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EGDS vs. STDS RCT Version 3 Dated 14 June 2013 ANZIC-RC/YS003
CONFIDENTIAL
Early Goal Directed Sedation vs. Standard Care Sedation
Sedation Practices in Intensive Care Evaluation:
SPICE III: A Prospective Multicentre Randomised Controlled Trial of
Early Goal Directed Sedation Compared with Standard Care in Mechanically Ventilated Patients in Intensive Care
Email: y.shehabi@unsw.edu.au
Investigators: Professor Rinaldo Bellomo
Professor Steve Webb
Professor Michael Reade
Dr Ian Seppelt
Dr Colin McArthur
Ms Frances Bass
Ms Leonie Weisbrodt
Dr Simon Erickson
Ms Belinda Howe
Ms Lynne Murray
Coordinating Centre: The Australian and New Zealand Intensive Care Research Centre
Department of Epidemiology and Preventive Medicine
School of Public Health and Preventive Medicine, Monash University
The Alfred Centre, 99 Commercial Road,
Melbourne, Victoria, 3004
AUSTRALIA
Phone: +61 3 9903 0247
Fax: +61 3 9903 0071
email: anzicrc@monash.edu
This study is endorsed by the Australian and New Zealand Intensive Care Society Clinical Trials Group (ANZICS CTG)
Chief Investigator: Dr Yahya Shehabi
Professor, University of New South Wales Clinical School of
Medicine Prince of Wales Hospital, Barker Street, Randwick,
NSW 2031 Telephone: +61 2 9382 4721 Facsimile: +61 2
9382 4870 Mobile: +61 419 296 986
EGDS vs. STDS RCT Version 3 Dated 14 June 2013 ANZIC-RC/YS003
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CONTENTS
1 MANAGEMENT COMMITTEE AUTHORISATION PAGE ............................................................................... 4
2 STUDY ADMINISTRATION STRUCTURE ..................................................................................................... 5
2.1 COORDINATING CENTRE AND DATA MANAGEMENT CENTRE ................................................................................ 5
2.1.1 Responsibilities................................................................................................................................ 5
2.2 MANAGEMENT COMMITTEE .......................................................................................................................... 5
2.2.1 Responsibilities................................................................................................................................ 5
2.2.2 Members ......................................................................................................................................... 5
2.3 CONTACT DETAILS........................................................................................................................................ 6
2.3.1 Chief investigator ............................................................................................................................ 6
2.3.2 Coordinating centre ........................................................................................................................ 6
3 ABBREVIATIONS ....................................................................................................................................... 7
4 SYNOPSIS ................................................................................................................................................. 8
4.1 BACKGROUND ............................................................................................................................................. 8
4.2 AIM .......................................................................................................................................................... 9
4.3 HYPOTHESIS................................................................................................................................................ 9
4.4 METHODS .................................................................................................................................................. 9
4.5 SIGNIFICANCE............................................................................................................................................ 10
5 BACKGROUND AND RATIONALE ............................................................................................................. 11
6 STUDY OBJECTIVES ................................................................................................................................. 17
6.1 AIM ........................................................................................................................................................ 17
6.2 HYPOTHESIS.............................................................................................................................................. 17
7 STUDY OUTCOME MEASURES ................................................................................................................ 17
7.1 PRIMARY OUTCOME ................................................................................................................................... 17
7.2 SECONDARY OUTCOMES .............................................................................................................................. 17
8 OVERALL STUDY DESIGN ........................................................................................................................ 18
8.1 STUDY DESIGN ........................................................................................................................................... 18
8.2 STUDY POPULATION ................................................................................................................................... 18
8.3 INCLUSION CRITERIA ................................................................................................................................... 18
8.4 EXCLUSION CRITERIA ................................................................................................................................... 18
9 STUDY PROCEDURES .............................................................................................................................. 19
9.1 RANDOMISATION ....................................................................................................................................... 19
9.2 CONSENT ................................................................................................................................................. 19
9.3 SUPPLIED DEXMEDETOMIDINE PRODUCT ......................................................................................................... 20
9.3.1 Accountability ............................................................................................................................... 20
9.3.2 Handling and dispensing ............................................................................................................... 20
9.3.3 Drug preparations and dilutions ................................................................................................... 20
9.4 BACKGROUND TREATMENT- SEDATIVE AND ANALGESIC TREATMENT .................................................................... 20
9.5 STUDY INTERVENTION- EARLY GOAL-DIRECTED SEDATION ................................................................................. 21
9.5.1 Early Goal-Directed Sedation Appendix 1 A .................................................................................. 21
9.5.2 RASS -3 to -5: Oversedation. ......................................................................................................... 21
9.5.3 (RASS +2 to +4) Breakthrough agitation in EGDS .......................................................................... 21
9.5.4 Neuromuscular blockade required for EGDS group ...................................................................... 22
9.6 STUDY INTERVENTION- STANDARD CARE SEDATION ARM APPENDIX 1 B ............................................................... 22
9.6.1 Standard Care Sedation Arm Appendix 1 B ................................................................................... 22
9.6.2 Management of agitation and delirium ....................................................................................... 22
9.6.3 Neuromuscular blockade required for standard care sedation group ......................................... 22
9.7 DISCONTINUATION OF TREATMENT ................................................................................................................ 22
9.8 BLINDING OF STUDY TREATMENTS ................................................................................................................. 23
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10 ETHICS ................................................................................................................................................ 23
10.1 GUIDING PRINCIPLES................................................................................................................................... 23
10.2 ETHICAL ISSUES OF THE STUDY ...................................................................................................................... 23
10.3 ETHICS COMMITTEE APPROVAL ..................................................................................................................... 24
10.4 CONFIDENTIALITY OF PATIENT DATA ............................................................................................................... 24
10.5 INFORMATION AND CONSENT DOCUMENTS ..................................................................................................... 24
11 DATA MANAGEMENT ......................................................................................................................... 24
11.1 DATA COLLECTION METHODS ....................................................................................................................... 24
11.2 DATA VARIABLES COLLECTED ........................................................................................................................ 25
11.2.1 At enrolment ................................................................................................................................. 25
11.2.2 Duration of ICU admission until discharge or day 28, whichever occurs first ............................... 25
11.2.3 Episode outcome data at ICU and Hospital discharge .................................................................. 26
11.2.4 Episode end of study outcomes..................................................................................................... 26
11.3 DATA MANAGEMENT .................................................................................................................................. 26
11.4 DATA QUALITY .......................................................................................................................................... 26
11.5 MONITORING............................................................................................................................................ 27
