# Post-intensive care syndrome. What clinicians and researchers must know

Fanny Vardon-Bounes, Carolin Fleischmann-Struzek, Nicola Latronico, Raphaël Cinotti

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Fanny Vardon-Bounes, Carolin Fleischmann-Struzek, Nicola Latronico, Raphaël Cinotti. Post-intensive care syndrome. What clinicians and researchers must know. Anaesthesia Critical Care & Pain Medicine, 2025, 45 (1), pp.101620. 10.1016/j.accpm.2025.101620. hal-05393418

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## Review article

# Post-intensive care syndrome. What clinicians and researchers must know

<figure><img src="image_3.png" /></figure>

Fanny Vardon<sup>a,b</sup>, Carolin Fleischmann-Struzek<sup>c</sup>, Nicola Latronico<sup>d,e,f</sup>, Raphaël Cinotti<sup>g,h,*</sup>

## ARTICLE INFO

Article history:

Available online 28 September 2025

Keywords:

Post-intensive care syndrome

Quality of life

Mental health

## ABSTRACT

The COVID-19 pandemic has highlighted intensive care as a cornerstone of modern medicine. In spite of global aging and the increase of comorbidities in the general population, a large proportion of patients survive their hospitalization in the Intensive Care Unit (ICU). Nevertheless, these positive results are challenged by the higher mortality rates than other non-critically ill populations after discharge. Moreover, there is growing evidence that ICU survivors display a high rate of mental health disorders (anxiety and depression symptoms, post-traumatic stress disorders), somatic impairment (muscle atrophy, neuropathy, and myopathy with persistent muscle weakness, chronic kidney disease, chronic respiratory failure), or cognitive impairment. Patient's relatives also suffer from mental health disorders (anxiety and depression symptoms, complicated bereavement). All these chronic health issues significantly impair the quality of life and increase healthcare costs. Post-Intensive Care Syndrome (PICS) is a term that encompasses all these complications. The COVID-19 pandemic has highlighted PICS as a public health concern. This review summarizes the most recent findings on PICS. It addresses epidemiological data about the frequency of somatic disorders, cognitive impairment, and mental health problems in both patients and their relatives and describes the pathophysiology mechanisms underlying PICS. The review also provides insights into management experimentations and treatment interventions that have been tested so far to improve the outcome of critically ill survivors. Finally, the review proposes measures to implement PICS management in follow-up centers and a research agenda to pave the future research on this topic.

© 2025 The Authors. Published by Elsevier Masson SAS on behalf of Société Française d'Anesthésie et de Réanimation (SFAR). This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

## Introduction

### General background

The ongoing improvement of medical management in critically ill patients leads to a growing number of survivors after hospitalization in the intensive care unit (ICU) in spite of global

ageing, severity of the inpatient population, and the increased complexity and invasiveness of treatments [1]. The major medical efforts deployed in the ICU are yet challenged by high mortality rates after patients' discharge from the ICU: 10% die before hospital discharge [2] and 21% die within a year [1]. Survivors face a significant burden of long-term impairments, which are summarized as Post-Intensive Care Syndrome (PICS). PICS was first introduced by the Society of Critical Care Medicine in 2010 [3] and has gained interest in the medical community ever since. The recent COVID-19 pandemic has stressed the potential public health concern of chronic illness following ICU discharge [4] and made PICS more visible to the public.

<footnote><sup>a</sup> University Hospital of Toulouse, Anaesthesia, Critical Care and Perioperative Medicine, Toulouse, France</footnote>

<footnote><sup>b</sup> University of Toulouse III INSERM U1297, Institute of Cardiovascular and Metabolic Diseases, Toulouse, France</footnote>

<footnote><sup>c</sup> Institute of Infectious Diseases and Infection Control, Jena University Hospital, Jena, Germany</footnote>

<footnote><sup>d</sup> University Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Italy</footnote>

<footnote><sup>e</sup> Alessandra BONO<sup>†</sup> University Research Center on Long Term Outcome (LOTO) in Survivors of Critical Illness, University of Brescia, Italy</footnote>

<footnote><sup>f</sup> Department of Emergency, Spedali Civili University Hospital, Brescia, Italy</footnote>

<footnote><sup>g</sup> CHU Nantes, Nantes Université, Department of Anaesthesia and Critical Care, Hôtel Dieu, F-44000, Nantes, France</footnote>

<footnote><sup>h</sup> UMR 1246 SPHERE "MethodS in Patients-centered Outcomes and Health Research", University of Nantes, University of Tours, INSERM, IRS2 22 Boulevard Benoni Goulin, 44200, Nantes, France</footnote>

<footnote>* Corresponding author.</footnote>

<footnote>E-mail address: raph.cinotti@gmail.com (R. Cinotti).</footnote>
## Common and complex – impact of PICS on patients, families

PICS is a multi-dimensional syndrome recently identified, with substantial mortality and morbidity, affecting all stakeholders in the environment of critical illness (patients, relatives, and healthcare professionals). PICS is receiving growing interest from the medical and research community, but remains complex to apprehend and measure [17]: the selection bias occurring in most ICU survivors' follow-ups [5,6] makes it difficult to truly estimate its frequency and risk factors. Recently, PICS has gained in complexity by encompassing the mental health issues faced by patients' informal caregivers and families, ranging from anxiety and depression symptoms [7,8] to complicated grief [9], which are denoted as PICS-family (PICS-F).

