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Critical Illness and Mechanical VentilationPhase 3SPICE III RCTNCT01728558

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

A Phase 3 study testing Early goal Directed Sedation in people with Critical Illness and Mechanical Ventilation, run by Australian and New Zealand Intensive Care Research Centre at 74 sites in 8 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Early goal Directed Sedation
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
4,000 participants
Where
74 sitesin 8 countries
Study dates
Nov 2013to Dec 2018
Phase
Phase 3
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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.

Who cannot join

  • 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.
Show all 15Show fewer
  • 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.

Trial locations and contacts

74 sites in 8 countries.

74 sites in 8 countries

Australia29 sites

  • Albury Hospital

    Albury, New South Wales, 2640

  • Bendigo Hospital

    Bendigo, Victoria, 3550

  • Blacktown Hospital

    Blacktown, New South Wales, 2148

  • Sunshine Coast Hospital (Nambour Hospital)

    Buderim, Queensland, 4556

  • Dandenong Hospital

    Dandenong, Victoria, 3175

  • St Vincent's Hospital Sydney

    Darlinghurst, New South Wales, 2010

  • Lyell McEwan Hospital

    Elizabeth Vale, South Australia, 5112

  • Northern Hospital

    Epping, Victoria, 3076

  • Geelong Hospital

    Geelong, Victoria, 3220

  • Gosford Hospital

    Gosford, New South Wales, 2250

  • Austin Hospital

    Heidelberg, Victoria, 3084

  • Royal Brisbane and Women's hospital

    Herston, Queensland, 4029

  • Royal Hobart Hospital

    Hobart, Tasmania, 7000

  • Hornsby Ku-ring-gai Hospital

    Hornsby, New South Wales, 2077

  • Launceston General Hospital

    Launceston, Tasmania, 7250

  • Royal Melbourne Hospital

    Melbourne, Victoria, 3050

  • Monash Medical Centre

    Melbourne, Victoria, 3168

  • Nepean Hospital

    Penrith, New South Wales, 2750

  • St John Of God, Subiaco

    Perth, Western Australia, 6008

  • Redcliffe Hospital

    Redcliffe, Queensland, 4020

  • Central Gippsland Health Service

    Sale, Victoria, 3850

  • Gold Coast Hospital & Health Service

    Southport, Queensland, 4215

  • Royal North Shore Hospital

    St Leonards, New South Wales, 2065

  • Prince of Wales Hospital

    Sydney, New South Wales, 2031

  • Royal Darwin Hospital

    Tiwi, Northern Territory, 0811

  • Toowoomba Hospital

    Toowoomba, Queensland, 4350

  • Knox Private Hospital

    Wantirna, Victoria, 3152

  • Westmead Hospital

    Westmead, New South Wales, 2145

  • Princess Alexandra Hospital

    Woolloongabba, Queensland, 4102

Other trials in Australia

United Kingdom21 sites

  • Queen Elizabeth Hospital, Birmingham

    Birmingham, B15 2TH

  • Royal Bournemouth Hospital

    Bournemouth, BH7 7DW

  • University Hospitals Bristol

    Bristol, BS1 3NU

  • Kings College Hospital

    Brixton, London, SE5 9RS

  • University Hospital of Wales

    Cardiff, CF14 4XW

  • University Hospital of Coventry and Warwick

    Coventry, CV2 2DX

  • Derriford Hospital

    Crownhill, Plymouth, PL6 8DH

  • Dorset County Hospital

    Dorchester, DT1 2JY

  • Royal Infirmary of Edinburgh

    Edinburgh, EH16 4SA

  • Western General Hospital

    Edinburgh, EH4 2XU

  • University Hospital of North Tees

    Hardwick, Stockton-on-Tees, TS19 8PE

  • Freeman Hospital

    High Heaton, Newcastle Upon Tyne, NE7 7DN

  • Queen Elizabeth Hospital King's Lynn

    Kings Lynn, Norfolk, PE30 4ET

  • Royal Liverpool University Hospital

    Liverpool, L7 8XP

  • St Thomas Hospital

    London, SE1 7EH

  • St George's Hospital

    London, SW17 0QT

  • University College Hospital

    London, WC1E 6BT

  • Altnagelvin Hospital

    Londonderry, BT47 6SB

  • Royal Victoria Infirmary

    Newcastle upon Tyne, NE1 4LP

  • Princess Royal University Hospital

    Orpington, BR6 8ND

  • Royal Berkshire Hospital

    Reading, RG1 5LE

Other trials in United Kingdom

Malaysia9 sites

  • Penang General Hospital

    George Town, Pulau Pinang, 10990

  • Raja Perempuan Zainab II Hospital

    Kota Bharu, Kelantan, 15200

  • Universiti Sains Malaysia Hospital

    Kota Bharu, Kelantan, 16150

  • Queen Elizabeth Hospital

    Kota Kinabalu, Sabah, 88200

  • Institut Jantung Negara

    Kuala Lumpur, 50400

  • Kuala Lumpar General Hospital

    Kuala Lumpur, 50586

  • University Malaya Medical Center

    Kuala Lumpur, 50603

  • Sarawak General Hospital

    Kuching, Sarawak, 93586

  • Melaka General Hospital

    Malacca, 75400

Other trials in Malaysia

New Zealand8 sites

  • Christchurch Hospital

    Addington, Christchurch, 8011

  • Auckland City hospital

    Auckland, 1023

  • Dunedin Hospital

    Dunedin, 9016

