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Dexmedetomidine (Precedex®)
Haley Gill, BSP
VCH-PHC Pharmacy Resident 2009-2010
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Outline
• Current indications
• Differences & possible advantages over
current sedation agents
• Pharmacology
• Dosing
• Cost
• Review of Literature
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Health Canada
• Precedex®
• NOC issued December 2009
• Dexmedetomidine (DXM) 100mcg/ml
solution
• Continuous IV infusion
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Health Canada - Approved Indications
• ICU Sedation:
– post-surgical mechanically ventilated patients
– Infusion must NOT exceed 24 hours
– Not necessary to D/C prior to extubation
– ↓ dose by 50% after extubation
• Conscious Sedation (non-intubated
patients):
– Monitored Anesthesia Care
– Awake Fiberoptic Intubation
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DXM vs. Other ICU Sedation Agents
• Minimal respiratory depression
• Thought to induce less delirium – does not
bind to GABA receptors
• Analgesic sparing
• Does not provide adequate & reliable
amnesia
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Pharmacology
• MOA
– highly selective α2-adrenoreceptor agonist
– Similar to clonidine but 8 X more selective for α2
α2-adrenoreceptors
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Pancreatic β-cells
↓ insulin secretion
Platelets
Aggregation
Nerve Terminals
↓ release of NE
Vascular Smooth muscle
Contraction
Pharmacology
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Pharmacology
Onset of Action
5-10 min
Peak effect: 15-30 min
Duration of Action
60-120 min
Metabolism
Hepatic via N-glucuronidation,
N-methylation, & CYP2A6
Elimination t1/2
~ 6 min
Terminal: ~2 hrs
Urine 95%
Feces 4%
Excretion
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Drug Interactions
Enzyme
CYP 2A6
Action
substrate
CYP 1A2,
2C9, 3A4
weak inhibitor
CYP 2D6
strong inhibitor
Drugs
amiodarone
isoniazid
ketoconazole
warfarin
Simvastatin
codeine
**theoretical interactions – likely of little clinical significance**
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Drug Interactions
• Beta-blockers: rebound hypertensive effect
when the α2-agonist is abruptly withdrawn
• Mirtazapine: α2-antagonist (opposing
effects)
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Dosing
• ICU sedation
– Load: 1 mcg/kg IV over 10 minutes
– Maintenance: 0.2-0.7 mcg/kg/hr IV (0.2-1.4 mcg/kg/hr
reported in RCT’s)
– titration no more frequently than every 30 minutes may
↓ the incidence of hypotension
• Procedural sedation
– Load: 0.5 – 1 mcg/kg over 10 minutes
– Maintenance: 0.6 mcg/kg/hr (usual range: 0.2-1
mcg/kg/hr)
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Dosing
• No specific recommendations for renal or
hepatic dysfunction
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Adverse Effects
• Hypotension (2454%)
• Bradycardia (5-14%)
• Respiratory
depression (37%;
placebo 32%)
• Atrial fibrillation (4-5%)
• Hypovolemia (3%)
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•
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•
•
•
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↓ urine output
Pleural effusion
Hypocalcemia (1%)
Nausea (3-9%)
Xerostomia (3-4%)
Hyperglycemia
Cost
Drug
Unit Cost
Cost/day for 70 kg pt
DXM 100mcg/ml
2 ml vial = $63
$105.84 - $370.44
(0.2 – 0.7mcg/kg/hr)
Propofol 10mg/ml
100 ml bottle = $8.78
$14.75 – $88.50
(1 – 6mg/kg/hr)
Midazolam 5mg/ml
10 ml vial = $12.25
$29.40 – $58.80
(5 – 10mg/hr)
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Effect of Sedation with Dexmedetomidine vs Lorazepam on Acute
Brain Dysfunction in Mechanically Ventilated Patients
(MENDS)
Pandharipande P, et al
JAMA 2007;298(22):2644-2653
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MENDS
Objective
To determine whether DXM reduces the duration of delirium and coma in
mechanically ventilated ICU patients while providing adequate sedation as
compared to lorazepam
Design
P-MC-DB-RCT
Patients
n = 106 medical/surgical ICU patients requiring ventilation for >24 hrs
Treatment
DXM 0.15 – 1.5 mcg/kg/hr vs lorazepam 1 – 10 mg/hr
Results
Delirium-free & coma-free days: DXM 7 vs. loraz 3 (p=0.01)
Prevalence of delirium or coma: DXM 87% vs. loraz 98% (p=0.03)
Time @ target sedation (RASS): 80% vs. 67% (p=0.04)
Ventilator-free days: DXM 22 vs. loraz 18 (p=0.22)
Length of ICU stay (days): DXM 7.5 vs. loraz 9 (p=0.92)
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MENDS
Results
28-day mortality:
DXM 17% vs. loraz 27% (p=0.18)
Open-label fentanyl use (median dose/day):
DXM 575 mcg vs. loraz 150 mcg (p=0.006)
Bradycardia:
DXM 17% vs. loraz 4% (p=0.03)
Atrial Fibrillation:
DXM 6% vs. loraz 0% (p=0.08)
Conclusion DXM patients had more days alive without coma or delirium
↑ bradycardia with DXM
↑ fentanyl use with DXM
Max duration of DXM = 120 hr
Average dose DXM = 0.74mcg/kg/h
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Dexmedetomidine vs Midazolam for Sedation of
Critically Ill Patients
(SEDCOM)
Riker R, et al
JAMA 2009;31(5):489-499
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SEDCOM
Objective
To compare efficacy & safety of prolonged sedation with DXM vs.
