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CRSTI Research News - February 2001
Sildenafil - a Replacement for Inhaled Nitric Oxide in Cardiac Surgery?
by Michael A. E. Ramsay, M.D., FRCA
Nitric oxide is endogenously produced within the vascular endothelium and functions as a natural vasodilator. Its discovery led to the awarding of the Nobel Prize in medicine to Furchgott, Ignarro and Murad in 1998. They identified nitric oxide as a signal molecule in the nervous system, as a weapon against infection and as a modulator of blood pressure. This discovery led to the investigation of the role of inhaled nitric oxide (INO) as a means of treating pulmonary hypertension.
Its brief duration of action limits its action to the pulmonary vasculature and only to those vessels perfusing ventilated alveoli. Therefore it can improve oxygenation of the blood by increasing the perfusion of the ventilated alveoli as well as reducing pulmonary vascular resistance. The role of INO in treating primary pulmonary hypertension of the newborn has been well established; its role in cardiac surgery still awaits the results of randomized controlled studies.
Currently available intravenous pulmonary vasodilators such as epoprostenol, milrinone or nitroglycerine also cause systemic vasodilatation and therefore the resulting systemic hypotension limits the efficacy of these agents. This is especially pertinent for patients with cardiac disease, where coronary perfusion may be adversely affected by a decline in perfusion pressure. Increases in pulmonary vascular resistance can greatly complicate the post-operative course of patients who have undergone cardiac surgery.
Inhaled nitric oxide is a selective pulmonary vasodilator in patients with pulmonary hypertension. Pulmonary hypertension causes an increase in right ventricular work and if severe, or if an acute increase in pressure occurs, right ventricular failure may result. The successful role of INO in weaning patients off cardiopulmonary bypass who have developed acute elevations in pulmonary artery pressure has been well reported.
The nitric oxide stimulates intracellular cyclic guaninemonophosphate that causes vascular smooth muscle relaxation. This vasodilatation is terminated by the action of phosphodiesterases (PDEs) that degrade the guanine monophosphate. Milrinone is a PDE 3 inhibitor and by this action enhances the action of endogenous nitric oxide and causes pulmonary, but also systemic, vasodilatation.
Phosphodiesterase 5 is found in high concentrations in the lung and is also a powerful degrader of guanine monophosphate in vascular smooth muscle.
Sildenafil (Viagra, Pfizer Laboratories, NY) is a selective inhibitor of PDE 5; the isoenzyme that hydrolyses guanine monophosphate in the corpus cavernosum, thereby potentiating the effect of locally produced nitric oxide and maintaining vasodilatation.
It has been hypothesized that because of the high concentrations of PDE 5 in the lung, sildenafil might also potentiate pulmonary vasodilatation. Several case reports now exist suggesting that sildenafil is effective in ameliorating rebound pulmonary hypertension following the withdrawal of INO in children after congenital heart surgery, and in facilitating weaning of INO and milrinone in a teenager following placement of a biventricular assist device.
A letter in the New England Journal of Medicine reports on its use in a 21 year-old man with primary pulmonary hypertension. Sildenafil at a daily dose of 500mgs in divided doses significantly reduced pulmonary artery pressure.
Recently INO has become more difficult to obtain, therefore at Baylor University Medical Center in Dallas we have been investigating the role of sildenafil in the management of pulmonary hypertension during weaning from cardiopulmonary bypass.
These early experiences with sildenafil for the treatment of pulmonary hypertension demonstrate some promise that certainly warrants a controlled clinical study. The opportunity to treat pulmonary hypertension by an oral medication, as opposed to the inhalation or intravenous routes would be a major advance in management. The side effects of therapy maybe well tolerated!
Case Report
A 54-year-old male underwent cardiac transplantation for ischemic cardiomyopathy. Pre-operative pulmonary artery pressures measured 70/20 mm Hg; mean of 41mm Hg and a PVR of 282 dynes.cm.sec-5. Following implantation of the new graft and weaning from cardiopulmonary bypass, the pulmonary artery pressures gradually increased to 54/22 mm Hg, mean 36 mm Hg. and a PVR of 278 dynes. cm. sec-5. Sildenafil 100mgs was then crushed into 60 ccs of saline and the slurry produced syringed down the nasogastric tube. Over the next 30 minutes the pulmonary artery pressures declined to 38/19 mm Hg, mean 32 mm Hg, PVR 154 dynes. cm. sec-5 and the cardiac output increased from 8.9 L/min to 13.5 L/min. systemic arterial blood pressure increased from 78//39 mm Hg to 91/46 mm Hg.This improvement was sustained post-operatively.
Research Staff Profile
Karen Combs
Personnel/Office Manager
Karen Combs is the Personnel/Office Manager for the Cardiopulmonary Research Science & Technology Institute (CRSTI). Karen provides administrative support to the Chief Executive Officer and Chief Operating Officer. She is responsible for the organization's human resources, accounts payable and receivable, and payroll processing.