12 STATISTICAL CONSIDERATIONS .......................................................................................................... 27
12.1 STATISTICAL AND ANALYTICAL PLAN ............................................................................................................... 27
13 SAFETY ............................................................................................................................................... 27
13.1 DATA SAFETY MANAGEMENT COMMITTEE ..................................................................................................... 27
13.2 ADVERSE EVENTS ....................................................................................................................................... 28
13.3 SERIOUS ADVERSE EVENTS ........................................................................................................................... 28
13.3.1 Definition of a SAE ........................................................................................................................ 28
13.3.2 SAE Reporting ............................................................................................................................... 29
14 FUNDING ............................................................................................................................................ 29
15 PUBLICATION ..................................................................................................................................... 29
16 REFERENCES ....................................................................................................................................... 30
17 APPENDIX 1: ....................................................................................................................................... 33
17.1 EARLY GOAL DIRECTED SEDATION ALGORITHM ................................................................................................ 33
17.2 B: STANDARD SEDATION ALGORITHM ............................................................................................................ 34
EGDS vs. STDS RCT Version 3 Dated 14 June 2013 ANZIC-RC/YS003
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1 MANAGEMENT COMMITTEE AUTHORISATION PAGE
We, the management committee, have read the attached protocol and authorize it as the official protocol for the study entitled Early Goal Directed Sedation verses Standard Care: A prospective, multicentre, randomised, controlled trial. Chief Investigator
Date
14 June 2013
Yahya Shehabi
Management Committee
Date
14 June 2013
Rinaldo Bellomo
Management Committee
Date
14 June 2013
Steve Webb
Management Committee
Date
14 June 2013
Michael Reade
Management Committee
Date
14 June 2013
Ian Seppelt
Management Committee
Date
14 June 2013
Colin McArthur
Management Committee
Date
14 June 2013
Frances Bass
Management Committee
Date
14 June 2013
Leonie Weisbrodt
Management Committee
Date
14 June 2013
Simon Erickson
Management Committee
Date
14 June 2013
Belinda Howe
Management Committee
Date
14 June 2013
Lynne Murray
EGDS vs. STDS RCT Version 3 Dated 14 June 2013 ANZIC-RC/YS003
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2 STUDY ADMINISTRATION STRUCTURE
2.1 Coordinating Centre and Data Management Centre
2.1.1 Responsibilities
Responsible for all aspects of study management including:
• Management of study budget and liaison with funding bodies
• Final protocol
• Case Report Form design
• Database development, maintenance and administration
• Data management
• Protocol training of principal investigators and research coordinators
• Preparation and arrangement of investigator payments
• Management of regulatory affairs (e.g. Therapeutic Goods Administration etc)
• Management of study set up including assistance with HREC applications
• Randomisation schedule
• Monitoring and close-out site visits
• Organisation of investigator meetings
• Liaison with independent Data and Safety Monitoring Committee
• Data analysis and collaboration on publications
2.2 Management Committee
2.2.1 Responsibilities
Responsible for overseeing all aspects of the study management including:
• Liaison with coordinating centre staff
• Funding applications, negotiations and communications
• Study budget
• Development and approval of final protocol and study materials
• Development and approval of data management systems
• General study management issues
• Liaison with independent Data and Safety Monitoring Committee
• Data analysis and collaboration on publications
2.2.2 Members
Professor Yahya Shehabi (Chair) Director ICU Research, Prince of Wales Hospital
Professor Rinaldo Bellomo Director of ICU Research, Austin Hospital
Professor Steve Webb Senior Staff Specialist, Royal Perth Hospital
Professor Michael Reade Staff Specialist, Royal Brisbane Hospital
Dr Ian Seppelt Senior Staff Specialist, Nepean Hospital
Dr Colin McArthur Intensive Care Consultant, Auckland City Hospital
Ms Frances Bass Research Manager, Royal North Shore Hospital
Ms Leonie Weisbrodt CNC Intensive Care Research, Nepean Hospital
Dr Simon Erickson Staff Specialist, Princess Margaret Hospital for Children
Ms Belinda Howe Senior Project Manager, ANZIC-RC
Ms Lynne Murray Senior Research Manager, ANZIC RC,
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2.3 Contact Details
2.3.1 Chief investigator
2.3.2 Coordinating centre
Belinda Howe
Project Manager
Australia and New Zealand Intensive Care Research Centre
Department of Epidemiology and Preventive Medicine
School of Public Health and Preventive Medicine
Monash University, Level 6, The Alfred Centre,
99 Commercial Road, Melbourne VIC 3004, Australia
Telephone: +61 3 9903 0340
Facsimile: +61 3 9903 0152
Mobile: +61 (0) 413 433 414
Email: belinda.howe@monash.edu
Dr Yahya Shehabi
Professor, University of New South Wales Clinical
School of Medicine
Prince of Wales Hospital
Barker Street, Randwick, NSW 2031
Telephone: +61 2 9382 4721
Facsimile: +61 2 9382 4870
Mobile: +61 419 296 986
Email: y.shehabi@unsw.edu.au
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3 ABBREVIATIONS
AE Adverse Event ANZ Australia and New Zealand ANZIC-RC Australian and New Zealand Intensive Care Research Centre ANZICS Australian and New Zealand Intensive Care Society APACHE II Acute Physiology and Chronic Health Evaluation II CAM-ICU Confusion Assessment Method for the Intensive Care Unit CRF Case Report Form CPOT Critical Care Pain Observation Tool CTG Clinical Trials Group Dex Dexmedetomidine DSMC Data Safety and Management Committee EQ-5D EuroQOL 5D EGDS Early Goal Directed Sedation STDS Standard Sedation GABA Gamma Aminobutyric Acid GCP Good Clinical Practice HR Hour HREC Human Research and Ethics Committee HRQoL Health Related Quality of Life ICU Intensive Care Unit IQCODE Informant Questionnaire on Cognitive Decline in the Elderly Kg Kilogram MAP Mean Arterial Pressure NHMRC National Health and Medical Research Council RASS Richmond Agitation and Sedation Score RCT Randomised Controlled Trial SAE Serious Adverse Event SCCM Society Critical Care Medicine SDM Substitute Decision Maker SPICE Sedation Practices in Intensive Care Evaluation TGA Therapeutic Goods Administration
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4 SYNOPSIS
4.1 Background
The use of sedative drugs in intensive care is ubiquitous. More than 50,000 critically ill patients in
Australia undergo ventilation and sedation every year [1]. The 2012 Society Critical Care Medicine
guidelines on the management of pain, agitation and delirium reviewed more than 18,000 published
articles and concluded that there was no evidence to judge that any of the commonly used sedative
medications midazolam, propofol and dexmedetomidine were superior, and so definitive studies on
sedation practice are urgently required [2]. Over the last decade, however, clinical practice has moved
towards the use of lighter levels of sedation whenever clinically safe, better management of pain, and
recognition of delirium as occurring commonly in patients with critical illness [3].
There is growing evidence that the centrally mediated alpha-2 agonist sedative dexmedetomidine
facilitates rousable sedation, shortens ventilation time, and attenuates the occurrence of delirium, as
shown in the results of the dexmedetomidine vs midazolam or propofol for sedation during prolonged
mechanical ventilation (MIDEX and PRODEX JAMA 2012) randomised controlled trial (RCT) [4] and
the Safety and Efficacy of Dexmedetomidine Compared With Midazolam (SEDCOM JAMA 209) RCT
[5]. Whether these advantages are associated with improvement in patient-centered outcomes, such
as long-term mortality and cognitive function, is not known. These RCTs have one or more
methodological problems including inadequate sample size to detect differences in patient centered
end-points, late randomisation after patients have already received up to 96 hours of non-protocol
sedative therapy, and the use of rigid protocols that do not reflect standard practice.
The Sedation Practice in Intensive Care Evaluation (SPICE) longitudinal observational cohort [6]
study showed that Australian and New Zealand (ANZ) intensive care clinicians used midazolam
and/or propofol and/or dexmedetomidine in 66.7%, 80.1% and 27% of patients respectively,
commonly in combination. The use of dexmedetomidine, however, is unlikely to have decreased since
the study was conducted in 2010. The study also showed that deep sedation is common early (within
first 48 hours) after initiation of mechanical ventilation and independently predicts delayed time to
extubation and higher risk of hospital and 180-day mortality.
The SPICE investigators concluded that future trials testing different strategies for achieving sedation
in patients who are critically ill should have the following features:
• Randomisation should occur soon after intubation or arrival in the ICU (early);
• Dexmedetomidine should be used as the primary sedative agent and that use of
benzodiazepines should be minimized;
• Sedation should be titrated to achieve light sedation (goal directed);
• Should have sufficient statistical power to detect plausible differences in patient centred end-
points, particularly mortality; and
• The control group should receive standard care, with predominant use of midazolam or
propofol or both, as determined by the treating clinician, and if directed to a sedation target as
determined by the treating clinician.
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The feasibility of delivering a sedative intervention that had these design features was tested in a pilot
trial comparing a dexmedetomidine based algorithm focused on Early Goal Directed Sedation (EGDS)
with Standard Sedation. The practicality of delivering EGDS was confirmed with significant reductions
in deep sedation within 24 hours of initiating mechanical ventilation and in days with delirium [7] .
