Monitored Anesthesia Care Monitored Anesthesia Care with Dexmedetomidine: A with Dexmedetomidine: A Prospective, Randomized, Prospective, Randomized,

Double-Blind, Multicenter TrialDouble-Blind, Multicenter Trial

This study was funded by Hospira Inc.This study was funded by Hospira Inc.

Dr. Keith CandiottiDr. Keith CandiottiDepartment of AnesthesiologyDepartment of Anesthesiology

University of MiamiUniversity of Miami

MAC Investigators

• Martin W. Allard• Alex Y. Bekker• Sergio D. Bergese • Keith A. Candiotti • Eric L. Diamond• Dennis D. Doblar • Thomas J. Ebert • Marc Feldmam • Robert B. Fisher • Tong J. Gan • Steven Gayer• Ira J. Gottlieb• Craig T. Hartrick

• Gary R. Haynes• Fima Lenkovsky• Terri Monk• Paul A. Moore • Thomas N. Pajewski• Beverly K. Philip• Michael A.E. Ramsay• Ruben Ricardo• Bernhard Riedel• Charles R. Roberson• Fred E. Shapiro• Jeffrey H. Silverstein• Tracey L. Stierer.

• A 2006 review of closed claims in the ASA A 2006 review of closed claims in the ASA Closed Claims Database reveals that Closed Claims Database reveals that oversedation leading to respiratory depression oversedation leading to respiratory depression played a major role in patient injuries during played a major role in patient injuries during MAC.MAC.

• MAC claims were fewer than GA overall MAC claims were fewer than GA overall

• Claims for death or permanent brain damage Claims for death or permanent brain damage were 40%, similar to GAwere 40%, similar to GA11

11Bhananker SM et al. Bhananker SM et al. AnesthesiologyAnesthesiology 2006;104:228-34. 2006;104:228-34.

• Most commonly used drugs are midazolam, Most commonly used drugs are midazolam, propofol and fentanyl.propofol and fentanyl.

• All 3 of these drugs is known to cause All 3 of these drugs is known to cause respiratory depression-especially in respiratory depression-especially in combination.combination.

11Bhananker SM et al. Bhananker SM et al. AnesthesiologyAnesthesiology 2006;104:228-34. 2006;104:228-34.

• DEX is a centrally acting alpha-2 receptor DEX is a centrally acting alpha-2 receptor antagonist that does not produce significant antagonist that does not produce significant respiratory depression.respiratory depression.1-31-3

• Dex has an analgesic-sparing effect, reducing Dex has an analgesic-sparing effect, reducing opioid requirements both during and after opioid requirements both during and after surgery.surgery.33

• The agent also possess a sympatholytic effect The agent also possess a sympatholytic effect that can mitigate tachycardia and HTN.that can mitigate tachycardia and HTN.33

11 Ebert TJ et al. Ebert TJ et al. AnesthesiologyAnesthesiology 2000;93:382-94. 2000;93:382-94. 22 Venn RM et al. Venn RM et al. Crit CareCrit Care 2000;4:302-8. 2000;4:302-8. 33 Arain SR et al. Arain SR et al. AAAA 2002;95:461-6 2002;95:461-6

• DEX is currently approved for use in initially DEX is currently approved for use in initially intubated patients in an intensive care setting.intubated patients in an intensive care setting.

• This trial was designed to evaluate the safety This trial was designed to evaluate the safety and efficacy of DEX in non-intubated patients in and efficacy of DEX in non-intubated patients in a large multicenter trial (26 sites) using it as the a large multicenter trial (26 sites) using it as the primary sedative agent.primary sedative agent.

• FDA trial designed to compare against a placebo FDA trial designed to compare against a placebo group using midazolam and fentanyl for rescue.group using midazolam and fentanyl for rescue.

Study DesignStudy Design

• Randomized 2:2:1 Randomized 2:2:1

• LOADLOAD– DEX 0.5 mcg/kg loadDEX 0.5 mcg/kg load

– DEX 1 mcg/kg loadDEX 1 mcg/kg load

– Saline PlaceboSaline Placebo

• MAINTENANCEMAINTENANCE– Both DEX groups 0.6 mcg/kg/hr (titrated)Both DEX groups 0.6 mcg/kg/hr (titrated)

