Analysis of Weaning of Analgosedation and Kinetics of Emergence in Critically Ill Patients (AWAKE-ICU)

AWAKE-ICU: Analysis of Weaning of Analgosedation and Kinetics of Emergence in Critically Ill Patients

The goal of this prospective multicenter observational study is to characterize early trajectories of consciousness recovery following the first valid structured awakening trial in mechanically ventilated critically ill adults, a phase that is not captured by current weaning classifications.

The main questions it aims to answer are:

1. What trajectories of consciousness recovery occur during the first 72 hours after the first valid structured awakening trial?
2. Are different early consciousness trajectories associated with clinically relevant outcomes, including successful liberation from mechanical ventilation, delirium, duration of mechanical ventilation, ventilator-free days, mortality, and long-term functional and cognitive outcomes?

Participants will:

1. Undergo standardized serial assessments of consciousness during the first 72 hours after the first valid structured awakening trial using the Richmond Agitation-Sedation Scale (RASS) and a standardized motor command assessment.
2. Receive daily assessments for delirium and weaning-related outcomes during the ICU stay.
3. Be followed for clinical outcomes during hospitalization and for functional and cognitive recovery up to 1 year after ICU admission.

Study Overview

• Status: Not yet recruiting
• Conditions: Delirium; Critical Illness; Mechanical Ventilation; Sedation and Analgesia; Critical Care Medicine; Weaning Invasive Mechanical Ventilation
• Intervention / Treatment: Procedure: Structured Awakening Evaluation (SAE)

Detailed Description

Background

Recovery of consciousness following interruption of analgosedation is a critical step during liberation from invasive mechanical ventilation. Although Structured Awakening Evaluations (SAEs) are increasingly incorporated into routine intensive care practice, emergence from analgosedation remains highly heterogeneous and poorly characterized. Existing weaning classifications primarily focus on the duration and outcome of ventilator liberation but do not adequately characterize the transitional phase between analgosedation interruption and recovery of consciousness, despite this being a prerequisite for meaningful participation in the weaning process.

Early emergence from analgosedation may determine a patient's ability to participate in spontaneous breathing trials, achieve successful liberation from mechanical ventilation, develop delirium, and ultimately recover after critical illness. However, the trajectories of emergence during the first days following the first valid SAE and their relationship with clinically relevant outcomes remain largely unknown.

Study Objectives

The primary objective of AWAKE-ICU is to characterize early trajectories of emergence from analgosedation during the first 72 hours following the first valid Structured Awakening Evaluation (SAE) in mechanically ventilated critically ill adults.

Secondary objectives are to evaluate the association between early emergence trajectories and clinically relevant outcomes, including spontaneous breathing trial performance, successful liberation from mechanical ventilation, duration of mechanical ventilation, ventilator-free days, delirium, tracheostomy, ICU and hospital length of stay, mortality, and long-term functional, cognitive, and health-related quality-of-life outcomes up to one year.

Study Design

AWAKE-ICU is a prospective, multicenter, observational cohort study conducted in adult intensive care units. Consecutive eligible patients receiving invasive mechanical ventilation will undergo standardized serial assessments during the first 72 hours following their first valid SAE. Emergence from analgosedation will be evaluated using the Richmond Agitation-Sedation Scale (RASS) together with the ability to follow standardized motor commands, allowing classification into predefined trajectories of consciousness recovery.

Participants will be followed throughout their ICU and hospital stay and subsequently at 90 days and 12 months after ICU admission. By providing the first standardized characterization of emergence from analgosedation after a Structured Awakening Evaluation, AWAKE-ICU aims to improve understanding of this critical transition and to generate evidence supporting more individualized approaches to ventilator liberation and recovery after critical illness.

• Study Type: Observational
• Enrollment (Estimated): 500

Contacts and Locations

• Study Contact: Name: Patricia Rodríguez Villamizar, MD, PhD; Phone Number: +34 699 220 215; Email: patricia.rodriguez.villamizar@gmail.com

Participation Criteria

Eligibility Criteria

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

• Sampling Method: Non-Probability Sample

Study Population

Consecutive adult critically ill patients receiving invasive mechanical ventilation for at least 24 hours who undergo a first valid Structured Awakening Evaluation (SAE) following continuous analgosedation during their ICU stay. The study focuses on patients without acute primary structural brain injury or active neuroprotective sedation, in whom recovery of consciousness, ventilator liberation, and subsequent clinical and patient-centered outcomes can be prospectively characterized.