In spite of methodological issues and limitations in the literature (small sample size, monocentric designs, lack of external validation cohorts), it is currently considered that one survivor out of 2 will still experience PICS in the year following discharge [10]. Co-occurring problems (cognitive disorders, disability, or depression) will occur in 20% of survivors by 12 months after discharge [10]. Given the large number of patients receiving ICU care all over the world and the magnitude of survivorship, PICS deserves better attention from local, regional, and national health agencies to guarantee a sustainable workforce of ICU staff in the future. It is mandatory to investigate its pathomechanisms, explore diagnostic and therapeutic opportunities to improve patient outcomes and their families, and to respond to future unanticipated major health challenges. In the following review, we will discuss recent findings on the pathogenesis of PICS and its management.

## Pathophysiology and outcomes

### Pathophysiological concepts

PICS is an umbrella term describing new or worsening impairments in physical, cognitive, and mental health status arising in subjects surviving critical illness and persisting beyond acute care hospitalization. Underneath this terminology, there is major heterogeneity in terms of pathophysiology, population, and outcomes. To date, PICS is characterized by a prolonged state of catabolism, inflammation, and immune system dysregulation [11]. Chronic immune dysregulation could have a key role in PICS. For example, it has been recently demonstrated that the initial inflammatory response leads to an epigenetically modified status of lung alveolar macrophages [12]. This reprogramming of the immune system towards a tolerogenic response of the host could have major consequences on patients' very long-term outcomes, including recurrent severe infections and rehospitalizations [13]. In a nationwide French claims database, survivors of sepsis also showed a lower risk of cancer when matched to non-severe infection survivors [14]. The authors found that sepsis triggered a specific macrophage-lymphocyte T response that could be responsible for this result [14]. While the development of long-term cancer after sepsis is not immediately related to PICS, these challenging results imply that our understanding of the pathomechanisms in the chronic phase after acute illness is far from being understood and urgently requires cutting-edge translational research programs.

### Definition and discussion of the outcomes relevant to patients

Physical impairment is a major component of PICS. After COVID-19, 22-29% patients display a 6-min walk test below the

lower threshold of the normal range, and 22-56% patients a significant reduction below 80% in diffusion capacity for carbon monoxide, 6 months after COVID-19 onset [15]; ICU-treated patients are more affected than other non-critically ill patients [15]. After acute kidney injury requiring renal replacement therapy, only 50% of patients recover normal kidney function one year after ICU hospitalisation [16]. In a single centre cohort of 1,300 patients, 20% required chronic dialysis one year after discharge, alongside a significant increase in major cardiovascular events [16]. Finally, the musculoskeletal system is significantly affected by osteoporosis, evaluated via bone mineral density and ICU-acquired weakness, evaluated through clinical scores (Medical Research Council), ultrasonography, or electrophysiological assessment [17]. ICU-acquired weakness could be present in up to 70% of patients when assessed with electrophysiological testing and is associated with increased mortality, 5 years after discharge, underlining the long-lasting effects of PICS [18]. However, prolonged longitudinal cohorts scarcely provide multiple time points of evaluation, and the evolution of the syndrome is unknown.

Mental health impairment is a second major component of PICS and has been clearly identified as a major issue for patients and their caregivers. In a systematic review involving 36 cohorts and 4000 patients, symptoms of post-traumatic stress disorders were found in 25-45% of survivors and were still present in 35% of patients at 1 year [19]. In another systematic review, including 48 studies [20], the authors found that 29%-34% of survivors displayed depressive symptoms, with no improvement in the year after discharge.

Finally, neuro-cognitive impairment is a third major component of PICS, which can affect 58% of survivors [21-23]. In this major component, pleiotropic complications include chronic pain (48% of survivors [6]), fatigue (63%) [15], and sleep disorders (26%) [15]. These complications could have intricated causes (e.g., muscle weakness, positioning [6]), but emphasize the complexity of the brain-body interactions and their burden on mental/cognitive health. Altogether, PICS affects health-related quality of life which remains far below the general population [24], decreases functional independence (25% of dependant patients in a German multi-centric cohort 3 years after sepsis [21]), is associated with increased long-term mortality (45% mortality post-sepsis [21]), and is at risk for life disruption (8%) or work discontinuation (12%) [25].

