Discussion
The major findings of our study are that early use of corticosteroids in critically ill patients with COVID-19 was associated with: (i) lower ICU mortality when compared to delayed or no use of corticosteroids; (ii) shorter ICU LOS; (iii) decreased organ dysfunction, and (iv) fewer days on MV, with no increase in medical or infectious complications. These findings remained statistically significant after adjusting for age, gender, comorbidities, severity, and PaO2/FiO2 at admission.
To study the influence of corticosteroids on mortality in our cohort, we set a cut-off point of 48 h after admission to ICU based on the comparison of survivors vs. non-survivors where we found that the onset time for using corticosteroids was clinically relevant. Furthermore, we consider this period long enough for an experienced clinician to assess patients’ response to initial support and therapy and modify them accordingly. We have tried to solve the question placed by many clinicians: shall I start corticosteroids in this patient? Like an intention-to-treat analysis, patients receiving corticosteroids after 48 h of ICU admission were not excluded because the decision to start therapy in this group was probably guided by other uncontrolled factors.
Several recent publications support the early and selective use of corticosteroids in symptomatic patients infected with SARS-COV-2. The RECOVERY trial found a reduction in 28-day mortality in hospitalized COVID-19 patients treated with dexamethasone if they required oxygen or MV [
4]. The prospective meta-analysis of 7 randomized trials performed by the WHO Rapid Evidence Appraisal for COVID-19 Therapies Working Group found that 28-day all-cause mortality in critically ill patients with COVID-19 was lower among those who received corticosteroids compared with those who received usual care or placebo (summary odds ratio, 0.66) [
5]. Our study reinforces those results and sheds more light by providing new and more complete information. Of note, these findings are in contrast with previous reports on corticosteroid therapy in past outbreaks of other coronaviruses (SARS-CoV, MERS-CoV), or other viral pneumonia (Influenza, Respiratory Syncytial Virus) [
12‐
16].
Our sensitivity analysis showed that early use of corticosteroids was not as effective in women, in those with lower risk of death –younger patients with good oxygenation and less inflammation—and neither in those with greater risk or severity –cancer, diabetics, D-Dimer > 1500 ng/mL, APACHE score > 14—. These findings suggest that patient characteristics should be assessed before prescribing corticosteroids.
In clinical practice, corticosteroids are used in most critically ill patients [
16]. The extensive use of corticosteroids in our cohort reflects the severity of our patients (almost 60% directly admitted to ICU upon arrival to the hospital, 81.9% with invasive mechanical ventilation in the first 48 h after ICU admission, and with a mean PaO2/FiO2 = 150). Since observational studies are prone to selection bias, we used inverse probability of treatment weighting to tackle this problem. Corticosteroid therapy is further entangled by other factors that merit discussion, including timing, type of corticosteroids, duration of treatment, and dosing.
Our average time to corticosteroids administration was 12 days after symptom onset (Additional file
2: Table S1), like the 13 days in the RECOVERY study for mechanically ventilated patients [
4]. The decision to initiate corticosteroid therapy in our patients was guided when signs of hyperinflammation and severity of respiratory failure were evident. The delay or non-use of corticosteroids in 45% of our patients may reflect the controversy on their benefit/harm profile, WHO recommendations [
1], or significant changes in clinical evolution. Ideally, we should start corticosteroid therapy in the initial phases of the hyperinflammatory state. Early use in the absence of hyperinflammation could be harmful, especially in the initial stage of viral replication [
4,
17,
18]. Similar to the RECOVERY trial, we have also found that corticosteroids were not associated with a reduction in mortality among those patients with symptoms duration under 7 days. One possible explanation is that corticosteroids may slow viral clearance in such an early phase. However, studies on viral clearance have yielded contradictory results [
19‐
22]. Unfortunately, we did not collect time to viral clearance.
