1. The Art of Sedation in ICU
Yasser Zaghloul MD PhD, FCARCSI (Ireland)

2. Sedation comes from the Latin word sedare.
Sedare = to calm or to allay fear
Hypnosis
Analgesia
± Muscle
Relaxation

3. Sedation comes from the Latin word sedare.
Sedare = to calm or to allay fear
Hypnosis
Analgesia
± Muscle
Relaxation

4. Why sedation is necessary?
To improve patient comfort.
Reduce stress.
Facilitate interventions.
Allow effective ventilation.
Encourage sleep.
?? Prevent post-ICU psychosis.

6. Inadequate Sedation
All ICU patients suffer from severe sleep deprivation.
REM sleep is 6% ( Normal 25 %).
Stress  neuroendocrine response
( ACTH, GH, Aldosterone, Adrenaline, .....)
Release of cytokines  inflammatory response.

7. Non-pharmacological interventions
Good nursing.
Psychological:
- Explanation Reassurance.
Physical:
- Touching & message Environment
- Prevent constipation Physiotherapy.
- Tracheostomy.

8. Sedation-Analgesia Medications
IV Anaesthetics:
- Prpofol Thiopentone.
- Ketamine Etomidate.
Benzodiazepines:
- Midazolam.
- Lorazepam

9. Sedation-Analgesia Medications
Opiodis:
- Morphine
- Fentanyl.
- Remifentanil
α-2 receptors agonists:
Clonidine.
Dexmedetomidine .

10. Sedation-Analgesia Medications
Others:
- Inhalation anaesthetics (Sevoflurane).
- Phenothiazines.
- Butyrophenones (Haloperidol).
- Local Anaesthetics.

11. Choice of the sedative drug
Short-term Vs long-term sedation.
Pain & painful Procedures.
Organ problems (Renal, hepatic, brain, CVS).
Drug withdrawal (Alcohol, heroin, .....)
Prescriber & Prescription.

12. Which Medication?
Soliman et al, Brit J Anaesth 2001;87:186-92

13. IV Anaesthetics; Thiopentone
Acts on the GABAA.
Zero order kinetics (accumulation).
Provides a cerebral protection effect.
Main uses in ICU:
- High ICP.
- Status epilepticus

14. IV Anaesthetics; Propofol
(CH3)2CH
CH(CH3)2 OH
2,6 di-isopropyl phenol
Short-term sedation (< 48 h)

15. IV Anaesthetics; Propofol
Mechanisms of actions:
- Acts on GABAA receptors in the hippocampus.
- Inhibits of NMDA.
 IOP, ICP & CMRO2.

16. IV Anaesthetics; Propofol
Decreases (10 – 30%):
- HR.
- SBP, DBP & MAP.
- SVR.
- CI.
- SV.

17. Target concentrations with ‘Diprifusor’ TCI
Full ‘Diprivan’ PFS is loaded correctly
Finger grip Tag = PMR (Programmaable Magnetic Resonance*)
Aerial
‘Diprifusor’ TCI Subsystem Recognition software/electronics ‘Diprifusor’ TCI Software/ 2 microprocessors
Pump software
Pump hardware

18. Target concentrations with ‘Diprifusor’ TCI38
Target concentrations with ‘Diprifusor’ TCI
1200
↑ Tc
End 8
Calculated concentration
(automatic calculation and display by system)
Target concentration
(selected by anaesthetist, displayed)
Titration 5 6 6 2 3
Age
Wt. Tc 4 4
Infusion rate (ml/h)
100
Blood concentration (µg/ml) 4
1 Start ‘Diprifusor’ TCI with initial target concentration of 6 mg/ml
Rapid bolus (1,200 ml/h) to reach target
2 Variable-rate infusion to maintain initial target
3 10 minutes, select lower target of 4 mg/ml (titrate downwards)
Infusion stops until blood concentration falls to lower target
Resumption of infusion at decreased rate to maintain new target
4 20 minutes, select higher target of 6 mg/ml (titrate upwards)
Another bolus to reach new target
Resumption of infusion at increased rate to maintain higher target
5 30 minutes, end of ‘Diprifusor’ TCI
Blood concentration falls ...
What happens when an initial target concentration has been set?
A ‘Diprifusor’ System can be considered as a “smart pump”. ‘Diprifusor’ TCI Software “commands” the syringe pump to deliver a rapid infusion at a rate of 1,200 ml/h until the pharmacokinetic model calculates that the selected target concentration has been reached. Variable-rate infusions are then provided automatically to maintain the selected target concentration.
The target concentration can be changed at any time by the anaesthetist — and is displayed.
Selection of a higher target concentration results in administration of a bolus followed by infusion at an increased rate. Selection of a lower target concentration results in a temporary discontinuation of infusion followed by resumption at a lower rate. The calculated concentration is displayed continuously both during and after stopping drug infusion. The display of both the selected target concentration and the calculated concentration provides feedback to the anaesthetist.
These principles apply to the commercially-available pumps that incorporate ‘Diprifusor’ as well as to the ‘Diprifusor’ System used for clinical trials. 50 2 1 4 8 12 16 20 24 28
Start; 6µg/ml
Time (hours)

19. IV Anaesthetics; Propofol
Propofol infusion syndrome:
- Rare but fatal.
- 1st described in children.
- Infusion ≥ 5 mg/kg/hr or ≥ 48 hours.

