1. Sedation and Pain Management
in ICU
Gagan Kumar MD
Fellow, Pulmonary & Critical Care
Medical College of Wisconsin

2. Why do we need sedation & pain
control ?
•
•
•
•
Patient comfort
Facilitate patient-ventilator synchrony
Optimize oxygenation.
Delirium and delusional memories influence
the likelihood of patients having long term
psychological effects

3. Chest 2008;133;552-565

4. Predisposing and precipitating factors
•
•
•
•
Medical conditions. E.g. chronic pain, arthritis
Postoperative factors
Interventions. E.g. IMV
Withdrawal or rebound of chronic symptoms
occur if home medications are withheld for
too long

5. Sedation

6. Sedatives
Analgesics
Hypnotics

8. Delirium
• 80% of ICU patients have delirium
fluctuating mental status
disorganized thinking
altered level of consciousness*
*may or may not be accompanied by agitation

9. Hypoactive delirium
Calm
appearance
Obtundation
Psychomotor
retardation
Inattention
Decreased
mobility

10. Recommendation
• Routine assessment for the presence of
delirium is recommended. (The CAM-ICU is a
promising tool for the assessment of delirium
in ICU patients.) (Grade of recommendation
B)

11. Delirium Evaluation
•
•
•
•
Confusion Assessment Method for the ICU
Cognitive Test for Delirium
Delirium Screening Checklist (ICDSC)
Nursing Rating Scale for ICU Delirium
• Unfortunately these are “rarely performed”.

12. CAM-ICU
• Critical care nurses can complete delirium assessments with the
CAM-ICU in an average of 2 minutes with an accuracy of 98%
• Routine assessment for the presence of delirium is recommended.
(The CAM-ICU is a promising tool for the assessment of delirium in
ICU patients.) (Grade of recommendation B)
Ely EW, Margolin R, Francis J, et al: Evaluation of delirium in critically ill patients:
Validation of the confusion assessment method for the intensive care unit (CAMICU).
Crit Care Med 2001; 29:1370–1379

13. Neuroleptic agents
• Chlorpromazine
– anticholinergic, sedative, and α-adrenergic antagonist effects
• Haloperidol
• Droperidol
– more potent than haloperidol
– associated with frightening dreams
– higher risk of inducing hypotension because of its direct
vasodilating and antiadrenergic effects
• Exert a stabilizing effect on cerebral function by
antagonizing dopamine-mediated neurotransmission at
the cerebral synapses and basal ganglia.

14. Haloperidol
• Long half-life (18–54 hours)
• Loading regimen starting with a 2-mg
dose, followed by repeated doses (double the
previous dose) every 15–20 minutes while
agitation persists

15. Advantages
• Hallucinations, delusions, and Unstructured
thought patterns, is inhibited, but the
patient’s interest in the environment is
diminished, producing a characteristic flat
cerebral affect.
• These agents also exert a sedative effect.

16. Disadvantages
• Dose dependent QT prolongation
– A history of cardiac disease appears to predispose patients
– Incidence of torsades de pointes associated with
halperidol use is unknown, although a historical casecontrolled study suggests it may be 3.6%
• Slowly eliminated active metabolite of haloperidol
appears to cause EPS
– discontinuing the neuroleptic agent
– diphenhydramine or benztropine mesylate
• May prolong the duration of posttraumatic amnesia

17. Atypical Neurolepts
• No data regarding the newer atypical agents, such as
‘risperidone’ and ‘quetiapine’ (seroquel) in delirium in
ICU.
• Other atypical antipsychotics:
– Olanzapine (Zyprexa)
– Aripiprazole (Abilify)
– Ziprasidone (Geodon)
definition of "atypicality" was based upon the absence of extrapyramidal side
effects, but there is now a clear understanding that atypical antipsychotics
can still induce these effects ,though to a lesser degree

18. Quetiapine
• Second generation atypical antipsychotic
• Serotonin and Dopamine antagonist
• Most sedating of all anti-psychotics
• Disadvantages
– Neuroleptic malignant syndrome
– Tardive dyskinesia