Interestingly, patients who never received corticosteroids had higher mortality than early treated patients, a difference that was not observed when we compare them with ever-treated patients, that includes early plus delayed treatment. Delayed corticosteroids, when advanced organ damage already exists, might be ineffective and even detrimental, as previously described in ARDS [
23], with increased infectious complications and mortality, counteracting the positive effect of early treatment. The absence of benefit with too early use of corticosteroids (within 7 days of symptom onset), together with the beneficial effect of early use, and the worst results with delayed use, reveals a U-shaped time-outcome relationship. Although we do not know the optimal time to start corticosteroids, probably patients with elevated inflammatory markers after seven days of symptoms, requiring oxygen or ventilatory support may benefit the most, whereas those who have not received corticosteroids in early phases, probably will not benefit afterwards.
To the best of our knowledge, recommendations about dose and duration of corticosteroid treatment are empiric. With large doses and long treatments, the potential for adverse effects increases, and the possible benefit is lost [
24]. The Italian National Institute for Infectious Diseases recommends a 10-day regimen: 5-days full dose of methylprednisolone 1 mg/Kg daily or dexamethasone 20 mg daily, and five days for tapering [
25]. In general, most regimens for acute hyperinflammatory states recommend treatments shorter than two weeks [
25,
26]. Most common dose regimens range between 0.5–2 mg/kg/day of methylprednisolone, equivalent to 0.1–0.4 mg/kg/day of dexamethasone, defined in our study as moderate-to-high doses. The cut-off points were defined before the publication of the RECOVERY trial that used a fixed dexamethasone dose (6 mg) lower than described in the literature for ARDS [
10]. We observed a greater mortality reduction with a moderate-to-high dose regimen, similar to other studies [
6,
9,
27]. Although our classification is artificial, it favours a higher dose of corticosteroids. As a result of the RECOVERY trial, the NIH and the WHO recommend a low fixed dose of daily dexamethasone [
7,
8], and numerous studies with different corticosteroids and doses were prematurely stopped without completion [
5,
9], but future comparative studies with higher doses are warranted [
6,
10].
Also, the beneficial effects of early corticosteroids in our patients expand beyond an absolute reduction in all-cause mortality, including a shorter ICU LOS, less organ dysfunction, and an increase in ventilator-free days.
This study has several strengths. First, this multicentre nationwide prospective data collection with over 1,000 patients from 36 ICUs provides a very detailed description of all gathered data from ICU admission to death or ICU discharge. Second, to the best of our knowledge, this is the first observational study that prospectively explores the association between different doses and timings of corticosteroid therapy in COVID-19 patients and ICU mortality. Third, we have used IPW to control for confounding with pre-specified demographic, comorbidities, and severity parameters. However, we acknowledge some limitations of our study. First, the observational nature of our study design, which may be subject to biases. Although we adjusted for likely confounders, some unmeasured confounding is still possible. Second, we cannot exclude missing data for some variables and potential for inaccuracies in the electronic health records due to the burden of care experienced by participating clinicians during the pandemic. However, due to the nature of our registry, we consider that selection bias was not favoured, and our analyses are valid. Third, although moderate-to-high doses of dexamethasone were most effective, no firm conclusions can be drawn on the drug or the dose, as our hypothesis and the definition of variables in the protocol preclude to do so, and doses predefined as low are not completely equivalent and could be controversial. Finally, at the time of the analysis, 149 (13.5%) patients did not have a definitive outcome regarding status at ICU discharge and were not included in the main analysis, although included in the sensitivity analyses.
Acknowledgements
We thank all patients and their families involved in the study. We would like the names of the individual members of the COVID-19 Spanish ICU Network Group to be searchable through their individual PubMed records.
