Prevalence and risk factors for delirium in critically ill patients with COVID-19 (COVID-D): a multicentre cohort study

Brenda T Pun, Rafael Badenes, Gabriel Heras La Calle, Onur M Orun, Wencong Chen, Rameela Raman, Beata-Gabriela K Simpson, Stephanie Wilson-Linville, Borja Hinojal Olmedillo, Ana Vallejo de la Cueva, Mathieu van der Jagt, Rosalía Navarro Casado, Pilar Leal Sanz, Günseli Orhun, Carolina Ferrer Gómez, Karla Núñez Vázquez, Patricia Piñeiro Otero, Fabio Silvio Taccone, Elena Gallego Curto, Anselmo Caricato, Hilde Woien, Guillaume Lacave, Hollis R O'Neal Jr, Sarah J Peterson, Nathan E Brummel, Timothy D Girard, E Wesley Ely, Pratik P Pandharipande, COVID-19 Intensive Care International Study Group, Jacques Creteur, Elisa Govea Bogossian, Lorenzo Peluso, Felipe González-Seguel, Viviane Hidalgo-Calibin, Pablo Carreño-Montenegro, Verónica Rojas, Eduardo Tobar, Antonio Ramírez-Palma, Karen Herrera-Davis, Alexis Ferré, Stéphane Legriel, Thomas Godet, Ugo Fraisse, Bruno Gonçalves, Aurélien Mazeraud, Myrto Tzimou, Frank Rasulo, Silvia Beretta, Mattia Marchesi, Chiara Robba, Denise Battaglini, Paolo Pelosi, Anna Teresa Mazzeo, Alberto Noto, Giuseppe Servillo, Annachiara Marra, Salvatore Lucio Cutuli, Gabriele Pintaudi, Eleonora Stival, Eloisa Sofia Tanzarella, Erik Roman-Pognuz, Chiara Maria Concetta Massaro, Muhammed Elhadi, Lisa Smit, Theresa Olasveengen, Isabel Jesus Pereira, Carla Margarida Teixeira, Alice Santos, Miguel Valente, Cristina Granja, Rita Pereia, João Silva, Blanca Furquet, Mónica García Simón, Daniel A Godoy Torres, Berta Monleón, Esteban Morcillo, Nekane Romero, Ainhoa Serrano, Sara Torrico Sánchez, Francisco Luis Pérez Caballero, Isabel Peña Luna, Ignacio Baeza Gómez, Milagros Calizaya Vargas, Jordi Morillas Pérez, Genís Carrasco Gómez, Ricard Molina Latorre, Sheila Moya Gutiérrez, Irene Patricia Barón Barrera, Cristina Delgado Palacios, Beatriz García Góngora, Laura Labrador Romero, Laura Galarza, Ignacio Catalán-Monzón, Enver Rodriguez-Martínez, Cristina Murcia Gubianas, Ariadna Bellès, María Esther Rodriguez Delgado, Jesús Caballero, Dulce Morales, Andrés Pujol, Jorge Rubio, Eva Álvarez Torres, Estefanía Carvajal Revuelta, Isabel de la Calle Gil, Blanca Fernández Tomás, Berta Gallego Rodríguez, Matilde González Serrano, Paloma LaTorre Andreu, Aris Pérez Lucendo, Elena Abril Palomares, Elena González González, María Cruz Martín Delgado, Carlos Muñoz De Cabo, Pablo T Aznar, Carlos A Calvo, Ignacio Garutti, Fernando Higuero, David Martínez-Gascueña, Emilio Maseda, Itziar Insausti, Ana Montero Feijoo, Alejandro Suarez-de-la-Rica, Beatriz Del Moral Barbudo, Yago García Blanco-Traba, Maria Claudia Giménez Santamarina, Alba Gonzalo Millán, Sergio Llorente Damas, David Pestaña Lagunas, Isabel Reyes García, Alejandro Ruiz Perea, Álvaro Ortega Guerrero, María Jesús Mármol Cubillo, David Díaz Muñoz, Silvia García de Castrillón I Ramal, Xavier Andorrà Sunyer, María de Las Nieves