Mental health is also a key problem in PICS-F. Significant symptoms of anxiety and depression could affect 80% of relatives [7,8]. The rate of psychological disorders appears to be comparable among families regardless of the cause of admission. In a French nationwide cohort of relatives of COVID-19 patients [8] 41% of them experienced significant symptoms of anxiety. In another French cohort of relatives of moderate-to-severe traumatic brain injury patients, 51% of them suffered from significant symptoms of anxiety [7]. Although there is no statistical comparison between these cohorts, symptoms of anxiety rates appear to be in the same range in two very different contexts. Similarly, significant depression symptom rates look strikingly the same, with 31% in relatives of COVID-19 patients [8] and 35% in relatives of traumatic brain injury [7]. Other psychological issues for relatives range from significant post-traumatic stress disorder symptoms (35%) [8] or complicated grief (15-20%) [9]. Families also suffer from financial burden after the hospitalization of their loved ones [26]. Finally, patients' children should not be forgotten, considering their specific needs and apprehension of the situation [27]. Other visiting healthy parents or relatives are often unable to adequately cope with their child [28] and need specific multidisciplinary management.
# State of the art of PICS management

## Organisation of healthcare systems

PICS management requires adequate screening and multidisciplinary care, but there are no approved treatments of proven efficacy. In spite of national guidelines [29], the timing of evaluation, complications that ought to be screened, and methods of evaluation bear huge variations across different health care systems worldwide [30]. The first challenge is to perform an efficient follow-up and PICS screening in ICU survivors. In several published experiences, around 80% of survivors are ineligible to follow up [5,31] for various reasons: lack of resources, including reduced availability of dedicated healthcare professionals, low clinical severity (patients staying in the ICU for a short time, inappropriate admissions), patients' refusal to participate, or lost to follow-up. Finally, PICS management remains insufficient: in France, only 30% of ICUs offer a follow-up visit, among which only 5% of discharged patients benefit from this follow-up [32]. Consequently, there is room for improvement in critically ill survivors' management [32].

Several risk factors have been consistently reported in several studies, but as stated before, there are methodological issues in these works that preclude robust tailoring of PICS screening (selection bias, lack of external validation of findings). Thus, the development of an easy-to-use, large-scale scale and efficient screening is a major challenge to improve outcomes. The input of eHealth could be a real asset in the coming years. In a recent review, Lai et al. [33] have identified 13 different studies focusing on the feasibility of eHealth implementation. Although these strategies appear promising, much remains to be evaluated: psychological and cognitive alterations can be easily assessed, while physical ones can be less so (e.g., muscle strength, ability to walk and move quickly); the analysis of barriers such as literacy or acceptability by users have not been explored adequately as well as the utility of eHealth (self-perceived, medical input, cost-effectiveness). Nonetheless, eHealth should definitely be explored as a potential asset in the screening and management of PICS.

In other settings of chronic disease, such as cancer or cardiovascular diseases, it appears mandatory and obvious to perform a dedicated follow-up of patients. However, the impact of follow-up on ICU survivors' outcomes remains controversial to this day, and there are few data on the subject. In a multicenter randomized-controlled trial in 425 ICU survivors [31], Sharshar et al. organized a dedicated follow-up during one year after discharge involving a multidisciplinary team including ICU physician, a psychologist, and a social worker, versus a standard follow-up in the control group. The primary endpoint was a composite outcome including one-year death and severe-to-extreme impairment of at least one EuroQoL-5D-5 L dimension. Surprisingly, the outcome was worse in the dedicated follow-up than in the standard group, mainly because of worse anxiety and depression symptoms in the intervention group. These results are challenging but raise important hypotheses. First, there is little detail about what was done in the intervention group, and one might assume that the follow-up did not effectively address patients' needs. This hypothesis is reinforced by the fact that 50% of patients in both groups felt that the follow-up program was not satisfactory regarding their personal issues. Unfortunately, there is no description of the reasons for dissatisfaction, which could range from patients' health conditions to social and economic causes that cannot be changed by a standard follow-up program. Moreover, assessing the efficacy of complex interventions such as post-ICU interventions, which have multiple components (medical, psychological, and social assessments), is methodologically challenging [34].

Tailoring PICS screening to patients' needs appears paramount if we aim to improve outcomes. First, institutions and authorities must engage adequate resources, which are yet to be delineated. Second, one could advocate that PICS' chronic health issues are specific and should receive dedicated interventions that are yet to be discovered. For instance, psychotropic medications given in the general community for anxiety-depression disorders could be inefficient in PICS mental health disorders because of different neurobiological pathophysiology. Finally, the interesting study by Sharshar et al. raises the question of targeting health-related quality of life as an outcome in these studies. Health-related quality of life is complex and depends on numerous factors, such as social and personal environment, or the patient's situation before ICU admission, for which medical management may have little impact. In definite, there is currently scarce evidence that suggests how we should handle PICS in ICU survivors. Considering the complexity of PICS, there is room for innovation and experimentation in the field.

