1. Sedation & Analgesia Dr Samir Sahu, Dr Niraj Mishra,
Dr Samir Mishra, Dr D. Bindhani,
Dr Sanghamitra Mishra, Dr Rakesh Roy

2. Pharmacological Principles
Volume of Distribution
Hydrophilic – low – morphine
Lipophilic – high – midazolam
Hepatic dysfunction – flow dependant – morphine
P-450 – midazolam. Fentanyl
Genetic variability – midazolam, Fentanyl

3. Analgesics Drug Onset Half-life Lipophylity Metabolism
Active Metabolit
Genetic Variation
Fentanyl
<1 min
2-4 hr
+++
CYP3A4/5
Yes
Morphine
5-10 min
3-4 hr ++
Glucoronidation

4. Opoids - Complications
Hypotension
Respiratory depression
Gastric retention & ileus
Constipation

5. Sedatives Drugs Onset Half-life Lipophil Metabolism Active Metabolites
Genetic
Midazolam
2-5 min
3-12 hrs
+++
Hydroxyl
Yes
Lorazepam
5-20 min
10-20 hrs ++
Glucuroni No
Diazepam
20-50 hrs
Hydroxy
Propofol
1-2 min
hrs

6. Benzodiazepines - complications
Delirium
Post traumatic stress disorder

7. Propofol Decreases ICP Not affected by renal & hepatic failure
Hypotension
Immunosuppressant effects
Change Infusion sets every 12 hours
Propofol related infusion syndrome (PRIS) (>83 mcg/kg/min>48 hrs)

8. Unwanted side-effects of sedative agents
General
Over sedation
Delayed awakening/extubation
Benzodiazepines
Hypotension
Respiratory depression
Agitation/Confusion
Clonidine
Hypotension
Rebound HTN
Bradycardia
Propofol
Hypertriglyceridemia
CVS depression
Hypotension
Opioids
Abuse potential
Respiratory depression
Lack of orientation
Constipation

9. Dexmedetomidine Highly selective alpha-2 agonist
Anxiolysis, cooperative sedation without respiratory depression
Onset – 15 min
Peak concentration within 1 hr of infusion
Hepatic metabolism
Not significantly affected by renal failure

10. Overview of Current Sedative and Analgesic Agents
Current choices for sustained sedation in the critically ill include
the benzodiazepines (amnesia)
the opiates (analgesia)
Propofol (easily titratable and less likely to accumulate)
(Semin Respir Crit Care Med. 2001;22(2):165-74)

11. Dexdine vs. Other Sedative/Analgesics Comparison of Clinical Effects
BDZ
Propofol
Opiods
Haloperidol
Dexdine
Sedation 
Anxiolytic
Analgesic
Maintain arousability during sedation & Facilitate weaning
No respiratory depression
Control Delirium

12. Dexdine vs. Other Sedative/Analgesics Comparison of Adverse Effects
BDZ
Propofol
Opiods
Haloperidol
Dexdine
Prolonged weaning 
Respiratory depression
Hypotension
Constipation
Deliriogenic
Tachycardia
Morphine
Bradycardia
Fentanyl

13. What are your practices ?

14. Practices in different ICUs
Short term sedation
Long term sedation
Analgesia
Bolus/infusion

15. Current Sedation Practice
Used in 70% of MV patients
Trend towards lighter sedation guided by sedation assessment tool
Nurse driven sedation protocol
Daily sedation interruption

16. How often the target is achieved?
Target of interventions (sedation) 2,3
Optimum sedation, (neither under- nor over-sedation)
Free from anxiety & pain
Calm & cooperative patient
How often the target is achieved?
Continuous sedation carries the risks associated with oversedation and may increase the duration of mechanical ventilation (MV)1,2
MV patients accrue significantly more cost during their ICU stay than non-MV patients 3
Sedation should be titrated to achieve a cooperative patient and daily wake-up2,3
1. Crit Care. 2000;4(suppl 1):S110, 2. NEJM 2000;342: , 3. Crit Care Med.2005;33:
1. Crit Care. 2000;4(suppl 1):S110, 2. NEJM 2000;342: , 3. Crit Care Med.2005;33:

17. SCCM guidelines 2002 Short term < 24 – propofol or midazolam
Long term >24 – lorazepam
Analgesia – morphine or fentanyl

