Clinical trial NCT01728558: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Critical Illness and Mechanical Ventilation
Keywords: Sedation
Delirium
Goal Directed
Dexmedetomidine
Mortality
Mechanical ventilation
Intensive care
Critically Ill
Lead sponsor: Australian and New Zealand Intensive Care Research Centre
Sponsor class: OTHER
Collaborators: name: National Health and Medical Research Council, Australia
First posted: 2012-11-20
Enrollment: 4000
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Mortality
timeFrame: Day 90 post randomisation
Secondary outcomes:
measure: Ventilation free days
timeFrame: at 28 days following randomisation
measure: Proportion of RASS measurements in target range
timeFrame: up to day 28
measure: Incidence and duration of delirium measured by delirium free days
timeFrame: up to 28 days
measure: Length of ICU stay
timeFrame: up to 180 days
measure: Proportion of patients who receive a tracheostomy Proportion of patients who require: re-intubation, physical restraints,or unplanned extubation,
timeFrame: up to day 28
measure: Cumulative dose of midazolam, propofol, dexmedetomidine, fentanyl, and morphine
timeFrame: up to 28 days
measure: Duration of treatment with midazolam, propofol, dexmedetomidine, fentanyl, and morphine
timeFrame: up to 28 days
measure: Mortality at hospital discharge
timeFrame: at hospital discharge up to 180 days
measure: Length of hospital stay
timeFrame: up to 180 days
measure: Readmission to ICU
timeFrame: at 90 days
measure: EQ-5D questionnaire
timeFrame: at 180 days
measure: Cognitive function
timeFrame: at 180 days
measure: Mortality at ICU discharge
timeFrame: up to 180 days
measure: Full time institutional dependency at 180 days
timeFrame: up to 180 days
measure: Discharge destination
timeFrame: up to 180 days
Other outcomes:
Locations:
city: Albury
country: Australia
facility: Albury Hospital
state: New South Wales
city: Blacktown
country: Australia
facility: Blacktown Hospital
state: New South Wales
city: Darlinghurst
country: Australia
facility: St Vincent's Hospital Sydney
state: New South Wales
city: Gosford
country: Australia
facility: Gosford Hospital
state: New South Wales
city: Hornsby
country: Australia
facility: Hornsby Ku-ring-gai Hospital
state: New South Wales
city: Penrith
country: Australia
facility: Nepean Hospital
state: New South Wales
city: St. Leonards
country: Australia
facility: Royal North Shore Hospital
state: New South Wales
city: Sydney
country: Australia
facility: Prince of Wales Hospital
state: New South Wales
city: Westmead
country: Australia
facility: Westmead Hospital
state: New South Wales
city: Tiwi
country: Australia
facility: Royal Darwin Hospital
state: Northern Territory
city: Buderim
country: Australia
facility: Sunshine Coast Hospital (Nambour Hospital)
state: Queensland
city: Herston
country: Australia
facility: Royal Brisbane and Women's hospital
state: Queensland
city: Redcliffe
country: Australia
facility: Redcliffe Hospital
state: Queensland
city: Southport
country: Australia
facility: Gold Coast Hospital & Health Service
state: Queensland
city: Toowoomba
country: Australia
facility: Toowoomba Hospital
state: Queensland
city: Woolloongabba
country: Australia
facility: Princess Alexandra Hospital
state: Queensland
city: Elizabeth Vale
country: Australia
facility: Lyell McEwan Hospital
state: South Australia
city: Hobart
country: Australia
facility: Royal Hobart Hospital
state: Tasmania
city: Launceston
country: Australia
facility: Launceston General Hospital
state: Tasmania
city: Bendigo
country: Australia
facility: Bendigo Hospital
state: Victoria
city: Dandenong
country: Australia
facility: Dandenong Hospital
state: Victoria
city: Epping
country: Australia
facility: Northern Hospital
state: Victoria
city: Geelong
country: Australia
facility: Geelong Hospital
state: Victoria
city: Heidelberg
country: Australia
facility: Austin Hospital
state: Victoria
city: Melbourne
country: Australia
facility: Royal Melbourne Hospital
state: Victoria
city: Melbourne
country: Australia
facility: Monash Medical Centre
state: Victoria
city: Sale
country: Australia
facility: Central Gippsland Health Service
state: Victoria
city: Wantirna
country: Australia
facility: Knox Private Hospital
state: Victoria
city: Perth
country: Australia
facility: St John Of God, Subiaco
state: Western Australia
city: Dublin
country: Ireland
facility: St Vincent's University Hospital
state: Dublin 4
city: Dublin
country: Ireland
facility: St James's University Hospital
state: Dublin 8
city: Milan
country: Italy
facility: Ospedale San Raffaele
city: Kota Bharu
country: Malaysia
