UP STUDY - Decipher Persistent Critical Illness Through in Deep Clinical Phenotyping. (UPSt_UCI)

Persistent Critical Illness (PCI) is a condition that affects some patients who remain in the Intensive Care Unit (ICU) for a long time, usually more than 10-14 days. It is estimated to occur in 5-20% of critically ill patients. A recent Portuguese study found that more than 14% of ICU patients stayed longer than 14 days. PCI is often associated with ongoing need for life support, such as mechanical ventilation or medications to maintain blood pressure. However, patients may also experience severe muscle weakness, repeated infections, or other complications, which makes this group very diverse.

One of the main risk factors for prolonged ICU stay is sepsis, a severe infection that affects the whole body. Other factors-such as prior health conditions, use of corticosteroids, sedation practices, early versus late mobilization, fluid and antibiotic management, and delirium treatment-may also influence the development and course of PCI.

This study aims to identify different clinical patterns ("clusters") among critically ill patients who remain in the ICU for more than 10 days. Patients will be followed until hospital discharge, and up to one year if data are available. Understanding these different patterns will help develop more personalized and effective care strategies for each patient profile.

The study is a multicenter retrospective cohort including adult patients (≥18 years) admitted to participating ICUs for more than 5 days between 2021 and 2023. Data collected will include demographic, clinical, and laboratory information, details of organ support (such as mechanical ventilation or vasopressors), medications, nutrition, and rehabilitation practices.

Statistical and machine learning methods will be used to identify groups of patients with similar clinical trajectories and to assess how these groups are related to outcomes such as survival, recovery of organ function, or long-term disability.

Expected results are the identification of distinct clinical clusters of PCI that combine clinical and laboratory data, and the development of tailored management strategies to improve recovery and outcomes for patients with PCI.

Study Overview

• Status: Recruiting
• Conditions: Critical Illness; Critical Care; Critical Care, Intensive Care; Critical Care Medicine; Recovery Outcomes

• Study Type: Observational
• Enrollment (Estimated): 7000

Contacts and Locations

• Study Contact: Name: Susana Fernandes, MD PhD.; Phone Number: 351 21 798 5100; Email: susanamfernandes@medicina.ulisboa.pt
• Study Contact Backup: Name: Mariana Santos, PhD; Phone Number: 351 21 798 5100; Email: marianamsantos@medicina.ulisboa.pt

Study Locations

• Portugal
  • Lisbon District
    • Lisbon, Lisbon District, Portugal
      • Recruiting
      • Centro Hospitalar de São João / ULS São João
      • Contact: José Artur Paiva, MD PhD; Phone Number: 351 225 512 100; Email: japaiva@ulssjoao.min-saude.pt
      • Principal Investigator: José Artur Paiva, MD PhD
      • Sub-Investigator: Cristiana Paulo, MD PhD
    • Lisbon, Lisbon District, Portugal
      • Recruiting
      • Hospital de Vila Franca de Xira / ULS Estuário do Tejo
      • Contact: João Gonçalves Pereira, MD PhD; Phone Number: 351 263 006 500; Email: joaogpster@gmail.com
      • Principal Investigator: João Gonçalves Pereira, MD PhD
      • Sub-Investigator: André Oliveira, MD PhD
    • Lisbon, Lisbon District, Portugal
      • Recruiting
      • Hospital Santa Maria / ULS Santa Maria
      • Contact: Susana Fernandes, MD PhD; Phone Number: 351 217 805 000; Email: susanamfernandes@medicina.ulisboa.pt
      • Contact: Mariana Santos, PhD; Email: marianamsantos@medicina.ulisboa.pt
      • Principal Investigator: Susana Fernandes, MD PhD
      • Sub-Investigator: João Ribeiro, MD PhD
    • Lisbon, Lisbon District, Portugal
      • Recruiting
      • Hospital Garcia de Orta / ULS Almada-Seixal
      • Contact: Antero Fernandes, MD PhD; Phone Number: 351 212 940 294; Email: antevafe@gmail.com
      • Principal Investigator: Antero Fernandes, MD PhD
      • Sub-Investigator: Rui Gomes, MD PhD
    • Lisbon, Lisbon District, Portugal
      • Recruiting
      • Hospital Prof. Doutor Fernando Fonseca / ULS Amadora -Sintra
      • Contact: Paulo Teles Freitas, MD PhD; Phone Number: 351 214 348 200; Email: ptf@netcabo.pt
      • Principal Investigator: Paulo Teles Freitas, MD PhD
      • Sub-Investigator: Tiago Ramires, MD PhD
      • Sub-Investigator: Cristiana Gonçalves, MD PhD
    • Lisbon, Lisbon District, Portugal
      • Recruiting
      • Hospital São Francisco Xavier / Centro Hospitalar de Lisboa Ocidental
      • Contact: Pedro Póvoa, MD PhD; Phone Number: 351 210 431 000; Email: pedrorpovoa@gmail.com
      • Principal Investigator: Pedro Póvoa, MD PhD
      • Sub-Investigator: João Frutuoso, MD PhD
  • Porto District
    • Vila Nova de Gaia, Porto District, Portugal
      • Not yet recruiting
      • Hospital de VIla Nova de Gaia-Espinho / ULS Gaia e Espinho
      • Contact: Rute Alves, MD PhD; Email: ruteifalves@gmail.com
      • Principal Investigator: Rute Alves, MD PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

