
==== Front
Can J Anaesth
Can J Anaesth
Canadian Journal of Anaesthesia
0832-610X
1496-8975
Springer International Publishing Cham

39251486
2811
10.1007/s12630-024-02811-4
Reports of Original Investigations
Characterization of postintensive care syndrome in a prospective cohort of survivors of COVID-19 critical illness: a 12-month follow-up study
Caractérisation du syndrome post-soins intensifs dans une cohorte prospective de personnes survivant à une maladie grave liée à la COVID-19 : une étude de suivi de 12 moishttp://orcid.org/0000-0003-0267-0617
Fernández-Gonzalo Sol MSc, PhD 123
http://orcid.org/0000-0001-9839-7357
Navarra-Ventura Guillem MSc, PhD g.navarra@uib.es

1414
Gomà Gemma MSc 14
Godoy-González Marta MSc 13
Oliveras Laia MSc 1
Ridao Sais Natalia MD 5
Espinal Cristina MD 1
Fortià Cristina MD 1
De Haro Candelaria MD, PhD 14
Ochagavía Ana MD, PhD 14
Jodar Merce MSc, PhD 236
Forné Carles MSc, PhD 78
Santos-Pulpon Verónica MSc 1
Sarlabous Leonardo MSc, PhD 14
Bacardit Neus MSc, PhD 9
Subirà Carles MD, PhD 410
Fernández Rafael MD, PhD 410
Palao Diego MD, PhD 21112
Roca Oriol MD, PhD 1413
Blanch Lluís MD, PhD 14
López-Aguilar Josefina MSc, PhD 14
1 grid.488873.8 0000 0004 6346 3600 Critical Care Department, Hospital Universitari Parc Taulí, Institut d’Investigació i Innovació Parc Taulí (I3PT-CERCA), Sabadell, Spain
2 grid.413448.e 0000 0000 9314 1427 Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain
3 https://ror.org/052g8jq94 grid.7080.f 0000 0001 2296 0625 Department of Clinical and Health Psychology, International Excellence Campus, Universitat Autònoma de Barcelona, Bellaterra, Cerdanyola del Vallès, Barcelona, Spain
4 grid.413448.e 0000 0000 9314 1427 Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain
5 grid.7080.f 0000 0001 2296 0625 Physical and Rehabilitation Medicine Department, Parc Taulí Hospital Universitari, Institut d’Investigació i Innovació Parc Taulí (I3PT-CERCA), Universitat Autònoma de Barcelona, Sabadell, Spain
6 grid.7080.f 0000 0001 2296 0625 Neurology Department, Parc Taulí Hospital Universitari, Institut d’Investigació i Innovació Parc Taulí (I3PT-CERCA), Universitat Autònoma de Barcelona, Sabadell, Spain
7 Heorfy Consulting, Lleida, Spain
8 https://ror.org/050c3cw24 grid.15043.33 0000 0001 2163 1432 Department of Basic Medical Sciences, University of Lleida, Lleida, Spain
9 https://ror.org/00bxg8434 grid.488391.f 0000 0004 0426 7378 Mental Health Department, Althaia Xarxa Assistencial Universitària de Manresa, IRIS Research Institute, Manresa, Spain
10 https://ror.org/00bxg8434 grid.488391.f 0000 0004 0426 7378 Critical Care Department, Althaia Xarxa Assistencial Universitària de Manresa, IRIS Research Institute, Manresa, Spain
11 grid.7080.f 0000 0001 2296 0625 Mental Health Department, Parc Taulí Hospital Universitari, Institut d’Investigació i Innovació Parc Taulí (I3PT-CERCA), Universitat Autònoma de Barcelona, Sabadell, Spain
12 https://ror.org/052g8jq94 grid.7080.f 0000 0001 2296 0625 Department of Psychiatry and Forensic Medicine, International Excellence Campus, Universitat Autònoma de Barcelona, Bellaterra, Cerdanyola del Vallès, Barcelona, Spain
13 https://ror.org/052g8jq94 grid.7080.f 0000 0001 2296 0625 Department of Medicine, International Excellence Campus, Universitat Autònoma de Barcelona, Bellaterra, Cerdanyola del Vallès, Barcelona, Spain
14 https://ror.org/03e10x626 grid.9563.9 0000 0001 1940 4767 Department of Medicine, University of the Balearic Islands, IUNICS, IdISBa, Palma, Mallorca, Spain
9 9 2024
9 9 2024
2024
71 9 12821301
1 6 2023
14 2 2024
5 3 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by-nc/4.0/ Open Access This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/.
Purpose

Studies integrating an exhaustive longitudinal long-term follow-up of postintensive care syndrome (PICS) in critically ill COVID-19 survivors are scarce. We aimed to 1) describe PICS-related sequelae over a 12-month period after intensive care unit (ICU) discharge, 2) identify relevant demographic and clinical factors related to PICS, and 3) explore how PICS-related sequelae may influence health-related quality of life (HRQoL) in critically ill COVID-19 survivors.

Methods

We conducted a prospective cohort study in adult critically ill survivors of SARS-CoV-2 infection that did or did not need invasive mechanical ventilation (IMV) during the COVID-19 pandemic in Spain (March 2020 to January 2021). We performed a telemedicine follow-up of PICS-related sequelae (physical/functional, cognitive, and mental health) and HRQoL with five data collection points. We retrospectively collected demographic and clinical data. We used multivariable mixed-effects models for data analysis.

Results

We included 142 study participants in the final analysis, with a median [interquartile range] age of 61 [53–68] yr; 35% were female and 59% needed IMV. Fatigue/dyspnea, pain, impaired muscle function, psychiatric symptomatology and reduced physical HRQoL were prominent sequelae early after ICU discharge. Over the 12-month follow-up, functionality and fatigue/dyspnea improved progressively, while pain remained stable. We observed slight fluctuations in anxiety symptoms and perception of cognitive deficit, whereas posttraumatic stress disorder (PTSD) and depressive symptoms improved, with a mild rebound at the end of the follow-up. Female sex, younger age, and the need for IMV were risk factors for PICS, while having higher cognitive reserve was a potential protective factor. Physical HRQoL scores showed a general improvement over time, whereas mental HRQoL remained stable. Shorter ICU stay, better functionality, and lower scores for fatigue/dyspnea and pain were associated with better physical HRQoL, while lower scores for anxiety, depression, and PTSD were associated with better mental HRQoL.

Conclusions

Postintensive care syndrome was common in COVID-19 critical illness survivors and persisted in a significant proportion of patients one year after ICU discharge, impacting HRQoL. The presence of risk factors for PICS may identify patients who are more likely to develop the condition and who would benefit from more specific and closer follow-up after ICU admission.

Study registration

ClinicalTrials.gov (NCT04422444); first submitted 9 June 2020.

Supplementary Information

The online version contains supplementary material available at 10.1007/s12630-024-02811-4.

Résumé

Objectif

Les études intégrant un suivi longitudinal exhaustif à long terme des syndromes post-soins intensifs (SPSI) chez les survivant·es gravement malades de la COVID-19 sont rares. Notre objectif était 1) de décrire les séquelles liées au SPSI sur une période de 12 mois après la sortie de l’unité de soins intensifs (USI), 2) d’identifier les facteurs démographiques et cliniques pertinents liés au SPSI, et 3) d’explorer comment les séquelles liées au SPSI peuvent influencer la qualité de vie liée à la santé (QVLS) chez les survivant·es gravement malades de la COVID-19.

Méthode

Nous avons mené une étude de cohorte prospective chez des adultes gravement malades survivant·es d’une infection par le SRAS-CoV-2 qui ont eu ou non besoin d’une ventilation mécanique invasive (VMI) pendant la pandémie de COVID-19 en Espagne (mars 2020 à janvier 2021). Nous avons effectué un suivi par télémédecine des séquelles liées au SPSI (santé physique/fonctionnelle, cognitive et mentale) et à la QVLS avec cinq points de collecte de données. Nous avons rétrospectivement colligé des données démographiques et cliniques. Des modèles multivariés à effets mixtes ont été utilisés pour l’analyse des données.