Noci Moreno, Rosa María Pérez Manrique, Emilio Del Campo Molina, María Elena Martínez Quintana, Sol Fernandez-Gonzalo, Gemma Gomà Fernández, Guillem Navarra-Ventura, Anna Baró Serra, Cristina Fuster, Oriol Plans Galván, Diana Gil-Castillejos, Mario Dalorzo González, Francisco Javier Morán Gallego, Irene Paredes Borrachero, Patricia Rodríguez Villamizar, Juan Romeu Prieto, María José Sánchez Carretero, Susana Gallardo Sánchez, Filadelfo Bustos Molina, María Luisa García Pérez, Paula Castello-Mora, Jaume Puig, María Rosa Sanchis-Martin, Carmen Andrea Sanchis-Veryser, María Pilar Vicente-Fernández, Rafael Zaragoza, Laura Lizama, Irene Torres, Cristina Álvarez, Paula Ramírez, Meri Martin Cerezuela, María Jesús Montero, Jose García Cantos, Paola Valls, Nerea Aretxabala Cortajarena, Pablo García Domelo, Laura González Cubillo, Marta Martín Martínez, Inés Pérez Francisco, Yolanda Poveda Hernández, Amaia Quintano Rodero, César Rodriguez Nuñez, Martin Siegemund, Anna Estermann, Núria Zellweger, Imen Ben Saida, Mohamed Boussarsar, Figen Esen, Perihan Ergin Özcan, Christopher Berkey, Christine Harb, Morgan H Tandy, Ellis Morgan, Karen Shephard, Robert C Hyzy, Michael Kenes, Kristine Nelson, Robert E Hosse, Katie M Vance, C Adrian Austin, Aaron Lerner, Emily Sanders, Robert A Balk, David A Bennett, Andrew R Vogel, Lucia Chowdhury, Kiran Devulapally, Michelle Woodham, Sarah Cohen, Nihal Patel, Catherine M Kuza, Mandeep Sing, Spencer Roberson, Kelly Drumright, Sameep Sehgal, Sara C LaHue, Vanja C Douglas, Aarti Sarwal, Brenda T Pun, Rafael Badenes, Gabriel Heras La Calle, Onur M Orun, Wencong Chen, Rameela Raman, Beata-Gabriela K Simpson, Stephanie Wilson-Linville, Borja Hinojal Olmedillo, Ana Vallejo de la Cueva, Mathieu van der Jagt, Rosalía Navarro Casado, Pilar Leal Sanz, Günseli Orhun, Carolina Ferrer Gómez, Karla Núñez Vázquez, Patricia Piñeiro Otero, Fabio Silvio Taccone, Elena Gallego Curto, Anselmo Caricato, Hilde Woien, Guillaume Lacave, Hollis R O'Neal Jr, Sarah J Peterson, Nathan E Brummel, Timothy D Girard, E Wesley Ely, Pratik P Pandharipande, COVID-19 Intensive Care International Study Group, Jacques Creteur, Elisa Govea Bogossian, Lorenzo Peluso, Felipe González-Seguel, Viviane Hidalgo-Calibin, Pablo Carreño-Montenegro, Verónica Rojas, Eduardo Tobar, Antonio Ramírez-Palma, Karen Herrera-Davis, Alexis Ferré, Stéphane Legriel, Thomas Godet, Ugo Fraisse, Bruno Gonçalves, Aurélien Mazeraud, Myrto Tzimou, Frank Rasulo, Silvia Beretta, Mattia Marchesi, Chiara Robba, Denise Battaglini, Paolo Pelosi, Anna Teresa Mazzeo, Alberto Noto, Giuseppe Servillo, Annachiara Marra, Salvatore Lucio Cutuli, Gabriele Pintaudi, Eleonora Stival, Eloisa Sofia Tanzarella, Erik Roman-Pognuz, Chiara Maria Concetta Massaro, Muhammed Elhadi, Lisa Smit, Theresa Olasveengen, Isabel Jesus Pereira, Carla Margarida Teixeira, Alice Santos, Miguel Valente, Cristina Granja, Rita Pereia, João Silva, Blanca Furquet, Mónica García