This study will include adult patients (≥18 years old) who are consecutively admitted to participating intensive care units (ICUs) and remain in the ICU for 5 or more days. The focus will be on patients who survive the early phase of critical illness, allowing the formation of a relatively homogeneous cohort of early ICU survivors.

The population will comprise patients with a wide range of critical illnesses, including sepsis, respiratory failure, cardiovascular instability, and multi-organ dysfunction, who require ongoing organ support such as invasive mechanical ventilation or vasopressors. Patients with prolonged ICU stays exceeding 10 days who continue to require organ support will be further characterized as having Persistent Critical Illness.

Description

Inclusion Criteria:

• Adult patients aged 18 years or older;
• ICU length of stay equal to or greater than 5 days.

Exclusion Criteria:

• Patients with an ICU stay < 5 days;
• Patients discharged from the ICU early due to lack of ward availability, rather than clinical recovery;
• Patients who do not survive the early phase of critical illness (i.e., early ICU deaths).

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort
Adult patients (≥18 years) admitted to participating ICUs for more than 5 days.; Adult patients (≥18 years) admitted to participating intensive care units (ICUs) who remained in the ICU for more than 5 days.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Need for one or more continuous organ support treatment at Day 10	Data from patients who remain in the ICU for more than 10 days requiring ongoing organ support, such as invasive mechanical ventilation, renal replacement therapy or vasopressors, will be used to identify those who develop Persistent Critical Illness and to enable subsequent cluster analysis of their clinical trajectories.	The first 10 days in the ICU

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
All cause mortality stratified by Persistent Critical Illness (PCI) clusters	Clinical outcomes will be assessed and reported according to clusters of Persistent Critical Illness (PCI) identified using unsupervised machine learning analysis at Day 10 of ICU stay. Outcome includes: • All-cause mortality, reported as the proportion of participants who die during hospitalization and up to 1 year after cluster identification.	From cluster identification (Day 10) until hospital discharge or up to 1-year follow-up if available.
Organ dysfunction stratified by Persistent Critical Illness	Clinical outcomes will be assessed and reported according to clusters of Persistent Critical Illness (PCI) identified using unsupervised machine learning analysis at Day 10 of ICU stay. Outcome includes: • Organ dysfunction, assessed using the Sequential Organ Failure Assessment (SOFA) score, reported as mean (± SD) or median (IQR) values after cluster identification.	From cluster identification (Day 10) until hospital discharge or up to 1-year follow-up if available.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
ICU mortality	Death occurring at any time during the ICU stay.	Through ICU stay (up to 1 year).
Hospital mortality	Death occurring at any time during the hospital admission.	Through hospital stay (up to 2 years).
ICU length of stay	Total number of calendar days from ICU admission to ICU discharge.	Through ICU stay (up to 1 year).
Incidence of ICU-acquired infections	Number of clinically or microbiologically documented infections acquired ≥48 hours after ICU admission.	Through ICU stay (up to 1 year).
Hemoglobin trajectory	Longitudinal assessment of hemoglobin levels using repeated measurements obtained during the intensive care unit (ICU) stay.	Through ICU stay (up to 1 year).
C-reactive protein (CRP) trajectory	Longitudinal assessment of C-reactive protein levels using repeated measurements obtained during the intensive care unit stay.	Through ICU stay (up to 1 year).
Creatinine trajectory	Longitudinal assessment of creatinine levels using repeated measurements obtained during the intensive care unit stay.	Through ICU stay (up to 1 year).
Albumin trajectory	Longitudinal assessment of albumin levels using repeated measurements obtained during the intensive care unit stay.	Through ICU stay (up to 1 year).
Lactate trajectory	Longitudinal assessment of lactate levels using repeated measurements obtained during the intensive care unit stay.	Through ICU stay (up to 1 year).