19. Sedatives
Analgesics
Hypnotics

20. PAIN
Unrelieved pain evokes a stress response
• Tachycardia
• Increased myocardial oxygen consumption
• Hypercoagulability
• Immunosuppression
• Persistent catabolism
• Pulmonary dysfunction through localized
guarding of muscles

21. Pain evaluation
• Most reliable and valid indicator of pain is the patient’s self-report
– verbal rating scale (VRS)
– visual analogue scale (VAS)
– numeric rating scale (NRS)
• “unable to communicate”
• Surrogates /Family members could estimate the presence or
absence of pain in 73.5% of patients, they less accurately described
the degree of pain (53%)*
• Verbal descriptive scale vs. behavioral pain scale : moderate
correlation (r = 0.60)**
*Desbiens NA, Mueller-Rizner N: How well do surrogates assess the pain of seriously ill patients? Crit Care
Med 2000; 28: 1347–1352
** Mateo OM, Krenzischek DA: A pilot study to assess the relationship between behavioral manifestations of
pain and self-report of pain in post anesthesia care unit patients. J Post Anesth Nurs 1992; 7:15–21

22. Recommendations
• The level of pain reported by the patient must be
considered the current standard for assessment of pain
and response to analgesia whenever possible. Use of
the NRS is recommended to assess pain. (Grade of
recommendation B)
• Patients who cannot communicate should be assessed
through subjective observation of pain-related
behaviors (movement, facial expression, and posturing)
and physiological indicators (heart rate, blood
pressure, and respiratory rate) and the change in these
parameters following analgesic therapy. (Grade of
recommendation B)

23. Analgesics
Opiates
NSAIDs
Acetaminophen

24. Critically ill patients are different
• Pharmacokinetics of various drugs are altered
including - drug bioavailability, volume of
distribution, and clearance.
– Hepatic dysfunction
– Decreased hepatic blood flow
– Renal dysfunction
– Alteration in volume status
– Plasma protein binding

25. Opiates
• Comparative trials of opioids have not been performed in
critically ill patients.
• The selection of an agent depends on its pharmacology and
potential for adverse effects.
• Titrate opioid therapy using a validated pain assessment
tool (either verbal or nonverbal) or other physiologic
endpoints (eg, heart rate, blood pressure, or respiratory
rate)
• The oral, transdermal, and intramuscular routes of
administration are generally not recommended in patients
who are hemodynamically unstable

26. Opiates
• μ- and κ-receptors are most important for
analgesia.
• Although opioids may produce sedating effects,
they do not diminish awareness or provide
amnesia for stressful events.
• Tolerance: fentanyl > morphine
– Antagonism of central NMDA receptors through the
use of methadone/ketamine is another strategy that
may slow the development of tolerance

27. Metabolism of opiates
Fentanyl
Morphine
Hydromorphone
Oxidation
Glucoronization
Active
Inactive
Inactive

28. Fentanyl
•
•
•
•
•
μ-opioid receptors
Highly lipophilic
Rapid onset
T½ : 2-4hr
Repeated dosing may cause accumulation esp.
in renal dysfunction
• Less nausea, as well as less histaminemediated itching, in relation to morphine

29. Drug interactions
• Fentanyl is a substrate CYP3A4 and is affected by
– Inhibitors
•
•
•
•
Fluconazole
Ciprofloxacin
Diltiazem
Haloperidol
– Inducers
•
•
•
•
Phenytoin
Carbamazepine
Rifampin
Ritonavir

30. Fentanyl patch
• Patch usually provides consistent drug delivery but the
extent of absorption varies depending on
–
–
–
–
the permeability
temperature
perfusion
thickness of the skin
• There is a large inter-patient variability in peak plasma
concentrations.
• Not for acute analgesia : 12-24 hour delay to peak
effect and similar lag time to complete offset once the
patch is removed.

31. Morphine
•
•
•
•
Predominantly μ-opioid receptor
Metabolized primarily in the liver
Onset: 15-30min
T½ : 1.7-4.5hrs
• 60% of morphine is converted to morphine-3-glucuronide
(inactive), and 6–10% is converted to morphine-6-glucuronide
(1/2 as active).
• Hypotension may result from vasodilatation
• Active metabolite may cause prolonged sedation
in the presence of renal insufficiency.