facility: Raja Perempuan Zainab II Hospital
state: Kelantan
city: Kota Bharu
country: Malaysia
facility: Universiti Sains Malaysia Hospital
state: Kelantan
city: George Town
country: Malaysia
facility: Penang General Hospital
state: Pulau Pinang
city: Kota Kinabalu
country: Malaysia
facility: Queen Elizabeth Hospital
state: Sabah
city: Kuching
country: Malaysia
facility: Sarawak General Hospital
state: Sarawak
city: Kuala Lumpur
country: Malaysia
facility: Institut Jantung Negara
city: Kuala Lumpur
country: Malaysia
facility: Kuala Lumpar General Hospital
city: Kuala Lumpur
country: Malaysia
facility: University Malaya Medical Center
city: Melaka
country: Malaysia
facility: Melaka General Hospital
city: Grafton
country: New Zealand
facility: Auckland City Hospital CVICU
state: Auckland
city: Otahuhu
country: New Zealand
facility: Middlemore Hospital
state: Auckland
city: Addington
country: New Zealand
facility: Christchurch Hospital
state: Christchurch
city: Takapuna
country: New Zealand
facility: North Shore Hospital
state: North Shore City
city: Newtown
country: New Zealand
facility: Wellington Hospital
state: Wellington
city: Auckland
country: New Zealand
facility: Auckland City hospital
city: Dunedin
country: New Zealand
facility: Dunedin Hospital
city: Rotorua
country: New Zealand
facility: Rotorua Hospital
city: Riyadh
country: Saudi Arabia
facility: Prince Sultan Military Medical City
city: Riyadh
country: Saudi Arabia
facility: King Saud Medical City
city: Riyadh
country: Saudi Arabia
facility: King Abdulaziz Medical City
city: Bern
country: Switzerland
facility: Inselspital University Hospital Bern
city: Brixton
country: United Kingdom
facility: Kings College Hospital
state: London
city: High Heaton
country: United Kingdom
facility: Freeman Hospital
state: Newcastle Upon Tyne
city: King's Lynn
country: United Kingdom
facility: Queen Elizabeth Hospital King's Lynn
state: Norfolk
city: Crownhill
country: United Kingdom
facility: Derriford Hospital
state: Plymouth
city: Hardwick
country: United Kingdom
facility: University Hospital of North Tees
state: Stockton-on-Tees
city: Birmingham
country: United Kingdom
facility: Queen Elizabeth Hospital, Birmingham
city: Bournemouth
country: United Kingdom
facility: Royal Bournemouth Hospital
city: Bristol
country: United Kingdom
facility: University Hospitals Bristol
city: Cardiff
country: United Kingdom
facility: University Hospital of Wales
city: Coventry
country: United Kingdom
facility: University Hospital of Coventry and Warwick
city: Dorchester
country: United Kingdom
facility: Dorset County Hospital
city: Edinburgh
country: United Kingdom
facility: Royal Infirmary of Edinburgh
city: Edinburgh
country: United Kingdom
facility: Western General Hospital
city: Liverpool
country: United Kingdom
facility: Royal Liverpool University Hospital
city: Londonderry
country: United Kingdom
facility: Altnagelvin Hospital
city: London
country: United Kingdom
facility: St Thomas Hospital
city: London
country: United Kingdom
facility: St George's Hospital
city: London
country: United Kingdom
facility: University College Hospital
city: Newcastle Upon Tyne
country: United Kingdom
facility: Royal Victoria Infirmary
city: Orpington
country: United Kingdom
facility: Princess Royal University Hospital
city: Reading
country: United Kingdom
facility: Royal Berkshire Hospital
Study officials:
affiliation: University New South Wales, Prince of Wales Hospital, ANZIC-RC
name: Yahya Shehabi, MD, FCICM, FANZCA, EMBA
role: STUDY_CHAIR
affiliation: ANZIC-RC & Austin Hospital
name: Rinaldo Bellomo
role: PRINCIPAL_INVESTIGATOR
affiliation: ANZIC-RC & Royal Perth Hospital
name: Steve A. R Webb
role: PRINCIPAL_INVESTIGATOR
affiliation: ANZIC-RC, Royal Brisbane & Women's Hospital, Department of Military Medicine and Surgery,
name: Michael C Reade
role: PRINCIPAL_INVESTIGATOR
affiliation: ANZIC-RC
name: Belinda D Howe
role: PRINCIPAL_INVESTIGATOR
affiliation: ANZIC-RC, Nepean Hospital
name: Ian M Seppelt
role: PRINCIPAL_INVESTIGATOR
affiliation: ANZIC-RC, Auckland Hospital
name: Colin McArthur
role: PRINCIPAL_INVESTIGATOR
affiliation: ANZIC-RC,
name: Simon Erikson
role: PRINCIPAL_INVESTIGATOR
affiliation: ANZIC-RC
name: Lynne Murray
role: PRINCIPAL_INVESTIGATOR
affiliation: Institut Jantung Negara, Malaysia
name: Suhaini Kadiman
role: PRINCIPAL_INVESTIGATOR
affiliation: Inselspital, Bern, Switzerland
name: Jukka Takala
role: PRINCIPAL_INVESTIGATOR
affiliation: King Abdulaziz Medical Centre, KSA
name: Yaseen Arabi
role: PRINCIPAL_INVESTIGATOR
affiliation: University Hospital of Wales, UK
name: Matthew P Wise
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.