Collaborators and Investigators

• Sponsor: Lisbon Academic Medical Center - Centro Académico de Medicina de Lisboa
• Collaborators: Centro Hospitalar de Vila Nova de Gaia/Espinho; Centro Hospitalar Lisboa Ocidental; Centro Hospitalar De São João, E.P.E.; Hospital Vila Franca de Xira; Unidade Local de Saúde Almada-Seixal; Hospital Prof. Doutor Fernando Fonseca
• Investigators: Principal Investigator: Susana Fernandes, MD PhD, Lisbon School of Medicine

Publications and helpful links

General Publications

• Livingston E, Bucher K. Coronavirus Disease 2019 (COVID-19) in Italy. JAMA. 2020 Apr 14;323(14):1335. doi: 10.1001/jama.2020.4344. No abstract available.
• COVID-ICU Group on behalf of the REVA Network and the COVID-ICU Investigators. Clinical characteristics and day-90 outcomes of 4244 critically ill adults with COVID-19: a prospective cohort study. Intensive Care Med. 2021 Jan;47(1):60-73. doi: 10.1007/s00134-020-06294-x. Epub 2020 Oct 29.
• Fuest KE, Ulm B, Daum N, Lindholz M, Lorenz M, Blobner K, Langer N, Hodgson C, Herridge M, Blobner M, Schaller SJ. Clustering of critically ill patients using an individualized learning approach enables dose optimization of mobilization in the ICU. Crit Care. 2023 Jan 3;27(1):1. doi: 10.1186/s13054-022-04291-8.
• Shaw M, Viglianti EM, McPeake J, Bagshaw SM, Pilcher D, Bellomo R, Iwashyna TJ, Quasim T. Timing of Onset, Burden, and Postdischarge Mortality of Persistent Critical Illness in Scotland, 2005-2014: A Retrospective, Population-Based, Observational Study. Crit Care Explor. 2020 Apr 29;2(4):e0102. doi: 10.1097/CCE.0000000000000102. eCollection 2020 Apr.
• Voiriot G, Oualha M, Pierre A, Salmon-Gandonniere C, Gaudet A, Jouan Y, Kallel H, Radermacher P, Vodovar D, Sarton B, Stiel L, Brechot N, Preau S, Joffre J; la CRT de la SRLF. Chronic critical illness and post-intensive care syndrome: from pathophysiology to clinical challenges. Ann Intensive Care. 2022 Jul 2;12(1):58. doi: 10.1186/s13613-022-01038-0.
• Inoue S, Hatakeyama J, Kondo Y, Hifumi T, Sakuramoto H, Kawasaki T, Taito S, Nakamura K, Unoki T, Kawai Y, Kenmotsu Y, Saito M, Yamakawa K, Nishida O. Post-intensive care syndrome: its pathophysiology, prevention, and future directions. Acute Med Surg. 2019 Apr 25;6(3):233-246. doi: 10.1002/ams2.415. eCollection 2019 Jul.
• Pereira RA, Sousa M, Cidade JP, Melo L, Lopes D, Ventura S, Aragao I, Lima Neto RMF, Molinos E, Marques A, Cardoso N, Marino F, Monteiro FB, Oliveira AP, Silva RC, Real AMN, Banheiro BS, Reis R, Adao-Serrano M, Cracium A, Valadas A, Ribeiro JM, Povoa P, Tapadinhas C, Mendes V, Coelho L, Maia R, Freitas PT, Ferreira IA, Ramires T, Val-Flores LS, Cascao M, Alves R, Rodeia SC, Barrigoto C, Cardiga R, Silva MJFD, Vale B, Fonseca T, Rios AL, Camoes J, Perez D, Cabral S, Ribeiro MI, Mendes JJ, Gouveia J, Fernandes SM. What changed between the peak and plateau periods of the first COVID-19 pandemic wave? A multicentric Portuguese cohort study in intensive care. Rev Bras Ter Intensiva. 2022 Oct-Dec;34(4):433-442. doi: 10.5935/0103-507X.20210037-pt. Epub 2023 Mar 3.
• Cadd M, Nunn M. An A-E assessment of post-ICU COVID-19 recovery. J Intensive Care. 2021 Mar 20;9(1):29. doi: 10.1186/s40560-021-00544-w.
• Gupta E, Jacobs MD, George G, Roman J. Beyond the ICU: Frailty and Post-ICU Disability. Healthcare Use after Acute Respiratory Distress Syndrome and Severe Sepsis. Am J Respir Crit Care Med. 2019 Apr 15;199(8):1028-1030. doi: 10.1164/rccm.201805-0928RR. No abstract available.
• Yildirim S, Durmaz Y, San Y, Taskiran I, Cinleti BA, Kirakli C. Cost of Chronic Critically Ill Patients to the Healthcare System: A Single-center Experience from a Developing Country. Indian J Crit Care Med. 2021 May;25(5):519-523. doi: 10.5005/jp-journals-10071-23804.
• Span LF, Hermus AR, Bartelink AK, Hoitsma AJ, Gimbrere JS, Smals AG, Kloppenborg PW. Adrenocortical function: an indicator of severity of disease and survival in chronic critically ill patients. Intensive Care Med. 1992;18(2):93-6. doi: 10.1007/BF01705039.
• Harrison DA, Creagh-Brown BC, Rowan KM. Timing and burden of persistent critical illnessin UK intensive care units: An observational cohort study. J Intensive Care Soc. 2023 May;24(2):139-146. doi: 10.1177/17511437211047180. Epub 2021 Nov 5.
• Zhou Q, Qian H, Yang A, Lu J, Liu J. CLINICAL AND PROGNOSTIC FEATURES OF CHRONIC CRITICAL ILLNESS/PERSISTENT INFLAMMATION IMMUNOSUPPRESSION AND CATABOLISM PATIENTS: A PROSPECTIVE OBSERVATIONAL CLINICAL STUDY. Shock. 2023 Jan 1;59(1):5-11. doi: 10.1097/SHK.0000000000002035. Epub 2022 Nov 17.