Karen has twenty years of accounting management experience. She has developed several accounting and payroll systems for various retail, software and telecommunications companies. Since 1997, she has focused her talents in the medical field.
Prior to joining CRSTI, Karen served as Office Manager for COR Specialty Associates of North Texas, P.A. (CSANT). She previously served as Accounts Manager for Wireless Enterprises in Plano, Texas. Karen gained additional office management experience as Office Manager for Agave Software Design and Tandy Corporation.
Karen attended Trinity University in San Antonio and Texas Women's University in Denton toward a Bachelor of Science, with a minor in Marketing and English. Karen, her husband and their three children reside in Plano, Texas.
QUARTERLY CALENDAR
FEBRUARY
February 7 PHD Investigator Meeting
February 9 IRB Deadline at MCD Hospital
February 19 American Heart Luncheon at MCD
February 20 Education Committee Meeting
February 21 American Heart Luncheon at PHD
February 21 IRB Meeting at MCD Hospital
February 22 American Heart Luncheon at DCH
February 22 HRC Meeting at PHD
February 23 Advancements in Cardiac Surgery OPCAB Program
February 26 March HRC Deadline at PHD
MARCH
March 9 IRB Deadline at MCD Hospital
March 21 IRB Meeting at MCD Hospital
March 25 April HRB Deadline
March 29 HRC Meeting at PHD
March 30 Advancements in Cardiac Surgery OPCAB Program
APRIL
April 6 IRB Deadline at MCD Hospital
April 18 IRB Meeting at MCD Hospital
April 20 Cardiovascular Update 2001
April 26 HRC Meeting at PHD
April 30 May HRC Deadline at PHD
MAY
May 4 IRB Deadline at MCD Hospital
May 16 IRB Meeting at MCD Hospital
May 29 June HRC Deadline at PHD
MCD Hospital Investigator Meetings are held every Thursday morning at 7:00 a.m.
For more information regarding any of the meetings, please call 214-750-7005.
February - American Heart Month
Heart disease is the number one killer of Americans, claiming more lives than the next seven leading causes of death. Fortunately, significant advancements are being made in cardiac medicines and therapies to prevent and treat this deadly disease.
CRSTI has partnered with medical industry leaders and local hospitals to educate the community about these latest advancements by hosting a series of luncheons during February - American Heart Month.
"The Heart of Tomorrow's Medicine" luncheons will provide our industry partners an opportunity to share with the community their commitment to fighting cardiac disease. CRSTI will share what's on the horizon for cardiopulmonary research, as well as personal interviews from local researchers and their patients who are benefiting from research conducted here in our community. The program will also feature North Texas physicians participating in CRSTI research.
American Heart Month Luncheon Schedule
February 19 "Tomorrow's Medicine Today - Innovative Therapies to Treat Your Cardiac Disease" Dr. Mitchel Sklar Cardiologist North Texas Heart Center 12:00 to 1:30 Medical City Dallas Hospital Conference Room D
February 21 "A Woman's Heart - Silent Victim of Texas' Number One Disease" Drs. Teresa Menedez and Sara Samaan Cardiologists North Texas Heart Center 11:30 to 1:00 Presbyterian Hospital of Dallas Southeast Conference Room
February 22 "New Era Heart Surgery - Kinder, Gentler Approaches" Dr. Tea Acuff Cardiothoracic Surgeon COR Specialty Associates of North Texas 12:00 to 1:30 Denton Community Hospital Medical Office Building Conference Room
Additional information and locations: T: 214.750.7005.x109 or www.crsti.org
Cardiovascular Update 2001
April 20, 2001 Dallas, Texas
The 7th Annual Cardiovascular Update, an informative one-day conference consisting of concise presentations, is scheduled for Friday, April 20, 2001 in Dallas.
The program is designed for family practitioners, internists, cardiologists, physician assistants, nurse practitioners, nurses, and other health care providers who care for the cardiac patient. Faculty will be representative of cardiac specialists and experts in early disease detection, management and treatment. The educational program will offer category 1 credit towards the AMA PRA, including one hour of ethics. Topics include heart failure, coronary artery disease, imaging, electrophysiology, lipids, recent advancements and ethics. An activity day will be held on Saturday.
For additional information and to receive a brochure, contact Michelle at 214-750-7005 x-106. Registration is available on line at www.crsti.org.
ACKNOWLEDGEMENT OF SUPPORT
Cardiopulmonary Research Science and Technology Institute gratefully acknowledges the support it receives through individual and corporate contributions. With our fall campaign underway we are honored to acknowledge the contributions of St. Jude Medical, Gold level, and Hill Feinberg, President’s Club level.
We thank them for their support of CRSTI and our mission. It is through the support of individuals and corporations that we are able to continue the research, quality management and education of cardiac disease.