32. Hydromorphone
•
•
•
•
Hydrogenated ketone of morphine
6-8 times stronger than morphine
μ-opioid agonist
Lacks a active metabolite (hence drug of
choice in ESRD)
• Minimal histamine release.
• Glucuronidation in the liver
• Strongest of the anti-tussive drugs

33. Remifentanil
• Specific μ-receptor agonist
• Marketed by GlaxoSmithKline and Abbott as Ultiva
• Potent (250 times morphine)
• Onset : 1 minute
• T½ = 4 minutes after a 4 hour infusion.
• Synergism between remifentanil and hypnotic drugs
(such as propofol) the dose of the hypnotic can be
substantially reduced  Resulting in more
hemodynamic stability

34. Advantages
• Has ester linkage - rapid hydrolysis by nonspecific tissue and plasma esterases to
metabolized to remifentanil acid which is
almost inactive  excreted in kidneys
• No dose adjustments in renal or liver disease

35. Disdvantages
• Reduction in sympathetic nervous system tone
• Respiratory depression
• Pruritus is due to excessive serum histamine
levels
• Bolus injections of remifentanil may cause
‘thoracic muscle rigidity’ with difficult mask or
pressure-controlled ventilation
• Acute withdrawal syndrome

36. Alfentanil
• μ-agonist.
• analogue of fentanyl with
– around 1/4 the potency
– around 1/3 of the duration of action
– onset of effects 4x faster than fentanyl
• less cardiovascular complications but
stronger respiratory depression

37. Disadvantages
• Respiratory depression
• Hypotension – esp. in hemodynamically unstable
– sympatholysis
– vagally mediated bradycardia
– histamine release
•
•
•
•
Depression of the level of consciousness
Hallucinations
Gastric retention and ileus
May increase intracranial pressure with traumatic
brain injury, although the data are inconsistent.

38. Meperidine (Demerol)
• κ opioid receptor
• Also has
– strong anticholinergics effect
– local anesthetic activity due to blockage of sodium ion
channels.
– increases cerebral serotonin concentration
• Has an active metabolite (normeperidine) that causes
neuroexcitation (apprehension, tremors, delirium, and
seizures) – accumulates in renal insufficiency
• Interact with antidepressants (contraindicated with
MAOI and best avoided with SSRI)

39. PAMORAs
• Peripherally acting mu opioid receptor
antagonists
– Methylnaltrexone
– Alvimopan
• Do not cross the blood-brain barrier
• Antagonize the peripheral side effects of
opioids—notably constipation and ileus—while
preserving analgesia
• Methylnaltrexone reverses opioid-induced
delayed gastric emptying time

40. ? Advantages
• Pseudomonas aeruginosa: has mu opioid
receptors, which when activated produce
factors that enhance gut wall permeability.
• Methylnaltrexone blocks the production of
these factors !!!!

41. NSAIDs
• Nonselective, competitive inhibition of cyclooxygenase.
• Significant adverse effects
– Gastrointestinal bleeding: bleeding secondary to platelet
inhibition,
– renal insufficiency.
– Increased risk in
• hypovolemia or hypoperfusion
• Elderly
• CKD
• Asthma & Aspirin sensitivity.

42. Ketorolac (toradol)
• Parenteral NSAID
• Prolonged use (> 5 days) of ketorolac has been
associated with a two-fold increase in the risk
of renal failure and an increased risk of
gastrointestinal and operative- site bleeding

43. Acetaminophen
• Mild to moderate pain at best
• With an opioid, acetaminophen produces a greater
analgesic effect than higher doses of the opioid alone
• Potentially hepatotoxic especially in patients with
depleted glutathione stores resulting from hepatic
dysfunction or malnutrition.
• Acetaminophen should be maintained at
– less than 2 g per day for patients with a significant history
of alcohol intake or poor nutritional status
– less than 4 g per day for others

