVID-19 Pneumonia) study demonstrated a reduction in the incidence or duration of hospitalization and admission to intensive care,(267267 Rosas IO, Brau N, Waters M, Go RC, Hunter BD, Bhagani S, et al. Tocilizumab in hospitalized patients with severe Covid-19 pneumonia. N Engl J Med. 2021;384(16):1503-16.) and the EMPACTA (Evaluating Minority Patients With Actemra) study showed a reduced incidence of the need for mechanical ventilation and of death.(268268 Salama C, Han J, Yau L, Reiss WG, Kramer B, Neidhart JD, et al. Tocilizumab in patients hospitalized with Covid-19 pneumonia. N Engl J Med. 2021;384(1):20-30.) Most patients included in COVACTA were receiving ventilatory support and, in EMPACTA, receiving corticotherapy, suggesting that these factors alone or in combination may contribute to the differences in the therapeutic effect of tocilizumab.

The tocilizumab arms of the REMAP-CAP (Randomized Embedding Multifactorial Adaptive Platform for Community-acquired Pneumonia) trial(269269 REMAP-CAP Investigators, Gordon AC, Mouncey PR, Al-Beidh F, Rowan KM, Nichol AD, et al. Interleukin-6 receptor antagonists in critically ill patients with Covid-19. N Engl J Med. 2021;384(16):1491-502.) and RECOVERY(270270 RECOVERY Collaborative Group. Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. Lancet. 2021;397(10285):1637-45.) demonstrated, in selected populations of patients with COVID-19, a benefit of the drug with regard to mortality. The tocilizumab arm of REMAP-CAP recruited exclusively critically ill patients with COVID-19, requiring ventilatory support, in the first 24 hours of admission to intensive care and in the first days of hospitalization, with the majority (> 90%) undergoing concomitant corticosteroid therapy. REMAP-CAP showed a reduction in mortality as well as in the length of hospital stay and an increase in the number of days without organ support.(269269 REMAP-CAP Investigators, Gordon AC, Mouncey PR, Al-Beidh F, Rowan KM, Nichol AD, et al. Interleukin-6 receptor antagonists in critically ill patients with Covid-19. N Engl J Med. 2021;384(16):1491-502.) In the RECOVERY trial, a subgroup of patients hospitalized with COVID-19 with hypoxemia (SpO2 < 92% or need for supplemental oxygen) and a C-reactive protein concentration ≥ 7.5mg/dL was randomized for the administration of tocilizumab (versus placebo), with the majority (> 80%) receiving concomitant corticosteroid therapy and more than half receiving ventilatory support. RECOVERY showed a reduction in mortality as well as in the length of hospital stay, but this mortality benefit was restricted to patients receiving concomitant corticosteroid therapy.(270270 RECOVERY Collaborative Group. Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. Lancet. 2021;397(10285):1637-45.)

Some patients who receive conventional oxygen therapy, i.e., without the need for ventilatory support, with significant systemic inflammation and progressive hypoxemia, may benefit from the addition of tocilizumab to standard therapy, but there is currently insufficient evidence to define this subgroup of patients. Thus, considering the scarcity of IL-6 receptor blockers, this therapy should be prioritized for patients with greater need and greater probability of benefiting from the therapy.

There are different dosing schedules recommended for COVID-19, with the greatest concensus for 8mg/kg body weight (up to a maximum dose of 800mg) intravenously (slow perfusion). Some protocols recommend repeated administration after 12 hours if the response is incomplete (a maximum of two doses).

The use of tocilizumab should be avoided if there is significant immunosuppression, particularly in patients using other immunomodulatory biological drugs; in patients with alanine transaminase > 5 times the upper limit of normal; in patients with a high risk of gastrointestinal perforation (for example, diverticulitis); in patients with uncontrolled bacterial, fungal or viral infection (non-SARS-CoV-2); and in patients with an absolute neutrophil count < 500 cells/µL or platelet count < 50,000 cells/µL.

C-reactive protein is directly inhibited by IL-6 blockade and thus cannot be used as a marker for suspected concomitant infection or for monitoring the response to antimicrobial therapy; instead, procalcitonin should be used. The half-life of the drug is long, and its effect lasts, in most circumstances, at least three weeks.(264264 Cortegiani A, Ippolito M, Greco M, Granone V, Protti A, Gregoretti C, et al. Rationale and evidence on the use of tocilizumab in COVID-19: a systematic review. Pulmonology. 2021;27(1):52-66.)

Sarilumab, a direct inhibitor of IL-6, is a human monoclonal antibody used in the treatment of rheumatoid arthritis. The evidence regarding the efficacy of sarilumab in critically ill patients with COVID-19 comes from the REMAP-CAP trial, and the data are less robust than those for tocilizumab (less than 50 patients were included in the study),(269269 REMAP-CAP Investigators, Gordon AC, Mouncey PR, Al-Beidh F, Rowan KM, Nichol AD, et al. Interleukin-6 receptor antagonists in critically ill patients with Covid-19. N Engl J Med. 2021;384(16):1491-502.) making it an option only when the former is unavailable. The recommended dose regimen is 400mg intravenously (single dose).

The Surviving Sepsis Campaign guidelines for COVID-19(9898 Alhazzani W, Moller MH, Arabi YM, Loeb M, Gong MN, Fan E, et al. Surviving Sepsis Campaign: guidelines on the management of critically ill adults with Coronavirus Disease 2019 (COVID-19). Intensive Care Med. 2020;46(5):854-87.) were updated based on a recent Cochrane review(253253 Lewis SR, Pritchard MW, Thomas CM, Smith AF. Pharmacological agents for adults with acute respiratory distress syndrome. Cochrane Database Syst Rev. 2019;7(7):CD004477.) and the DEXA-ARDS study,(250250 Villar J, Ferrando C, Martínez D, Ambrós A, Muñoz T, Soler JA, Aguilar G, Alba F, González-Higueras E, Conesa LA, Martín-Rodríguez C, Díaz-Domínguez FJ, Serna-Grande P, Rivas R, Ferreres J, Belda J, Capilla L, Tallet A, Añón JM, Fernández RL, González-Martín JM; dexamethasone in ARDS network. Dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial. Lancet Respir Med. 2020;8(3):267-76.) which showed reductions in both mortality and duration of mechanical ventilation in patients with moderate to severe ARDS; however, these results should be applied with caution to COVID-19 because they include patients with nonviral ARDS. Other corticosteroid protocols (Table 6-Appendix 1) have a lower degree of evidence with regard to COVID-19, but sarilumab should only be considered for patients with severe forms of respiratory failure in the context of SARS-CoV-2 infection when there are formal contraindications to the previously described approaches and when the risk-benefit ratio may be more favorable.

Other immunomodulators

In critically ill patients infected with SARS-CoV-2, the nonroutine use of other antivirals outside the scope of clinical use protocols or clinical trials is recommended.

Anakinra is a recombinant protein that acts as an IL-1 receptor antagonist, is used in the treatment of rheumatoid arthritis and autoinflammatory syndromes and is considered one of the safest immunomodulators (rarely associated with opportunistic infections).(271271 Cavalli G, Dinarello CA. Anakinra Therapy for non-cancer inflammatory diseases. Front Pharmacol. 2018;9:1157.) In two observational studies in patients with severe COVID-19 (under NIV with PaO2/FiO2 < 200) in the hyperinflammatory phase (C-reactive protein > 10mg/dL and/or ferritin > 900ng/mL, after exclusion of bacterial infection), anakinra therapy with a high-dose protocol (5mg/kg twice a day, intravenously) was associated with sustained respiratory improvement and a reduction in admission to intensive care.(272272 Cavalli G, De Luca G, Campochiaro C, Della-Torre E, Ripa M, Canetti D, et al. Interleukin-1 blockade with high-dose anakinra in patients with COVID-19, acute respiratory distress syndrome, and hyperinflammation: a retrospective cohort study. Lancet Rheumatol. 2020;2(6):e325-31.,273273 Huet T, Beaussier H, Voisin O, Jouveshomme S, Dauriat G, Lazareth I, et al. Anakinra for severe forms of COVID-19: a cohort study. Lancet Rheumatol. 2020;2(7):e393-400.) The CORIMUNO-ANA-1 randomized trial, which included patients with mild to moderate COVID-19, concluded that anakinra can reduce mortality and the need for invasive mechanical ventilation (or ECLS) without significant adverse effects. However, the degree of evidence is low, given the lack of blinding and the wide confidence intervals for mortality and other endpoints.(274274 CORIMUNO-19 Collaborative group. Effect of anakinra versus usual care in adults in hospital with COVID-19 and mild-to-moderate pneumonia (CORIMUNO-ANA-1): a randomised controlled trial. Lancet Respir Med. 2021;9(3):295-304.)

Baricitinib is a reversible JAK (Janus kinase) 1 inhibitor approved for the treatment of rheumatoid arthritis and, in the context of COVID-19, caused a reduction in all-cause mortality and time to symptom resolution (associated with a better adverse effects profile), especially in patients undergoing NIV and HFNC therapy.(275275 Kalil AC, Patterson TF, Mehta AK, Tomashek KM, Wolfe CR, Ghazaryan V, Marconi VC, Ruiz-Palacios GM, Hsieh L, Kline S, Tapson V, Iovine NM, Jain MK, Sweeney DA, El Sahly HM, Branche AR, Regalado Pineda J, Lye DC, Sandkovsky U, Luetkemeyer AF, Cohen SH, Finberg RW, Jackson PE, Taiwo B, Paules CI, Arguinchona H, Erdmann N, Ahuja N, Frank M, Oh MD, Kim ES, Tan SY, Mularski RA, Nielsen H, Ponce PO, Taylor BS, Larson L, Rouphael NG, Saklawi Y, Cantos VD, Ko ER, Engemann JJ, Amin AN, Watanabe M, Billings J, Elie MC, Davey RT, Burgess TH, Ferreira J, Green M, Makowski M, Cardoso A, de Bono S, Bonnett T, Proschan M, Deye GA, Dempsey W, Nayak SU, Dodd LE, Beigel JH; ACTT-2 Study Group Members. Baricitinib plus remdesivir for hospitalized adults with Covid-19. N Engl J Med. 2021;384(9):795-807.) There are not yet enough data to validate this therapy in critically ill patients.

Colchicine is a drug that inhibits the polymerization of mitotic spindle proteins (i.e., stops cell division in metaphase) and is used as an antiinflammatory agent in the treatment of gout, pericarditis, inflammatory arthritis, familial Mediterranean fever and Behçet’s disease. The drug was studied in different clinical trials that cumulatively did not demonstrate efficacy with regard to mortality and other relevant endpoints but in which there was an increased incidence of adverse events, especially gastrointestinal events.(276276 Deftereos SG, Giannopoulos G, Vrachatis DA, Siasos GD, Giotaki SG, Gargalianos P, Metallidis S, Sianos G, Baltagiannis S, Panagopoulos P, Dolianitis K, Randou E, Syrigos K, Kotanidou A, Koulouris NG, Milionis H, Sipsas N, Gogos C, Tsoukalas G, Olympios CD, Tsagalou E, Migdalis I, Gerakari S, Angelidis C, Alexopoulos D, Davlouros P, Hahalis G, Kanonidis I, Katritsis D, Kolettis T, Manolis AS, Michalis L, Naka KK, Pyrgakis VN, Toutouzas KP, Triposkiadis F, Tsioufis K, Vavouranakis E, Martinèz-Dolz L, Reimers B, Stefanini GG, Cleman M, Goudevenos J, Tsiodras S, Tousoulis D, Iliodromitis E, Mehran R, Dangas G, Stefanadis C; GRECCO-19 investigators. Effect of colchicine vs standard care on cardiac and inflammatory biomarkers and clinical outcomes in patients hospitalized with coronavirus disease 2019: the GRECCO-19 randomized clinical trial. JAMA Netw Open. 2020;3(6):e2013136.

277 Lopes MI, Bonjorno LP, Giannini MC, Amaral NB, Menezes PI, Dib SM, et al. Beneficial effects of colchicine for moderate to severe COVID-19: a randomised, double-blinded, placebo-controlled clinical trial. RMD Open. 2021;7(1):e001455.
-278278 Tardif JC, Bouabdallaoui N, L’Allier PL, Gaudet D, Shah B, Pillinger MH, et al. Efficacy of colchicine in non-hospitalized patients with COVID-19. medRxiv. 2021:2021.01.26.21250494.)

Interferons (IFNs), of which there are three classes, type I (IFN-α and IFN-β), type II (IFN-) and type III, are a group of cytokines capable of inducing an antiviral-resistant state in noninfected tissue cells,(279279 Samuel CE. Antiviral actions of interferons. Clin Microbiol Rev. 2001;14(4):778-809, table of contents.) and SARS-CoV-2 is known to suppress the production of type I IFNs.(280280 Zhang Q, Bastard P, Liu Z, Le Pen J, Moncada-Velez M, Chen J, et al. Inborn errors of type I IFN immunity in patients with life-threatening COVID-19. Science. 2020;370(6515):eabd4570.) Although some studies, with obvious methodological limitations, have demonstrated the efficacy of IFN-β,(281281 Davoudi-Monfared E, Rahmani H, Khalili H, Hajiabdolbaghi M, Salehi M, Abbasian L, et al. A randomized clinical trial of the efficacy and safety of interferon beta-1a in treatment of severe COVID-19. Antimicrob Agents Chemother. 2020;64(9):e01061-20.) the results were not confirmed by the provisional SOLIDARITY results.(211211 WHO Solidarity Trial Consortium, Pan H, Peto R, Henao-Restrepo AM, Preziosi MP, Sathiyamoorthy V, et al. Repurposed Antiviral Drugs for Covid-19 - Interim WHO Solidarity Trial Results. N Engl J Med. 2021;384(6):497-511.) Inhaled IFN-β, an experimental formulation of the drug administered by nebulization, was evaluated in a randomized study in noncritical patients and was associated with a lower risk of progression to severe disease but without a significant impact on mortality.(282282 Monk PD, Marsden RJ, Tear VJ, Brookes J, Batten TN, Mankowski M, Gabbay FJ, Davies DE, Holgate ST, Ho LP, Clark T, Djukanovic R, Wilkinson TMA; Inhaled Interferon Beta COVID-19 Study Group. Safety and efficacy of inhaled nebulised interferon beta-1a (SNG001) for treatment of SARS-CoV-2 infection: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Respir Med. 2021;9(2):196-206.)

Anticoagulation

It is recommended that critically ill patients with COVID-19 with confirmation (or high clinical suspicion) of thromboembolic disease receive therapeutic strategies, including reperfusion (pharmacological and/or mechanical) and/or therapeutic anticoagulation regimens following standard institutional protocols.

It is recommended that critically ill patients with COVID-19, previously under a therapeutic anticoagulation regimen at home, maintain a therapeutic anticoagulation regimen. A transition from parenteral anticoagulant agents (for example, low molecular weight heparin or unfractionated heparin) to oral anticoagulants (for example, dicoumarin or new oral anticoagulants) is suggested.

It is recommended that critically ill patients with COVID-19 without evidence of thromboembolic disease should be medicated with a prophylactic anticoagulation regimen (standard or adjusted) in the absence of contraindications.

It is recommended that critically ill patients with COVID-19 receiving extracorporeal organ support (including veno-venous or veno-arterial extracorporeal life support and renal support therapy) receive antithrombotic therapy following standard institutional protocols.

Critically ill patients with confirmed or high clinical suspicion of COVID-19 (for example, ventilatory deterioration and/or sudden hemodynamic instability, especially in the presence of right ventricular dysfunction, in the context of pulmonary thromboembolism) and thromboembolic disease should receive therapeutic strategies that include reperfusion (pharmacological and/or mechanical) and/or therapeutic anticoagulation regimens following standard institutional protocols.(283283 Konstantinides SV, Meyer G, Becattini C, Bueno H, Geersing GJ, Harjola VP, Huisman MV, Humbert M, Jennings CS, Jiménez D, Kucher N, Lang IM, Lankeit M, Lorusso R, Mazzolai L, Meneveau N, Áinle FN, Prandoni P, Pruszczyk P, Righini M, Torbicki A, Van Belle E, Zamorano JL; The Task Force for the diagnosis and management of acute pulmonary embolism of the European Society of Cardiology (ESC). 2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS): the task force for the diagnosis and management of acute pulmonary embolism of the European Society of Cardiology (ESC). Eur Respir J. 2019;54(3):1901647.) Critically ill patients with COVID-19 receiving extracorporeal organ support (including veno-venous or veno-arterial extracorporeal life support and renal support therapy) should receive antithrombotic therapy following the established institutional protocols.

Other than these classic indications, there is no evidence of benefits of the preemptive use of a therapeutic anticoagulation regimen, and at least one observational study showed an increased risk of in-hospital mortality (2.3-fold increase in mortality), even in patients with higher inflammatory activity (increased C-reactive protein ≥ 20 mg/dL(284284 Motta JK, Ogunnaike RO, Shah R, Stroever S, Cedeño HV, Thapa SK, et al. Clinical outcomes with the use of prophylactic versus therapeutic anticoagulation in COVID-19. Crit Care Explor. 2020;2(12):e0309.)).

Figure 5 (Appendix 1) illustrates the recommendations for the use of different anticoagulation regimens for critically ill patients with COVID-19.

A prepublication(285285 The REMAP-CAP, ACTIV-4a, ATTACC Investigators, Zarychanski R. Therapeutic anticoagulation in critically ill patients with Covid-19 - Preliminary report. medRxiv. 2021:2021.03.10.21252749.) of a multiformat international study was recently made available; the study evaluated data from three randomized and independent controlled trials (REMAP-CAP, ACTIV-4 (Therapeutic Anticoagulation, Accelerating COVID-19 Therapeutic Interventions and Vaccines-4) and ATTACC (Antithrombotics Inpatient and Antithrombotic Therapy to Ameliorate Complications of COVID-19) and compared the efficacy of therapeutic and prophylactic anticoagulation regimens in hospitalized patients who did and did not require organ support (defined as vasopressor inotropic support, high-flow nasal oxygen therapy, invasive or noninvasive mechanical ventilation, or ECLS). After provisional analysis, the recruitment of patients was interrupted for the group of hospitalized patients who required organ support because of futility in relation to the primary objective (reduction in the need for organ support at 21 days) and a possible increased risk of bleeding (increased absolute number of patients with major hemorrhagic events) with the therapeutic anticoagulation regimen (in relation to the prophylactic regimen). These results are different from those for the group of hospitalized patients who did not require organ support, in which recruitment was also interrupted but because of the superiority of the therapeutic anticoagulation regimen (in relation to the prophylactic regimen) with regard to the primary objective.

Thus, the current evidence points to a prophylactic anticoagulation regimen as the primary anticoagulation strategy in critically ill patients (in need of organ support) in the absence of modifying situations or contraindications,(286286 Spyropoulos AC, Levy JH, Ageno W, Connors JM, Hunt BJ, Iba T, Levi M, Samama CM, Thachil J, Giannis D, Douketis JD; Subcommittee on Perioperative, Critical Care Thrombosis, Haemostasis of the Scientific, Standardization Committee of the International Society on Thrombosis and Haemostasis. Scientific and Standardization Committee communication: clinical guidance on the diagnosis, prevention and treatment of venous thromboembolism in hospitalized patients with COVID-19. J Thromb Haemost. 2020;18(8):1859-65.) especially the presence of active bleeding or thrombocytopenia (with a platelet count less than 25,000/µL).

This strategy is supported by all international organizations (Anticoagulation Forum, American College of Chest Physicians, International Society on Thrombosis and Hemostasis, Italian Society on Thrombosis and Hemostasis, North American Thrombosis Forum, European Society of Vascular Medicine and International Union of Angiology) who endorse such clinical guidelines.(287287 Barnes GD, Burnett A, Allen A, Blumenstein M, Clark NP, Cuker A, et al. Thromboembolism and anticoagulant therapy during the COVID-19 pandemic: interim clinical guidance from the anticoagulation forum. J Thromb Thrombolysis. 2020;50(1):72-81.

288 Moores LK, Tritschler T, Brosnahan S, Carrier M, Collen JF, Doerschug K, et al. Prevention, diagnosis, and treatment of VTE in patients with coronavirus disease 2019: CHEST Guideline and Expert Panel Report. Chest. 2020;158(3):1143-63.

289 Thachil J, Tang N, Gando S, Falanga A, Cattaneo M, Levi M, et al. ISTH interim guidance on recognition and management of coagulopathy in COVID-19. J Thromb Haemost. 2020;18(5):1023-6.

