1. Prof Yahya SHEHABI & Ms Belinda HOWE
Sedation Practice in Intensive Care Evaluation Early Goal Directed Sedation SPICE III Start-up Initiation Meeting
Prof Yahya SHEHABI & Ms Belinda HOWE

2. 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

4. 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

5. Sedation Practice in Intensive Care Evaluation The SPICE Program Endorsed by the ANZICS Clinical Trials Group

6. Supported by a Project Grant NHMRC Endorsed by Australian New Zealand Intensive Care Society Clinical Trials Group
Study Protocol

7. 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

8. 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

9. Design
Multi-centre multi-national prospective un-blinded 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

10. 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.

11. 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.

12. 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)

13. 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

14. 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

15. 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

17. Supported by a Project Grant NHMRC Endorsed by Australian New Zealand Intensive Care Society Clinical Trials Group
Algorithms

18. EGDS detailed Algorithm
Patient is mechanically ventilated
Adequate analgesia
Clinicians choice Opioid, other
Dexmedetomidine infusion
1 mcg/kg/hr. (No Loading)
Propofol mg/hr.
Sedation no longer needed
Stop Infusion
On-going Sedation
RASS
≥ 2
≤ -3
-2 to +1
↓ dexmedetomidine
0.2 mcg/kg/hr
every 30 minute
Dexmedetomidine
0 – 1 mcg/kg/hr.
Propofol
0 – 70 mg/hr.
Pain assessment
Sedation assessment
Stop propofol first

19. EGDS – when to give propofol ?

20. EGDS When to consider midazolam?
Palliation
Procedures
Tracheostomy, brochoscopy
Convulsions
Agitation unresponsive to EGDS protocol
EGDS at maximum dose not achieving target sedation

21. 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
Dexmed at max tolerated preferably > 1 mcg/kg/hr
Add ± Propofol infusion as needed up to 200 mg/hr
Quetiapine 12.5 to 100 mg per day
Haloperidol (up to 5 mg IVI every 4 hours), or both
Midazolam at the discretion of the treating clinician

22. Standard Care Sedation

23. 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
Optimize Propofol, midazolam or both
Quetiapine 12.5 to 100 mg per day
Haloperidol (up to 5 mg IVI every 4 hours)
Dexmedetomidine at the discretion of the treating clinician.

24. Supported by a Project Grant NHMRC Endorsed by Australian New Zealand Intensive Care Society Clinical Trials Group
Managing HR and BP

26. Adrenergic effects of dexmedetomidine

27. BP and HR effects
The hemodynamic response (mean 6 SD) to target, controlled infusions of dexmedetomidine. There were significant changes in cardiac output and heart rate after infusion step 1. Stroke volume remained unchanged until higher doses. Mean arterial blood pressure (MAP) showed a biphasic (low, then high) response to increasing infusions of dexmedetomidine. *Significant change from preinfusion baseline, P < 0.05.

28. Sedation and analgesia effects
Alertness
Sedation scores (mean 6 SD) in response to target, controlled infusions of dexmedetomidine. The composite Observer Assessment of Alertness/Sedation score can range from 9 to 20, with 20 indicating maximum alertness. VAS sedation (VASsed) is a visual analog scale with end points of very alert (0) to very sedated (100). §Significant change in variable during increasing dexmedetomidine infusions, determined with use of nonparametric statistics.

29. 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.

30. 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

31. Supported by a Project Grant NHMRC Endorsed by Australian New Zealand Intensive Care Society Clinical Trials Group
Study logistics

32. 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

33. Study Logistics- Randomisation
Login to website  Generic logins for randomisation only Enter randomisation information  Patients stratified by severe sepsis  Pt ID number, allocation on screen &

34. 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

35. 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

36. 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

37. RASS

38. 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

39. CAM-ICU

40. Consent Deferred consent - approved by REC
Pt randomised & then consultee declaration
Personal consultee
Nominated consultee
 Pt consent to continue if appropriate
 Document consent process

41. Consent Pt deceased prior to consent obtained?
REC approval data usage
 Consultee refuses?
Clarify: Treatment?
Data usage?
Follow Up? →Any contact?
→ Surveys only?

42. 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

43. 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

44. 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

45. 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.

46. AE/SAEs- Definition SPICE study is UNBLINDED → Bias
 Report equally events in both arms

47. Questions ?