18. Commonly used Agents Authors Sedation Analgesia Comments
Burry 2009(Canada)
Mida>Propofol
(24%) (19%)
Fentanyl>morphine
(22%) (16%)
40% antipsychotics
O’Connor 2009
(Aus & NZ)
Mida = Propofol
Morphine>fentanyl
Reschreiter 2008 (UK)
<24 hr Propofol
>24 hr Prop = mida
Alfentanil> fentanyl or morphine
Clonidine used for weaning
Payen 2007 (France)
(70%) (20%)
Sufentanil=fentanyl
(40%) (35%)
35% non opoids
Ahmad 2007 (Malaysia)
Midazolam
Morphine
Martin 2007 (Germany)
<24hr propofol(83)
>72 hr mida
<24 hr Sufentanil
>24 hr Remifentanil
Ketamine
Egerod 2006 (Danish)
Propofol> Mida
Fentanyl > Sufentanil
Phenobarb & Clonidine

19. Intermittent Dosing Morphine (56%) Lorazepam (61%) Midazolam (56%)
Haloperidol (81%)

20. Continuous Infusion France >90% Sweden 99% Australia >70%
Canada - 26% in few patients, 38% in 25-75% of patients, 26% in most patients
64% continuous & 10% boluses (Tanios, 2009)
Propofol(87%) & Fentanyl(96%) were more likely to administered as continuous infusion.

21. Do you practice daily interruption of Sedation ?

22. Daily Interruption
Daily interruption of sedative infusion … Kress et al, N Eng J Med 2000
Stop infusion till patient is awake or agitated
Restarted at half the original dose & titrated to clinical targets
Reduced duration of MV
Reduced duration of ICU stay
Better assessment of patients sedation needs
Reduces drug bioaccumulation

23. Safety Screen for Daily interruption
No active seizure
No alcohol withdrawal
No agitation
No paralysis
No myocardial ischaemia
Normal ICP

24. Daily Interruption
Canada 40%
Denmark 31%
Germany 34%

25. Do you have a Sedation & Analgesia Protocol in your ICU ?

26. Sedation Protocols Australia 54% Germany 52% US 64% UK 80% Canada 43%
Reduces duration of MV, ICU stay, reduces treatment delays, Improves communication, Standardizes therapy, increased dedicated education

27. Do you use any Sedation assessment scale in your ICU ?

28. Assessment Tools
Ramsay(1974) – most commonly used
RASS
SAS

29. Protocols, Assessment Tools & Daily Interruptions
Sedation Scale
Patel, 2009
22%
71%
88%
Ramsay 38%
RASS 26%
O’Connors,2009
(Aus & NZ)
20%
43% 8%
Reschreiter, 2008
(UK)
62%
54%
75% (GCS 56%)
SAS 25%
RASS 8%
Payen, 2007
(France)
78%
80%
Ramsay 66%
Martin, 2007
(Germany)
14%
38%
35%(Ramsay)

30. Pain Assessment Tools
CPOT – Critical Care Pain Observation Tool

31. Delirium Assessment Tool
CAM-ICU – confusion assessment method for the ICU

32. Local Survey Apollo Kalinga Cardiac Analgesia Fen/tra/p Tra/mor Fen
Sedatives
Mida
Mida/Lora
Mid MV
20-100%
0-20%
90-100
Short term
Mida/pro
Admn
infusion
bolus
Bolus
Daily int
yes
Yes
Safety scree No
Scale
Ramsay
RASS
Delirium
common
uncommon
Rare
Protocol
NMB
intubation
rarely
post

33. Patient Assessment Is the patient comfortable ?
Is the patient in pain ?
Is the patient agitated ?

34. ‘Wake up & Breath’
Girard et al, (Awakening & Breathing Controlled trial) :Lancet, 2008.
3.1 more ventilator free days
ICU stay & Hospital stay reduced by 4 days

35. Safety screen for SBT No agitation SpO2 >88% with FiO2 50%
PEEP < 8
No myocardial ischaemia
No vasopressors
Inspiratory effort

36. Determinants of Practice
Cost
Duration of action
Familiarity
Level of Experience
Level of Education

37. Strøm et al,Lancet 2010;375:
In the general intensive care unit of Odense University Hospital, Denmark, standard practice is a protocol of no sedation
No sedation or intermittent sedation.
The control group was sedated with 20 mg/mL of propofol for 48 hours and 1 mg/mL of midazolam thereafter, with daily interruption until awake.
Both groups received bolus doses of 2.5 or 5 mg of morphine.

38. Strøm et al,Lancet 2010;375:
Compared with the 58 remaining patients receiving interrupted sedation, the 55 patients receiving no sedation had significantly more days without ventilation (mean, 13.8 ± 11.0 days vs mean, 9.6 ± 10.0 days; mean difference, 4.2 days; 95% confidence interval [CI], ; P = .0191).

