Pulmonary Hypertension in the Critical Care Setting, Winter 2005

Advances in 

Pulmonary 

Hypertension 

Official Journal of the Pulmonary Hypertension Association 

Winter 2005 

Vol 4, No 4 

Pulmonary Hypertension 

in the Critical Care Setting 

Perioperative Management 

Ronald G. Pearl, PhD, MD 

Right Ventricular Failure 

Teresa De Marco, MD 

Dana McGlothin, MD 

Cases from the PH Service 

Roxana Sulica, MD 

Ramona Doyle, MD 

Roundtable Discussion: 

Acute Care Management 

New PH CD-ROM 

Available! See page 5

Table of Contents 

Guest Editors for this issue: 


Assistant Professor of Medicine 

Mount Sinai School of Medicine 

Director, Mount Sinai Pulmonary 

Hypertension Program 

Mount Sinai Medical Center 

New York, New York 

Ramona L. Doyle, MD 

Associate Professor of Medicine 

Medical Director, Lung and Heart- 

Lung Transplantation 

Co-Director, Vera M. Wall Center for 

Pulmonary Vascular Disease 

Stanford University Medical Center 

Stanford, California 

4 Profiles in Pulmonary 

Hypertension: 

Bertron M. Groves, MD 

6 Perioperative Management 

of PH 

16 Right Ventricular Failure 

in PAH 

27 Cases from the Pulmonary 

Hypertension Service 

31 PH Roundtable Discussion: 

Managing the Critically Ill 

Patient 

Publisher 

Pulmonary Hypertension Association 

Jack Stibbs, Chair of the Board 

Rino Aldrighetti, President 

Justine Elliot, Director of Medical Services 

Publishing Staff 

Stu Chapman, Executive Editor 

Susan Chapman, Managing Editor 

Heidi Green, Associate Editor 

Gloria Catalano, Production Director 

Michael McClain, Design Director 

PHA Office 


PO Box 8277 

Silver Spring, MD 20907-8277 

301-565-3004, 301-565-3994 (fax) 

www.phassociation.org 

Provided through an unrestricted educational grant 

from Actelion Pharmaceuticals, U.S., Inc. 

© 2005 by Pulmonary Hypertension Association. All rights 

reserved. None of the contents may be reproduced in any 

form whatsoever without the written permission of PHA. 

Editorial Offices 

Advances in Pulmonary Hypertension, DataMedica, 

P.O. Box 1688, Westhampton Beach, NY 11978 

Tel (631) 288-7733 Fax (631) 288-7744 

E-mail: sbelsonchapman@aol.com 

Advances in Pulmonary Hypertension is circulated to cardiologists, 

pulmonologists, rheumatologists and other selected 

physicians by the Pulmonary Hypertension Association. 

The contents are independently determined by the Editor 

and the Editorial Advisory Board. 

Cover image: 

Surgical team viewing cardiac catheterization at Christ Hospital, 

Cincinnati, Ohio. (Copyright, Photo Researchers, 2005) 

Editor’s Memo 

PHA Web Site— 

www.phassociation.org—Best Kept 

Secret on the Internet 

Whether you like to casually surf the Web and explore various medically 

oriented sites or directly seek specific information on a topic of interest, 

the Web site of the Pulmonary Hypertension Association (PHA) is an 

often overlooked treasure trove of valuable content. I say overlooked 

because we often view Web sites as part of a serendipitous search, as 

merely a means toward an end of retrieving the information we seek; 

but PHA’s site is a destination as well, a virtual labyrinth waiting to be 

discovered. And more people are discovering it—115,000 visitors per 

month to its 3000 pages, and 500 messages posted per week on its main message 

board. Physicians are always telling me how helpful it has been in directing them—or 

their patients and staff—to nuggets of information they could not have found otherwise. 

Where else, for example, could you find information on such diverse topics in pulmonary 

hypertension as active clinical trials, the latest meeting on how patient advocates 

will discuss key concerns with their congressional leaders, an interactive map to search 

for a prominent physician in any state specializing in pulmonary hypertension care, or 

special events like a Christmas tree fundraiser that benefits the pulmonary hypertension 

community? 

Navigating the site is easy. The topics are conveniently arranged to appeal to the 

visitor’s particular query or need. The links for healthcare professionals are clearly delineated 

and easily accessed. As the pulmonary hypertension community has grown, so has 

the need for an efficient roadmap with specific points of interest and signposts along the 

way to guide one toward a connection or network one seeks. This is extremely important 

at a time when improved communication at all levels—among patients, physicians, 

families, and allied healthcare personnel—can help in promoting clinical trial enrollment, 

an exchange of ideas on new treatment approaches, and an overall sense of where we 

stand in making such progress. In facilitating this communication PHA’s site serves as a 

forum and a vehicle to keep the pulmonary hypertension community working together. 

Proof of the site’s value comes from numerous tributes to its role in the lives of the 

pulmonary hypertension community. Consider this comment from a patient, Marilyn 

Haney, posted in the “Our Journeys” section of the site: “I was diagnosed in mid 2004 

with primary pulmonary hypertension. ‘I have what?’ Honestly, I had never heard of this 

disease. I dove right in to educate myself, beginning with my pulmonologist who referred 

me to PHA. The Web site, as well as A Patient’s Survival Guide, gave me a clear understanding 

of what PH is, what treatments are available, and what is currently happening 

to find a cure.” 

As helpful as the PHA site is, PHA acknowledges its limitations and advises everyone 

by posting this message: “The information provided on the PHA website is provided for 

general information only. It is not intended as legal, medical or other professional advice, 

and should not be relied upon as a substitute for consultations with qualified professionals 

who are familiar with your individual needs.” Yet the information provided on 

the site is perhaps the next best thing to a consultation in that it points patients and 

caregivers alike to the appropriate source or resource. By fulfilling that role, the site 

has become an integral part of the pulmonary hypertension community and we are 

grateful for its continuing evolution and the benefit it provides to us all. 

Vallerie V. McLaughlin, MD 

Editor-in-Chief 

Printed on recycled paper.

Editorial Advisory Board 

Editor-in-Chief 



Director, Pulmonary Hypertension 

Program 

University of Michigan Health 

System 

Ann Arbor, Michigan 

Immediate Past Editor 

Victor F. Tapson, MD 

Professor of Medicine 

Division of Pulmonary and Critical 

Care Medicine 

Duke University Medical Center 

Durham, North Carolina 

Associate Editors 

Richard Channick, MD 


Pulmonary and Critical Care Division 

University of California, 

San Diego Medical Center 

San Diego, California 



Division of Pulmonary/Critical 


Co-Director, Vera M. Wall Center 

for Pulmonary Vascular Disease 



Karen A. Fagan, MD 


University of Colorado Health 

Sciences Center 

Pulmonary Hypertension Center 

Denver, Colorado 

Ronald J. Oudiz, MD 


UCLA School of Medicine 

Director, Liu Center for 


Division of Cardiology 

Los Angeles Biomedical Research 

Institute at Harbor-UCLA Medical 

Center 

Torrance, California 

Olivier Sitbon, MD 

Consultant 

Center for Pulmonary Vascular 

Diseases 

Respiratory and Intensive 

Care Unit 

Antoine Beclere Hospital 

Paris-Sud University 

Clamart, France 

Editorial Board 

Gregory Ahearn, MD 

Medical Director 

Pulmonary Hypertensin Center 

St. Joseph’s Medical Center 

Phoenix, Arizona 

Jacques Benisty, MD, MPH 

Children’s Hospital Boston 

Harvard Medical School 

Boston, Massachusetts 

Raymond Benza, MD 


Director, Pulmonary Vascular 

Disease Program 

Section of Advanced Heart Failure, 

Transplant and Pulmonary 

Vascular Diseases 

University of Alabama 

at Birmingham 

Birmingham, Alabama 

Erika Berman Rosenzweig, MD 

Assistant Professor of Pediatrics 

Department of Pediatrics 

Columbia College of Physicians 

and Surgeons 


Todd Bull, MD 

Division of Pulmonary and 

Critical Care Medicine 




Murali Chakinala, MD 

Director, Pulmonary 

Hypertension Clinic 

Washington University School 

of Medicine 

St. Louis, Missouri 

Jeffrey Edelman, MD 




Oregon Health and Sciences 

University 

Portland, Oregon 

James P. Maloney, MD 

Associate Professor 

Pulmonary and Critical 





Robert Schilz, DO, PhD 

Medical Director of Lung 

Transplantation and Pulmonary 

Vascular Disease 

University Hospital 

of Cleveland 

Case Western Reserve 

University 

Cleveland, Ohio 




Director, Mount Sinai Pulmonary 


Mount Sinai Medical Center 


Editorial Mission 

Advances in Pulmonary Hypertension is committed 

to help physicians in their clinical decision 

making by informing them of important 

trends affecting their practice. Analyzing the 

impact of new findings and covering current 

information in the peer-reviewed literature, 

Advances in Pulmonary Hypertension is published 

four times a year. Advances in Pulmonary 

Hypertension is the official journal 

of the Pulmonary Hypertension Association. 