44. Sedatives
Analgesics
Hypnotics

45. Sedation Evaluation
Should be integral component of treatment
algorithms
• precise dosing
• reduced sedative and analgesic drug use
• shorter duration of MV
• reduced need for vasopressor therapy
• reduced incidence of over sedation
Recommendation: Sedation of agitated critically ill patients should be started only after
providing adequate analgesia and treating reversible physiological causes.
(Grade of recommendation C)

46. PTSD in ICU survivors
• PTSD may be experienced by 4–15% of ICU survivors*
• The Impact of Events Scale (IES) : used for measuring post-traumatic stress.
It has two subscales
– re-experiencing the trauma (e.g. nightmares)
– avoiding situations/thoughts that are associated with the trauma.
– Scores on the IES subscales for intrusions and avoidance have been stratified as
follows:
• 8 or less: mild or absent symptoms
• 9 to 19: medium level of symptoms
• 20 or more: high levels of symptoms
*Scragg P, Jones A, Fauvel N: Psychological problems following ICU treatment. Anaesthesia 2001; 56:9–14

47. Sedation evaluation Scales
•
•
•
•
•
Ramsay Sedation Scale
Sedation Agitation Scale
Motor Activity Assessment Scale
Richmond Agitation-Sedation Scale (RASS)
Adaptation to the Intensive Care Environment
(ATICE) instrument
• Minnesota Sedation Assessment Tool (MSAT).

49. Sessler CN, Gosnell M, Grap MJ, Brophy GT, O'Neal PV, Keane KA et al. The Richmond Agitation- Sedation Scale: validity and
reliability in adult intensive care patients. Am J Respir Crit Care Med 2002; 166:1338-1344

50. Measurement of Brain Activity
•
•
•
•
Bispectral index (BIS)
Patient state index
Cerebral state index
Narcotrend index
• Objective physiologic parameters
• Numerical display
• Near-continuous measurement

51. BIS
• Weighted sum of EEG parameters
– “algorithm is proprietary
information”
• Yields a single numerical value
from
– 0 (complete EEG suppression)
– to 100 (awake).
• 40 and 60 indicates an appropriate
level for general anesthesia

52. BIS
• Prone to artifacts
• ‘Electromyography‘ activity interferes with BIS measures of
sedation
• Confounding factors that may influence BIS scores
–
–
–
–
–
Hypoglycemia
Sleep
temperature
Age
Drugs
• aminophylline, epinephrine, and ketamine.
• Increase variability of BIS in the critically ill patient
• Cannot be relied upon in circulatory arrest or hypothermia

53. The majority of studies
reported correlations
between BIS and
subjective sedation
scores between r of
0.37 and r of 0.69.
r = 0.50
r2 of .252 implies that the BIS scores explained only 25.2% of the variance in SAS scores.
Correlation between the Sedation-Agitation Scale and the Bispectral Index in ventilated
patients in the intensive care unit. Heart Lung. 2009 Jul-Aug;38(4):336-45.

54. Mixed results
• BIS monitoring to be a helpful addition to traditional sedation monitoring
whereas others found that BIS monitoring was not helpful.
• Review of 19 studies with BIS - reported that more data are needed to
evaluate the routine use of BIS in the ICU*
• More research is necessary to evaluate the use of BIS monitoring in
sedated ICU patients
• BIS is likely to be useful when patients are
– “deeply comatose” or
– under “neuromuscular blockade”.
*LeBlanc JM, Dasta JF, Kane-Gill SL. Role of the bispectral index in sedation monitoring in
the ICU. Ann Pharmacother 2006;40:490-500

55. Sedative-Hypnotics
•
•
•
•
•
•
Benzodiazepines
Propofol
Dexmedetomidine
Ketamine
Etomidate
Thiopental

56. Benzodiazepines
• Increase the frequency
of chloride channel
opening events which
leads to inhibition of the
action potential
• Only anterograde
amnesia
• Have an opioid-sparing
effect by moderating
the anticipatory pain
response

57. Pharmacodynamic response
• Patient-related factors can affect the BZD
response
– age
– concurrent pathology
– prior alcohol use
– concurrent therapy with other sedative drugs
Higher volume of distribution and slower
clearance in elderly.

