Clinical trial NCT01967680: Non-sedation Versus Sedation With a Daily Wake-up Trial in Critically Ill Patients Receiving Mechanical Ventilation
Official title: Non-sedation Versus Sedation With a Daily Wake-up Trial in Critically Ill Patients Receiving Mechanical Ventilation. The NONSEDA-trial. An Investigator-initiated, Randomised, Clinical, Parallel-group, Multinational, Superiority Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Critical Illness
Respiration, Artificial
Lead sponsor: Odense University Hospital
Sponsor class: OTHER
Collaborators: name: The Danish Medical Research Council
name: Aase and Ejnar Danielsens Foundation
First posted: 2013-10-23
Enrollment: 700
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Background: Every year 30,000 Danish patients are admitted to Intensive Care Units (ICU), accounting for 2-3% of all patients in hospital and 30% of the yearly hospital expenditure. The mortality in the ICU is 12.7 % and the 30-day mortality is 21.2 % according to the national Danish Intensive Care Database. Through many years, the standard care has been to use continuous sedation of critically ill patients during me-chanical ventilation. However, recent research indicates that it is beneficial to reduce the sedation level in these patients. A randomised trial found that continuous sedation with a daily wake-up trial compared to continuous sedation reduced the time on me-chanical ventilation and the length of stay in the intensive care unit. Further, a ran-domised trial comparing continuous sedation with a daily wake-up trial to no sedation found that patients in the non-sedated group needed mechanical ventilation for a shorter time and had a shorter length of stay in the ICU and in the hospital. The trial also indicated a beneficial effect on mortality, however the trial was not a priori de-signed or powered with respect to mortality. No randomised trial has been published comparing sedation with no sedation, a priori powered to have all-cause mortality as primary outcome.

Objective: To assess the benefits and harms of non-sedation versus sedation with a daily wake-up trial in critically ill patients in ICU.

Design: The NONSEDA trial is an investigator-initiated, randomised, clinical, parallel-group, multinational, superiority trial designed to include 700 patients from at least six ICUs in Denmark, Norway and Sweden.

Inclusion criteria: Mechanically ventilated patients with expected duration of me-chanical ventilation \> 24 hours.

Exclusion criteria: non-intubated patients, patients with severe head trauma, coma at admission or status epilepticus, patients treated with therapeutic hypothermia, patients with PaO2/FiO2\<9 where sedation might be necessary to ensure sufficient oxygenation or place the patient in prone position.

Experimental intervention: Non-sedation supplemented with pain management during mechanical ventilation.

Control intervention: Sedation with a daily wake-up trial.

The primary hypothesis is that non-sedation compared to sedation and a daily wake-up trial will reduce mortality.

The secondary hypotheses are that non-sedation compared to sedation and a daily wake-up trial will:

* Reduce the incidence of a composite outcome of death, acute myocardial in-farction (AMI), stroke, pulmonary embolism and other thromboembolic events.
* Reduce the number of organ failures.
* Increase the days alive without mechanical ventilation.
* Increase the days alive outside the ICU.
* Increase the days alive outside the hospital.

Outcomes: The primary outcome is all-cause mortality at 90 days. Secondary out-comes are time to death in the trial period, the frequency of the trombo-embolic com-plications, acute renal failure, days alive without mechanical ventilation, days alive outside the ICU and hospital. Explorative outcomes are mortality at 28 days, organ failure and coma-free, delirium-free days.

Trial size: The investigators will include 700 participants (2 x 350) in order to detect or reject 25% relative risk reduction in mortality with a type I error risk of 5% and a type II error risk of 20% (power at 80%).


Eligibility criteria: Inclusion Criteria:

Endotracheally intubated Expected time on ventilator \> 24 h. 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

Primary outcomes:
measure: Mortality
timeFrame: 90 days
Secondary outcomes:
measure: Days until death
timeFrame: 1 year
measure: Cardiovascular event
timeFrame: 90 days
measure: Coma and deliriumfree days
timeFrame: 28 days
measure: RIFLE-score
timeFrame: 28 days
measure: Days until discharge
timeFrame: 28 days
measure: Days until the participant is without mechanical ventilation
timeFrame: 28 days
Other outcomes:
measure: Mortality
timeFrame: 28 days
measure: Discharge fro ICU
timeFrame: 90 days
measure: End of mechanical ventilation
timeFrame: 90 days
measure: Discharge from hospital
timeFrame: 90 days
measure: Number of organ failures
timeFrame: ICU-admission
measure: Accidental extubation
timeFrame: ICU-admission
measure: Accidental removal of cental venous line
timeFrame: ICU-admission
measure: Oxygenation
timeFrame: During ventilator treatment
measure: 1-year survival
timeFrame: 1 year from randomisation
Locations:
city: Esbjerg
country: Denmark
facility: Sydvestjysk Sygehus
state: Region Of Southern Denmark
city: AArhus
country: Denmark
facility: AArhus university Hospital, Noerrebrogade
city: Kolding
country: Denmark
facility: Kolding Hospital
city: Odense
country: Denmark
facility: Odense University Hospital
city: Svendborg
country: Denmark
facility: Svendborg Hospital
city: Tonsberg
country: Norway
facility: Vestfold Hospital
city: Tromsoe
country: Norway
facility: University Hospital of North Norway
city: Linkoping
country: Sweden
facility: Linkjøbing University Hospital
Study officials:
affiliation: Odense University Hospital
name: Palle Toft, Professor
role: STUDY_CHAIR
affiliation: Svendborg Hospital
name: Hanne Tanghus Olsen, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Kolding Sygehus
name: Helene K Nedergaard, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Odense University Hospital
name: Thomas Stroem, Postdoc
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: Oxlund J, Knudsen T, Strom T, Lauridsen JT, Jennum PJ, Toft P. Serum melatonin concentration in critically ill patients randomized to sedation or non-sedation. Ann Intensive Care. 2021 Mar 6;11(1):40. doi: 10.1186/s13613-021-00829-1.
citation: Olsen HT, Nedergaard HK, Strom T, Oxlund J, Wian KA, Ytrebo LM, Kroken BA, Chew M, Korkmaz S, Lauridsen JT, Toft P. Nonsedation or Light Sedation in Critically Ill, Mechanically Ventilated Patients. N Engl J Med. 2020 Mar 19;382(12):1103-1111. doi: 10.1056/NEJMoa1906759. Epub 2020 Feb 16.