Each article in this journal has been reviewed 

and approved by members of the Editorial 

Advisory Board. 

The Scientific Leadership 

Council of the Pulmonary 

Hypertension Association 

The scientific program of the Pulmonary 

Hypertension Association is guided by 

the association’s Scientific Leadership 

Council. The Council includes the following 

health care professionals: 

Robyn J. Barst, MD 

SLC Chair 

Columbia Presbyterian Medical 

Center Babies Hospital 


David B. Badesch, MD 

SLC Vice-Chair 

Chair, Nominations Committeee 

University of Colorado 

Health Sciences Center 


Raymond L. Benza, MD 


Birmingham, Alabama 

Richard N. Channick, MD 

UCSD Medical Center 



Vera M. Wall Center for 


Palo Alto, California 

C. Gregory Elliott, MD 

LDS Hospital 

University of Utah 

School of Medicine 

Salt Lake City, Utah 

Karen Fagan, MD 


Health Sciences Center 


Adaani Frost, MD 

Baylor College of Medicine 

Houston, Texas 

Sean Gaine, MD, PhD 

Mater Misericordiae Hospital 

Dublin, Ireland 

Nazzareno Galiè, MD 

Universita di Bologna 

Bologna, Italy 

Nicholas Hill, MD 

Division of Pulmonary, Critical Care 

and Sleep Medicine 

Tufts-New England Medical Center 

Boston, Massachusetts 

Marc Humbert, MD 

Hopital Antoine Beclere 

Clamart, France 

Dunbar Ivy, MD 



Michael J. Krowka, MD 

Mayo Clinic 

Rochester, Minnesota 

David Langleben, MD 

Jewish General Hospital 

Montreal, Quebec, Canada 

James E. Loyd, MD 

Vanderbilt University Medical Center 

Nashville, Tennessee 

Michael McGoon, MD 

Pulmonary Hypertension Clinic/ 

Mayo Clinic 

Rochester, Minnesota 


University of Michigan 

Health System 


John H. Newman, MD 

Vanderbilt Medical School 


Ronald J. Oudiz, MD 

Liu Center for Pulmonary Hypertension 

Los Angeles Biomedical Research Instit. 

Harbor-UCLA Medical Center 

Torrance, California 

Marlene Rabinovitch, MD 

Stanford University 

School of Medicine 


Ivan M. Robbins, MD 

Chair, Consensus Committee 

Vanderbilt University 


Lewis J. Rubin, MD 

Chair, Research Committee 

University of California at 

San Diego 


Julio Sandoval, MD 

Cardiopulmonary Department 

National Institute of 

Cardiology of Mexico 

Tlalpan, Mexico 

James Seibold, MD 

University of Michigan 

Health System 


Victor E. Tapson, MD 





Liaisons 

Natalie Kitterman, RN, BSN 

PH Resource Network Chair 

Salt Lake City, Utah 

JoAnne Sperando Schmidt 

Patient Liaison 

Carol E. Vreim, PhD 

Division of Lung Diseases, NHBLi 

Bethesda, Maryland 

Emeritus Members 

Bruce H. Brundage, MD 

St. Charles Medical 

Center-Bend 

Bend, Oregon 

Alfred P. Fishman, MD 

University of Pennsylvania 

Health System 

Philadelphia, Pennsylvania 

The Mission of the Scientific Leadership 

Council is to provide medical and scientific 

guidance and support to the PHA by: 

• Developing and disseminating knowledge 

for diagnosing and treating pulmonary 

hypertension 

• Advocating for patients with pulmonary 

hypertension 

• Increasing involvement of basic and clinical 

researchers and practitioners 

Advances in Pulmonary Hypertension 3

Bertron M. Groves, MD: Visionary 

Builder of Bridges Between 

Cardiologists and Pulmonologists 

Through Hemodynamics 

Bertron M. 

Groves, MD 

Whether voluminous or brief, a curriculum 

vitae (CV) serves as a road map to 

one’s medical career, charting the stepping 

stones through internship, fellowship, 

appointments, awards, publications, 

and speaking engagements. 

But the CV of Bertron M.Groves, MD, 

Professor of Medicine, University of 

Colorado Health Sciences Center, Denver, 

is much more. The entries—namely, 

the distinguished list of peer-reviewed and landmark publications—not 

only track the path he followed but signify 

milestones for all clinicians in the study of the relationship 

between hemodynamics and pulmonary hypertension. 

Much of the work done by Dr Groves sprouted from the 

legacy of his mentor, John T. Reeves, MD, a legendary figure 

in pulmonary hypertension at the University of Colorado 

Health Sciences Center, who died in a bicycle accident last 

year. Soon after joining the faculty at the University of 

Colorado in 1979, Dr Groves was managing the catheterization 

laboratory when he began doing research influenced 

by Dr Reeves. “It was obviously becoming critical to have 

someone involved in the hemodynamics of pulmonary 

hypertension, to get deeply involved,” recalled Dr Groves. 

“Jack Reeves took me under his wing and was my mentor 

for many years. We had a very rich collaboration and he 

really pulled me into the pulmonary hypertension world, 

and it felt right because my home was the catheterization 

lab at that time and still is.” 

Remembering the bench research of the early 1980s, 

he notes: “A lot of the studies we did were considered very 

risky and sort of on the fringe of what perhaps was appropriate. 

Some of my colleagues were openly critical of some 

of these studies because they feared that the likelihood of 

success would be too small to warrant the risk. In fact, 15 

years later we got prostacyclin approved by the FDA, and 

now it is influencing the management of pulmonary hypertension 

in a pretty broad spectrum.” 

Describing himself as “a purebred catheterization guy 

from the start,” Dr Groves explained how he began relating 

the work he was doing in the catheterization lab to pulmonary 

hypertension. “A lot of the studies that had been 

done were noninvasive and trying to use estimations of pulmonary 

pressure by various means, including echocardiography. 

As one who emphasized hemodynamics, that did not 

satisfy me, and I thought we could do the studies invasively 

and do them safely, even though there was a track record 

in the literature that some of these patients had sudden 

death in the catheterization procedures. That’s how I 

brought the two together and it has worked out very well for 

20 years.” 

Operation Everest: A Landmark Study 

in Pulmonary Hypertension 

Dr Groves said he considers himself “a bridge” between the 

pulmonologist and the cardiologist, applying lessons from 

interventional cardiology to the management of pulmonary 

hypertension. One of his most exciting research projects 

was the “Operation Everest” expedition in which an 

Everest-like environment was simulated in a hyperbaric 

chamber in Massachusetts at the US Army Research 

Institute. The concept was to take normal volunteers into 

the hypoxic chamber for 40 days and nights and pattern 

their exposure to hypoxia and altitude. 

“We were going to use echocardiographic estimation of 

the pulmonary hypertension they developed. I convinced 

them that instead of doing noninvasive assessments we 

should do serial cardiac catheterizations,” he added. “I 

agreed to do all the catheterizations on all of the subjects, 

and I commuted back and forth from Denver to Natick, 

Massachusetts, during those 40 days to do the serial studies 

that led to the hemodynamic definition of pulmonary 

hypertension. It was a fantastic experience with these 

numerous scientists who put it all together.” 

