Critical IllnessNONSEDANCT01967680
Non-sedation Versus Sedation With a Daily Wake-up Trial in Critically Ill Patients Receiving Mechanical Ventilation
A study testing Non-sedation for intubated, mechanically ventilated patients in people with Critical Illness and Respiration, Artificial, run by Palle Toft at 8 sites in 3 countries.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Critical Illness, Respiration, Artificial
- What is being tested?
- Non-sedation for intubated, mechanically ventilated patients
- Type of treatment
- Injection or infusion, Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 700 participants
- Where
- 8 sitesin 3 countries
- Study dates
- Jan 2014to Apr 2018
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Endotracheally intubated Expected time on ventilator > 24 h. Age ≥ 18 years Informed consent
Who cannot join
- 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
Trial locations and contacts
8 sites in 3 countries.
8 sites in 3 countries
Denmark5 sites
AArhus university Hospital, Noerrebrogade
Aarhus, 8000
Sydvestjysk Sygehus
Esbjerg, Region Syddanmark, 6700
Kolding Hospital
Kolding, 6000
Odense University Hospital
Odense, 5000
Svendborg Hospital
Svendborg, 5600
Norway2 sites
Vestfold Hospital
Tønsberg, 3103
University Hospital of North Norway
Tromsø, 9038
About this study
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
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.
Read more
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%).
- Conditions
- Critical Illness, Respiration, Artificial
- Being tested
- Non-sedation for intubated, mechanically ventilated patients, Controlgroup, sedation with daily wake-up trial
- Medical subject headings
- Critical Illness, Respiratory Aspiration
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Non-sedation for intubated, mechanically ventilated patientsProcedure or surgery
Controlgroup, sedation with daily wake-up trialProcedure or surgery
| Study group | Role | What they receive |
|---|---|---|
| Sedation with daily wake-up trial | Active comparator | The control group is sedated with continuous infusion to Ramsay score 3-4. During daytime, the patient is awakened as the intravenous infusion of sedatives is discontinued. After a successful wake-up, the infusion of sedative is resumed, starting on half of the pre-wake-up dose. If the patient becomes uncomfortable or agitated during the awakening, sedation is resumed, again starting with half the dosage. The infusion of sedatives is then adjusted to Ramsey score 3-4. Receives: Procedure: Controlgroup, sedation with daily wake-up trial |
| Non-sedation | Experimental | This 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 in the non-sedated group are 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 are treated with haloperidol according to the U.S. guidelines, 2002 and the Danish national guidelines.
If, despite these measures, it is necessary to sedate an agitated patient more than twice, or where sedation might be necessary to ensure sufficient oxygenation or prone position, the patient is sedated and treated like the control-group. Every day during the wake-up trial it is evaluated whether the patient is able to continue the intervention of non-sedation. Receives: Procedure: Non-sedation for intubated, mechanically ventilated patients |
What is being measured
The primary outcome is the main question the study is designed to answer.
Mortality
All cause mortality at 90 days after randomization
Measured: 90 days
Secondary outcomes (6)
Days until death
Days until death throughout the total observation period
Measured: 1 year
Cardiovascular event
Proportion of participants with a major cardiovascular outcome (acute myocardial infarction, cerebral infarction, cerebral hemorrhage, pulmonary embolus, deep vein thrombosis, other thrombo-embolic event) at 90 days after randomization.
Measured: 90 days
Coma and deliriumfree days
Number of coma- and delirium-free days (defined as RASS ≥ 3 and no positive CAM-ICU scorings the particular day) within 28 days from randomization
Measured: 28 days
RIFLE-score
Highest Rifle-score within 28 days from randomization (Rifle-categories: Rifle-R: Increase in serum creatinine x 1.5 from baseline OR urine output < 0.5 mL/kg/hr x 6 h.
Rifle-I: Increase in serum creatinine x 2 from baseline OR urine output < 0.5 mL/kg/hr x 12 h.
Rifle-F: Increase in serum creatinine x 3 from baseline OR urine output < 0.3 mL/kg/hr x 24h OR creatinine ≥ 350μmol/L with acute rise ≥ 44 μmol/L in < 24h)
Measured: 28 days
Days until discharge
Days until discharge from ICU (within 28 days from randomization).
Measured: 28 days
Days until the participant is without mechanical ventilation
Days until the participant is without mechanical ventilation (within 28 days from randomization).