Résultats

Nous avons inclus 142 participant·es à l’étude dans l’analyse finale, avec un âge médian [intervalle interquartile] de 61 [53-68] ans; 35 % étaient des femmes et 59 % avaient besoin de VMI. La fatigue/dyspnée, la douleur, l’altération de la fonction musculaire, la symptomatologie psychiatrique et la réduction de la QVLS physique étaient des séquelles importantes peu après la sortie de l’USI. Au cours du suivi de 12 mois, la fonctionnalité et la fatigue/dyspnée se sont améliorées progressivement, tandis que la douleur est restée stable. Nous avons observé de légères fluctuations des symptômes d’anxiété et de perception du déficit cognitif, tandis que le trouble de stress post-traumatique (ESPT) et les symptômes dépressifs se sont améliorés, avec un léger rebond à la fin du suivi. Le sexe féminin, un jeune âge et le besoin de VMI étaient des facteurs de risque de SPSI, tandis qu’une réserve cognitive plus élevée était un facteur potentiel de protection. Les scores physiques de la QVLS ont montré une amélioration générale au fil du temps, tandis que la QVLS mentale est restée stable. Un séjour plus court aux soins intensifs, une meilleure fonctionnalité et des scores plus faibles pour la fatigue/dyspnée et la douleur étaient associés à une meilleure QVLS physique, tandis que des scores plus faibles pour l’anxiété, la dépression et le ESPT étaient associés à une meilleure QVLS mentale.

Conclusion

Le syndrome post-soins intensifs était fréquent chez les survivant·es d’une maladie grave de la COVID-19 et a persisté chez une proportion importante de patient·es un an après leur sortie de l’unité de soins intensifs, ce qui a eu un impact sur la QVLS. La présence de facteurs de risque de SPSI peut identifier les patient·es qui sont plus susceptibles de développer la maladie et qui bénéficieraient d’un suivi plus spécifique et plus étroit après leur admission aux soins intensifs.

Enregistrement de l’étude

ClinicalTrials.gov (NCT04422444); première soumission le 9 juin 2020.

Keywords

COVID-19
critical care
intensive care unit
neuropsychiatric sequelae
physical outcomes
postintensive care syndrome
quality of life
telemedicine assessment
http://dx.doi.org/10.13039/501100004587 Instituto de Salud Carlos III COV20/00595 Fernández-Gonzalo Sol http://dx.doi.org/10.13039/100008666 Fundació la Marató de TV3 202118 (413/C/2021) López-Aguilar Josefina Universitat de Les Illes BalearsOpen Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature.

issue-copyright-statement© Canadian Anesthesiologists' Society 2024
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pmcThe term “postintensive care syndrome” (PICS)1–3 describes the onset of difficulties or deterioration in functionality, physical function, cognition and/or mental health after an intensive care unit (ICU) stay. It may persist for months or even years after discharge, affecting between 30% and 50% of survivors of critical illness.4

Critically ill patients undergoing invasive mechanical ventilation (IMV) may present complications related to ICU-acquired muscle weakness up to five years after ICU discharge, and cognitive impairment, anxiety, and/or depression have been recorded in 30% to 100% of cases.3,5

PICS has a direct impact on ICU survivors’ quality of life6,7 as well as on health care and societal costs. In fact, 83% of critically ill patients with acute respiratory distress syndrome (ARDS) or septic shock increase their health care use because of PICS within two years of ICU discharge.8 Several other demographic and clinical factors, such as older age, female sex, previous mental health problems, disease severity, and presence of delirium during ICU stay have been associated with the development of PICS.9,10 In contrast, cognitive reserve—i.e., the brain’s ability to actively cope with cerebral dysfunction by using pre-existing cognitive processing approaches or enlisting compensatory approaches—has been suggested to be a protective factor against the development of some of the sequelae, especially cognitive impairment, after ICU stay.1,11,12

Since ARDS is a leading factor for post-ICU sequelae, PICS has been a major concern in the context of the COVID-19 pandemic.13,14 In the last two years, a wide range of sequelae has been reported in COVID-19 survivors, both in ICU and non-ICU patients.15 Symptoms such as muscle weakness, fatigue, dyspnea, joint pain, anosmia, sleep difficulties, anxiety, and depression have been encompassed under the terms “postacute COVID-19 syndrome” or “long COVID-19.”16 These short- and long-term consequences are mostly related to the pulmonary impairment caused by SARS-CoV-2, while the neurologic impact may be related to the spread of virus to the brain across the blood–brain barrier and/or via transsynaptic transfer, through optic and olfactory nerve channels and vascular endothelial cells.17 These physical (e.g., fatigue or muscle weakness) and neuropsychiatric (e.g., concentration and sleep difficulties, anxiety, depression) consequences may last up to six months after hospital discharge, with more severely ill patients being at a higher risk of developing sequelae.15,18 Furthermore, the neurocognitive impairment and the psychiatric morbidity observed in COVID-19 survivors have already been associated with worse quality of life at two months after hospital discharge.19

The emergency situation during the first stages of the pandemic led to nonconventional isolation policies and the prohibition of visits during hospital and ICU admission. These circumstances may have increased the risk of PICS in COVID-19 ICU survivors. Nevertheless, data from long-term studies on severe COVID-19 ICU survivors and/or on the specific course of the sequelae of PICS after ICU discharge are scarce. Furthermore, the specific risk factors for PICS in survivors of COVID-19 and the impact of its sequelae on their quality of life have not been well studied. Thus, we designed and implemented a novel follow-up program for COVID-19 ICU survivors combining telemedicine and in-person visits, which allowed us to address the following objectives: 1) to characterize PICS-related sequelae in adult COVID-19 survivors by following the evolution of functional/physical, cognitive, and mental health outcomes during the first 12 months after ICU discharge; 2) to identify different demographic and clinical factors that are associated with PICS; and 3) to explore how the functional/physical, cognitive, and mental health consequences of PICS may influence health-related quality of life (HRQoL) in COVID-19 ICU survivors.

Methods

Design and participants

We conducted a prospective cohort study in patients admitted to two medical/surgical ICUs in Catalonia, Spain, between 13 March 2020 and 21 January 2021 (ClinicalTrials.gov, NCT04422444; first submitted 4 June 2020). We followed the STROBE guidelines for reporting the study results. We consecutively recruited participants during their first week after ICU discharge and enrolled them in a one-year follow-up program, which combined the use of telemedicine and on-site visits. The study was approved by the Institutional Review Board of the two hospitals (Parc Taulí Drug Research Ethics Committee, Sabadell, Spain; Ref.: 2020/577).

Critically ill survivors older than 18 yr who had been admitted to the participating ICUs with SARS-CoV-2 infection were eligible. Exclusion criteria included pre-existing severe mental illness, prior neurologic disorder, previous cognitive impairment or acquired brain damage, functional dependency prior to the ICU admission, sensory deficits (blindness or deafness), inability to speak and understand Spanish, and life expectancy < 12 months. We extracted data on previous psychiatric or neurologic diagnoses from patients’ medical records.

The telemedicine follow-up program

For this study, we created a telemedicine follow-up program comprising two main modules: 1) the Assessment Monitoring System (AMS) and 2) the Action Protocol for managing PICS-related sequelae (see Electronic Supplementary Material [ESM] eAppendix). The AMS compiled longitudinal data on several outcomes related to PICS: perception of performance of basic daily and instrumental activities; physical, cognitive, and emotional sequelae; and physical and mental HRQoL. We used the following self-administered questionnaires and expert-developed questions to screen for functional/physical, cognitive, and mental health sequelae: Barthel index,20 Lawton and Brody index,21 visual analog scale (VAS) for dyspnea/fatigue and pain,22 proximal musculature state and strength/coordination questions,23 Perceived Deficit Questionnaire (PDQ-20),24 Hospital Anxiety and Depression Scale (HADS),25 Davidson Trauma Scale (DTS),26 and 12-Item Short Form survey (SF-12).27 For functional and physical assessment measures, we used the cut-offs routinely used in clinical practice for post-ICU patients in our hospital. For cognitive and emotional measures, we used the cut-off values originally recommended for each instrument. Detailed information about AMS, as well as the cut-off values used to characterize PICS, are shown in the ESM eTable 1.