Returning to His Roots, Interventional Cardiology 

Today Dr Groves has returned to his roots, so to speak, interventional 

cardiology, having turned over the direction of the 

continued development of the pulmonary hypertension center 

and clinic to his protégé, David B. Badesch, MD, whom 

he trained. “I continue to do the hemodynamic work to 

make sure I train other cardiologists to do what I have been 

doing for him.” For Dr Badesch, the arrangement has been 

mutually beneficial, and he refers to Dr Groves as “a fantastic 

educator, always willing to share time and expertise 

as one of the true pioneers 20 years ago. He is one of the 

true experts on obtaining right heart hemodynamics and 

has been my mentor.” 

Looking toward new horizons in pulmonary hypertension, 

Dr Groves sees the trend toward trying to monitor the 

ongoing pulmonary pressure as the next focus. “The reason 

pulmonary hypertension was neglected for so long was that 

you couldn’t put your pulmonary artery in a cuff and go into 

the grocery store and measure what it was. Systemic hypertension 

has always been so easy to monitor and pulmonary 

hypertension has been so difficult. But now we have the 

invasive-type devices that are being developed to monitor 

chronic pulmonary artery pressure to see what happens over 

the full course of daily living. I’m expecting that there will 

be more of an emphasis on that in the next decade.” ■ 

4 Advances in Pulmonary Hypertension

Request Your 

Copy Now 

A Breakthrough in 

Medical Education 

New Complimentary 

CD-ROM Available 

Pulmonary Hypertension: An Interactive Guide to Diagnosis 

This companion piece to the Fall issue of Advances 

in Pulmonary Hypertension assists with diagnosis of 

pulmonary hypertension and is an invaluable resource 

for medical professionals in pulmonology, cardiology, 

rheumatology and primary care. 

Featuring comprehensive diagnostic 

information on: 

Physical examination 

Introduction on jugular venous pulse 

Please go to 

www.phassociation.org/medical/cd.asp 

to request your complimentary copy or 

check the box on the reply card found at 

the front of the journal. 

The production of this CD-ROM was supported by Grant 

Number Purchase Request (PR)# HCL33-2005-23060 and 

Contract Award # 254-2005-M-13200 and Purchase 

Request (PR)# HCL33-2004-09925 and Contract Award 

# 200-2004-M-10076 from the Centers for Disease Control 

and Prevention. Its contents are solely the responsibility of 

the Pulmonary Hypertension Association and do not necessarily 

represent the official views of the Centers 

for Disease Control and Prevention. 

The distribution of this CD-ROM is being made possible by 

an unrestricted educational grant from Myogen, Inc. 

7 cases providing comprehensive diagnostic 

information on: 

• Valvular pulmonic stenosis 

• Patent ductus arteriosus with pulmonary hypertension 

(Eisenmenger syndrome) 

• Restrictive ventricular septal defect (VSD) 

• Non-restrictive VSD with pulmonary hypertension 

(Eisenmenger) 

• Hypertensive heart disease, atrial fibrillation, PH, 

and tricuspid regurgitation 

• Pulmonary arterial hypertension with tricuspid 

regurgitation 

• Pulmonary arterial hypertension with tricuspid and 

pulmonic regurgitation 

Initial Diagnostic Testing 

Includes comprehensive and interactive information on: 

• ECG 

• Echocardiography 

• Chest x-ray • Computed tomography 

• V/Q scan • Right heart catheterization 

• MRI

Perioperative Management of PH: 

Covering All Aspects From Risk Assessment to 

Postoperative Considerations 


Professor and Chair, Department of Anesthesia 

Stanford University School of Medicine 


The pulmonary circulation is normally a low pressure, low 

resistance circulation. In patients with pulmonary arterial 

hypertension, altered vascular endothelial and smooth muscle 

function lead to a combination of vasoconstriction, localized 

thrombosis, and vascular growth and remodeling. These 

processes increase pulmonary vascular resistance, resulting in 

right ventricular failure, inadequate oxygenation, and ultimately 

death. Pulmonary hypertension markedly increases morbidity 

and mortality among patients undergoing surgery. 1-6 

Understanding the pathophysiology and etiology of pulmonary 

hypertension in the individual patient allows accurate risk 

assessment, optimization prior to surgery, and rational intraoperative 

and postoperative treatment. 7-12 

An approach to understanding the pathophysiology of an 

individual patient with pulmonary hypertension is derived 

from the equation for pulmonary vascular resistance: PVR = 

(PAP - LAP) x 80/CO, where PVR represents pulmonary vascular 

resistance (in dynes . s . cm -5 ), PAP represents mean pulmonary 

artery pressure (in mmHg), LAP represents left atrial 

pressure (in mmHg), and CO represents cardiac output (in 

L . min -1 ). Rearranging this equation for PAP demonstrates 

that PAP = LAP + (CO x PVR)/80. 

Thus, the three factors that account for increased PAP 

are increased left atrial pressure, increased cardiac output, 

and increased pulmonary vascular resistance. Therapy of the 

perioperative patient with pulmonary hypertension should 

involve an assessment of the quantitative contribution of 

each of these three components. For example, patients with 

mitral stenosis who have increased PAP due solely to 

increased left atrial pressure have uncomplicated perioperative 

courses, but patients with mitral stenosis who have 

increased PAP due to increased PVR from pulmonary vascular 

modeling commonly have severe right ventricular failure 

after mitral valve replacement and may not succeed in weaning 

from cardiopulmonary bypass. Pulmonary vasodilator 

therapy would be inappropriate in one patient but life-saving 

in the other. 

Similarly, patients with chronic left ventricular failure 

who undergo heart transplantation tend to do well perioperatively 

if the pulmonary hypertension is due solely to elevated 

left atrial pressure but may have severe right ventricular 

failure after transplantation if there is also a significant component 

of increased PVR. In patients with pulmonary arterial 

hypertension, analyzing whether cardiac output is maintained 

or is markedly decreased has significant prognostic 

value in assessing perioperative risk (see section on risk 

assessment). 

The current World Health Organization classification of 

pulmonary hypertension involves five major categories (pulmonary 

arterial hypertension, pulmonary venous hypertension, 

pulmonary hypertension associated with disorders of 

the respiratory system and/or hypoxemia, chronic thrombotic 

and/or embolic disease, and pulmonary hypertension due 

to disorders directly affecting the pulmonary vasculature). 

For the physician who is treating a perioperative patient with 

pulmonary hypertension, the equation for pulmonary artery 

pressure can be used to review the common etiologies. 

Increased left atrial pressure includes left ventricular failure 

and valvular heart disease (particularly mitral stenosis and/or 

regurgitation). Increased cardiac output includes patients 

with congenital heart disease with cardiac shunts such as 

ventricular septal defects. The major categories of chronically 

increased PVR are pulmonary disease (parenchymal or 

airway), hypoxia without pulmonary disease (hypoventilation 

syndromes, high altitude), pulmonary arterial obstruction 

(thromboembolism, schistosomiasis), and idiopathic pulmonary 

arterial hypertension. Because of pulmonary vascular 

remodeling, all these etiologies of pulmonary hypertension 

can result in increased PVR. 

In addition to these etiologies of chronic pulmonary 

hypertension, acute increases in PVR may result from hypoxia, 

hypercarbia, acidosis, increased sympathetic tone, and 

endogenous or exogenous pulmonary vasoconstrictors such 

as catecholamines, serotonin, thromboxane, and endothelin. 

13 Most perioperative patients with decompensated pulmonary 

hypertension have a combination of chronic pulmonary 

hypertension with an acute increase in PVR and 

therapy should be directed at reversing this acute PVR 

increase. 