– Placebo had saline infusionPlacebo had saline infusion

DEX 130

DEX 0.5 mg/kg10 min

DEX 130 PBO 65

DEX 1 mcg/kg10 min

0.6 mcg/kg/hr

titrate

0.6 mcg/kg/hr

titrate

PBO10 min

PBOInfusion

Midazolam/Fentanyl RescueMidazolam/Fentanyl Rescue

• Observer’s Assessment of Alertness/Sedation Scale used (OAA/S)

• 5=responds to name spoken in normal tone• 4=responds only after mild prodding or shaking• 3=responds only after name loudly and/or

repeatedly• 2=lethargic response to name spoken in normal

tone• 1=does not respond to mild prodding or shaking

• Study drug started at least 15 min prior to block Study drug started at least 15 min prior to block or local anestheticor local anesthetic

• Midazolam 0.5 mg doses given for OAA/S>4Midazolam 0.5 mg doses given for OAA/S>4

• Fentanyl was given for painFentanyl was given for pain

• Primary endpointPrimary endpoint– % patients not requiring midazolam for rescue based % patients not requiring midazolam for rescue based

on an OAA/S of ≤ 4.on an OAA/S of ≤ 4.• Secondary endpointSecondary endpoint

– Total rescue midazolam and/or fentanylTotal rescue midazolam and/or fentanyl– Time to rescueTime to rescue– Patients who converted to alternative therapyPatients who converted to alternative therapy– Readiness for D/CReadiness for D/C– Hemodynamic stabilityHemodynamic stability– Patient and Anesthesiologist SatisfactionPatient and Anesthesiologist Satisfaction

• Safety endpointsSafety endpoints– Cardiac and pulmonary etc.Cardiac and pulmonary etc.

• 326 in intent-to-treat 326 in intent-to-treat

• Randomization was goodRandomization was good

• Fewer patients in both DEX groups Fewer patients in both DEX groups required midazolam and used less (p< required midazolam and used less (p< 0.001)0.001)

• Both DEX groups required less fentanyl Both DEX groups required less fentanyl (p< 0.01)(p< 0.01)

Groups vs. PBO (p< 0.001)

Mean1.4 mg

Mean0.9 mg

Mean4.1 mg

• Anesthesiologists indicated that DEX was Anesthesiologists indicated that DEX was easier to control than PBO + midazolam easier to control than PBO + midazolam (p<0.009)(p<0.009)

• PBO required more fentanyl in PACU than PBO required more fentanyl in PACU than DEX 1 mcg load group (p≤0.068)DEX 1 mcg load group (p≤0.068)

• Patient satisfaction was higher with DEX Patient satisfaction was higher with DEX (p<0.009)(p<0.009)

• Most common AE with DEX were protocol Most common AE with DEX were protocol defined bradycardia and hypotension defined bradycardia and hypotension which were predominately mild to which were predominately mild to moderate in severity and did not require moderate in severity and did not require intervention.intervention.

• Mean decrease in SBP (p≤0.043) and Mean decrease in SBP (p≤0.043) and DBP (p<0.001) was greater in DEX than DBP (p<0.001) was greater in DEX than PBO group.PBO group.

• HR decrease in both DEX groups was HR decrease in both DEX groups was significant from baseline and vs. PBO significant from baseline and vs. PBO group (p<0.001)group (p<0.001)

• Incidence of significant respiratory Incidence of significant respiratory depression (RR < 8 or O2 Sat% < 90%) depression (RR < 8 or O2 Sat% < 90%) was lower in DEX treated patients was lower in DEX treated patients (p=0.018)(p=0.018)

• Coadministration of midazolam or fentanyl Coadministration of midazolam or fentanyl with DEX was not associated with an with DEX was not associated with an increase in hypotension, bradycardia or increase in hypotension, bradycardia or respiratory depression.respiratory depression.

• In PBO group midazolam and fentanyl In PBO group midazolam and fentanyl were associated with a respective 13.1 were associated with a respective 13.1 and 16.1% rate absolute respiratory and 16.1% rate absolute respiratory depression or need for intervention.depression or need for intervention.

• DEX is an effective baseline sedative for DEX is an effective baseline sedative for patients undergoing MAC for a variety of patients undergoing MAC for a variety of procedures.procedures.

• Less opioids are required and less Less opioids are required and less respiratory depression is seen with DEX.respiratory depression is seen with DEX.

• FDA decision based on this trial:FDA decision based on this trial:

“ “This supplemental new drug application This supplemental new drug application provides for the use of Precedex Injection provides for the use of Precedex Injection for sedation of nonintubated patients prior for sedation of nonintubated patients prior to and/or during surgical and other to and/or during surgical and other procedures”.procedures”.