Procedures

An ICU research nurse identified patients eligible for the study and reviewed the charts of patients discharged from the ICU daily to verify if they met the inclusion criteria. We contacted and enrolled participants in the study during the first week after their ICU discharge. Participants received private access to the telemedicine screening AMS and were assessed remotely at five timepoints (approximately one, three, six, nine, and 12 months after ICU discharge). Patients received a digital reminder (e-mail or text message to their phone) between one and five days before each assessment point to enhance their adherence to the AMS. We asked participants to complete PICS-related questionnaires and questions within 15 days of receiving the digital reminder. A physical therapist and a neuropsychologist performed the assessment by phone with participants who were not familiar with the use of mobile devices, computers, or did not have access to the internet.

We retrospectively collected demographic and clinical data from medical records, including sex, ICU and hospital length of stay, need for invasive or noninvasive mechanical ventilation, the severity of illness at ICU admission (Acute Physiology and Chronic Health Evaluation II [APACHE II]),28 presence of delirium during ICU stay, and comorbidities (Charlson Comorbidity Index [CCI]).29 We also recorded the hospital destination after ICU discharge and the periods corresponding to each pandemic phase. For participants who required IMV, we collected data regarding reintubation or the need for tracheostomy. Additionally, to ensure that participants > 65 yr of age did not have mild cognitive impairment, we administered the Spanish version of the Short Form of the Informant Questionnaire on Cognitive Decline in the Elderly (Short-IQCODE) to their relatives, using a cut-off point of > 3.56.30 Cognitive reserve was assessed with the Cognitive Reserve Questionnaire (CRQ),31 whose scores range from 0 to 25, allowing participants’ cognitive reserve to be classified in four levels: low (≤ 6), medium–low (7–9), medium–high (10–14), and high (≥ 15).

Statistical analysis

We report demographic and clinical data, and PICS-related outcomes using frequencies and percentages for categorical variables, and medians and interquartile range [IQR] for continuous variables. No imputation method was used to supply missing data.

We analyzed trends of PICS-related outcomes after ICU discharge using multivariable mixed-effects regression models. The one-month assessment after ICU (first assessment point) was considered as the reference measure for comparing the evolution of outcomes during the 12-month follow-up. Regarding continuous outcomes, we assumed a beta distribution for bounded outcomes, dividing by their ranges to obtain values between 0 and 1, i.e., Barthel index, Lawton and Brody index, dyspnea/fatigue (talking, dressing, walking at home, going up stairs), pain, PDQ-20, PTSD, HADS (anxiety, depression). We assumed a Gaussian distribution for z-score outcomes, i.e., SF-12 (physical and mental health), and a binomial distribution for dichotomized outcomes, including proximal muscle function of the lower limbs and strength and coordination of the upper limbs. Independent variables included months from ICU discharge (as natural splines), sex, age, CRQ, ICU length of stay, IMV, delirium, CCI, APACHE II, and pandemic wave. Regression models for physical and mental quality of life also included functional, physical, cognitive, and emotional outcomes as independent variables. All mixed-effects models included random effects in intercept and months from ICU discharge. Further details on the fitted models and the interpretation of the estimated parameters are provided in ESM eTable 2.

We used the R programming language (Foundation for Statistical Computing, Vienna, Austria) and the RStudio environment for the data analysis. We used the mixed model function of the GLMMadaptive package32 and the lme function of the nlme package to fit the mixed-effects models, and we visualized the results using the ggplot2 package.

Results

We enrolled 150 ICU COVID-19 survivors, 142 of whom eventually participated and were included in the final analysis (see flow chart in Fig. 1). All participants had a respiratory clinical presentation at admission, and 95% had an ARDS diagnosis. Table 1 displays the demographic and clinical data.Fig. 1 Flowchart of the study from intensive care unit admission to sample analysis

Table 1 Demographic and clinical data of the study sample

Variable	N = 142	
Age (yr), median [IQR]	61 [53–68]	
Female	50/142 (35%)	
COVID-19 pandemic wave in Spain	
 First wave (10 March 2020 to 31 July 2020)	69/142 (49%)	
 Second wave (1 August 2020 to 6 December 2020)	53/142 (37%)	
 Third wave (7 December 2020 to 18 January 2021)	20/142 (14%)	
APACHE II score at ICU admission	8 [5–11]	
Charlson comorbidity index, median [IQR]	2 [1–3]	
Maximum of respiratory support at ICU admission	
 No respiratory support	7/142 (5%)	
 Only high-flow nasal oxygen	88/142 (62%)	
 Only NIMV	18/142 (23%)	
 Both nasal high-flow oxygen and NIMV	5/142 (4%)	
 Only IMV	24/142 (17%)	
Need for IMV during ICU stay†	83/142 (59%)	
Duration of IMV* (days), median [IQR]	14 [8–32]	
Reintubation*	6/142 (7%)	
Tracheostomy*	35/142 (44%)	
Delirium during ICU stay	53/142 (38%)	
ICU length of stay (days), median [IQR]	9 [5–21]	
Hospital length of stay (days), median [IQR]	28 [17–44]	
Hospital discharge destination	
 Home	102/142 (90%)	
 Convalescence centre	10/142 (9%)	
 Other clinical centre	2/142 (2%)	
CRQ score, median [IQR]	10 [8–14]	
CRQ levels	
 Low	25/142 (18%)	
 Medium–low	36/142 (26%)	
 Medium–high	42/142 (31%)	
 High	34/142 (25%)	
Numbers are n/total N (%) values of nonmissing cases unless otherwise specified

*Data from patients who underwent IMV

†IMV alone or combined with other noninvasive forms of ventilation

APACHE II = Acute Physiology and Chronic Health Evaluation II; CRQ = cognitive reserve questionnaire; ICU = intensive care unit; IMV = invasive mechanical ventilation; IQR = interquartile range; NIMV = noninvasive mechanical ventilation

Detection and evolution of the PICS-related outcomes

Table 2 presents descriptive data for each PICS area (functional/physical, emotional, and cognitive) at the five screening assessment points. We considered the data obtained at the first assessment point (approximately one month after ICU discharge) as the reference PICS profile for comparing the evolution of symptoms over the course of the 12-month follow-up. At the first assessment, at least 25% of the patients reported complaints associated with 12 of the 15 outcomes assessed in this study, and at least 50% of participants reported deficits related to four of the 15 outcomes (see ESM eTable 3). Electronic Supplementary Material eTable 4 displays the number of reports collected at each assessment point and the moment when they were recorded.Table 2 Postintensive care syndrome-related outcomes at each screening assessment point