Perioperative Risk Assessment 

In the face of increased impedance to right ventricular ejec- 


tion, the compensatory reserves of the right ventricle are 

limited. Reduction in right ventricular stroke volume and 

cardiac output as well as ventricular interdependence, with 

decreased left ventricular filling and output, occur. In the 

patient with pulmonary hypertension, anesthesia and surgery 

may produce progressive hemodynamic deterioration 

and death due to additional increases in PVR combined with 

decreases in right ventricular function. For example, 

patients with pulmonary hypertension undergoing cardiac 

surgery may fail to wean off cardiopulmonary bypass due to 

inadequate myocardial right ventricular protection during 

the ischemic period of aortic cross-clamping, increased 

endogenous pulmonary vasoconstrictors, and decreased 

endogenous pulmonary vasodilators from pulmonary 

endothelial injury during cardiopulmonary bypass. Thus 

patients with pulmonary hypertension have markedly 

increased perioperative morbidity and mortality. 1-6 For 

patients with Eisenmenger syndrome undergoing cesarean 

section, mortality is as high as 70%. 14 Patients undergoing 

liver transplantation with pulmonary arterial hypertension 

have increased mortality related to the severity of the pulmonary 

hypertension, with mortality rates as high as 80% 

when mean PAP >45 mmHg. 5 Reports of successful outcomes 

of surgery in patients with severe pulmonary hypertension 

include curative procedures such as lung or heartlung 

transplantation, cesarean section, and relatively brief 

procedures with minor blood loss such as lung biopsy, cholecystectomy, 

femoral artery repair, and laparoscopic tubal ligation. 

15-20 

Survival in pulmonary arterial hypertension correlates 

with the ability of the right ventricle to compensate for the 

increased PVR as assessed by cardiac output, right atrial 

pressure, and functional status. These factors also appear to 

be major predictors of perioperative risk in the surgical 

patient. However, perioperative risk is also highly correlated 

to the surgical procedure. 3 Major procedures that result in 

the systemic inflammatory response syndrome may exacerbate 

pulmonary hypertension and increase the perioperative 

risk. Procedures with rapid blood loss may result in fatal 

hypotension in the patient requiring adequate venous return 

as compensation for increased right ventricular afterload. 

Finally, some procedures may pose special risks for the 

patient with pulmonary hypertension. For example, hip 

replacement surgery commonly involves pulmonary 

embolization of air, bone marrow, and cement during placement 

of the femoral component. Overall, the risk assessment 

requires balancing the functional reserve of the patient 

against the anticipated increased demands of the surgical 

procedure. 

Progressive or acute increases in pulmonary artery pressure 

leading to acute right heart failure are the major complications 

of anesthesia and surgery. A pulmonary vasodilator 

trial may provide additional prognostic information and 

guide therapy if perioperative right ventricular failure occurs. 

This approach is used in the evaluation for heart transplantation 

and has been advocated in occasional patients with 

pulmonary hypertension undergoing noncardiac surgery. 

Because of pulmonary selectivity inhaled nitric oxide is an 

ideal agent for screening for pulmonary vascular reactivity. 

In patients at an unacceptably high risk following optimization 

of therapy, consideration should be given to lung or 

heart-lung transplantation or chronic prostacyclin treatment 

to decrease the pulmonary hypertension to acceptable levels. 

1,21 

Preparation of the Patient for Anesthesia and Surgery 

Whichever anesthetic technique is chosen, surgery and 

anesthesia in patients with pulmonary hypertension are 

associated with significant morbidity and mortality. Prior to 

anesthesia and surgery such patients should be evaluated 

with electrocardiography, chest x-ray, arterial blood gas 

(ABG) measurement, and echocardiography. Evidence of 

significant right ventricular dysfunction should prompt 

reevaluation of the need for surgery. All attempts to reduce 

PAP prior to surgery should be performed, such as the 

administration of oxygen, bronchodilators, antibiotics, and 

steroids in the patient with lung disease, and vasodilators 

and inotropes in the patient with cardiac disease. Reduction 

of PAP is more likely to succeed prior to surgery than after 

the induction of anesthesia. Digoxin may have beneficial 

short-term effect on cardiac function and sympathetic activation 

in pulmonary arterial hypertension. 22 Patients receiving 

chronic therapy for pulmonary arterial hypertension 

should continue such therapy throughout the perioperative 

period. Discontinuation of continuous epoprostenol infusion 

(Flolan) can precipitate an acute pulmonary hypertensive 

crisis. Although prostacyclin inhibits platelet aggregation, 

excess surgical bleeding is not usually a problem. It is 

important to coordinate continuation of the prostacyclin 

infusion with the nursing staff that will care for the patient 

after surgery. Patients receiving chronic prostacyclin infusion 

should have the infusion continued throughout the perioperative 

period, and management of hypotension should be 

with additional therapy rather than with discontinuation of 

the prostacyclin infusion. 

Anesthetic Management 

The anesthetic management of patients with pulmonary 

hypertension undergoing noncardiac surgery has received 

relatively little attention in the literature. 6,7,9 Most discussion 

has been limited to obstetrical anesthesia case reports 

in adults and case series of repair of congenital heart 

defects in pediatrics. Most authors agree that the management 

of a specific anesthetic technique is as important as 

the choice of the technique. In the absence of evidencebased 

recommendations anesthesiologists need to focus on 

basic hemodynamic principles. 

Physiologic Considerations and Goals 

The anesthetic plan for the patient with pulmonary hypertension 

is designed to account for the underlying pathophysiology. 

The major abnormality is the elevated PVR, 

which increases right ventricular afterload, thereby increasing 

right ventricular work and decreasing right ventricular, 

and thus left ventricular, output. Based on the underlying 

pathophysiology, the major anesthetic considerations 

include: 

1) Preload: Maintenance of preload (intravascular vol- 


ume) at normal or increased levels is essential to maintain 

cardiac output in the face of increased ventricular afterload. 

2) Systemic vascular resistance: In normal hemodynamic 

states, this is a major determinant of left ventricular afterload 

(and, therefore, cardiac output). In pulmonary hypertension, 

cardiac output is limited by right ventricular function 

and is, therefore, independent of systemic vascular 

resistance. Since systemic blood pressure is related to the 

product of cardiac output and systemic vascular resistance, 

it is important to maintain systemic vascular resistance in 

the normal-to-high range, because cardiac output is unable 

to increase when systemic vascular resistance decreases. 

3) Contractility: Maintenance of normal-to-high contractility 

is essential to maintain cardiac output in the face of 

increased right ventricular afterload. 

4) Heart rate and rhythm: Sinus rhythm is important for 

adequate filling of a hypertrophied right ventricle. Stroke 

volume is limited by right ventricular afterload, so bradycardia 

should be avoided. 

5) Avoidance of myocardial ischemia: Right ventricular 

subendocardial ischemia due to myocardial oxygen supplydemand 

imbalance is common in pulmonary hypertension. 

Systemic hypotension and excessive increases in preload, 

contractility, and heart rate must be avoided. 

The above five physiologic considerations for pulmonary 

hypertension are similar to the considerations in the patient 

with aortic stenosis (since both situations involve excessive 

ventricular afterload, specifically right ventricular afterload 

in pulmonary hypertension and left ventricular afterload in 

aortic stenosis). Although many physicians are skilled at the 

management of aortic stenosis, a final consideration applies 

only in the case of pulmonary hypertension: 

6) Pulmonary vascular resistance: In pulmonary hypertension, 

this is the major factor governing right ventricular 

afterload and cardiac output. Therefore, increases in pulmonary 

vascular resistance must be avoided and therapy to 

decrease pulmonary vascular resistance may be required. 

Perioperative Monitoring 

Monitoring during anesthesia must be adequate to detect 

the causes and complications of increased pulmonary vascular 

resistance. Arterial oxygen saturation should be continuously 

monitored by pulse oximetry. Arterial catheterization 

is required both for beat-to-beat blood pressure monitoring 

and for frequent arterial blood gas measurements. 

