Pharmacy Services Dexmedetomidine (Precedex®) Haley Gill, BSP VCH-PHC Pharmacy Resident 2009-2010.

Pharmacy ServicesPharmacy Services

Dexmedetomidine (Precedex®)

Haley Gill, BSPVCH-PHC Pharmacy Resident 2009-2010


Outline

• Current indications

• Differences & possible advantages over current sedation agents

• Pharmacology

• Dosing

• Cost

• Review of Literature


Health Canada

• Precedex®

• NOC issued December 2009

• Dexmedetomidine (DXM) 100mcg/ml solution

• Continuous IV infusion


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


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


Pharmacology

• MOA – highly selective α2-adrenoreceptor agonist

– Similar to clonidine but 8 X more selective for α2

α2-adrenoreceptors Pancreatic β-cells ↓ insulin secretion

Platelets Aggregation

Nerve Terminals ↓ release of NE

Vascular Smooth muscle Contraction


Pharmacology


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

Excretion Urine 95%

Feces 4%


Drug Interactions

Enzyme Action Drugs

CYP 2A6 substrate amiodarone isoniazid

ketoconazole

CYP 1A2, 2C9, 3A4

weak inhibitor warfarin

Simvastatin

CYP 2D6 strong inhibitor codeine

**theoretical interactions – likely of little clinical significance**


Drug Interactions

• Beta-blockers: rebound hypertensive effect when the α2-agonist is abruptly withdrawn

• Mirtazapine: α2-antagonist (opposing effects)


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)


Dosing

• No specific recommendations for renal or hepatic dysfunction


Adverse Effects

• Hypotension (24-54%)

• Bradycardia (5-14%)• Respiratory

depression (37%; placebo 32%)

• Atrial fibrillation (4-5%)• Hypovolemia (3%)

• ↓ urine output• Pleural effusion • Hypocalcemia (1%)• Nausea (3-9%)• Xerostomia (3-4%)• Hyperglycemia


Cost

Drug Unit Cost Cost/day for 70 kg ptDXM 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)


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


MENDSObjective 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)


MENDSResults 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


Dexmedetomidine vs Midazolam for Sedation of Critically Ill Patients

(SEDCOM)

Riker R, et al

JAMA 2009;31(5):489-499


SEDCOMObjective 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)


SEDCOMResults 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


Dexmedetomidine versus propofol/midazolam for long-term sedation

during mechanical ventilation

Ruokonen E, et al

Intensive Care Med 2009;35:282-290


Ruokonen E, et alObjective 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)


Ruokonen E, et alResults 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)


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


Shehabi Y, et alObjective 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


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

• Duration > 24 hr appears safe• Appears safe in non-surgical population• May ↓ delirium• Main AE’s: bradycardia, hyperglycemia, AF


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

Pharmacy Services Dexmedetomidine (Precedex®) Haley Gill, BSP VCH-PHC Pharmacy Resident 2009-2010.

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Transcript of Pharmacy Services Dexmedetomidine (Precedex®) Haley Gill, BSP VCH-PHC Pharmacy Resident 2009-2010.