4.2 Aim
The primary aim of this study is to determine whether Early Goal-Directed Sedation, compared to
standard care sedation, reduces 90-day mortality in critically ill patients who are expected to require
mechanical ventilation for longer than 24 hours.
4.3 Hypothesis
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.
4.4 Methods
This study is a prospective, un-blinded, randomised controlled trial of Early Goal-Directed Sedation
compared with Standard care. The study will recruit patients who are intubated and ventilated in a
participating ICU, are expected to remain intubated the day after enrolment AND need immediate and
ongoing sedation.
Due to the immediate need to choose a sedative regimen for ongoing patient safety and comfort, it is
proposed that study enrolment will occur using deferred consent. Randomisation will occur via a
secured website and will be stratified by participating centre and by whether there is clinically
suspected or proven sepsis [8] at time of randomisation.
A total of 4000 patients will be recruited from approximately 35 study ICUs and assigned to the
intervention arm, Early Goal-Directed Sedation (EGDS) or the control arm, standard sedation
practice (STDS). (Refer to Study Flow Algorithm Appendix 1, A and B respectively).
Following randomisation, systematic pain assessment using a Yes/No (if able to report pain) or a
modified Critical Care Pain Observation tool [9](CPOT, if unable to report pain) will be conducted.
Analgesia will be accordingly optimised for patients in both groups as chosen by attending physician
including opioids (by bolus or infusion excluding remifentanil) or other agents as clinically indicated.
Patients in the EGDS arm will receive a dexmedetomidine infusion starting at 1 mcg/kg/hr without
loading dose to achieve a target Richmond Agitation Sedation Scale (RASS) [10] -2 to +1 at all times,
unless otherwise clinically indicated. If dexmedetomidine alone is insufficient, propofol will be
administered, by bolus or infusion (10-70 mg/hr) or both, to achieve the targeted level of sedation.
The use of midazolam is precluded in the EGDS group except for defined clinical situations (such as
palliation, procedural anaesthesia, seizure activity, adjunct to neuromuscular blockade and refractory
uncontrolled agitation) in which it can be used at the direction of the treating clinician. Patients in the
STDS will receive sedative medications (either midazolam or propofol or both) [6], as determined by
the treating clinician, to achieve clinically appropriate sedation target as chosen by the treating
clinician, although a target of RASS -2 to +1 is encouraged (default) at all times in this arm.
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The primary outcome is all-cause mortality assessed 90 days after randomisation.
Other major measurements will be: recording of administration of all sedative, analgesic and other
related medications; the RASS score (every 4 hours); the Confusion Assessment Method for
Intensive Care (CAM-ICU) [11] daily (at least Monday to Friday) in patients lightly sedated with a
RASS score > -3 (to assess delirium); a pain assessment (measured 4 hourly); major ICU
interventions including intubation, tracheostomy, vasopressors / inotropes, dialysis and mechanical
ventilation; baseline demographic information and co-morbidities; survival status at ICU and hospital
discharge: and cognitive function [12] and Health Related Quality of Life (HRQoL) [13] at 180 days.
Health economic evaluation will also be conducted from an institutional perspective. If the primary
outcome (90 day mortality reduction) is achieved, the cost of lives saved will also be evaluated.
Clinical costs will be obtained, where available, from sites to perform the economic analysis.
4.5 Significance
Once concluded, this trial will be the largest sedation RCT in critically ill ventilated patients ever to be
conducted. This trial will address many of the limitations of previous ICU sedation RCTs and thus its
results will have a global impact and would change practice worldwide. If the trial demonstrates an
improvement in one or more patient-centered outcomes, including mortality, cognitive function, and/or
HQRoL this would provide definitive evidence to clinicians and policymakers to guide the
management of critically ill patients who require sedation following admission to the ICU. The
economic and societal impact of a positive result would be enormous.
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5 BACKGROUND AND RATIONALE
Sedation is ubiquitous in intensive care
Every year, more than 3 million patients worldwide and 50,000 patients in Australia receive
mechanical ventilation and sedation in ICU [1]. Sedation is given to promote tolerance of endotracheal
intubation and associated life-sustaining interventions, including mechanical ventilation, and to relieve
anxiety and reduce distress [14] . Thus, sedation is vital to patient comfort, safety and survival.
Sedation can be associated with significant harm
Despite its ubiquitous use and contribution to comfort and safety, sedation carries significant risk. In
the context of critical illness with impaired liver and kidney function, sedative drugs and their active
metabolites can accumulate, leading to prolonged deep sedation (unintended drug-induced coma),
respiratory depression, immune suppression, and hypotension [15][16]. Prolonged sedation
contributes to immobility, weakness and prolongation of mechanical ventilation with attendant need
for tracheostomy and extended ICU stay[17]. Subsequent cessation of sedative medications, after
prolonged exposure, can lead to drug withdrawal syndromes[18]. These shortcomings expose ICU
patients to other major complications such as agitation requiring physical restraints [17], nosocomial
infection [19], pressure sores, critical illness neuropathy and myopathy [16], vascular thrombosis and
in some patients, sepsis, multiple organ failure and death. The incidence and severity of these
problems is rising in association with increasing complexity of surgery and admission of older patients
with multiple co-morbidities to intensive care [20]. Furthermore, older patients with high severity of
illness undergoing complex interventions are at high risk of associated delirium [21] [22].
Impact of delirium associated with sedation
Delirium is a common form of acute brain dysfunction that occurs in up to 80% of patients who are
treated with sedation whilst receiving mechanical ventilation [23]. The risk of delirium appears
particularly high when benzodiazepines are used [24]. The annual cost of in-hospital delirium
management in the United States exceeds US$ 7 billion [25]. Delirious patients are often agitated and
at significant risk of harming themselves and the staff who are caring for them. Patients who have
delirium can remove endotracheal tubes, indwelling catheters[26] and climb out of bed, all of which
are associated with risks of death and injury. It is challenging to provide safe and appropriate ICU
care for these patients. Paradoxically, delirious patients commonly receive more sedation and use of
physical restraints to control agitation [27] leading to a vicious cycle where delirium begets sedation,
which then begets more delirium. A review of 4000 patients in 19 observational studies reported that
delirium is linked to poor patient-centered outcomes up to one year after hospitalisation [28]. There is
evidence that ICU delirium and its duration are independently associated with the duration of
mechanical ventilation, ICU length of stay and 6 month mortality [29]. One third of patients who
survive admission to ICU but who experience delirium in ICU suffer moderate to severe cognitive
impairment at 6 months and more than 50% demonstrate persistent depression, anxiety and post-
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traumatic stress 1 year after hospitalisation [30][31]. As such, the public health burden, for patients,
families, and healthcare payers, is substantial.
Potential for sedation strategy to influence morbidity and mortality
GABAA (Gamma Aminobutyric Acid agonists)
Currently there are two drugs that act (directly or in-part) on the GABAA receptor that are used
commonly to provide sedation for patients admitted to an ICU [32][33]. These agents are midazolam,
and propofol. Although midazolam has a short half-life after a single injection, prolonged infusion
results in extended and exaggerated pharmacological activity due to accumulation of the drug and its
active metabolite, alpha-hydroxymidazolam. This is particularly important in ICU patients known to
have low serum albumin concentration and impaired kidney function [34], leading to dose dependent
central neuronal, respiratory and cardiovascular depression substantially contributing to all the
problems listed above. Propofol has more favourable pharmacokinetics, with substantially less risk of
accumulation, but its use can cause a range of adverse effects including hypotension, respiratory
depression and apnoea, hypertriglyceridaemia, pancreatitis and the rare, poorly understood,
unpredictable, and often lethal propofol infusion syndrome [35][36]. Furthermore, midazolam and
propofol have no analgesic effects, and are usually given in combination with an opioid such as
morphine or fentanyl. The addition of opioids adds new problems including reduced airway reflexes
and respiratory drive, impaired bowel motility (ileus and intolerance of nasogastric feeding), drug
tolerance and withdrawal, and, possibly, dependence [37]. Opioids also exaggerate the effects of
other sedatives and active metabolites of opioids accumulate in ICU patients leading to prolongation
of their side effects. These common and potentially serious problems suggest that a different
approach to sedation may offer substantial benefit.