midazolam for mechanically ventilated patients
Design
P-MC-DB-RCT
Patients
n = 366 medical/surgical ICU patients with expected ventilation for >24 hrs
Treatment
DXM 0.2 – 1.4 mcg/kg/hr vs midazolam 0.02 – 0.1 mg/kg/hr
Results
Time @ target sedation (RASS): DXM 77.3% vs. midaz 75.1% (p=0.18)
Duration of study drug treatment (days): DXM 3.5 vs. midaz 4.1 (p=0.01)
Time to extubation (days): DXM 3.7 vs. midaz 5.6 (p=0.01)
Length of ICU stay (days): DXM 5.9 vs. midaz 7.6 (p=0.24)
Delirium: DXM 54% vs. midaz 76.6% (p<0.001)
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SEDCOM
Results
Mean delirium-free days: DXM 2.5 vs. midaz 1.7 (p=0.002)
Open-label midazolam use: DXM 63% vs. midaz 49% (p=0.02)
Fentanyl use: DXM 73.8% vs. midaz 97% (p=0.25)
30 day mortality: DXM 22.5% vs. midaz 25.4% (p=0.6)
Bradycardia: DXM 42.2% vs. midaz 18.9% (p<0.01)
Hyperglycemia: DXM 56.6% vs. midaz 42.6% (p=0.02)
Conclusion No difference in time at target sedation level
↓ time to extubation & ↓ delirium in DXM group
↑ use of midazolam in DXM group
↑ bradycardia & ↑ hyperglycemia in DXM group
Average dose DXM = 0.83 mcg/kg/h
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Dexmedetomidine versus
propofol/midazolam for long-term sedation
during mechanical ventilation
Ruokonen E, et al
Intensive Care Med 2009;35:282-290
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Ruokonen E, et al
Objective
To compare DXM with standard care (SC) (propofol or midazolam) for
long-term sedation in terms of maintaining target sedation and length of
ICU stay
Design
P-MC-DB-DD-RCT
Patients
n = 85 ICU patients with need for sedation >24 hrs
Treatment
DXM ≤1.4 mcg/kg/hr vs propofol or midazolam
Results
Time @ target sedation RASS: DXM 64% vs. SC 63% NSS
•RASS -4: DXM 42% vs. SC 62%
•RASS 0 to -3: DXM 74% vs. 64%
Length of ICU stay (days): DXM 6.6 vs. SC 6.8 [HR 0.766 (p=0.275)]
Duration of ventilation: DXM 77.2 h vs. SC 110.6 h (p=0.109)
Delirium: DXM 43.5% vs. SC 25% (p=0.035)
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Ruokonen E, et al
Results
Serious Adverse Events:
DXM 100% (3 bradycardia, 1 arrest) vs. SC 95.5%
Conclusion
DXM comparable to standard sedation when light sedation target
DXM less effective when deep sedation target (RASS -4)
↑ delirium in DXM group but more CAM-ICU assessments in this group
Average DEX dose 0.8mcg/kg/hr
Average duration 40 h (Max duration 14 days)
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The effect of dexmedetomidine on agitation
during weaning of mechanical ventilation in
critically ill patients
Shehabi Y, et al
Anaesth Intensive Care 2010;38:82-90
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Shehabi Y, et al
Objective
To evaluate the effects of DXM on resolution of agitation during weaning
from mechanical ventilation of critically ill patients who failed conventional
therapy
Design
P-OL-O
Patients
n = 28 ICU patients who developed agitation and/or delirium upon weaning
from sedation
Treatment
DXM 0.4 mcg/kg/hr for 2 hours, titrated up by 0.2 mcg/kg/hr every 30 min
to max dose of 1 mcg/kg/hr
Results
• baseline: 77% of patients outside of target MAAS, 23% within target
• 6 h: 93% within target (p<0.001)
•12 h: 87% within target (p<0.001)
73.3% of patients were extubated
Median ventilation time after DXM infusion = 70 h
Conclusion
DXM provided resolution of agitation and facilitated extubation
Median infusion time of DXM = 62 h
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Summary of Evidence
• DXM effective at achieving target sedation
• DXM not as effective when deep sedation
required
– ↑ use of additional sedation agents in DXM group
• Higher doses of DXM appear safe
– No withdrawal/rebound effects seen
– loading dose often not used
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Duration > 24 hr appears safe
Appears safe in non-surgical population
May ↓ delirium
Main AE’s: bradycardia, hyperglycemia, AF
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Place in Therapy
• Light sedation
• Medical or surgical patients
• Patients who may be at increased risk for
delirium
• Patients who are unable to be weaned due
to agitation
• Limited data in dialysis patients, severe
liver disease, HR <50
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