Monitoring of preload requires consideration of the altered 

physiology in pulmonary hypertension. In the absence of 

pulmonary hypertension, cardiac output is determined by 

left ventricular function, and the relevant preload is left ventricular 

filling, which is usually monitored by pulmonary 

artery occlusion pressure (PAOP). However, with severe pulmonary 

hypertension, cardiac output is limited by right ventricular 

function, and the relevant preload is right ventricular 

filling, which may correspond to right atrial or central 

venous pressures. Therefore in severe pulmonary hypertension, 

volume administration should be governed by central 

venous pressure rather than PAOP. However, with moderate 

pulmonary hypertension, cardiac output varies with both left 

and right ventricular performance. In these cases, the normal 

relationships between central venous pressure and 

PAOP may be altered, so that central venous pressure is no 

longer an indicator of left ventricular preload. Monitoring 

both central venous pressure and PAOP and observing the 

response to volume administration is the best method for 

accurately assessing preload in patients with pulmonary 

hypertension. Intraoperative volume assessment can be performed 

with transesophageal echocardiography, which 

demonstrates the filling of both ventricles. 

Pulmonary artery catheterization may be valuable for 

perioperative management of the pulmonary hypertension 

patient. First, it allows measurement of both central venous 

pressure and PAOP and determination of preload. Second, it 

allows measurement of cardiac output and calculation of 

pulmonary and systemic vascular resistance. Third, it allows 

measurement of pulmonary artery pressure, which is necessary 

for proper management of systemic hypotension or the 

use of pulmonary vasodilator therapy. The measurement of 

mixed venous oxygen saturation allows continuous assessment 

of arterial oxygenation and cardiac output in patients 

with pulmonary hypertension. The risk of pulmonary artery 

catheterization in patients with pulmonary hypertension is 

increased because of the high mortality of associated 

arrhythmias, pulmonary artery rupture, and venous air 

embolism or thromboembolism. In addition, thermodilution 

cardiac output determinations may be misleading when pulmonary 

hypertension is associated with anatomic shunting 

or significant tricuspid regurgitation. If there is a left-to-right 

shunt, thermodilution will measure pulmonary, rather than 

systemic, blood flow since the cold indicator will be diluted 

by shunted blood. If there is a right-to-left shunt, thermodilution 

will measure systemic rather than pulmonary blood 

flow, since some of the cold indicator will pass through the 

shunt. Pulmonary artery catheterization is usually not indicated 

in patients with intracardiac shunting because of the 

high risk of catheter misdirection and the limited additional 

information over measurement of central venous pressure 

alone. 

Choice of Anesthetic Technique 

All types of anesthetic techniques have been successfully 

used in individual pulmonary hypertension patients. 7 The 

choice of anesthetic technique is usually based on pathophysiological 

considerations. Since general anesthesia in 

pulmonary hypertension patients has significant risks, limited 

regional anesthesia (eg, axillary block for upper extremity 

surgery, ankle block for foot surgery) should be considered 

when appropriate. The use of neuraxial regional techniques 

(spinal or epidural block) with sympatholytic effects may 

decrease systemic vascular resistance and produce systemic 

hypotension when cardiac output is fixed due to pulmonary 

hypertension. Thus, spinal anesthesia may be contraindicated 

in most patients. Epidural anesthesia has been successful 

in selected patients, 2 particularly when the magnitude of 

the block is limited, eg, in management of labor. Epidural 

anesthesia allows a slow onset of block and titration of the 

extent of block so that adverse hemodynamic effects may be 

recognized early and corrected. However, extreme caution is 

mandatory to avoid excessive sympatholytic effects. 


For Patients with Pulmonary Arterial 

Hypertension WHO Class III or IV 

Tracleer– 

The Cornerstone 

of Oral Therapy 

To learn more: Call 1-866-228-3546 or visit www.TRACLEER.com 

Please see the following brief summary of prescribing information.

In Pulmonary Arterial Hypertension WHO Class III or IV 

Start with Tracleer 

The oral endothelin receptor antagonist backed by long-term data 

■ Improves exercise ability ■ Improves hemodynamics (CI, PAP, PVR, RAP) 

Reduces risk of clinical worsening 

Event-free (%) 

BREATHE-1 All patients (n=144 in the Tracleer group and n=69 in the control group) participated in the first 16 weeks. 

A subset of this population (n=35 in the Tracleer group and n=13 in the control group) continued for up to 28 weeks. 

Stay with Tracleer 

Long-term data for patients treated with Tracleer 

% of event-free patients 

100 

50 

Time from randomization to clinical worsening 

(Kaplan-Meier estimates) 1 

p=0.0038 

89% 

Tracleer 

p=0.0015 

63% 

Control 

0 

0 4 8 12 16 20 24 28 

Time (weeks) 

100 

90 

80 

70 

60 

50 

0 

Kaplan-Meier estimates with 99.9% CI. 

All bosentan-treated PAH patients. 3 

93% 

84% 

0 6 

12 18 

24 

235 225 

219 206 146 

Months 

Patients at risk 

71 % 

Relative 

Risk Reduction 

84 % 

Still Alive 

at 2 Years 

Tracleer significantly reduced risk of 

clinical worsening by 71% relative to 

control at week 28. 1 

■ Clinical worsening defined as combined endpoint 

of death, hospitalization or discontinuation 

due to worsening PAH, or initiation of 

epoprostenol therapy 1 

■ A statistically significant difference was 

apparent as early as week 16 1 

■ Treatment effect was notable because both the 

Tracleer groups and the control groups could 

have received background therapy, which 

excluded IV epoprostenol but may have included 2 : 

—Vasodilators 

–Calcium channel blockers 

–ACE inhibitors 

—Digoxin 

—Diuretics 

—Anticoagulants 

In the 2 Tracleer pivotal trials and their 

open-label extensions (n=235), 93% and 

84% of patients were still alive at 

1 year and 2 years, respectively, after 

the start of treatment with Tracleer. 2 

■ Without a control group, these data must be 

interpreted cautiously and cannot be interpreted 

as an improvement in survival 2 

■ These estimates may be influenced by the 

presence of epoprostenol treatment, which 

was administered to 43 of the 235 patients 2 

■ Patients in the Tracleer trials may have also 

been receiving vasodilators (calcium channel 

blockers or ACE inhibitors), digoxin, 

anticoagulants, and/or diuretics 2 

Liver and pregnancy warnings 

■ Requires attention to two significant concerns 

—Potential for serious liver injury: Liver monitoring of all patients is essential prior 

to initiation of treatment and monthly thereafter 

—High potential for major birth defects: Pregnancy must be excluded and prevented 

by two forms of birth control; monthly pregnancy tests should be obtained 

■ Contraindicated for use with cyclosporine A and glyburide 

For additional information about Tracleer or to report 

any adverse events, please call T.A.P. at 1-866-228-3546. 

To learn more: Call 1-866-228-3546 

or visit www.TRACLEER.com 

The Cornerstone of Oral Therapy 

Please see brief summary of prescribing information and full reference list on following page. 

© 2005 Actelion Pharmaceuticals US, Inc. All rights reserved. ACTU TRA JA 014 0205

62.5 mg and 125 mg 

film-coated tablets 

Brief Summary: Please see package insert for full prescribing information. 

Use of TRACLEER ® requires attention to two significant concerns: 1) potential for serious liver injury, and 2) potential 

damage to a fetus. 

WARNING: Potential liver injury. TRACLEER ® causes at least 3-fold (upper limit of normal; ULN) elevation of liver 

aminotransferases (ALT and AST) in about 11% of patients, accompanied by elevated bilirubin in a small number of 

cases. Because these changes are a marker for potential serious liver injury, serum aminotransferase levels must 

be measured prior to initiation of treatment and then monthly (see WARNINGS: Potential Liver Injury and DOSAGE 

AND ADMINISTRATION). To date, in a setting of close monitoring, elevations have been reversible, within a few 

days to 9 weeks, either spontaneously or after dose reduction or discontinuation, and without sequelae. Elevations 

in aminotransferases require close attention (see DOSAGE AND ADMINISTRATION). TRACLEER ® should generally 

be avoided in patients with elevated aminotransferases (> 3 x ULN) at baseline because monitoring liver injury may 

be more difficult. If liver aminotransferase elevations are accompanied by clinical symptoms of liver injury (such as 

nausea, vomiting, fever, abdominal pain, jaundice, or unusual lethargy or fatigue) or increases in bilirubin ≥ 2 x ULN, 

treatment should be stopped. There is no experience with the re-introduction of TRACLEER ® in these circumstances. 