Alpha 2 Adrenergic receptor agonists
The alpha2 agonist dexmedetomidine emerged over the last 15 years as a viable alternative to
traditional sedatives for mechanically ventilated patients and its use has significantly increased across
the world and in ANZ. The 2013 SCCM International Guidelines [2] recommend the use of
dexmedetomidine and/or propofol for ICU sedation of mechanically ventilated patients to promote light
sedation. Alpha2 receptors are distributed widely in the body with high density in brain, spinal cord,
cardiac conduction system, myocardium, renal medulla, pancreas and vascular smooth muscle [38].
The primary effect of activation of α2 receptors is a reduction of noradrenaline release from nerve
terminals, lowering plasma and cerebrospinal noradrenaline levels and producing central non-GABA
mediated sedation and spinal non-opioid mediated analgesia. There is also a strong sympatholytic
effect producing bradycardia (10-15% reduction) and a bimodal (hypotension at low dose and
hypertension at medium to high dose) effect on systemic blood pressure [39]. Clonidine is a well-
known α2 receptor agonist used primarily for its antihypertensive effect; however, the drug of this class
better suited to sedation is the more CNS-selective dexmedetomidine. In contrast to traditional
sedatives, α2 mediated sedation with dexmedetomidine is characterised by rousable sedation,
analgesia, minimal respiratory depression and minimal tolerance or accumulation[40].
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Evidence for the safety and efficacy of α2 receptor agonists
Pre-treatment with α2 agonist dexmedetomidine was neuroprotective in animal models of incomplete
cerebral ischemia[41][42]. Similarly, higher survival was observed in pre-treated rat models of
sepsis[43]. Several phase II clinical RCTs have found that dexmedetomidine improves a variety of
surrogate end-points when compared with GABA receptor agonists. There are 5 double-blind RCTs
involving 1782 patients comparing dexmedetomidine with midazolam, lorazepam or propofol. These
trials consistently show reduced coma, shorter ventilation time and ICU stay, and a lower incidence
and shorter duration of delirium in patients who receive dexmedetomidine (Table 1) [5][44][45]. A
meta-analysis (2010) in non-elective critically ill patients treated with dexmedetomidine showed a
trend towards lower mortality (RR 0.85 95% CI 0.64-1.31) [46]. The most recent large RCT (Propofol
vs dexmedetomidine and Midazolam vs dexmedetomidine, PRODEX and MIDEX) [4] in 2012
confirmed the safety and efficacy of dexmedetomidine as an alternative sedative drug for
mechanically ventilated patients for longer than 24 hours. It also confirmed the safety of dosing
dexmedetomidine up to 1.5µg/kg/hour. These studies have led to the registration of dexmedetomidine
in Europe for use in ICU sedation to a maximum dose of 1.5µg/kg/hour with no time restriction. Based
on the body of evidence available to-date, the most recent 2012 International Sedation Clinical
Practice Guidelines produced by a special taskforce of the Society of Critical Care Medicine [2]
suggested that midazolam, propofol, dexmedetomidine or combinations be used for ICU sedation in
mechanically ventilated critically ill patients.
Table 1: Randomised Trials of dexmedetomidine vs. traditional sedative drugs
Evidence for safety and efficacy of light sedation
Sedation research over the last 15 years has focused on reducing sedation depth as a means of
reducing ICU complications. A randomised trial of daily interruption of sedation vs. standard practice
shortened median ventilation time by 2.4 days and ICU stay by 3.6 days [47]. A pilot randomised trial
of a protocol of no sedation (but adequate analgo-sedation) [48] resulted in 4.2 more ventilation free
days and 8.7 fewer ICU days compared with standard care. Patients randomised to receive no
sedation, however, experienced significant agitation. A nurse implemented sedation protocol was also
Trial (n=) Patients Intervention Comparator Outcome
SEDCOM 5 (375)
JAMA 2009
ICU Ventilated > 24 hrs
DEX infusion + rescue midazolam
Midazolam Reduced ventilation time and reduced delirium
MENDS 44
(103)
JAMA 2007
ICU Ventilated > 24 hrs
DEX infusion with fentanyl
Lorazepam Reduced coma and delirium
DEXCOM 43
(306)
Anesthesiol 2010
Cardiac Surgery > 60 yrs old
DEX infusion to target sedation
Morphine with propofol rescue
Reduced delirium duration
and ventilation time
MIDEX (500) 4
JAMA 2012
ICU Ventilated > 24 hrs
DEX infusion + rescue propofol
Midazolam Reduced ventilation time, ICU stay and agitation
PRODEX (498) 4
JAMA 2012
ICU Ventilated > 24 hrs
DEX infusion + rescue midazolam
Propofol Reduced ventilation time and agitation
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shown to reduce ventilation time, sedation load and ICU stay[49]. The Awakening and Breathing RCT,
incorporating coordinated daily awakening with ventilation weaning [50] showed a 32% reduction in 1
year mortality (HR 0.68, 95% CI 0.50-0.92; P=0.01). A protocolised approach to sedation, analgesia
and reducing the risk of delirium [51] was associated with significant reduction in prevalence of deep
sedation, ventilation time, ICU stay and a 6.5% absolute reduction in hospital mortality (P=0.009). All
these studies suggest that decreasing sedation depth by targeting light sedation may improve
survival.
Table 2: Summary of key studies targeting reduced sedation depth.
Limitations of current sedation research
Despite widespread use of sedative drugs, existing sedation practices and published clinical practice
guidelines are based on expert opinion and low quality trial evidence. Most clinical trials of sedation
practice have been inadequately powered and did not account for the model of care, thus lacking
external validity [4,5,43,44,47]. In addition, most shared significant limitations: First, control groups
did not match current best practice leading to mal-alignment with actual practice [52]. As such they
lack both relevance and validity; Second, clinical trials have focused on comparisons of drug A and B,
despite the fact that patients are often sedated with a combination of drugs; Third, the use of sedation
monitoring and delirium assessments was not universal; Fourth, randomisation did not occur until up
to 96 hours after initiation of mechanical ventilation, leading to significant contamination at baseline
and reduced separation between the intervention and the control group[4,5,]; Fifth, few studies have
assessed long-term patient-centred outcomes; Sixth, the intervention was sometimes administered
by research staff rather than clinical staff, thus limiting generalizability [47]. Finally, there have not
been any large phase III trials using mortality as the primary outcome, thus no strong sedation
recommendations can be made. For these reasons, even after reviewing more than 18,000 published
studies, the most recent International Guidelines on Pain, Agitation and Delirium did not deliver
conclusive recommendations [2] to clinicians to adopt a specific approach, or use a specific agent for
sedation management of critically ill ICU patients.
