08045-02 ANES

Intramural Research Project
Z01 CL-08044-02 ANES
October 1, 1999 to September 30, 2000

Title of Project:
Effect of Intravenous Clonidine on the Postoperative Narcotic Requirement in Patients Undergoing Isolated Hepatic Perfusion

Principal Investigator:
L.C. Bachenheimer, M.D.
ANES, CC, NIH
Bethesda, MD 20892

Other Personnel:
H. R. Alexander, Jr., M.D., Surgery Branch, NCI
S. Steinberg, Ph.D., DCS, NCI
G.M. Susla, Pharm.D., Pharmacy Department, CC
A. Burstein, Pharm.D., Pharmacy Department, CC
K. Pacak, M.D., Ph.D., D.Sc., Pediatric and Reproductive Endocrinology Branch, NICHD
K.S. Williams, M.D., CC/DASS

Collaborating Unit:
None

Staff-Years:
0.15

Human Subjects:
x (a) Human subjects (b) Human tissues (c) Neither
(a1) Minors (a2) Interviews

Summary of Work: Preliminary studies to evaluate the stability of fentanyl and clonidine in human blood have just been completed. These were necessary to finalize the schedule for research blood draws. After this schedule is finalized, the protocol will be resubmitted to the NCI Institute Review Board for final approval.

Patients undergoing isolated hepatic perfusion who are expected to be extubated at the end of the case will, in a prospectively randomized fashion, receive either placebo or Clonidine, 5 mcg/kg intravenously, at the end of the surgical procedure. After awakening and extubation, rescue intravenous morphine will be titrated as needed. Narcotic requirement and patient rating of pain during the first 36 hours, plasma fentanyl and clonidine levels during the first 24 hours and catecholamine levels during the first 12 hours will be followed as well as events of respiratory depression, hypotension and bradycardia requiring pharmacologic intervention.

Intramural Research Project
Z01 CL-08045-02 ANES
October 1, 1999 to September 30, 2000

Title of Project:
Role of G-proteins in the Hemodynamic Interactions of Fentanyl and Isoproterenol

Principal Investigator:
H.L. Preas II, M.D.
ANES, CC, NIH
Bethesda, MD 20892

Other Personnel:
C. Natanson, M.D., CCMD
S. Solomon, Ph.D., CCMD
A. Hilton, CCMD
S. Richmond, CCMD
M. Fernandez, M.D., CCMD
J. Bacher, DVM, VRP
M. Thomas, DVM, VRP
M. Williams, VRP (contractor)
M. Bur, VRP (contractor)
D. Lancaster, VRP (contractor)
L. Brinster, DVM, VRP (contractor)

Collaborating Unit:
None

Staff-Years:
0

Human Subjects:
(a) Human subjects (b) Human tissues (c) Neither
(a1) Minors (a2) Interviews

Summary of Work: Fentanyl is a commonly used narcotic that has wide applications in general anesthesia and critical care settings. We have previously shown that fentanyl, an opioid agonist, when administered to canines: (1) blocked b-adrenergic hemodynamic responses to epinephrine and isoproterenol; (2) did not effect the a-adrenergic effects of epinephrine or phenylephrine. These studies were extended to define the mechanism of fentanyl-catecholamine interactions by performing similar studies in canines with pertussis toxin, an inhibitor of G-protein signaling. These studies have implications for understanding the mechanism that accounts for altered hemodynamic responses due to fentanyl in anesthesia and in critically ill patients.

The pilot portion of this protocol which used four dogs was completed in September 1999. Based on these results, the main portion of this protocol was begun. Twenty dogs will be enrolled in this phase of the study. All 20 will have completed parts one and two in phase two by June 16, 2000. For those dogs scheduled to have a third study, this protocol will be completed by September 16, 2000.