290 Marietta M, Ageno W, Artoni A, De Candia E, Gresele P, Marchetti M, et al. COVID-19 and haemostasis: a position paper from Italian Society on Thrombosis and Haemostasis (SISET). Blood Transfus. 2020;18(3):167-9.
-291291 Bikdeli B, Madhavan MV, Jimenez D, Chuich T, Dreyfus I, Driggin E, Nigoghossian C, Ageno W, Madjid M, Guo Y, Tang LV, Hu Y, Giri J, Cushman M, Quéré I, Dimakakos EP, Gibson CM, Lippi G, Favaloro EJ, Fareed J, Caprini JA, Tafur AJ, Burton JR, Francese DP, Wang EY, Falanga A, McLintock C, Hunt BJ, Spyropoulos AC, Barnes GD, Eikelboom JW, Weinberg I, Schulman S, Carrier M, Piazza G, Beckman JA, Steg PG, Stone GW, Rosenkranz S, Goldhaber SZ, Parikh SA, Monreal M, Krumholz HM, Konstantinides SV, Weitz JI, Lip GYH; Global COVID-19 Thrombosis Collaborative Group, Endorsed by the ISTH, NATF, ESVM, and the IUA, Supported by the ESC Working Group on Pulmonary Circulation and Right Ventricular Function. COVID-19 and thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy, and follow-up: JACC state-of-the-art review. J Am Coll Cardiol. 2020;75(23):2950-73.) In these standards, heparins (low molecular weight or unfractionated) are the anticoagulants of choice, even in patients undergoing home anticoagulation therapy with other agents,(292292 Smith K, Krajewski KC, Krajewski MP. Practical considerations in prevention and treatment of venous thromboembolism in hospitalized patients with COVID-19. Am J Health Syst Pharm. 2020;77(21):1739-45.) for the history of their use in intensive care but also for their pleotropic effects, especially their antiinflammatory activity.(293293 Thachil J. The versatile heparin in COVID-19. J Thromb Haemost. 2020;18(5):1020-2.) However, the dosage for the prophylactic anticoagulation regimen is controversial. In critically ill patients without COVID-19, there is a growing body of evidence that demonstrates that the doses commonly used in prophylactic anticoagulation regimens are inadequate and that higher doses are necessary.(294294 Zenáhlíková Z, Kvasnicka J, Kudrnová Z, Sudrová M, Brzezková R, Mazoch J, et al. FXa inhibition and coagulation changes during DVT prophylaxis by enoxaparin over the course of a 15-day follow-up in septic patients. Clin Appl Thromb Hemost. 2010;16(5):584-90.,295295 Robinson S, Zincuk A, Larsen UL, Ekstrom C, Nybo M, Rasmussen B, et al. A comparative study of varying doses of enoxaparin for thromboprophylaxis in critically ill patients: a double-blinded, randomised controlled trial. Crit Care. 2013;17(2):R75.) Some international standards recommend the use of higher doses in critically ill patients with COVID-19(287287 Barnes GD, Burnett A, Allen A, Blumenstein M, Clark NP, Cuker A, et al. Thromboembolism and anticoagulant therapy during the COVID-19 pandemic: interim clinical guidance from the anticoagulation forum. J Thromb Thrombolysis. 2020;50(1):72-81.,290290 Marietta M, Ageno W, Artoni A, De Candia E, Gresele P, Marchetti M, et al. COVID-19 and haemostasis: a position paper from Italian Society on Thrombosis and Haemostasis (SISET). Blood Transfus. 2020;18(3):167-9.) and adjustments to the formulation/dose based on weight, in accordance with the guidelines considered in other scenarios,(296296 Rocca B, Fox KA, Ajjan RA, Andreotti F, Baigent C, Collet JP, et al. Antithrombotic therapy and body mass: an expert position paper of the ESC Working Group on Thrombosis. Eur Heart J. 2018;39(19):1672-86f.) with possible monitoring of anti-Xa activity to reduce the bleeding risk(292292 Smith K, Krajewski KC, Krajewski MP. Practical considerations in prevention and treatment of venous thromboembolism in hospitalized patients with COVID-19. Am J Health Syst Pharm. 2020;77(21):1739-45.) and/or renal function.(292292 Smith K, Krajewski KC, Krajewski MP. Practical considerations in prevention and treatment of venous thromboembolism in hospitalized patients with COVID-19. Am J Health Syst Pharm. 2020;77(21):1739-45.) In the prepublication that analyzes REMAP-CAP, ACTIV-4 and ATTACC,(285285 The REMAP-CAP, ACTIV-4a, ATTACC Investigators, Zarychanski R. Therapeutic anticoagulation in critically ill patients with Covid-19 - Preliminary report. medRxiv. 2021:2021.03.10.21252749.) 51.3% of patients included in the prophylactic regimen group used intermediate doses of anticoagulant, corresponding to the adjusted doses in the prophylactic anticoagulation regimen. A recent randomized controlled trial with patients with critical COVID-19 showed no statistically significant differences between standard and adjusted prophylactic anticoagulation regimens (enoxaparin 1mg/kg per day; not the optimal dose from the pharmacokinetic point of view); thus, there is still no concensus on the choice for the ideal scheme.

Table 7 (Appendix 1) provides the different prophylactic (standard and adjusted) and therapeutic anticoagulation regimens available for critically ill patients with COVID-19.

Other therapies

In critically ill patients infected with SARS-CoV-2, it is recommended not to use convalescent plasma therapy outside the scope of clinical use protocols or clinical trials.

Therapy with convalescent plasma is based on the principle of passive immunity, a technique in which plasma rich in antibodies from individuals in the convalescence phase of an infectious disease is administered to others in the acute phase of the same disease to confer short-term immunity.(297297 Xu Z, Zhou J, Huang Y, Liu X, Xu Y, Chen S, et al. Efficacy of convalescent plasma for the treatment of severe influenza. Crit Care. 2020;24(1):469.) In the specific context of COVID-19, neutralizing antibodies are those that bind to the spike protein and prevent its interaction with the ACE2 receptor or block its conformational changes, preventing fusion to the membrane of host cells.(298298 Li L, Zhang W, Hu Y, Tong X, Zheng S, Yang J, et al. Effect of convalescent plasma therapy on time to clinical improvement in patients with severe and life-threatening COVID-19: a randomized clinical trial. JAMA. 2020;324(5):460-70.) Although a recent Cochrane review(299299 Valk SJ, Piechotta V, Chai KL, Doree C, Monsef I, Wood EM, et al. Convalescent plasma or hyperimmune immunoglobulin for people with COVID-19: a rapid review. Cochrane Database Syst Rev. 2020;5(5):CD013600.) revealed a high degree of uncertainty regarding the efficacy of convalescent plasma therapy, the FDA approved this therapy for critically ill patients.(300300 Tanne JH. Covid-19: FDA approves use of convalescent plasma to treat critically ill patients. BMJ. 2020;368:m1256.) The evidence stems from multiple randomized clinical trials that compared convalescent plasma with standard treatment in patients with mild,(301301 Libster R, Pérez Marc G, Wappner D, Coviello S, Bianchi A, Braem V, Esteban I, Caballero MT, Wood C, Berrueta M, Rondan A, Lescano G, Cruz P, Ritou Y, Fernández Viña V, Álvarez Paggi D, Esperante S, Ferreti A, Ofman G, Ciganda Á, Rodriguez R, Lantos J, Valentini R, Itcovici N, Hintze A, Oyarvide ML, Etchegaray C, Neira A, Name I, Alfonso J, López Castelo R, Caruso G, Rapelius S, Alvez F, Etchenique F, Dimase F, Alvarez D, Aranda SS, Sánchez Yanotti C, De Luca J, Jares Baglivo S, Laudanno S, Nowogrodzki F, Larrea R, Silveyra M, Leberzstein G, Debonis A, Molinos J, González M, Perez E, Kreplak N, Pastor Argüello S, Gibbons L, Althabe F, Bergel E, Polack FP; Fundación INFANT-COVID-19 Group. Early high-titer plasma therapy to prevent severe Covid-19 in older adults. N Engl J Med. 2021;384(7):610-8.) moderate(302302 Gharbharan A, Jordans CC, Geurtsvankessel C, den Hollander JG, Karim F, Mollema FP, et al. Convalescent plasma for COVID-19. A randomized clinical trial. medRxiv. 2020:2020.07.01.20139857.

303 Avendaño-Solà C, Ramos-Martínez A, Muñez-Rubio E, Ruiz-Antorán B, de Molina RM, Torres F, et al. Convalescent plasma for COVID-19: a multicenter, randomized clinical trial. medRxiv. 2020:2020.08.26.20182444.
-304304 Agarwal A, Mukherjee A, Kumar G, Chatterjee P, Bhatnagar T, Malhotra P; PLACID Trial Collaborators. Convalescent plasma in the management of moderate covid-19 in adults in India: open label phase II multicentre randomised controlled trial (PLACID Trial). BMJ. 2020;371:m3939.) and severe COVID-19,(298298 Li L, Zhang W, Hu Y, Tong X, Zheng S, Yang J, et al. Effect of convalescent plasma therapy on time to clinical improvement in patients with severe and life-threatening COVID-19: a randomized clinical trial. JAMA. 2020;324(5):460-70.,305305 AlQahtani M, Abdulrahman A, Almadani A, Alali SY, Al Zamrooni AM, Hejab AH, et al. Randomized controlled trial of convalescent plasma therapy against standard therapy in patients with severe COVID-19 disease. Sci Rep. 2021;11(1):9927.,306306 Simonovich VA, Burgos Pratx LD, Scibona P, Beruto MV, Vallone MG, Vázquez C, Savoy N, Giunta DH, Pérez LG, Sánchez MDL, Gamarnik AV, Ojeda DS, Santoro DM, Camino PJ, Antelo S, Rainero K, Vidiella GP, Miyazaki EA, Cornistein W, Trabadelo OA, Ross FM, Spotti M, Funtowicz G, Scordo WE, Losso MH, Ferniot I, Pardo PE, Rodriguez E, Rucci P, Pasquali J, Fuentes NA, Esperatti M, Speroni GA, Nannini EC, Matteaccio A, Michelangelo HG, Follmann D, Lane HC, Belloso WH; PlasmAr Study Group. A randomized trial of convalescent plasma in Covid-19 severe pneumonia. N Engl J Med. 2021;384(7):619-29.) who showed improvements in dyspnea but without significant differences in relation to other outcomes (mortality, need for invasive mechanical ventilation, admission to intensive care and time to hospital discharge) and at the expense of an increase in serious adverse events. In Portugal, a working group was created for the development and proposal of a National Program for Convalescent Plasma Transfusion for the Treatment of Patients with COVID-19.(307307 República Portuguesa. Gabinete do Secretaria de Estado da Saúde.Despacho n.º 5160/2020 de 4 de maio de 2020. Cria o grupo de trabalho para desenvolvimento e criação de proposta de Programa Nacional de Transfusão de Plasma Convalescente COVID-19 (PNTPC) para o tratamento de pacientes com COVID-19. Diário da República n.º 86, Série II, p.56-7. Disponível em https://dre.pt/application/conteudo/132964793
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)

In critical patients infected with SARS-CoV-2, it is recommended not to use therapy with mesenchymal stem cells outside the scope of clinical use protocols or clinical trials.

Mesenchymal stem cells isolated from various donor sites (bone marrow, placenta, fat or umbilical cord) can be administered intravenously, producing powerful and comprehensive immunomodulatory functions.(308308 Gao F, Chiu SM, Motan DA, Zhang Z, Chen L, Ji HL, et al. Mesenchymal stem cells and immunomodulation: current status and future prospects. Cell Death Dis. 2016;7(1):e2062.) The safety and efficacy of the administration of these cells, especially those from umbilical cord tissue, have been clearly documented in multiple clinical trials,(309309 Lalu MM, McIntyre L, Pugliese C, Fergusson D, Winston BW, Marshall JC, Granton J, Stewart DJ; Canadian Critical Care Trials Group. Safety of cell therapy with mesenchymal stromal cells (SafeCell): a systematic review and meta-analysis of clinical trials. PLoS One. 2012;7(10):e47559.) especially for inflammatory diseases involving the immune system, such as graft-versus-host disease.(310310 Hashmi S, Ahmed M, Murad MH, Litzow MR, Adams RH, Ball LM, et al. Survival after mesenchymal stromal cell therapy in steroid-refractory acute graft-versus-host disease: systematic review and meta-analysis. Lancet Haematol. 2016;3(1):e45-52.) Multiple randomized clinical trials have compared mesenchymal stem cell therapy with standard therapy for patients with mild to severe COVID-19,(311311 Shu L, Niu C, Li R, Huang T, Wang Y, Huang M, et al. Treatment of severe COVID-19 with human umbilical cord mesenchymal stem cells. Stem Cell Res Ther. 2020;11(1):361.

312 Shi L, Huang H, Lu X, Yan X, Jiang X, Xu R, et al. Effect of human umbilical cord-derived mesenchymal stem cells on lung damage in severe COVID-19 patients: a randomized, double-blind, placebo-controlled phase 2 trial. Signal Transduct Target Ther. 2021;6(1):58.
-313313 Lanzoni G, Linetsky E, Correa D, Messinger Cayetano S, Alvarez RA, Kouroupis D, et al. Umbilical cord mesenchymal stem cells for COVID-19 acute respiratory distress syndrome: a double-blind, phase 1/2a, randomized controlled trial. Stem Cells Transl Med. 2021;10(5):660-73.) but the confidence for all results (mortality and duration of ventilation) was very low because of the high risk of bias and inaccuracy.

The use of mesenchymal stem cells for the treatment of patients with COVID-19 has biological plausibility, but randomized and quality-controlled studies are needed before the use of this intervention can be considered outside the scope of the clinical use protocols or clinical trials.(314314 Herberts CA, Kwa MS, Hermsen HP. Risk factors in the development of stem cell therapy. J Transl Med. 2011;9:29.) In Portugal, a company provides technology, resources and products pro bono and in a timely manner. The current form of access is through an application for an Authorization for Exceptional Use (AUE) required by hospitals (after careful evaluation by the Pharmacy and Therapeutic Committee), but the inclusion of patients in a clinical trial is being considered.

In critically ill patients infected with SARS-CoV-2, it is recommended not to use therapy with neutralizing antibodies outside the scope of clinical use protocols or clinical trials.

Bamlanivimab is an IgG1 recombinant human monoclonal antibody that neutralizes the SARS-CoV-2 spike protein. The BLAZE-1 (outpatients with mild COVID-19) and ACTIV-3/TICO (patients with moderate to severe COVID-19) trials showed no improvement in any outcome (mortality, hospitalization, virological clearance, clinical recovery rate and adverse effects) compared to standard therapy.(315315 Gottlieb RL, Nirula A, Chen P, Boscia J, Heller B, Morris J, et al. Effect of bamlanivimab as monotherapy or in combination with etesevimab on viral load in patients with mild to moderate COVID-19: a randomized clinical trial. JAMA. 2021;325(7):632-44.,316316 ACTIV-3/TICO LY-CoV555 Study Group, Lundgren JD, Grund B, Barkauskas CE, Holland TL, Gottlieb RL, et al. A Neutralizing monoclonal antibody for hospitalized patients with Covid-19. N Engl J Med. 2021;384(10):905-14.)

REGN-COV2 is a combination of two neutralizing antibodies (casirivimab and imdevimab) against the SARS-CoV-2 spike protein. The drug is being studied in patients with mild to moderate COVID-19 (nonhospitalized), and preliminary data have not shown clinical efficacy compared to placebo.(317317 Weinreich DM, Sivapalasingam S, Norton T, Ali S, Gao H, Bhore R, Musser BJ, Soo Y, Rofail D, Im J, Perry C, Pan C, Hosain R, Mahmood A, Davis JD, Turner KC, Hooper AT, Hamilton JD, Baum A, Kyratsous CA, Kim Y, Cook A, Kampman W, Kohli A, Sachdeva Y, Graber X, Kowal B, DiCioccio T, Stahl N, Lipsich L, Braunstein N, Herman G, Yancopoulos GD; Trial Investigators. REGN-COV2, a neutralizing antibody cocktail, in outpatients with Covid-19. N Engl J Med. 2021;384(3):238-51.)

Other drugs

In critically ill patients infected with SARS-CoV-2, routine nonsuspension of chronic therapy with renin-angiotensin system inhibitors (angiotensin converting enzyme (ACE) inhibitors or angiotensin 2 receptor antagonists) or statins is recommended.

There are no randomized controlled studies that have analyzed the benefit of maintaining or discontinuing chronic therapy with angiotensin converting enzyme inhibitors (ACEIs) or angiotensin 2 receptor antagonists in patients infected (or with a risk of infection) with SARS-CoV-2. Multiple observational studies have demonstrated that it is unlikely that the continuous use of these drugs is associated with an increased risk of disease severity (or death) and that there is a quantifiable risk of decompensation of heart failure or worsening of blood pressure control if chronic therapy is abruptly discontinued.(318318 Mackey K, Kansagara D, Vela K. Update Alert 4: Risks and impact of angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers on SARS-CoV-2 infection in adults. Ann Intern Med. 2020;173(9):W147-8.

319 Flacco ME, Acuti Martellucci C, Bravi F, Parruti G, Cappadona R, Mascitelli A, et al. Treatment with ACE inhibitors or ARBs and risk of severe/lethal COVID-19: a meta-analysis. Heart. 2020;106(19):1519-24.

320 Baral R, White M, Vassiliou VS. Effect of renin-angiotensin-aldosterone system inhibitors in patients with COVID-19: a systematic review and meta-analysis of 28,872 patients. Curr Atheroscler Rep. 2020;22(10):61.
-321321 Barochiner J, Martínez R. Use of inhibitors of the renin-angiotensin system in hypertensive patients and COVID-19 severity: a systematic review and meta-analysis. J Clin Pharm Ther. 2020;45(6):1244-52.) Thus, the Sociedade Portuguesa de Cardiologia,(322322 Sociedade Portuguesa de Cardiologia. Posição da Sociedade Portuguesa de Cardiologia sobre a utilização de IECA e ARA II no contexto da pandemia do COVID-19. 15 março 2020. Disponíivel em https://spc.pt/wp-content/uploads/2020/03/POSI%C3%87%C3%83O-IECA-e-ARA-II-com-COVID19.pdf
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) along with multiple scientific societies (e.g., American Heart Association (AHA) and American College of Cardiology (ACC)),(323323 Bozkurt B, Kovacs R, Harrington B. Joint HFSA/ACC/AHA Statement Addresses Concerns Re: Using RAAS Antagonists in COVID-19. J Card Fail. 2020;26(5):370.) considers that there is no clinical or scientific evidence to support the routine interruption of chronic therapy with drugs in this group for patients infected with (or with a risk of infection) with SARS-CoV-2. In the specific context of critically ill patients infected with SARS-CoV-2, the risks and benefits of therapy should be weighed in each case, considering the different comorbidities and organ dysfunctions.

Despite the concern with the hepatotoxicity of statins, mainly because an increase in transaminases is common in SARS-CoV-2 infection, the evidence points to a low risk of toxicity,(324324 Cohen DE, Anania FA, Chalasani N; National Lipid Association Statin Safety Task Force Liver Expert Panel. An assessment of statin safety by hepatologists. Am J Cardiol. 2006;97(8A):77C-81C.) and multiple scientific societies (for example, AHA and ACC)(323323 Bozkurt B, Kovacs R, Harrington B. Joint HFSA/ACC/AHA Statement Addresses Concerns Re: Using RAAS Antagonists in COVID-19. J Card Fail. 2020;26(5):370.) recommend the continuation of statin therapy in hospitalized patients infected with SARS-CoV-2.

In critically ill patients infected with SARS-CoV-2, it is recommended not to discontinue or avoid treatment with nonsteroidal antiinflammatory drugs (NSAIDs) when clinically indicated.

Concern about the possible adverse effects of NSAIDs was raised by anecdotal reports of the rapid progression of some patients infected with SARS-CoV-2 who taking these drugs.(325325 Day M. Covid-19: ibuprofen should not be used for managing symptoms, say doctors and scientists. BMJ. 2020;368:m1086.) In the absence of clinical or population data that substantiate this fact, EMA(326326 European Medicines Agency (EMA). EMA gives advice on the use of non-steroidal anti-inflammatories for COVID-19. 2020 Mar 18. Available from https://www.ema.europa.eu/en/news/ema-gives-advice-use-non-steroidal-anti-inflammatories-covid-19
https://www.ema.europa.eu/en/news/ema-gi...
) and the WHO(327327 World Health Organization (WHO). The use of non-steroidal anti-inflammatory drugs (NSAIDs) in patients with COVID-19. Scientific brief. 2020 Apr 19. Available from https://www.who.int/news-room/commentaries/detail/the-use-of-non-steroidal-anti-inflammatory-drugs-(nsaids)-in-patients-with-covid-19
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) do not recommend discontinuation or avoidance of NSAID therapy when clinically indicated. Thus, consistent with the general approach to fever in adults, paracetamol should be the preferred antipyretic, with NSAIDs used as second-line drugs (at the lowest effective dose).

Criteria for cure and suspension of isolation

It is recommended that obtaining a cure criterion (and consequent suspension of isolation) of patients with severe or critical COVID-19 (or severe immunosuppression, regardless of the severity of the disease) does not depend on laboratory criteria but rather on the cumulative fulfillment of criteria: (1) clinical (significant improvement of symptoms with apyrexia, without use of antipyretics, for three consecutive days) and (2) temporal (20 days since the onset of symptoms).