Current sedation practice in Australia and New Zealand
The study management committee conducted a prospective longitudinal observational cohort study of
251 mechanically ventilated patients within the first 24 hours of ICU admission who were expected to
require mechanical ventilation and sedation for greater than 24 hours in 25 ICUs in Australia and New
Zealand (ANZ) in 2010 [6]. These patients were representative of ANZ ICU patients with a mean age
of 62 years, a mean APACHE II score of 20.8, a median duration of mechanical ventilation of 5.1
Trial Patients Intervention Comparator Outcome
Awakening and Breathing Trial
49
n=(336)
Lancet 2008
Ventilated > 12 hrs
Daily awakening + Spont breathing trial
Usual care Reduced ventilation time, reduced ICU stay, reduced coma, reduced mortality
Protocolised analgesia sedation
50
trial n=(1214)
Anesth Analg 2010
Sedated with ICU stay > 24hrs
Protocolised sedation analgesia and delirium Mx
Standard care
Reduced ventilation time, ICU stay, coma, delirium and mortality
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days, a hospital mortality of 21%, and 180 day mortality of 26%. This study found that 3 of every 4,
one of every 3 and one of every 4 ventilated ICU patients received propofol, midazolam or
dexmedetomidine, respectively. It also found a high incidence (76%) of deep sedation especially in
the first 48 hours [Figure 1] and a high incidence of delirium (50.7% of all assessable patients). After
adjusting for many relevant co-variants using proportional hazard Cox regression, early deep sedation
independently predicted delayed time to extubation (HR 0.90, 95% CI 0.87-0.94,P <0.001) and
increased hazard of 6-month mortality (HR 1.08, 95% CI 1.01-1.16, P=0.026). The first 48 hours after
initiation of mechanical ventilation has not been accounted for in many sedation trials due to late
randomisation. The above findings strongly suggest that future sedation trials should take into
consideration this important period.
Figure 1: Daily (0-28) Distribution of RASS sedation levels.
Key elements of a new candidate sedation paradigm- Early Goal-Directed Sedation
Based on the above observations, the Management Committee recognise that key elements of any
plausible strategy directed at improving patient centered outcomes associated with sedation MUST
include:
1. Early delivery of proposed intervention, shortly after initiating mechanical ventilation;
2. Regular and frequent assessment of patient wakefulness/sedative state;
3. Effective analgesia provided simultaneously and according to pain assessment
4. Avoidance of benzodiazepines and minimisation of use of propofol;
5. Reduced overall sedation depth with targeted light sedation;
Recent evidence from phase II studies [Table 1, 2] suggests that, for the first time, this might now be
possible, through a strategy combining light sedation with early and titrated use of the alpha2
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adrenoreceptor (α2) agonist dexmedetomidine. In combination, we term the elements of this bundle
‘Early Goal-Directed Sedation’ (EGDS).
There are several reasons why dexmedetomidine might facilitate the delivery of EGDS: it would be
expected to provide rousable sedation; reduce overall sedation depth; facilitate wakefulness and
ventilator weaning; avoid benzodiazepine use and minimise the use of propofol; reduce the incidence
and duration of delirium and finally, via its analgesic effect, produce an opioid sparing effect.
Early Goal-Directed Sedation (EGDS) Pilot RCT
The feasibility of delivering EGDS was tested in randomised prospective pilot study [7] conducted in 6
intensive care units in ANZ compared with standard care. Patients were randomised within a median
[IQR] of 1.1[0.46-1.9] hours following ICU ventilation. The percentage of EGDS patients in the lightly
sedated range on day 1, 2 and 3 was 63.2%, 90.5% and 90% compared with 14.3%, 53.3% and 60%
(P=0.005; 0.011; 0.036) for STDS patients [Figure 2]. There was a trend to higher delirium free days
with (EGDS patients 101/175 (58%) vs. STDS patients 54/114 (47%), P=0.09. Only 1(5%) EGDS
patient required physical restraints vs. 5(31%) (P=0.03) in STDS patients. This pilot confirmed the
feasibility and practicality of the EGDS and showed significant separation between the 2 treatment
arms (higher RASS assessments between (-2 to +1), in the first 48 hours 203/307(66%) vs.
(74/197(38%) (P=0.001) in the EGDS vs. STDS, respectively) with minimisation of other sedatives in
the EGDS. Recruitment rate of 0.75 subjects per site per week confirmed the feasibility of completing
a large RCT within 30 to 36 months.
Figure 2: Precent of patients lightly sedated on each day up to 7 days
Summary
In summary, in the presence of a plausible alternative, current sedation management in intensive care
may have unacceptable short and long-term consequences on tens of thousands of patients per year
in Australia and millions of patients worldwide. The human and the societal cost associated with these
problems are enormous. Providing high-level evidence to guide clinicians towards a safer paradigm of
innovative and targeted sedation is an urgent clinical and economic imperative. EGDS is an attractive
candidate intervention to improve outcome, the feasibility of has been proven in representative ICUs
in ANZ.
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6 STUDY OBJECTIVES
6.1 Aim
The primary aim of the study is to determine whether Early Goal-Directed Sedation therapy,
compared to standard care sedation, reduces 90-day mortality in critically ill patients who are
expected to require mechanical ventilation for longer than 24 hours.
6.2 Hypothesis
Early Goal-Directed Sedation (EGDS), compared to standard sedation practice, reduces
90-day all-cause mortality in mechanically ventilated critically ill patients.
The null hypothesis is that there is no difference in the risk of death between patients treated using
Early Goal-Directed Sedation and standard sedation therapy.
7 STUDY OUTCOME MEASURES
7.1 Primary outcome
The primary outcome measure of this study is death from all causes at day 90 post randomisation.
7.2 Secondary outcomes
ICU outcomes:
Ventilation free days at 28 days following randomisation
Proportion of RASS measurements in target range
Incidence and duration of delirium (delirium free days at 28 days)
Mortality at ICU discharge
Length of ICU stay
Proportion of patients who receive a tracheostomy
Proportion of patients who require re-intubation
Proportion of patients who require physical restraints
Proportion of patients with unplanned extubation
Process related outcomes
Cumulative dose of midazolam, propofol, dexmedetomidine, fentanyl, and morphine
Duration of treatment with midazolam, propofol, dexmedetomidine, fentanyl, and morphine
Hospital outcome
Mortality at hospital discharge
Length of hospital stay
Readmission to ICU
Discharge destination
Post-hospital outcomes
Cost-effectiveness; institutional perspective and cost of lives saved (if positive).
Cognitive function and Health Related Quality of Life at 180 days
Full time institutional dependency at 180 days
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8 OVERALL STUDY DESIGN
8.1 Study design
The proposed trial is a prospective, multicentre, un-blinded, randomised controlled trial of Early Goal-
Directed Sedation compared with Standard care. The study will maximise external validity by
including patients admitted to ICUs in a range of hospitals, including tertiary, metropolitan, rural, and
regional hospitals.
8.2 Study population
This study plans to recruit 4000 patients who meet the entry criteria from approximately 35 intensive
care units.
The trial will include patients admitted to participating ICUs who meet all of the inclusion criteria and
have none of the exclusion criteria.
8.3 Inclusion criteria
The inclusion criteria are:
1. Subject has been intubated and is receiving mechanical ventilation
2. The treating clinician expects that the patient will remain intubated until the day after
tomorrow (unlikely to be extubated the following day).
3. The patient requires immediate ongoing sedative medication for comfort, safety, and to
facilitate the delivery of life support measures.
8.4 Exclusion criteria
Patients will be excluded from the study if any of the following criteria apply:
1. Age less than 18 years
2. Patient is pregnant and/or lactating
3. Has been intubated (excluding time spent intubated within an operating theatre or transport)
for greater than 12 hours in an intensive care unit
4. Proven or suspected acute primary brain lesion such as traumatic brain injury, intracranial
haemorrhage, stroke, or hypoxic brain injury.
5. Proven or suspected spinal cord injury or other pathology that may result in permanent or
prolonged weakness
6. Admission as a consequence of a suspected or proven drug overdose or burns.
7. Administration of ongoing neuromuscular blockade
8. Mean arterial blood (MAP) pressure that is less than 50 mmHg despite adequate resuscitation
and vasopressor therapy at time of randomisation
9. 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
10. Known sensitivity to any of the study medications or the constituents of propofol (egg, soya
or peanut protein)
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11. Acute fulminant hepatic failure
12. Patient has been receiving full time residential nursing care.
13. 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.
