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2 nd Annual Ellison Pierce Symposium Positioning Your ORs For The Future. New Drugs & Delivery Techniques. Keith B. Thomasset, PharmD, BCPS Clinical Manager – Pharmacy Services. Boston University School of Medicine May 19, 2006. 3:30- 4:00pm. QUESTION:.

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new drugs delivery techniques

2nd Annual Ellison Pierce Symposium

Positioning Your ORs For The Future

New Drugs & Delivery Techniques

Keith B. Thomasset, PharmD, BCPS

Clinical Manager – Pharmacy Services

Boston University School of Medicine

May 19, 2006

3:30- 4:00pm

slide2

QUESTION:

Which of the following is not an approved indication for utilizing morphine sulfate extended release liposomal injection:
  • Elective cesarean section
  • Lobectomy
  • Total knee arthroplasty
  • Lower abdominal surgery

Cross-Tab Label

0 / 10

sugammadex org 25969 is a reversal agent for rocuronium and contains what type of carrier matrix

QUESTION:

Sugammadex (Org 25969) is a reversal agent for rocuronium and contains what type of carrier matrix?
  • Lipid emulsion
  • Propylene glycol
  • Cyclodextrin
  • Tween-80

Cross-Tab Label

0 / 10

slide4

QUESTION:

When administering the first dose of cefazolin as an agent for surgical infection prophylaxis at 6:30AM for a case of 5 hours duration, assuming normal blood loss, the next dose should be administered:

  • At 9:00AM
  • At 10:30AM
  • At 2:30 PM
  • Another dose is not required

Cross-Tab Label

0 / 10

objectives
Objectives
  • Describe the advantages of liposomal based morphine sulfate for anesthesia practice
  • Appraise the role of Sugammadex (Org 25969) in the reversal of rocuronium muscle relaxation
  • Outline the importance of proper antimicrobial timing prior to surgical incision
depodur morphine sulfate extended release liposomal injection
DepoDur®(Morphine sulfate extended release liposomal injection)
  • Liposomal formulation of morphine sulfate
    • Epidural administration – lumbar level
    • 48 hour pain relief
  • Studied in:
    • Hip arthroplasty
    • Knee arthroplasty
    • Lower abdominal surgery
    • Elective cesarean section
depodur
DepoDur®

DepoFoam®

SkyePharma. Data on File. Endo Pharmaceuticals Inc.: Chadds Ford, PA; April 21, 2004.

liposomal vs conventional epidural opioids
Difficult to provide prolonged pain relief

Multiple injections

Epidural continuous infusion

High doses result

Adverse effects

Indwelling epidural catheter

Infection risk

Spinal hematoma

Liposomal formulation

Single injection

No indwelling catheter

Decreases post operative pain requirements

PCA

Decrease rescue opioid doses

Decreased adverse effects

No indwelling catheter

Decrease infection risk

Decrease spinal hemoatome risk

Liposomal vs. Conventional Epidural Opioids
advantages
Advantages
  • Decreased post operative opioid use
    • Decreased utilization of rescue doses
    • Decreased time to rescue therapy
      • Potential to prevent rescue therapy requirements
  • Decrease adverse effects
  • Potential decreased post operative nausea and vomiting
  • Potential improvement in patient flow
    • Quicker movement through the system
      • Quicker movement through the system
post op opioid use
Post-Op Opioid Use

Lower Abdominal Surgery

Anesth Anal 2005;100:1069.

time to rescue therapy
Time to Rescue Therapy

Hip Arthroplasty

Anesthesiology 2005;102(5):1018.

patients requiring no rescue therapy
Patients Requiring No Rescue Therapy

Elective Cesarean Delivery

Anesth Anal 2005;100:1155.

adverse effects precautions
Greater than 10% incidence

Decreased oxygen saturation

Hypotension

Urinary retention

N/V/H

Constipation

Pruritis

Pyrexia

Dizziness

Incidence between 5-10%

Hypoxia

Tachycardia

Insomnia

Incidence < 5%

Paralytic ileus

Abdominal distention

Hypertension

Bladder spasm

Potential interaction with epidural anesthetics

Reduced sustained release activity

Under further investigation

Adverse Effects & Precautions
depodur14
DepoDur®
  • Administration
    • Lumbar epidural administration
      • prior to surgery
      • after clamping of umbilical cord during cesarean section
  • Dosing
    • Orthopedic surgery of lower extremity – 15mg
    • Lower abdominal or pelvic surgery – 10-15mg
    • Elective cesarean section – 10mg
neuromuscular blockade reversal
Neuromuscular Blockade Reversal

www.medlib.med.utah.edu/ kw/mg/mml/ms_illus002.gif

common agents
Common Agents

Neostigmine

0.5-2mg IV

Acetylcholinesterase inhibitor

Edrophonium

10mg IV

  • Reversal
  • Atropine
  • 0.6-1.2mg IV
  • Antimuscarinic agent

Glycopyrrolate0.2-0.4 mg IV

limitations
Limitations
  • Not agent specific
  • Nonselective acetylcholine neurotransmission
    • Bradycardia
    • Hypersalivation
    • Bronchoconstriction
  • Interpatient variability of effect
  • Lack of effect against profound neuromuscular block
  • Require recurrence of first twitch during train-of-four stimulation
agent specific reversal
Agent Specific Reversal