Outcome	Screening assessment point	P value for trend	
1st	2nd	3rd	4th	5th	
Functional and physical outcomes	
 Barthel index (score 0–100)	100 [85–100]	100 [90–100]	100 [90–100]	100 [95–100]	100 [95–100]	0.08	
 Lawton and Brody index (score 0–8)	7 [6–8]	8 [7–8]	8 [7–8]	8 [7–8]	8 [7–8]	 < 0.001	
 Dyspnea/Fatigue—Talking (VAS 0–10)	0.8 [0–4]	0.5 [0–3]	0 [0–3]	0 [0–2]	0 [0–2]	0.44	
 Dyspnea/Fatigue—Dressing (VAS 0–10)	0.5 [0–4]	0.5 [0–2]	0 [0–1.5]	0 [0–1]	0 [0–3]	0.53	
 Dyspnea/Fatigue—Walking at home (VAS 0–10)	0.5 [0–3]	0 [0–3]	0 [0–1]	0 [0–0.5]	0 [0–1]	0.03	
 Dyspnea/Fatigue—Going up stairs (VAS 0–10)	3 [0–7]	3 [0.5–6]	2 [0–5]	1 [0–5]	1 [0–5]	0.02	
 Pain (VAS 0–10)	4 [0–6]	3 [0–6]	4 [1–7]	3 [0–6]	3.5 [0–6]	0.47	
 Proximal muscle function of the lower limbs, n/total N (%)	 < 0.001	
 When you get up from a chair…?	
   I do it alone without using my arms	42/86 (49%)	42/98 (43%)	65/111 (59%)	63/99 (64%)	62/96 (65%)		
   I do it alone, but I need to use my arms	42/86 (49%)	55/98 (56%)	46/111 (41%)	36/99 (36%)	34/96 (35%)		
   I need someone to help me	2/86 (2%)	1/98 (1%)	0/111 (0%)	0/99 (0%)	0/96 (0%)		
 Strength/coordination upper limbs, n/total N (%)	0.71	
 Can I take a full bottle of water and fill a glass using only my dominant hand?	
  Yes	75/86 (87%)	85/98 (87%)	102/111 (92%)	86/99 (87%)	82/96 (85%)		
  No	11/86 (13%)	13/98 (13%)	9/111 (8%)	13/99 (13%)	14/96 (15%)		
Cognitive outcomes	
 PDQ-20 (score 0–68)	18 [10–27]	20 [9–28]	19 [8–33]	21 [10–35]	23 [10–36]	 < 0.001	
Emotional outcomes	
 Davidson Trauma Scale (score 0–136)	17.5 [8–39]	18 [8–36]	16 [6–34]	15 [6–33]	13 [6–30]	0.19	
 HADS-Anxiety subscale (score 0–21)	6 [3–10]	6 [3–10]	5 [2–9]	6 [2–9]	5 [2–8]	0.19	
 HADS-Depression subscale (score 0–21)	5 [2–8]	5 [2–89]	4 [1–7]	4 [1–9]	3 [1–9]	0.70	
Health-related quality of life outcomes	
 SF-12 Physical Health (z score)	−1.6 [−2.3 to −0.6]	−1.4 [−2.3 to −0.3]	−1 [−2.1 to 0.1]	−0.95 [−1.9 to 0.3]	−0.8 [−2 to 0.4]	 < 0.001	
 SF-12 Mental Health (z score)	0.04 [−1 to 1]	−0.03 [−1 to 0]	0.04 [−1 to 1]	0.21 [−1 to 1]	0.1 [−1 to 1]	0.32	
Numbers are median [interquartile range] of nonmissing cases unless otherwise specified

P values for trend obtained from the statistical significance of the marginal effect of slope for time, included as independent variable (in a linear fashion) in mixed-effects models

Timing of screening assessment points: 1st: approximately 1 month after ICU discharge; 2nd: approximately 3 months after ICU discharge; 3rd: approximately 6 months after ICU discharge; 4th: approximately 9 months after ICU discharge; 5th: approximately 12 months after ICU discharge

HADS = Hospital Anxiety and Depression Scale; PDQ = Perceived Deficit Questionnaire; VAS = visual analog scale

Evolution of functional and physical outcomes

At one month after ICU discharge (reference), 26% and 38% of participants reported impairment related to basic and instrumental activities of daily living (ADL), respectively. Forty-four per cent reported dyspnea and/or fatigue when performing tasks requiring light effort, and 70% when performing tasks requiring moderate effort. Pain was reported by 64% of participants, proximal muscle weakness by 51%, and impaired strength and coordination by 13%. Scores on the Barthel index of basic ADL remained stable over time (P = 0.08). In contrast, the scores on the Lawton and Brody index of instrumental ADL rose over time (P < 0.001), showing the greatest improvement between the first and the second assessment point (see Fig. 2A). Perception of fatigue and/or dyspnea during both light effort (talking, P = 0.44; dressing, P = 0.53; walking at home, P = 0.03) and moderate effort (going up stairs, P = 0.02) presented a downward trend over the five assessments, with the greatest improvements emerging between the first and the second for light effort, and between the second and the third for moderate effort (see Fig. 2B). Pain remained stable over time (P = 0.47) (see Fig. 2C). The percentage of participants reporting mild or moderate impairment in proximal muscle function of the lower limbs decreased between the second and the third assessment point, while the percentage of participants with severe impairment decreased between the first assessment point and the second (P < 0.001) (see Fig. 2D). A low proportion of the sample (13%) presented impaired strength and coordination of the upper limbs, features that remained stable over time (P = 0.71) (see Fig. 2E).Fig. 2 Distribution of the postintensive care syndrome and health-related quality of life outcomes for each screening assessment point. (A) Distribution of functionality outcomes for each screening assessment point, (B) distribution of physical outcomes (dyspnea/fatigue during tasks requiring light and moderate effort) for each assessment point, (C) distribution of physical outcomes (pain) for each assessment point, (D) distribution of physical outcomes (proximal muscle function of the lower limbs) for each assessment point, (E) distribution of physical outcomes (strength/coordination of the upper limbs) for each assessment point, (F) distribution of cognitive and emotional outcomes (perception of cognitive deficit, PTSD symptoms, and anxiety-depressive symptoms) for each assessment point, and (G) distribution of quality of life (physical and mental health-related) from 1 to 5 assessment points. The dashed lines (– – –) indicate the score for moderate to severe symptoms.

HADS = Hospital Anxiety and Depression Scale; PDQ-20 = Perceived Deficit Questionnaire (20 items); PTSD = posttraumatic stress disorder; VAS = visual analog scale (from 0 to 10)

Evolution of cognitive and emotional outcomes

At one month after ICU discharge, 22% of participants reported the presence of cognitive dysfunction, 38% PTSD symptoms, 41% anxiety, and 31% depression. The perception of cognitive deficit showed fluctuations during the follow-up, with slight increases in the scores at the fifth assessment point (P < 0.001). Although not statistically significant, PTSD (P = 0.19) and depression (P = 0.70) symptoms decreased steadily from the second to the last assessment; however, the dispersion in these PTSD scores seemed to increase slightly at the fourth and fifth assessments. Conversely, anxiety symptoms showed a stable trend, with an apparent reduction of dispersion from the fourth assessment point onwards (P = 0.19) (see Fig. 2F).

Evolution of health-related quality of life

We recorded a negative impact on physical HRQoL in 64% of the sample at one month after ICU discharge, and 24% presented a decrease in mental HRQoL. Physical HRQoL scores showed a general improvement over time (P < 0.001), the greatest change being between the second and the third assessments. In contrast, mental HRQoL scores remained stable over the five assessments (P = 0.32) (see Fig. 2G).

Factors associated with postintensive care syndrome outcomes

Figure 3 summarizes the statistically significant factors for PICS sequelae and HRQoL identified by multivariable mixed-effects regression analysis. Table 3 details the results of the multivariable regression models.Fig. 3 Summary diagram of the multivariable mixed-effect models of the postintensive care syndrome sequelae and health-related quality of life

± = sign of the estimate coefficient; IMV = invasive mechanical ventilation; Fat/Dysp. = fatigue/dyspnea; HRQoL = health-related quality of life; PTSF = posttraumatic stress disorder

Table 3 Factors associated with performance of basic and instrumental activities of daily living, physical, cognitive, emotional and physical and mental health-related quality of life outcomes in ICU COVID-19 survivors

