Non-sedation Versus Sedation With a Daily Wake-up Trial in Critically Ill Patients Receiving Mechanical Ventilation - Effects on Physical Function

Substudy of Non-Seda Trial (NCT01967680): Non-sedation Versus Sedation With a Daily Wake-up Trial in Critically Ill Patients Receiving Mechanical Ventilation - Effects on Physical Function. An Investigator-initiated, Randomised, Clinical, Parallel-group, Multinational, Superiority Trial

Critically ill, ventilator-treated patients rapidly loose much of their muscle mass and strength. This can attribute to prolonged admission, prolonged mechanical ventilation, increased mortality and might have a negative impact on the physical function, degree of independence and quality of life. The pathophysiological background for the loss of muscle mass as well as possible effective treatment is still not well established. In the NONSEDA-trial we randomise critically ill patients to non-sedation or sedation with a daily wake-up trial during mechanical ventilation in the intensive care unit (ICU). It has never been assessed whether non-sedation reduces the loss of muscle mass and strength.

Aim: To assess the effects of non-sedation versus sedation with a daily wake-up trial on physical function after discharge from ICU.

Hypothesis: that non-sedation during ventilator-treatment will improve the physical function after ICU-discharge, compared with standard treatment of sedation with a daily wake-up.

Study Overview

• Status: Completed
• Conditions: Muscular Atrophy; Critically Ill
• Intervention / Treatment: Other: Non-sedation; Other: Sedation, control

• Study Type: Interventional
• Enrollment (Actual): 205
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Denmark
  • Kolding, Denmark, 6000
    • Lillebaelt Hospital, Kolding

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Endotracheally intubated
• Expected time on ventilator > 24 hours
• Age ≥ 18 years
• Informed consent

Exclusion Criteria:

• Severe head trauma where therapeutic coma is indicated
• Therapeutic hypothermia where therapeutic coma is indicated
• Status epilepticus where therapeutic coma is indicated
• Patient has participated in the study before
• Patient is transferred from another ICU with length of stay > 48 hours
• Patient is comatose at admission
• PaO2/FiO2 ≤ 9, if sedation is necessary for oxygenation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Non-sedation; The experimental group will not receive sedatives. Patients are thoroughly and repeatedly informed by the staff of where they are, what have happened, and what type of treatment they are going to receive. Participants will be awake and have a natural sleep rhythm. In case these patients develop and outward delirium, it is necessary to have a nurse or other caregiver at the bedside in order to calm the patient. Patients with delirium will be treated with haloperidol.	Other: Non-sedation
Active Comparator: Sedation with daily wake-up; The control group will be sedated to Ramsay score 3-4. The first 48 hours the patients will be sedated with propofol, after 48 hours midazolam will be used. During daytime, the patient will be awakened as the intravenous infusion of sedatives will be discontinued. The patient will be considered to be awake when he/she can perform at least three of the following four tasks: Open the eyes to verbal commands.; Follow the examiner's instructions with the eyes.; Squeeze hands on request.; Stick out the tongue on request. After a successful wake-up, the infusion of sedative will be resumed, starting on half of the pre-wake-up dose and adjusted to Ramsey score 3-4.	Other: Sedation, control; Other Names: Standard treatment, continuous iv-sedation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Physical function	Co-primary outcome of: patient-reported quality of life, as measured by SF-36v2, physical component and degree of independence in activities of daily living, as measured by Barthel Index. Since this is a co-primary outcome, the type I error probability associated with the test of the null hypothesis should be less than 0,025.	3 months after ICU-discharge

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
6 minute walk	Walking distance in the 6 minute walk test at 3 months follow-up	3 months after ICU-discharge
Handgrip	Handgrip-strength at 3 month follow-up	3 months after ICU-discharge
Thigh muscle size	Muscle size, measured as cross section area of the rectus femoris muscle at 3 months follow-up	3 months after ICU-discharge
Biomechanical data	Muscle strength, measured using biomechanical measurements - Maximal voluntary contraction (MVC), rate of force developement (RFD) and endurance at 25% of MVC at 3 months follow-up	3 months after ICU-discharge

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Biomechanical data	Muscle strength - Maximal voluntary contraction (MVC), rate of force developement (RFD) and endurance at 25% of MVC at ICU-discharge.	Within 24 hours of ICU-discharge
Handgrip	Handgrip-strength at ekstubation and at ICU-discharge.	Within 24 hours of ICU-discharge
Thigh muscle size	Muscle size, measured as cross section area of the rectus femoris muscle at ekstubation and at ICU-discharge	Within 24 hours of ICU-discharge

Collaborators and Investigators

• Sponsor: Palle Toft
• Collaborators: University of Southern Denmark; Sygehus Lillebaelt; The Danish Council for Strategic Research
• Investigators: Principal Investigator: Helene K Nedergaard, MD, Lillebaelt Hospital, Kolding

Publications and helpful links

General Publications

• Strom T, Martinussen T, Toft P. A protocol of no sedation for critically ill patients receiving mechanical ventilation: a randomised trial. Lancet. 2010 Feb 6;375(9713):475-80. doi: 10.1016/S0140-6736(09)62072-9. Epub 2010 Jan 29.
• Nedergaard HK, Jensen HI, Olsen HT, Strom T, Lauridsen JT, Sjogaard G, Toft P. Effect of non-sedation on physical function in survivors of critical illness - A substudy of the NONSEDA randomized trial. J Crit Care. 2021 Apr;62:58-64. doi: 10.1016/j.jcrc.2020.11.017. Epub 2020 Nov 24.
• Nedergaard HK, Jensen HI, Lauridsen JT, Sjogaard G, Toft P. Non-sedation versus sedation with a daily wake-up trial in critically ill patients receiving mechanical ventilation--effects on physical function: study protocol for a randomized controlled trial: a substudy of the NONSEDA trial. Trials. 2015 Jul 23;16:310. doi: 10.1186/s13063-015-0856-1.

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2014
• Primary Completion (Actual): June 1, 2017
• Study Completion (Actual): March 1, 2019

Study Registration Dates

• First Submitted: January 9, 2014
• First Submitted That Met QC Criteria: January 10, 2014
• First Posted (Estimate): January 14, 2014

Study Record Updates

• Last Update Posted (Actual): March 15, 2019
• Last Update Submitted That Met QC Criteria: March 14, 2019
• Last Verified: March 1, 2019

More Information

Terms related to this study

• Keywords: non-sedation
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Neurologic Manifestations; Disease Attributes; Neuromuscular Manifestations; Pathological Conditions, Anatomical; Atrophy; Muscular Atrophy; Critical Illness
• Other Study ID Numbers: S-20130025a