14. Patient has an underlying disease that makes survival to 90 days unlikely
15. Patient has been previously enrolled in the SPICE study.
9 STUDY PROCEDURES
9.1 Randomisation
Randomisation will be conducted through a password-protected, secure website using a central,
computer-based randomisation program. Treatment allocation will be stratified by site and by whether
there is presence or absence of suspected/ proven sepsis [8].
Patients who satisfy inclusion criteria and have no exclusion criteria will be randomly assigned in a 1:1
ratio to either Early Goal-Directed Sedation or to standard care sedation using a block randomisation
with variable block size.
9.2 Consent
This is a process of care sedation trial where the sedative agents used in both arm, individually or in
combination are accepted sedatives currently used for mechanically ventilated ICU patients. Many
RCTs have documented the efficacy and safety in isolation of the 3 agents (propofol, midazolam and
dexmedetomidine) used in this trial. These agents have also been recommended by the most recent
International Sedation Guidelines 2013 [(2] and have been deemed not different in providing sedation
to ventilated ICU patients. This study will compare a process of care in sedation using one of the
above agents on its own or in combination as required to maintain a desired sedation level.
The choice of sedation in patients who require mechanical ventilation will have to be made
immediately following initiation of mechanical ventilation for comfort, safety and to facilitate standard
life saving ICU procedures. Therefore, there is urgency in the initiation of sedation and its
management
By virtue of the study’s entry criteria none of the patients who are eligible for this study will be
competent to provide informed consent. The approach to obtaining consent in this study will be
based on that developed from the guidelines in Chapter 4.4 of the NHMRC National Statement [53]
and also from the ANZICS Clinical Trials Group Ethics Handbook for Researchers [54]. The process
for obtaining consent will be according to the following hierarchy:
1. Delayed consent: Where it is not possible or practicable for the patient or the substitute decision
maker (SDM) to consider the study and give consent within an appropriate timeframe, the patient
may be enrolled without prior consent, provided the procedure is in accord with the requirements
of the site’s Human Research Ethics Committee and applicable legislation. When appropriate,
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the SDM, and, in turn, the participant, will be informed of the study and will be able to withdraw
consent for ongoing participation at any time.
2. Informed consent from substitute decision maker (SDM): Where possible, and as authorised by
law, which varies between jurisdictions, consent will be obtained from the participant’s legally
authorised representative.
3. Once subjects are recovered and are able to consider the information sheet, they will be offered
the opportunity to withdraw from study follow-up.
9.3 Supplied dexmedetomidine product
9.3.1 Accountability
Drug accountability is the responsibility of the Principal Investigator which may be delegated to the
study staff at each site.
The site’s allocated supply of dexmedetomidine may only be administered to patients enrolled in this
study and in accordance with this protocol.
A drug accountability log is to be kept to record the study drug:
a) receipt;
b) dispensed to each patient; and
c) date of dispensing.
Any expired dexmedetomidine can be destroyed on site after documentation in the Inventory Log.
Expired drug can be destroyed according to local standard practice. All records and drug
accountability log should be made available for inspection by the project officer.
9.3.2 Handling and dispensing
Hospira Ltd (Melbourne – Australia) will supply, free of charge, to each participating site,
dexmedetomidine sufficient for recruited patients. This will be used for trial purposes only. Research
coordinator/pharmacy will inform Hospira Ltd when resupply is required.
9.3.3 Drug preparations and dilutions
Dexmedetomidine (200 mcg/2mls) will be diluted, in normal saline so that every ml/hr infused = 0.1
mcg/kg/hr. Dexmedetomidine infusion will be given using a dedicated intravenous line and no flushes
are to be given through that line at any time. ICUs that already use a different dilution method for
dexmedetomidine can continue to use their usual dilution. Dexmedetomidine will not be administered
as a bolus.
Other sedative and analgesic infusions should be prepared as per the ICU’s normal practice.
9.4 Background Treatment- Sedative and analgesic treatment
Patients in both groups will, simultaneously, and according to systematic pain assessment, receive
analgesia typically with opioid medications, as determined by the treating clinician. Titration of all
sedatives, within clinically accepted dose ranges, can be administered as clinically appropriate by the
treating clinician in both arms. There is inadequate data on the interaction between remifentanil and
dexmedetomidine, remifentanil is rarely used in ICUs in ANZ to for patients requiring mechanical
ventilation for > 24 hours, therefore, remifentanil use will be precluded in both study arms. Patients in
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both arms will have 4 hourly pain assessments using a Yes/No (if able to report pain) or a modified
critical care pain observation tool (CPOT, if unable to report pain), sedation monitoring using
Richmond Agitation Sedation Scale (RASS) and daily delirium assessment using the Confusion
Assessment Method for Intensive Care (CAM-ICU). All aspects of treatment, other than the sedation
therapy, will be determined by the treating clinician.
9.5 Study intervention- Early Goal-Directed Sedation
9.5.1 Early Goal-Directed Sedation Appendix 1 A
Patients randomised to the EGDS arm will receive a sedative infusion of Dexmedetomidine shortly
after initiation of mechanical ventilation. Dexmedetomidine infusion will be commenced without a
loading dose at a rate of 1.0 mcg/kg/hour and will be varied between 0 – 1.0 mcg/kg/hr to maintain
light sedation (patient able to maintain eye contact > 10 sec) as per RASS sedation range of -2 to +1.
This level of sedation will be the target throughout the study unless otherwise specified by the treating
clinician.
Dexmedetomidine infusion will be continued until sedation is no longer clinically indicated up to a
maximum of 28 days after enrolment.
Supplemental propofol can be used, always at the lowest effective dose, to:
a) Provide sedation during commencement and initial titration of dexmedetomidine infusion;
b) Optimize sedation and achieve the level of sedation specified by the treating clinician at any time
when dexmedetomidine alone and at maximum or maximum tolerated dose was deemed insufficient
to provide patient comfort and safety;
c) Provide rescue sedation for immediate control of sudden breakthrough agitation at any time.
In addition, boluses and/or infusion of opioids, as chosen by the treating clinician, will be administered
simultaneously, if required, at a dose specified by the treating clinician to provide analgesia.
Injectable clonidine and remifentanil will not be administered to any patient. Benzodiazepines (such
as midazolam, diazepam and clonazepam) will not be administered to any patient in this arm, unless
deemed absolutely necessary by the treating clinician for conditions such as convulsions, palliation,
procedural anaesthesia, concomitant neuromuscular blockade or refractory agitation. If present,
breakthrough agitation will be treated by a protocolised algorithm described below.
9.5.2 RASS -3 to -5: Oversedation.
a) If propofol is being administered, reduce by 20 mg/hr every 15 min until light sedation is
achieved. Cease propofol if necessary.
b) Once propofol is no longer being administered, reduce Dexmedetomidine in increments of 0.2
µg/kg/ml every 30 minutes until light sedation is achieved.
9.5.3 (RASS +2 to +4) Breakthrough agitation in EGDS
1. Increase dexmedetomidine infusion to maximum dose of 1.0 µg/kg/hour if not already at this
dose.
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2. Administer boluses of propofol or increase propofol infusion rate or both, as needed. The
maximum dose of propofol used to treat agitation is up to 200 mg/hr.
3. Administer intravenous haloperidol boluses 1.0 to 5 mg as clinically required OR a non-
benzodiazepine antipsychotic agent, as chosen by the treating physician, such as quetiapine
12.5 to 100 mg twice daily enterally with lower doses for elderly patients.[55]
4. If significant agitation persists and patient safety and comfort are not being achieved, one or
more benzodiazepine such as midazolam can be administered, by bolus or infusion or both, as
chosen by the treating clinician.
9.5.4 Neuromuscular blockade required for EGDS group
Patients in the EGDS arm who require neuromuscular blockade after randomisation must receive
adequate sedation (preferably propofol) to prevent awareness during paralysis. Concurrent
dexmedetomidine infusion may continue during this period, however, once there is no need for further
neuromuscular blockade, sedative management should continue as per intervention protocol.