Factors	Basic and instrumental activities of daily living and physical outcomes (1)	
Barthel index	Lawton and Brody Index	Dyspnea/fatigue
Talking	Dyspnea/fatigue
Dressing	
Estimate (95% CI)	P value	Estimate (95% CI)	P value	Estimate (95% CI)	P value	Estimate (95% CI)	P value	
Intercept	3.44 (2.12 to 4.75)	 < 0.001	1.81 (0.40 to 3.23)	0.01	0.14 (−1.30 to 1.58)	0.85	−0.58 (−1.93 to 0.78)	0.41	
N1 (months)	0.36 (−0.03 to 0.75)	0.07	0.62 (0.21 to 1.03)	0.003	−0.36 (−0.82 to 0.11)	0.13	−0.29 (−0.74 to 0.16)	0.21	
N2 (months)	0.33 (−0.02 to 0.68)	0.06	0.69 (0.26 to 1.13)	0.002	−0.35 (−0.76 to 0.06)	0.09	−0.32 (−0.74 to 0.10)	0.13	
N3 (months)	0.59 (−0.19 to 1.37)	0.14	1.13 (0.34 to 1.93)	0.005	−0.20 (−0.99 to 0.60)	0.63	−0.08 (−0.97 to 0.82)	0.87	
N4 (months)	0.21 (−0.14 to 0.56)	0.24	0.63 (0.30 to 0.95)	 < 0.001	−0.22 (−0.54 to 0.10)	0.18	−0.21 (−0.53 to 0.13)	0.23	
Female (vs male)	−0.56 (−0.90 to −0.21)	0.001	−0.45 (−0.80 to −0.09)	0.01	0.34 (−0.01 to 0.70)	0.06	0.40 (0.08 to 0.71)	0.01	
Age, yr	−0.002 (−0.03 to 0.02)	0.86	0.01 (−0.02 to 0.03)	0.70	−0.03 (−0.06 to −0.01)	0.02	−0.02 (−0.04 to 0.01)	0.14	
CRQ (vs low)	
Medium–low	−0.26 (−0.77 to 0.25)	0.32	0.18 (−0.27 to 0.63)	0.44	0.21 (−0.33 to 0.75)	0.45	−0.04 (−0.54 to 0.46)	0.87	
Medium–high	0.42 (−0.11 to 0.95)	0.12	0.64 (0.17 to 1.11)	0.008	−0.24 (−0.73 to 0.25)	0.34	−0.34 (−0.84 to 0.15)	0.18	
High	1.00 (0.49 to 1.50)	 < 0.001	1.05 (0.49 to 1.62)	 < 0.001	−0.82 (−1.33 to −0.31)	0.002	−0.75 (−1.27 to −0.23)	0.005	
ICU length of stay, days	−0.01 (−0.02 to 0.003)	0.20	−0.01 (−0.02 to 0.01)	0.29	0.01 (−0.01 to 0.02)	0.26	0.01 (−0.01 to 0.02)	0.32	
IMV (vs no)	−0.43 (−0.87 to 0.01)	0.06	−0.63 (−1.04 to −0.21)	0.003	0.34 (−0.12 to 0.79)	0.15	0.60 (0.16 to 1.05)	0.008	
Presence of delirium during ICU stay (vs no)	−0.04 (−0.47 to 0.39)	0.85	0.27 (−0.17 to 0.70)	0.23	−0.08 (−0.49 to 0.32)	0.70	−0.002 (−0.41 to 0.41)	0.99	
Charlson Comorbidity Index	−0.07 (−0.23 to 0.09)	0.37	−0.06 (−0.24 to 0.11)	0.47	0.18 (0.02 to 0.35)	0.03	0.01 (−0.16 to 0.17)	0.96	
APACHE II at ICU admission	0.002 (−0.04 to 0.04)	0.95	0.02 (−0.02 to 0.06)	0.27	−0.03 (−0.07 to 0.01)	0.14	−0.03 (−0.07 to 0.01)	0.19	
COVID-19 wave (vs 1st)	
2nd wave	−0.11 (−0.50 to 0.28)	0.59	−0.23 (−0.67 to 0.20)	0.30	−0.14 (−0.58 to 0.30)	0.55	0.16 (−0.28 to 0.59)	0.47	
3rd wave	0.09 (−0.42 to 0.59)	0.73	−0.09 (−0.64 to 0.47)	0.77	−0.02 (−0.64 to 0.60)	0.95	0.07 (−0.48 to 0.61)	0.81	
Factors	Physical outcomes (2)	
Dyspnea/fatigue
Walking at home	Dyspnea/fatigue
Going up stairs	Pain	
Estimate (95% CI)	P value	Estimate (95% CI)	P value	Estimate (95% CI)	P value	
Intercept	−0.49 (−1.62 to 0.65)	0.40	0.63 (−0.92 to 2.18)	0.43	−0.40 (−2.08 to 1.26)	0.64	
N1 (months)	−0.53 (−0.99 to −0.07)	0.02	−0.49 (−0.89 to −0.08)	0.02	0.26 (−0.16 to 0.67)	0.22	
N2 (months)	−0.59 (−1.07 to −0.10)	0.02	−0.28 (−0.69 to 0.14)	0.20	−0.11 (−0.43 to 0.20)	0.49	
N3 (months)	−0.81 (−1.74 to 0.11)	0.08	0.19 (−0.60 to 0.99)	0.63	0.03 (−0.69 to 0.75)	0.94	
N4 (months)	−0.49 (−0.83 to −0.14)	0.006	−0.44 (−0.75 to −0.13)	0.006	−0.13 (−0.44 to 0.18)	0.40	
Female (vs male)	0.49 (0.20 to 0.78)	0.001	0.45 (0.07 to 0.83)	0.02	0.48 (0.07 to 0.89)	0.02	
Age, yr	−0.02 (−0.04 to −0.0004)	0.05	−0.03 (−0.06 to −0.002)	0.03	−0.004 (−0.03 to 0.02)	0.76	
CRQ (vs low)	
Medium–low	0.21 (−0.15 to 0.56)	0.26	0.27 (−0.30 to 0.84)	0.35	0.41 (−0.08 to 0.90)	0.10	
Medium–high	−0.09 (−0.50 to 0.32)	0.68	−0.43 (−1.00 to 0.14)	0.14	−0.37 (−1.00 to 0.27)	0.26	
High	−0.38 (−0.79 to 0.02)	0.06	−0.93 (−1.50 to −0.37)	0.001	−0.70 (−1.34 to −0.06)	0.03	
ICU length of stay, days	0.01 (0.001 to 0.02)	0.03	0.01 (−0.002 to 0.03)	0.10	−0.003 (−0.02 to 0.01)	0.73	
IMV (vs no)	0.19 (−0.15 to 0.53)	0.27	0.48 (−0.02 to 0.98)	0.06	0.58 (0.08 to 1.08)	0.02	
Presence of delirium during ICU stay (vs no)	−0.21 (−0.56 to 0.15)	0.25	−0.19 (−0.63 to 0.26)	0.41	−0.15 (−0.65 to 0.36)	0.57	
Charlson Comorbidity Index	0.08 (−0.05 to 0.20)	0.23	0.24 (0.04 to 0.45)	0.02	0.03 (−0.17 to 0.23)	0.78	
APACHE II at ICU admission	−0.01 (−0.05 to 0.02)	0.45	−0.03 (−0.08 to 0.02)	0.20	−0.04 (−0.09 to 0.01)	0.16	
COVID-19 wave (vs 1st)	
2nd	−0.04 (−0.39 to 0.31)	0.82	0.06 (−0.43 to 0.55)	0.81	−0.03 (−0.60 to 0.54)	0.93	
3rd	−0.14 (−0.61 to 0.33)	0.56	0.15 (−0.51 to 0.80)	0.66	−0.15 (−0.85 to 0.56)	0.69	
Factors	Physical outcomes (3)	
Proximal muscle function
Lower limbs	Strength/coordination
Upper limbs	
Estimate (95% CI)	OR (95% CI)	P value	Estimate (95% CI)	OR (95% CI)	P value	
Intercept	0.47 (−2.10 to 3.05)		0.72	8.60 (3.47 to 13.72)		0.001	
N1 (months)	−0.85 (−1.49 to −0.21)		0.009	1.51 (−0.55 to 3.57)		0.15	
N2 (months)	−0.76 (−1.41 to −0.10)		0.02	0.75 (−1.23 to 2.73)		0.46	
N3 (months)	−0.13 (−1.36 to 1.10)		0.83	0.13 (−2.97 to 3.24)		0.93	
N4 (months)	−1.08 (−1.61 to −0.54)		 < 0.001	1.19 (−0.75 to 3.12)		0.23	
Female (vs male)	0.35 (−0.26 to 0.96)	1.42 (0.77 to 2.61)	0.26	−3.02 (−4.54 to −1.50)	0.05 (0.01 to 0.22)	 < 0.001	
Age, yr	−0.01 (−0.06 to 0.03)	0.99 (0.94 to 1.03)	0.61	−0.06 (−0.14 to 0.02)	0.94 (0.87 to 1.02)	0.13	
CRQ (vs low)	
Medium–low	−0.03 (−0.92 to 0.86)	0.97 (0.40 to 2.37)	0.96	−0.62 (−1.91 to 0.66)	0.54 (0.15 to 1.94)	0.34	
Medium–high	−0.68 (−1.71 to 0.35)	0.51 (0.18 to 1.42)	0.20	−0.38 (−1.66 to 0.91)	0.69 (0.19 to 2.48)	0.56	
High	−1.35 (−2.41 to −0.28)	0.26 (0.09 to 0.75)	0.01	0.94 (−0.78 to 2.66)	2.55 (0.46 to 14.3)	0.29	
ICU length of stay, days	0.001 (−0.02 to 0.02)	1.00 (0.98 to 1.02)	0.92	−0.03 (−0.06 to 0.01)	0.98 (0.94 to 1.01)	0.18	
IMV (vs no)	0.41 (−0.35 to 1.16)	1.50 (0.71 to 3.19)	0.29	−1.22 (−2.69 to 0.25)	0.30 (0.07 to 1.28)	0.10	