Simón, Daniel A Godoy Torres, Berta Monleón, Esteban Morcillo, Nekane Romero, Ainhoa Serrano, Sara Torrico Sánchez, Francisco Luis Pérez Caballero, Isabel Peña Luna, Ignacio Baeza Gómez, Milagros Calizaya Vargas, Jordi Morillas Pérez, Genís Carrasco Gómez, Ricard Molina Latorre, Sheila Moya Gutiérrez, Irene Patricia Barón Barrera, Cristina Delgado Palacios, Beatriz García Góngora, Laura Labrador Romero, Laura Galarza, Ignacio Catalán-Monzón, Enver Rodriguez-Martínez, Cristina Murcia Gubianas, Ariadna Bellès, María Esther Rodriguez Delgado, Jesús Caballero, Dulce Morales, Andrés Pujol, Jorge Rubio, Eva Álvarez Torres, Estefanía Carvajal Revuelta, Isabel de la Calle Gil, Blanca Fernández Tomás, Berta Gallego Rodríguez, Matilde González Serrano, Paloma LaTorre Andreu, Aris Pérez Lucendo, Elena Abril Palomares, Elena González González, María Cruz Martín Delgado, Carlos Muñoz De Cabo, Pablo T Aznar, Carlos A Calvo, Ignacio Garutti, Fernando Higuero, David Martínez-Gascueña, Emilio Maseda, Itziar Insausti, Ana Montero Feijoo, Alejandro Suarez-de-la-Rica, Beatriz Del Moral Barbudo, Yago García Blanco-Traba, Maria Claudia Giménez Santamarina, Alba Gonzalo Millán, Sergio Llorente Damas, David Pestaña Lagunas, Isabel Reyes García, Alejandro Ruiz Perea, Álvaro Ortega Guerrero, María Jesús Mármol Cubillo, David Díaz Muñoz, Silvia García de Castrillón I Ramal, Xavier Andorrà Sunyer, María de Las Nieves Noci Moreno, Rosa María Pérez Manrique, Emilio Del Campo Molina, María Elena Martínez Quintana, Sol Fernandez-Gonzalo, Gemma Gomà Fernández, Guillem Navarra-Ventura, Anna Baró Serra, Cristina Fuster, Oriol Plans Galván, Diana Gil-Castillejos, Mario Dalorzo González, Francisco Javier Morán Gallego, Irene Paredes Borrachero, Patricia Rodríguez Villamizar, Juan Romeu Prieto, María José Sánchez Carretero, Susana Gallardo Sánchez, Filadelfo Bustos Molina, María Luisa García Pérez, Paula Castello-Mora, Jaume Puig, María Rosa Sanchis-Martin, Carmen Andrea Sanchis-Veryser, María Pilar Vicente-Fernández, Rafael Zaragoza, Laura Lizama, Irene Torres, Cristina Álvarez, Paula Ramírez, Meri Martin Cerezuela, María Jesús Montero, Jose García Cantos, Paola Valls, Nerea Aretxabala Cortajarena, Pablo García Domelo, Laura González Cubillo, Marta Martín Martínez, Inés Pérez Francisco, Yolanda Poveda Hernández, Amaia Quintano Rodero, César Rodriguez Nuñez, Martin Siegemund, Anna Estermann, Núria Zellweger, Imen Ben Saida, Mohamed Boussarsar, Figen Esen, Perihan Ergin Özcan, Christopher Berkey, Christine Harb, Morgan H Tandy, Ellis Morgan, Karen Shephard, Robert C Hyzy, Michael Kenes, Kristine Nelson, Robert E Hosse, Katie M Vance, C Adrian Austin, Aaron Lerner, Emily Sanders, Robert A Balk, David A Bennett, Andrew R Vogel, Lucia Chowdhury, Kiran Devulapally, Michelle Woodham, Sarah Cohen, Nihal Patel, Catherine M Kuza, Mandeep Sing, Spencer Roberson, Kelly Drumright, Sameep Sehgal, Sara C LaHue, Vanja C Douglas, Aarti Sarwal