9.6 Study intervention- Standard Care Sedation Arm Appendix 1 B
9.6.1 Standard Care Sedation Arm Appendix 1 B
Patients randomised to the standard care sedation arm will receive sedative drugs chosen by the
treating clinician. Based on the information from our longitudinal cohort [6] and the EGDS Pilot trial,
most patients in this group are likely to receive midazolam (1-8 mg/hour), propofol (50-200 mg/hour),
or both. These agents will be infused to achieve light sedation whenever clinically appropriate as
specified by the treating clinician. Light sedation (RASS -2 to +1) is the default target sedation
otherwise.
The use of remifentanil or dexmedetomidine for initial and maintenance sedation will be precluded.
9.6.2 Management of agitation and delirium
Breakthrough delirious agitation is common, particularly during discontinuation of sedative
medications. If this occurs, patients in the standard care arm should have their current sedation
prescriptions optimised, with subsequent treatment including the administration of enteral quetiapine
50 to 200 mg per day or intravenous haloperidol (up to 5 mg IVI every 4 hours), or both. If the
patient’s RASS remains greater than +2 despite these interventions, dexmedetomidine can be used
as a drug of last resort at the discretion of the senior treating clinician.
9.6.3 Neuromuscular blockade required for standard care sedation group
Patients in the standard care arm who require neuromuscular blockade after randomisation must
receive adequate sedation as per standard care at the discretion of the treating clinician to prevent
awareness during paralysis.
9.7 Discontinuation of treatment
Primary sedative infusion in both arms of the study will be continued until sedation is no longer
required or up to 28 days of therapy. Sedative or analgesic infusion may continue after extubation if
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clinically required. If sedation is deemed necessary beyond 28 days after enrolment, the choice of
sedative regimen will be determined solely by the treating clinician.
9.8 Blinding of study treatments
This is a trial of a protocolised process of care and therefore the treating clinicians cannot be blinded
to trial arm allocation. Whilst blinding is a highly desirable feature in RCTs it is not feasible in
answering this research question. Bias will be minimised by ensuring concealment of treatment
allocation prior to central randomisation, by protocolising treatment in the Early Goal-Directed
Sedation group and by using all-cause 90-day mortality as a robust outcome measure that is not
subject to ascertainment bias. The pilot study conducted previously provides robust evidence that
this trial design will achieve separation between intervention and control arms.
10 ETHICS
10.1 Guiding principles
This study is to be performed in accordance with the ethical principles of the Declaration of Helsinki
(June 1964 and amended 1975, 1983, 1989, 1996, 2000, 2008 and Note of Clarification 2002 and
2004), ICH GCP Notes for Guidance on Good Clinical Practice (CPMP/ICH/135/95) annotated with
Therapeutic Goods Administration comments and NHMRC National Statement on Ethical Conduct in
Human Research (2007).
10.2 Ethical issues of the study
Patients who will be eligible for this study are mechanically ventilated and critically ill, and require
sedative medications for comfort, safety and to facilitate standard life saving ICU procedures. Critical
illness commonly leads to an altered mental state which will affect the patient's mental capacity. In
addition, their cognitive capacity is temporarily diminished due to a combination of factors such as the
severity of their illness and standard intensive care treatments including ventilatory assistance,
sedatives and analgesics. The presence of agitation and or delirium and the need for comfort
sedation further delays the return of the patient's ability to make informed decisions during their stay
in the intensive care unit.
Eligible patients will need immediate administration of sedative medications by infusion. The decision
about which medication is to be prescribed therefore needs to be made urgently. The sedative
medications to be compared in this trial are all currently and commonly used, and have been shown
to be safe and effective to achieve comfort and safety for patients who are receiving, mechanical
ventilation in an ICU.
As a consequence [because of the immediacy of the situation and the urgent need to make a decision
about choice of drug] it is proposed to enrol patients in the study without prior informed consent [see
paragraphs 4.4.13 and 4.4.14, National Statement on Ethical Conduct in Human Research, at
http://www.nhmrc.gov.au/_files_nhmrc/file/publications/synopses/e72-jul09.pdf.
Consent from the patient’s ‘person responsible’ needs to be obtained in order for the patient to be
eligible to continue to participate in the study. If the patient’s ‘person responsible’ declines consent for
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ongoing participation, the patient will no longer receive study treatment. The participant will be
informed about the study as soon as possible and consent obtained for ongoing participation.
10.3 Ethics committee approval
In Australia, this protocol will be submitted to a Human Research and Ethics Committee constituted
according to the NHMRC National Statement on Ethical Conduct in Human Research (2007) for each
institution or a Lead HREC. In New Zealand, this protocol will be submitted to the appropriate Health
and Disability Ethics Committee, accredited by the Health Research Council and constituted in
accordance with the Operational Standard for Ethics Committees March 2002. Approval of the
protocol and related documents will be obtained prior to the start of the study at each site.
It is the Investigator’s responsibility to ensure that all conditions for approval of the study are met and
that amendments to the protocol are reported to the HREC as required by that Committee.
10.4 Confidentiality of patient data
Patients will be randomised via a secure website and will be allocated a unique study number. The
site research coordinator will compile an enrolment log including the patient’s name, date of birth,
hospital identification number, unique study number and date and time of randomisation. The
enrolment log which contains identifiable information will not leave the research office of the study
site. The enrolment log and study data will be kept separately in the locked research office at the
study site. .All other study data will be identified by the unique study number only. Study data is
entered into a secure, password protected data base. No identifying data will be entered into the
database.
Follow up of patients at 90 will be conducted by the research staff at the study site via telephone call.
The research staff at the study site will perform the follow up IQCODE and EQ-5D surveys via
telephone at 180 days. Sites can have the option of posting the surveys prior to the telephone call if
they deem this will streamline the telephone interview. .
10.5 Information and consent documents
Patient and next-of-kin (Person Responsible) information sheets, and consent forms will be developed
based on site requirements and local regulatory requirements.
11 DATA MANAGEMENT
11.1 Data collection methods
Streamlined data collection instruments and procedures will be used to minimise the work in study
centres. The case report form (CRF) will be developed by the ANZIC-RC and made available to the
participating sites as a paper CRF for ease of data collection. All data will be collected by trained staff
at each study site using the paper CRF and the Research Coordinators will enter all required data
described in the protocol onto the CRFs directly from the source data. Information recorded in the
CRF should accurately reflect the subject’s medical/ hospital notes and must be completed as soon
as it is made available. The intent of this process is to improve the quality of the clinical study by
providing prompt feedback to the Investigators on the progress of the data submitted and to enhance
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the ability to collect early safety information in a more timely fashion to fully comply with the intent of
GCP requirements. Collected data will then be entered into a secure, password protected web based
CRF.
11.2 Data variables collected
The table below provides a summary and time schedule of the data to be collected in the trial CRF:
11.2.1 At enrolment
• Demographic data (initials, date of birth, age, sex, estimated body weight)
• Date and time of hospital admission
• Date and time of ICU admission, readmission to same ICU within same hospital stay
• Source of ICU admission
• Components of APACHE II score
• ICU admission diagnosis (APACHE III diagnosis code)
• Date and time of first intubation
• Treatment group and randomization number
• Inclusion / exclusion check list
• Name and dose of all intravenously administered sedative and analgesic agents administered
in this hospital between time of intubation and time of randomisation.