The determination of the cure criteria for SARS-CoV-2-infected individuals is essential to maximize the suspension of unnecessary isolations, with the distribution of patients to clean areas, without compromising the safety of other patients and health professionals.(328328 República Portuguesa. Serviço Nacional de Saúde. Direçao Geral de Saúde. Norma 004/2020 - COVID-19: Abordagem do doente com suspeita ou confirmação de COVID-19. 23 Mar 2020, atualizada 14 out 2020. Disponível em https://backoffice.ump.pt/files/files/Norma_004_2020_act_14_10_2020.pdf
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)

The presence of SARS-CoV-2 virus genetic material in a biological sample is regarded as a positive test, but such positivity does not necessarily imply that the virus is viable, i.e., transmit from person to person. Most SARS-CoV-2-infected individuals are not NAAT positive approximately 2 weeks after infection, but approximately 5%-10% of infected individuals, especially critically ill patients and those with severe immunosuppression, remain positive after this period, and occasionally, patients with previous negative tests return positive tests after a short period of time (< 3 months).(329329 European Centre for Disease Prevention and Control (ECDC). Novel coronavirus (SARS-CoV-2). Discharge criteria for confirmed COVID-19 cases - When is it safe to discharge COVID-19 cases from the hospital or end home isolation? Technical Report. 2020. Available from https://www.ecdc.europa.eu/sites/default/files/documents/COVID-19-Discharge-criteria.pdf
https://www.ecdc.europa.eu/sites/default...
,330330 World Health Organization (WHO). Criteria for releasing COVID-19 patients from isolation. Scientific Brief. 2020 Jun 17. Available from https://www.who.int/publications/i/item/criteria-for-releasing-covid-19-patients-from-isolation
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)

The recommendations of the DGS,(328328 República Portuguesa. Serviço Nacional de Saúde. Direçao Geral de Saúde. Norma 004/2020 - COVID-19: Abordagem do doente com suspeita ou confirmação de COVID-19. 23 Mar 2020, atualizada 14 out 2020. Disponível em https://backoffice.ump.pt/files/files/Norma_004_2020_act_14_10_2020.pdf
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) which are based on the guidelines issued by the WHO(330330 World Health Organization (WHO). Criteria for releasing COVID-19 patients from isolation. Scientific Brief. 2020 Jun 17. Available from https://www.who.int/publications/i/item/criteria-for-releasing-covid-19-patients-from-isolation
https://www.who.int/publications/i/item/...
) and by the ECDC,(329329 European Centre for Disease Prevention and Control (ECDC). Novel coronavirus (SARS-CoV-2). Discharge criteria for confirmed COVID-19 cases - When is it safe to discharge COVID-19 cases from the hospital or end home isolation? Technical Report. 2020. Available from https://www.ecdc.europa.eu/sites/default/files/documents/COVID-19-Discharge-criteria.pdf
https://www.ecdc.europa.eu/sites/default...
) recommend a strategy to define a cure criterion - and consequent suspension of isolation - for patients with severe or critical COVID-19 (or severe immunosuppression, regardless of the severity of the disease) determined by clinical criteria, such as significant improvement of symptoms with apyrexia (without use of antipyretics) for three consecutive days, and temporality, such as 20 days since the onset of symptoms, without the need for laboratory criteria (NAAT negative for SARS-CoV-2).

Severe immunosuppression situations can occur in the context of active malignancy (particularly for patients undergoing chemotherapy, radiotherapy or immunotherapy/biologicals); allogeneic transplantation of hematopoietic progenitor cells within less than 1 year or graft-versus-host disease; lung transplantation or other organ transplantation within 6 months or rejection within 3 months; biological therapy and/or prednisolone-equivalent dose > 20mg/day for more than 14 days; HIV infection without therapy and with a CD4+ T cell count < 200 cells/mm3; and primary immunodeficiency (severe combined immunodeficiency syndrome, X-linked agammaglobulinemia, interferon receptor deficiency and hyper-IgE syndrome).(328328 República Portuguesa. Serviço Nacional de Saúde. Direçao Geral de Saúde. Norma 004/2020 - COVID-19: Abordagem do doente com suspeita ou confirmação de COVID-19. 23 Mar 2020, atualizada 14 out 2020. Disponível em https://backoffice.ump.pt/files/files/Norma_004_2020_act_14_10_2020.pdf
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)

CONCLUSION

The COVID-19 pandemic is an important cause of morbidity and mortality for which scientific knowledge has grown and changed at an accelerated pace. Given the nature of the pandemic and considering the constant changes in clinical and political knowledge, it is necessary to review and summarize the scientific literature to inform and decide on best practices from an evidence-based perspective. These recommendations provide recommendations/suggestions for the organization of health services and management of patients with COVID-19 in intensive care departments, being specifically oriented to the Portuguese reality, African Countries of Portuguese Official Language and East Timor. Its need is urgent in a world of constant disinformation and change, in which certain actions have a great prognostic impact on patients. The present recommendations should be continuously reviewed to reflect advances in our understanding and treatment of this pathology, constituting a living and up-to-date document.