Description

Inclusion Criteria:

Adult critically ill patients with acute respiratory failure or requiring invasive mechanical ventilation in the context of critical illness will be consecutively enrolled. Eligible participants must meet all of the following criteria:

• Age ≥18 years.
• Receiving invasive mechanical ventilation for ≥24 hours.
• Prior exposure to continuous analgosedation before undergoing a first valid Structured Awakening Evaluation (SAE) during the ICU stay, as defined by the study's operational criteria.
• Availability of sufficient clinical information to identify the baseline time point (t0) and characterize the first valid Structured Awakening Evaluation according to the study's operational definitions.
• Provision of informed consent for participation in the study.

Exclusion Criteria:

1. Acute primary structural brain injury in which the level of consciousness is primarily determined by the neurological condition or constitutes a therapeutic target, including but not limited to:

   • Moderate or severe traumatic brain injury.
   • Subarachnoid hemorrhage.
   • Ischemic or hemorrhagic stroke.
   • Central nervous system infections.
   • Other structural brain injuries requiring therapeutic sedation or goal-directed intensive neurological monitoring.

2. Ongoing therapeutic sedation for neurological indications at the time of the first valid Structured Awakening Evaluation (SAE), including:

   • Intracranial hypertension management.
   • Status epilepticus.
   • Other neuroprotective strategies requiring deep sedation.
3. ICU admission following cardiac arrest with return of spontaneous circulation and suspected hypoxic-ischemic brain injury or the need for targeted therapeutic sedation.
4. Insufficient clinical information to accurately identify the baseline time point (t0) and characterize the architecture of the first valid Structured Awakening Evaluation.
5. Patients receiving extracorporeal life support (ECLS/ECMO), in whom assessment of hemodynamic and respiratory stability before initiation of awakening and liberation from invasive mechanical ventilation is substantially more complex.

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort

Intervention / Treatment

Mechanically Ventilated Critically Ill Adults; Adult critically ill patients receiving invasive mechanical ventilation who undergo a first valid Structured Awakening Evaluation (SAE), defined according to the study protocol, following interruption or reduction of continuous analgosedation. Participants will undergo standardized serial assessments of emergence from analgosedation during the first 72 hours and will be followed throughout hospitalization and up to one year to evaluate clinical, functional and cognitive outcomes.