11.2.2 Duration of ICU admission until discharge or day 28, whichever occurs first
Every 4 hours:
• Actual RASS
• Target RASS
• Pain assessment: (assessed by bed side nurse)
o Patient can communicate: Is the patient in pain? Yes / No
o Patient can’t communicate: Does the patient appear in pain? Yes / No (Critical Care
Pain Observation Tool C-POT)
Daily
• CAM-ICU (when RASS > -3) (Monday to Friday) and weekends as possible
• Name and daily dose of all administered parenteral bolus and infusion of sedative and
analgesic agents mg (mcg) / kg / day. Collect concentration of infusions and total volume
infused in addition to total dose given by boluses
• If deeply sedated, indication for deep sedation
• Use of neuromuscular blockade other than for intubation/tracheostomy/procedure
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• Use of physical restraints
• Occurrence of administration of vasopressors/inotropes
• Administration of dialysis
• Occurrence of out of ICU transport
• Occurrence of a mobilization episode (tilt table, sitting on side of bed or in a chair, out of bed,
standing, stationary walking or an actual walk
• One or more episodes of extubation or de-cannulation
• Time of extubation or decannulation, if occurred on that day
• Unplanned extubation or decannulation
• Ventilation time (hours) Reintubation or recannulation
o Time of re-intubation or re-cannulation if occurred on that day
11.2.3 Episode outcome data at ICU and Hospital discharge
• Date and time of ICU discharge
• Survival status at ICU discharge
• Date and time of hospital discharge
• Survival status at hospital discharge
• Tracheostomy performed and, if yes, date and time
11.2.4 Episode end of study outcomes
• Survival status at 90, 180 day
• Dependency status at 180 day
o Full time nursing home or rehabilitation centre
•
• Cognitive function measured by Informant Questionnaire on Cognitive Decline in the Elderly
(IQCODE) at 180 days post randomisation by phone [56]
• HRQoL measured by EQ-5D (by phone) at 180-day [12] [57]
11.3 Data management
Data entry and data management will be coordinated by the Project Manager and the ANZIC-RC,
including programming and data management support.
11.4 Data quality
Several procedures to ensure data quality and protocol standardisation will help to minimise bias.
These include:
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� Start-up meeting for all research coordinators and investigators will be held prior to study
commencement to ensure consistency in procedures;
� A detailed dictionary will define the data to be collected on the case report form;
� The data management centre will perform timely validation of data, queries and corrections if
errors are found during quality control checks;
� Data monitoring will occur as described below.
11.5 Monitoring
The study will be monitored by a representative of the ANZIC-RC. A site initiation teleconference or
visit will be conducted before site activation; at least 1 routine monitoring visit will be conducted during
the recruitment period; and a close out visit. Email and telephone communication will supplement site
visits.
A monitoring report will be prepared following each visit and reviewed by the management committee
if appropriate. A follow up letter will be sent to the principal investigator and research coordinator at
the site and will be filed in the site investigator file.
Medical records, any other relevant source documents and the site investigator files must be made
available to the ANZIC-RC representative for these monitoring visits during the course of the study
and at the completion of the study as needed.
12 STATISTICAL CONSIDERATIONS
12.1 Statistical and analytical plan
The sample size for this study has been calculated based on the mortality of 25.8% observed in our
recently conducted study [6]. A study population of 4000 patients will provide 90% power at a two-
sided significance level of 0.05 to detect an absolute difference in risk (either an increase or
decrease) in 90-day mortality between the intervention and control groups of 4.5%. This effect size is
53% of the pooled effect size (OR 0.67 95% CI 0.53-0.84) of the two main protocolised bundled
sedation strategy trials (Table 2) and also a difference in absolute risk (number needed to treat=22)
that would be considered clinically important and likely to influence practice. This study size also
allows for a potential withdrawal and loss to follow-up rate of 5% (all ANZICS CTG trials have had
withdrawal/loss to follow up rates <5%). One interim analysis will be conducted when 2000 patients
have been followed-up for 180 days. Any additional reviews of the data or formal interim analyses
may be performed at the discretion of the Data Safety Monitoring Committee.
13 SAFETY
13.1 Data Safety Management Committee
An independent Data and Safety and Monitoring Committee (DSMC), comprising experts in clinical
trials, biostatistics and intensive care medicine will be established before patient enrolment to review
all trial protocols.
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The DSMC will be forwarded a copy of all serious adverse events (SAE) reports as soon as they
become available to the ANZIC-RC. The DSMC will review all SAE reports that they receive and
report back to the management committee of the study if any further action is required.
The DSMC will provide assistance in the preparation of any Adverse Drug Reaction Reports to the
Therapeutic Goods Administration (TGA) in Australia, the Centre for Adverse Reactions Monitoring
(CARM) under the guidance of the Medicines Adverse Reactions Committee (MARC) in New
Zealand.
One midpoint interim analysis (after primary outcome data is available for 2000 patients) will be
performed to assess accumulated safety data. .The DSMC may, in its absolute discretion, request
assessment of any trial data at any time.
13.2 Adverse events
Adverse events (AEs) are defined as any untoward medical occurrence in a patient or clinical
investigation subject administered an investigational intervention and which does not necessarily have
to have a causal relationship with this treatment (adapted from the Note for Guidance on Clinical
Safety Data Management: Definitions and Standards for Expedited Reporting (CPMP/ICH/377/95 July
2000).
It is recognised that the intensive care patient population will experience a number of common
aberrations in laboratory values, signs and symptoms due to the severity of the underlying disease
and the impact of standard therapies. These will not necessarily constitute an adverse event unless
they require significant intervention or are considered to be of concern in the investigator’s clinical
judgement.
In all cases, the condition or disease underlying the symptom, sign or laboratory value should be
reported e.g. renal failure rather than hyperkalaemia, and agitation rather than self-extubation.
13.3 Serious adverse events
13.3.1 Definition of a SAE
SAEs are defined in accordance with the Note for Guidance on Clinical Safety Data Management:
Definitions and Standards for Expedited Reporting (CPMP/ICH/377/95) (July 2000) as any untoward
medical occurrence that:
• Results in death
• Is life-threatening
• Requires inpatient hospitalisation or prolongation of existing hospitalisation
• Results in persistent or significant disability/incapacity
• Is a congenital anomaly/birth defect
• Is an important medical event which may require intervention to prevent one of the previously
listed outcomes
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The baseline mortality of intensive care patients enrolled in trials will be high due to the critical illness
that has necessitated their ICU admission. They will frequently develop life-threatening organ
failure(s) unrelated to study interventions and despite optimal management. Therefore, consistent
with the advice of Cook et al, events that are part of the natural history of the primary disease process
or expected complications of critical illness will not be reported as serious adverse events in this trial.
[58] Additionally, events already defined and reported as study outcomes e.g. mortality, re-admission
to ICU, will not be labelled and reported separately as adverse events or SAEs unless they are
considered to be causally related to the study intervention or are otherwise of concern in the
investigator’s judgement.
13.3.2 SAE Reporting
SAEs which occur from the time of commencement of study treatment to day 90 will be reported to
the coordinating centre (ANZIC-RC). SAEs should be reported to the ANZIC-RC within 24 hours of
study staff becoming aware of the event. Minimum information to report will include:
• Patient initials and study number
• Nature of the event
• Commencement and cessation of the event
• An investigator’s opinion of the relationship between study involvement and the event (not
related, unlikely, possibly, probably or definitely related).
• Whether treatment was required for the event and what treatment was administered.
14 FUNDING
Study funding has been secured from a National Health and Medical Research Council project grant.
Dexmedetomidine is supplied free of charge to the study by Hospira Inc USA.
15 PUBLICATION
The study will be conducted and published in the name of the SPICE Investigators, the ANZIC-RC
and the ANZICS CTG. The principal publication from the study will be in the name of the SPICE
Investigators with full credit assigned to all collaborating Investigators, Research Coordinators and
Institutions. Where individual names are required for publication they will be those of the Writing
Committee, with the Chair of the Writing Committee listed first and subsequent authors listed
alphabetically.
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17 APPENDIX 1:
17.1 Early Goal Directed Sedation Algorithm
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17.2 B: Standard Sedation Algorithm
Recommended