References

  • 1
    World Health Organization. Coronavirus disease 2019 (COVID-19) Situation report. 2020. Available from: https://www.who.int/emergencies/diseases/novel-coronavirus-2019/situation-reports
    » https://www.who.int/emergencies/diseases/novel-coronavirus-2019/situation-reports
  • 2
    República Portuguesa. Serviço Nacional de Saúde. Direçao Geral de Saúde. Relatório de Situação. 2020. Disponível em: https://covid19.min-saude.pt/relatorio-de-situacao/
    » https://covid19.min-saude.pt/relatorio-de-situacao/
  • 3
    Mendes JJ, Mergulhão P, Froes F, Paiva JA, Gouveia J. Recommendations from the Sociedade Portuguesa de Cuidados Intensivos and Infection & Sepsis Group for intensive care approach to COVID-19. Rev Bras Ter Intensiva. 2020;32(1):2-10.
  • 4
    Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, Schünemann HJ; GRADE Working Group. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ. 2008;336(7650):924-6.
  • 5
    Boulkedid R, Abdoul H, Loustau M, Sibony O, Alberti C. Using and reporting the Delphi method for selecting healthcare quality indicators: a systematic review. PLoS One. 2011;6(6):e20476.
  • 6
    Tang X, Wu C, Li X, Song Y, Yao X, Wu X, et al. On the origin and continuing evolution of SARS-CoV-2. Natl Sci Rev. 2020;7(6):1012-23.
  • 7
    Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, Zhao X, Huang B, Shi W, Lu R, Niu P, Zhan F, Ma X, Wang D, Xu W, Wu G, Gao GF, Tan W; China Novel Coronavirus Investigating and Research Team. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med. 2020;382(8):727-33.
  • 8
    Xie M, Chen Q. Insight into 2019 novel coronavirus - An updated interim review and lessons from SARS-CoV and MERS-CoV. Int J Infect Dis. 2020;94:119-24.
  • 9
    República Portuguesa. Serviço Nacional de Saúde. Instituto Nacional de Saúde Doutor Ricardo Jorge. Covid-19: curva epidémica e parâmetros de transmissibilidade. 2021. Disponível em: http://www.insa.min-saude.pt/category/areas-de-atuacao/epidemiologia/covid-19-curva-epidemica-e-parametros-de-transmissibilidade/
    » http://www.insa.min-saude.pt/category/areas-de-atuacao/epidemiologia/covid-19-curva-epidemica-e-parametros-de-transmissibilidade/
  • 10
    Wu JT, Leung K, Leung GM. Nowcasting and forecasting the potential domestic and international spread of the 2019-nCoV outbreak originating in Wuhan, China: a modelling study. Lancet. 2020;395(10225):689-97.
  • 11
    Abdool Karim SS, de Oliveira T. New SARS-CoV-2 Variants - Clinical, Public Health, and Vaccine Implications. N Engl J Med. 2021;384(19):1866-8.
  • 12
    Madhi SA, Baillie V, Cutland CL, Voysey M, Koen AL, Fairlie L, Padayachee SD, Dheda K, Barnabas SL, Bhorat QE, Briner C, Kwatra G, Ahmed K, Aley P, Bhikha S, Bhiman JN, Bhorat AE, du Plessis J, Esmail A, Groenewald M, Horne E, Hwa SH, Jose A, Lambe T, Laubscher M, Malahleha M, Masenya M, Masilela M, McKenzie S, Molapo K, Moultrie A, Oelofse S, Patel F, Pillay S, Rhead S, Rodel H, Rossouw L, Taoushanis C, Tegally H, Thombrayil A, van Eck S, Wibmer CK, Durham NM, Kelly EJ, Villafana TL, Gilbert S, Pollard AJ, de Oliveira T, Moore PL, Sigal A, Izu A; NGS-SA Group; Wits-VIDA COVID Group. Efficacy of the ChAdOx1 nCoV-19 Covid-19 Vaccine against the B.1.351 Variant. N Engl J Med. 2021;384(20):1885-98.
  • 13
    European Centre for Disease Prevention and Control (ECDC). Risk Assessment: Risk related to the spread of new SARS-CoV-2 variants of concern in the EU/EEA - first update. 2021. Available from: https://www.ecdc.europa.eu/en/publications-data/covid-19-risk-assessment-spread-new-variants-concern-eueea-first-update
    » https://www.ecdc.europa.eu/en/publications-data/covid-19-risk-assessment-spread-new-variants-concern-eueea-first-update
  • 14
    República Portuguesa. Serviço Nacional de Saúde. Instituto Nacional de Saúde Doutor Ricardo Jorge. Diversidade genética do novo coronavírus SARS-CoV-2 (COVID-19) em Portugal - Relatório de situação]. 2021. Disponível em: https://insaflu.insa.pt/covid19/relatorios/INSA_SARS_CoV_2_DIVERSIDADE_GENETICA_relatorio_situacao_2021-09-14.pdf
    » https://insaflu.insa.pt/covid19/relatorios/INSA_SARS_CoV_2_DIVERSIDADE_GENETICA_relatorio_situacao_2021-09-14.pdf
  • 15
    Chan JF, Yuan S, Kok KH, To KK, Chu H, Yang J, et al. A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster. Lancet. 2020;395(10223):514-23.
  • 16
    He X, Lau EH, Wu P, Deng X, Wang J, Hao X, et al. Temporal dynamics in viral shedding and transmissibility of COVID-19. Nat Med. 2020;26(5):672-5.
  • 17
    Gandhi M, Yokoe DS, Havlir DV. Asymptomatic Transmission, the Achilles’ Heel of Current Strategies to Control Covid-19. N Engl J Med. 2020;382(22):2158-60.
  • 18
    World Health Organization (WHO). Coronavirus disease (COVID-19): how is it transmitted? 2020. Available from: https://www.who.int/news-room/q-a-detail/coronavirus-disease-covid-19-how-is-it-transmitted
    » https://www.who.int/news-room/q-a-detail/coronavirus-disease-covid-19-how-is-it-transmitted
  • 19
    van Doremalen N, Bushmaker T, Morris DH, Holbrook MG, Gamble A, Williamson BN, et al. Aerosol and surface stability of SARS-CoV-2 as compared with SARS-CoV-1. N Engl J Med. 2020;382(16):1564-7.
  • 20
    Kampf G, Todt D, Pfaender S, Steinmann E. Persistence of coronaviruses on inanimate surfaces and their inactivation with biocidal agents. J Hosp Infect. 2020;104(3):246-51.
  • 21
    Anderson EL, Turnham P, Griffin JR, Clarke CC. Consideration of the aerosol transmission for COVID-19 and public health. Risk Anal. 2020;40(5):902-7.
  • 22
    Tran K, Cimon K, Severn M, Pessoa-Silva C, Conly J. Aerosol-generating procedures and risk of transmission of acute respiratory infections: a systematic review. CADTH Technol Overv. 2013;3(1):e3201.
  • 23
    Wu Y, Guo C, Tang L, Hong Z, Zhou J, Dong X, et al. Prolonged presence of SARS-CoV-2 viral RNA in faecal samples. Lancet Gastroenterol Hepatol. 2020;5(5):434-5.
  • 24
    Wang W, Xu Y, Gao R, Lu R, Han K, Wu G, et al. Detection of SARS-CoV-2 in different types of clinical specimens. JAMA. 2020;323(18):1843-4.
  • 25
    Hoffmann M, Kleine-Weber H, Schroeder S, Kruger N, Herrler T, Erichsen S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell. 2020;181(2):271-80.e8.
  • 26
    Hou YJ, Okuda K, Edwards CE, Martinez DR, Asakura T, Dinnon KH 3rd, et al. SARS-CoV-2 reverse genetics reveals a variable infection gradient in the respiratory tract. Cell. 2020;182(2):429-46.e14.
  • 27
    Miesbach W. Pathological role of angiotensin II in severe COVID-19. TH Open. 2020;4(2):e138-e44.
  • 28
    Varga Z, Flammer AJ, Steiger P, Haberecker M, Andermatt R, Zinkernagel AS, et al. Endothelial cell infection and endotheliitis in COVID-19. Lancet. 2020;395(10234):1417-8.
  • 29
    Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ; HLH Across Speciality Collaboration, UK. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020;395(10229):1033-4.
  • 30
    Connors JM, Levy JH. COVID-19 and its implications for thrombosis and anticoagulation. Blood. 2020;135(23):2033-40.
  • 31
    Siddiqi HK, Mehra MR. COVID-19 illness in native and immunosuppressed states: a clinical-therapeutic staging proposal. J Heart Lung Transplant. 2020;39(5):405-7.
  • 32
    Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497-506.
  • 33
    Xu X, Han M, Li T, Sun W, Wang D, Fu B, et al. Effective treatment of severe COVID-19 patients with tocilizumab. Proc Natl Acad Sci U S A. 2020;117(20):10970-5.
  • 34
    Brochard L, Slutsky A, Pesenti A. Mechanical ventilation to minimize progression of lung injury in acute respiratory failure. Am J Respir Crit Care Med. 2017;195(4):438-42.
  • 35
    Gattinoni L, Chiumello D, Caironi P, Busana M, Romitti F, Brazzi L, et al. COVID-19 pneumonia: different respiratory treatments for different phenotypes? Intensive Care Medicine. 2020;46(6):1099-102.
  • 36
    Gattinoni L, Coppola S, Cressoni M, Busana M, Rossi S, Chiumello D. Covid-19 does not lead to a “typical” acute respiratory distress syndrome. Am J Respir Crit Care Med. 2020;201(10):1299-300.
  • 37
    Copin MC, Parmentier E, Duburcq T, Poissy J, Mathieu D; Lille COVID-19 ICU and Anatomopathology Group. Time to consider histologic pattern of lung injury to treat critically ill patients with COVID-19 infection. Intensive Care Med. 2020;46(6):1124-6.
  • 38
    Dolhnikoff M, Duarte-Neto AN, de Almeida Monteiro RA, da Silva LF, de Oliveira EP, Saldiva PH, et al. Pathological evidence of pulmonary thrombotic phenomena in severe COVID-19. J Thromb Haemost. 2020;18(6):1517-9.
  • 39
    Puelles VG, Lutgehetmann M, Lindenmeyer MT, Sperhake JP, Wong MN, Allweiss L, et al. Multiorgan and renal tropism of SARS-CoV-2. N Engl J Med. 2020;383(6):590-2.
  • 40
    Gupta A, Madhavan MV, Sehgal K, Nair N, Mahajan S, Sehrawat TS, et al. Extrapulmonary manifestations of COVID-19. Nat Med. 2020;26(7):1017-32.
  • 41
    Sungnak W, Huang N, Bécavin C, Berg M, Queen R, Litvinukova M, Talavera-López C, Maatz H, Reichart D, Sampaziotis F, Worlock KB, Yoshida M, Barnes JL; HCA Lung Biological Network. SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes. Nat Med. 2020;26(5):681-7.
  • 42
    Dorward DA, Russell CD, Um IH, Elshani M, Armstrong SD, Penrice-Randal R, et al. Tissue-specific immunopathology in fatal COVID-19. Am J Respir Crit Care Med. 2021;203(2):192-201
  • 43
    Datta SD, Talwar A, Lee JT. A proposed framework and timeline of the spectrum of disease due to SARS-CoV-2 infection: illness beyond acute infection and public health implications. JAMA. 2020;324(22):2251-2.
  • 44
    Rodriguez-Morales AJ, Cardona-Ospina JA, Gutiérrez-Ocampo E, Villamizar-Peña R, Holguin-Rivera Y, Escalera-Antezana JP, Alvarado-Arnez LE, Bonilla-Aldana DK, Franco-Paredes C, Henao-Martinez AF, Paniz-Mondolfi A, Lagos-Grisales GJ, Ramírez-Vallejo E, Suárez JA, Zambrano LI, Villamil-Gómez WE, Balbin-Ramon GJ, Rabaan AA, Harapan H, Dhama K, Nishiura H, Kataoka H, Ahmad T, Sah R; Latin American Network of Coronavirus Disease 2019-COVID-19 Research (LANCOVID-19). Clinical, laboratory and imaging features of COVID-19: a systematic review and meta-analysis. Travel Med Infect Dis. 2020;34:101623.
  • 45
    Wu C, Chen X, Cai Y, Xia J, Zhou X, Xu S, et al. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China. JAMA Intern Med. 2020;180(7):934-43.
  • 46
    Ai T, Yang Z, Hou H, Zhan C, Chen C, Lv W, et al. Correlation of chest CT and RT-PCR testing in coronavirus disease 2019 (COVID-19) in China: a report of 1014 cases. Radiology. 2020;296(2):E32-E40.
  • 47
    Garg S, Kim L, Whitaker M, O’Halloran A, Cummings C, Holstein R, et al. Hospitalization Rates and Characteristics of Patients Hospitalized with Laboratory-Confirmed Coronavirus Disease 2019 - COVID-NET, 14 States, March 1-30, 2020. MMWR Morb Mortal Wkly Rep. 2020;69(15):458-64.
  • 48
    Nogueira PJ, de Araujo Nobre M, Costa A, Ribeiro RM, Furtado C, Bacelar Nicolau L, et al. The role of health preconditions on COVID-19 deaths in Portugal: evidence from surveillance data of the first 20293 infection cases. J Clin Med. 2020;9(8):2368.
  • 49
    Ricoca Peixoto V, Vieira A, Aguiar P, Sousa P, Carvalho C, Thomas DR, et al. Determinants of hospitalizations, intensive care unit admission and death among 20,293 reported cases in Portugal, March to April 2020. Euro Surveill. 2021;26(33):2001059.
  • 50
    Wilkerson RG, Adler JD, Shah NG, Brown R. Silent hypoxia: a harbinger of clinical deterioration in patients with COVID-19. Am J Emerg Med. 2020;38(10):2243.e5-2243.e6.
  • 51
    Chen G, Wu D, Guo W, Cao Y, Huang D, Wang H, et al. Clinical and immunological features of severe and moderate coronavirus disease 2019. J Clin Invest. 2020;130(5):2620-9.
  • 52
    Liu T, Zhang J, Yang Y, Ma H, Li Z, Zhang J, et al. The role of interleukin-6 in monitoring severe case of coronavirus disease 2019. EMBO Mol Med. 2020;12(7):e12421.
  • 53
    Sinha P, Matthay MA, Calfee CS. Is a “cytokine storm” relevant to COVID-19? JAMA Intern Med. 2020;180(9):1152-4.
  • 54
    Camporota L, Vasques F, Sanderson B, Barrett NA, Gattinoni L. Identification of pathophysiological patterns for triage and respiratory support in COVID-19. Lancet Respir Med. 2020;8(8):752-4.
  • 55
    Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395(10229):1054-62.
  • 56
    Qin C, Zhou L, Hu Z, Zhang S, Yang S, Tao Y, et al. Dysregulation of immune response in patients with coronavirus 2019 (COVID-19) in Wuhan, China. Clin Infect Dis. 2020;71(15):762-8.
  • 57
    Helms J, Tacquard C, Severac F, Leonard-Lorant I, Ohana M, Delabranche X, Merdji H, Clere-Jehl R, Schenck M, Fagot Gandet F, Fafi-Kremer S, Castelain V, Schneider F, Grunebaum L, Anglés-Cano E, Sattler L, Mertes PM, Meziani F; CRICS TRIGGERSEP Group (Clinical Research in Intensive Care and Sepsis Trial Group for Global Evaluation and Research in Sepsis). High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study. Intensive Care Med. 2020;46(6):1089-98.
  • 58
    Al-Ani F, Chehade S, Lazo-Langner A. Thrombosis risk associated with COVID-19 infection. A scoping review. Thromb Res. 2020;192:152-60.
  • 59
    Bilaloglu S, Aphinyanaphongs Y, Jones S, Iturrate E, Hochman J, Berger JS. Thrombosis in hospitalized patients with COVID-19 in a New York City Health System. JAMA. 2020;324(8):799-801.
  • 60
    Tang N, Bai H, Chen X, Gong J, Li D, Sun Z. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost. 2020;18(5):1094-9.
  • 61
    Mao R, Qiu Y, He JS, Tan JY, Li XH, Liang J, et al. Manifestations and prognosis of gastrointestinal and liver involvement in patients with COVID-19: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol. 2020;5(7):667-78.
  • 62
    Nobel YR, Phipps M, Zucker J, Lebwohl B, Wang TC, Sobieszczyk ME, et al. Gastrointestinal symptoms and coronavirus disease 2019: a case-control study from the United States. Gastroenterology. 2020;159(1):373-5.e2.
  • 63
    Clerkin KJ, Fried JA, Raikhelkar J, Sayer G, Griffin JM, Masoumi A, et al. COVID-19 and cardiovascular disease. Circulation. 2020;141(20):1648-55.
  • 64
    Creel-Bulos C, Hockstein M, Amin N, Melhem S, Truong A, Sharifpour M. Acute cor pulmonale in critically ill patients with Covid-19. N Engl J Med. 2020;382(21):e70.
  • 65
    Richardson S, Hirsch JS, Narasimhan M, Crawford JM, McGinn T, Davidson KW, et al. Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City Area. JAMA. 2020;323(20):2052-9. Erratum in JAMA. 2020;323(20):2098.
  • 66
    Shi S, Qin M, Shen B, Cai Y, Liu T, Yang F, et al. Association of cardiac injury with mortality in hospitalized patients with COVID-19 in Wuhan, China. JAMA Cardiol. 2020;5(7):802-10.
  • 67
    Mao L, Jin H, Wang M, Hu Y, Chen S, He Q, et al. Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China. JAMA Neurol. 2020;77(6):683-90.
  • 68
    Spinato G, Fabbris C, Polesel J, Cazzador D, Borsetto D, Hopkins C, et al. Alterations in smell or taste in mildly symptomatic outpatients with SARS-CoV-2 infection. JAMA. 2020;323(20):2089-90.
  • 69
    Hirsch JS, Ng JH, Ross DW, Sharma P, Shah HH, Barnett RL, Hazzan AD, Fishbane S, Jhaveri KD; Northwell COVID-19 Research Consortium; Northwell Nephrology COVID-19 Research Consortium. Acute kidney injury in patients hospitalized with COVID-19. Kidney Int. 2020;98(1):209-18.
  • 70
    Cheng Y, Luo R, Wang K, Zhang M, Wang Z, Dong L, et al. Kidney disease is associated with in-hospital death of patients with COVID-19. Kidney Int. 2020;97(5):829-38.
  • 71
    Cummings MJ, Baldwin MR, Abrams D, Jacobson SD, Meyer BJ, Balough EM, et al. Epidemiology, clinical course, and outcomes of critically ill adults with COVID-19 in New York City: a prospective cohort study. Lancet. 2020;395(10239):1763-70.
  • 72
    Valeri AM, Robbins-Juarez SY, Stevens JS, Ahn W, Rao MK, Radhakrishnan J, et al. Presentation and outcomes of patients with ESKD and COVID-19. J Am Soc Nephrol. 2020;31(7):1409-15.
  • 73
    Chen M, Zhou W, Xu W. Thyroid function analysis in 50 patients with COVID-19: a retrospective study. Thyroid. 2021;31(1):8-11.
  • 74
    CDC COVID-19 Response Team. Preliminary estimates of the prevalence of selected underlying health conditions among patients with coronavirus disease 2019 - United States, February 12-March 28, 2020. MMWR Morb Mortal Wkly Rep. 2020;69(13):382-6.
  • 75
    Recalcati S. Cutaneous manifestations in COVID-19: a first perspective. J Eur Acad Dermatol Venereol. 2020;34(5):e212-e213.
  • 76
    World Health Organization (WHO). COVID-19 Clinical management: living guidance. 25 January 2021. Available from: file:///C:/Users/elisabete.freitas/Downloads/WHO-2019-nCoV-clinical-2021.1-eng.pdf
  • 77
    República Portuguesa. Serviço Nacional de Saúde. Direçao Geral de Saúde. Norma 019/2020 - Estratégia nacional de testes para SARS-CoV-2. 2020. Disponível em: https://covid19.min-saude.pt/wp-content/uploads/2021/03/Norma_019_2020_act_26_02_2021.pdf
    » https://covid19.min-saude.pt/wp-content/uploads/2021/03/Norma_019_2020_act_26_02_2021.pdf
  • 78
    Crozier A, Rajan S, Buchan I, McKee M. Put to the test: use of rapid testing technologies for covid-19. BMJ. 2021;372:n208.
  • 79
    Miller JM, Binnicker MJ, Campbell S, Carroll KC, Chapin KC, Gilligan PH, et al. A Guide to Utilization of the Microbiology Laboratory for Diagnosis of Infectious Diseases: 2018 Update by the Infectious Diseases Society of America and the American Society for Microbiology. Clin Infect Dis. 2018;67(6):e1-e94.
  • 80
    Landry ML. Immunoglobulin M for acute infection: true or false? Clin Vaccine Immunol. 2016;23(7):540-5.
  • 81
    Heymann DL. Data sharing and outbreaks: best practice exemplified. Lancet. 2020;395(10223):469-70.
  • 82
    American College of Radiology (ACR). ACR recommendations for the use of chest radiography and computed tomography (CT) for suspected COVID-19 infection. March 11, 2020. Available from: https://www.acr.org/Advocacy-and-Economics/ACR-Position-Statements/Recommendations-for-Chest-Radiography-and-CT-for-Suspected-COVID19-Infection
    » https://www.acr.org/Advocacy-and-Economics/ACR-Position-Statements/Recommendations-for-Chest-Radiography-and-CT-for-Suspected-COVID19-Infection
  • 83
    Bouadma L, Lescure FX, Lucet JC, Yazdanpanah Y, Timsit JF. Severe SARS-CoV-2 infections: practical considerations and management strategy for intensivists. Intensive Care Med. 2020;46(4):579-82.
  • 84
    Kim D, Quinn J, Pinsky B, Shah NH, Brown I. Rates of co-infection between SARS-CoV-2 and other respiratory pathogens. JAMA. 2020;323(20):2085-6.
  • 85
    van Arkel AL, Rijpstra TA, Belderbos HN, van Wijngaarden P, Verweij PE, Bentvelsen RG. COVID-19-associated Pulmonary Aspergillosis. Am J Respir Crit Care Med. 2020;202(1):132-5.
  • 86
    Vergano M, Bertolini G, Giannini A, Gristina GR, Livigni S, Mistraletti G, et al. Clinical ethics recommendations for the allocation of intensive care treatments in exceptional, resource-limited circumstances: the Italian perspective during the COVID-19 epidemic. Crit Care. 2020;24(1):165.
  • 87
    National Institute for Health and Care Excellence (NICE). COVID-19 rapid guideline: critical care in adults. NICE guideline [NG159]. March 20, 2020. Available from: https://www.nice.org.uk/guidance/ng159
    » https://www.nice.org.uk/guidance/ng159
  • 88
    Moutel G. Anticipating the role of the intensive care unit in healthcare and life trajectories. Ann Transl Med. 2017;5(Suppl 4):S37.
  • 89
    Dove ES, Kelly SE, Lucivero F, Machirori M, Dheensa S, Prainsack B. Beyond individualism: is there a place for relational autonomy in clinical practice and research? Clin Ethics. 2017;12(3):150-65.
  • 90
    Robert R, Kentish-Barnes N, Boyer A, Laurent A, Azoulay E, Reignier J. Ethical dilemmas due to the Covid-19 pandemic. Ann Intensive Care. 2020;10(1):84.
  • 91
    Kon AA, Davidson JE, Morrison W, Danis M, White DB; American College of Critical Care Medicine; American Thoracic Society. Shared Decision Making in ICUs: An American College of Critical Care Medicine and American Thoracic Society Policy Statement. Crit Care Med. 2016;44(1):188-201.
  • 92
    Christian MD, Sprung CL, King MA, Dichter JR, Kissoon N, Devereaux AV, Gomersall CD; Task Force for Mass Critical Care; Task Force for Mass Critical Care. Triage: care of the critically ill and injured during pandemics and disasters: CHEST consensus statement. Chest. 2014;146(4 Suppl):e61S-74S.
  • 93
    República Portuguesa. Serviço Nacional de Saúde. Direçao Geral de Saúde. Norma 07/2020. Prevenção e Controlo de Infeção por SARS-CoV-2 (COVID-19): Equipamentos de Proteção Individual (EPI). 29/03/2020. Disponível em https://www.dgs.pt/directrizes-da-dgs/normas-e-circulares-normativas/norma-n-0072020-de-29032020-pdf.aspx
    » https://www.dgs.pt/directrizes-da-dgs/normas-e-circulares-normativas/norma-n-0072020-de-29032020-pdf.aspx
  • 94
    World Health Organization. Rational use of personal protective equipment for coronavirus disease 2019 (COVID-19). 2020.
  • 95
    European Centre for Disease Prevention and Control (ECDC). Guidance for wearing and removing personal protective equipment in healthcare settings for the care of patients with suspected or confirmed COVID-19. 28 Feb 2020. Available from https://www.ecdc.europa.eu/en/publications-data/guidance-wearing-and-removing-personal-protective-equipment-healthcare-settings
    » https://www.ecdc.europa.eu/en/publications-data/guidance-wearing-and-removing-personal-protective-equipment-healthcare-settings
  • 96
    Loeb M, Dafoe N, Mahony J, John M, Sarabia A, Glavin V, et al. Surgical mask vs N95 respirator for preventing influenza among health care workers: a randomized trial. JAMA. 2009;302(17):1865-71.
  • 97
    Long Y, Hu T, Liu L, Chen R, Guo Q, Yang L, et al. Effectiveness of N95 respirators versus surgical masks against influenza: A systematic review and meta-analysis. J Evid Based Med. 2020;13(2):93-101.
  • 98