Investigators of the COVID-19 Spanish ICU Network are: Hospital Clínic de Barcelona, Department of Anesthesiology and Critical Care: Marina Vendrell, Gerard Sánchez-Etayo, Amalia Alcón, Isabel Belda, Mercé Agustí, Albert Carramiñana, Isabel Gracia, Miriam Panzeri, Irene León, Jaume Balust, Ricard Navarro, María José Arguís, María José Carretero, Cristina Ibáñez, Juan Perdomo, Antonio López, Manuel López-Baamonde, Tomás Cuñat, Marta Ubré, Antonio Ojeda, Andrea Calvo, Eva Rivas, Paola Hurtado, Roger Pujol, Nuria Martín, Javier Tercero, Pepe Sanahuja, Marta Magaldi, Miquel Coca, Elena del Rio, Julia Martínez-Ocon, Paula Masgoret, Monserrat Tio, Angel Caballero, Raquel Risco, Raquel Bergé, Lidia Gómez, Nicolás de Riva, Ana Ruiz, Beatriz, Tena, Sebastián Jaramillo, José María Balibrea, Francisco Borja de Lacy, Ana Otero, Ainitze Ibarzabal, Raquel Bravo, Anna Carreras, Daniel Martín-Barreda, Alfonso Jesús Alias, Mariano Balaguer, Jorge Aliaga, Alex Almuedo, Joan Ramón Alonso, Rut Andrea, Gerard Sergi Angelès, Marilyn Arias, Fátima Aziz, Joan Ramon Badía, Enric Barbeta, Toni Torres, Guillem Batiste, Pau Benet, Xavi Borrat, María Borrell, Ernest Bragulat, Inmaculada Carmona, Manuel Castellà, Pedro Castro, Joan Ceravalls, Oscar Comino, Claudia Cucciniello, Clàudia De Deray, Oriol De Diego, Paula De la Matta, Marta Farrero, Javier Fernández, Sara Fernández, Anna Fernández, Miquel Ferrer, Ana Fervienza, María Tallo Forga, Daniel Forné, Clàudia Galán, Andrea Gómez, Eduard Guasch, María Hernández-Tejero, Adriana Jacas, Beltrán Jiménez, Pere Leyes, Teresa López, José Antonio Martínez, Graciela Martínez-Pallí, Jordi Mercadal, Guido Muñoz, José Muñoz, Ricard Navarro, Josep María Nicolás, José Tomás Ortiz, Anna Peiró, Manuel Pérez, Esteban Poch, Margarida Pujol, Eduard Quintana, Bartomeu Ramis, Enric Reverter, Irene Rovira, Pablo Ruiz, Elena Sandoval, Stefan Schneider, Oriol Sibila, Carla Solé, Alex Soriano, Dolors Soy, M. Suárez, Adrián Téllez, Néstor David Toapanta, Antoni Torres, Xavier Urra. Hospital Universitario Río Hortega: César Aldecoa, Alicia Bordell, Silvia Martín, Judith Andrés. Hospital Universitario Cruces: Alberto Martínez Ruiz, Gonzalo Tamayo Medel, Iñaki Bilbao Villasante, Fernando Iturri Clavero, Covadonga Peralta Álvarez, Julia T. Herrera Díez, Andrea García Trancho, Iñaki Sainz Mandiola, Carmen Ruano Suarez, Angela Ruiz Bocos, Eneritz Urrutia Izagirre, Pablo Ortiz de Urbina Fernández, Naiara Apodaka López, Leire Prieto Molano, Eunate Ganuza Martínez, Iratxe Vallinas Hidalgo, Karmele de Orte Sancho, Celia González Paniagua, Gemma Ortiz Labrador, Mireia Pérez Larrañaga, Marta López Miguelez, Estíbaliz Bárcena Andrés, Erik Urutxurtu Laureano, Maria Jesús Maroño Boedo, Blanca Escontrela Rodríguez, Aitziber Ereñozaga Camiruaga, Deiene Lasuen Aguirre, Ainhoa Zabal Maeztu, Ane Guereca Gala, Iker Castelo Korro, Andrés Álvarez Campo, Alejandro Carcelen Viana, Alejandro Alberdi Enríquez, Xabier Ormazábal Rementeria, Alberto Sánchez Campos, Rosa Gutiérrez Rico, Pablo