1. 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

2. Elective cesarean section Lobectomy Total knee arthroplasty
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

3. 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

4. Another dose is not required
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

5. 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

6. 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

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

8. 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
Decrease infection risk
Decrease spinal hemoatome risk

9. 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

10. Post-Op Opioid Use
Lower Abdominal Surgery
Anesth Anal 2005;100:1069.

11. Time to Rescue Therapy Hip Arthroplasty
Anesthesiology 2005;102(5):1018.

12. Patients Requiring No Rescue Therapy
Elective Cesarean Delivery
Anesth Anal 2005;100:1155.

13. Adverse Effects & Precautions
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
Greater than 10% incidence
Decreased oxygen saturation
Hypotension
Urinary retention
N/V/H
Constipation
Pruritis
Pyrexia
Dizziness

14. DepoDur® Administration Dosing 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

15. Neuromuscular Blockade Reversal
kw/mg/mml/ms_illus002.gif

16. Common Agents Neostigmine Edrophonium Atropine
0.5-2mg IV
Acetylcholinesterase inhibitor
Edrophonium
10mg IV
Reversal
Atropine
mg IV
Antimuscarinic agent
Glycopyrrolate mg IV

17. 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

18. 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

19. 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

20. Other Potential Exogenous Targets
Affinity highest with aminosteroid NMBAs
Others
Atropine
Verapamil
Non-NMBA Steroid Compounds
Hydrocortisone
Prednisone
Methylprednisone
Anesthesiology 2006; 104(4)

21. 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

22. 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

23. Dosing
Anesthesiology 103(4), p. 701

24. Time to Reversal Dose (mg/kg) Placebo 0.1 0.5 1 2 3 4 8
Avg. time to reversal (min)
15-60 43
1.4-31
1-17
1-3.3
1-1.2
Anesthesiology 2005; 103(4)
Anesthesiology 2006;104(4)
Br J of Anesthesia 2006;96(1)

25. 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)

26. Conclusion STAY TUNED 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

27. 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

28. Goal Outcomes Antimicrobial Specific
Evidence-based recommendations
Correct drug
Correct dose
Correct duration
Including intra-operative dosing

29. Bratzler, D. W. et al. Arch Surg 2005;140:174-182.
It’s All About Timing
Bratzler, D. W. et al. Arch Surg 2005;140:

30. Timing of Doses
Incision should occur within 60 minutes of antimicrobial administration
Initial Dosing
Cefazolin, Cefoxitin, Cefotetan, Clindamycin
Administer over minutes
Vancomycin, Gentamicin, Metronidazole
Administer over at least 1 hour (1 gm/hr for vancomycin)

31. 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

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

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

34. 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

35. Boston Medical Center Scorecard
Figure based on compliance of the following combined points: antibiotics (correct agent, correct timing, correct discontinuation)

36. Boston Medical Center Scorecard

37. Boston Medical Center Scorecard