58. Midazolam (Versed)
• High lipid solubility
• Onset: 2-3 minutes
• Duration: variable (Accumulates in
fats)
• Avoid if hepatic/renal failure
• Inhibition of midazolam metabolism
has been reported with inhibitors of
cytochrome P450
–
–
–
–
propofol
diltiazem
Erythromycin
Itraconazole
• Obese (high lipid soluble) or
patients with reduced serum
albumin levels have prolonged
sedative effect
Cyt P450
α-Hydroxymidazolam
(active)

59. Lorazepam (Ativan)
•
•
•
•
Less lipid solubility
Onset: 5-10min
T½ : 12- to 15hrs
Propylene glycol is
diluent used to facilitate
drug solubility*
Conjugation
Inactive metabolite
In liver failure, lorazepam
accumulates lesser than
midazolam.
*Crit Care Med 2002 Vol. 30, No. 1

60. Lorazepam & Propylene glycol*
• Propylene glycol : hyperosmolarity, acute tubular necrosis,
lactic acidosis, metabolic acidosis
• Toxicity is typically observed after*
–
–
–
–
–
–
–
prolonged ( >7 d)
high-dose (average of >18 mg/h)
continuous lorazepam infusion
renal and hepatic derangement
pregnancy
age less than 4 years
metronidazole
• An infusion of 2 mg/h of lorazepam will lead to 19.9 g of
propylene glycol per day (> 11 times the WHO’s
recommended daily intake for a 70 kg adult.)
• Monitor a daily serum osmolal gap (if 50 mg or 1 mg/kg )

61. Lorazepam vs. Midazolam
Swart EL, van Schijndel RJ, van Loenen AC, et al. Continuous infusion of lorazepam versus
medazolam in patients in the intensive care unit: sedation with lorazepam is easier to manage
and is more cost-effective. Crit Care Med 1999;27:1461–1465

62. Recommendations
• Midazolam or diazepam should be used for rapid
sedation of acutely agitated patients. (Grade of
recommendation C)
• Midazolam is recommended for short term use only, as
it produces unpredictable awakening and time to
extubation when infusions continue longer than 48–72
hours. (Grade of recommendation A)
• Lorazepam is recommended for the sedation of most
patients via intermittent i.v. administration or
continuous infusion. (Grade of recommendation B)

63. Advantages & Disadvantages
• Possess anticonvulsant effects
• Benzodiazepine antagonist: flumazenil - is not
recommended after prolonged benzodiazepine therapy risks of inducing withdrawal symptoms and increasing
myocardial oxygen consumption. If you have to give, use
lower dose of 0.15 mg*.
• Moderate hypotension: MAP ↓ by 10 to 25%
• No analgesia
• Paradoxical agitation : may be the result of drug-induced
amnesia or disorientation
*Breheny FX: Reversal of midazolam sedation with flumazenil. Crit Care Med 1992;
20:736–739

64. PTSD & BZD
• The amount of benzodiazepine administered
during the ICU stay correlates with the severity of
PTSD symptoms (n=43)*.
*Girard TD, Shintani AK, Jackson JC, et al. Risk factors for post-traumatic stress disorder
symptoms following critical illness requiring mechanical ventilation: a prospective cohort study.
Crit Care 2007;11(1):R28.

65. Propofol
• Potentiation and direct activation of GABAA receptors.
• Increase extracellular dopamine and may block
dopamine reuptake
• Onset: 1-2min
• T ½ : 1-3 hrs
• Elimination by hepatic conjugation  inactive
metabolites
• No changes in kinetic parameters have been reported
in patients with renal or hepatic dysfunction
• Consensus recommendations that administration of
propofol be limited to 24 to 48 h*.
*Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically
ill adult. Crit Care Med 2002 Vol. 30, No. 1

