Early Goal-Directed Sedation Compared With Standard Care in Mechanically Ventilated Critically Ill Patients (SPICE III RCT)

• Sponsor: Australian and New Zealand Intensive Care Research Centre
• Collaborator: National Health and Medical Research Council, Australia
• Information provided by (Responsible Party): Australian and New Zealand Intensive Care Research Centre

Tracking Information

• First Submitted Date: November 4, 2012
• First Posted Date: November 20, 2012
• Last Update Posted Date: February 9, 2018
• Study Start Date: November 2013
• Estimated Primary Completion Date: May 2018 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: November 13, 2012): Mortality [ Time Frame: Day 90 post randomisation ]
• Original Primary Outcome Measures: Same as current
• Change History: Complete list of historical versions of study NCT01728558 on ClinicalTrials.gov Archive Site

Current Secondary Outcome Measures (submitted: November 2, 2013)

• Ventilation free days [ Time Frame: at 28 days following randomisation ]
• Proportion of RASS measurements in target range [ Time Frame: up to day 28 ]
• Incidence and duration of delirium measured by delirium free days [ Time Frame: up to 28 days ]
• Length of ICU stay [ Time Frame: up to 180 days ]
• Proportion of patients who receive a tracheostomy Proportion of patients who require: re-intubation, physical restraints,or unplanned extubation, [ Time Frame: up to day 28 ]
• Cumulative dose of midazolam, propofol, dexmedetomidine, fentanyl, and morphine [ Time Frame: up to 28 days ]
• Duration of treatment with midazolam, propofol, dexmedetomidine, fentanyl, and morphine [ Time Frame: up to 28 days ]
• Mortality at hospital discharge [ Time Frame: at hospital discharge up to 180 days ]
• Length of hospital stay [ Time Frame: up to 180 days ]
• Readmission to ICU [ Time Frame: at 90 days ]
• EQ-5D questionnaire [ Time Frame: at 180 days ]
• Cognitive function [ Time Frame: at 180 days ]
• Mortality at ICU discharge [ Time Frame: up to 180 days ]
• Full time institutional dependency at 180 days [ Time Frame: up to 180 days ]
• Discharge destination [ Time Frame: up to 180 days ]

Original Secondary Outcome Measures (submitted: November 13, 2012)

• Ventilation free days [ Time Frame: at 28 days following randomisation ]
• Proportion of RASS measurements in target range [ Time Frame: up to day 28 ]
• Incidence and duration of delirium measured by delirium free days [ Time Frame: up to 28 days ]
• Length of ICU stay [ Time Frame: up to 180 days ]
• Proportion of patients who receive a tracheostomy Proportion of patients who require: re-intubation, physical restraints,or unplanned extubation, [ Time Frame: up to day 28 ]
• Cumulative dose of midazolam, propofol, dexmedetomidine, fentanyl, and morphine [ Time Frame: up to 28 days ]
• Duration of treatment with midazolam, propofol, dexmedetomidine, fentanyl, and morphine [ Time Frame: up to 28 days ]
• Mortality at hospital discharge [ Time Frame: at hospital discharge up to 180 days ]
• Length of hospital stay [ Time Frame: up to 180 days ]
• Readmission to ICU [ Time Frame: at 90 days ]
• EQ-5D questionnaire [ Time Frame: at 180 days ]
• Cognitive function [ Time Frame: at 180 days ]
• Full time institutional dependency at 180 days [ Time Frame: at 180 days ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Early Goal-Directed Sedation Compared With Standard Care in Mechanically Ventilated Critically Ill Patients
• Official Title: Early Goal-Directed Sedation Compared With Standard Care in Mechanically Ventilated Critically Ill Patients: a Prospective Multicentre Randomised Controlled Trial

Brief Summary

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.

Detailed Description

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.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Critical Illness and Mechanical Ventilation

Intervention

• Other: Early goal Directed Sedation
• Other: Standard care sedation

Study Arms

• Early Goal Directed Sedation

  Early Goal Directed Sedation process of care involves:

  1. Early delivery of proposed intervention, shortly after initiating mechanical ventilation;
  2. Effective analgesia provided simultaneously and early (analgesia first).
  3. Regular and frequent assessment of patient wakefulness/sedative state;
  4. Avoidance of benzodiazepines and minimisation of use of propofol;
  5. Reduced overall sedation depth with targeted light sedation; Patients randomised to the EGDS arm will receive a sedative infusion of Dexmedetomidine withor without minimal propofol in order to maintain a RASS of -2 to +1.

  Dexmedetomidine infusion will be continued until sedation is no longer clinically indicated up to a maximum of 28 days after enrolment.

  Intervention: Other: Early goal Directed Sedation
• Active Comparator: Standard care Sedation Arm
  Patients randomised to the standard care sedation arm will receive process of care sedation directed by the treating clinician. Based on the information from our observational study and the EGDS Pilot trial, most patients in this group are likely to receive midazolam and /or propofol. These agents will be infused to achieve the default target of Light sedation (RASS -2 to +1) whenever clinically appropriate and as specified by the treating clinician. The use remifentanil or dexmedetomidine for initial and maintenance sedation will be precluded.
  Intervention: Other: Standard care sedation

• Publications *: Shehabi Y, Bellomo R, Reade MC, Bailey M, Bass F, Howe B, McArthur C, Seppelt IM, Webb S, Weisbrodt L; Sedation Practice in Intensive Care Evaluation (SPICE) Study Investigators; ANZICS Clinical Trials Group. Early intensive care sedation predicts long-term mortality in ventilated critically ill patients. Am J Respir Crit Care Med. 2012 Oct 15;186(8):724-31. doi: 10.1164/rccm.201203-0522OC. Epub 2012 Aug 2.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: November 13, 2012): 4000
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: August 2018
• Estimated Primary Completion Date: May 2018 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, New Zealand

Administrative Information

• NCT Number: NCT01728558
• Other Study ID Numbers: ANZIC-RC/YS003
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Australian and New Zealand Intensive Care Research Centre
• Study Sponsor: Australian and New Zealand Intensive Care Research Centre
• Collaborators: National Health and Medical Research Council, Australia

Investigators

• Study Chair: Yahya Shehabi, MD, FCICM, FANZCA, EMBA; University New South Wales, Prince of Wales Hospital, ANZIC-RC
• Principal Investigator: Rinaldo Bellomo; ANZIC-RC & Austin Hospital
• Principal Investigator: Steve A. R Webb; ANZIC-RC & Royal Perth Hospital
• Principal Investigator: Michael C Reade; ANZIC-RC, Royal Brisbane & Women's Hospital, Department of Military Medicine and Surgery,
• Principal Investigator: Belinda D Howe; ANZIC-RC
• Principal Investigator: Ian M Seppelt; ANZIC-RC, Nepean Hospital
• Principal Investigator: Colin McArthur; ANZIC-RC, Auckland Hospital
• Principal Investigator: Simon Erikson; ANZIC-RC,
• Principal Investigator: Lynne Murray; ANZIC-RC
• Principal Investigator: Suhaini Kadiman; Institut Jantung Negara, Malaysia
• Principal Investigator: Jukka Takala; Inselspital, Bern, Switzerland
• Principal Investigator: Yaseen Arabi; King Abdulaziz Medical Centre, KSA
• Principal Investigator: Matthew P Wise; University Hospital of Wales, UK

• PRS Account: Australian and New Zealand Intensive Care Research Centre
• Verification Date: February 2018