Barbier Damborenea, Marta Guerenabarrena Momeñe, Borja Cuesta Ruiz, Alejandro López Rico, Ana Rojo Polo, Covadonga García Grijelmo, Mikel Celorrio Reta, Eneko Martín Arroyo, Leire Artaza Aparicio, Iñaki Ituarte Aspiazu, Ane Igeregi Basabe, Itxaso Merino Julian, Isabel Diaz Rico, Maria Paz Martínez. Hospital del Mar: Ramón Adalia Bartolomé, Luigi Zattera, Irina Adalid Hernandez, Leire Larrañaga Altuna, Aina Serrallonga Castells, Adriana Vílchez Garcia, María Núñez, Lorena Román, Isabel Ramos Delgado, Adela Benítez-Cano Martínez, Mireia Chanzá Albert, Juan Carlos Álvarez García, Luis Aguilera Cuchillo, Sandra Beltrán de Heredia, Jesús Carazo Cordobés, Carlos Alberto García Bernedo, Fernando Escolano Villén. Hospital General Universitario de Ciudad Real: Francisco Javier Redondo Calvo, Rubén Villazala González, Victor Baladron González, Patricia Faba, Omar Montenegro, Natalia Bejarano Ramírez. Complejo Asistencial Universitario León: Sergio Marcos Contreras, Alejandro Garcia Rodríguez, Saleta Rey Vázquez, Cristina Garcia Pérez, Eva Higuera Miguelez, Irene Pérez Blanco, David García Rivera. Hospital Urduliz: Ane Martín de la Fuente, Marta Pardo, Vanessa Rodriguez, Unai Bengoetxea. Hospital Universitario de la Princesa: Fernando Ramasco, Sheila Olga Santidrián Bernal, Alvar Santa Cruz Hernando, Antonio Planas Roca, Carlos Figueroa Yusta, Esther García Villabona, Carmen Vallejo Lantero, Eva Patiño Rodriguez, Alvaro Esquivel Toledo, David Arribas Méndez, Mar Orts Rodriguez, Rosa Méndez Hernández, Jesús Nieves Alonso, Inés Imaz Artazcoz, Sonia Expósito Carazo, Carlos Román Guerrero, Elena Rojo Rodríguez, Ricardo Moreno González, Julia Hernando Santos, Jara Torrente Pérez, Esperanza Mata Mena, Manuel José Muñoz Martínez, Enrique Alday Muñoz, Patricia Martin Serrano, Laura Cotter Muñoz, Amadea Mjertan, Diego Gutierrez Martínez, Carmen Rodríguez García, Olaya Alonso Viejo, Juan Alvarez Pereira, Ana Carmona Bonet, Diana Parrado López, Eva de Dios Tomas, Rafael Martín Celemin, María Luisa Meilan Paz, Luis Quecedo Gutiérrez, Noemí Diaz Velasco, Gabriel Martin Hernández, Francisco Garcia del Corral, Gloria Hernandez Arias, David Rodriguez Cuesta, Ana Gómez Rice, Encarna Mateos Sevillano, Natalia Olmos Molpeceres. Hospital Povisa: Beatriz Domínguez, Ana Vázquez Lima. Hospital Ramón y Cajal: Ángel Candela, Ismael A Acevedo Bambaren, Maria Isabel Albala Blanco, Paloma Alonso Montoiro, Fernando Álvarez Utrera, Juan Avellanosa Esteruelas, Amal Azzam López, Alberto José Balvis Balvis, Tommaso Bardi, María Beltrán Martín, Jacobo Benatar Haserfaty, Alberto Berruezo Camacho, Laura Betolaza Weimer, María del Mar Carbonell Soto, Cristina Carrasco Seral, Cristina Cerro Zaballos, Elizabeth Claros Llamas, Pilar Coleta Orduna, Ingrid P. Cortes Forero, Pascual Agustín Crespo Aliseda, María Angélica de Pablo Pajares, Yolanda Díez Remesal, Trinidad Dorado Díaz, Noemí Echevarría Blasco, María Elena Elías Martín, Javier Felices Triviño, Natalia Fernández López, Cristina Fernández