## PICS and therapeutic innovation

As our understanding of PICS pathophysiology is far from being fully elucidated, different therapeutic interventions have been assessed in either murine models of sepsis or in sepsis survivors, and some trials were designed in critically ill survivors [11]: interferon gamma, granulocyte colony-stimulating factor or anti-PD1 targeting immune dysregulation, testosterone or IGF-1 targeting catabolism, and finally interleukin receptor antagonists, omega-3 fatty acids or even probiotics targeting the chronic inflammatory response. Some interventions, like interleukin-6 receptor antagonist, have shown positive results on 90-day mortality in patients with severe COVID-19 [35]. Whether some interventions could be useful in PICS survivors remains to be demonstrated. Only cutting-edge translational research programs ensuring a continuum from the ICU to the later stage of the disease will allow full understanding and provide major outcome improvement [14,36].

## Summary of PICS management

In Table 1, we propose a management for PICS. First, screening should be started in the first 3 months after discharge or even yearly, if resources are available, as suggested by some recommendations [30] with detection of mental health issues (Hospital Anxiety and Depression Scale, Post-traumatic stress checklist), cognitive impairment (Montreal Cognitive Assessment), and physical impairment. This allows a rapid detection of new or worsening symptoms with the objective of reducing the risk of persisting disabilities and chronic diseases. Ideally, a serial assessment is highly encouraged but remains challenging in terms of resources.

Second, focusing on health problems for which there are effective treatments can be a useful method of demonstrating the role of follow-up programs in the eyes of patients and other health care providers and facilitating the integration of such programs into the clinical routine of intensive care. For example, up to 45% of ICU survivors complain of significant pain that could interfere with many activities of daily living [6]. Therefore, assessing pain and treating it is certainly highly valued and important. The same reasoning can be made with other deficits, such as psychological, cognitive, and physical deficits that require the establishment of facilitated access pathways to multispecialty and multiprofessional care so that patients can receive the care they need efficiently.

Third, this strategy does not preclude research programs, with a broad exploration of PICS in patients or their families. Different organisational systems can be tested (remote follow-up, one-day
<table><caption>**Table 1**
Proposition for PICS management.</caption><thead><tr><td>Targets of management</td><td>Details of each target</td></tr></thead><tbody><tr><td>1 Timing of evaluation</td><td>Month 3. Allows a rapid detection of health-care issues Month 6. Depending on local resources, this second evaluation could be useful to verify the adequate management of issues, and the evolution of health impairments.</td></tr><tr><td>2 Mental Health</td><td>Anxiety and depression (i.e. HADS scale) Post-traumatic stress disorders (i.e. PCL-5)</td></tr><tr><td>3 Cognitive impairment</td><td>MOCA</td></tr><tr><td>4 Other outcomes</td><td>Prior to screen these specific health issues, ICU teams should pre-plan potential patient management with dedicated healthcare professionals Pain Nutrition Respiratory disorders</td></tr><tr><td>5 Organisation for institutions</td><td>Remote follow-up. Potential benefit of eHealth One-day on-site visit The choice depends mostly on local resources.</td></tr><tr><td>6 Interaction with primary care</td><td>Improve the continuum of care through dedicated communications with rehabilitation specialists, general practitioners</td></tr></tbody></table>

Legend: HADS: Hospital Anxiety and Depression Scale. PCL: Post-traumatic stress disorder checklist. MOCA: Montreal Cognitive Assessment. NB. There are several tools available for the screening of many issues (fatigue, disability). We provide tools in this agenda based upon our experiences and what we deem as an appropriate feasibility/acceptability/helpful management ratio.

on-site visit), adapting them to the patients' conditions; for example, remote follow-up may be indicated in a patient who cannot come in person because he lives far away, has no one to accompany him, is too debilitated, or has deficits that prevent him from moving. To this day, no specific type of follow-up can be strongly recommended with a high level of evidence. eHealth could be of great help, but as stated before, much remains to be done on this topic. Finally, good coordination with primary care and the patient's general practitioner is key to ensuring sustainable management. Again, there is no straightforward way to build the continuum of care, and it is likely that centres willing to develop this activity will need to test different approaches prior to constructing a successful system.

