Monitored Anesthesia Care with Dexmedetomidine: A Prospective, Randomized, Double-Blind, Multicenter Trial

Dr. Keith Candiotti Department of Anesthesiology University of Miami This study was funded by Hospira Inc.

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 Closed Claims Database reveals that oversedation leading to respiratory depression played a major role in patient injuries during MAC.

• MAC claims were fewer than GA overall • Claims for death or permanent brain damage were 40%, similar to GA 1 1 Bhananker SM et al.

Anesthesiology

2006;104:228-34.

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

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

1 Bhananker SM et al.

Anesthesiology

2006;104:228-34.

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

1-3 • Dex has an analgesic-sparing effect, reducing opioid requirements both during and after surgery.

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

3 1 Ebert TJ et al.

Anesthesiology

2000;93:382-94. 2 3 Arain SR et al.

AA

2002;95:461-6 Venn RM et al.

Crit Care

2000;4:302-8.

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

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

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

Study Design

• Randomized 2:2:1 • LOAD – DEX 0.5 mcg/kg load – DEX 1 mcg/kg load – Saline Placebo • MAINTENANCE – Both DEX groups 0.6 mcg/kg/hr (titrated) – Placebo had saline infusion

DEX 130 DEX 130 PBO 65 DEX 0.5 mg/kg 10 min DEX 1 mcg/kg 10 min PBO 10 min 0.6 mcg/kg/hr titrate 0.6 mcg/kg/hr titrate PBO Infusion Midazolam/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 or local anesthetic • Midazolam 0.5 mg doses given for OAA/S>4 • Fentanyl was given for pain

• • •

Primary endpoint

– % patients not requiring midazolam for rescue based on an OAA/S of ≤ 4.

Secondary endpoint

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

Safety endpoints

– Cardiac and pulmonary etc.

• 326 in intent-to-treat • Randomization was good • Fewer patients in both DEX groups required midazolam and used less (p< 0.001) • Both DEX groups required less fentanyl (p< 0.01)

Mean 1.4 mg Mean 0.9 mg Mean 4.1 mg Groups vs. PBO (p< 0.001)

• Anesthesiologists indicated that DEX was easier to control than PBO + midazolam (p<0.009) • PBO required more fentanyl in PACU than DEX 1 mcg load group (p≤0.068) • Patient satisfaction was higher with DEX (p<0.009)

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

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

• HR decrease in both DEX groups was significant from baseline and vs. PBO group (p<0.001) • Incidence of significant respiratory depression (RR < 8 or O2 Sat% < 90%) was lower in DEX treated patients (p=0.018)

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

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

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

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

• FDA decision based on this trial: “This supplemental new drug application provides for the use of Precedex Injection for sedation of nonintubated patients prior to and/or during surgical and other procedures”.