1) The document discusses guidelines developed by Dr. Papadakos for sedation of critically ill patients, including the first use guidelines for propofol in neurosurgery patients and development of protocols for sedation in critically ill patients. 2) It describes goals of sedation in the ICU as well as characteristics of an ideal sedation agent. Common sedative drugs used in the ICU like benzodiazepines, propofol, and dexmedetomidine are discussed along with their mechanisms of action, pharmacodynamics, clinical effects, and limitations. 3) Sedation scales used to assess level of sedation like the Ramsay and SAS scales are also summarized.

1. Sedation In the Neuro-ICU
2009
PJ Papadakos MD FCCM
Director CCM
Professor Anesthesiology,
Surgery and Neurosurgery
Rochester NY USA

2. University of Rochester
Developed the first use guidelines for evaluation of
Neurosurgery patients with Propofol (Ireland et al.,
Proceedings American Association of Neurological
Surgeons . 1992)
Development of Fast Tracking for Open Heart
Surgery. 1991
Development of use protocols for sedation in Critically
ill patients 1993.
Development of guidelines for Dexmedetomidine in
Burn patients 2001

3. University of Rochester
Developed the first use guidelines for evaluation of
Neurosurgery patients with Propofol (Ireland et al.,
Proceedings American Association of Neurological
Surgeons . 1992)
Development of Fast Tracking for Open Heart
Surgery. 1991
Development of use protocols for sedation in Critically
ill patients 1993.
Development of guidelines for Dexmedetomidine in
Burn patients 2001

4. Articles on Sedation

5. Several Practice Standards
are in the Literature
In 2001 a large conference was held:
Crit Care Med 2002 Vol 30 #1

6. ICU Sedation
ICU sedation is a complex clinical
problem
Current therapeutic approaches all
have potential adverse side effects
Agitated patients are often
hypertensive, increase stress
hormones, and require more intensive
nursing care

7. Goals of Sedation in the
ICU
Patient comfort
Control of pain
Anxiolysis and amnesia
Blunting adverse autonomic and
hemodynamic responses
Facilitate nursing management
Facilitate mechanical ventilation
Avoid self-extubation
Reduce oxygen consumption

8. Characteristics of an Ideal
Sedation Agent for the ICU
Lack of respiratory depression
Analgesia, especially for surgical patients
Rapid onset, titratable, with a short
elimination half-time
Sedation with ease of orientation and
arousability
Anxiolytic
Hemodynamic stability

9. Agitated Patients
Can injure themselves or others
Self-extubation, decannulation, wound dehiscence

Peripheral oxygen consumption
Risks of hypoxemia, organ ischemia

Physiologic stress
Change in immune response, wound healing,

coagulation, release cytokines
Require more intensive nursing care
Restraints

Risks of excessive sedation


10. Sedative Drugs

11. Most commonly used
drugs in the ICU

12. Why do we use these
drugs
Pain
Agitation
Anxiety
Keep patient intubated
Protect Patient from Harm
?Cytokine Modulation?

13. Causes of Anxiety

14. Factors Provoking
Anxiety Pain
Fear
Memory Loss
Sleep Deprivation
Confusion
Inconsiderate Providers Loss of Control
ICU
Chemical/Physiologic
Psychosis Surgical Stress
Imbalance
Medications Temperature
Alarms Noises
Mechanical Devices Lights
Nonchanging Environment
Tesar, Stern. J Intensive Care Med. 1986;1:137-148. Harvey. Am J Crit Care. 1996;5:7-16.
Crippen. Crit Care Clin. 1990;6:369-392.

15. To Use these drugs
We need a common language to
speak to all levels of care givers

16. Sedation Scales
Should be used in every unit.

17. Faces Pain Rating Scale
0 3 4 5
1 2
0 1 2 3 4 5 6 7 8 9 10
No Worst
Moderate
pain possible pain
pain
Adapted with permission from Chambers, Craig. Pain. 1998;78:29.
Sriwatanakul et al. Clin Pharmacol Ther. 1982;32:143-148.

18. Ramsay Sedation Scale
Score Definition
1 Anxious, agitated, or restless
2 Cooperative, oriented, and tranquil
3 Responds to commands
4 Asleep, but with brisk response to light glabellar tap
or loud auditory stimuli
5 Asleep, sluggish response to light glabellar tap or
loud auditory stimuli
6 Asleep, no response
Adapted with permission from Ramsay et al. BMJ. 1974;2:656-659.

