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The Art of Sedation in ICU

Yasser Zaghloul   MD PhD, FCARCSI   (Ireland)
• Sedation comes from the Latin word sedare.
• Sedare = to calm or to allay fear




          Hypnosis          Analgesia




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




          Hypnosis          Analgesia




                     ± Muscle
                    Relaxation
Why sedation is necessary?
•   To improve patient comfort.
•   Reduce stress.
•   Facilitate interventions.
•   Allow effective ventilation.
•   Encourage sleep.
•   ?? Prevent post-ICU psychosis.
Art of sedation in icu
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.
Non-pharmacological interventions
• Good nursing.


• Psychological:
  - Explanation.      - Reassurance.


• Physical:
  - Touching & message.     - Environment
  - Prevent constipation    - Physiotherapy.
  - Tracheostomy.
Sedation-Analgesia Medications

• IV Anaesthetics:
 - Prpofol           - Thiopentone.
 - Ketamine          - Etomidate.


• Benzodiazepines:
 - Midazolam.
 - Lorazepam
Sedation-Analgesia Medications
• Opiodis:
 - Morphine
 - Fentanyl.
 - Remifentanil


• α-2 receptors agonists:
  – Clonidine.
  – Dexmedetomidine .
Sedation-Analgesia Medications
• Others:
 - Inhalation anaesthetics (Sevoflurane).

 - Phenothiazines.

 - Butyrophenones (Haloperidol).

 - Local Anaesthetics.
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.
Which Medication?
90

80

70

60

50
                                                            Midazolam
40                                                          Propofol
30

20

10

 0
     France   Norway    Finland    Belgium     Italy



                       Soliman et al, Brit J Anaesth 2001;87:186-92
IV Anaesthetics; Thiopentone
• Acts on the GABAA.


• Zero order kinetics (accumulation).


• Provides a cerebral protection effect.


• Main uses in ICU:
  - High ICP.
  - Status epilepticus
IV Anaesthetics; Propofol
                 OH



(CH3)2CH                     CH(CH3)2




                                  2,6 di-isopropyl phenol



             Short-term sedation (< 48 h)
IV Anaesthetics; Propofol
• Mechanisms of actions:
  - Acts on GABAA receptors in the hippocampus.
 - Inhibits of NMDA.



  IOP, ICP & CMRO2.
IV Anaesthetics; Propofol

• Decreases (10 – 30%):
  - HR.
  - SBP, DBP & MAP.
  - SVR.
  - CI.
  - SV.
Target concentrations with ‘Diprifusor’ TCI

  Full ‘Diprivan’ PFS                             Finger grip Tag = PMR
  is loaded correctly                       (Programmaable Magnetic Resonance*)




                                                        Aerial


        ‘Diprifusor’ TCI Subsystem
         Recognition software/electronics               Pump
            ‘Diprifusor’ TCI Software/                 software
                2 microprocessors



                                  Pump hardware
Target concentrations with ‘Diprifusor’ TCI

                                1200                                                                                                    8




                                                                                                            c
       Tit                                         Calculated concentration
                                                                                                                                     d
                                                                                                                                   En




                                                                                                            ↑T
                                                   (automatic calculation and display by system)
             rat
                    ion




                                                                                                                                            Blood concentration (µg/ml)
                                                   Target concentration
                                                   (selected by anaesthetist, displayed)
                                                                                                                           5
                                                                                                                               6
              Infusion rate (ml/h)



                                                                                                                                        6
                                               2               3
Age                                                                                                4

Wt.                                  100                                                                                       4        4

Tc
                                      50                                                                                                2




                                               1
                                       0                                                                                                0
                                           0       4               8               12                  16        20   24           28
                  l
              g/m                                                              Time (hours)

       t;   6µ
  Star
IV Anaesthetics; Propofol
• Propofol infusion syndrome:
  - Rare but fatal.


 - 1st described in children.


 - Infusion ≥ 5 mg/kg/hr or ≥ 48 hours.
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.
IV Anaesthetics - Ketamine
IV Anaesthetics - Ketamine
• Phencyclidine derivative.


• High lipid solubility (5–10 times > thiopental)
  crosses BBB faster.


• Non-competitive antagonism at NMDA receptor
IV Anaesthetics - Ketamine
  HR, BP.


  CBF, ICP & CMRO2.


• Bronchial smooth muscle relaxant.


• Excellent analgesic.


• Dose: 5-30 µg/kg/min.
Opioids; Morphine




• Isolated in 1803 by the German pharmacist Friedrich Adam.
• Named it 'morphium' after Morpheus, the Greek god of dreams.
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).
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.
Remfentnil Acid




95%




  1.5%
Plasma concentration after long term infusion

Context –sensitive half-time                                                                  After 240 min
                                                100             Fentanyl 262 min
       concentration at effect site (minutes)




                                                75
              Time to 50% drop in




                                                                                                        Alfentanil 59 min


                                                50                                                      Sufentanil 34 min


                                                25

                                                                                     Remifentanil 3.7 min
                                                 0
                                                      0   100      200        300       400       500         600
                                                                 Duration of infusion (minutes)
Unwanted side-effects of opioids


                Opioids

Vasodilation                       Confusion

                        Gut motility
          Respiratory   depression
          depression
Benzodiazepines
Benzodiazepines; Midazolam
• Water-soluble  lipid soluble in
  the body.


