Transcript up UK SPICE Shehabi Howe Aug 2015

Sedation Practice in Intensive Care Evaluation
Early Goal Directed Sedation SPICE III
Start-up Initiation Meeting
Prof Yahya SHEHABI & Ms Belinda HOWE
Disclosure
• SPICE Program is endorsed by ANZICS
Clinical Trials Group
– Managed by the ANZIC RC Monash University
• SPICE III RCT is funded by an Australian
Government NHMRC Grant
• Malaysian SPICE sites funded by IJN
Foundation grant
• The study drug Dexmedetomidine is
provided by Orion to study sites
2
Early Goal Directed Sedation
Elements and Hypothesis
• It is plausible that strategy combining:
– Early commencement of sedative intervention
– Effective analgesia
– Utilizing dexmedetomidine as a primary sedative
agent
• Rousable sedation and reduced overall sedation depth
• Facilitate wakefulness and ventilation weaning
• Reduce overall sedative and opioid load
– Targeted light sedation RASS -2 to +1.
– Avoiding and minimizing benzodiazepines
• Is feasible and likely to reduce early deep
sedation and improve clinical outcomes
4
Sedation Practice in Intensive
Care Evaluation
The SPICE Program
Endorsed by the ANZICS
Clinical Trials Group
Supported by a Project Grant NHMRC 2012
Endorsed by Australian New Zealand
Intensive Care Society Clinical Trials Group
6
Hypothesis
Early Goal-Directed Sedation (EGDS),
compared to standard sedation practice,
reduces 90-day all-cause mortality in
critically ill patients who require
mechanical ventilation
Study Aim
• To investigate the clinical effectiveness of an
Early Goal Directed Sedation Strategy on
– 90 day All-Cause mortality
– Cognitive function at 180 days
– Institutional dependency at 180 days
Design
• Multi-centre multi-national prospective unblinded randomised controlled trial
– Recruit 4000 patients to detect 4.5% ARR in prim
outcome with 90% power and α = 0.05
• Central randomisation via secured website
– Stratify by site and suspected or proven sepsis
• EGDS compared with current practice
– Interim analysis at 2000 patients.
• Delayed consent
Study Population – Who is Included ?
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.
Exclusion Criteria
• Age < 18 years
• Pregnant and/or lactating
• Has been intubated for greater than 12 hours in an
intensive care unit (excluding time spent intubated
within an operating theatre or transport)
• Proven or suspected acute primary brain lesion
that may result in global impairment of conscious
level or cognition, such as traumatic brain injury,
intracranial haemorrhage, stroke, or hypoxic brain
injury.
11
Exclusion Criteria
• Proven or suspected cervical spinal cord injury or
pathology that may result in permanent or prolonged
weakness
• Admitted as a consequence of a drug overdose or
burns
• Receiving or expected to need ongoing
neuromuscular blockade
• Known sensitivity to any of the study medications or
the constituents of propofol (egg, soya or peanut
protein)
12
Exclusion Criteria
• Mean arterial blood pressure (MAP) that is less than
50 mmHg despite adequate resuscitation and
vasopressor therapy at time of randomisation
• Heart rate less than 55 beats per minute unless the
patient is being treated with a beta-blocker or a high
grade atrio-ventricular block in the absence of a
functioning pacemaker
• Acute fulminant hepatic failure
13
Exclusion Criteria
• Patient has been receiving full time residential
nursing care
• Death is deemed to be imminent or inevitable
during this admission and either the attending
physician, patient or substitute decision maker is not
committed to active treatment
• Patient has an underlying disease that makes
survival to 90 days unlikely
• Patient has been previously enrolled in the
SPICE study
14
Study measurements
At randomization and 4 hrly thereafter
• Pain assessment
–Visual Analogue Scale in patients able to communicate
–Critical Care Pain Observation Tool (CPOT) if patient unable to
report pain
• Sedation assessment
–Richmond Agitation Sedation Scale RASS
Within 24 hours of randomization and daily thereafter
• Delirium assessment
–Confusion Assessment Method in Intensive Care CAM-ICU
16
Study Outcomes
Supported by a Project Grant NHMRC 2012
Endorsed by Australian New Zealand
Intensive Care Society Clinical Trials Group
1
7
EGDS detailed Algorithm
Patient is mechanically ventilated
Sedation
assessment
Pain
assessment
Clinicians choice
Opioid, other
On-going
Sedation
Adequate
analgesia
RASS
≤ -3
Dexmedetomidine infusion
1 mcg/kg/hr. (No Loading)
RASS
≥2
RASS
-2 to +1
Propofol 10-70 mg/hr.