CONTRAINDICATION: Pregnancy. TRACLEER ® (bosentan) is very likely to produce major birth defects if used by pregnant 

women, as this effect has been seen consistently when it is administered to animals (see CONTRAINDICATIONS). 

Therefore, pregnancy must be excluded before the start of treatment with TRACLEER ® and prevented thereafter by 

the use of a reliable method of contraception. Hormonal contraceptives, including oral, injectable, transdermal, and 

implantable contraceptives should not be used as the sole means of contraception because these may not be 

effective in patients receiving TRACLEER ® (see Precautions: Drug Interactions). Therefore, effective contraception 

through additional forms of contraception must be practiced. Monthly pregnancy tests should be obtained. 

Because of potential liver injury and in an effort to make the chance of fetal exposure to TRACLEER ® (bosentan) as 

small as possible, TRACLEER ® may be prescribed only through the TRACLEER ® Access Program by calling 1 866 228 

3546. Adverse events can also be reported directly via this number. 

INDICATIONS AND USAGE: TRACLEER ® is indicated for the treatment of pulmonary arterial hypertension in patients with 

WHO Class III or IV symptoms, to improve exercise ability and decrease the rate of clinical worsening. 

CONTRAINDICATIONS: TRACLEER ® is contraindicated in pregnancy, with concomitant use of cyclosporine A, with coadministration 

of glyburide, and in patients who are hypersensitive to bosentan or any component of the medication. 

Pregnancy Category X. TRACLEER ® is expected to cause fetal harm if administered to pregnant women. The similarity of 

malformations induced by bosentan and those observed in endothelin-1 knockout mice and in animals treated with other 

endothelin receptor antagonists indicates that teratogenicity is a class effect of these drugs. There are no data on the use 

of TRACLEER ® in pregnant women. TRACLEER ® should be started only in patients known not to be pregnant. For female 

patients of childbearing potential, a prescription for TRACLEER ® should not be issued by the prescriber unless the patient 

assures the prescriber that she is not sexually active or provides negative results from a urine or serum pregnancy test 

performed during the first 5 days of a normal menstrual period and at least 11 days after the last unprotected act of sexual 

intercourse. Follow-up urine or serum pregnancy tests should be obtained monthly in women of childbearing potential 

taking TRACLEER ® . The patient must be advised that if there is any delay in onset of menses or any other reason to suspect 

pregnancy, she must notify the physician immediately for pregnancy testing. If the pregnancy test is positive, the physician 

and patient must discuss the risk to the pregnancy and to the fetus. 

WARNINGS: Potential Liver Injury: Elevations in ALT or AST by more than 3 x ULN were observed in 11% of bosentan-treated 

patients (N = 658) compared to 2% of placebo-treated patients (N = 280). The combination of hepatocellular injury (increases 

in aminotransferases of > 3 x ULN) and increases in total bilirubin (≥ 3 x ULN) is a marker for potential serious liver injury. 1 

Elevations of AST and/or ALT associated with bosentan are dose-dependent, occur both early and late in treatment, 

usually progress slowly, are typically asymptomatic, and to date have been reversible after treatment interruption or 

cessation. These aminotransferase elevations may reverse spontaneously while continuing treatment with TRACLEER ® . 

Liver aminotransferase levels must be measured prior to initiation of treatment and then monthly. If elevated aminotransferase 

levels are seen, changes in monitoring and treatment must be initiated. If liver aminotransferase elevations are 

accompanied by clinical symptoms of liver injury (such as nausea, vomiting, fever, abdominal pain, jaundice, or unusual 

lethargy or fatigue) or increases in bilirubin ≥ 2 x ULN, treatment should be stopped. There is no experience with the 

re-introduction of TRACLEER ® in these circumstances. Pre-existing Liver Impairment: TRACLEER ® should generally be 

avoided in patients with moderate or severe liver impairment. In addition, TRACLEER ® should generally be avoided in 

patients with elevated aminotransferases (> 3 x ULN) because monitoring liver injury in these patients may be more difficult. 

PRECAUTIONS: Hematologic Changes: Treatment with TRACLEER ® caused a dose-related decrease in hemoglobin and 

hematocrit. The overall mean decrease in hemoglobin concentration for bosentan-treated patients was 0.9 g/dl (change 

to end of treatment). Most of this decrease of hemoglobin concentration was detected during the first few weeks of bosentan 

treatment and hemoglobin levels stabilized by 4–12 weeks of bosentan treatment. In placebo-controlled studies of all 

uses of bosentan, marked decreases in hemoglobin (> 15% decrease from baseline resulting in values of < 11 g/dl) 

were observed in 6% of bosentan-treated patients and 3% of placebo-treated patients. In patients with pulmonary 

arterial hypertension treated with doses of 125 and 250 mg b.i.d., marked decreases in hemoglobin occurred in 3% 

compared to 1% in placebo-treated patients. A decrease in hemoglobin concentration by at least 1 g/dl was observed 

in 57% of bosentan-treated patients as compared to 29% of placebo-treated patients. In 80% of cases, the decrease 

occurred during the first 6 weeks of bosentan treatment. During the course of treatment the hemoglobin concentration 

remained within normal limits in 68% of bosentan-treated patients compared to 76% of placebo patients. The explanation 

for the change in hemoglobin is not known, but it does not appear to be hemorrhage or hemolysis. It is recommended 

that hemoglobin concentrations be checked after 1 and 3 months, and every 3 months thereafter. If a marked 

decrease in hemoglobin concentration occurs, further evaluation should be undertaken to determine the cause and 

need for specific treatment. Fluid retention: In a placebo-controlled trial of patients with severe chronic heart failure, there 

was an increased incidence of hospitalization for CHF associated with weight gain and increased leg edema during the first 

4-8 weeks of treatment with TRACLEER ® . In addition, there have been numerous post-marketing reports of fluid retention in 

patients with pulmonary hypertension, occurring within weeks after starting TRACLEER ® . Patients required intervention with 

a diuretic, fluid management, or hospitalization for decompensating heart failure. 

Information for Patients: Patients are advised to consult the TRACLEER ® Medication Guide on the safe use of TRACLEER ® . 

The physician should discuss with the patient the importance of monthly monitoring of serum aminotransferases and 

urine or serum pregnancy testing and of avoidance of pregnancy. The physician should discuss options for effective 

contraception and measures to prevent pregnancy with their female patients. Input from a gynecologist or similar expert 

on adequate contraception should be sought as needed. 

Drug Interactions: Bosentan is metabolized by CYP2C9 and CYP3A4. Inhibition of these isoenzymes may increase the 

plasma concentration of bosentan. Bosentan is an inducer of CYP3A4 and CYP2C9. Consequently, plasma 

concentrations of drugs metabolized by these two isoenzymes will be decreased when TRACLEER ® is co-administered. 

Contraceptives: Co-administration of bosentan and the oral hormonal contraceptive Ortho-Novum® produced decreases of 

norethindrone and ethinyl estradiol levels by as much as 56% and 66%, respectively, in individual subjects. Therefore, 

hormonal contraceptives, including oral, injectable, transdermal, and implantable forms, may not be reliable when 

TRACLEER ® is co-administered. Women should practice additional methods of contraception and not rely on hormonal 

contraception alone when taking TRACLEER ® . Cyclosporine A: During the first day of concomitant administration, trough 

concentrations of bosentan were increased by about 30-fold. Steady-state bosentan plasma concentrations were 

3- to 4-fold higher than in the absence of cyclosporine A (see CONTRAINDICATIONS). Tacrolimus: Co- administration of 

tacrolimus and bosentan has not been studied in man. Co-administration of tacrolimus and bosentan resulted in markedly 

increased plasma concentrations of bosentan in animals. Caution should be exercised if tacrolimus and bosentan are used 

together. Glyburide: An increased risk of elevated liver aminotransferases was observed in patients receiving concomitant 

therapy with glyburide (see CONTRAINDICATIONS). Alternative hypoglycemic agents should be considered. Bosentan is 

also expected to reduce plasma concentrations of other oral hypoglycemic agents that are predominantly metabolized by 