Abstract

Background: To date, 750 000 patients with COVID-19 worldwide have required mechanical ventilation and thus are at high risk of acute brain dysfunction (coma and delirium). We aimed to investigate the prevalence of delirium and coma, and risk factors for delirium in critically ill patients with COVID-19, to aid the development of strategies to mitigate delirium and associated sequelae.

Methods: This multicentre cohort study included 69 adult intensive care units (ICUs), across 14 countries. We included all patients (aged ≥18 years) admitted to participating ICUs with severe acute respiratory syndrome coronavirus 2 infection before April 28, 2020. Patients who were moribund or had life-support measures withdrawn within 24 h of ICU admission, prisoners, patients with pre-existing mental illness, neurodegenerative disorders, congenital or acquired brain damage, hepatic coma, drug overdose, suicide attempt, or those who were blind or deaf were excluded. We collected de-identified data from electronic health records on patient demographics, delirium and coma assessments, and management strategies for a 21-day period. Additional data on ventilator support, ICU length of stay, and vital status was collected for a 28-day period. The primary outcome was to determine the prevalence of delirium and coma and to investigate any associated risk factors associated with development of delirium the next day. We also investigated predictors of number of days alive without delirium or coma. These outcomes were investigated using multivariable regression.

Findings: Between Jan 20 and April 28, 2020, 4530 patients with COVID-19 were admitted to 69 ICUs, of whom 2088 patients were included in the study cohort. The median age of patients was 64 years (IQR 54 to 71) with a median Simplified Acute Physiology Score (SAPS) II of 40·0 (30·0 to 53·0). 1397 (66·9%) of 2088 patients were invasively mechanically ventilated on the day of ICU admission and 1827 (87·5%) were invasively mechanical ventilated at some point during hospitalisation. Infusion with sedatives while on mechanical ventilation was common: 1337 (64·0%) of 2088 patients were given benzodiazepines for a median of 7·0 days (4·0 to 12·0) and 1481 (70·9%) were given propofol for a median of 7·0 days (4·0 to 11·0). Median Richmond Agitation-Sedation Scale score while on invasive mechanical ventilation was -4 (-5 to -3). 1704 (81·6%) of 2088 patients were comatose for a median of 10·0 days (6·0 to 15·0) and 1147 (54·9%) were delirious for a median of 3·0 days (2·0 to 6·0). Mechanical ventilation, use of restraints, and benzodiazepine, opioid, and vasopressor infusions, and antipsychotics were each associated with a higher risk of delirium the next day (all p≤0·04), whereas family visitation (in person or virtual) was associated with a lower risk of delirium (p<0·0001). During the 21-day study period, patients were alive without delirium or coma for a median of 5·0 days (0·0 to 14·0). At baseline, older age, higher SAPS II scores, male sex, smoking or alcohol abuse, use of vasopressors on day 1, and invasive mechanical ventilation on day 1 were independently associated with fewer days alive and free of delirium and coma (all p<0·01). 601 (28·8%) of 2088 patients died within 28 days of admission, with most of those deaths occurring in the ICU.

Interpretation: Acute brain dysfunction was highly prevalent and prolonged in critically ill patients with COVID-19. Benzodiazepine use and lack of family visitation were identified as modifiable risk factors for delirium, and thus these data present an opportunity to reduce acute brain dysfunction in patients with COVID-19.

Funding: None.

Translations: For the French and Spanish translations of the abstract see Supplementary Materials section.

Copyright © 2021 Elsevier Ltd. All rights reserved.