Presence of delirium during ICU stay (vs no)	0.16 (−0.59 to 0.92)	1.18 (0.55 to 2.51)	0.67	0.95 (−0.38 to 2.28)	2.58 (0.68 to 9.77)	0.16	
Charlson Comorbidity Index	0.04 (−0.26 to 0.35)	1.04 (0.77 to 1.42)	0.78	−0.14 (−0.61 to 0.33)	0.87 (0.54 to 1.40)	0.56	
APACHE II at ICU admission	0.02 (−0.05 to 0.09)	1.02 (0.95 to 1.10)	0.54	−0.0002 (−0.13 to 0.13)	1.00 (0.88 to 1.14)	0.99	
COVID-19 wave (vs 1st)	
2nd	0.46 (−0.29 to 1.21)	1.58 (0.75 to 3.36)	0.23	0.51 (−0.78 to 1.79)	1.66 (0.46 to 6.01)	0.44	
3rd	−0.92 (−2.25 to 0.42)	0.40 (0.11 to 1.52)	0.18	−0.52 (−2.57 to 1.52)	0.59 (0.08 to 4.58)	0.62	
Factors	Cognitive and emotional outcomes	
PDQ-20	Davidson Trauma Scale	HADS-A	HADS-D	
Estimate (95% CI)	P value	Estimate (95% CI)	P value	Estimate (95% CI)	P value	Estimate (95% CI)	P value	
Intercept	0.40 (−1.06 to 1.85)	0.59	0.02 (−1.37 to 1.41)	0.98	0.52 (−0.82 to 1.86)	0.45	0.07 (−1.47 to 1.62)	0.93	
N1 (months)	0.11 (−0.07 to 0.30)	0.23	−0.31 (−0.58 to −0.04)	0.03	−0.20 (−0.45 to 0.05)	0.11	−0.16 (−0.38 to 0.07)	0.19	
N2 (months)	0.16 (0.01 to 0.30)	0.04	0.02 (−0.24 to 0.27)	0.91	−0.04 (−0.28 to 0.21)	0.78	0.13 (−0.15 to 0.41)	0.37	
N3 (months)	0.26 (−0.05 to 0.57)	0.10	−0.24 (−0.75 to 0.27)	0.36	−0.11 (−0.55 to 0.34)	0.64	0.12 (−0.42 to 0.66)	0.67	
N4 (months)	0.24 (0.12 to 0.36)	 < 0.001	−0.15 (−0.35 to 0.06)	0.17	−0.14 (−0.33 to 0.04)	0.13	−0.09 (−0.29 to 0.11)	0.39	
Female (vs male)	0.25 (−0.11 to 0.62)	0.17	0.36 (0.03 to 0.68)	0.03	0.54 (0.23 to 0.85)	0.001	0.52 (0.16 to 0.88)	0.005	
Age, yr	−0.03 (−0.05 to −0.005)	0.04	−0.03 (−0.06 to −0.01)	0.02	−0.02 (−0.05 to 0.004)	0.10	−0.03 (−0.06 to −0.003)	0.04	
CRQ (vs low)	
Medium–low	0.23 (−0.29 to 0.76)	0.38	0.24 (−0.26 to 0.73)	0.35	0.39 (−0.07 to 0.84)	0.10	0.22 (−0.36 to 0.80)	0.45	
Medium–high	0.11 (−0.39 to 0.60)	0.66	0.15 (−0.35 to 0.65)	0.56	0.07 (−0.38 to 0.52)	0.77	−0.20−0.82 to 0.42)	0.52	
High	−0.20 (−0.79 to 0.39)	0.51	−0.27 (−0.79 to 0.26)	0.32	−0.42 (−0.97 to 0.13)	0.14	−0.89 (−1.53 to −0.25)	0.007	
ICU length of stay, days	−0.01 (−0.03 to 0.002)	0.07	−0.01 (−0.02 to 0.01)	0.30	−0.01 (−0.02 to 0.002)	0.07	−0.005 (−0.02 to 0.01)	0.43	
IMV (vs no)	0.16 (−0.31 to 0.64)	0.50	0.51 (0.05 to 0.97)	0.03	0.25 (−0.19 to 0.70)	0.27	0.65 (0.13 to 1.18)	0.01	
Presence of delirium during ICU stay (vs no)	0.30 (−0.15 to 0.75)	0.19	0.27 (−0.15 to 0.68)	0.21	0.31 (−0.07 to 0.69)	0.11	0.07 (−0.45 to 0.58)	0.80	
Charlson Comorbidity Index	0.10 (−0.06 to 0.26)	0.23	0.05 (−0.13 to 0.23)	0.62	−0.03 (−0.21 to 0.14)	0.73	0.10 (−0.09 to 0.29)	0.31	
APACHE II at  ICU admission	−0.02 (−0.06 to 0.03)	0.47	−0.04 (−0.09 to 0.01)	0.11	−0.03 (−0.07 to 0.01)	0.16	−0.02 (−0.06 to 0.03)	0.53	
COVID-19 wave (vs 1st)	
2nd	0.02 (−0.44 to 0.47)	0.95	0.19 (−0.25 to 0.63)	0.40	−0.06 (−0.51 to 0.40)	0.81	0.35 (−0.11 to 0.80)	0.14	
3rd	−0.42 (−1.07 to 0.22)	0.20	−0.17 (−0.78 to 0.43)	0.58	−0.37 (−0.96 to 0.21)	0.21	−0.03 (−0.61 to 0.56)	0.93	
Factors	Health related quality of life outcomes (1)	
SF12-physical health	SF12-mental health	
Estimate (95% CI)	P value	Estimate (95% CI)	P value	
Intercept	−1.65 (−3.26 to −0.04)	0.05	1.38 (−0.25 to 3.00)	0.10	
N1 (months)	0.48 (0.23 to 0.74)	 < 0.001	−0.02 (−0.32 to 0.28)	0.90	
N2 (months)	0.53 (0.30 to 0.76)	 < 0.001	0.15 (−0.13 to 0.42)	0.30	
N3 (months)	1.01 (0.55 to 1.46)	 < 0.001	−0.02 (−0.56 to 0.52)	0.95	
N4 (months)	0.30 (0.11 to 0.48)	0.002	0.07 (−0.15 to 0.29)	0.52	
Female (vs male)	−0.21 (−0.47 to 0.06)	0.13	−0.09 (−0.32 to 0.14)	0.43	
Age, yr	0.01 (−0.01 to 0.02)	0.57	−0.0004 (−0.02 to 0.02)	0.96	
CRQ (vs low)	
Medium–low	−0.18 (−0.55 to 0.19)	0.34	0.22 (−0.10 to 0.55)	0.18	
Medium–high	0.16 (−0.22 to 0.53)	0.43	0.21 (−0.12 to 0.53)	0.22	
High	0.17 (−0.22 to 0.57)	0.39	0.30 (−0.04 to 0.65)	0.08	
ICU length of stay, days	−0.01 (−0.02 to −0.00)	0.04	0.01 (−0.003 to 0.01)	0.21	
IMV (vs no)	−0.07 (−0.40 to 0.25)	0.66	−0.19 (−0.47 to 0.09)	0.19	
Presence of delirium during ICU stay (vs no)	0.24 (−0.08 to 0.55)	0.14	0.19 (−0.07 to 0.46)	0.16	
Charlson Comorbidity Index	0.01 (−0.11 to 0.13)	0.87	0.02 (−0.08 to 0.12)	0.67	
APACHE II at ICU admission	−0.02 (−0.05 to 0.01)	0.20	0.01 (−0.02 to 0.04)	0.42	
COVID-19 wave (vs 1st)	
2nd	−0.05 (−0.36 to 0.27)	0.78	0.28 (0.01 to 0.55)	0.04	
3rd	0.15 (−0.27 to 0.57)	0.48	0.04 (−0.32 to 0.40)	0.82	
Barthel index	−0.002 (−0.01 to 0.01)	0.78	−0.004 (−0.02 to 0.01)	0.50	
Lawton and Brody index	0.16 (0.08 to 0.24)	 < 0.001	−0.04 (−0.13 to 0.06)	0.44	
Dyspnea/Fatigue—Talking	0.01 (−0.04 to 0.05)	0.76	−0.03 (−0.08 to 0.03)	0.33	
Dyspnea/Fatigue—Dressing	−0.06 (−0.11 to −0.01)	0.03	0.05 (−0.01 to 0.11)	0.11	
Dyspnea/Fatigue—Walking at home	0.05 (−0.003 to 0.10)	0.06	−0.02 (−0.08 to 0.04)	0.49	
Dyspnea/Fatigue—Going up stairs	−0.09 (−0.12 to −0.06)	 < 0.001	−0.01 (−0.05 to 0.02)	0.54	
Pain	−0.11 (−0.14 to −0.09)	 < 0.001	0.03 (−0.01 to 0.06)	0.13	
Factors	Health related quality of life outcomes (2)	
SF12-physical health	SF12-mental health	
Estimate (95% CI)	P value	Estimate (95% CI)	P value	
Proximal muscle function in lower limbs (vs I do it alone)	
Alone with arms supported	−0.45 (−0.62 to −0.27)	 < 0.001	0.05 (−0.15 to 0.24)	0.62	
I need someone to help me	−0.81 (−1.54 to −0.08)	0.03	−0.37 (−1.22 to 0.49)	0.41	
Strength/coordination—Upper limbs (vs no)	0.06 (−0.18 to 0.31)	0.61	−0.08 (−0.35 to 0.19)	0.58	
PDQ-20	−0.01 (−0.02 to −0.0002)	0.08	−0.01 (−0.01 to 0.003)	0.22	
Davidson Trauma Scale (PTSD)	−0.01 (−0.01 to −0.0001)	0.06	−0.01 (−0.02 to −0.004)	0.003	
HADS-Anxiety	0.05 (0.02 to 0.07)	0.003	−0.08 (−0.11 to −0.04)	 < 0.001	
HADS-Depression	−0.02 (−0.05 to 0.004)	0.11	−0.08 (−0.10 to −0.05)	 < 0.001	
Bold indicates those factors that were statistically significant in the analysis (P > 0.05)

