The Use of sedative drugs in intensive care is widespread. A cohort study conducted in Australia and New Zealand in 2010 revealed a high prevalence of deep sedation within the first 48 hours of mechanical ventilation which was independently linked to prolonged ventilation, hospital and 180 days mortality. Clinical practice is moving towards the use of lighter levels of sedation. Recent RCTs in Europe (JAMA 2012) and previous RCTs (JAMA 2009) supports growing evidence that dexmedetomidine facilitates rousable sedation, shortens ventilation time and attenuates delirium when compared to midazolam and propofol.

The investigators confirmed in a pilot study the feasibility, efficacy and safety of a process of care known as Early Goal Directed Sedation (EGDS) that delivers:

1. Early randomization after intubation or arrival in the ICU (intubated).
2. Early Adequate analgesia after randomization.
3. Goal directed sedation titrated to achieve light sedation.
4. Dexmedetomidine based algorithm as the primary sedative agent with avoidance of benzodiazepines.

The aim of this study is to assess the effectiveness of Early Goal Directed Sedation when compared to standard care sedation in critically ill patients.

The study hypothesis is that Early Goal-Directed Sedation (EGDS), compared to standard care sedation, reduces 90-day all-cause mortality in critically ill patients who require mechanical ventilation.

This is a large-scale study into the effectiveness of a novel approach for sedation in ventilated critically ill patients. The primary aim of this study is to determine whether Early Goal Directed Sedation therapy, compared to standard care sedation, reduces 90-day mortality in critically ill patients ventilated > 24 hrs.

The study will be a randomized, unblinded, controlled trial conducted in approximately 35-50 intensive care units (ICUs) and will recruit 4000 mechanically ventilated patients (life support) who are expected to remain on the ventilator > 24 hours AND require immediate ongoing sedative medication for comfort, safety, and to facilitate the delivery of life support measures, including mechanical ventilation.

Patients with primary brain injury or prolonged weakness are excluded. Participants will be randomized into one of 2 study groups. All patients will receive adequate analgesia at randomization at the discretion of treating clinician. All randomized patients will have Light sedation as the default target unless otherwise clinically indicated. The intervention group will receive EGDS with dexmedetomidine as the primary sedative agent to achieve light sedation, with the addition of propofol as required. The use of benzodiazepines in the intervention group is not allowed, with the exception of specific, defined circumstances.

The control group will have sedation according to usual practice as chosen by the treating clinician. The use of dexmedetomidine is not allowed, with the exception of specific, defined circumstances.

Deidentified data will be collected and will include; Baseline demographic information; Doses of all sedative, analgesic and other related medications; Pain, sedation and delirium scores and major treatments such as ventilation time, tracheostomy and dialysis. Patients surviving to hospital discharge will be contacted by phone to determine independent survival status at 90 days and again at 180 days plus Health Related Quality of Life and cognitive function assessment.

Inclusion Criteria:

• Patient has been intubated and is receiving mechanical ventilation
• The treating clinician expects that the patient will remain intubated until the day after tomorrow (unlikely to be extubated the following day).
• The patient requires immediate ongoing sedative medication for comfort, safety, and to facilitate the delivery of life support measures.

Exclusion Criteria:

• Age less than 18 years
• Patient is pregnant and/or lactating
• Has been intubated (excluding time spent intubated within an operating theatre or transport) for greater than 12 hours in an intensive care unit.
• Proven or suspected acute primary brain lesion such as traumatic brain injury, intracranial haemorrhage, stroke, or hypoxic brain injury.
• Proven or suspected spinal cord injury or other pathology that may result in permanent or prolonged weakness.
• Admission as a consequence of a suspected or proven drug overdose or burns.
• Administration of ongoing neuromuscular blockade.
• A mean arterial blood (MAP) pressure that is less than 50 mmHg despite adequate resuscitation and vasopressor therapy at time of randomisation
• Heart rate less than 55 beats per minute unless the patient is being treated with a beta-blocker or a high grade atrio-ventricular block in the absence of a functioning pacemaker.
• Known sensitivity to any of the study medications or the constituents of propofol (egg, soya or peanut protein)
• Acute fulminant hepatic failure
• Patient has been receiving full time residential nursing care.
• Death is deemed to be imminent or inevitable during this admission and either the attending physician, patient or substitute decision maker is not committed to active treatment.
• Patient has an underlying disease that makes survival to 90 days unlikely
• Patient has been previously enrolled in the SPICE study.