Procedure: Structured Awakening Evaluation (SAE); A standardized clinical evaluation performed after interruption or reduction of continuous analgosedation according to the study protocol. The Structured Awakening Evaluation is part of routine clinical care and serves exclusively to define cohort entry and characterize emergence from analgosedation. No experimental intervention is assigned or administered as part of this observational study.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Trajectory of consciousness recovery during the first 72 hours following the first valid Structured Awakening Evaluation (SAE)	Distribution (%) of patients classified as State A, B, C or NI according to RASS and standardized command-following assessment at baseline, 6, 12, 24, 48 and 72 hours after the first valid SAE.	At baseline (initiation of the index Structured Awakening Evaluation) and at 6, 12, 24, 48, and 72 hours after initiation of the index SAE.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Early favorable recovery of consciousness	Percentage of participants achieving State A at any predefined assessment within the first 24 hours following the first valid Structured Awakening Evaluation (SAE). State A is defined as RASS ≥ -2 with correct performance of at least 3 of 4 standardized simple commands.	From initiation of the index Structured Awakening Evaluation through 24 hours, with assessments at baseline and at 6, 12, and 24 hours.
Time to first extubation attempt	Time in days from initiation of the index Structured Awakening Evaluation to the first removal of the endotracheal tube, excluding removal performed as part of tracheostomy.	From initiation of the index SAE until the first extubation attempt, tracheostomy, death, ICU discharge, or Day 28 after the index SAE, whichever occurs first, assessed up to 28 days.
Ventilator-free days at Day 28	Number of days alive and free from invasive mechanical ventilation during the first 28 days following the first valid Structured Awakening Evaluation (SAE). Participants who die before Day 28 or remain on invasive mechanical ventilation throughout the entire observation period will be assigned 0 ventilator-free days. In participants who undergo reintubation, only the days following the final extubation that is not followed by another reintubation within the 28-day observation period will be counted as ventilator-free days.	Day 28 after the first valid SAE.
Delirium-free days at Day 28	Number of days during the first 28 days following the first valid Structured Awakening Evaluation (SAE) on which the participant is alive, remains in the intensive care unit, is evaluable for delirium, and has no delirium on the daily assessment. A participant will be considered evaluable for delirium when at least one valid assessment can be performed during that day with a Richmond Agitation-Sedation Scale (RASS) score ≥ -2. A delirium day will be defined as a day with at least one valid positive assessment using a validated delirium assessment tool, preferably the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU). Days on which delirium cannot be evaluated will not be counted as either delirium days or delirium-free days. Participants who die before Day 28 will not accumulate delirium-free days after death.	Day 28 after the first valid SAE.
Intensive care unit length of stay	Number of days from admission to the intensive care unit to ICU discharge or death.	From ICU admission through ICU discharge or death, assessed up to 12 months after ICU admission.
Hospital length of stay	Number of days from hospital admission to hospital discharge or death.	From hospital admission through hospital discharge or death, assessed up to 12 months after ICU admission.
Intensive care unit mortality	Percentage of participants who die during the index ICU stay before ICU discharge.	From ICU admission through ICU discharge or death, assessed up to 12 months after ICU admission.
In-hospital mortality	Percentage of participants who die during the index hospitalization before hospital discharge.	From hospital admission until hospital discharge, assessed up to 12 months after ICU admission.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tolerance of the index Structured Awakening Evaluation	Percentage of participants whose index Structured Awakening Evaluation (SAE) is completed and tolerated without early interruption or reversal because of clinically relevant instability, according to the predefined study criteria.	Assessed during the index Structured Awakening Evaluation, within 2 hours of SAE initiation.
Intercurrent clinical factors during the first 72 hours after the index Structured Awakening Evaluation	Percentage of participants experiencing each prespecified intercurrent clinical factor during the first 72 hours after the index Structured Awakening Evaluation (SAE), including pain, agitation, patient-ventilator asynchrony, hemodynamic instability, respiratory deterioration, delirium, and changes in analgosedation. Participants may experience more than one intercurrent factor during the observation period.	From initiation of the index Structured Awakening Evaluation through 72 hours after initiation of the index SAE.