## Research agenda

The improvement of PICS in the coming years will require bold research initiatives in the field of methodology, epidemiology, and healthcare systems innovations, with a mandatory intertwining with fundamental research. First, an effort must be made regarding the methodology of clinical research to improve consistency, comparability, and provide meaningful interventions in the future, considering Patient-Reported Outcome Measures (PROMs). The scientific community should be able to promote reproducible studies and encourage the development of Core Outcome Sets in the different settings of PICS [37]. There are already some initiatives: a remarkable effort has been made in the COVID-19 [38], and survivors of Acute Respiratory Distress Syndrome [37] and there are similar ongoing projects in TBI patients [39] but these Core Outcome Sets need to be disseminated and routinely used in research projects. Core Outcome Sets require multidisciplinary collaborations involving patients and relatives. To this day, participative research projects with patients remain confidential in ICU research and must be encouraged. In addition to health concepts that should be evaluated, Core Outcome Set initiatives should also attempt to reach consensus on the best scales and tools, their use (thresholds, adequate analysis), their cultural validation, and access (payment or open). Considering the multiple causes of admission in the ICU and aspects of PICS, several Core Outcome Set initiatives must be undertaken (e.g., mental health, chronic organ failure). Moreover, one should also consider the dire need to develop specific instruments that also include patient-important outcomes and incorporate the specific needs of ICU survivors, which are often not covered by generic instruments [40]. This first step is paramount to improving the quality of research on the topic.

The second step is to promote multicentric and ideally international cohorts with prolonged follow-up, which can provide valuable scientific information [6,21,41]. These initiatives could

leverage ambitious grants on an international level. Furthermore, given the global initiative on digital health national databases, innovative epidemiological approaches are also mandatory: these databases may lack granularity, but they can allow the assessment of large follow-up programmes tracking the evolution over time of diseases, use of medication, and clinical outcomes. These databases are available and could allow a vast field of exploration and unanswered questions in the field of PICS [14]. The follow-up of ICU survivors is a huge challenge. Several initiatives exist and are mostly based on local resources: in-person visit, remote visit, and digital follow-up. The rise of eHealth is a potential game changer in the field. Innovative digital solutions may promote screening of PICS and early rehabilitation [33], but there is a lack of well-driven, ambitious programs to delineate acceptability, attrition, and digital health literacy. Moreover, the lack of a clear benefit of a systematic post-ICU follow-up [31] raises substantial questions: What is the optimal timing for PICS screening? What should we screen and leverage? How can we assess the efficacy of complex, multi-component interventions in patients with different discharge dispositions (rehabilitation centers, home, long-term facility care units)? And finally, is PICS a specific entity for which dedicated medical or psychological interventions are yet unknown? Thus, the third step of the research agenda is the elaboration of ambitious research programs on the experimentation of innovative clinical pathways and management of PICS. These programs should encompass both patients and their families, becoming more commonly informal caregivers.

Rather than being seen as a supplement to ICU care and research, PICS should be routinely integrated into clinical trials. Mortality remains the cornerstone of many ICU trials, with many disappointing results in the past decades [42]. Mortality is often multi-factorial, and it is unlikely that a single intervention may alter this outcome. Although it remains mandatory to evaluate in-ICU or 28-day mortality in trials, the routine addition of PICS outcomes in line with the intervention tested in the ICU appears to be a key step to improve our understanding of critical care diseases and patients' outcomes in the future. Thus, this fourth step of our research agenda will help us understand the disease, identify interventions that could bring a true benefit to the patient based also on PROMs, and help us rethink clinical trials in the field, to tackle the litany of negative results on mortality that has been ongoing for more than 20 years [42].

Finally, in order to better understand PICS and the pathophysiology behind critical illness, the elaboration of cutting-edge bedside-to-bench translational programs is an urgent need [14]. The realisation of bio-banking with blood, respiratory tract, and urine samples is feasible. Bio-banking requires adequate funding, of course, but a combination of in-ICU and PICS data in longitudinal cohorts will allow us to understand the disease in collaboration
<table><caption>**Table 2**
Proposition of a research agenda for Post-Intensive Care Syndrome.</caption><thead><tr><td>Main axis of the agenda</td><td>Main goals of each axis</td></tr></thead><tbody><tr><td>1 Methodology</td><td>Elaboration of Core Outcome Sets Participative research programs with patients and caregivers Standardize methods for PICS research programs: methods for outcome exploration, thresholds Standardize the analysis of PICS: statistical plan, competition between mortality and outcomes, appropriate analysis of multi-component interventions</td></tr><tr><td>2 Epidemiological studies</td><td>Promote multicentric, international cohorts with follow-up Promote the use of national health database (claims) Explore the consequences of in-ICU events on PICS leveraging benefits to eHealth (massive data storage) Use of Artificial Intelligence models</td></tr><tr><td>3 Refine outcomes in trials</td><td>Promote the use of follow-up in trials with PICS outcomes in line with the interventions</td></tr><tr><td>4 Management pathway</td><td>Explore the assets and drawbacks of digital pathway Fill the gap of knowledge of the efficacy/failure of existing interventions (in-person, remote visits) Explore the collaboration that must be developed between the hospital and primary care in the context of strained resources.</td></tr><tr><td>5 Translational research</td><td>Biobanking during ICU and follow-up for survivors Expand collaborations with fundamental research Explore immune-inflammatory disorders Explore genetic susceptibility and reprogramming Promote animal models</td></tr></tbody></table>

with fundamental science researchers. These programs are ambitious and will also need to leverage substantial funding through dedicated grants, but they are mandatory if we want to identify and develop major innovations, in line with the current breakthroughs in cancer therapies. Table 2 summarizes our proposed research Agenda.