Stop propofol first
↓ dexmedetomidine
0.2 mcg/kg/hr
every 30 minute
RASS
-2 to +1
Sedation no longer needed
Stop Infusion
RASS
-2 to +1
RASS
-2 to +1
Dexmedetomidine
0 – 1 mcg/kg/hr.
Propofol
0 – 70 mg/hr.
EGDS – when to give propofol ?
EGDS
When to consider midazolam?
• Palliation
• Procedures
– Tracheostomy, brochoscopy
• Convulsions
• Agitation unresponsive to EGDS protocol
• EGDS at maximum dose not achieving target
sedation
EGDS Process of Care
Managing Agitation
Breakthrough delirious agitation is common, particularly
during discontinuation of sedative medications. If this
occurs, patients in the EGDS arm should have
1. Dexmed at max tolerated preferably > 1 mcg/kg/hr
2. Add ± Propofol infusion as needed up to 200 mg/hr
3. Quetiapine 12.5 to 100 mg per day
4. Haloperidol (up to 5 mg IVI every 4 hours), or both
5. Midazolam at the discretion of the treating clinician
2
2
Standard Care Sedation
Standard Process of Care
Managing Agitation
Breakthrough delirious agitation is common,
particularly during discontinuation of sedative
medications. If this occurs, patients in the standard
care arm should have
1.Optimize Propofol, midazolam or both
2.Quetiapine 12.5 to 100 mg per day
3.Haloperidol (up to 5 mg IVI every 4 hours)
4.Dexmedetomidine at the discretion of the
treating clinician.
Supported by a Project Grant NHMRC 2012
Endorsed by Australian New Zealand
Intensive Care Society Clinical Trials Group
2
4
Adrenergic effects of dexmedetomidine
BP and HR effects
Sedation and analgesia effects
Alertness
Heart Rate and Blood Pressure Change
•
•
•
•
•
•
Patients receiving sedative infusions and analgesics to provide comfort and pain
relief. Therefore, a reduction in blood pressure and heart rate is expected with
reduced anxiety, agitation and sympathetic drive.
Dexmedetomidine is known to produce a reduction in heart rate in most patients.
This occurs with doses as low as 0.1 mcg/kg/hr and is dose related to a max of 1
mcg/kg/hr. Peak effect occurs at 8 to 12 hours after initiation of dexmedetomidine.
Most patients will have a reduction in Heart Rate (HR) that is NOT clinically
relevant i.e. BP is stable and therefore may not require intervention.
Less than 5% of patients may have a reduction in HR that may be clinically
relevant i.e. HR < 55/min with a low BP and hence needs treatment.
It takes 6 to 8 hours for the sympatholytic and bradycardia effect to recover
following dexmedetomidine dose reduction or cessation of the infusion.
Dexmedetomidine produces a bimodal effect on BP dependent on plasma
concentration achieved:
– At low dose, 0.1- around 0.7 mcg/kg/hr - produces a dose dependent reduction
in BP.
– At higher dose, greater than 0.7 mcg/kg/hr - produces a dose dependent
increase in BP.
Managing HR and BP
• HR is < 55/min + adequate BP with CV stability  observe (check
perfusion status).
•
• HR is < 55/min + borderline or low BP:
– You may give atropine 300 mcg IVI to reduce possible vagal effect.