Figures

Figure 1
Figure 1
Study flow diagram ICU=intensive care unit. *All patients who were COVID-19 positive and admitted to an ICU from the first reported case in each ICU until April 28th, 2020, were considered for inclusion.
Figure 2
Figure 2
Mental status and respiratory support status in the 21-day study period (n=2088) (A) Mental status over time. Coma was defined as a day when the patients were unresponsive to verbal stimulation (Richmond Agitation-Sedation Scale score of –4 or –5 or Glasgow Coma Scale score of

Figure 3

Forest plot of daily probability…

Figure 3

Forest plot of daily probability of delirium All patients who had at least…

Figure 3
Forest plot of daily probability of delirium All patients who had at least 90% delirium or coma assessments during their index ICU stay and 2 days of ICU stay were included in this analysis (n=2049). Other states, such as comatose, awake without delirium, deceased, and discharged (from index ICU) were considered as competing risks for this multinomial regression analysis. Risk factors with scores greater than 1 (and not crossing 1) were associated with a statistically higher risk of delirium the following day. ICU=intensive care unit. OR=odds ratio. SAPS II=Simplified Acute Physiology Score II. *For all continuous variables (age, SAPS II, proportion of ABCDE elements performed), comparisons shown in parentheses correspond to the 75th vs 25th percentile values for that variable. †p values shown represent the overall p values for the variable and are not associated with the level to level comparisons within these variables, which are represented by the 95% CIs. ‡Bundle element F was assessed separately since COVID-19 presents a unique circumstance in which in-person visitation was restricted at most of the participating sites.

Figure 4

Forest plot of days alive…

Figure 4

Forest plot of days alive and free of coma or delirium All patients…

Figure 4
Forest plot of days alive and free of coma or delirium All patients who had at least 90% delirium or coma assessments during their index intensive care unit stay were included in this analysis (n=2062). Risk factors with an OR of less than 1 indicate a negative patient outcome (fewer days alive and free of brain dysfunction coma or delirium). OR=odds ratio. SAPS II=Simplified Acute Physiology Score II. *For all continuous variables (age, SAPS II, proportion of ABCDE elements performed), comparisons shown in parentheses correspond to the 75th vs 25th percentile values for that variable. †p values shown represent the overall p values for the variable and are not associated with the level to level comparisons within these variables, which are represented by the 95% CIs.
Figure 3
Figure 3
Forest plot of daily probability of delirium All patients who had at least 90% delirium or coma assessments during their index ICU stay and 2 days of ICU stay were included in this analysis (n=2049). Other states, such as comatose, awake without delirium, deceased, and discharged (from index ICU) were considered as competing risks for this multinomial regression analysis. Risk factors with scores greater than 1 (and not crossing 1) were associated with a statistically higher risk of delirium the following day. ICU=intensive care unit. OR=odds ratio. SAPS II=Simplified Acute Physiology Score II. *For all continuous variables (age, SAPS II, proportion of ABCDE elements performed), comparisons shown in parentheses correspond to the 75th vs 25th percentile values for that variable. †p values shown represent the overall p values for the variable and are not associated with the level to level comparisons within these variables, which are represented by the 95% CIs. ‡Bundle element F was assessed separately since COVID-19 presents a unique circumstance in which in-person visitation was restricted at most of the participating sites.
Figure 4
Figure 4
Forest plot of days alive and free of coma or delirium All patients who had at least 90% delirium or coma assessments during their index intensive care unit stay were included in this analysis (n=2062). Risk factors with an OR of less than 1 indicate a negative patient outcome (fewer days alive and free of brain dysfunction coma or delirium). OR=odds ratio. SAPS II=Simplified Acute Physiology Score II. *For all continuous variables (age, SAPS II, proportion of ABCDE elements performed), comparisons shown in parentheses correspond to the 75th vs 25th percentile values for that variable. †p values shown represent the overall p values for the variable and are not associated with the level to level comparisons within these variables, which are represented by the 95% CIs.

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Source: PubMed

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