Early Goal-Directed Sedation Compared With Standard Care in Mechanically Ventilated Critically Ill Patients

NCT ID: NCT01728558

Last Updated: 2019-08-20

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE3

Total Enrollment

4000 participants

Study Classification

INTERVENTIONAL

Study Start Date

2013-11-30

Study Completion Date

2018-12-31

Brief Summary

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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

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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.

Conditions

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Critical Illness and Mechanical Ventilation

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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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.

Group Type OTHER

Early goal Directed Sedation

Intervention Type OTHER

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.

Group Type ACTIVE_COMPARATOR

Standard care sedation

Intervention Type OTHER

Interventions

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Early goal Directed Sedation

Intervention Type OTHER

Standard care sedation

Intervention Type OTHER

Eligibility Criteria

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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.
Minimum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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National Health and Medical Research Council, Australia

OTHER

Sponsor Role collaborator

Australian and New Zealand Intensive Care Research Centre

OTHER

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Yahya Shehabi, MD, FCICM, FANZCA, EMBA

Role: STUDY_CHAIR

University New South Wales, Prince of Wales Hospital, ANZIC-RC

Rinaldo Bellomo

Role: PRINCIPAL_INVESTIGATOR

ANZIC-RC & Austin Hospital

Steve A. R Webb

Role: PRINCIPAL_INVESTIGATOR

ANZIC-RC & Royal Perth Hospital

Michael C Reade

Role: PRINCIPAL_INVESTIGATOR

ANZIC-RC, Royal Brisbane & Women's Hospital, Department of Military Medicine and Surgery,

Belinda D Howe

Role: PRINCIPAL_INVESTIGATOR

ANZIC-RC

Ian M Seppelt

Role: PRINCIPAL_INVESTIGATOR

ANZIC-RC, Nepean Hospital

Colin McArthur

Role: PRINCIPAL_INVESTIGATOR

ANZIC-RC, Auckland Hospital

Simon Erikson

Role: PRINCIPAL_INVESTIGATOR

ANZIC-RC,

Lynne Murray

Role: PRINCIPAL_INVESTIGATOR

ANZIC-RC

Suhaini Kadiman

Role: PRINCIPAL_INVESTIGATOR

Institut Jantung Negara, Malaysia

Jukka Takala

Role: PRINCIPAL_INVESTIGATOR

Inselspital, Bern, Switzerland

Yaseen Arabi

Role: PRINCIPAL_INVESTIGATOR

King Abdulaziz Medical Centre, KSA

Matthew P Wise

Role: PRINCIPAL_INVESTIGATOR

University Hospital of Wales, UK

Locations

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Albury Hospital

Albury, New South Wales, Australia

Site Status

Blacktown Hospital

Blacktown, New South Wales, Australia

Site Status

St Vincent's Hospital Sydney

Darlinghurst, New South Wales, Australia

Site Status

Gosford Hospital

Gosford, New South Wales, Australia

Site Status

Hornsby Ku-ring-gai Hospital

Hornsby, New South Wales, Australia

Site Status

Nepean Hospital

Penrith, New South Wales, Australia

Site Status

Royal North Shore Hospital

St Leonards, New South Wales, Australia

Site Status

Prince of Wales Hospital

Sydney, New South Wales, Australia

Site Status

Westmead Hospital

Westmead, New South Wales, Australia

Site Status

Royal Darwin Hospital

Tiwi, Northern Territory, Australia

Site Status

Sunshine Coast Hospital (Nambour Hospital)