The terms Ni (months) denote the basis for a natural cubic spline with five knots, three internal knots at months 3, 6, and 9, and two boundary knots at months 1 and 12

CI = confidence interval; CRQ = cognitive reserve questionnaire; HADS = Hospital Anxiety and Depression Scale; ICU = intensive care unit; IMV = invasive mechanical ventilation; OR = odds ratio; PDQ = Perceived Deficits Questionnaire; PTSD = posttraumatic stress disorder

Factors associated with pics-related functional and physical outcomes

We found a significant association between female sex and lower scores on both the Barthel and the Lawton and Brody indexes. Similarly, patients who required IMV also presented poorer scores on both functional indexes, although the association only reached significance in the Lawton and Brody index. In contrast, participants with higher cognitive reserve showed better scores on both indexes.

Participants who were female, of younger age, with longer ICU stays or more comorbidities, and who had undergone IMV presented greater fatigue and/or dyspnea during tasks involving light effort, and females, younger participants, and patients with more comorbidities at ICU admission presented greater fatigue and/or dyspnea during tasks involving moderate effort. In contrast, participants with higher levels of cognitive reserve showed lower fatigue and/or dyspnea when performing tasks involving both light and moderate effort.

We found an association between female sex and IMV during ICU stay and higher levels of pain. Participants with higher levels of cognitive reserve showed lower levels of pain and fewer difficulties with tasks involving the lower limbs. We also found an association between female sex and difficulties with strength and coordination of the upper limbs. For further information, see Table 3 and ESM eFigs 1–3.

Factors associated with PICS-related cognitive and emotional outcomes

Younger participants had higher scores on the perception of cognitive deficit questionnaire. Furthermore, females, younger patients, and those undergoing IMV had worse results on the PTSD questionnaire. Females also presented higher scores on the anxiety and depression subscales. Additionally, younger patients who needed IMV scored higher on the depression subscale, while those with the highest level of cognitive reserve had lower scores on this subscale. For further information, see Table 3 and ESM eFig. 4.

Factors associated with health-related quality of life and the impact of the pics-related sequelae on physical and mental health-related quality of life

Participants with shorter ICU stay showed better physical HRQoL. Patients from the second pandemic wave exhibited better mental HRQoL than their peers in the first and third waves.

Regarding the impact of PICS-related sequelae on physical HRQoL, higher scores on the Lawton and Brody index, lower scores for fatigue/dyspnea during tasks requiring light and moderate effort and for pain, and better proximal muscle function in the lower limbs were the most relevant factors for a better evolution. Surprisingly, we also found an association between higher levels of anxiety and better physical HRQoL. We observed better mental HRQoL in participants with lower scores on anxiety, depression, and PTSD. For further information, see Table 3 and ESM eFig. 5.

Discussion

This is one of a few studies to perform a comprehensive and continuous one-year follow-up of PICS-related sequelae in critically ill COVID-19 survivors that allowed the description of the evolution of symptoms, the identification of factors associated with PICS, and the evaluation of their impact on HRQoL. The characterization of PICS in our cohort of critically ill COVID-19 survivors suggests the concomitant presence of different sequelae and a distinct evolution of physical vs cognitive and emotional symptoms over the 12-month post-ICU follow-up. Several factors, such as younger age, female sex, undergoing IMV, longer ICU stay, and higher level of comorbidities, emerged as potential risk factors for PICS-related sequelae, while cognitive reserve had a protective role. We also found an association between PICS and lower HRQoL in critically ill COVID-19 patients.

The functional, physical, cognitive, and emotional difficulties detected in this study support the growing number of reports32–36 suggesting the development of prolonged PICS after COVID-19 critical illness. Abnormal scores in basic and instrumental ADL had returned to normal levels at the six-month follow-up in most of our patients. After 12 months of follow-up, our cohort still reported the presence of fatigue, difficulties in tasks requiring proximal muscle activation or strength/coordination and, above all, pain. Our results are in line with those of previous studies suggesting that impaired performance of ADL at hospital discharge37 progressively improves during the first months of survival.38 Nevertheless, our results add to the currently available evidence by showing that fatigue, dyspnea, muscular weakness, and pain are not only common after acute COVID-19 but may even persist beyond two–three39 to six months after infection,40 especially in the most severe cases of the disease.41,42 In particular, our results suggest that chronic pain is a common, persistent sequela of PICS in both COVID-1943 and non-COVID-19 critical care survivors.44

Both short- and long-term cognitive impairment are well-recognized sequelae of PICS in non-COVID-19 ICU survivors.45 Recent results also associate it with long COVID,46 especially in critical and severe cases of the disease.18,47,48 The low rates of cognitive impairment in our study may be attributed in part to the self-perception method used to assess deficit. In fact, subjective cognition has not shown a clinically relevant correlation with objective cognition using neuropsychological test assessments in either non-COVID-19 or COVID-19 ICU survivors,48 or in other clinical populations.49

In this study, anxiety symptoms remained stable during follow-up. Nevertheless, despite the steady improvement of depressive and PTSD symptoms during the one-year follow-up, we observed a mild rebound in the last months, when more than a quarter of patients showed clinically relevant symptoms. Interestingly, this final rise in the dispersion of psychiatric symptomatology coexists with a progressive increase in the perception of a cognitive deficit, which has been closely related to emotional status,50 from six to 12 months post ICU. Neuropsychiatric sequelae are common in around half of non-COVID-1951–53 and in COVID-19 patients during the first months following ICU discharge, with a general improvement of symptoms over time.54 The circumstances of the pandemic could explain the lack of improvement in the anxiety levels in our sample, as mental health status worsened both in the general population55 and in COVID-19 survivors.56 Nevertheless, levels of anxiety were unchanged over time in non-COVID-19 ICU survivors and in other populations with chronic conditions,51 suggesting that this is a symptom that can potentially become chronic.

