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

NCT ID: NCT01967680

Last Updated: 2018-04-06

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 700 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-01-31
• Study Completion Date: 2018-04-30

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%).

Conditions

Critical Illness; Respiration, Artificial

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

Sedation with daily wake-up trial

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.

Group Type: ACTIVE_COMPARATOR

Controlgroup, sedation with daily wake-up trial

Intervention Type: PROCEDURE

Non-sedation

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.

Group Type: EXPERIMENTAL

Non-sedation for intubated, mechanically ventilated patients

Intervention Type: PROCEDURE

Interventions

Non-sedation for intubated, mechanically ventilated patients

Intervention Type: PROCEDURE

Controlgroup, sedation with daily wake-up trial

Intervention Type: PROCEDURE

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

The Danish Medical Research Council

OTHER

Sponsor Role: collaborator

Aase and Ejnar Danielsens Foundation

OTHER

Sponsor Role: collaborator

Palle Toft

OTHER

Sponsor Role: lead

Responsible Party

Palle Toft

Professor

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Palle Toft, Professor

Role: STUDY_CHAIR

Odense University Hospital

Hanne Tanghus Olsen, MD

Role: PRINCIPAL_INVESTIGATOR

Svendborg Hospital

Helene K Nedergaard, MD

Role: PRINCIPAL_INVESTIGATOR

Kolding Sygehus

Thomas Stroem, Postdoc

Role: PRINCIPAL_INVESTIGATOR

Odense University Hospital

Locations

Sydvestjysk Sygehus

Esbjerg, Region Syddanmark, Denmark

AArhus university Hospital, Noerrebrogade

Aarhus, , Denmark

Kolding Hospital

Kolding, , Denmark

Odense University Hospital

Odense, , Denmark

Svendborg Hospital

Svendborg, , Denmark

University Hospital of North Norway

Tromsø, , Norway

Vestfold Hospital

Tønsberg, , Norway

Linkjøbing University Hospital

Linköping, , Sweden

Countries

Denmark; Norway; Sweden

References

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.

Reference Type: BACKGROUND

PMID: 20116842 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 33677695 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 32068366 (View on PubMed)

Other Identifiers

S-20130025

Identifier Type: -

Identifier Source: org_study_id