## Conclusion

PICS encompasses the multiple complications that a critically ill patient and their relatives may encounter after ICU discharge. These complications range from chronic somatic impairment, mental health issues, cognitive impairment, and neuro-psychological disorders, leading to higher mortality and morbidity, reduced quality of life, and healthcare costs compared to other patients. In spite of growing evidence suggesting the magnitude of this problem, there are numerous unanswered questions. On both clinical and research levels, multidisciplinary, ambitious programs are needed that provide meaningful evidence in the future. On the clinical level, associating ICU specialists, primary care physicians, other medical specialists, but also other healthcare professionals (e.g., neuropsychologists and psychologists, speech therapists, physiotherapists) seems mandatory to leverage relevant daily management. On the research level, translational research with fundamental science or social sciences and humanities is a key goal. International collaborations between critical care specialists and other research teams would be profitable to leverage meaningful grants and research programs. Only ambitious initiatives will shape Intensive Care in the future and positively impact outcomes.

## CRediT authorship contribution statement

All authors attest that they meet the current International Committee of Medical Journal Editors (ICMJE) criteria for Authorship.

## Funding

This work did not receive any grant from funding agencies in the public, commercial, or not-for-profit sectors.

## Declaration of competing interest

The authors do not declare any conflict of interest about this review.

## References

[1] Gayat E, Cariou A, Deye N, Vieillard-Baron A, Jaber S, Damoisel C, et al. Determinants of long-term outcome in ICU survivors: results from the FROG-ICU study. Crit Care 2018;22. http://dx.doi.org/10.1186/s13054-017-1922-8.

[2] Azoulay E, Adrie C, Lassence AD, Pochard F, Moreau D, Thiery G, et al. Determinants of postintensive care unit mortality: a prospective multicenter study. Crit Care Med 2003;31:428–32. http://dx.doi.org/10.1097/01.ccm.0000048622.01013.88.

[3] Needham DM, Davidson J, Cohen H, Hopkins RO, Weinert C, Wunsch H, et al. Improving long-term outcomes after discharge from intensive care unit. Crit Care Med 2012;40:502–9. http://dx.doi.org/10.1097/ccm.0b013e318232da75.

[4] Parotto M, Gyöngyösi M, Howe K, Myatra SN, Ranzani O, Shankar-Hari M, et al. Post-acute sequelae of COVID-19: understanding and addressing the burden of multisystem manifestations. Lancet Respir Med 2023;11:739–54. http://dx.doi.org/10.1016/S2213-2600(23)00239-4.

[5] Mason CK, Adie SK, Shea MJ, Konerman MC, Thomas MP, McSparron JI, et al. Post-intensive cardiac care outpatient long-term outreach clinic (PICCOLO clinic): defining health care needs and outcomes among coronary care unit survivors. Am Hear J Plus: Cardiol Res Pr 2024;38100363. http://dx.doi.org/10.1016/j.ahjo.2024.100363.

[6] Bourdiol A, Legros V, Vardon-Bounes F, Rimmele T, Abraham P, Hoffmann C, et al. Prevalence and risk factors of significant persistent pain symptoms after critical care illness: a prospective multicentric study. Critical Care Lond Engl 2023;27:199. http://dx.doi.org/10.1186/s13054-023-04491-w.

[7] Cinotti R, Chopin A, Moyer JD, Huet O, Lasocki S, Cohen B, et al. Anxiety and depression symptoms in relatives of moderate-to-severe traumatic brain injury survivors – A multicentre cohort. Anaesth Crit Care Pa 2023;42101232. http://dx.doi.org/10.1016/j.accpm.2023.101232.

[8] Azoulay E, Resche-Rigon M, Megarbane B, Reuter D, Labbé V, Cariou A, et al. Association of COVID-19 acute respiratory distress syndrome with symptoms of posttraumatic stress disorder in family members after ICU discharge. JAMA 2022;327:1042–50. http://dx.doi.org/10.1001/jama.2022.17.

[9] Kentish-Barnes N, Chevret S, Valade S, Jaber S, Kerhuel L, Guisset O, et al. A three-step support strategy for relatives of patients dying in the intensive care unit: a cluster randomised trial. Lancet 2022;399:656–64. http://dx.doi.org/10.1016/s0140-6736(21)02176-0.