66. Advantages
• Sedation + Amnesia
– propofol did not produce amnesia as often as
midazolam in ICU but does in volunteers*
• Reduces airway resistance
• Neuroinhibitory effects:
– decrease cerebral blood flow and metabolism
– Reduce elevated intracranial pressure (ICP)
• Does not prolong the QT interval
• In postoperative patients with sedation <36 h,
weaning is faster with propofol
Weinbroum AA, Halpern P, Rudick V, et al: Midazolam versus propofol for long-term sedation in
the ICU: A randomized prospective comparison. Intensive Care Med 1997; 23:1258–1263

67. Disadvantages
• Suppresses sympathetic activity :
– myocardial depression
– peripheral vasodilation
• Decrease in MAP* (about 10mmHg):
– relative risk 2.5 [95% CI, 1.3 to 4.5] 4.5]
– number-needed-to treat :12
• Prolonged use (>48 hours) of high doses of propofol (66
μg/kg/min infusion) has been associated with lactic
acidosis, bradycardia, and lipidemia in pediatric patients
*Walder B, Elia N, Henzi I, et al. A lack of evidence of superiority of propofol versus midazolam
for sedation in mechanically ventilated critically ill patients: a qualitative and quantitative
systematic review. Anesth Analg 2001; 92:975–983

68. Disadvantages
• Does not provide analgesia
• Increased ‘serum triglycerides’:
– relative risk 12.1 [95%CI, 2.9 to 49.7];
– number-needed-to-treat= 6
•
•
•
•
1.1 kcal/mL from fat
Pain upon peripheral venous injection
Pancreatitis (increased ‘serum lipase’)
Zinc depletion

69. Disadvantages
• Vehicle may cause allergic reaction - Prepared in “egg” &
“soyabean oil”
• Requires a dedicated i.v. catheter when administered as a
continuous infusion because of the potential for drug
incompatibility and infection. Hence may contain
preservatives
• May have “Sodium metabisulfite” (propofol, Gensia Sicor)
which may produce allergic reactions in susceptible patients.
• May have “Edetic acid” (Diprivan, AstraZeneca) and the
manufacturer recommends a drug holiday after more than
seven days of infusion to minimize the risk of trace element
abnormalities.

70. Green urine
• Urine may turn green from
excretion of “phenol
metabolites”
http://lifeinthefastlane.com/2009/11/unusual-urine-002/

71. Propofol Infusion Syndrome*
Propofol increases the activity of malonyl coenzyme A
↓
inhibits carnitine palmitoyl transferase I (CPT I)
↓
long-chain FFA cannot enter the mitochondrion.
Uncouples β-spiral oxidation &
respiratory chain at complex II
↓
medium- nor short-chain FFA,
cannot freely cross the mitochondrion
membranes, hence cannot be utilized.
Low energy production
↓
lead to cardiac and peripheral muscle necrosis
*Vasile B, Rasulo F, Candiani A, et al. The pathophysiology of propofol infusion syndrome: a
simple name for a complex syndrome. Intensive Care Med 2003; 29:1417–1425

72. From Vasile B, Rasulo F, Candiani A, et al. The pathophysiology of propofol infusion syndrome: a
simple name for a complex syndrome. Intensive Care Med 2003; 29:1417–1425

73. PRIS
Clinical features
– rhabdomyolysis,
• metabolic acidosis
• renal failure
– cardiac failure
• Risks
–
–
–
–
Critical illness, head injury, SAH, Status epilepticus
Catecholamine infusion
Glucocorticoids
High dose propofol (≥5mg/Kg/Hr X >48hrs)
Fong JJ, Sylvia L, Ruthazer R, et al. Predictors of mortality in patients with suspected
propofol infusion syndrome. Crit Care Med 2008;36:2281–7.

