Analysis of Weaning of Analgosedation and Kinetics of Emergence in Critically Ill Patients

Official title

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

Overview

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.

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.

Interventions

• 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.

Primary outcome measures

• Trajectory of consciousness recovery during the first 72 hours following the first valid Structured Awakening Evaluation (SAE) [Time frame: 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 (8)

• Early favorable recovery of consciousness [Time frame: 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 frame: 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 [Time frame: Day 28 after the first valid SAE.]
• Delirium-free days at Day 28 [Time frame: Day 28 after the first valid SAE.]
• Intensive care unit length of stay [Time frame: From ICU admission through ICU discharge or death, assessed up to 12 months after ICU admission.]
• Hospital length of stay [Time frame: From hospital admission through hospital discharge or death, assessed up to 12 months after ICU admission.]
• Intensive care unit mortality [Time frame: From ICU admission through ICU discharge or death, assessed up to 12 months after ICU admission.]
• In-hospital mortality [Time frame: From hospital admission until hospital discharge, assessed up to 12 months after ICU admission.]

Eligibility criteria

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

• 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.
• 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.
• ICU admission following cardiac arrest with return of spontaneous circulation and suspected hypoxic-ischemic brain injury or the need for targeted therapeutic sedation.
• Insufficient clinical information to accurately identify the baseline time point (t0) and characterize the architecture of the first valid Structured Awakening Evaluation.
• 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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Observational model

Cohort

Study locations

Center list to be confirmed — check the primary protocol.

Publications

• 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 PMID 29498938
• 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. PMID 41838085
• 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. PMID 40705075
• 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, C PMID 30113379
• 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. JA PMID 23180503
• 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): PMID 36693401

Identifiers

NCT: NCT07710066 · AWAKE-ICU-01

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