Martín, Natalia Ferreiro Pozuelo, Luis Gajate Martín, Clara Gallego Santos, Diego Gil Mayo, María Gómez Rojo, Claudia González Cibrián, Elena Herrera López, Borja Hinojal Olmedillo, Berta Iglesias Gallego, Sassan Khonsari, María Nuria Mane Ruiz, María Manzanero Arroyo, Ana María Mariscal Ortega, Sara Martín Burcio, María del Carmen Martín González, Ascensión Martín Grande, Jose Juan Martín López, Cecilia Martín Rabes, Marcos Martínez Borja, Nilda Martínez Castro, Adolfo Martínez Pérez, Snejana Matcan, Cristina Medrano Viñas, Lisset Miguel Herrera, Adrián Mira Betancur, María Montiel Carbajo, Javier Moya Moradas, Lorena Muñoz Pérez, Mónica Nuñez Murias, Eva Ordiales González, Óscar Ordoñez Recio, Miguel Ángel Palomero Rodriguez, Diego Parise Roux, Lucia Pereira Torres, David Pestaña Lagunas, Juana María Pinto Corraliza, Marian Prieto Rodrigo, Inmaculada Rodriguez Diaz-Regaño, David Rodriguez Esteban, Víctor Rojas Pernia, Álvaro Ruigómez Saiz, Bárbara Saavedra Villarino, Noemí Samaranch Palero, Gloria Santos Pérez, Jaume Serna Pérez, Ana Belén Serrano Romero, Jesús Tercero López, Carlos Tiscar García, Marta de la Torre Concostrina, Eva María Ureta Mesa, Eva Velasco Olarte, Judith Villahoz Martínez, Raúl Villalaba Palacios, Gema Villanueva García, Cristina Vogel de Medeiros. Hospital Universitario Severo Ochoa: Soraya Gholamian Ovejero, Marta Vicente Orgaz, Patricia Lloreda Herradon, Cristina Crespo Gómez. Hospital Universitario de Gran Canaria Dr. Negrín: Tatiana Sarmiento-Trujillo. Hospital de Terrassa: Noemí García Medina, María Martínez García, Carles Espinós Ramírez, Nabil Mouhaffel Rivero, Jose Antonio Bernia Gil. Hospital Central de la Cruz Roja San José y Santa Adela: Sonsoles Martín. Hospital de la Santa Creu i Sant Pau: María Victoria Moral, Josefina Galán, Pilar Paniagua, Sergio Pérez, Albert Bainac, Ana Arias, Elsa Ramil, Jorge Escudero. Clínica Universidad de Navarra: Departamento de Anestesiología y Cuidados Intensivos: Pablo Monedero, Carmen Cara, Andrea Lara, Elena Mendez Martínez, Jorge Mendoza, Íñigo Rubio Baines, Carmen Sala Trull, Pablo Montero López. Medicina Preventiva y Salud Pública: Alfredo Gea, Alejandro Montero. Hospital Universitario Dr. Peset Aleixandre: Rocío Armero Ibañez, Juan Vicente Llau Pitarch, Fernando Rauer Alcóver, Cristina Álvarez Herreros, Cyntia Sánchez Martín, Lucía López Ocáriz Olmos, Marta Navas Moruno. Complejo Hospitalario Universitario de Cáceres: Fernando García Montoto. MF. Mirón Rodriguez, Laura Fuentes Coco, Cristina Hernández Gamito, Antonio Barba Orejudo, Luis Gerardo Smith Vielma, Yasmina González Marín, Francisco de Borja Amador Penco, Marta Donoso Domínguez, Silvia Esquivel Ramírez. Hospital Clínico Universitario de Valencia: José Antonio Carbonell, Berta Monleón López, Sara Martínez-Castro, Gerardo Aguilar. Hospital Universitario a Coruña: María Gestal, Pablo Casas, Angel Outeiro Rosato, Andrea Naveiro Pan, María Alonso Portela, Adrián García Romar, Eva Mosquera Rodríguez, Diego Ruanova Seijo, Pablo Rama