    Alhazzani W, Moller MH, Arabi YM, Loeb M, Gong MN, Fan E, et al. Surviving Sepsis Campaign: guidelines on the management of critically ill adults with Coronavirus Disease 2019 (COVID-19). Intensive Care Med. 2020;46(5):854-87.
  • 99
    Brooks JT, Beezhold DH, Noti JD, Coyle JP, Derk RC, Blachere FM, et al. Maximizing fit for cloth and medical procedure masks to improve performance and reduce SARS-CoV-2 transmission and exposure, 2021. MMWR Morb Mortal Wkly Rep. 2021;70(7):254-7.
  • 100
    Rhodes A, Ferdinande P, Flaatten H, Guidet B, Metnitz PG, Moreno RP. The variability of critical care bed numbers in Europe. Intensive Care Med. 2012;38(10):1647-53.
  • 101
    Paiva JA, Almeida-Sousa JP, Araújo R, Bento L, Branco M, Câmara M, Catorze N, Gomes R, Martins AP, Mergulhão P, Nunez D, Gouveia J; Task Force Medicina Intensiva da DGS para COVID-19. Linhas orientadoras dos planos de contingência dos Serviços e da Rede de Medicina Intensiva para o doente COVID-19 crítico. 2020. Disponível em https://www.spci.pt/media/covid-19/Task-Force-Medicina-Intensiva-COVID19-final-v4.pdf
    » https://www.spci.pt/media/covid-19/Task-Force-Medicina-Intensiva-COVID19-final-v4.pdf
  • 102
    Wax RS, Christian MD. Practical recommendations for critical care and anesthesiology teams caring for novel coronavirus (2019-nCoV) patients. Can J Anaesth. 2020;67(5):568-76.
  • 103
    Vargas M, De Marco G, De Simone S, Servillo G. Logistic and organizational aspects of a dedicated intensive care unit for COVID-19 patients. Crit Care. 2020;24(1):237.
  • 104
    Rose L, Yu L, Casey J, Cook A, Metaxa V, Pattison N, et al. Communication and virtual visiting for families of patients in intensive care during COVID-19: A UK National Survey. Ann Am Thorac Soc. 2021 Feb 22. doi: 10.1513/AnnalsATS.202012-1500OC.
    » https://doi.org/10.1513/AnnalsATS.202012-1500OC
  • 105
    van den Boom W, Hoy M, Sankaran J, Liu M, Chahed H, Feng M, et al. The search for optimal oxygen saturation targets in critically ill patients: observational data from large ICU databases. Chest. 2020;157(3):566-73.
  • 106
    Chu DK, Kim LH, Young PJ, Zamiri N, Almenawer SA, Jaeschke R, et al. Mortality and morbidity in acutely ill adults treated with liberal versus conservative oxygen therapy (IOTA): a systematic review and meta-analysis. Lancet. 2018;391(10131):1693-705.
  • 107
    Winck JC, Scala R. Non-invasive respiratory support paths in hospitalized patients with COVID-19: proposal of an algorithm. Pulmonology. 2021;27(4):305-12.
  • 108
    Binks AC, Parkinson SM, Sabbouh V. Oxygen: under or over a surgical facemask for COVID-19 patients? Anaesthesia. 2020;75(12):1691-2.
  • 109
    Mermilliod G, Hansen P, Salemi C. Prolonged, multipatient use of oxygen humidifier bottles. Infect Control Hosp Epidemiol. 1994;15(2):70-1.
  • 110
    Rhame FS, Streifel A, McComb C, Boyle M. Bubbling humidifiers produce microaerosols which can carry bacteria. Infect Control. 1986;7(8):403-7.
  • 111
    Cheung JC, Ho LT, Cheng JV, Cham EY, Lam KN. Staff safety during emergency airway management for COVID-19 in Hong Kong. Lancet Respir Med. 2020;8(4):e19.
  • 112
    Hui DS, Chow BK, Lo T, Tsang OT, Ko FW, Ng SS, et al. Exhaled air dispersion during high-flow nasal cannula therapy versus CPAP via different masks. Eur Respir J. 2019;53(4):1802339.
  • 113
    Leonard S, Volakis LI, DeBellis R, Kahlon A, Mayar S, Dungan II GC. Transmission Assessment Report: High Velocity Nasal Insufflation (HVNI) Therapy Application in Management of COVID-19. VAPOTHERM, 2020. Available from: https://content.vapotherm.com/hubfs/COVID-19%20Transmission%20Assessment%20Report.pdf
    » https://content.vapotherm.com/hubfs/COVID-19%20Transmission%20Assessment%20Report.pdf
  • 114
    Raoof S, Nava S, Carpati C, Hill NS. High flow, non-invasive ventilation and awake (non-intubation) proning in covid-19 patients with respiratory failure. Chest. 2020;158(5):1992-2002.
  • 115
    Siempos II, Xourgia E, Ntaidou TK, Zervakis D, Magira EE, Kotanidou A, et al. Effect of early vs. delayed or no intubation on clinical outcomes of patients with COVID-19: an observational study. Front Med (Lausanne). 2020;7:614152.
  • 116
    Lee YH, Choi KJ, Choi SH, Lee SY, Kim KC, Kim EJ, et al. Clinical significance of timing of intubation in critically ill patients with COVID-19: a multi-center retrospective study. J Clin Med. 2020;9(9):2847.
  • 117
    Papoutsi E, Giannakoulis VG, Xourgia E, Routsi C, Kotanidou A, Siempos II. Effect of timing of intubation on clinical outcomes of critically ill patients with COVID-19: a systematic review and meta-analysis of non-randomized cohort studies. Crit Care. 2021;25(1):121.
  • 118
    Dupuis C, Bouadma L, de Montmollin E, Goldgran-Toledano D, Schwebel C, Reignier J, et al. Association between early invasive mechanical ventilation and day-60 mortality in acute hypoxemic respiratory failure related to coronavirus disease-2019 pneumonia. Crit Care Explor. 2021;3(1):e0329.
  • 119
    Frat JP, Thille AW, Mercat A, Girault C, Ragot S, Perbet S, Prat G, Boulain T, Morawiec E, Cottereau A, Devaquet J, Nseir S, Razazi K, Mira JP, Argaud L, Chakarian JC, Ricard JD, Wittebole X, Chevalier S, Herbland A, Fartoukh M, Constantin JM, Tonnelier JM, Pierrot M, Mathonnet A, Béduneau G, Delétage-Métreau C, Richard JC, Brochard L, Robert R; FLORALI Study Group; REVA Network. High-flow oxygen through nasal cannula in acute hypoxemic respiratory failure. N Engl J Med. 2015;372(23):2185-96.
  • 120
    Rochwerg B, Granton D, Wang DX, Helviz Y, Einav S, Frat JP, et al. High flow nasal cannula compared with conventional oxygen therapy for acute hypoxemic respiratory failure: a systematic review and meta-analysis. Intensive Care Med. 2019;45(5):563-72.
  • 121
    Ferreyro BL, Angriman F, Munshi L, Del Sorbo L, Ferguson ND, Rochwerg B, et al. Association of noninvasive oxygenation strategies with all-cause mortality in adults with acute hypoxemic respiratory failure: a systematic review and meta-analysis. JAMA. 2020;324(1):57-67.
  • 122
    Rochwerg B, Solo K, Darzi A, Chen G, Khamis AM; COVID-19 Systematic Urgent Review Group Effort (SURGE) Study Authors, et al. Update alert: ventilation techniques and risk for transmission of coronavirus disease, including COVID-19. Ann Intern Med. 2020;173(6):W122.
  • 123
    Wang K, Zhao W, Li J, Shu W, Duan J. The experience of high-flow nasal cannula in hospitalized patients with 2019 novel coronavirus-infected pneumonia in two hospitals of Chongqing, China. Ann Intensive Care. 2020;10(1):37.
  • 124
    Roca O, Caralt B, Messika J, Samper M, Sztrymf B, Hernández G, et al. An index combining respiratory rate and oxygenation to predict outcome of nasal high-flow therapy. Am J Respir Crit Care Med. 2019;199(11):1368-76.
  • 125
    Noeman-Ahmed Y, Gokaraju S, Powrie DJ, Amran DA, El Sayed I, Roshdy A. Predictors of CPAP outcome in hospitalized COVID-19 patients. Respirology. 2020;25(12):1316-9.
  • 126
    Burns GP, Lane ND, Tedd HM, Deutsch E, Douglas F, West SD, et al. Improved survival following ward-based non-invasive pressure support for severe hypoxia in a cohort of frail patients with COVID-19: retrospective analysis from a UK teaching hospital. BMJ Open Respir Res. 2020;7(1):e000621.
  • 127
    Calligaro GL, Lalla U, Audley G, Gina P, Miller MG, Mendelson M, et al. The utility of high-flow nasal oxygen for severe COVID-19 pneumonia in a resource-constrained setting: a multi-centre prospective observational study. EClinicalMedicine. 2020;28:100570.
  • 128
    Hui DS, Chow BK, Lo T, Ng SS, Ko FW, Gin T, et al. Exhaled air dispersion during noninvasive ventilation via helmets and a total facemask. Chest. 2015;147(5):1336-43.
  • 129
    Vargas F, Thille A, Lyazidi A, Campo FR, Brochard L. Helmet with specific settings versus facemask for noninvasive ventilation. Crit Care Med. 2009;37(6):1921-8.
  • 130
    Osadnik CR, Tee VS, Carson-Chahhoud KV, Picot J, Wedzicha JA, Smith BJ. Non-invasive ventilation for the management of acute hypercapnic respiratory failure due to exacerbation of chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2017;7(7):CD004104.
  • 131
    Vital FM, Ladeira MT, Atallah AN. Non-invasive positive pressure ventilation (CPAP or bilevel NPPV) for cardiogenic pulmonary oedema. Cochrane Database Syst Rev. 2013;(5):CD005351.
  • 132
    Grieco DL, Menga LS, Cesarano M, Rosà T, Spadaro S, Bitondo MM, Montomoli J, Falò G, Tonetti T, Cutuli SL, Pintaudi G, Tanzarella ES, Piervincenzi E, Bongiovanni F, Dell’Anna AM, Delle Cese L, Berardi C, Carelli S, Bocci MG, Montini L, Bello G, Natalini D, De Pascale G, Velardo M, Volta CA, Ranieri VM, Conti G, Maggiore SM, Antonelli M; COVID-ICU Gemelli Study Group. Effect of Helmet Noninvasive Ventilation vs High-Flow Nasal Oxygen on Days Free of Respiratory Support in Patients With COVID-19 and Moderate to Severe Hypoxemic Respiratory Failure: The HENIVOT Randomized Clinical Trial. JAMA. 2021;325(17):1731-43.
  • 133
    Duan J, Han X, Bai L, Zhou L, Huang S. Assessment of heart rate, acidosis, consciousness, oxygenation, and respiratory rate to predict noninvasive ventilation failure in hypoxemic patients. Intensive Care Med. 2017;43(2):192-9.
  • 134
    Aliberti S, Radovanovic D, Billi F, Sotgiu G, Costanzo M, Pilocane T, et al. Helmet CPAP treatment in patients with COVID-19 pneumonia: a multicentre cohort study. Eur Respir J. 2020;56(4):2001935.
  • 135
    Carteaux G, Millán-Guilarte T, De Prost N, Razazi K, Abid S, Thille AW, et al. Failure of noninvasive ventilation for de novo acute hypoxemic respiratory failure: role of tidal volume. Crit Care Med. 2016;44(2):282-90.
  • 136
    Ding L, Wang L, Ma W, He H. Efficacy and safety of early prone positioning combined with HFNC or NIV in moderate to severe ARDS: a multi-center prospective cohort study. Crit Care. 2020;24(1):28.
  • 137
    Sun Q, Qiu H, Huang M, Yang Y. Lower mortality of COVID-19 by early recognition and intervention: experience from Jiangsu Province. Ann Intensive Care. 2020;10(1):33.
  • 138
    Caputo ND, Strayer RJ, Levitan R. Early self-proning in awake, non-intubated patients in the emergency department: a single ED’s experience during the COVID-19 pandemic. Acad Emerg Med. 2020;27(5):375-8.
  • 139
    Weatherald J, Solverson K, Zuege DJ, Loroff N, Fiest KM, Parhar KK. Awake prone positioning for COVID-19 hypoxemic respiratory failure: a rapid review. J Crit Care. 2021;61:63-70.
  • 140
    Blez D, Soulier A, Bonnet F, Gayat E, Garnier M. Monitoring of high-flow nasal cannula for SARS-CoV-2 severe pneumonia: less is more, better look at respiratory rate. Intensive Care Med. 2020;46(11):2094-5.
  • 141
    Cable C, Bell D, Gallo de Moraes A, Kaul V. Timing of intubation in patients with COVID-19. Chest NetWorks. 2021. Available from: https://www.chestnet.org/topic-collections/covid-19/covid-in-focus/timing-of-intubation-in-patients-with-covid-19
    » https://www.chestnet.org/topic-collections/covid-19/covid-in-focus/timing-of-intubation-in-patients-with-covid-19
  • 142
    Vaporidi K, Akoumianaki E, Telias I, Goligher EC, Brochard L, Georgopoulos D. Respiratory drive in critically ill patients. Pathophysiology and clinical implications. Am J Respir Crit Care Med. 2020;201(1):20-32.
  • 143
    Vivier E, Mekontso Dessap A, Dimassi S, Vargas F, Lyazidi A, Thille AW, et al. Diaphragm ultrasonography to estimate the work of breathing during non-invasive ventilation. Intensive Care Med. 2012;38(5):796-803.
  • 144
    Peng PW, Ho PL, Hota SS. Outbreak of a new coronavirus: what anaesthetists should know. Br J Anaesth. 2020;124(5):497-501.
  • 145
    Papazian L, Aubron C, Brochard L, Chiche JD, Combes A, Dreyfuss D, et al. Formal guidelines: management of acute respiratory distress syndrome. Ann Intensive Care. 2019;9(1):69.
  • 146
    Acute Respiratory Distress Syndrome Network, Brower RG, Matthay MA, Morris A, Schoenfeld D, Thompson BT, et al. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med. 2000;342(18):1301-8.
  • 147
    Walkey AJ, Goligher EC, Del Sorbo L, Hodgson CL, Adhikari NK, Wunsch H, et al. Low tidal volume versus non-volume-limited strategies for patients with acute respiratory distress syndrome. A systematic review and meta-analysis. Ann Am Thorac Soc. 2017;14(Suppl 4):S271-9.
  • 148
    Amato MB, Meade MO, Slutsky AS, Brochard L, Costa EL, Schoenfeld DA, et al. Driving pressure and survival in the acute respiratory distress syndrome. N Engl J Med. 2015;372(8):747-55.
  • 149
    Guérin C, Reignier J, Richard JC, Beuret P, Gacouin A, Boulain T, Mercier E, Badet M, Mercat A, Baudin O, Clavel M, Chatellier D, Jaber S, Rosselli S, Mancebo J, Sirodot M, Hilbert G, Bengler C, Richecoeur J, Gainnier M, Bayle F, Bourdin G, Leray V, Girard R, Baboi L, Ayzac L; PROSEVA Study Group. Prone positioning in severe acute respiratory distress syndrome. N Engl J Med. 2013;368(23):2159-68.
  • 150
    Papazian L, Forel JM, Gacouin A, Penot-Ragon C, Perrin G, Loundou A, Jaber S, Arnal JM, Perez D, Seghboyan JM, Constantin JM, Courant P, Lefrant JY, Guérin C, Prat G, Morange S, Roch A; ACURASYS Study Investigators. Neuromuscular blockers in early acute respiratory distress syndrome. N Engl J Med. 2010;363(12):1107-16.
  • 151
    Jonkman AH, de Vries HJ, Heunks LM. Physiology of the respiratory drive in ICU patients: implications for diagnosis and treatment. Crit Care. 2020;24(1):104.
  • 152
    Brower RG, Lanken PN, MacIntyre N, Matthay MA, Morris A, Ancukiewicz M, Schoenfeld D, Thompson BT; National Heart, Lung, and Blood Institute ARDS Clinical Trials Network. Higher versus lower positive end-expiratory pressures in patients with the acute respiratory distress syndrome. N Engl J Med. 2004;351(4):327-36.
  • 153
    Meade MO, Cook DJ, Guyatt GH, Slutsky AS, Arabi YM, Cooper DJ, Davies AR, Hand LE, Zhou Q, Thabane L, Austin P, Lapinsky S, Baxter A, Russell J, Skrobik Y, Ronco JJ, Stewart TE; Lung Open Ventilation Study Investigators. Ventilation strategy using low tidal volumes, recruitment maneuvers, and high positive end-expiratory pressure for acute lung injury and acute respiratory distress syndrome: a randomized controlled trial. JAMA. 2008;299(6):637-45.
  • 154
    Mercat A, Richard JC, Vielle B, Jaber S, Osman D, Diehl JL, Lefrant JY, Prat G, Richecoeur J, Nieszkowska A, Gervais C, Baudot J, Bouadma L, Brochard L; Expiratory Pressure (Express) Study Group. Positive end-expiratory pressure setting in adults with acute lung injury and acute respiratory distress syndrome: a randomized controlled trial. JAMA. 2008;299(6):646-55.
  • 155
    Writing Group for the Alveolar Recruitment for Acute Respiratory Distress Syndrome Trial (ART) Investigators, Cavalcanti AB, Suzumura EA, Laranjeira LN, Paisani DM, Damiani LP, et al. 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. JAMA. 2017;318(14):1335-45.
  • 156
    Ball L, Robba C, Maiello L, Herrmann J, Gerard SE, Xin Y, Battaglini D, Brunetti I, Minetti G, Seitun S, Vena A, Giacobbe DR, Bassetti M, Rocco PR, Cereda M, Castellan L, Patroniti N, Pelosi P; GECOVID (GEnoa COVID-19) group. Computed tomography assessment of PEEP-induced alveolar recruitment in patients with severe COVID-19 pneumonia. Crit Care. 2021;25(1):81.
  • 157
    Chen L, Del Sorbo L, Grieco DL, Junhasavasdikul D, Rittayamai N, Soliman I, et al. Potential for lung recruitment estimated by the recruitment-to-inflation ratio in acute respiratory distress syndrome. A clinical trial. Am J Respir Crit Care Med. 2020;201(2):178-87.
  • 158
    Gebistorf F, Karam O, Wetterslev J, Afshari A. Inhaled nitric oxide for acute respiratory distress syndrome (ARDS) in children and adults. Cochrane Database Syst Rev. 2016;2016(6):CD002787.
  • 159
    Longobardo A, Montanari C, Shulman R, Benhalim S, Singer M, Arulkumaran N. Inhaled nitric oxide minimally improves oxygenation in COVID-19 related acute respiratory distress syndrome. Br J Anaesth. 2021;126(1):e44-6.
  • 160
    Podcast Sociedade Portuguesa de Cuidados Intensivos (SPCI). Webninar COVID-19 - 23 Março 2020. Learning with the Italian experience. Com o Dr. Tommaso Mauri, Professor José Artur Paiva, Dr. João Gouveia e Dr. Filipe Froes. Available from: https://www.spci.pt/webinar-covid19-23-marco-2020
    » https://www.spci.pt/webinar-covid19-23-marco-2020
  • 161
    Subirà C, Hernández G, Vázquez A, Rodríguez-García R, González-Castro A, García C, et al. Effect of pressure support vs T-piece ventilation strategies during spontaneous breathing trials on successful extubation among patients receiving mechanical ventilation: a randomized clinical Trial. JAMA. 2019;321(22):2175-82.
  • 162
    MacIntyre NR, Cook DJ, Ely EW Jr, Epstein SK, Fink JB, Heffner JE, Hess D, Hubmayer RD, Scheinhorn DJ; American College of Chest Physicians; American Association for Respiratory Care; American College of Critical Care Medicine. Evidence-based guidelines for weaning and discontinuing ventilatory support: a collective task force facilitated by the American College of Chest Physicians; the American Association for Respiratory Care; and the American College of Critical Care Medicine. Chest. 2001;120(6 Suppl):375S-95S.
  • 163
    Rosano A, Martinelli E, Fusina F, Albani F, Caserta R, Morandi A, et al. Early percutaneous tracheostomy in coronavirus disease 2019: association with hospital mortality and factors associated with removal of tracheostomy tube at ICU discharge. A cohort study on 121 patients. Crit Care Med. 2021;49(2):261-70.
  • 164
    Sociedade Portuguesa de Otorrinolaringologia e Cirurgia da Cabeça e Pescoço (SPORL-CCP), Colégio da Especialidade de Otorrinolaringologia da Ordem dos Médicos. Recomendações para a realização de traqueotomia em doente com COVID-19. 24 de março de 2020. Disponível em: https://www.sporl.pt/traqueotomia
    » https://www.sporl.pt/traqueotomia
  • 165
    Sociedade Portuguesa de Pneumologia. Comissão de Técnicas Endoscópicas. Documento de posição da Sociedade Portuguesa de Pneumologia para a realização de broncoscopias durante o surto de COVID-19. 2020. Disponível em: https://www.sppneumologia.pt/uploads/subcanais2_conteudos_ficheiros/posicao-da-spp-para-a-realizacao-de-broncoscopias-durante-a-pandemia-do-coronavirus-(2).pdf
    » https://www.sppneumologia.pt/uploads/subcanais2_conteudos_ficheiros/posicao-da-spp-para-a-realizacao-de-broncoscopias-durante-a-pandemia-do-coronavirus-(2).pdf
  • 166
    Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention (2020 update). Available from: https://webmed.irkutsk.ru/doc/pdf/ginareport.pdf
    » https://webmed.irkutsk.ru/doc/pdf/ginareport.pdf
  • 167
    Rajagopal K, Keller SP, Akkanti B, Bime C, Loyalka P, Cheema FH, et al. Advanced Pulmonary and Cardiac Support of COVID-19 Patients: Emerging Recommendations from ASAIO-A “Living Working Document”. ASAIO J. 2020;66(6):588-98.
  • 168
    Zeng Y, Cai Z, Xianyu Y, Yang BX, Song T, Yan Q. Prognosis when using extracorporeal membrane oxygenation (ECMO) for critically ill COVID-19 patients in China: a retrospective case series. Crit Care. 2020;24(1):148.
  • 169
    Ramanathan K, Antognini D, Combes A, Paden M, Zakhary B, Ogino M, et al. Planning and provision of ECMO services for severe ARDS during the COVID-19 pandemic and other outbreaks of emerging infectious diseases. Lancet Respir Med. 2020;8(5):518-26.
  • 170
    Henry BM. COVID-19, ECMO, and lymphopenia: a word of caution. Lancet Respir Med. 2020;8(4):e24.
  • 171
    EuroELSO. Coronavirus. Survey on ECMO use. Available from: https://www.euroelso.net/covid-19/covid-19-survey/
    » https://www.euroelso.net/covid-19/covid-19-survey/
  • 172
    Abrams D, Brodie D. Extracorporeal Membrane Oxygenation for Adult Respiratory Failure: 2017 Update. Chest. 2017;152(3):639-49.
  • 173
    Badulak J, Antonini MV, Stead CM, Shekerdemian L, Raman L, Paden ML, Agerstrand C, Bartlett RH, Barrett N, Combes A, Lorusso R, Mueller T, Ogino MT, Peek G, Pellegrino V, Rabie AA, Salazar L, Schmidt M, Shekar K, MacLaren G, Brodie D; ELSO COVID-19 Working Group Members. Extracorporeal Membrane Oxygenation for COVID-19: Updated 2021 Guidelines from the Extracorporeal Life Support Organization. ASAIO J. 2021;67(5):485-95
  • 174
    Camporota L, Meadows C, Ledot S, Scott I, Harvey C, Garcia M, Vuylsteke A; NHS England ECMO Service. Consensus on the referral and admission of patients with severe respiratory failure to the NHS ECMO service. Lancet Respir Med. 2021;9(2):e16-7.
  • 175
    Lazzeri C, Bonizzoli M, Batacchi S, Cianchi G, Franci A, Fulceri GE, et al. Cardiac involvment in COVID-19-related acute respiratory distress syndrome. Am J Cardiol. 2020;132:147-9.
  • 176
    Doyen D, Moceri P, Ducreux D, Dellamonica J. Myocarditis in a patient with COVID-19: a cause of raised troponin and ECG changes. Lancet. 2020;395(10235):1516.
  • 177
    Salamanca J, Díez-Villanueva P, Martínez P, Cecconi A, González de Marcos B, Reyes G, et al. COVID-19 “Fulminant Myocarditis” successfully treated with temporary mechanical circulatory support. JACC Cardiovasc Imaging. 2020;13(11):2457-9.
  • 178
    Barbaro RP, Odetola FO, Kidwell KM, Paden ML, Bartlett RH, Davis MM, et al. Association of hospital-level volume of extracorporeal membrane oxygenation cases and mortality. Analysis of the extracorporeal life support organization registry. Am J Respir Crit Care Med. 2015;191(8):894-901.
  • 179
    Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315(8):801-10.
  • 180
    Wu Z, McGoogan JM. Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72314 Cases From the Chinese Center for Disease Control and Prevention. JAMA. 2020;323(13):1239-42.
  • 181
    Yang X, Yu Y, Xu J, Shu H, Xia J, Liu H, et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med. 2020;8(5):475-81.
  • 182
    Malbrain ML, Van Regenmortel N, Saugel B, De Tavernier B, Van Gaal PJ, Joannes-Boyau O, et al. Principles of fluid management and stewardship in septic shock: it is time to consider the four D’s and the four phases of fluid therapy. Ann Intensive Care. 2018;8(1):66.