Diagnostic testing prompted by delayed awakening	Percentage of participants who undergo at least one electroencephalogram (EEG) and/or neuroimaging study after the first valid Structured Awakening Evaluation (SAE) because of clinically documented delayed recovery of consciousness.	From completion of the index Structured Awakening Evaluation through ICU discharge, death, or 28 days after the index SAE, whichever occurs first.
Clinically relevant findings on diagnostic testing for delayed awakening	Percentage of participants undergoing EEG and/or neuroimaging for delayed awakening in whom at least one clinically relevant finding is identified. Relevant EEG findings include epileptiform activity, status epilepticus, severe diffuse encephalopathy, or other clinically relevant patterns. Relevant neuroimaging findings include acute structural lesions, signs of hypoxic-ischemic injury, or other clinically relevant abnormalities.	From completion of the index Structured Awakening Evaluation through ICU discharge, death, or Day 28 after the index SAE, whichever occurs first.
Health-related quality of life assessed using the EuroQol 5-Dimension 5-Level (EQ-5D-5L) index	The EQ-5D-5L index value will be derived from participants' responses across the five dimensions of the EuroQol 5-Dimension 5-Level questionnaire using the Spanish EQ-5D-5L value set. Index values range from -0.416 to 1, where 1 represents full health, 0 represents a health state equivalent to death, and negative values represent health states valued as worse than death. Higher index values indicate better health-related quality of life. The outcome will be assessed among participants with available follow-up data.	At 90 days and 12 months after ICU admission.
Functional status assessed using the Barthel Index	Total Barthel Index score assessing independence in activities of daily living. Scores range from 0 to 100, with higher scores indicating greater functional independence. The outcome will be assessed among participants with available follow-up data.	At 90 days and 12 months after ICU admission.
Living arrangement at follow-up	Percentage of participants in each prespecified living-arrangement category: home without support, home with support, nursing or residential care facility, hospital, or other setting. Each participant will be assigned to one category at each follow-up assessment.	At 90 days and 12 months after ICU admission.
All-cause mortality at 90 days and 12 months	Percentage of participants who have died from any cause by each prespecified follow-up time point, among participants with available vital-status information.	At 90 days and 12 months after ICU admission.
Symptoms of anxiety and depression assessed using the Patient Health Questionnaire-4 (PHQ-4)	Total score on the Patient Health Questionnaire-4 assessing symptoms of anxiety and depression. Total scores range from 0 to 12, with higher scores indicating greater psychological symptom burden and a worse mental health outcome. The outcome will be assessed among participants able to complete the questionnaire and with available follow-up data.	At 90 days and 12 months after ICU admission.
Cognitive performance assessed using the Modified Telephone Interview for Cognitive Status (mTICS)	Total score on the Modified Telephone Interview for Cognitive Status obtained through direct structured telephone assessment. Scores range from 0 to 50, with higher scores indicating better cognitive performance. The outcome will be assessed among participants whose clinical, communicative, and cognitive condition permits a valid direct assessment and who have available follow-up data.	At 90 days and 12 months after ICU admission.
Informant-reported cognitive decline assessed using the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE)	Mean item score on the Informant Questionnaire on Cognitive Decline in the Elderly, administered to a valid informant when a valid direct cognitive assessment using the mTICS cannot be completed. Mean scores range from 1 to 5, with higher scores indicating greater informant-reported cognitive decline and a worse cognitive outcome. The outcome will be assessed among participants with an available valid informant and follow-up data.	At 90 days and 12 months after ICU admission.
Emergency department visits after hospital discharge	Number of emergency department visits occurring between hospital discharge and each prespecified follow-up assessment. Higher counts indicate greater healthcare resource utilization. The outcome will be assessed among participants with available follow-up information.	Assessed at 90 days and 12 months after ICU admission, covering events from hospital discharge to each follow-up time point.
Hospital readmissions after hospital discharge	Number of unplanned or planned hospital readmissions occurring between hospital discharge and each prespecified follow-up assessment. Higher counts indicate greater healthcare resource utilization. The outcome will be assessed among participants with available follow-up information.	Assessed at 90 days and 12 months after ICU admission, covering events from hospital discharge to each follow-up time point.
Intensive care unit readmissions after hospital discharge	Number of intensive care unit readmissions occurring between hospital discharge and each prespecified follow-up assessment. Higher counts indicate greater healthcare resource utilization. The outcome will be assessed among participants with available follow-up information.	Assessed at 90 days and 12 months after ICU admission, covering events from hospital discharge to each follow-up time point.