Sugammadex (Org 25969)

  • Cyclodextrin compound
    • Encapsulate lipophilic molecules
    • Highly water soluble
    • No endogenous targets
    • Biological tolerance

Anesthesiology 99(3) p. 633

J Med Chem 45(9) p. 1807

agent specific reversal19
Agent Specific Reversal
  • Mechanism of Action
    • Hydrophillic exterior and hydrophobic interior
      • Encapsulation of rocuronium molecule
      • Prevention of interactions with nicotinic receptors
    • Increased excretion of complex
      • 1:1 complex

Anesthesiology 103(4), p. 696

other potential exogenous targets
Other Potential Exogenous Targets
  • Affinity highest with aminosteroid NMBAs
  • Others
    • Atropine
    • Verapamil
    • Non-NMBA Steroid Compounds
      • Hydrocortisone
      • Prednisone
      • Methylprednisone

Anesthesiology 2006; 104(4)

limitations21
Limitations
  • Not agent specific
  • Non-selective acetylcholine neurotransmission
    • Bradycardia
    • Hypersalivation
    • Bronchoconstriction
  • Interpatient variability of effect
  • Lack of effect against profound neuromuscular block
  • Only effective once partial spontaneous recovery has occurred
sugammadex org 25969
Sugammadex® (Org 25969)
  • Not agent specific – specific to amniosteroid NMBAs
  • Adverse effects
    • Bradycardia – not identified to date
    • Hypersalivation – not identified to date
    • Bronchoconstriction – not identified to date
  • Interpatient variability of effect – scant data
  • Lack of effect against profound neuromuscular block – scant human data
dosing
Dosing

Anesthesiology 103(4), p. 701

time to reversal
Time to Reversal

Anesthesiology 2005; 103(4)

Anesthesiology 2006;104(4)

Br J of Anesthesia 2006;96(1)

dosing and data dilemma
Dosing and Data Dilemma
  • Mostly dose finding studies
    • 0.1mg/kg - 8mg/kg
    • Single vs. multiple dose per patient
  • All human studies with rocuronium
    • Intermittent/single bolus or continuous infusion
  • All placebo controlled

Anesthesiology 2005; 103(4)

Anesthesiology 2006;104(4)

Br J of Anesthesia 2006;96(1)

conclusion
Conclusion
  • Elimination half life is ~ 100 min
    • Totally agent removal at 400 min (6.5 hours)
    • Renal failure???
  • Data suggests no recurarization for 90 minutes
    • Any for time period > 90 minutes?
  • More safety and efficacy data needed
  • Ideal dose yet to be determined
  • Impact on daily practice
    • Cost effectiveness

STAY TUNED

decreasing the risk of surgical site infections
Decreasing the Risk of Surgical Site Infections
  • Maintain high levels of inspired oxygen
  • Maintain peri-operative normothermia
  • Avoid shaving operative site
  • Maintain adequate glucose control
  • Appropriate use of peri-operative antibiotics
goal outcomes antimicrobial specific
Goal OutcomesAntimicrobial Specific
  • Evidence-based recommendations
  • Correct drug
  • Correct dose
  • Correct duration
    • Including intra-operative dosing
slide29

It’s All About Timing

Bratzler, D. W. et al. Arch Surg 2005;140:174-182.

timing of doses
Timing of Doses

Incision should occur within 60 minutes of antimicrobial administration

  • Initial Dosing
    • Cefazolin, Cefoxitin, Cefotetan, Clindamycin
      • Administer over 10-15 minutes
    • Vancomycin, Gentamicin, Metronidazole
      • Administer over at least 1 hour (1 gm/hr for vancomycin)
slide31

Timing of Doses

  • Intra-operative Dosing
    • Redose
      • Large amount of intra-operative blood loss (~1500mL)
      • Approximately 2X half life of antimicrobial
    • Cefazolin, Cefoxitin, Clindamycin
      • Q4 hours intra-op
    • Vancomycin
      • Q6 hours intra-op
    • Cefotetan, Levofloxacin, Gentamicin
      • Not needed intra-op due to prolonged duration
slide32

Antimicrobial Choice

Bratzler, D. W. et al. Arch Surg 2005;140:174-182.

slide33

When to Stop

Bratzler, D. W. et al. Arch Surg 2005;140:174-182.

bmc antimicrobial prophylaxis plan
Develop agreement

Choice

Dosing

Administration

Redosing

Intergroup

Surgery

Anesthesia

ID

Pharmacy

ITS

Implementation

Adminstration time

Intraop reminders

Stickers

Pagers

Standard Orders

Physician order entry

Orders per guidelines

Auto stops

BMC Antimicrobial Prophylaxis Plan
boston medical center scorecard
Boston Medical Center Scorecard

Figure based on compliance of the following combined points: antibiotics (correct agent, correct timing, correct discontinuation)