  • 183
    Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Crit Care Med. 2017;45(3):486-552.
  • 184
    Brown RM, Wang L, Coston TD, Krishnan NI, Casey JD, Wanderer JP, et al. Balanced crystalloids versus saline in sepsis. A secondary analysis of the SMART clinical trial. Am J Respir Crit Care Med. 2019;200(12):1487-95.
  • 185
    Lewis SR, Pritchard MW, Evans DJ, Butler AR, Alderson P, Smith AF, et al. Colloids versus crystalloids for fluid resuscitation in critically ill people. Cochrane Database Syst Rev. 2018;8(8):CD000567.
  • 186
    Bednarczyk JM, Fridfinnson JA, Kumar A, Blanchard L, Rabbani R, Bell D, et al. Incorporating dynamic assessment of fluid responsiveness into goal-directed therapy: a systematic review and meta-analysis. Crit Care Med. 2017;45(9):1538-45.
  • 187
    Bentzer P, Griesdale DE, Boyd J, MacLean K, Sirounis D, Ayas NT. Will this hemodynamically unstable patient respond to a bolus of intravenous fluids? JAMA. 2016;316(12):1298-309.
  • 188
    Gamper G, Havel C, Arrich J, Losert H, Pace NL, Müllner M, et al. Vasopressors for hypotensive shock. Cochrane Database Syst Rev. 2016;2(2):CD003709.
  • 189
    Asfar P, Meziani F, Hamel JF, Grelon F, Megarbane B, Anguel N, Mira JP, Dequin PF, Gergaud S, Weiss N, Legay F, Le Tulzo Y, Conrad M, Robert R, Gonzalez F, Guitton C, Tamion F, Tonnelier JM, Guezennec P, Van Der Linden T, Vieillard-Baron A, Mariotte E, Pradel G, Lesieur O, Ricard JD, Hervé F, du Cheyron D, Guerin C, Mercat A, Teboul JL, Radermacher P; SEPSISPAM Investigators. High versus low blood-pressure target in patients with septic shock. N Engl J Med. 2014;370(17):1583-93.
  • 190
    Moller MH, Granholm A, Junttila E, Haney M, Oscarsson-Tibblin A, Haavind A, et al. Scandinavian SSAI clinical practice guideline on choice of inotropic agent for patients with acute circulatory failure. Acta Anaesthesiol Scand. 2018;62(4):420-50.
  • 191
    Rygard SL, Butler E, Granholm A, Moller MH, Cohen J, Finfer S, et al. Low-dose corticosteroids for adult patients with septic shock: a systematic review with meta-analysis and trial sequential analysis. Intensive Care Med. 2018;44(7):1003-16.
  • 192
    Hernández G, Ospina-Tascón GA, Damiani LP, Estenssoro E, Dubin A, Hurtado J, et al. Effect of a resuscitation strategy targeting peripheral perfusion status vs serum lactate levels on 28-day mortality among patients with septic shock: the ANDROMEDA-SHOCK randomized clinical trial. JAMA. 2019;321(7):654-64.
  • 193
    Pan J, Peng M, Liao C, Hu X, Wang A, Li X. Relative efficacy and safety of early lactate clearance-guided therapy resuscitation in patients with sepsis: a meta-analysis. Medicine (Baltimore). 2019;98(8):e14453.
  • 194
    Khwaja A. KDIGO clinical practice guidelines for acute kidney injury. Nephron Clin Pract. 2012;120(4):c179-84.
  • 195
    STARRT-AKI Investigators; Canadian Critical Care Trials Group; Australian and New Zealand Intensive Care Society Clinical Trials Group; United Kingdom Critical Care Research Group; Canadian Nephrology Trials Network; Irish Critical Care Trials Group, Bagshaw SM, Wald R, Adhikari NK, Bellomo R, da Costa BR, Dreyfuss D, et al. Timing of initiation of renal-replacement therapy in acute kidney injury. N Engl J Med. 2020;383(3):240-51.
  • 196
    Jaber S, Paugam C, Futier E, Lefrant JY, Lasocki S, Lescot T, Pottecher J, Demoule A, Ferrandière M, Asehnoune K, Dellamonica J, Velly L, Abback PS, de Jong A, Brunot V, Belafia F, Roquilly A, Chanques G, Muller L, Constantin JM, Bertet H, Klouche K, Molinari N, Jung B; BICAR-ICU Study Group. Sodium bicarbonate therapy for patients with severe metabolic acidaemia in the intensive care unit (BICAR-ICU): a multicentre, open-label, randomised controlled, phase 3 trial. Lancet. 2018;392(10141):31-40.
  • 197
    Raza A, Estepa A, Chan V, Jafar MS. Acute renal failure in critically ill COVID-19 patients with a focus on the role of renal replacement therapy: a review of what we know so far. Cureus. 2020;12(6):e8429.
  • 198
    Russell CD, Fairfield CJ, Drake TM, Turtle L, Seaton RA, Wootton DG, Sigfrid L, Harrison EM, Docherty AB, de Silva TI, Egan C, Pius R, Hardwick HE, Merson L, Girvan M, Dunning J, Nguyen-Van-Tam JS, Openshaw PJM, Baillie JK, Semple MG, Ho A; ISARIC4C investigator. Co-infections, secondary infections, and antimicrobial use in patients hospitalised patients with COVID-19 during the first pandemic wave the ISARIC WHO CCP-UK study: a prospective, multicentre cohort study. Lancet Microbe. 2021;2(8):e354-65.
  • 199
    Llitjos JF, Bredin S, Lascarrou JB, Soumagne T, Cojocaru M, Leclerc M, et al. Increased susceptibility to intensive care unit-acquired pneumonia in severe COVID-19 patients: a multicentre retrospective cohort study. Ann Intensive Care. 2021;11(1):20.
  • 200
    Peters C, Williams K, Un EA, Little L, Saad A, Lendrum K, et al. Use of procalcitonin for antibiotic stewardship in patients with COVID-19: a quality improvement project in a district general hospital. Clin Med (Lond). 2021;21(1):e71-6.
  • 201
    Williams EJ, Mair L, de Silva TI, Green DJ, House P, Cawthron K, et al. Evaluation of procalcitonin as a contribution to antimicrobial stewardship in SARS-CoV-2 infection: a retrospective cohort study. J Hosp Infect. 2021;110:103-7.
  • 202
    Rouzé A, Martin-Loeches I, Povoa P, Makris D, Artigas A, Bouchereau M, Lambiotte F, Metzelard M, Cuchet P, Boulle Geronimi C, Labruyere M, Tamion F, Nyunga M, Luyt CE, Labreuche J, Pouly O, Bardin J, Saade A, Asfar P, Baudel JL, Beurton A, Garot D, Ioannidou I, Kreitmann L, Llitjos JF, Magira E, Mégarbane B, Meguerditchian D, Moglia E, Mekontso-Dessap A, Reignier J, Turpin M, Pierre A, Plantefeve G, Vinsonneau C, Floch PE, Weiss N, Ceccato A, Torres A, Duhamel A, Nseir S; coVAPid study Group. Relationship between SARS-CoV-2 infection and the incidence of ventilator-associated lower respiratory tract infections: a European multicenter cohort study. Intensive Care Med. 2021;47(2):188-98.
  • 203
    Blonz G, Kouatchet A, Chudeau N, Pontis E, Lorber J, Lemeur A, et al. Epidemiology and microbiology of ventilator-associated pneumonia in COVID-19 patients: a multicenter retrospective study in 188 patients in an un-inundated French region. Crit Care. 2021;25(1):72.
  • 204
    Wang J, Yang Q, Zhang P, Sheng J, Zhou J, Qu T. Clinical characteristics of invasive pulmonary aspergillosis in patients with COVID-19 in Zhejiang, China: a retrospective case series. Crit Care. 2020;24(1):299.
  • 205
    Bartoletti M, Pascale R, Cricca M, Rinaldi M, Maccaro A, Bussini L, Fornaro G, Tonetti T, Pizzilli G, Francalanci E, Giuntoli L, Rubin A, Moroni A, Ambretti S, Trapani F, Vatamanu O, Ranieri VM, Castelli A, Baiocchi M, Lewis R, Giannella M, Viale P; PREDICO study group. Epidemiology of invasive pulmonary aspergillosis among COVID-19 intubated patients: a prospective study. Clin Infect Dis. 2020:ciaa1065.
  • 206
    Lo MK, Jordan R, Arvey A, Sudhamsu J, Shrivastava-Ranjan P, Hotard AL, et al. GS-5734 and its parent nucleoside analog inhibit Filo-, Pneumo-, and Paramyxoviruses. Sci Rep. 2017;7:43395.
  • 207
    Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020;30(3):269-71.
  • 208
    Williamson BN, Feldmann F, Schwarz B, Meade-White K, Porter DP, Schulz J, et al. Clinical benefit of remdesivir in rhesus macaques infected with SARS-CoV-2. Nature. 2020;585(7824):273-6.
  • 209
    Beigel JH, Tomashek KM, Dodd LE, Mehta AK, Zingman BS, Kalil AC, Hohmann E, Chu HY, Luetkemeyer A, Kline S, Lopez de Castilla D, Finberg RW, Dierberg K, Tapson V, Hsieh L, Patterson TF, Paredes R, Sweeney DA, Short WR, Touloumi G, Lye DC, Ohmagari N, Oh MD, Ruiz-Palacios GM, Benfield T, Fätkenheuer G, Kortepeter MG, Atmar RL, Creech CB, Lundgren J, Babiker AG, Pett S, Neaton JD, Burgess TH, Bonnett T, Green M, Makowski M, Osinusi A, Nayak S, Lane HC; ACTT-1 Study Group Members. Remdesivir for the treatment of Covid-19 - Final report. N Engl J Med. 2020;383(19):1813-26.
  • 210
    Goldman JD, Lye DC, Hui DS, Marks KM, Bruno R, Montejano R, Spinner CD, Galli M, Ahn MY, Nahass RG, Chen YS, SenGupta D, Hyland RH, Osinusi AO, Cao H, Blair C, Wei X, Gaggar A, Brainard DM, Towner WJ, Muñoz J, Mullane KM, Marty FM, Tashima KT, Diaz G, Subramanian A; GS-US-540-5773 Investigators. Remdesivir for 5 or 10 days in patients with severe Covid-19. N Engl J Med. 2020;383(19):1827-37.
  • 211
    WHO Solidarity Trial Consortium, Pan H, Peto R, Henao-Restrepo AM, Preziosi MP, Sathiyamoorthy V, et al. Repurposed Antiviral Drugs for Covid-19 - Interim WHO Solidarity Trial Results. N Engl J Med. 2021;384(6):497-511.
  • 212
    Wang Y, Zhang D, Du G, Du R, Zhao J, Jin Y, et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet. 2020;395(10236):1569-78.
  • 213
    Alhazzani W, Evans L, Alshamsi F, Moller MH, Ostermann M, Prescott HC, et al. Surviving Sepsis Campaign Guidelines on the Management of Adults With Coronavirus Disease 2019 (COVID-19) in the ICU: First Update. Crit Care Med. 2021;49(3):e219-34.
  • 214
    Arabi YM, Mandourah Y, Al-Hameed F, Sindi AA, Almekhlafi GA, Hussein MA, Jose J, Pinto R, Al-Omari A, Kharaba A, Almotairi A, Al Khatib K, Alraddadi B, Shalhoub S, Abdulmomen A, Qushmaq I, Mady A, Solaiman O, Al-Aithan AM, Al-Raddadi R, Ragab A, Balkhy HH, Al Harthy A, Deeb AM, Al Mutairi H, Al-Dawood A, Merson L, Hayden FG, Fowler RA; Saudi Critical Care Trial Group. Corticosteroid Therapy for Critically Ill Patients with Middle East Respiratory Syndrome. Am J Respir Crit Care Med. 2018;197(6):757-67.
  • 215
    Spagnuolo V, Guffanti M, Galli L, Poli A, Querini PR, Ripa M, et al. Viral clearance after early corticosteroid treatment in patients with moderate or severe covid-19. Sci Rep. 2020;10(1):21291.
  • 216
    Li Q, Li W, Jin Y, Xu W, Huang C, Li L, et al. Efficacy Evaluation of early, low-dose, short-term corticosteroids in adults hospitalized with non-severe COVID-19 pneumonia: a retrospective cohort study. Infect Dis Ther. 2020;9(4):823-36.
  • 217
    Cao B, Wang Y, Wen D, Liu W, Wang J, Fan G, et al. A trial of lopinavir-ritonavir in adults hospitalized with severe Covid-19. N Engl J Med. 2020;382(19):1787-99.
  • 218
    Magagnoli J, Narendran S, Pereira F, Cummings TH, Hardin JW, Sutton SS, et al. Outcomes of hydroxychloroquine usage in United States veterans hospitalized with COVID-19. Med (N Y). 2020;1(1):114-27.e3.
  • 219
    RECOVERY Collaborative Group. Lopinavir-ritonavir in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. Lancet. 2020;396(10259):1345-52.
  • 220
    Chen J, Xia L, Liu L, Xu Q, Ling Y, Huang D, et al. Antiviral activity and safety of darunavir/cobicistat for the treatment of COVID-19. Open Forum Infect Dis. 2020;7(7):ofaa241.
  • 221
    Hayden FG, Shindo N. Influenza virus polymerase inhibitors in clinical development. Curr Opin Infect Dis. 2019;32(2):176-86.
  • 222
    Udwadia ZF, Singh P, Barkate H, Patil S, Rangwala S, Pendse A, et al. Efficacy and safety of favipiravir, an oral RNA-dependent RNA polymerase inhibitor, in mild-to-moderate COVID-19: a randomized, comparative, open-label, multicenter, phase 3 clinical trial. Int J Infect Dis. 2021;103:62-71.
  • 223
    Ivashchenko AA, Dmitriev KA, Vostokova NV, Azarova VN, Blinow AA, Egorova AN, et al. AVIFAVIR for Treatment of Patients with Moderate COVID-19: Interim Results of a Phase II/III Multicenter Randomized Clinical Trial. Clin Infect Dis. 2021;73(3):531-4.
  • 224
    Lou Y, Liu L, Yao H, Hu X, Su J, Xu K, et al. Clinical outcomes and plasma concentrations of baloxavir marboxil and favipiravir in COVID-19 patients: an exploratory randomized, controlled trial. Eur J Pharm Sci. 2021;157:105631.
  • 225
    Chu CM, Cheng VC, Hung IF, Wong MM, Chan KH, Chan KS, Kao RY, Poon LL, Wong CL, Guan Y, Peiris JS, Yuen KY; HKU/UCH SARS Study Group. Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings. Thorax. 2004;59(3):252-6.
  • 226
    Chan KS, Lai ST, Chu CM, Tsui E, Tam CY, Wong MM, et al. Treatment of severe acute respiratory syndrome with lopinavir/ritonavir: a multicentre retrospective matched cohort study. Hong Kong Med J. 2003;9(6):399-406.
  • 227
    Yao X, Ye F, Zhang M, Cui C, Huang B, Niu P, et al. 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). Clin Infect Dis. 2020;71(15):732-9.
  • 228
    Gao J, Tian Z, Yang X. Breakthrough: chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. Biosci Trends. 2020;14(1):72-3.
  • 229
    Gautret P, Lagier JC, Parola P, Hoang VT, Meddeb L, Mailhe M, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents. 2020;56(1):105949.
  • 230
    Multicenter Collaboration Group of Department of Science and Technology of Guangdong Province and Health Commission of Guangdong Province for chloroquine in the treatment of novel coronavirus pneumonia. [Expert consensus on chloroquine phosphate for the treatment of novel coronavirus pneumonia]. Zhonghua Jie He He Hu Xi Za Zhi. 2020;43(3):185-8. Chinese.
  • 231
    Self WH, Semler MW, Leither LM, Casey JD, Angus DC, Brower RG, et al. Effect of Hydroxychloroquine on clinical status at 14 days in hospitalized patients with COVID-19: a randomized clinical trial. JAMA. 2020;324(21):2165-76.
  • 232
    RECOVERY Collaborative Group, Horby P, Mafham M, Linsell L, Bell JL, Staplin N, et al. Effect of hydroxychloroquine in hospitalized patients with Covid-19. N Engl J Med. 2020;383(21):2030-40.
  • 233
    Ulrich RJ, Troxel AB, Carmody E, Eapen J, Backer M, DeHovitz JA, et al. Treating COVID-19 with hydroxychloroquine (TEACH): a multicenter, double-blind randomized controlled trial in hospitalized patients. Open Forum Infect Dis. 2020;7(10):ofaa446.
  • 234
    Lyngbakken MN, Berdal JE, Eskesen A, Kvale D, Olsen IC, Rueegg CS, et al. A pragmatic randomized controlled trial reports lack of efficacy of hydroxychloroquine on coronavirus disease 2019 viral kinetics. Nat Commun. 2020;11(1):5284.
  • 235
    Abd-Elsalam S, Esmail ES, Khalaf M, Abdo EF, Medhat MA, Abd El Ghafar MS, et al. Hydroxychloroquine in the treatment of COVID-19: a multicenter randomized controlled study. Am J Trop Med Hyg. 2020;103(4):1635-9.
  • 236
    Tang W, Cao Z, Han M, Wang Z, Chen J, Sun W, et al. Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial. BMJ. 2020;369:m1849.
  • 237
    Chen L, Zhang ZY, Fu JG, Feng ZP, Zhang SZ, Han QY, et al. Efficacy and safety of chloroquine or hydroxychloroquine in moderate type of COVID-19: a prospective open-label randomized controlled study. medRxiv. 2020:2020.06.19.20136093.
  • 238
    Chen Z, Hu J, Zhang Z, Jiang S, Han S, Yan D, et al. Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial. medRxiv. 2020:2020.03.22.20040758.
  • 239
    Chen J, Liu D, Liu L, Liu P, Xu Q, Xia L, et al. [A pilot study of hydroxychloroquine in treatment of patients with moderate COVID-19]. Zhejiang Da Xue Xue Bao Yi Xue Ban. 2020;49(2):215-9. Chinese.
  • 240
    Chen CP, Lin YC, Chen TC, Tseng TY, Wong HL, Kuo CY, Lin WP, Huang SR, Wang WY, Liao JH, Liao CS, Hung YP, Lin TH, Chang TY, Hsiao CF, Huang YW, Chung WS, Cheng CY, Cheng SH; Taiwan HCQ Study Group. A multicenter, randomized, open-label, controlled trial to evaluate the efficacy and tolerability of hydroxychloroquine and a retrospective study in adult patients with mild to moderate coronavirus disease 2019 (COVID-19). PLoS One. 2020;15(12):e0242763.
  • 241
    Dubée V, Roy PM, Vielle B, Parot-Schinkel E, Blanchet O, Darsonval A, et al. Hydroxychloroquine in mild-to-moderate coronavirus disease 2019: a placebo-controlled double blind trial. Clin Microbiol Infect. 2021;27(8):1124-30.
  • 242
    Cavalcanti AB, Zampieri FG, Rosa RG, Azevedo LC, Veiga VC, Avezum A, Damiani LP, Marcadenti A, Kawano-Dourado L, Lisboa T, Junqueira DL, de Barros E Silva PG, Tramujas L, Abreu-Silva EO, Laranjeira LN, Soares AT, Echenique LS, Pereira AJ, Freitas FG, Gebara OC, Dantas VC, Furtado RH, Milan EP, Golin NA, Cardoso FF, Maia IS, Hoffmann Filho CR, Kormann AP, Amazonas RB, Bocchi de Oliveira MF, Serpa-Neto A, Falavigna M, Lopes RD, Machado FR, Berwanger O; Coalition Covid-19 Brazil I Investigators. Hydroxychloroquine with or without azithromycin in mild-to-moderate Covid-19. N Engl J Med. 2020;383(21):2041-52.
  • 243
    Skipper CP, Pastick KA, Engen NW, Bangdiwala AS, Abassi M, Lofgren SM, et al. Hydroxychloroquine in nonhospitalized adults with early COVID-19 : a randomized trial. Ann Intern Med. 2020;173(8):623-31.
  • 244
    Mitja O, Corbacho-Monné M, Ubals M, Tebe C, Peñafiel J, Tobias A, Ballana E, Alemany A, Riera-Martí N, Pérez CA, Suñer C, Laporte P, Admella P, Mitjà J, Clua M, Bertran L, Sarquella M, Gavilán S, Ara J, Argimon JM, Casabona J, Cuatrecasas G, Cañadas P, Elizalde-Torrent A, Fabregat R, Farré M, Forcada A, Flores-Mateo G, Muntada E, Nadal N, Narejos S, Gil-Ortega AN, Prat N, Puig J, Quiñones C, Reyes-Ureña J, Ramírez-Viaplana F, Ruiz L, Riveira-Muñoz E, Sierra A, Velasco C, Vivanco-Hidalgo RM, Sentís A, G-Beiras C, Clotet B, Vall-Mayans M; BCN PEP-CoV-2 RESEARCH GROUP. Hydroxychloroquine for early treatment of adults with mild Covid-19: a randomized-controlled trial. Clin Infect Dis. 2020:ciaa1009.
  • 245
    Axfors C, Schmitt AM, Janiaud P, Van’t Hooft J, Abd-Elsalam S, Abdo EF, et al. Mortality outcomes with hydroxychloroquine and chloroquine in COVID-19 from an international collaborative meta-analysis of randomized trials. Nat Commun. 2021;12(1):2349.
  • 246
    República Portuguesa. Serviço Nacional de Saúde. Direção Geral da Saúde. Infarmed. Comunicado de imprensa. Infarmed e DGS recomendam suspensão do uso de hidroxicloroquina em doentes com COVID-19. 28 maio 2020. Disponível em https://www.infarmed.pt/web/infarmed/infarmed/-/journal_content/56/15786/3701591
    » https://www.infarmed.pt/web/infarmed/infarmed/-/journal_content/56/15786/3701591
  • 247
    Caly L, Druce JD, Catton MG, Jans DA, Wagstaff KM. The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antiviral Res. 2020;178:104787.
  • 248
    Hill A, Abdulamir A, Ahmed S, Asghar A, Babalola OE, Basri R, et al. Meta-analysis of randomized trials of ivermectin to treat SARS-CoV-2 infection. Research Square (preprint). 2021;doi: 10.21202/rs.3.rs-148845/v1.
    » https://doi.org/10.21202/rs.3.rs-148845/v1
  • 249
    López-Medina E, López P, Hurtado IC, Dávalos DM, Ramirez O, Martínez E, et al. Effect of ivermectin on time to resolution of symptoms among adults with mild COVID-19: a randomized clinical trial. JAMA. 2021;325(14):1426-35.
  • 250
    Villar J, Ferrando C, Martínez D, Ambrós A, Muñoz T, Soler JA, Aguilar G, Alba F, González-Higueras E, Conesa LA, Martín-Rodríguez C, Díaz-Domínguez FJ, Serna-Grande P, Rivas R, Ferreres J, Belda J, Capilla L, Tallet A, Añón JM, Fernández RL, González-Martín JM; dexamethasone in ARDS network. Dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial. Lancet Respir Med. 2020;8(3):267-76.
  • 251
    Bozzette SA, Sattler FR, Chiu J, Wu AW, Gluckstein D, Kemper C, et al. A controlled trial of early adjunctive treatment with corticosteroids for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. California Collaborative Treatment Group. N Engl J Med. 1990;323(21):1451-7.
  • 252
    Rodrigo C, Leonardi-Bee J, Nguyen-Van-Tam J, Lim WS. Corticosteroids as adjunctive therapy in the treatment of influenza. Cochrane Database Syst Rev. 2016;3:CD010406.
  • 253
    Lewis SR, Pritchard MW, Thomas CM, Smith AF. Pharmacological agents for adults with acute respiratory distress syndrome. Cochrane Database Syst Rev. 2019;7(7):CD004477.
  • 254
    Russell CD, Millar JE, Baillie JK. Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury. Lancet. 2020;395(10223):473-5.
  • 255
    Fang X, Mei Q, Yang T, Li L, Wang Y, Tong F, et al. Low-dose corticosteroid therapy does not delay viral clearance in patients with COVID-19. J Infect. 2020;81(1):147-78.
  • 256
    Wang Y, Jiang W, He Q, Wang C, Liu B, Zhou P, et al. Early, low-dose and short-term application of corticosteroid treatment in patients with severe COVID-19 pneumonia: single-center experience from Wuhan, China. medRxiv. 2020:2020.03.06.20032342.
  • 257
    Lee KH, Yoon S, Jeong GH, Kim JY, Han YJ, Hong SH, et al. Efficacy of corticosteroids in patients with SARS, MERS and COVID-19: a systematic review and meta-analysis. J Clin Med. 2020;9(8):2392.
  • 258
    RECOVERY Collaborative Group, Horby P, Lim WS, Emberson JR, Mafham M, Bell JL, et al. Dexamethasone in hospitalized patients with Covid-19. N Engl J Med. 2021;384(8):693-704.
  • 259
    Jeronimo CM, Farias ME, Val FF, Sampaio VS, Alexandre MA, Melo GC, Safe IP, Borba MG, Netto RL, Maciel AB, Neto JR, Oliveira LB, Figueiredo EF, Oliveira Dinelly KM, de Almeida Rodrigues MG, Brito M, Mourão MP, Pivoto João GA, Hajjar LA, Bassat Q, Romero GA, Naveca FG, Vasconcelos HL, de Araújo Tavares M, Brito-Sousa JD, Costa FT, Nogueira ML, Baía-da-Silva DC, Xavier MS, Monteiro WM, Lacerda MV; Metcovid Team. Methylprednisolone as adjunctive therapy for patients hospitalized with coronavirus 2019 (COVID-19; Metcovid): a randomised, double-blind, phase IIb, placebo-controlled trial. Clin Infect Dis. 2021;72(9):e373-81.
  • 260
    Tomazini BM, Maia IS, Cavalcanti AB, Berwanger O, Rosa RG, Veiga VC, Avezum A, Lopes RD, Bueno FR, Silva MV, Baldassare FP, Costa EL, Moura RA, Honorato MO, Costa AN, Damiani LP, Lisboa T, Kawano-Dourado L, Zampieri FG, Olivato GB, Righy C, Amendola CP, Roepke RM, Freitas DH, Forte DN, Freitas FG, Fernandes CC, Melro LM, Junior GF, Morais DC, Zung S, Machado FR, Azevedo LC; COALITION COVID-19 Brazil III Investigators. Effect of dexamethasone on days alive and ventilator-free in patients with moderate or severe acute respiratory distress syndrome and COVID-19: the CoDEX randomized clinical trial. JAMA. 2020;324(13):1307-16.
  • 261