President’s Club
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COR Specialty Associates of North Texas (CSANT)
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North Texas Heart Center (NTHC)
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Blue Ribbon
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Eclipse Surgical Technologies, Inc.
James Edgerton, M.D.
Hill Feinberg
Heartport, Inc.
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Merck & Co., Inc.
Presbyterian Hospital of Dallas
St. Jude Medical |
Gold
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Guidant Corporation
Medtronic, Inc.
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Michael J. Mack, M.D.
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Bronze
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3M Pharmaceuticals
Acuson
Aventis
Bayer Diagnostics
COR Therapeutics, Inc.
Sanofi Pharmaceuticals, Inc.
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Mallinckrodt, Inc.
Medical City Dallas Hospital
Pfizer,
Roche Laboratories, Inc.
U.S. Pharmaceuticals
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Abbot Laboratories
Abiomed
Tea Acuff, M.D.
Agilent Technologies
American Echo, Inc.
Astra Pharmaceuticals, L.P.
ATL Ultrasound, Inc.
Biosound, Inc.
Bristol-Myers Squibb, U.S. Pharmaceuticals
Camtronics
Chase Medical , Inc.
Jorge Cheirif, M.D.
DuPont Pharmaceuticals
GE Medical
Gill & Dody Weaver Foundation
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Glaxo Pharmaceuticals
Darryl Kawalsky, M.D.
Mitch Magee, M.D.
David Moore, M.D.
Parke-Davis, Inc.
Stacie Prasifka
Dr. and Mrs. Jed Rosenthal
Dr. and Mrs. Michael Rothkopf
Dr. and Mrs. Scruggs
Mitch Sklar, M.D.
SmithKline Beacham
Strasburger & Price
Marshall Sprigg
Solvay Pharmaceuticals
Sonosite
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| Contributor |
Edd Allen
Robert and Helen Almes
Maxine Becker
Nicholas Cade
Larry Crocker
Bernyce Crownover
Sandra Dooley
Anne Dyson
Linda Edgerton
Marguerite Gibson
Mark Golman, Esq.
John Green
Neal and Kriste Haile
Bob Haley
Charles Hamm
Leslie Hurst
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Elizabeth Jones
William Karl, Jr.
Michael Kelleghan
Leon Lasater
Katherine Marrale
Rex and Betty Minton
Nancy Paschen
Marshal Phillips
Irene Powell
Marie Shepherd
Ladelle Smith
Lori Swalm
Joyce Swim
Herbert Unger
Joy Wood
Herbert Yosten
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Sylvia Acuff
Tea Acuff, M.D.
Allan Anderson, M.D.
Allen Anderson, M.D.
Paul Anderson, M.D.
Ronald Aranoff, M.D.
Katrina Bassel, M.D.
Thomas Beveridge, M.D.
Jeffery Bower, M.D.
Richard Bowman, M.D.
Geneva Boyle, M.D.
Baxter Brinkmann
Barry Brooks, M.D.
David Brown, M.D.
Roger Camp, M.D.
David Carroll, CC
Jorge Cheirif, M.D.
Dan Cox Ph.D
J. Brian DeVille, M.D.
Todd Dewey, M.D.
James Edgerton, M.D.
Hill A. Feinberg
Bonnie Floyd, M.D.
David Fosdick, M.D.
Allister I. Fyfe, M.D, Ph.D.
Mark Golman
John Green
Carolyn Gunter
Kristie Haile, PA-C
Neal Haile
Lt. General Charles Hamm
Mark Harvey, M.D.
Khanh Hoang, M.D.
Lannie Hughes, M.D.
Jodie Hurwitz, M.D.
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Darryl Kawalsky, M.D.
Patrick Kennedy, M.D.
James Knochel, M.D.
Michael Mack, M.D.
Mitchell Magee, M.D.
Phil Maples, Ph.D.
Megumi Mathison, M.D.
Christy McKeighen
Teresa Menendez, M.D.
Steven Meyer, M.D.
Lawrence Mills, M.D.
David Moore, M.D.
David Musselman, M.D.
John Nemunaitis, M.D.
David Ogden, M.D.
Dan Phillips
Merlene Phillips
Melvin Platt, M.D.
Stacie Prasifka
Thomas Rawles, CCD
Steve Rinner, M.D.
J. Edward Rosenthal, M.D.
William Ryan, M.D.
Michael Savin, M.D.
Eric Shaw, PA-C
Mitchel Sklar, M.D.
Crys Sory, M.D.
John Tan, M.D.
Ronald Underwood, M.D.
Juliette Wait, M.D.
Bruce Wall, M.D.
David Weill, M.D.
Charles White, M.D.
Christopher R.C. Williams, M.D.
Worthy Wornack, M.D.
Christopher Wyndham, M.D.
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RESEARCH PROTOCOLS
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