• Produces sedation, anxiolysis
  and amensia.


• Withdrawal agitation.
α2-Adrenergic agonists
                                 Clonidine




                         Dexmedetomidine
α2 – agonists
• Sedation-hypnosis:
 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
α2 – agonists; Dexmedetomidine
• 94% protein bound.


• Narrow therapeutic range (0.5 - 1.0 ng/mL)


• It undergoes conjugation & N-methylation.


• Approved only for sedation ≤ 24 h.
α2 – agonists
• Haemodynamics Effects:
 -  heart rate.

 - Initial  then  BP.

 -  SVR.

 -  CO


• No respiratory depression
Unwanted side-effects of sedative agents

                                 General
                    Over sedation
             Delayed awakening/extubation
Benzodiazepines                          α 2-agonists
     Hypotension                                        Hypotension
Respiratory depression
                                                        Bradycardia
 Agitation/Confusion
                                         Ketamine
                         Propofol        Hypertension
                  Hypertriglyceridemia
                                          Secretions
                    CVS depression
                     Hypotension           Dysphoria
Drug    Elimination h1/2 (h)

Prpofol                  4–7

Dexmedetomidine          2-3

Ketamine               2.5 – 2.8

Midazolam              1.7 – 2.6
Assessment of Sedation
• Ramsay Sedation Score.

• Motor Activity Assessment Scale

• Richmond Agitation–Sedation Scale.

• Sedation – Agitation Score.

• Modified Glasgow Coma Score.
Ramsay Sedation Score
Level 1       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
Bispectral Index
Is any place for neuro-
muscular Blockers in ICU?
Mehta S et al. Crit Care Med 2006; 34: 374
Art of sedation in icu
The Art of Sedation

* Under sedation:              * Over sedation:
•   Fighting the ventilator.   • Tolerance, tachyphylaxis.
•   V/Q mismatch.              • Withdrawal syndrome.
•   Accidental extubation.     • Delirium.
•   Catheter displacement.     • Prolonged ventilation.
•   CV stress  ischemia.      • CV depression.
•   Anxiety, awareness.          neuro testing.
•   Post-traumatic stress      • Sleep disturbance.
    disorder.
Thank You
Yasser Zaghloul

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Art of sedation in icu

  • 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? 90 80 70 60 50 Midazolam 40 Propofol 30 20 10 0 France Norway Finland Belgium Italy 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 OH (CH3)2CH CH(CH3)2 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 Finger grip Tag = PMR is loaded correctly (Programmaable Magnetic Resonance*) Aerial ‘Diprifusor’ TCI Subsystem Recognition software/electronics Pump ‘Diprifusor’ TCI Software/ software 2 microprocessors Pump hardware
  • 18. Target concentrations with ‘Diprifusor’ TCI 1200 8 c Tit Calculated concentration d En ↑T (automatic calculation and display by system) rat ion Blood concentration (µg/ml) Target concentration (selected by anaesthetist, displayed) 5 6 Infusion rate (ml/h) 6 2 3 Age 4 Wt. 100 4 4 Tc 50 2 1 0 0 0 4 8 12 16 20 24 28 l g/m Time (hours) t; 6µ Star
  • 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.
  • 28. Plasma concentration after long term infusion Context –sensitive half-time After 240 min 100 Fentanyl 262 min concentration at effect site (minutes) 75 Time to 50% drop in Alfentanil 59 min 50 Sufentanil 34 min 25 Remifentanil 3.7 min 0 0 100 200 300 400 500 600 Duration of infusion (minutes)
  • 29. Unwanted side-effects of opioids Opioids Vasodilation Confusion Gut motility Respiratory depression depression
  • 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: 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 (0.5 - 1.0 ng/mL) • It undergoes conjugation & N-methylation. • Approved only for sedation ≤ 24 h.
  • 35. α2 – agonists • Haemodynamics Effects: -  heart rate. - Initial  then  BP. -  SVR. -  CO • No respiratory depression
  • 36. Unwanted side-effects of sedative agents General Over sedation Delayed awakening/extubation Benzodiazepines α 2-agonists Hypotension Hypotension Respiratory depression Bradycardia Agitation/Confusion Ketamine Propofol Hypertension Hypertriglyceridemia Secretions CVS depression Hypotension 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 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
  • 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. • Tolerance, tachyphylaxis. • V/Q mismatch. • Withdrawal syndrome. • Accidental extubation. • Delirium. • Catheter displacement. • Prolonged ventilation. • CV stress  ischemia. • CV depression. • Anxiety, awareness.   neuro testing. • Post-traumatic stress • Sleep disturbance. disorder.

Hinweis der Redaktion

  1. 38 1 Start ‘Diprifusor’ TCI with initial target concentration of 6  g/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  g/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  g/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.