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

NCT01967680 | Completed DMC

• 1 other identifier: S-20130025
• Study Type: interventional
• Target: 700
• Locations: 3 countries
• Sites: 8

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

Outcome Measures

Primary Outcomes (1)

• Mortality

  All cause mortality at 90 days after randomization

  90 days

Secondary Outcomes (6)

• Days until death

  1 year

• Cardiovascular event

  90 days

• Coma and deliriumfree days

  28 days

• RIFLE-score

  28 days

• Days until discharge

  28 days

Other Outcomes (9)

• Mortality

  28 days

• Discharge fro ICU

  90 days

• End of mechanical ventilation

  90 days

Study Arms (2)

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.

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.

Procedure: Non-sedation for intubated, mechanically ventilated patients

Interventions

Non-sedation for intubated, mechanically ventilated patients PROCEDURE

Non-sedation

Controlgroup, sedation with daily wake-up trial PROCEDURE

Sedation with daily wake-up trial

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Endotracheally intubated Expected time on ventilator \> 24 h. Age ≥ 18 years Informed consent

You may not qualify if:

• 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

Sponsors & Collaborators

• Palle Toft: lead
• The Danish Medical Research Council: collaborator
• Aase and Ejnar Danielsens Foundation: collaborator

Study Sites (8)

Sydvestjysk Sygehus

Esbjerg, Region Syddanmark, 6700, Denmark

Location

AArhus university Hospital, Noerrebrogade

Aarhus, 8000, Denmark

Location

Kolding Hospital

Kolding, 6000, Denmark

Location

Odense University Hospital

Odense, 5000, Denmark

Location

Svendborg Hospital

Svendborg, 5600, Denmark

Location

University Hospital of North Norway

Tromsø, 9038, Norway

Location

Vestfold Hospital

Tønsberg, 3103, Norway

Location

Linkjøbing University Hospital

Linköping, Sweden

Location

Related Publications (3)

• 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.

  PMID: 20116842 BACKGROUND

• 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.

  PMID: 33677695 DERIVED

• 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.

  PMID: 32068366 DERIVED

MeSH Terms

Conditions

Critical Illness; Respiratory Aspiration

Condition Hierarchy (Ancestors)

Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Respiration Disorders; Respiratory Tract Diseases

Study Officials

• Palle Toft, Professor

  Odense University Hospital

  STUDY CHAIR

• Hanne Tanghus Olsen, MD

  Svendborg Hospital

  PRINCIPAL INVESTIGATOR

• Helene K Nedergaard, MD

  Kolding Sygehus

  PRINCIPAL INVESTIGATOR

• Thomas Stroem, Postdoc

  Odense University Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: October 18, 2013
• First Posted: October 23, 2013
• Study Start: January 1, 2014
• Primary Completion: April 1, 2018
• Study Completion: April 1, 2018
• Last Updated: April 6, 2018

Record last verified: 2018-04

Locations

DK (5); SE (1); NO (2)