[10] Marra A, Pandharipande PP, Girard TD, Patel MB, Hughes CG, Jackson JC, et al. Co-occurrence of post-intensive care syndrome problems among 406 survivors of critical illness. Crit Care Med 2018;46:1393–401. http://dx.doi.org/10.1097/ccm.00000000000003218.

[11] Chadda KR, Puthuchery Z. Persistent inflammation, immunosuppression, and catabolism syndrome (PICS): a review of definitions, potential therapies, and research priorities. Br J Anaesth 2024;132:507–18. http://dx.doi.org/10.1016/j.bja.2023.11.052.

[12] Roquilly A, Jacqueline C, Davieau M, Mollé A, Sadek A, Fourgeux C, et al. Alveolar macrophages are epigenetically altered after inflammation, leading to long-term lung immunoparalysis. Nat Immunol 2020;18:1133–92. http://dx.doi.org/10.1038/s41590-020-0673-x.

[13] Wang T, Derhovanessian A, Cruz SD, Belperio JA, Deng JC, Hoo GS. Subsequent infections in survivors of sepsis. J Intensiv Care Med 2012;29:87–95. http://dx.doi.org/10.1177/0885066612467162.

[14] Broquet A, Gourain V, Goronflot T, Mabecque VL, Sinha D, Ashayeripanah M, et al. Sepsis-trained macrophages promote antitumoral tissue-resident T cells. Nat Immunol 2024;25:802–19. http://dx.doi.org/10.1038/s41590-024-01819-8.

[15] Huang C, Huang L, Wang Y, Li X, Ren L, Gu X, et al. 6-month consequences of COVID-19 in patients discharged from hospital: a cohort study. Lancet 2021;397:220–32. http://dx.doi.org/10.1016/S0140-6736(20)32656-8.

[16] Corte WD, Dhondt A, Vanholder R, Waele JD, Decruyenaere J, Sergoyne V, et al. Long-term outcome in ICU patients with acute kidney injury treated with renal replacement therapy: a prospective cohort study. Crit Care 2016;20:256. http://dx.doi.org/10.1186/s13054-016-1409-2.

[17] Vanhorebeek I, Latronico N, Berghe GV den. ICU-acquired weakness. Intensiv Care Med 2020;46:637–53. http://dx.doi.org/10.1007/s00134-020-05944-4.

[18] Aerde NV, Meersseman P, Debaveye Y, Wilmer A, Gunst J, Casaer MP, et al. Five-year impact of ICU-acquired neuromuscular complications: a prospective, observational study. Intensiv Care Med 2020;46:1184–93. http://dx.doi.org/10.1007/s00134-020-05927-5.
[19] Parker AM, Sricharoenchai T, Raparla S, Schneck KW, Bienvenu OJ, Needham DM. Posttraumatic stress disorder in critical illness survivors: a metaanalysis. Crit Care Med 2015;43:1121-9. http://dx.doi.org/10.1097/ccm.0000000000000882.

[20] Rabiee A, Nikayin S, Hashem MD, Huang M, Dinglas VD, Bienvenu OJ, et al. Depressive symptoms after critical illness. Crit Care Med 2016;44:1744-53. http://dx.doi.org/10.1097/ccm.0000000000001811.

[21] Fleischmann-Struzek C, Born S, Kesselmeier M, Ely EW, Töpfer K, Romeike H, et al. Functional dependence following intensive care unit-treated Sepsis: three-year follow-up results from the prospective Mid-German Sepsis Cohort (MSC). Lancet Reg Heal Eur 2024;46101066. http://dx.doi.org/10.1016/j.lanepe.2024.101066.

[22] Honarmand K, Lalli RS, Priestap F, Chen JL, McIntyre CW, Owen AM, et al. Natural history of cognitive impairment in critical illness survivors: a systematic review. Am J Respir Crit Care Med 2019;0:193-201. http://dx.doi.org/10.1164/rccm.201904-0816ci.

[23] Iwashyna TJ, Ely EW, Smith DM, Langa KM. Long-term cognitive impairment and functional disability among survivors of severe sepsis. JAMA 2010;304:1787-94. http://dx.doi.org/10.1001/jama.2010.1553.

[24] Cinotti R, Roquilly A, Chopin A, Martin FP, Morato Y, Lerebourg C, et al. Relationship between health-related quality-of-life and functional outcome 6 months after moderate to severe TBI. Ann Phys Rehabil Med 2023;66101715. http://dx.doi.org/10.1016/j.rehab.2022.101715.

[25] Pelt DCV, Milbrandt EB, Qin L, Weissfeld LA, Rotondi AJ, Schulz R, et al. Informal caregiver burden among survivors of prolonged mechanical ventilation. Am J Respir Crit Care Med 2007;175:167-73. http://dx.doi.org/10.1164/rccm.200604-493oc.

[26] Khandelwal N, Engelberg RA, Hough CL, Cox CE, Curtis JR. The patient and family member experience of financial stress related to critical illness. J Palliat Med 2020;23:972-6. http://dx.doi.org/10.1089/jpm.2019.0369.

