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

• ClinicalTrials.gov Identifier: NCT01967680
• Recruitment Status: Completed
• First Posted: October 23, 2013
• Last Update Posted: April 6, 2018
• Sponsor: Palle Toft
• Collaborators: The Danish Medical Research Council; Aase and Ejnar Danielsens Foundation
• Information provided by (Responsible Party): Palle Toft, Odense University Hospital

Study Description

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%).

Condition or disease	Intervention/treatment	Phase
Critical Illness; Respiration, Artificial	Procedure: Non-sedation for intubated, mechanically ventilated patients; Procedure: Controlgroup, sedation with daily wake-up trial	Not Applicable

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 700 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Outcomes Assessor)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: January 2014
• Actual Primary Completion Date: April 2018
• Actual Study Completion Date: April 2018

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: 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.	Procedure: Controlgroup, sedation with daily wake-up trial
Experimental: 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.	Procedure: Non-sedation for intubated, mechanically ventilated patients

Outcome Measures

Primary Outcome Measures :

1. Mortality [ Time Frame: 90 days ]
   All cause mortality at 90 days after randomization

Secondary Outcome Measures :

1. Days until death [ Time Frame: 1 year ]
   Days until death throughout the total observation period
2. Cardiovascular event [ Time Frame: 90 days ]
   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.
3. Coma and deliriumfree days [ Time Frame: 28 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
4. RIFLE-score [ Time Frame: 28 days ]

   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)

5. Days until discharge [ Time Frame: 28 days ]
   Days until discharge from ICU (within 28 days from randomization).
6. Days until the participant is without mechanical ventilation [ Time Frame: 28 days ]
   Days until the participant is without mechanical ventilation (within 28 days from randomization).

Other Outcome Measures:

1. Mortality [ Time Frame: 28 days ]
   All cause mortality at 28 days after randomisation.
2. Discharge fro ICU [ Time Frame: 90 days ]
   Days until discharge from the intensive care unit (within 90 days from randomization)
3. End of mechanical ventilation [ Time Frame: 90 days ]
   Days until the participant is without without mechanical ventilation (within 90 days from randomization)
4. Discharge from hospital [ Time Frame: 90 days ]
   Days until discharge from the hospital (within 90 days from randomization).
5. Number of organ failures [ Time Frame: ICU-admission ]
   Organ failure when the patient is discharged from the ICU.
6. Accidental extubation [ Time Frame: ICU-admission ]
   Number of accidental extubations requiring re-intubation within 1 hour
7. Accidental removal of cental venous line [ Time Frame: ICU-admission ]
   Number of accidental removals of central venous lines, requiring re-insertion within 4 hours
8. Oxygenation [ Time Frame: During ventilator treatment ]

   Worst oxygenation status measured by

   • highest fraction of oxygen in inspired air (FiO2)
   • worst paO2/FiO2-ratio registered daily
9. 1-year survival [ Time Frame: 1 year from randomisation ]
   Number of patients alive 1 year after randomisation in each group

Eligibility Criteria

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

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

Contacts and Locations

Locations

Denmark

Sydvestjysk Sygehus

Esbjerg, Region Of Southern Denmark, Denmark, 6700

AArhus university Hospital, Noerrebrogade

AArhus, Denmark, 8000

Kolding Hospital

Kolding, Denmark, 6000

Odense University Hospital

Odense, Denmark, 5000

Svendborg Hospital

Svendborg, Denmark, 5600

Norway

Vestfold Hospital

Tonsberg, Norway, 3103

University Hospital of North Norway

Tromsoe, Norway, 9038

Sweden

Linkjøbing University Hospital

Linkoping, Sweden

Sponsors and Collaborators

Palle Toft

The Danish Medical Research Council

Aase and Ejnar Danielsens Foundation

Investigators

• Study Chair: Palle Toft, Professor; Odense University Hospital
• Principal Investigator: Hanne Tanghus Olsen, MD; Svendborg Hospital
• Principal Investigator: Helene K Nedergaard, MD; Kolding Sygehus
• Principal Investigator: Thomas Stroem, Postdoc; Odense University Hospital

More Information

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.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

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.

• Responsible Party: Palle Toft, Professor, Odense University Hospital
• ClinicalTrials.gov Identifier: NCT01967680
• Other Study ID Numbers: S-20130025
• First Posted: October 23, 2013
• Last Update Posted: April 6, 2018
• Last Verified: April 2018

Additional relevant MeSH terms:

Critical Illness; Disease Attributes; Pathologic Processes