74. PRIS
Fong JJ, Sylvia L, Ruthazer R, et al. Predictors of mortality in patients with suspected
propofol infusion syndrome. Crit Care Med 2008;36:2281–7

75. Midazolam vs. Propofol
Walder et al. A Lack of Evidence of Superiority of Propofol Versus Midazolam for Sedation in Mechanically
Ventilated Critically Ill Patients: A Qualitative and Quantitative Systematic Review. Anesth Analg
2001;92:975–83

76. Recommendations
• Propofol is the preferred sedative when rapid
awakening (e.g., for neurologic assessment or
extubation) is important. (Grade of
recommendation B)
• Triglyceride concentrations should be monitored
after two days of propofol infusion, and total
caloric intake from lipids should be included in the
nutrition support prescription. (Grade of
recommendation B)
Crit Care Med 2002 Vol. 30, No. 1

77. Dexmedetomidine
• Centrally acting α2 agonist
– (like clonidine but 7 times
stronger)
• first approved in 1999 by
the FDA
• Hepatic Cytochrome P450
and glucuronidation
(clearance may decrease by
50% in severe liver Dz)
• T½ : 6min then 2hrs
• Highly protein bound

78. Dexmedetomidine
Anxiolysis
Sedation
Amnesia
Sympath
olytic
Analgesia

79. • Arousability is maintained at deep levels of
sedation, with good correlation between the level
of sedation (Richmond agitation-sedation scale)
and the bispectral (BIS) EEG
• Sedation induced by dexmedetomidine has the
respiratory pattern and EEG changes
commensurate with natural sleep – “activates
endogenous non–rapid eye movement sleep–
promoting pathways”

80. Mechanism of action
• Reduction of central CNS activity (alpha 2a) – hypotension
• Reduction of presynaptic NE release (alpha 2a & 2c) –
hypotension
• Stimulation of Vascular Smooth Muscle cells (alpha 2b) –
increase BP
• Stimulation of endothelium
• Stimulation of central imidazoline receptors
• Vagomimetic activity - bradycardia
• Suppress shivering (alpha-2B in the hypothalamic
thermoregulatory center)
• Attenuation of ischemia-reperfusion injury
• Withdrawal of drugs: alcohol

81. SEDCOM study
Safety and Efficacy of Dexmedetomidine Compared With Midazolam
Riker et al. Dexmedetomidine vs Midazolam for Sedation of Critically Ill Patients . JAMA.
2009;301(5):489-499

82. SEDCOM study
Safety and Efficacy of Dexmedetomidine Compared With Midazolam
Riker et al. Dexmedetomidine vs Midazolam for Sedation of Critically Ill Patients JAMA.
2009;301(5):489-499

83. MENDS study
Pandharipande et al. Effect of dexmedetomidine versus lorazepam on outcome in patients with
sepsis: an a priori-designed analysis of the MENDS randomized controlled trial. Critical Care
2010, 14:R38

84. Dexmedetomidine vs. lorazepam
Riker et al. Altering Intensive Care Sedation Paradigms to Improve Patient Outcomes. Crit
Care Clin 25 (2009) 527–538

85. Advantages
•
•
•
•
Reduction in the incidence of delirium
Reduction in time on mechanical ventilation
Reduction in tachycardia and hypertension
Opiate sparing
• Hypotension appears to be similar between
benzodiazepines and dexmedetomidine.
• Little effect on respiratory drive/alertness but “may cause
upper airway obstruction”
• Unlike clonidine, cessation of administration does not
appear to be associated with rebound hypertension or
agitation

86. Bradycardia
• Bradycardia (doses of ≤0.7 μg/kg/h, bradycardia
occurred in less than 15% of patients)*
• Average response is 20% reduction in HR
• Usually is not clinically significant unless patient
has co-existing cardiac disease
• Baroreflexes are reset but intact – hence HTN will
reduce HR further
• Observed asystole/sinus pauses are from vagal
stimmulus.
• Treatment: atropine
Jones et al. High-dose dexmedetomidine for sedation in the intensive care unit: an evaluation of
clinical efficacy and safety Ann Pharmacother. 2011 Jun;45(6):740-7.

87. Hemodynamic
response
at high-bolus IV doses (50–75 mg), a transient
initial hypertensive response may be seen
because of activation of peripheral vascular
alpha-2 receptors before the central
sympatholytic effect on the vasomotor center
Venn RM et al. Br. J Anaeth. 2001;87: 684-690

88. Respiratory response
Ebert et al. The Effects of Increasing Plasma Concentrations of Dexmedetomidine in Humans.
Anesthesiology, V 93, No 2, Aug 2000

89. Disadvantages
• Hypotension is observed in 20- 30%*
• Expensive $$$$
• Tolerance to the drug has been seen and there
are concerns for a rebound effect when used
beyond 24 to 48 h (in animals)
• Dystonia has been reported and may be due to its
effect on acetylcholine release
• Deep sedation levels may be attained less easily
• Amnesia < that with BZD
Jones et al. High-dose dexmedetomidine for sedation in the intensive care unit: an evaluation of
clinical efficacy and safety Ann Pharmacother. 2011 Jun;45(6):740-7.