Previous studies have reported similar rates of long-term depressive symptoms in COVID-1943 and in non-COVID-19 ICU patients.57 In contrast, the prevalence of long-term PTSD symptomatology in this study surpasses the rates described by other authors in ICU survivors with or without COVID-19.43,53 Although differences between countries in the management and follow-up of critically ill patients during the pandemic may play a role, our results support the idea previously suggested by other authors58 that some of the emotional difficulties may worsen or appear later in certain COVID-19 ICU survivors.

As for the identification of risk factors, younger age and female sex emerged as potential risk factors for developing PICS-related sequelae, especially in the mental health dimension. Previous studies have associated older age with the risk of developing PICS10,44 related to physical impairment, but the findings regarding the impact of age and sex in the mental health status of ICU survivors are less conclusive.10,51–53 In other cohorts of ICU patients with COVID-19, females59 and older patients33,36,37,42 seemed more prone to developing physical and functional impairment after their ICU stay. Nevertheless, our results support the idea of an age-related advantage in the emotional and psychological resilience to traumatic events during the pandemic.60 It is worth noting that, during the first waves of the pandemic, ICU survivors were younger than those previously described in prepandemic studies, and indeed the impact on mental health in younger ICU patients with different personal and social demands (e.g., work and family commitments) deserves further research.

Regarding clinical factors, we found associations between undergoing IMV, longer ICU stay, and higher level of comorbidities at admission and poorer functionality and higher levels of fatigue and dyspnea during the follow-up. Moreover, IMV was also a risk factor for PTSD and depressive symptoms. Despite the lack of a control group, our results are consistent with the literature findings in critically ill cohorts with and without COVID-19, suggesting that illness severity and management during ICU stay may be associated with long-term sequelae.18,34,35,37,53,54,59

Contrary to previous reports,19,48 we found that the presence of delirium was not related to cognitive sequelae. Nevertheless, this negative result may be explained by our method for collecting data on delirium due to the pandemic (i.e., retrospectively and estimated from clinical reports) and the assessment based on subjective rather than objective cognition. Cognitive reserve emerged as a potential protective factor for depressive symptoms and, intriguingly, for most of the functional and physical domains assessed in this study. Previous studies have associated cognitive reserve with better outcomes in cognitive and mental health status in ICU survivors with and without COVID-19,1,48 but its role in physical functioning has received less attention. Our results suggest that a high level of cognitive reserve may be related to a better prognosis of PICS, possibly due to a better understanding and management of the medical information available and a greater ability to seek recovery resources and to develop coping strategies to deal with PICS sequelae. The influence of socioeconomic status and social/family support may also be important.

We observed that physical HRQoL improved during follow-up. While more than half of patients presented impairment immediately after discharge, this proportion fell to a quarter at 12 months. For its part, mental HRQoL did not appear to be as affected as physical HRQoL or to show the same pattern of improvement. These results are partially consistent with previous reports showing that physical and mental HRQoL seem to be equally diminished in COVID-19 ICU survivors,19,33,42 although those papers highlight the importance of assessing physical and mental HRQoL separately. We found associations between factors such as longer ICU stay as well as functional and physical difficulties and lower physical HRQoL. In turn, survivors presenting fewer emotional symptoms and patients treated during the second pandemic wave showed better mental HRQoL during the follow-up period. Our results are in agreement with those of other studies regarding the impact of ICU stay and its physical sequelae (e.g., fatigue) on quality of life in COVID-19 survivors.42,61 They also highlight the impact of emotional sequelae and the potential protective factors on survivors’ quality of life. Why participants with higher levels of anxiety showed a better physical HRQoL is unclear, although it may be attributable to a potential differentiation in the evolution of physical and emotional recovery and its impact on HRQoL in COVID-19 ICU survivors.

This study has limitations. First, because of the pandemic, data collection was based on telemedicine reports. Nevertheless, the participation of an interdisciplinary team of experts behind the development of the evaluation approach and the continuous follow-up of participants should be considered a strength. Second, we collected patients’ outcomes through self-reported questionnaires, which may have potentially caused bias. Furthermore, it would have been desirable to have a control group of critically ill non-COVID-19 patients concurrently treated in similar circumstances to evaluate the existence of different PICS profiles for critically ill patients with or without COVID-19. Nevertheless, our study also has important strengths, including its longitudinal design and the statistical analysis based on mixed-effects regression models.

Conclusion

Postintensive care syndrome in COVID-19 critically ill patients presents physical, cognitive, and emotional sequelae that persist beyond one year after ICU discharge. Female sex, younger age, and the need for IMV during ICU stay emerged as potential risk factors for sequelae, suggesting the importance of illness severity and management in the development of PICS long-term consequences in COVID-19 ICU survivors. Conversely, higher levels of cognitive reserve seem to be a potential protective factor. Postintensive care syndrome-related sequelae are associated with lower quality of life in COVID-19 survivors, albeit with a tendency to improve during the first year post ICU. The knowledge of the distinct evolution of physical and neuropsychiatric sequelae, and of the presence of risk factors for PICS may help to identify patients who are at higher risk for developing PICS and who would benefit from more specific and closer follow-up after ICU admission.

Supplementary Information

Below is the link to the electronic supplementary material.Supplementary file1 (PDF 1312 KB)

Author contributions

Sol Fernández-Gonzalo, Guillem Navarra-Ventura, Natalia Ridao Sais, Merce Jodar, and Josefina López-Aguilar designed the study. Sol Fernández-Gonzalo, Gemma Gomà, Cristina Espinal, Cristina Fortià, and Candelaria De Haro performed the patient selection and inclusion. Sol Fernández-Gonzalo and Cristina Fortià performed the statistical analysis. Gemma Gomà, Verónica Santos-Pulpon, and Leonardo Sarlabous ran the database and the electronic case report form. Sol Fernández-Gonzalo, Marta Godoy-González, Laia Oliveras, Natalia Ridao Sais, and Neus Bacardit performed the neuropsychological and functional-physical assessments. Sol Fernández-Gonzalo, Guillem Navarra-Ventura, Natalia Ridao Sais, Ana Ochagavía, Merce Jodar, Cristina Espinal, Rafael Fernández, Diego Palao, Oriol Roca, Lluís Blanch, and Josefina López-Aguilar participated in the interpretation of the results. Sol Fernández-Gonzalo, Guillem Navarra-Ventura, Merce Jodar, and Diego Palao provided psychological and neuropsychological expertise in designing the protocol and drafted the manuscript.

Acknowledgements

The authors would like to thank the Digital Systems Department of Hospital Parc Taulí for the support in developing the telemedicine assessment system, and to Michael Maudsley for his invaluable support in editing the manuscript. Special acknowledgements are due to all the patients who voluntarily agreed to participate in the PICS-COVID-19 study.

Disclosures

All authors declare no conflict of interests.

Funding statement

Open Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature. This work was funded by the project COV20/00595, integrated in the FONDO – COVID19 for the execution of SARS-COV-2 and COVID19 disease research projects (Royal Decree-Law 8/2020, of March 17), the Project 202118 (413/C/2021) financed with the support of Fundació La Marató de TV3 and the CERCA Programme/Generalitat de Catalunya. The FONDO-COVID19 has been managed by the ISCIII in coordination with the Sub-Directorate General for Evaluation and Promotion of Research and the CTE-COVID19.

Data availability statement

The data sets used and analyzed during this study are available from the corresponding author on reasonable request.

Editorial responsibility

This submission was handled by Dr. Patricia S. Fontela, Associate Editor, Canadian Journal of Anesthesia/Journal canadien d’anesthésie.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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