  • Auckland City Hospital CVICU

    Grafton, Auckland, 1023

  • Wellington Hospital

    Newtown, Wellington Region, 6021

  • Middlemore Hospital

    Otahuhu, Auckland, 1640

  • Rotorua Hospital

    Rotorua, 3010

  • North Shore Hospital

    Takapuna, North Shore City, 0622

Other trials in New Zealand

Saudi Arabia3 sites

  • Prince Sultan Military Medical City

    Riyadh, 12233

  • King Saud Medical City

    Riyadh, 12746

  • King Abdulaziz Medical City

    Riyadh, 14611

Other trials in Saudi Arabia

Ireland2 sites

  • St Vincent's University Hospital

    Dublin, Dublin 4

  • St James's University Hospital

    Dublin, Dublin 8

Other trials in Ireland

Italy1 site

  • Ospedale San Raffaele

    Milan, 20132

Other trials in Italy

Switzerland1 site

  • Inselspital University Hospital Bern

    Bern, 3010

Other trials in Switzerland

About this study

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

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:

Read more
  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.

Read the 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.

Being tested
Early goal Directed Sedation, Standard care sedation
Keywords
Sedation, Delirium, Goal Directed, Dexmedetomidine, Mortality, Mechanical ventilation, Intensive care, Critically Ill
Medical subject headings
Critical Illness, Delirium

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Early goal Directed SedationOther

  • Standard care sedationOther

Study groups in NCT01728558
Study groupRoleWhat they receive
Early Goal Directed SedationOtherEarly 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.
Receives: Other: Early goal Directed Sedation
Standard care Sedation ArmActive comparatorPatients 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.
Receives: Other: Standard care sedation

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Mortality

    Measured: Day 90 post randomisation

Secondary outcomes (15)

  1. Ventilation free days

    Measured: at 28 days following randomisation

  2. Proportion of RASS measurements in target range

    Measured: up to day 28

  3. Incidence and duration of delirium measured by delirium free days

    Measured: up to 28 days

  4. Length of ICU stay

    Measured: up to 180 days

  5. Proportion of patients who receive a tracheostomy Proportion of patients who require: re-intubation, physical restraints,or unplanned extubation,

    Measured: up to day 28

  6. Cumulative dose of midazolam, propofol, dexmedetomidine, fentanyl, and morphine

    Measured: up to 28 days

  7. Duration of treatment with midazolam, propofol, dexmedetomidine, fentanyl, and morphine

    Measured: up to 28 days

  8. Mortality at hospital discharge

    Measured: at hospital discharge up to 180 days

  9. Length of hospital stay

    Measured: up to 180 days

  10. Readmission to ICU

    Measured: at 90 days

  11. EQ-5D questionnaire

    Measured: at 180 days

  12. Cognitive function

    Measured: at 180 days

  13. Mortality at ICU discharge

    Measured: up to 180 days

  14. Full time institutional dependency at 180 days

    Measured: up to 180 days

  15. Discharge destination

    Measured: up to 180 days

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted20 Nov 2012 (estimated)
  2. Study startNov 2013
  3. Primary completionAug 2018
  4. Study completionDec 2018

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
4,000 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01728558
Sponsor's protocol ID
ANZIC-RC/YS003
Acronym
SPICE III RCT
Status last verified
Apr 2019
First submitted
4 Nov 2012
Last updated
20 Aug 2019
Results posted
No
Data monitoring committee
Yes

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.

    PubMed 22859526

  • 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.

    PubMed 36215171

  • 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.

    PubMed 32678054

  • 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.

    PubMed 31112380

  • 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.

    PubMed 29926288

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Early goal Directed Sedation in people with Critical Illness and Mechanical Ventilation, run by Australian and New Zealand Intensive Care Research Centre at 74 sites in 8 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 3 inclusion and 15 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 20 Aug 2019. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 74 sites in Australia, United Kingdom, Malaysia, New Zealand, Saudi Arabia and 3 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Mortality (time frame: Day 90 post randomisation). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01728558, which also lists 5 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 20 Aug 2019.

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