90. Ketamine
• NMDA receptor
• Σ opiate receptor
• provides analgesia and apparent anesthesia with
relative hemodynamic stability - ‘‘battlefield
anesthetic’’
• dissociative anesthesia:
– unresponsive to nociceptive stimuli, but
– keep their eyes open and
– Maintain their reflexes : Blood pressure is
maintained, and spontaneous breathing and laryngeal
reflexes are preserved.

91. Pharmacokinetics
• Onset: 1 min
• T½ : 10-15min
• Actions:
increases myocardial
oxygen demand
– Positive inotropic action
– Induces vasoconstriction
– Inhibits endothelial nitric oxide production
– Bronchodilator activity
– Increase oral secretions

92. Advantages
• Provides analgesia + amnestic + sedative effects
• Preserves respiratory drive - "awake" intubation
• Release of catecholamines –
–
–
–
–
–
↑ heart rate,
↑contractility,
↑MAP
↑ cerebral blood flow
causes bronchodilation
• most hemodynamically stable of all of the available
sedative induction agents
• beneficial effects on stunned myocardium
• minimize the adverse sympathetic stimulation of
laryngoscopy

93. Advantages
• low-dose (60–120 mg/kg/h) ketamine
infusions in combination with opioids may not
be associated with untoward effects and may
improve outcomes in the critically ill.
– morphine consumption decreased
– does not inhibit bowel mobility
– Ketamine antagonizes the NMDA receptor to block
central sensitization and hyperalgesia
– Anti-inflammatory properties

94. Disadvantages
• Re-emergence phenomenon: experience
disturbing dreams
• ↑ intracranial pressure
• Increased oral secretions
• Potential for exacerbating myocardial
ischemia.
• ? Risk for elevating ICP – “does not increase
cerebral blood flow or ICP if normal carbon
dioxide levels are maintained”

95. • This slide is intentionally left blank…

96. Cost
Crit Care Clin 25 (2009) 431–449

97. How to implement ?

98. No sedation
• single centre and unblinded
• 18% of the inter vention group did not tolerate the no sedation strategy
• both groups received some sedation with morphine
Lancet 2010; 375: 475–80

99. Intermittent vs. Continuous sedation
• Intermittent therapy or provision of schedule
daily interruption of sedation (DIS) is often
employed to avoid excessive and prolonged
effects
• Focusing first on providing analgesia rather
than initially on anxiolysis may provide more
effective and shorter duration of MV

100. Intermittent vs. Continuous sedation
Kollef MH, Levy NT, Ahrens TS, et al. The use of continuous i.v. sedation is associated with
prolongation of mechanical ventilation. Chest 1998; 114:541–548

101. Combination of sedatives + analgesics
is better
Richman PS, Baram D, Varela M, et al. Sedation during mechanical ventilation: a trial of
benzodiazepine and opiate in combination. Crit Care Med 2006; 34:1395–1401

102. Daily interruption of sedative drug infusions decreases the duration
of mechanical ventilation and the length of stay in the ICU
Kress JP, Pohlman AS, O’Connor MF, et al. Daily interruption of sedative infusions in critically ill
patients undergoing mechanical ventilation. N Engl J Med 2000; 342(20):1471–7.

103. Daily interruption of sedation &
analgesia
• Allows better assessment of a patient’s sedative needs
• Reduces drug bioaccumulation
• Reduced incidence of posttraumatic stress disorder
• Reduced complications of critical illness
• More ventilator-free days and earlier ICU and hospital
discharge, at the expense of a higher incidence of selfextubation

104. Paralytics
…. that’s for next time

105. Questions & Comments