early goal directed sedation vs. standard care sedation ... · dr ian seppelt senior staff...

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: [email protected]

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: [email protected]

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


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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


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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


Date

14 June 2013

Steve Webb


Date

14 June 2013

Michael Reade


Date

14 June 2013

Ian Seppelt


Date

14 June 2013

Colin McArthur


Date

14 June 2013

Frances Bass


Date

14 June 2013

Leonie Weisbrodt


Date

14 June 2013

Simon Erickson


Date

14 June 2013

Belinda Howe


Date

14 June 2013

Lynne Murray


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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


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



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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


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


DEX infusion + rescue propofol

Midazolam Reduced ventilation time, ICU stay and agitation

PRODEX (498) 4

JAMA 2012


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

early goal directed sedation vs. standard care sedation ... · dr ian seppelt senior staff...

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