20. Propofol Infusion Syndrome
Clinical features:
- Cardiomyopathy with acute cardiac failure.
- Myopathy.
- Metabolic acidosis, K+
- Hepatomegaly.
Inhibition of FFA entry into mitochondria  failure of its metabolism.

21. IV Anaesthetics - Ketamine

22. IV Anaesthetics - Ketamine
Phencyclidine derivative.
High lipid solubility (5–10 times > thiopental) crosses BBB faster.
Non-competitive antagonism at NMDA receptor

23. IV Anaesthetics - Ketamine
 HR, BP.
 CBF, ICP & CMRO2.
Bronchial smooth muscle relaxant.
Excellent analgesic.
Dose: 5-30 µg/kg/min.

24. Opioids; Morphine
Isolated in 1803 by the German pharmacist Friedrich Adam.
Named it 'morphium' after Morpheus, the Greek god of dreams.

25. Opioids - Morphine
Plasma levels do not correlate with clinical effect.
Low lipid solubility causes slow equilibration across BBB.
Metabolized in the liver by conjugation.
Morphine-6-glucuronide (active).

26. Remifentanil Piperidine derivative. Selective mu-receptor agonist.
Potency similar to fentanyl.
Terminal half-life < 10 min.
Rapid blood-brain equilibrium.
Metabolised by non-specific esterases.

27. Remfentnil Acid
95%
1.5%

28. Plasma concentration after long term infusion
After 240 min
Context –sensitive half-time
Fentanyl 262 min
100 75
Alfentanil 59 min
Time to 50% drop in concentration at effect site (minutes)
Sufentanil 34 min 50 25
Remifentanil 3.7 min
100
200
300
400
500
600
Duration of infusion (minutes)

29. Unwanted side-effects of opioids
Vasodilation
Confusion
Respiratory depression
Gut motility depression

30. Benzodiazepines

31. Benzodiazepines; Midazolam
Water-soluble  lipid soluble in the body.
Produces sedation, anxiolysis and amensia.
Withdrawal agitation.

32. α2-Adrenergic agonists
Clonidine
Dexmedetomidine

33. α2 – agonists Sedation-hypnosis: Analgesia:
by an action on α2-receptors in the locus ceruleus.
Analgesia:
by an action on α2-receptors within the locus ceruleus and the spinal cord

34. α2 – agonists; Dexmedetomidine
94% protein bound.
Narrow therapeutic range ( ng/mL)
It undergoes conjugation & N-methylation.
Approved only for sedation ≤ 24 h.

35. α2 – agonists Haemodynamics Effects: No respiratory depression
-  heart rate.
- Initial  then  BP.
-  SVR.
-  CO
No respiratory depression

36. Unwanted side-effects of sedative agents
General
Over sedation
Delayed awakening/extubation
Benzodiazepines
Hypotension
Respiratory depression
Agitation/Confusion
2-agonists
Hypotension
Bradycardia
Propofol
Hypertriglyceridemia
CVS depression
Hypotension
Ketamine
Hypertension
Secretions
Dysphoria

37. Drug
Elimination h1/2 (h)
Prpofol
4 – 7
Dexmedetomidine
2 - 3
Ketamine
2.5 – 2.8
Midazolam
1.7 – 2.6

38. Assessment of Sedation
Ramsay Sedation Score.
Motor Activity Assessment Scale
Richmond Agitation–Sedation Scale.
Sedation – Agitation Score.
Modified Glasgow Coma Score.

39. Ramsay Sedation Score Level 1 Level 2 Level 3 Level 4 Level 5 Level 6
Awake, anxious, agitated, restlessness
Level 2
Awake, cooperative, tranquil.
Level 3
Respond to commands.
Level 4
Asleep, brisk response to stimuli.
Level 5
Asleep, sluggish response to stimuli.
Level 6
Asleep, no response

40. Bispectral Index

41. Is any place for neuro-muscular Blockers in ICU?

42. Mehta S et al. Crit Care Med 2006; 34: 374

44. The Art of Sedation * Under sedation: * Over sedation:
Fighting the ventilator.
V/Q mismatch.
Accidental extubation.
Catheter displacement.
CV stress  ischemia.
Anxiety, awareness.
Post-traumatic stress disorder.
* Over sedation:
Tolerance, tachyphylaxis.
Withdrawal syndrome.
Delirium.
Prolonged ventilation.
CV depression.
 neuro testing.
Sleep disturbance.

45. Thank You
Yasser Zaghloul