Study record dates

Study Major Dates

• Study Start (Actual): January 13, 2025
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2027

Study Registration Dates

• First Submitted: December 3, 2025
• First Submitted That Met QC Criteria: March 30, 2026
• First Posted (Actual): April 3, 2026

Study Record Updates

• Last Update Posted (Actual): April 13, 2026
• Last Update Submitted That Met QC Criteria: April 8, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Critical care; Critical Illness; Persistant Critical Illness
• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Pathological Conditions, Signs and Symptoms; Critical Illness
• Other Study ID Numbers: UP STUDY

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Individual participant data collected in this study will be made available to other researchers. All data will undergo a thorough anonymization process prior to sharing to prevent direct or indirect identification of participants. Each patient will be assigned an internal numeric code, consisting of two digits representing the center of origin and four sequential digits assigned by order of admission. No personal identifiers (e.g., name, national ID number, full date of birth, address) are collected.

The anonymized dataset will be accompanied by a data dictionary, describing each variable and its format, to allow full interpretation and reuse of the data. This approach ensures participant confidentiality and complies with ethical and legal requirements, while enabling secondary analyses, replication studies, or meta-analyses by other researchers.

• IPD Sharing Time Frame: The individual participant data and accompanying data dictionary will be made available after the completion of dat of interest for the study publication, starting December 1, 2028, and will remain accessible for years thereafter.

IPD Sharing Access Criteria

De-identified individual participant data and the corresponding data dictionary will be made available to qualified researchers whose proposed use of the data has been reviewed and approved by the study's coordinating center or ethics committee. Before sharing, all datasets will be verified, curated, and securely stored in accordance with applicable data protection regulations and current ethical and scientific recommendations.

Researchers will have access to fully anonymized datasets containing all study variables, excluding any directly or indirectly identifiable information. Data will be shared upon reasonable request through a secure, controlled-access repository, following submission of a research proposal and a data use agreement that ensures confidentiality and appropriate data use.

The anonymized dataset and related documentation will be deposited in a certified open research repository, such as Zenodo, Dryad, or Figshare, and will be assigned a Digital Object Identifier (DOI).

• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No