    Dequin PF, Heming N, Meziani F, Planteféve G, Voiriot G, Badié J, François B, Aubron C, Ricard JD, Ehrmann S, Jouan Y, Guillon A, Leclerc M, Coffre C, Bourgoin H, Lengellé C, Caille-Fénérol C, Tavernier E, Zohar S, Giraudeau B, Annane D, Le Gouge A; CAPE COVID Trial Group and the CRICS-TriGGERSep Network. Effect of hydrocortisone on 21-day mortality or respiratory support among critically ill patients with COVID-19: a randomized clinical trial. JAMA. 2020;324(13):1298-306.
  • 262
    Angus DC, Derde L, Al-Beidh F, Annane D, Arabi Y, Beane A, et al. Effect of hydrocortisone on mortality and organ support in patients with severe COVID-19: the REMAP-CAP COVID-19 corticosteroid domain randomized clinical trial. JAMA. 2020;324(13):1317-29.
  • 263
    WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group, Sterne JA, Murthy S, Diaz JV, Slutsky AS, Villar J, et al. Association between administration of systemic corticosteroids and mortality among critically ill patients with COVID-19: a meta-analysis. JAMA. 2020;324(13):1330-41.
  • 264
    Cortegiani A, Ippolito M, Greco M, Granone V, Protti A, Gregoretti C, et al. Rationale and evidence on the use of tocilizumab in COVID-19: a systematic review. Pulmonology. 2021;27(1):52-66.
  • 265
    Salvarani C, Dolci G, Massari M, Merlo DF, Cavuto S, Savoldi L, Bruzzi P, Boni F, Braglia L, Turrà C, Ballerini PF, Sciascia R, Zammarchi L, Para O, Scotton PG, Inojosa WO, Ravagnani V, Salerno ND, Sainaghi PP, Brignone A, Codeluppi M, Teopompi E, Milesi M, Bertomoro P, Claudio N, Salio M, Falcone M, Cenderello G, Donghi L, Del Bono V, Colombelli PL, Angheben A, Passaro A, Secondo G, Pascale R, Piazza I, Facciolongo N, Costantini M; RCT-TCZ-COVID-19 Study Group. Effect of tocilizumab vs standard care on clinical worsening in patients hospitalized with COVID-19 pneumonia: a randomized clinical trial. JAMA Intern Med. 2021;181(1):24-31.
  • 266
    Stone JH, Frigault MJ, Serling-Boyd NJ, Fernandes AD, Harvey L, Foulkes AS, Horick NK, Healy BC, Shah R, Bensaci AM, Woolley AE, Nikiforow S, Lin N, Sagar M, Schrager H, Huckins DS, Axelrod M, Pincus MD, Fleisher J, Sacks CA, Dougan M, North CM, Halvorsen YD, Thurber TK, Dagher Z, Scherer A, Wallwork RS, Kim AY, Schoenfeld S, Sen P, Neilan TG, Perugino CA, Unizony SH, Collier DS, Matza MA, Yinh JM, Bowman KA, Meyerowitz E, Zafar A, Drobni ZD, Bolster MB, Kohler M, D’Silva KM, Dau J, Lockwood MM, Cubbison C, Weber BN, Mansour MK; BACC Bay Tocilizumab Trial Investigators. Efficacy of tocilizumab in patients hospitalized with Covid-19. N Engl J Med. 2020;383(24):2333-44.
  • 267
    Rosas IO, Brau N, Waters M, Go RC, Hunter BD, Bhagani S, et al. Tocilizumab in hospitalized patients with severe Covid-19 pneumonia. N Engl J Med. 2021;384(16):1503-16.
  • 268
    Salama C, Han J, Yau L, Reiss WG, Kramer B, Neidhart JD, et al. Tocilizumab in patients hospitalized with Covid-19 pneumonia. N Engl J Med. 2021;384(1):20-30.
  • 269
    REMAP-CAP Investigators, Gordon AC, Mouncey PR, Al-Beidh F, Rowan KM, Nichol AD, et al. Interleukin-6 receptor antagonists in critically ill patients with Covid-19. N Engl J Med. 2021;384(16):1491-502.
  • 270
    RECOVERY Collaborative Group. Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. Lancet. 2021;397(10285):1637-45.
  • 271
    Cavalli G, Dinarello CA. Anakinra Therapy for non-cancer inflammatory diseases. Front Pharmacol. 2018;9:1157.
  • 272
    Cavalli G, De Luca G, Campochiaro C, Della-Torre E, Ripa M, Canetti D, et al. Interleukin-1 blockade with high-dose anakinra in patients with COVID-19, acute respiratory distress syndrome, and hyperinflammation: a retrospective cohort study. Lancet Rheumatol. 2020;2(6):e325-31.
  • 273
    Huet T, Beaussier H, Voisin O, Jouveshomme S, Dauriat G, Lazareth I, et al. Anakinra for severe forms of COVID-19: a cohort study. Lancet Rheumatol. 2020;2(7):e393-400.
  • 274
    CORIMUNO-19 Collaborative group. Effect of anakinra versus usual care in adults in hospital with COVID-19 and mild-to-moderate pneumonia (CORIMUNO-ANA-1): a randomised controlled trial. Lancet Respir Med. 2021;9(3):295-304.
  • 275
    Kalil AC, Patterson TF, Mehta AK, Tomashek KM, Wolfe CR, Ghazaryan V, Marconi VC, Ruiz-Palacios GM, Hsieh L, Kline S, Tapson V, Iovine NM, Jain MK, Sweeney DA, El Sahly HM, Branche AR, Regalado Pineda J, Lye DC, Sandkovsky U, Luetkemeyer AF, Cohen SH, Finberg RW, Jackson PE, Taiwo B, Paules CI, Arguinchona H, Erdmann N, Ahuja N, Frank M, Oh MD, Kim ES, Tan SY, Mularski RA, Nielsen H, Ponce PO, Taylor BS, Larson L, Rouphael NG, Saklawi Y, Cantos VD, Ko ER, Engemann JJ, Amin AN, Watanabe M, Billings J, Elie MC, Davey RT, Burgess TH, Ferreira J, Green M, Makowski M, Cardoso A, de Bono S, Bonnett T, Proschan M, Deye GA, Dempsey W, Nayak SU, Dodd LE, Beigel JH; ACTT-2 Study Group Members. Baricitinib plus remdesivir for hospitalized adults with Covid-19. N Engl J Med. 2021;384(9):795-807.
  • 276
    Deftereos SG, Giannopoulos G, Vrachatis DA, Siasos GD, Giotaki SG, Gargalianos P, Metallidis S, Sianos G, Baltagiannis S, Panagopoulos P, Dolianitis K, Randou E, Syrigos K, Kotanidou A, Koulouris NG, Milionis H, Sipsas N, Gogos C, Tsoukalas G, Olympios CD, Tsagalou E, Migdalis I, Gerakari S, Angelidis C, Alexopoulos D, Davlouros P, Hahalis G, Kanonidis I, Katritsis D, Kolettis T, Manolis AS, Michalis L, Naka KK, Pyrgakis VN, Toutouzas KP, Triposkiadis F, Tsioufis K, Vavouranakis E, Martinèz-Dolz L, Reimers B, Stefanini GG, Cleman M, Goudevenos J, Tsiodras S, Tousoulis D, Iliodromitis E, Mehran R, Dangas G, Stefanadis C; GRECCO-19 investigators. Effect of colchicine vs standard care on cardiac and inflammatory biomarkers and clinical outcomes in patients hospitalized with coronavirus disease 2019: the GRECCO-19 randomized clinical trial. JAMA Netw Open. 2020;3(6):e2013136.
  • 277
    Lopes MI, Bonjorno LP, Giannini MC, Amaral NB, Menezes PI, Dib SM, et al. Beneficial effects of colchicine for moderate to severe COVID-19: a randomised, double-blinded, placebo-controlled clinical trial. RMD Open. 2021;7(1):e001455.
  • 278
    Tardif JC, Bouabdallaoui N, L’Allier PL, Gaudet D, Shah B, Pillinger MH, et al. Efficacy of colchicine in non-hospitalized patients with COVID-19. medRxiv. 2021:2021.01.26.21250494.
  • 279
    Samuel CE. Antiviral actions of interferons. Clin Microbiol Rev. 2001;14(4):778-809, table of contents.
  • 280
    Zhang Q, Bastard P, Liu Z, Le Pen J, Moncada-Velez M, Chen J, et al. Inborn errors of type I IFN immunity in patients with life-threatening COVID-19. Science. 2020;370(6515):eabd4570.
  • 281
    Davoudi-Monfared E, Rahmani H, Khalili H, Hajiabdolbaghi M, Salehi M, Abbasian L, et al. A randomized clinical trial of the efficacy and safety of interferon beta-1a in treatment of severe COVID-19. Antimicrob Agents Chemother. 2020;64(9):e01061-20.
  • 282
    Monk PD, Marsden RJ, Tear VJ, Brookes J, Batten TN, Mankowski M, Gabbay FJ, Davies DE, Holgate ST, Ho LP, Clark T, Djukanovic R, Wilkinson TMA; Inhaled Interferon Beta COVID-19 Study Group. Safety and efficacy of inhaled nebulised interferon beta-1a (SNG001) for treatment of SARS-CoV-2 infection: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Respir Med. 2021;9(2):196-206.
  • 283
    Konstantinides SV, Meyer G, Becattini C, Bueno H, Geersing GJ, Harjola VP, Huisman MV, Humbert M, Jennings CS, Jiménez D, Kucher N, Lang IM, Lankeit M, Lorusso R, Mazzolai L, Meneveau N, Áinle FN, Prandoni P, Pruszczyk P, Righini M, Torbicki A, Van Belle E, Zamorano JL; The Task Force for the diagnosis and management of acute pulmonary embolism of the European Society of Cardiology (ESC). 2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS): the task force for the diagnosis and management of acute pulmonary embolism of the European Society of Cardiology (ESC). Eur Respir J. 2019;54(3):1901647.
  • 284
    Motta JK, Ogunnaike RO, Shah R, Stroever S, Cedeño HV, Thapa SK, et al. Clinical outcomes with the use of prophylactic versus therapeutic anticoagulation in COVID-19. Crit Care Explor. 2020;2(12):e0309.
  • 285
    The REMAP-CAP, ACTIV-4a, ATTACC Investigators, Zarychanski R. Therapeutic anticoagulation in critically ill patients with Covid-19 - Preliminary report. medRxiv. 2021:2021.03.10.21252749.
  • 286
    Spyropoulos AC, Levy JH, Ageno W, Connors JM, Hunt BJ, Iba T, Levi M, Samama CM, Thachil J, Giannis D, Douketis JD; Subcommittee on Perioperative, Critical Care Thrombosis, Haemostasis of the Scientific, Standardization Committee of the International Society on Thrombosis and Haemostasis. Scientific and Standardization Committee communication: clinical guidance on the diagnosis, prevention and treatment of venous thromboembolism in hospitalized patients with COVID-19. J Thromb Haemost. 2020;18(8):1859-65.
  • 287
    Barnes GD, Burnett A, Allen A, Blumenstein M, Clark NP, Cuker A, et al. Thromboembolism and anticoagulant therapy during the COVID-19 pandemic: interim clinical guidance from the anticoagulation forum. J Thromb Thrombolysis. 2020;50(1):72-81.
  • 288
    Moores LK, Tritschler T, Brosnahan S, Carrier M, Collen JF, Doerschug K, et al. Prevention, diagnosis, and treatment of VTE in patients with coronavirus disease 2019: CHEST Guideline and Expert Panel Report. Chest. 2020;158(3):1143-63.
  • 289
    Thachil J, Tang N, Gando S, Falanga A, Cattaneo M, Levi M, et al. ISTH interim guidance on recognition and management of coagulopathy in COVID-19. J Thromb Haemost. 2020;18(5):1023-6.
  • 290
    Marietta M, Ageno W, Artoni A, De Candia E, Gresele P, Marchetti M, et al. COVID-19 and haemostasis: a position paper from Italian Society on Thrombosis and Haemostasis (SISET). Blood Transfus. 2020;18(3):167-9.
  • 291
    Bikdeli B, Madhavan MV, Jimenez D, Chuich T, Dreyfus I, Driggin E, Nigoghossian C, Ageno W, Madjid M, Guo Y, Tang LV, Hu Y, Giri J, Cushman M, Quéré I, Dimakakos EP, Gibson CM, Lippi G, Favaloro EJ, Fareed J, Caprini JA, Tafur AJ, Burton JR, Francese DP, Wang EY, Falanga A, McLintock C, Hunt BJ, Spyropoulos AC, Barnes GD, Eikelboom JW, Weinberg I, Schulman S, Carrier M, Piazza G, Beckman JA, Steg PG, Stone GW, Rosenkranz S, Goldhaber SZ, Parikh SA, Monreal M, Krumholz HM, Konstantinides SV, Weitz JI, Lip GYH; Global COVID-19 Thrombosis Collaborative Group, Endorsed by the ISTH, NATF, ESVM, and the IUA, Supported by the ESC Working Group on Pulmonary Circulation and Right Ventricular Function. COVID-19 and thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy, and follow-up: JACC state-of-the-art review. J Am Coll Cardiol. 2020;75(23):2950-73.
  • 292
    Smith K, Krajewski KC, Krajewski MP. Practical considerations in prevention and treatment of venous thromboembolism in hospitalized patients with COVID-19. Am J Health Syst Pharm. 2020;77(21):1739-45.
  • 293
    Thachil J. The versatile heparin in COVID-19. J Thromb Haemost. 2020;18(5):1020-2.
  • 294
    Zenáhlíková Z, Kvasnicka J, Kudrnová Z, Sudrová M, Brzezková R, Mazoch J, et al. FXa inhibition and coagulation changes during DVT prophylaxis by enoxaparin over the course of a 15-day follow-up in septic patients. Clin Appl Thromb Hemost. 2010;16(5):584-90.
  • 295
    Robinson S, Zincuk A, Larsen UL, Ekstrom C, Nybo M, Rasmussen B, et al. A comparative study of varying doses of enoxaparin for thromboprophylaxis in critically ill patients: a double-blinded, randomised controlled trial. Crit Care. 2013;17(2):R75.
  • 296
    Rocca B, Fox KA, Ajjan RA, Andreotti F, Baigent C, Collet JP, et al. Antithrombotic therapy and body mass: an expert position paper of the ESC Working Group on Thrombosis. Eur Heart J. 2018;39(19):1672-86f.
  • 297
    Xu Z, Zhou J, Huang Y, Liu X, Xu Y, Chen S, et al. Efficacy of convalescent plasma for the treatment of severe influenza. Crit Care. 2020;24(1):469.
  • 298
    Li L, Zhang W, Hu Y, Tong X, Zheng S, Yang J, et al. Effect of convalescent plasma therapy on time to clinical improvement in patients with severe and life-threatening COVID-19: a randomized clinical trial. JAMA. 2020;324(5):460-70.
  • 299
    Valk SJ, Piechotta V, Chai KL, Doree C, Monsef I, Wood EM, et al. Convalescent plasma or hyperimmune immunoglobulin for people with COVID-19: a rapid review. Cochrane Database Syst Rev. 2020;5(5):CD013600.
  • 300
    Tanne JH. Covid-19: FDA approves use of convalescent plasma to treat critically ill patients. BMJ. 2020;368:m1256.
  • 301
    Libster R, Pérez Marc G, Wappner D, Coviello S, Bianchi A, Braem V, Esteban I, Caballero MT, Wood C, Berrueta M, Rondan A, Lescano G, Cruz P, Ritou Y, Fernández Viña V, Álvarez Paggi D, Esperante S, Ferreti A, Ofman G, Ciganda Á, Rodriguez R, Lantos J, Valentini R, Itcovici N, Hintze A, Oyarvide ML, Etchegaray C, Neira A, Name I, Alfonso J, López Castelo R, Caruso G, Rapelius S, Alvez F, Etchenique F, Dimase F, Alvarez D, Aranda SS, Sánchez Yanotti C, De Luca J, Jares Baglivo S, Laudanno S, Nowogrodzki F, Larrea R, Silveyra M, Leberzstein G, Debonis A, Molinos J, González M, Perez E, Kreplak N, Pastor Argüello S, Gibbons L, Althabe F, Bergel E, Polack FP; Fundación INFANT-COVID-19 Group. Early high-titer plasma therapy to prevent severe Covid-19 in older adults. N Engl J Med. 2021;384(7):610-8.
  • 302
    Gharbharan A, Jordans CC, Geurtsvankessel C, den Hollander JG, Karim F, Mollema FP, et al. Convalescent plasma for COVID-19. A randomized clinical trial. medRxiv. 2020:2020.07.01.20139857.
  • 303
    Avendaño-Solà C, Ramos-Martínez A, Muñez-Rubio E, Ruiz-Antorán B, de Molina RM, Torres F, et al. Convalescent plasma for COVID-19: a multicenter, randomized clinical trial. medRxiv. 2020:2020.08.26.20182444.
  • 304
    Agarwal A, Mukherjee A, Kumar G, Chatterjee P, Bhatnagar T, Malhotra P; PLACID Trial Collaborators. Convalescent plasma in the management of moderate covid-19 in adults in India: open label phase II multicentre randomised controlled trial (PLACID Trial). BMJ. 2020;371:m3939.
  • 305
    AlQahtani M, Abdulrahman A, Almadani A, Alali SY, Al Zamrooni AM, Hejab AH, et al. Randomized controlled trial of convalescent plasma therapy against standard therapy in patients with severe COVID-19 disease. Sci Rep. 2021;11(1):9927.
  • 306
    Simonovich VA, Burgos Pratx LD, Scibona P, Beruto MV, Vallone MG, Vázquez C, Savoy N, Giunta DH, Pérez LG, Sánchez MDL, Gamarnik AV, Ojeda DS, Santoro DM, Camino PJ, Antelo S, Rainero K, Vidiella GP, Miyazaki EA, Cornistein W, Trabadelo OA, Ross FM, Spotti M, Funtowicz G, Scordo WE, Losso MH, Ferniot I, Pardo PE, Rodriguez E, Rucci P, Pasquali J, Fuentes NA, Esperatti M, Speroni GA, Nannini EC, Matteaccio A, Michelangelo HG, Follmann D, Lane HC, Belloso WH; PlasmAr Study Group. A randomized trial of convalescent plasma in Covid-19 severe pneumonia. N Engl J Med. 2021;384(7):619-29.
  • 307
    República Portuguesa. Gabinete do Secretaria de Estado da Saúde.Despacho n.º 5160/2020 de 4 de maio de 2020. Cria o grupo de trabalho para desenvolvimento e criação de proposta de Programa Nacional de Transfusão de Plasma Convalescente COVID-19 (PNTPC) para o tratamento de pacientes com COVID-19. Diário da República n.º 86, Série II, p.56-7. Disponível em https://dre.pt/application/conteudo/132964793
    » https://dre.pt/application/conteudo/132964793
  • 308
    Gao F, Chiu SM, Motan DA, Zhang Z, Chen L, Ji HL, et al. Mesenchymal stem cells and immunomodulation: current status and future prospects. Cell Death Dis. 2016;7(1):e2062.
  • 309
    Lalu MM, McIntyre L, Pugliese C, Fergusson D, Winston BW, Marshall JC, Granton J, Stewart DJ; Canadian Critical Care Trials Group. Safety of cell therapy with mesenchymal stromal cells (SafeCell): a systematic review and meta-analysis of clinical trials. PLoS One. 2012;7(10):e47559.
  • 310
    Hashmi S, Ahmed M, Murad MH, Litzow MR, Adams RH, Ball LM, et al. Survival after mesenchymal stromal cell therapy in steroid-refractory acute graft-versus-host disease: systematic review and meta-analysis. Lancet Haematol. 2016;3(1):e45-52.
  • 311
    Shu L, Niu C, Li R, Huang T, Wang Y, Huang M, et al. Treatment of severe COVID-19 with human umbilical cord mesenchymal stem cells. Stem Cell Res Ther. 2020;11(1):361.
  • 312
    Shi L, Huang H, Lu X, Yan X, Jiang X, Xu R, et al. Effect of human umbilical cord-derived mesenchymal stem cells on lung damage in severe COVID-19 patients: a randomized, double-blind, placebo-controlled phase 2 trial. Signal Transduct Target Ther. 2021;6(1):58.
  • 313
    Lanzoni G, Linetsky E, Correa D, Messinger Cayetano S, Alvarez RA, Kouroupis D, et al. Umbilical cord mesenchymal stem cells for COVID-19 acute respiratory distress syndrome: a double-blind, phase 1/2a, randomized controlled trial. Stem Cells Transl Med. 2021;10(5):660-73.
  • 314
    Herberts CA, Kwa MS, Hermsen HP. Risk factors in the development of stem cell therapy. J Transl Med. 2011;9:29.
  • 315
    Gottlieb RL, Nirula A, Chen P, Boscia J, Heller B, Morris J, et al. Effect of bamlanivimab as monotherapy or in combination with etesevimab on viral load in patients with mild to moderate COVID-19: a randomized clinical trial. JAMA. 2021;325(7):632-44.
  • 316
    ACTIV-3/TICO LY-CoV555 Study Group, Lundgren JD, Grund B, Barkauskas CE, Holland TL, Gottlieb RL, et al. A Neutralizing monoclonal antibody for hospitalized patients with Covid-19. N Engl J Med. 2021;384(10):905-14.
  • 317
    Weinreich DM, Sivapalasingam S, Norton T, Ali S, Gao H, Bhore R, Musser BJ, Soo Y, Rofail D, Im J, Perry C, Pan C, Hosain R, Mahmood A, Davis JD, Turner KC, Hooper AT, Hamilton JD, Baum A, Kyratsous CA, Kim Y, Cook A, Kampman W, Kohli A, Sachdeva Y, Graber X, Kowal B, DiCioccio T, Stahl N, Lipsich L, Braunstein N, Herman G, Yancopoulos GD; Trial Investigators. REGN-COV2, a neutralizing antibody cocktail, in outpatients with Covid-19. N Engl J Med. 2021;384(3):238-51.
  • 318
    Mackey K, Kansagara D, Vela K. Update Alert 4: Risks and impact of angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers on SARS-CoV-2 infection in adults. Ann Intern Med. 2020;173(9):W147-8.
  • 319
    Flacco ME, Acuti Martellucci C, Bravi F, Parruti G, Cappadona R, Mascitelli A, et al. Treatment with ACE inhibitors or ARBs and risk of severe/lethal COVID-19: a meta-analysis. Heart. 2020;106(19):1519-24.
  • 320
    Baral R, White M, Vassiliou VS. Effect of renin-angiotensin-aldosterone system inhibitors in patients with COVID-19: a systematic review and meta-analysis of 28,872 patients. Curr Atheroscler Rep. 2020;22(10):61.
  • 321
    Barochiner J, Martínez R. Use of inhibitors of the renin-angiotensin system in hypertensive patients and COVID-19 severity: a systematic review and meta-analysis. J Clin Pharm Ther. 2020;45(6):1244-52.
  • 322
    Sociedade Portuguesa de Cardiologia. Posição da Sociedade Portuguesa de Cardiologia sobre a utilização de IECA e ARA II no contexto da pandemia do COVID-19. 15 março 2020. Disponíivel em https://spc.pt/wp-content/uploads/2020/03/POSI%C3%87%C3%83O-IECA-e-ARA-II-com-COVID19.pdf
    » https://spc.pt/wp-content/uploads/2020/03/POSI%C3%87%C3%83O-IECA-e-ARA-II-com-COVID19.pdf
  • 323
    Bozkurt B, Kovacs R, Harrington B. Joint HFSA/ACC/AHA Statement Addresses Concerns Re: Using RAAS Antagonists in COVID-19. J Card Fail. 2020;26(5):370.
  • 324
    Cohen DE, Anania FA, Chalasani N; National Lipid Association Statin Safety Task Force Liver Expert Panel. An assessment of statin safety by hepatologists. Am J Cardiol. 2006;97(8A):77C-81C.
  • 325
    Day M. Covid-19: ibuprofen should not be used for managing symptoms, say doctors and scientists. BMJ. 2020;368:m1086.
  • 326
    European Medicines Agency (EMA). EMA gives advice on the use of non-steroidal anti-inflammatories for COVID-19. 2020 Mar 18. Available from https://www.ema.europa.eu/en/news/ema-gives-advice-use-non-steroidal-anti-inflammatories-covid-19
    » https://www.ema.europa.eu/en/news/ema-gives-advice-use-non-steroidal-anti-inflammatories-covid-19
  • 327
    World Health Organization (WHO). The use of non-steroidal anti-inflammatory drugs (NSAIDs) in patients with COVID-19. Scientific brief. 2020 Apr 19. Available from https://www.who.int/news-room/commentaries/detail/the-use-of-non-steroidal-anti-inflammatory-drugs-(nsaids)-in-patients-with-covid-19
    » https://www.who.int/news-room/commentaries/detail/the-use-of-non-steroidal-anti-inflammatory-drugs-(nsaids)-in-patients-with-covid-19
  • 328
    República Portuguesa. Serviço Nacional de Saúde. Direçao Geral de Saúde. Norma 004/2020 - COVID-19: Abordagem do doente com suspeita ou confirmação de COVID-19. 23 Mar 2020, atualizada 14 out 2020. Disponível em https://backoffice.ump.pt/files/files/Norma_004_2020_act_14_10_2020.pdf
    » https://backoffice.ump.pt/files/files/Norma_004_2020_act_14_10_2020.pdf
  • 329
    European Centre for Disease Prevention and Control (ECDC). Novel coronavirus (SARS-CoV-2). Discharge criteria for confirmed COVID-19 cases - When is it safe to discharge COVID-19 cases from the hospital or end home isolation? Technical Report. 2020. Available from https://www.ecdc.europa.eu/sites/default/files/documents/COVID-19-Discharge-criteria.pdf
    » https://www.ecdc.europa.eu/sites/default/files/documents/COVID-19-Discharge-criteria.pdf
  • 330
    World Health Organization (WHO). Criteria for releasing COVID-19 patients from isolation. Scientific Brief. 2020 Jun 17. Available from https://www.who.int/publications/i/item/criteria-for-releasing-covid-19-patients-from-isolation
    » https://www.who.int/publications/i/item/criteria-for-releasing-covid-19-patients-from-isolation
  • 331
    Ards Definition Task Force, Ranieri VM, Rubenfeld GD, Thompson BT, Ferguson ND, Caldwell E, et al. Acute respiratory distress syndrome: the Berlin Definition. JAMA. 2012;307(23):2526-33.
  • 332
    Annane D, Pastores SM, Rochwerg B, Arlt W, Balk RA, Beishuizen A, et al. Guidelines for the Diagnosis and Management of Critical Illness-Related Corticosteroid Insufficiency (CIRCI) in Critically Ill Patients (Part I): Society of Critical Care Medicine (SCCM) and European Society of Intensive Care Medicine (ESICM) 2017. Crit Care Med. 2017;45(12):2078-88.