Maceiras. Complexo Universitario de Ferrol: Francisco Castro-Ceoane, Esther Moreno López. Hospital Clínico Universitario Lozano Blesa: Sergio Gil, Julia Guillén Antón, Patricia García-Consuegra Tirado, Aurora Callau Calvo, Laura Forés Lisbona, María Carbonell Romero, Belén Albericio Gil, Laura Pradal Jarne, María Soria Lozano, Diego Loscos López, Andrea Patiño Abarca. Universal Doctors: Jordi Serrano. UBIKARE: Javier Pérez-Asenjo, Ángel Díez-Domínguez, Ion Zubizarreta, Jon Ramos, Iosu Fernández. Hospital Universitario La Paz: Emilio Maseda, Alejandro Suárez de la Rica, Javier Veganzones, Itziar Insausti, Javier Sagra, Sofía Díaz Carrasco, Ana Montero Feijoo, Julio Yagüe. Hospital Universitario Gregorio Marañon: Ignacio Garutti, Javier Hortal, Patricia Piñeiro, Matilde Piñeiro, Matilde Zaballos, Jamil cedeño, Pablo García-Olivares, Alberto Garriido, Jose Eugenioi Guerrero. Hospital San Joan Despí Moises Broggi:
Eva Bassas Parga, Carmen Deiros Garcia, Elisenda Pujol Rosa, Ana Tejedor Navarro, Roser Font Gabernet, Maria José Bernat, Meritxell Serra Valls, Cristina Cobaleda Garcia-Bernalt, Jesus Fernanz Anton, Adriana Aponte Sierra, Lucia Gil Gomez, Olaia Guenaga Vaqueiro, Susana Hernandez Marin, Laura Pardo Pinzon, Sira Garcia Aranda, Carlos Briones Orejuela, Edgar Cortes Sánchez, Alejandro Romero Fernández, Esther Fernández SanJosé, Patricia Iglesias Garsabal, Guillermo Isidro Lopez, Ana Vicol, Sara Espejo Malagon, María Sanabra Loewe, Laura Grau Torradeflo, Lourdes Blanco Alcaide, Gloria Buenaventura Sanclemente, Pere Serra Pujol, Gustavo Cuadros Mendoza, Miroslawa Konarska, Fedra Bachs Almenara, Agnieszka Golska, Aleix Carmona Blesa, Arantxa Mas Serra. Hospital Universitario Infanta Leonor: Javier Ripolles Melchor, Ana Nieto Moreno, Káteri Chao Novo, Sandra Gadín López, Elena Nieto Moreno, Bérénice Gutiérrez Tonal, Elena Lucena de Pablo, Barbara Algar Yañez, Beatriz Vázquez Rivero, Beatriz Nozal Mateo, Marina de Retes, Norma Aracil Escoda, Cristina Gallardo Mayo, Rosa Sanz González, Alicia Ruiz Escobar, Maria Laura Pelegrina López, Marina Valenzuela Peña, David Stolle Dueñas, Ane Abad Motos, Alfredo Abad-Gurumeta, Ana Tirado Errazquin, Elena Sáez Ruiz, Nerea Gómez Pérez, Francisco de Borja Bau González. Hospital sanitas CIMA: Cesar Morcillo Serra, Jessica Souto Higueras. Hospital Universitario y Politécnico La Fé: Rosario Vicente, Raquel Ferrandis, Silvia Polo Martín, Azucena Pajares Moncho, Ignacio Moreno Puigdollers, Juan Pérez Artacho Cortés, Ana Moret Calvo, Ana Pi Peña, María Catalán Fernández. Complexo hospitalario Universitario de Pontevedra: Marina Varela, Pilar Díaz Parada, Raquel Rey Carlín, Sarra Barreiro Aragunde. Hospital Arnau de Vilanova: María Isabel Forés Chiva. Hospital General de Alicante: A. Javier Agulló. Hospital Universitario Infanta Sofía: Antonio Pérez Ferrer. Hospital Universitario San Juan de Alicante: María Galiana. Hospital Nuestra Señora de Meritxell SAAS: Antoni Margarit, Válerie Mourre del Rio, Eva Heras Muxella, Anna Vidal.