Collaborators and Investigators

• Sponsor: Patricia Rodriguez Villamizar
• Collaborators: Fundación para la Investigación Biomédica Hospital Universitario 12 de Octubre
• Investigators: Principal Investigator: Patricia Rodríguez Villamizar, MD, PhD, Hospital Universitario 12 de Octubre

Publications and helpful links

General Publications

• Devlin JW, Skrobik Y, Gelinas C, Needham DM, Slooter AJC, Pandharipande PP, Watson PL, Weinhouse GL, Nunnally ME, Rochwerg B, Balas MC, van den Boogaard M, Bosma KJ, Brummel NE, Chanques G, Denehy L, Drouot X, Fraser GL, Harris JE, Joffe AM, Kho ME, Kress JP, Lanphere JA, McKinley S, Neufeld KJ, Pisani MA, Payen JF, Pun BT, Puntillo KA, Riker RR, Robinson BRH, Shehabi Y, Szumita PM, Winkelman C, Centofanti JE, Price C, Nikayin S, Misak CJ, Flood PD, Kiedrowski K, Alhazzani W. Clinical Practice Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU. Crit Care Med. 2018 Sep;46(9):e825-e873. doi: 10.1097/CCM.0000000000003299.
• Shehabi Y, Bellomo R, Kadiman S, Ti LK, Howe B, Reade MC, Khoo TM, Alias A, Wong YL, Mukhopadhyay A, McArthur C, Seppelt I, Webb SA, Green M, Bailey MJ; Sedation Practice in Intensive Care Evaluation (SPICE) Study Investigators and the Australian and New Zealand Intensive Care Society Clinical Trials Group. Sedation Intensity in the First 48 Hours of Mechanical Ventilation and 180-Day Mortality: A Multinational Prospective Longitudinal Cohort Study. Crit Care Med. 2018 Jun;46(6):850-859. doi: 10.1097/CCM.0000000000003071.
• Mehta S, Burry L, Cook D, Fergusson D, Steinberg M, Granton J, Herridge M, Ferguson N, Devlin J, Tanios M, Dodek P, Fowler R, Burns K, Jacka M, Olafson K, Skrobik Y, Hebert P, Sabri E, Meade M; SLEAP Investigators; Canadian Critical Care Trials Group. Daily sedation interruption in mechanically ventilated critically ill patients cared for with a sedation protocol: a randomized controlled trial. JAMA. 2012 Nov 21;308(19):1985-92. doi: 10.1001/jama.2012.13872.
• Pham T, Heunks L, Bellani G, Madotto F, Aragao I, Beduneau G, Goligher EC, Grasselli G, Laake JH, Mancebo J, Penuelas O, Piquilloud L, Pesenti A, Wunsch H, van Haren F, Brochard L, Laffey JG; WEAN SAFE Investigators. Weaning from mechanical ventilation in intensive care units across 50 countries (WEAN SAFE): a multicentre, prospective, observational cohort study. Lancet Respir Med. 2023 May;11(5):465-476. doi: 10.1016/S2213-2600(22)00449-0. Epub 2023 Jan 21.
• Szarpak L, Aleksandrowicz D, Karczewska K, Kotfis K. Neurotoxicity of ICU sedatives: we should end the surrogate debate and standardize long-term brain outcomes with a core neuro-outcome set. Intensive Care Med. 2026 May;52(5):1167-1168. doi: 10.1007/s00134-026-08354-0. Epub 2026 Mar 16. No abstract available.
• Landoni G, Kotani Y, Lomivorotov V. Neurotoxicity of sedative drugs: a matter of concern in adults? Intensive Care Med. 2025 Oct;51(10):1901-1903. doi: 10.1007/s00134-025-08030-9. Epub 2025 Jul 24. No abstract available.

Study record dates

Study Major Dates

• Study Start (Estimated): September 1, 2026
• Primary Completion (Estimated): September 1, 2027
• Study Completion (Estimated): September 1, 2028

Study Registration Dates

• First Submitted: July 1, 2026
• First Submitted That Met QC Criteria: July 16, 2026
• First Posted (Actual): July 17, 2026

Study Record Updates

• Last Update Posted (Actual): July 17, 2026
• Last Update Submitted That Met QC Criteria: July 16, 2026
• Last Verified: July 1, 2026

More Information

Terms related to this study

• Keywords: Mechanical Ventilation; Mechanical Ventilation Weaning; Emergence from Analgosedation; Structured Awakening Evaluation; Recovery of Consciousness; Richmond Agitation-Sedation Scale (RASS); Motor Command Assessment; Consciousness Trajectories; Delayed Awakening
• Additional Relevant MeSH Terms: Neurologic Manifestations; Nervous System Diseases; Mental Disorders; Pathologic Processes; Disease Attributes; Confusion; Neurobehavioral Manifestations; Neurocognitive Disorders; Perceptual Disorders; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Delirium; Critical Illness; Agnosia
• Other Study ID Numbers: AWAKE-ICU-01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified individual participant data underlying the published results will be made available upon reasonable request to the Principal Investigator after publication of the primary results, subject to approval of a research proposal, data use agreement, and compliance with applicable ethical and data protection regulations.
• IPD Sharing Time Frame: Beginning 6 months after publication of the primary manuscript up to 5 years after publication
• IPD Sharing Access Criteria: Reasonable scientific proposal approved by the steering committee and execution of a data-sharing agreement
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE

Drug and device information, study documents

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