Critical Illness, Respiration, Artificial
Conditions
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%).
Interventions
PROCEDURENon-sedation for intubated, mechanically ventilated patients
PROCEDUREControlgroup, sedation with daily wake-up trial
Sponsors
The Danish Medical Research Council
Aase and Ejnar Danielsens Foundation
Palle Toft
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mortality | 90 days | All cause mortality at 90 days after randomization |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Days until the participant is without mechanical ventilation | 28 days | Days until the participant is without mechanical ventilation (within 28 days from randomization). |
| Days until death | 1 year | Days until death throughout the total observation period |
| Cardiovascular event | 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. |
| Coma and deliriumfree days | 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 |
| RIFLE-score | 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) |
| Days until discharge | 28 days | Days until discharge from ICU (within 28 days from randomization). |
Other
| Measure | Time frame | Description |
|---|---|---|
| Accidental removal of cental venous line | ICU-admission | Number of accidental removals of central venous lines, requiring re-insertion within 4 hours |
| Oxygenation | During ventilator treatment | Worst oxygenation status measured by * highest fraction of oxygen in inspired air (FiO2) * worst paO2/FiO2-ratio registered daily |
| 1-year survival | 1 year from randomisation | Number of patients alive 1 year after randomisation in each group |
| Mortality | 28 days | All cause mortality at 28 days after randomisation. |
| Discharge fro ICU | 90 days | Days until discharge from the intensive care unit (within 90 days from randomization) |
| End of mechanical ventilation | 90 days | Days until the participant is without without mechanical ventilation (within 90 days from randomization) |
| Discharge from hospital | 90 days | Days until discharge from the hospital (within 90 days from randomization). |
| Number of organ failures | ICU-admission | Organ failure when the patient is discharged from the ICU. |
| Accidental extubation | ICU-admission | Number of accidental extubations requiring re-intubation within 1 hour |
Countries
Denmark, Norway, Sweden
Outcome results
None listed