Appendix 1 - Figures and tables

Table 1
Definitions of COVID-19 severity
Table 2
Systematized protocol for endotracheal intubation in the context of COVID-19
Table 3
Systematized extubation protocol in the context of COVID-19
Table 4
Referral of critically ill patients with respiratory failure associated with COVID-19 for extracorporeal respiratory support
Table 5
Referral of critically ill patients with cardiogenic shock associated with COVID-19 for extracorporeal cardiorespiratory support
Table 6
Most common corticosteroid regimens in ARDS studies
Table 7
Prophylactic (standard and adjusted) and therapeutic anticoagulation schemes for critically ill patients with COVID-19
Figure 1
Pathophysiology of COVID-19.
Figure 2
COVID-19 stages and potential specific and supportive therapies.
Figure 3
Strategy of oxygen therapy and ventilatory support in respiratory failure due to COVID-19.
Figure 4
Use of corticosteroids and other immunomodulators in critically ill patients with COVID-19.
Figure 5
Recommendations for the use of different anticoagulation regimens for critically ill patients with COVID-19.

Appendix 2 - Summary of Recommendations

Diagnosis of SARS-CoV-2 infection

It is recommended that all patients requiring hospitalization in intensive care units undergo a diagnostic test to identify SARS-CoV-2.

It is recommended that the initial diagnostic test in patients requiring hospitalization in intensive care units be a molecular nucleic acid amplification test (NAAT) using a sample from the upper respiratory tract (exudate from the nasopharynx and oropharynx collected with a swab) in the context of pneumonia, whenever possible, to the lower respiratory tract (for example, bronchial secretions collected by endotracheal aspirate).

It is suggested that when NAAT results cannot be obtained in less than 12 hours (or if NAATs are not available), a rapid antigen test should be used, and a confirmatory NAAT should be conducted as soon as possible if the rapid antigen test result is negative.

It is suggested that during hospitalization, between the third and fifth day after the initial negative test and periodically every 5 days (counted from the last test), NAATs should be used for screening.

It is recommended not to use serological tests in the acute phase.

It is recommended not to use chest CT as the first diagnostic test in patients with suspected SARS-CoV-2 infection.

Diagnosis of co-infection and superinfection

The collection of blood cultures (at least two sets of aerobic and anaerobic blood cultures) from the lower respiratory tract is recommended for the investigation of other microbiological agents and antigenuria for Legionella pneumophila and Streptococcus pneumoniae.

It is suggested to consider requesting other tests (for example, NAATs for other viruses, e.g., influenza, and other respiratory viruses, serology for atypical microorganisms, galactomannan detection) based clinical symptoms and epidemiology.

Criteria for admission to intensive care units

It is recommended that patients with severe or critical COVID-19 criteria be referred early to intensive care units.

It is recommended that admission to the intensive care unit be based on a case-by-case assessment that includes the presentation and severity of acute disease, the reversibility and favorable prognosis of acute disease, history of comorbidities, and poor functional status and frailty prior to the acute situation motivating admission.

It is recommended that whenever there is no possibility of a local response, referral and transfer of the patient should be based on the intensive care referral network so that the necessary care can be provided.

It is recommended that the decision to admit (or not) be accompanied by the development of a care plan based on a decision model shared with the patient or with his or her family; collegial methodology, ideally multiprofessional and multispecialty, coordinated by an experienced intensivist; and the use of national and international standards and guidelines.

Personal protective equipment

It is recommended that all health professionals involved in the provision of clinical care to patients with (or suspected of) infection by coronavirus severe acute respiratory syndrome 2 (SARS-CoV-2) use universal protection, contact protection and droplet protection. These measures include hand hygiene and the use of specific, disposable (single use) and waterproof personal protective equipment: surgical mask, eye protection, cap, smock, clean gloves (covering the cuff) and footwear protection (ideally, waterproof shoes and exclusive use in isolation areas or, optionally, waterproof shoe covers).

Personal protective equipment

It is recommended that all health professionals involved in the provision of clinical care to patients with (or suspected of) infection by coronavirus severe acute respiratory syndrome 2 (SARS-CoV-2) use universal protection, contact protection and droplet protection. These measures include hand hygiene and the use of specific, disposable (single use) and waterproof personal protective equipment: surgical mask, eye protection, cap, smock, clean gloves (covering the cuff) and footwear protection (ideally, waterproof shoes and exclusive use in isolation areas or, optionally, waterproof shoe covers).

It is recommended that all health professionals involved in the provision of potentially aerosol-generating clinical care (for example, intubation, secretion aspiration, and bronchoscopy) or prolonged contact (> 15 minutes) and/or intimate contact (for example, placement of a central venous catheter, surgery, and cardiopulmonary resuscitation maneuvers) to patients with (or suspected of) SARS-CoV-2 infection use airway protection. These measures include hand hygiene and the use of specific, disposable (single use) and waterproof personal protective equipment: respirator with a facial filter, eye protection (with side protection), cap, smock (with cuffs that tighten or with elastics and that cover up to the middle of the leg or ankle) and apron, clean gloves (covering the cuff of the gown) and footwear protection (ideally waterproof shoes and exclusive use in isolation areas or, optionally, waterproof shoe covers).

It is suggested that full protection (waterproof, with built-in hood and neck protection) be limited to professionals with training and practical experience for this purpose.

It is suggested that an order and technique for placement (donning) and removal (doffing) of personal protective equipment be strictly adhered to (ideally using a mirror or surveillance by another health professional), ensuring proper sealing of the face mask, with additional care during the removal procedure to avoid contamination of oneself, others and the environment.

It is recommended that all health professionals involved in the provision of clinical care have training and practical experience in the procedures for donning and doffing personal protective equipment prior to contact with patients.

Organization of services

It is recommended that the management of all level 2 (intermediate) and 3 (intensive) patients in the hospital (regardless of the service in which they are located) be performed by intensive care unit specialists in strict coordination with the Clinical Management, Directorate-General of Health and Ministry of Health.

It is recommended that in hospitals where there is more than one intensive care unit, a cohort area of confirmed critical cases of COVID-19 be created and a cohort area of suspected critically ill patients (for transient hospitalization) be considered, namely, establishing criteria for activation.

Isolation in a single room with negative pressure, a shower, private bathroom and adequate ventilation system, with capacity for at least 6-12 air changes/hour, is recommended. Once these resources are exhausted, it is recommended that patients be isolated in a single room with a ventilation system capable of at least 6-12 air changes/hour. When individual isolation rooms are not available, isolation in a cohort is recommended, respecting a minimum distance greater than 1 m between patients.

The delimitation of risk areas and predefined routes for professionals, patients and waste is recommended.

It is recommended to restrict visitations to all patients and limit the number of professionals in contact with patients (ideally with dedicated professionals), with the implementation of alternative, remote ways of communication between patients and families and between clinical teams, patients and families, regardless of the place of isolation.

Oxygen therapy, respiratory support and adjuvant therapies

In patients with COVID-19, it is recommended to administer conventional oxygen therapy (through a nasal cannula or a Venturi mask) if peripheral oxygen saturation (SpO2) < 90%, with the goal of an SpO2 between 92% and 96%.

When using nasal cannulae, it is suggested to place a surgical mask over the oxygen supply device.

When using a Venturi mask, a device that incorporates a filtering medium in the exhalation ports or, optionally, the placement of a surgical mask under the oxygen supply device is suggested.

It is suggested, in patients with COVID-19, in the failure of conventional oxygen therapy (peripheral oxygen saturation-SpO2 < 92% with fraction of inspired oxygen (FiO2) > 0.6, increased respiratory work and/or respiratory rate ≥ 30 cpm) consider, in the absence of criteria for endotracheal intubation, a trial of non-invasive ventilatory therapies (high-flow nasal cannulae (HFNC) or noninvasive mechanical ventilation (NIV)) provided that (1) professionals use contact, droplet and airway precautions (ideally in rooms or areas with negative pressure) and strategies aimed at minimizing aerosol production are used; (2) a protocol suitable for respiratory failure is established and implemented; (3) the technique is initiated in a highly monitored environment to avoid delays in endotracheal intubation in the event of failure of response; and (4) failure criteria are established and respected.

It is suggested that the choice between noninvasive ventilatory therapies (HFNC and NIV)) is based on weigh individual risks and benefits as well as on the availability of equipment/interfaces and local experience of the staff.

It is suggested that if a decision to use high-flow oxygen therapy via nasal cannula is made (1) a surgical mask should be placed over the nasal cannulae; (2) nasal cannulas should be adapted to the size of the nostrils, with a flow rate of 50 - 60L/minute and FiO2 titrated for SpO2 between 92% and 96%; (3) the ROX index should be evaluated at 2, 6 and 12 hours, with maintenance of support if ≥ 4.88, in the absence of criteria for endotracheal intubation; and (4) in case of failure, treatment should be optimized, considering increased support up to 60L/minute in a prone position, a transition to NIV or endotracheal intubation (and invasive ventilatory support).

It is suggested that if noninvasive mechanical ventilation is initiated, (1) interfaces with maximum sealing should be used, as well as specific ventilators and ventilatory circuits with antibacterial/antiviral filters; (2) ideally, non-invasive ventilation (NIV) helmets or, optionally, face masks (or oronasal) capable of specific configurations for continuous positive airway pressure (CPAP; up to a maximum of 12 - 14cmH2O) or bilevel positive airway pressure (BPAP; with support pressure to maintain tidal volume between 6 and 8mL/kg), FiO2 titrated to SpO2 between 92% and 96% should be used; (3) PaO2/FiO2 should be evaluated at 1 hour with maintenance of support and improvement (ΔPaO2/FiO2) ≥ 30%, in the absence of criteria for endotracheal intubation; and (4) in case of failure, therapy should be optimized, considering increased support in a prone position, eventual transition to HFNC therapy in a prone position or endotracheal intubation (and invasive ventilatory support).

A structured prone protocol (when awake) is suggested for all patients under HFNC therapy or NIV able to comply with orders, as long as clinically tolerated.

A structured protocol for weaning from noninvasive ventilatory therapy is suggested.

It is suggested that the decision of endotracheal intubation be based on a composite evaluation of the oxygenation state (as assessed by the ROX index and/or PaO2/FiO2) and ventilation (respiratory acidosis with pH < 7.30) but also on the respiratory effort perceived by the patient.

We suggest a structured protocol for endotracheal intubation, performed by an experienced operator, using contact, droplet and airway precautions (ideally in a negative pressure room).

It is suggested that after intubation and invasive ventilatory support, the following be used: (1) a classic ventilation strategy based on the ARDS Network protocol (tidal volume of 4 - 6mL/kg of ideal body weight with an upper limit plateau pressure < 30cmH2O) with minimum respiratory rate for pH > 7.30 associated with a driving pressure < 15cmH2O; (2) ventral decubitus for minimum periods of 16 hours if PaO2/FiO2 < 150mmHg; (3) neuromuscular blockers for ≤ 48 hours if PaO2/FiO2 < 150mmHg or severe dyssynchrony or elevated respiratory drive not controlled by optimized analgesics; and (4) in mild ARDS (PaO2/FiO2 between 200 - 300mmHg), the use of low PEEP, and in moderate to severe ARDS (PaO2/FiO2 < 200mmHg), application of high PEEP only after an evaluation of recruitment potential.

It is recommended that routine use of inhaled nitric oxide is not used. A structured protocol for weaning and extubation of invasive ventilatory support is suggested.

It is suggested to consider tracheotomy from the 10th day of mechanical ventilation.

Bronchofibroscopy and inhalation therapy

It is suggested to reserve bronchofibroscopy for urgent situations (for example, atelectasis with ventilatory impairment and critical obstruction of the central airway) or when the examination results may lead to a significant modification in the therapeutic strategy (for example, suspicion of coinfection or superinfection).

It is suggested that if a decision is made to perform bronchofibroscopy, the technique should be performed by the most experienced operator, and airway precautions should be used (with, ideally, the procedure occurring in a negative pressure room).

Disposable video bronchoscopes and the operator to the rear of the patient’s head are suggested.

It is suggested that when the administration of inhalation therapy is clinically indicated, pneumatic, ultrasonic or oscillatory membrane nebulization systems should not be used.

Extracorporeal life support

It is recommended that critically ill patients with respiratory failure associated with COVID-19 be referred for extracorporeal respiratory support after optimized invasive mechanical ventilation and associated adjuvant strategies fail.

It is recommended that critically ill patients with cardiogenic shock associated with COVID-19 be referred for extracorporeal cardiorespiratory support when conventional therapy fails.

It is recommended that the referral of critically ill patients with respiratory failure and/or cardiogenic shock associated with COVID-19 and indications for extracorporeal life support be restricted to reference centers recognized by the Ministry of Health and the General Directorate of Health.

It is recommended that the interhospital transfer of critically ill patients with respiratory failure and/or cardiogenic shock associated with COVID-19 and indications for extracorporeal life support occur within the reference center and be conducted, whenever possible, by an in loco dedicated rescue team.

Other organ support

A conservative fluid therapy strategy is recommended for critically ill patients with COVID-19, especially in the absence of shock.

It is recommended that septic shock in critically ill patients with COVID-19 be treated based on the clinical guidelines applicable to patients with septic shock not associated with COVID-19.

It is recommended that nonpulmonary organ dysfunction in critically ill patients with COVID-19 be managed based on the clinical guidelines applicable to non-COVID-19 patients.

Coinfection, superinfection and antimicrobials

In critically ill patients with suspected severe pneumonia combined with seasonal influenza, it is recommended to start antibiotic therapy for influenza and reassess the clinical picture after obtaining cultural and laboratory results.

In critically ill patients with COVID-19, in the presence of septic shock, it is recommended to administer antibiotic therapy until obtaining cultural results that allow the affirmation or exclusion of the coexistence of bacterial infection.

It is recommended to reassess decisions regarding antibiotic therapy initiated at admission up to 72 hours, depending on the microbiological results available, the clinical evolution and inflammatory biomarkers (namely, procalcitonin).

For critically ill patients with COVID-19, it is recommended to maintain a high index of suspicion for nosocomial infection (namely, ventilator-associated pneumonia).

In critical patients with COVID-19 without a microbiological diagnosis or with unfavorable progression under appropriate antibiotic therapy, it is suggested to consider invasive pulmonary aspergillosis associated with COVID-19.

Antiviral drugs

In critically ill patients infected with SARS-CoV-2 who require a noninvasive ventilatory strategy (NIV or HFNC therapy), invasive ventilatory support, extracorporeal respiratory support or vasopressors are recommended; remdesivir is not recommended.

In critical patients infected with SARS-CoV-2 who require conventional oxygen therapy, it is suggested to consider the use of remdesivir in the first 72 hours after the first positive SARS-CoV-2 test.

It is suggested that in patients infected with SARS-CoV-2 previously treated with remdesivir with clinical deterioration, requiring escalation of ventilatory support and corticosteroid therapy, remdesivir should be maintained until the completion of the therapeutic course.

In critically ill patients infected with SARS-CoV-2, the nonroutine use of other antivirals outside the scope of clinical use protocols or clinical trials is recommended.

Corticosteroids and immunomodulators

It is recommended that patients with COVID-19 who do not require oxygen therapy or ventilatory support should not be treated with corticosteroids unless indicated for other reasons (for example, previous therapy, acute asthma, exacerbation of chronic obstructive pulmonary disease or septic shock without response to vasopressors).

It is recommended that patients with COVID-19 who require oxygen therapy or ventilatory support (invasive mechanical ventilation, noninvasive mechanical ventilation or high-flow oxygen therapy by nasal cannula with a flow greater than 30 L/minute and FiO2 > 0.40) and are beyond 7 days since the onset of symptoms should be treated with dexamethasone 6 mg per day intravenously or enterically for up to 10 days.

It is suggested that for previous indications, if dexamethasone is not available, hydrocortisone (50 mg every 6 hours, intravenously), methylprednisolone (32mg daily, intravenously) or prednisolone (40 mg daily, intravenously or enterally) should be administered.

It is suggested that patients with COVID-19 with C-reactive protein ≥ 7.5mg/dL, ventilatory support (invasive mechanical ventilation, noninvasive mechanical ventilation or high-flow oxygen therapy by nasal cannula with a flow greater than 30L/minute and FiO2 > 0.40) and clinical deterioration (escalation of ventilatory support and/or worsening of PaO2/FiO2), despite corticosteroid therapy, should be treated with 8mg/kg tocilizumab (up to a maximum of 800mg) intravenously (taken only) in the first 24 hours after the start of support (must be < 14 days of hospitalization), once contraindications and other causes of deterioration of respiratory failure are excluded (for example, bacterial infection, pulmonary thromboembolism, and heart failure).

It is suggested that in for previous indications, if tocilizumab is not available, sarilumab (400mg) should be administered intravenously (single dose).

It is suggested that patients with COVID-19 receiving ventilatory support (invasive mechanical ventilation, noninvasive mechanical ventilation or high-flow oxygen therapy by nasal cannula with a flow greater than 30 L/minute and FiO2 > 0.40) with moderate to severe ARDS (PaO2/FiO2 < 200) and contraindications for tocilizumab should be considered for other corticotherapy protocols.

In critically ill patients infected with SARS-CoV-2, it is recommended not to use other immunomodulators outside the scope of clinical use protocols or clinical trials.

Anticoagulation

It is recommended that critically ill patients with COVID-19 with confirmation (or high clinical suspicion) of thromboembolic disease receive therapeutic strategies, including reperfusion (pharmacological and/or mechanical) and/or therapeutic anticoagulation regimens following standard institutional protocols.

It is recommended that critically ill patients with COVID-19, previously under a therapeutic anticoagulation regimen at home, maintain a therapeutic anticoagulation regimen. A transition from parenteral anticoagulant agents (for example, low molecular weight heparin or unfractionated heparin) to oral anticoagulants (for example, dicoumarin or new oral anticoagulants) is suggested.

It is recommended that critically ill patients with COVID-19 without evidence of thromboembolic disease should be medicated with a prophylactic anticoagulation regimen (standard or adjusted) in the absence of contraindications.

It is recommended that critically ill patients with COVID-19 receiving extracorporeal organ support (including veno-venous or veno-arterial extracorporeal life support and renal support therapy) receive antithrombotic therapy following standard institutional protocols.

Other therapies

In critically ill patients infected with SARS-CoV-2, it is recommended not to use convalescent plasma therapy outside the scope of clinical use protocols or clinical trials.

In critical patients infected with SARS-CoV-2, it is recommended not to use therapy with mesenchymal stem cells outside the scope of clinical use protocols or clinical trials.

In critically ill patients infected with SARS-CoV-2, it is recommended not to use therapy with neutralizing antibodies outside the scope of clinical use protocols or clinical trials.

In critically ill patients infected with SARS-CoV-2, routine nonsuspension of chronic therapy with renin-angiotensin system inhibitors (angiotensin converting enzyme (ACE) inhibitors or angiotensin 2 receptor antagonists) or statins is recommended.

In critically ill patients infected with SARS-CoV-2, it is recommended not to discontinue or avoid treatment with nonsteroidal antiinflammatory drugs (NSAIDs) when clinically indicated.

Criteria for cure and suspension of isolation

It is recommended that obtaining a cure criterion (and consequent suspension of isolation) of patients with severe or critical COVID-19 (or severe immunosuppression, regardless of the severity of the disease) does not depend on laboratory criteria but rather on the cumulative fulfillment of criteria: (1) clinical (significant improvement of symptoms with apyrexia, without use of antipyretics, for three consecutive days) and (2) temporal (20 days since the onset of symptoms).

Publication Dates

  • Publication in this collection
    24 Jan 2022
  • Date of issue
    2021

History

  • Received
    07 May 2021
  • Accepted
    20 July 2021
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