CYP2C9 or CYP3A4. The possibility of worsened glucose control in patients using these agents should be considered. Ketoconazole: 

Co-administration of bosentan 125 mg b.i.d. and ketoconazole, a potent CYP3A4 inhibitor, increased the plasma concentrations 

of bosentan by approximately 2-fold. No dose adjustment of bosentan is necessary, but increased effects of bosentan 

should be considered. Simvastatin and Other Statins: Co-administration of bosentan decreased the plasma concentrations 

of simvastatin (a CYP3A4 substrate), and its active ß-hydroxy acid metabolite, by approximately 50%. The plasma concentrations 

of bosentan were not affected. Bosentan is also expected to reduce plasma concentrations of other 

statins that have significant metabolism by CYP3A4, eg, lovastatin and atorvastatin. The possibility of reduced statin efficacy 

should be considered. Patients using CYP3A4 metabolized statins should have cholesterol levels monitored after TRA- 

CLEER ® is initiated to see whether the statin dose needs adjustment. Warfarin: Co-administration of bosentan 500 mg 

b.i.d. for 6 days decreased the plasma concentrations of both S-warfarin (a CYP2C9 substrate) and R-warfarin (a CYP3A4 

substrate) by 29 and 38%, respectively. Clinical experience with concomitant administration of bosentan and warfarin 

in patients with pulmonary arterial hypertension did not show clinically relevant changes in INR or warfarin dose 

(baseline vs. end of the clinical studies), and the need to change the warfarin dose during the trials due to changes in 

INR or due to adverse events was similar among bosentan- and placebo-treated patients. Digoxin, Nimodipine and 

Losartan: Bosentan has been shown to have no pharmacokinetic interactions with digoxin and nimodipine, and losartan 

has no effect on plasma levels of bosentan. 

Carcinogenesis, Mutagenesis, Impairment of Fertility: Two years of dietary administration of bosentan to mice produced 

an increased incidence of hepatocellular adenomas and carcinomas in males at doses about 8 times the maximum 

recommended human dose [MRHD] of 125 mg b.i.d., on a mg/m 2 basis. In the same study, doses greater than about 32 times 

the MRHD were associated with an increased incidence of colon adenomas in both males and females. In rats, dietary 

administration of bosentan for two years was associated with an increased incidence of brain astrocytomas in males at 

doses about 16 times the MRHD. Impairment of Fertility/Testicular Function: Many endothelin receptor antagonists have 

profound effects on the histology and function of the testes in animals. These drugs have been shown to induce atrophy 

of the seminiferous tubules of the testes and to reduce sperm counts and male fertility in rats when administered for longer 

than 10 weeks. Where studied, testicular tubular atrophy and decreases in male fertility observed with endothelin receptor 

antagonists appear irreversible. In fertility studies in which male and female rats were treated with bosentan at oral doses 

of up to 50 times the MRHD on a mg/m 2 basis, no effects on sperm count, sperm motility, mating performance or fertility 

were observed. An increased incidence of testicular tubular atrophy was observed in rats given bosentan orally at doses 

as low as about 4 times the MRHD for two years but not at doses as high as about 50 times the MRHD for 6 months. An 

increased incidence of tubular atrophy was not observed in mice treated for 2 years at doses up to about 75 times the 

MRHD or in dogs treated up to 12 months at doses up to about 50 times the MRHD. There are no data on the effects of 

bosentan or other endothelin receptor antagonists on testicular function in man. 

Pregnancy, Teratogenic Effects: Category X 

SPECIAL POPULATIONS: Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many 

drugs are excreted in human milk, breastfeeding while taking TRACLEER ® is not recommended. Pediatric Use: Safety and 

efficacy in pediatric patients have not been established. Use in Elderly Patients: Clinical experience with TRACLEER ® in 

subjects aged 65 or older has not included a sufficient number of such subjects to identify a difference in response 

between elderly and younger patients. 

ADVERSE REACTIONS: Safety data on bosentan were obtained from 12 clinical studies (8 placebo-controlled and 4 

open-label) in 777 patients with pulmonary arterial hypertension, and other diseases. Treatment discontinuations due to 

adverse events other than those related to pulmonary hypertension during the clinical trials in patients with pulmonary 

arterial hypertension were more frequent on bosentan (5%; 8/165 patients) than on placebo (3%; 2/80 patients). In this 

database the only cause of discontinuations > 1%, and occurring more often on bosentan was abnormal liver function. In 

placebo-controlled studies of bosentan in pulmonary arterial hypertension and for other diseases (primarily chronic heart 

failure), a total of 677 patients were treated with bosentan at daily doses ranging from 100 mg to 2000 mg and 288 patients 

were treated with placebo. The duration of treatment ranged from 4 weeks to 6 months. For the adverse drug reactions 

that occurred in ≥ 3% of bosentan-treated patients, the only ones that occurred more frequently on bosentan than on 

placebo (≥ 2% difference) were headache (16% vs. 13%), flushing (7% vs. 2%), abnormal hepatic function (6% vs. 2%), leg 

edema (5% vs. 1%), and anemia (3% vs. 1%). Additional adverse reactions that occurred in > 3% of bosentan-treated 

pulmonary arterial hypertension patients were: nasopharyngitis (11% vs. 8%), hypotension (7% vs. 4%), palpitations (5% vs. 

1%), dyspepsia (4% vs. 0%), edema (4% vs. 3%), fatigue (4% vs. 1%), and pruritus (4% vs. 0%). Post-marketing experience: 

hypersensitivity, rash. 

Long-term Treatment: The long-term follow-up of the patients who were treated with TRACLEER ® in the two pivotal 

studies and their open-label extensions (N=235) shows that 93% and 84% of patients were still alive at 1 and 2 years, 

respectively, after the start of treatment with TRACLEER ® . These estimates may be influenced by the presence of 

epoprostenol treatment, which was administered to 43/235 patients. Without a control group, these data must be 

interpreted cautiously and cannot be interpreted as an improvement in survival. 

Special Considerations: Patients with Congestive Heart Failure (CHF): Based on the results of a pair of studies with 1613 

subjects, bosentan is not effective in the treatment of CHF with left ventricular dysfunction. 

OVERDOSAGE: Bosentan has been given as a single dose of up to 2400 mg in normal volunteers, or up to 2000 mg/day for 

2 months in patients, without any major clinical consequences. The most common side effect was headache of mild to 

moderate intensity. In the cyclosporine A interaction study, in which doses of 500 and 1000 mg b.i.d. of bosentan were given 

concomitantly with cyclosporine A, trough plasma concentrations of bosentan increased 30-fold, resulting in severe 

headache, nausea, and vomiting, but no serious adverse events. Mild decreases in blood pressure and increases in heart 

rate were observed. There is no specific experience of overdosage with bosentan beyond the doses described above. 

Massive overdosage may result in pronounced hypotension requiring active cardiovascular support. 

DOSAGE AND ADMINISTRATION: TRACLEER ® treatment should be initiated at a dose of 62.5 mg b.i.d. for 

4 weeks and then increased to the maintenance dose of 125 mg b.i.d. Doses above 125 mg b.i.d. did not appear to confer 

additional benefit sufficient to offset the increased risk of liver injury. Tablets should be administered morning and evening 

with or without food. 

Dosage Adjustment and Monitoring in Patients Developing Aminotransferase Abnormalities 

ALT/AST levels 

Treatment and monitoring recommendations 

> 3 and ≤ 5 x ULN Confirm by another aminotransferase test; if confirmed, reduce the daily dose or 

interrupt treatment, and monitor aminotransferase levels at least every 2 weeks. If the 

aminotransferase levels return to pre-treatment values, continue or re-introduce the 

treatment as appropriate (see below). 

> 5 and ≤ 8 x ULN Confirm by another aminotransferase test; if confirmed, stop treatment and monitor 

aminotransferase levels at least every 2 weeks. Once the aminotransferase levels 

return to pre-treatment values, consider re-introduction of the treatment (see below). 

> 8 x ULN Treatment should be stopped and reintroduction of TRACLEER ® should not be considered. 