Buderim, Queensland, Australia

Site Status

Royal Brisbane and Women's hospital

Herston, Queensland, Australia

Site Status

Redcliffe Hospital

Redcliffe, Queensland, Australia

Site Status

Gold Coast Hospital & Health Service

Southport, Queensland, Australia

Site Status

Toowoomba Hospital

Toowoomba, Queensland, Australia

Site Status

Princess Alexandra Hospital

Woolloongabba, Queensland, Australia

Site Status

Lyell McEwan Hospital

Elizabeth Vale, South Australia, Australia

Site Status

Royal Hobart Hospital

Hobart, Tasmania, Australia

Site Status

Launceston General Hospital

Launceston, Tasmania, Australia

Site Status

Bendigo Hospital

Bendigo, Victoria, Australia

Site Status

Dandenong Hospital

Dandenong, Victoria, Australia

Site Status

Northern Hospital

Epping, Victoria, Australia

Site Status

Geelong Hospital

Geelong, Victoria, Australia

Site Status

Austin Hospital

Heidelberg, Victoria, Australia

Site Status

Royal Melbourne Hospital

Melbourne, Victoria, Australia

Site Status

Monash Medical Centre

Melbourne, Victoria, Australia

Site Status

Central Gippsland Health Service

Sale, Victoria, Australia

Site Status

Knox Private Hospital

Wantirna, Victoria, Australia

Site Status

St John Of God, Subiaco

Perth, Western Australia, Australia

Site Status

St Vincent's University Hospital

Dublin, Dublin 4, Ireland

Site Status

St James's University Hospital

Dublin, Dublin 8, Ireland

Site Status

Ospedale San Raffaele

Milan, , Italy

Site Status

Raja Perempuan Zainab II Hospital

Kota Bharu, Kelantan, Malaysia

Site Status

Universiti Sains Malaysia Hospital

Kota Bharu, Kelantan, Malaysia

Site Status

Penang General Hospital

George Town, Pulau Pinang, Malaysia

Site Status

Queen Elizabeth Hospital

Kota Kinabalu, Sabah, Malaysia

Site Status

Sarawak General Hospital

Kuching, Sarawak, Malaysia

Site Status

Institut Jantung Negara

Kuala Lumpur, , Malaysia

Site Status

Kuala Lumpar General Hospital

Kuala Lumpur, , Malaysia

Site Status

University Malaya Medical Center

Kuala Lumpur, , Malaysia

Site Status

Melaka General Hospital

Malacca, , Malaysia

Site Status

Auckland City Hospital CVICU

Grafton, Auckland, New Zealand

Site Status

Middlemore Hospital

Otahuhu, Auckland, New Zealand

Site Status

Christchurch Hospital

Addington, Christchurch, New Zealand

Site Status

North Shore Hospital

Takapuna, North Shore City, New Zealand

Site Status

Wellington Hospital

Newtown, Wellington Region, New Zealand

Site Status

Auckland City hospital

Auckland, , New Zealand

Site Status

Dunedin Hospital

Dunedin, , New Zealand

Site Status

Rotorua Hospital

Rotorua, , New Zealand

Site Status

Prince Sultan Military Medical City

Riyadh, , Saudi Arabia

Site Status

King Saud Medical City

Riyadh, , Saudi Arabia

Site Status

King Abdulaziz Medical City

Riyadh, , Saudi Arabia

Site Status

Inselspital University Hospital Bern

Bern, , Switzerland

Site Status

Kings College Hospital

Brixton, London, United Kingdom

Site Status

Freeman Hospital

High Heaton, Newcastle Upon Tyne, United Kingdom

Site Status

Queen Elizabeth Hospital King's Lynn

Kings Lynn, Norfolk, United Kingdom

Site Status

Derriford Hospital

Crownhill, Plymouth, United Kingdom

Site Status

University Hospital of North Tees

Hardwick, Stockton-on-Tees, United Kingdom

Site Status

Queen Elizabeth Hospital, Birmingham

Birmingham, , United Kingdom

Site Status

Royal Bournemouth Hospital

Bournemouth, , United Kingdom

Site Status

University Hospitals Bristol

Bristol, , United Kingdom

Site Status

University Hospital of Wales

Cardiff, , United Kingdom

Site Status

University Hospital of Coventry and Warwick

Coventry, , United Kingdom

Site Status

Dorset County Hospital

Dorchester, , United Kingdom

Site Status

Royal Infirmary of Edinburgh

Edinburgh, , United Kingdom

Site Status

Western General Hospital

Edinburgh, , United Kingdom

Site Status

Royal Liverpool University Hospital

Liverpool, , United Kingdom

Site Status

St Thomas Hospital

London, , United Kingdom

Site Status

St George's Hospital

London, , United Kingdom

Site Status

University College Hospital

London, , United Kingdom

Site Status

Altnagelvin Hospital

Londonderry, , United Kingdom

Site Status

Royal Victoria Infirmary

Newcastle upon Tyne, , United Kingdom

Site Status

Princess Royal University Hospital

Orpington, , United Kingdom

Site Status

Royal Berkshire Hospital

Reading, , United Kingdom

Site Status

Countries

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Australia Ireland Italy Malaysia New Zealand Saudi Arabia Switzerland United Kingdom

References

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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.

Reference Type BACKGROUND
PMID: 22859526 (View on PubMed)

Shehabi Y, Serpa Neto A, Bellomo R, Howe BD, Arabi YM, Bailey M, Bass FE, Bin Kadiman S, McArthur CJ, Reade MC, Seppelt IM, Takala J, Wise MP, Webb SA; SPICE III Study Investigators. Dexmedetomidine and Propofol Sedation in Critically Ill Patients and Dose-associated 90-Day Mortality: A Secondary Cohort Analysis of a Randomized Controlled Trial (SPICE III). Am J Respir Crit Care Med. 2023 Apr 1;207(7):876-886. doi: 10.1164/rccm.202206-1208OC.

Reference Type DERIVED
PMID: 36215171 (View on PubMed)

Cioccari L, Luethi N, Bailey M, Shehabi Y, Howe B, Messmer AS, Proimos HK, Peck L, Young H, Eastwood GM, Merz TM, Takala J, Jakob SM, Bellomo R; ANZICS Clinical Trials Group and the SPICE III Investigators. The effect of dexmedetomidine on vasopressor requirements in patients with septic shock: a subgroup analysis of the Sedation Practice in Intensive Care Evaluation [SPICE III] Trial. Crit Care. 2020 Jul 16;24(1):441. doi: 10.1186/s13054-020-03115-x.

Reference Type DERIVED
PMID: 32678054 (View on PubMed)

Shehabi Y, Howe BD, Bellomo R, Arabi YM, Bailey M, Bass FE, Bin Kadiman S, McArthur CJ, Murray L, Reade MC, Seppelt IM, Takala J, Wise MP, Webb SA; ANZICS Clinical Trials Group and the SPICE III Investigators. Early Sedation with Dexmedetomidine in Critically Ill Patients. N Engl J Med. 2019 Jun 27;380(26):2506-2517. doi: 10.1056/NEJMoa1904710. Epub 2019 May 19.

Reference Type DERIVED
PMID: 31112380 (View on PubMed)

Moore JPR, Anstey C, Murray L, Fraser JF, Singer M. Allostasis and sedation practices in intensive care evaluation: an observational pilot study. Intensive Care Med Exp. 2018 Jun 20;6(1):13. doi: 10.1186/s40635-018-0179-0.

Reference Type DERIVED
PMID: 29926288 (View on PubMed)

Other Identifiers

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ANZIC-RC/YS003

Identifier Type: -

Identifier Source: org_study_id

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