Measured: 28 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted23 Oct 2013 (estimated)
- Study startJan 2014
- Primary completionApr 2018
- Study completionApr 2018
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Critical IllnessStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind
- Who is masked
- Outcomes assessor
- Enrolment
- 700 participants (actual)
Sponsor and investigators
- Lead sponsor
- Palle Toft
- Sponsor type
- University, hospital or other
- Collaborators
- The Danish Medical Research Council, Aase and Ejnar Danielsens Foundation
- Responsible party
- Sponsor-investigator, Palle Toft, Odense University Hospital
- Investigators
- Palle Toft, Professor, Study chair, Odense University HospitalHanne Tanghus Olsen, MD, Principal investigator, Svendborg HospitalHelene K Nedergaard, MD, Principal investigator, Kolding SygehusThomas Stroem, Postdoc, Principal investigator, Odense University Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01967680
- Sponsor's protocol ID
- S-20130025
- Acronym
- NONSEDA
- Status last verified
- Apr 2018
- First submitted
- 18 Oct 2013
- Last updated
- 6 Apr 2018
- Results posted
- No
- Data monitoring committee
- Yes
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.
PubMed 20116842Oxlund 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.
PubMed 33677695Olsen 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.
PubMed 32068366
Study at a glance
From the registry record, last updated by the sponsor on 6 Apr 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT01967680
- Acronym / sponsor ID
- NONSEDA / S-20130025
- Conditions
- Critical Illness, Respiration, Artificial
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 700 participants (actual)
- Lead sponsor
- Palle ToftUniversity, hospital or other
- Collaborators
- The Danish Medical Research Council, Aase and Ejnar Danielsens Foundation
- Study start
- Jan 2014 (actual)
- Primary completion
- Apr 2018 (actual)
- Study completion
- Apr 2018 (actual)
- First posted
- 23 Oct 2013 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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%).
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind (outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Sedation with daily wake-up trial | Active comparator | Procedure: Controlgroup, sedation with daily wake-up trialThe control group is sedated with continuous infusion to Ramsay score 3-4. During daytime, the patient is awakened as the intravenous infusion of sedatives is discontinued. After a successful wake-up, the infusion of sedative is resumed, starting on half of the pre-wake-up dose. If the patient becomes uncomfortable or agitated during the awakening, sedation is resumed, again starting with half the dosage. The infusion of sedatives is then adjusted to Ramsey score 3-4. |
| Non-sedation | Experimental | Procedure: Non-sedation for intubated, mechanically ventilated patientsThis 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 in the non-sedated group are 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 are treated with haloperidol according to the U.S. guidelines, 2002 and the Danish national guidelines. If, despite these measures, it is necessary to sedate an agitated patient more than twice, or where sedation might be necessary to ensure sufficient oxygenation or prone position, the patient is sedated and treated like the control-group. Every day during the wake-up trial it is evaluated whether the patient is able to continue the intervention of non-sedation. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (1 listed)
- Endotracheally intubated Expected time on ventilator > 24 h. Age ≥ 18 years Informed consent
Key exclusion criteria (1 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Non-sedation for intubated, mechanically ventilated patients | Procedure or surgery | Non-sedation |
| Controlgroup, sedation with daily wake-up trial | Procedure or surgery | Sedation with daily wake-up trial |
Primary outcome
Mortality
Time frame: 90 days
All cause mortality at 90 days after randomization
6 secondary outcomes
Days until death
Time frame: 1 year
Cardiovascular event
Time frame: 90 days
Coma and deliriumfree days
Time frame: 28 days
RIFLE-score
Time frame: 28 days
Days until discharge
Time frame: 28 days
Days until the participant is without mechanical ventilation
Time frame: 28 days
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 6 Apr 2018.
- Background: PubMed 20116842Strom 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.
- Derived from this study: PubMed 33677695Oxlund 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.
- Derived from this study: PubMed 32068366Olsen 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Palle Toft, Professor study chair
Odense University Hospital
Hanne Tanghus Olsen, MD principal investigator
Svendborg Hospital
Helene K Nedergaard, MD principal investigator
Kolding Sygehus
8 sites in 3 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Non-sedation for intubated, mechanically ventilated patients in people with Critical Illness and Respiration, Artificial, run by Palle Toft at 8 sites in 3 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 1 inclusion and 1 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 6 Apr 2018. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 8 sites in Denmark, Norway, Sweden. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Mortality (time frame: 90 days). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01967680, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 6 Apr 2018.