19. SAS: Sedation-Agitation
Scale Description
Score Definition
7 Dangerous agitation Striking staff, thrashing
6 Very agitated Does not calm, needs
restraints
5 Agitated Calms with verbal instructions
4 Calm and cooperative Follows commands
3 Sedated Difficult to arouse
2 Very sedated Does not follow commands
1 Unarousable No response to noxious
stimuli
.

20. Drugs to Use:

21. Pharmacologic Agents
Opioids1
Morphine sulfate

 Fentanyl and Remifentanyl
Benzodiazepines1
Lorazepam

 Midazolam
Sedative/hypnotics1
Propofol

Butyrophenones1
Haloperidol

Agonists2
2
Dexmedetomidine


23. Benzodiazepines:
Mechanisms of Action
Benzodiazepines
GABAA receptor modulation in CNS1

Facilitate binding of GABA1

Hyperpolarize cells, more resistant to

excitation
Receptors mainly postsynaptic

1. Lerch, Park. Br Med Bull. 1999;55:76-95.

24. Benzodiazepines:
Pharmacodynamics
Amnesia
Sedation/anxiolysis
Anticonvulsant
Relief of muscle spasm
Lerch, Park. Br Med Bull. 1999;55:89.

25. Lorazepam: Clinical
Effects
Sedation, anxiolysis, and amnesia1
Preferred for prolonged sedation2
Slower onset of action than
midazolam2,3
Propylene glycol toxicity with higher
doses1
Less hypotension than with midazolam2
Retrograde and anterograde amnesia4
1. Lerch, Park. Br Med Bull. 1999;55, 90. 2. Shafer. Crit Care Med. 1998;26:952-953.
3. Wagner, O’Hara. Clin Pharmacokinet. 1997;33:430, 434. 4. Harvey. Am J Crit Care. 1996;5:11.

26. Benzodiazepines:
Reversal Agents
Flumazenil
Transiently antagonizes the benzodiazepine

component of ventilatory depression and
sedation during use with opioids
Reverses CNS and circulatory side effects of

benzodiazepines within 2 minutes
Useful for diagnostic evaluation

Stoelting. Pharmacology and Physiology in Anesthetic Practice. 3rd ed. 1999:138.

27. Benzodiazepines
Advantages Limitations
• Amnesia1 • Weaning prolonged2,3
• Anxiolysis1 • Polyethylene glycol toxicity3
• Sedation1 • Respiratory depression2,4
• Hypotension2
• Lack of analgesia4
• Oversedation/deep sedation2
• Dependence/tolerance2
• Paradoxic agitation2
1. Pepperman. Care of the Critically Ill. 1989;5:197. 2. Harvey. Am J Crit Care. 1996;5:10, 11.
3. Lerch, Park. Br Med Bull. 1999;55:89, 90. 4. Crippen. Crit Care Clin. 1990;6:380.

28. Propofol:
Mechanisms of Action
Not well-understood
GABAA receptor modulation is most
likely
Davies. Can J Physiol Pharmacol. 1998;76:46.

29. Propofol:
Pharmacodynamics
Sedation/anesthesia1
Decreases ICP1,2
Decreases SNS activity1,2
Cardiovascular depression1,3
Decreases ventilation time1
1. Wagner, O’Hara. Clin Pharmacokinet. 1997;33:434, 436. 2. Harvey. Am J Crit Care. 1996;5:12.
3. Lerch, Park. Br Med Bull. 1999;55:90,

30. Propofol: Clinical Effects
Anesthesia and sedation1
Rapid onset of action1,2
Very short half-life2
Decrease in BP and HR from sympathetic
effects1
Decreases ventilation time3,4
Time to extubation faster than with midazolam3,4
1. Lerch, Park. Br Med Bull. 1999:55:90. 2. Harvey. Am J Crit Care. 1996;5:7-16. 3. Wagner,
O’Hara. Clin Pharmacokinet. 1997;33:434. 4. Ostermann et al. JAMA. 2000;283:1457.

31. Propofol
Limitations
Advantages
• Respiratory depression (enhanced
• Sedation1
by opioids)1
• Hypnosis1
• Hypotension1
• Anxiolysis1
• Decreased contractility2
• Muscle relaxation1 • Lack of analgesia3
•  ICP1 • Hypertriglyceridemia1
•  Cerebral metabolic • Preservative issues4
rate1 • Potential for infection necessitates
need for regular changing of lines5
• Relief of bronchospasm1
1. Harvey. Am J Crit Care.1996;5:7-16. 2. Lerch, Park. Br Med Bull. 1999;55:90. 3. Wagner,
O’Hara. Clin Pharmacokinet. 1997;33:435. 4. Propofol [package insert]. 5. Prielipp et al. Crit
Care Clin. 1995;11:986.

