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

Study Overview
=================
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%).

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

Conditions
-----------------
Critical Illness, Respiration, Artificial

Intervention / Treatment
-----------------
* Procedure: Non-sedation for intubated, mechanically ventilated patients
* Procedure: Controlgroup, sedation with daily wake-up trial


Participation Criteria
=================
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Sedation with daily wake-up trial<br>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<br> <br> |
| Experimental: Non-sedation<br>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<br> <br> |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mortality | All cause mortality at 90 days after randomization | 90 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Days until death | Days until death throughout the total observation period | 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. | 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 | 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) | 28 days | 
| Days until discharge | Days until discharge from ICU (within 28 days from randomization). | 28 days | 
| Days until the participant is without mechanical ventilation | Days until the participant is without mechanical ventilation (within 28 days from randomization). | 28 days |