39. Strøm et al,Lancet 2010;375:
Patients in the no-sedation group also had a shorter stay in the intensive care unit (hazard ratio [HR], 1.86; 95% CI, ; P = .0316) and a shorter stay in the hospital for the first 30 days studied (HR, 3.57; 95% CI, ; P = .0039). Accidental extubations, the need for computed tomography or magnetic resonance imaging brain scans, and ventilator-associated pneumonia were similar in both groups. However, the no-sedation group had more frequent agitated delirium than the intermittent sedation group (n = 11 [20%] vs n = 4 [7%]; P = .0400).

40. Strøm et al,Lancet 2010;375:
In an accompanying editorial, Dr. Laurent Brochard, from Centre Hospitalier Albert Chenevier–Henri Mondor, and Université Paris-Est, Créteil, France, notes the study limitations but calls the overall results "impressive and promising."
"Use of this strategy will mean that more attention needs to be paid in the daily care of patients, and caregivers will need increased empathy towards patients," Dr. Brochard writes. "Hopefully, these findings will prove beneficial to patients."

41. Sangeeta Mehta, SLEAP Investigators and the Canadian Critical Care Trials Group. JAMA. Published online October 17, 2012.
for critically ill patients receiving mechanical ventilation....a sedation protocol that targeted light sedation, daily sedation interruption did not reduce the duration of mechanical ventilation, offered no additional benefits for patients, and may have increased both sedation and analgesic use and nurse workload.

42. Included surgical and medical patients.
Sangeeta Mehta, SLEAP Investigators and the Canadian Critical Care Trials Group. JAMA. Published online October 17, 2012.
A sedation strategy adding daily interruption to a control group strategy of protocolized sedation that targeted light sedation, which is likely superior to "usual care" of an earlier era.
Reflecting "actual practice in ICUs with variable workloads and ICU staffing models.
Included surgical and medical patients.
The most commonly administered medications to facilitate sedation were midazolam and fentanyl

43. Sangeeta Mehta, SLEAP Investigators and the Canadian Critical Care Trials Group. JAMA. Published online October 17, 2012.
The 2 groups also had similar outcomes for durations of stay in the ICU or hospital, hospital mortality, rates of unintentional extubation, delirium, or tracheostomy.
The interruption group had higher mean daily doses of benzodiazepines and opioids.
Nurse workload was estimated to be higher in the interruption group vs the control group.
Evidence existed that interruption of sedation was more effective for surgical or trauma patients vs medical patients.

44. Pharmaco-economics Cost of drugs Reduced ventilator days
Reduced ICU days

45. CT in ICU sedation- 1
Dexdine vs Midazolam
DXMD( µg/kg/hour) or Midazolam ( mg/kg/hour)
N: 375, adult mechanically ventilated patients; Duration: > 24 hr 10 20 30 40 50 60 70 80
% of patient suffering from Delirium
Enrollment 1 2 3 4 5 6
Treatment Day
Dexmedetomidine reduces
the prevalence of Delirium
Dexmedetomidine
Midazolam
3.7 days
5.6 days 2 4 6
Time to extubation in days
Dexmedetomidine-treated patients
spend less time on ventilator
Dexmedetomidine
Midazolam
P= .01
P= .01
DXMD therapy significantly reduced (vs Midazolam)
Median time to extubation by 1.9 days (3.7 vs 5.6 days, P= .01)
Incidence of delirium by 22.6% (P < .001)
Significantly less tachycardia & HTN requiring treatment
JAMA 2009;301(5):

46. A Cost-Minimization Analysis of Dexmedetomidine Compared With Midazolam for Long-term Sedation in the Intensive Care Unit Dasta JF, Kane-Gill SL, Pencina M, et al Crit Care Med.2010;
Patients who received dexmedetomidine experienced less delirium, fewer nosocomial infections, less tachycardia and hypertension (but more bradycardia), and a shorter time to extubation than patients treated with midazolam. From these data, it appears that the use of dexmedetomidine may be more cost effective, despite higher drug acquisition costs, than the commonly used benzodiazepine anxiolytic medications.

47. Summary
Chose your drugs according to availability, costs & overall benefits
Develop a protocol (Protocolized target-based sedation & analgesia)
Practice daily interruption of continuous sedation
Use an assessment tool to stay at your goal (Indentify goals using validated tools for pain, agitation & sedation
Nurse driven protocol

48. THANK YOU Dexdine Dexmedetomidine Hydrochloride
Good evening everybody. At the outset, I would like to thank you all for sparing your valuable time for this CME on Dexdine.
Dexdine, Dexmedetomidine Hydrochloride, the sedative that ensures patient comfort and safety
Macleods Pharmaceuticals Ltd
21st May 2010; Bhubaneshwar