32. The Stress Response
and Immunomodulation
In Sedated ICU Patients

33. Crit Care Med 2006 Vol.34 #2 453-460

35. Sedation
May affect Patient outcome
through affect on cytokine release

36. Propofol with EDTA
There is a difference

37. Herr et al, Intensive
Care Medicine; 2000; 26
In a surgical ICU
Serious Adverse Events 25 vs 8%
Mortality 17.5 vs 2%
11 deaths in plain propofol vs 1 among
the propofol with EDTA

39. Propofol with EDTA
Boost lipoidal antixidant defenses in
tissue
Chelator of heavy metals Iron is
important for cytokine secretion
Decrease Trace elements
Decreased Free Radicals

40. What we wish to
investigate
Do different drugs affect levels of
cytokines released by the lung
Can they protect the compartment of
the lung from systemic cytokine release
Do they prevent the release of cytokines
from the lung

41. How does Propofol
with EDTA Affect
Cytokine Levels
Erasmus MC Rotterdam
Papadakos, Lachmann Haitsma
ATS 2006

42. Propofol with EDTA affect
on electrolytes:

43. Dexmedetomidine

44. Physiology of alpha
receptor

45. Peripheral Receptors
2
A
2A
B
2B
2A

46. Central Sites of Action:
2 Agonists
Sedation
Anxiolysis
Sympathetic inhibition
Analgesia

47. Agonists
2
Dexmedetomidine
Clonidine
Selectivity: 2: 1
Selectivity: 2: 1
1620:13
200:11
t1/2 10 hrs1 t1/2 2 hrs3
PO, patch, epidural2 Intravenous3
Antihypertensive1 Sedative-analgesic3
Analgesic adjunct1 Primary sedative
IV formulation not
Only IV 2 available for
available in US
use in the US

48. Clinical Effects of 2
Agonists
Sedation/hypnosis1
Anxiolysis1
Analgesia1
Decreased sympathetic activity1
Decreased BP and HR2
Vasoconstriction at high doses1
Kamibayashi, Maze. Anesthesiology. 2000;93:1345-1349. 2. Wagner, O’Hara. Clin
Pharmacokinet. 1997;33:426-453.

49. Dexmedetomidine:
Indications
 Sedation of initially intubated and MV patients
during treatment in the ICU
Contraindications
 Caution in patients with advanced heart block
Drug interactions
 Vagal effects can be counteracted by IV
administration of anticholinergic agents
Disease effecting clearance
 Clearance is lower in patients with hepatic
impairment

50. Dexmedetomidine
Advantages Limitations
• Has sedative, analgesic, • May reduce HR and BP (caution in
and anxiolytic effects1 hypovolemia, shock, and heart
block)4
• Respiratory stability2
• Potentiates effects of opioids,
• Predictable hemodynamic
sedatives and anesthetics4
response1
• Dry mouth4
• Arousable and oriented patient3
• Vasoconstriction at high dose4
• No need to discontinue before
extubation4
• Antishivering5
1. Aantaa et al. Drugs of the Future. 1993;18:49-56. 2. Frangoulidou et al. In: Redefining Sedation.
1998:40-50. 3. Mantz, Singer. In: Redefining Sedation. 1998:23-29. 4. Precedex™ [package
insert]. 5. Kamibayashi, Maze. Anesthesiology. 2000;93:1345-1349.

51. Other interesting
Drugs

52. COX – 2 Inhibitors
Prostaglandin Modulation

53. Recent Data:
May have important role in treatment of
Septic Patients
Normalization of Endotoxin
Attenuation of macrophage depression
of hematopoietic proliforation
Augmentation of white cell count
Shoup M et al J Trauma Inj Inf Crit Care 1998;45:215-219

54. Several Studies in Burn
Injury
Highly affective in murine burn injury
80% increase in COX-2 protein
compared to control at 4 hours post
injury

55. COX-2 Drugs have
however been recalled
for increased Cardiac
Risk

56. Neurontin
Increases GABA Levels

57. Neurontin
Decreases requirement of narcotics
Decreases Alcohol Withdrawal

58. We now use this Drug
commonly in Withdrawal
Syndromes

59. The Fine Balance in
Patient Comfort

60. The Fine Balance in
Patient Comfort
Anxiety
Agitation
Hypertension
Tachycardia
Arrhythmias
Myocardial ischemia
Wound disruption
Patient injury

61. The Fine Balance in
Patient Comfort
Depersonalization
Delayed emergence
Delayed weaning
Pressure injury
Venous stasis
Muscle atrophy
Increased cost

62. Sedation
Modulates immune
system
Provides comfort
Modulates Length of
Stay
Affects health care
costs