[27] Lewandowski LA. Needs of children during the critical illness of a parent or sibling. Crit Care Nurs Clin North Am 1992;4:573-85.

[28] Belser T, Exl MT, Nydahl P, Zumstein-Shaha M, Jeitziner M-M. Experiences of parents visiting an adult family member in the intensive care unit accompanied by their underaged children: a qualitative study. Aust Crit Care 2024;37:783-9. http://dx.doi.org/10.1016/j.aucc.2024.02.004.

[29] Santé HA de. Diagnostic et prise en charge despatients adultes avec un syndrome post-réanimation (PICS) et de leur entourage; 2023.

[30] Mikkelsen ME, Still M, Anderson BJ, Bienvenu OJ, Brodsky MB, Brummel N, et al. Society of critical care medicine's international consensus conference on prediction and identification of long-term impairments after critical illness. Crit Care Med 2020;48:1670-9. http://dx.doi.org/10.1097/ccm.00000000000004586.

[31] Sharshar T, Grimaldi-Bensouda L, Siami S, Cariou A, Salah AB, Kalfon P, et al. A randomized clinical trial to evaluate the effect of post-intensive care multi-

disciplinary consultations on mortality and the quality of life at 1 year. Intensiv Care Med 2024;50:665-77. http://dx.doi.org/10.1007/s00134-024-07359-x.

[32] Agbakou M, Combet M, Martin M, Blonz G, Desmedt L, Seguin A, et al. Post-intensive care syndrome screening: a French multicentre survey. Ann Intensiv Care 2024;14:109. http://dx.doi.org/10.1186/s13613-024-01341-y.

[33] Lai DJ, Liu Z, Johnston E, Dikomitis L, D'Oliveira T, Shergill S. Exploring the effectiveness of eHealth interventions in treating Post Intensive Care Syndrome (PICS) outcomes: a systematic review. Crit Care 2024;28:317. http://dx.doi.org/10.1186/s13054-024-05089-6.

[34] Rosa RG, Walsh TS. Navigating complex interventions in post-ICU care: insights from a randomized clinical trial of post-intensive care multidisciplinary consultations. Intensiv Care Med 2024;50:725-7. http://dx.doi.org/10.1007/s00134-024-07414-7.

[35] Investigators R-C, Gordon AC, Mouncey PR, Al-Beidh F, Rowan KM, Nichol AD, et al. Interleukin-6 receptor antagonists in critically ill patients with Covid-19. N Engl J Med 2021;384:1491-502. http://dx.doi.org/10.1056/nejmoa2100433.

[36] Wong AC, Devason AS, Umana IC, Cox TO, Dohnalová L, Litichevskiy L, et al. Serotonin reduction in post-acute sequelae of viral infection. Cell 2023;186:4851-4867.e20. http://dx.doi.org/10.1016/j.cell.2023.09.013.

[37] Needham DM, Sepulveda KA, Dinglas VD, Chessare CM, Friedman LA, Clifton 3rd OB, et al. Core outcome measures for clinical research in acute respiratory failure survivors. An international modified Delphi consensus study. Am J Respir Crit Care Med 2017;196:1122-30. http://dx.doi.org/10.1164/rccm.201702-0372oc.

[38] Gorst SL, Seylanova N, Dodd SR, Harman NL, O'Hara M, Terwee CB, et al. Core outcome measurement instruments for use in clinical and research settings for adults with post-COVID-19 condition: an international Delphi consensus study. Lancet Respir Med 2023;11:1101-14. http://dx.doi.org/10.1016/s2213-2600(23)00370-3.

[39] Cinotti R, Derouin Y, Chenet A, Oujamaa L, Glize B, Launey Y, et al. Standardized outcomes for randomized controlled trials targeting early interventions in patients with moderate-to-severe traumatic brain injury: protocol for the development of a core outcome set. JMIR Res Protoc 2025;14e54525. http://dx.doi.org/10.2196/54525.

[40] Streich K, Hartog CS, Fleischmann-Struzek C, Rose N, Bichmann A, Kesselmeier M, et al. Psychometric properties of the reintegration to normal living index for sepsis survivors. Qual Life Res 2023;32:2415-23. http://dx.doi.org/10.1007/s11136-023-03403-3.

[41] Latronico N, Eikermann M, Ely EW, Needham DM. Improving management of ARDS: uniting acute management and long-term recovery. Crit Care 2024;28:58. http://dx.doi.org/10.1186/s13054-024-04810-9.

[42] Heyland D, Muscedere J, Wischmeyer PE, Cook D, Jones G, Albert M, et al. A randomized trial of glutamine and antioxidants in critically ill patients. N Engl J Med 2013;368:1489-97. http://dx.doi.org/10.1056/nejmoa1212722.