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

1
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.
2
MAC Investigators

• 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.

• 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

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MAC

• 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 GA1

1Bhananker SM et al. Anesthesiology
2006104228-34.
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MAC

• Most commonly used drugs are midazolam, propofol
  and fentanyl.
• All 3 of these drugs is known to cause
  respiratory depression-especially in combination.

1Bhananker SM et al. Anesthesiology
2006104228-34.
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Dexmedetomidine

• 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 200093382-94.
2 Venn RM et al. Crit Care 20004302-8. 3
Arain SR et al. AA 200295461-6
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Dexmedetomidine

• 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.

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Study Design

• Randomized 221
• 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

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Study Design
PBO 65
DEX 130
DEX 130
DEX 0.5 mg/kg 10 min
DEX 1 mcg/kg 10 min
PBO 10 min
Load
Maintenance
0.6 mcg/kg/hr titrate
PBO Infusion
0.6 mcg/kg/hr titrate
Midazolam/Fentanyl Rescue
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Study Design

• Observers Assessment of Alertness/Sedation Scale
  used (OAA/S)
• 5responds to name spoken in normal tone
• 4responds only after mild prodding or shaking
• 3responds only after name loudly and/or
  repeatedly
• 2lethargic response to name spoken in normal
  tone
• 1does not respond to mild prodding or shaking

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Study Design

• Study drug started at least 15 min prior to block
  or local anesthetic
• Midazolam 0.5 mg doses given for OAA/Sgt4
• Fentanyl was given for pain

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Study Design

• 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.

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Results-Endpoints

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

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Midazolam
Mean 1.4 mg
Mean 0.9 mg
Mean 4.1 mg
Groups vs. PBO (plt 0.001)
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Fentanyl(p lt 0.001)
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Results-Endpoints

• Anesthesiologists indicated that DEX was easier
  to control than PBO midazolam (plt0.009)
• PBO required more fentanyl in PACU than DEX 1 mcg
  load group (p0.068)
• Patient satisfaction was higher with DEX (plt0.009)

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Results-Safety

• 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 (p0.043) and DBP (plt0.001)
  was greater in DEX than PBO group.

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Results-Safety

• HR decrease in both DEX groups was significant
  from baseline and vs. PBO group (plt0.001)
• Incidence of significant respiratory depression
  (RR lt 8 or O2 Sat lt 90) was lower in DEX
  treated patients (p0.018)

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Respiratory Depression(O2 Sat lt 90, CV RR lt 8)
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PACU D/C(p 0.068)
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Results-Safety

• 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.

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Conclusions

• 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.

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Conclusions

• 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.