– If no improvement within 5 min, consider a low dose dobutamine 2
mcg/kg/min or adrenaline 0.05 mcg/kg/min (Clinician’s choice).
– ? reduce Dexmedetomidine infusion by 0.2 mcg/kg/hr. Please note the
long offset time for bradycardia. Maintain RASS target as per protocol.
– You may increase dobutamine / adrenaline to the desired effect.
•
• Low BP + normal HR or borderline bradycardia = treat per usual with
fluid boluses and/or vasopressor of choice.
– Metaraminol 0.5 mg bolus for immediate temporising effect.
– Noradrenaline infusion (0.05 mcg/kg/min for sustained effect
Supported by a Project Grant NHMRC 2012
Endorsed by Australian New Zealand
Intensive Care Society Clinical Trials Group
3
1
Study Logistics- Screening
 Screening & randomisation → 24/7
 Screen all pts who are
commenced on IMV or
arrive in ICU on IMV
 If meet ALL inclusions
But have an exclusion → Screening log
 Access to phone number for queries
Study Logistics- Randomisation
Login to website https://spicestudy.org
 Generic logins for randomisation only
Enter randomisation information
 Patients stratified by severe sepsis
 Pt ID number, allocation on screen & email
Dexmedetomidine or Standard Care
DEX supplied by Orion
- for 10 EGDS pts at a time
DEX can be made up as per unit protocol
DEX dosing tool is optional
DEX dispensing log & reconciliation log
-
Patient randomised- What Next?
 SPICE study Tool package
- EGDS with DEX or
- Standard Care – Clinician’s choice
 If EGDS with DEX, use DEX stock
for study only
 Commence DEX shortly after randomisation
RASS & Pain Assessments
 RASS most valid and reliable sedation assessment tool
for measuring quality & depth of sedation in adult ICU
patients (SCCM PAD, 2013)
 Aim RASS -2 to +1, in both study arms
 If RASS aim is NOT -2 to +1 e.g. Deep
sedation (RASS -3 to -5) document reason -CRF form 3
 Pain assessments- YES/ NO based on CCPOT
 Assess RASS & Pain 4 hourly (±2) from
randomisation until ICU discharge or D28-CRF form 3
RASS
CAM-ICU
 the most valid and reliable delirium monitoring
tool in adult ICU patients (SCCM PAD, 2013)
 Perform CAM-ICU only if RASS -2 to +1
 Assess once per day minimum
 Continue until ICU discharge or D28 -CRF form 3

CAM-ICU +ve = Delirium,
CAM-ICU –ve = NO Delirium,
Unable to assess
CAM-ICU
Consent
 Deferred consent - approved by REC
 Pt randomised & then consultee
declaration
- Personal consultee
- Nominated consultee
 Pt consent to continue if appropriate
 Document consent process
Consent
Pt deceased prior to consent obtained?
REC approval data usage
 Consultee refuses?
Clarify: Treatment?
Data usage?
Follow Up? →Any contact?
→ Surveys only?
Follow Up
D90 Follow Up
 Vital status only
Primary outcome is D90 status
D180 Follow Up
Vital status & location, EQ5D, IQCode
Completed over the phone
SAEs- Definition
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
ICH GCP July 2000
SAEs- Definition
Guidance from SPICE DSMC:
DO NOT report as SAEs events already defined and
reported as study outcomes
e.g. mortality, re-admission to ICU
DO report as SAEs events which are:
 Unexpected event
 Possibly related to the study
 of concern in the investigator’s judgement
AE/SAEs- Definition
 Bradycardia (HR<55) requiring intervention
- pacing, pharmacological support, or modification of
dexmeditomidine or other medication dose
 Hypotension which is clinically significant
Is it SAE?
Fatal or life threatening
If NOT, then AE.
AE/SAEs- Definition
SPICE study is UNBLINDED → Bias
 Report equally events in both arms
Questions ?