There is no experience with re-introduction of TRACLEER ® in these circumstances. 

If TRACLEER ® is re-introduced it should be at the starting dose; aminotransferase levels should be checked within 3 days 

and thereafter according to the recommendations above. If liver aminotransferase elevations are accompanied by clinical 

symptoms of liver injury (such as nausea, vomiting, fever, abdominal pain, jaundice, or unusual lethargy or fatigue) or 

increases in bilirubin ≥ 2 x ULN, treatment should be stopped. There is no experience with the re-introduction of TRACLEER ® 

in these circumstances. Use in Women of Child-bearing Potential: TRACLEER ® treatment should only be initiated in women 

of child-bearing potential following a negative pregnancy test and only in those who practice adequate contraception that 

does not rely solely upon hormonal contraceptives, including oral, injectable, transdermal or implantable contraceptives. 

Input from a gynecologist or similar expert on adequate contraception should be sought as needed. Urine or serum pregnancy 

tests should be obtained monthly in women of childbearing potential taking TRACLEER ® . Dosage Adjustment in 

Renally Impaired Patients: The effect of renal impairment on the pharmacokinetics of bosentan is small and does not 

require dosing adjustment. Dosage Adjustment in Geriatric Patients: Clinical studies of TRACLEER ® did not include sufficient 

numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects. In general, 

caution should be exercised in dose selection for elderly patients given the greater frequency of decreased hepatic, 

renal, or cardiac function, and of concomitant disease or other drug therapy in this age group. Dosage Adjustment in 

Hepatically Impaired Patients: The influence of liver impairment on the pharmacokinetics of TRACLEER ® has not been evaluated. 

Because there is in vivo and in vitro evidence that the main route of excretion of TRACLEER ® is biliary, liver impairment 

would be expected to increase exposure to bosentan. There are no specific data to guide dosing in hepatically 

impaired patients; caution should be exercised in patients with mildly impaired liver function. TRACLEER ® should generally 

be avoided in patients with moderate or severe liver impairment. Dosage Adjustment in Children: Safety and efficacy in 

pediatric patients have not been established. Dosage Adjustment in Patients with Low Body Weight: In patients with a body 

weight below 40 kg but who are over 12 years of age the recommended initial and maintenance dose is 62.5 mg b.i.d. 

Discontinuation of Treatment: There is limited experience with abrupt discontinuation of TRACLEER ® . No evidence for 

acute rebound has been observed. Nevertheless, to avoid the potential for clinical deterioration, gradual dose reduction 

(62.5 mg b.i.d. for 3 to 7 days) should be considered. 

HOW SUPPLIED: 62.5 mg film-coated, round, biconvex, orange-white tablets, embossed with identification marking “62,5”. 

NDC 66215-101-06: Bottle containing 60 tablets. 125 mg film-coated, oval, biconvex, orange-white tablets, embossed with 

identification marking “125”. NDC 66215-102-06: Bottle containing 60 tablets. 

Rx only. 

STORAGE: Store at 20°C – 25°C (68°F – 77°F). Excursions are permitted between 15°C and 30°C (59°F and 86°F). [See USP 

Controlled Room Temperature]. 

Reference: 1. Zimmerman HJ. Hepatotoxicity - The adverse effects of drugs and other chemicals on the liver. Second ed. 

Philadelphia: Lippincott, 1999. 

References for previous page: 1. Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial 

hypertension. N Engl J Med. 2002;346:896–903. 2. Tracleer (bosentan) full prescribing information. Actelion 

Pharmaceuticals US, Inc. 2003. 3. Data on file, Actelion Pharmaceuticals. 

To learn more: Call 1-866-228-3546 or visit www.TRACLEER.com 

Manufactured by: 

Marketed by: 

Patheon Inc. 

Actelion Pharmaceuticals US, Inc. 

Mississauga, Ontario, CANADA 

South San Francisco, CA 

© 2005 Actelion Pharmaceuticals US, Inc. All rights reserved. ACTU TRA PI 006 0105

Thoracic epidural blockade has only minor hemodynamic 

effects but must be titrated slowly to avoid bradycardia. 

Excess sedation, which may decrease systemic vascular 

resistance and produce respiratory depression, should be 

avoided when regional anesthesia is used. Intrathecal and 

epidural narcotics may provide excellent pain relief postoperatively 

or during labor without sympathetic blockade or 

respiratory depression. 

General anesthesia remains the method of choice for 

major surgery in patients with pulmonary hypertension. 

Several techniques of general anesthesia are possible. 

Potent inhalational agents may decrease systemic vascular 

resistance, contractility, and heart rate, thereby producing 

hypotension and low cardiac output. The marked reduction 

in contractility and the increased incidence of dysrhythmias 

that occur with halothane are poorly tolerated. Isoflurane, 

sevoflurane, and desflurane have less effect on contractility 

and may result in beneficial pulmonary vasodilation; however, 

the marked reductions in systemic vascular resistance 

may result in systemic hypotension. In patients with adequate 

functional reserve sevoflurane can be used as it is 

shorter-acting and more readily titratable than isoflurane 

and unlike desflurane does not produced tachycardia during 

rapid increases in concentration. Narcotic-nitrous oxide 

techniques maintain systemic vascular resistance, but may 

produce hypoxia and decreased contractility; in addition, 

nitrous oxide increases pulmonary resistance in patients 

with pulmonary hypertension. 

“Balanced” anesthetic techniques may have all the 

above disadvantages but are frequently chosen as a means 

of limiting the adverse effects of a single technique. One 

anesthetic technique that maintains preload, systemic afterload, 

and contractility without increasing pulmonary vascular 

resistance is the high-dose narcotic-oxygen technique 

used in cardiac anesthesia. This appears to be the technique 

of choice in the patient with severe pulmonary hypertension 

undergoing major surgery. In addition to producing hemodynamic 

stability, the use of 100% oxygen may produce pulmonary 

vasodilation in some patients. In patients undergoing 

short procedures with intense stimulation such as bronchoscopy 

a remifentanil infusion can provide short-acting 

analgesia. The choice of induction agents for general anesthesia 

is based on similar considerations. Anesthetic induction 

of the patient with pulmonary hypertension is an unstable 

period during which patients are prone to develop systemic 

hypotension and cardiovascular collapse. In addition, 

patients with right-to-left anatomic shunting have markedly 

increased responses to intravenous agents and delayed 

response to inhalation agents. For rapid-sequence induction 

etomidate maintains systemic hemodynamics without 

affecting pulmonary resistance. In contrast, pentothal and 

propofol may adversely affect systemic resistance, venous 

return, and contractility. Although ketamine maintains systemic 

hemodynamics, questions have been raised about 

possible increases in pulmonary vascular resistance with 

this agent. Studies suggest that there is little or no increase 

in pulmonary vascular resistance when ventilation is controlled, 

and that any increase that may occur with ketamine 

will be less than the increase in systemic vascular resistance. 

Ketamine is therefore unlikely to produce systemic 

hypotension or reverse a left-to-right anatomic shunt. 

Ventilatory management may markedly affect pulmonary 

vascular resistance. Alveolar hypoxia is a potent pulmonary 

vasoconstrictor and use of high inspired oxygen concentrations 

may result in additional pulmonary vasodilation in 

some patients. Hypercarbia is a potent pulmonary vasoconstrictor, 

and hypocarbia is a pulmonary vasodilator. 

Hyperventilation may decrease the pulmonary hypertensive 

responses to various stimuli. Pulmonary vascular resistance 

is dependent on functional residual capacity (FRC), such 

that it is increased whenever FRC is increased from its normal 

value. Pulmonary vascular resistance increases when 

lung volumes above normal FRC result in compression of 

small intra-alveolar vessels. Pulmonary vascular resistance 

also increases when lung volumes below normal FRC produce 

increased large-vessel resistance due to hypoxic pulmonary 

vasoconstriction. Ventilatory parameters may affect 

both FRC and peak lung volume. FRC is usually decreased 

during general anesthesia. This reduction in FRC can be 

reversed with positive end-expiratory pressure (PEEP), 

resulting in a decrease in pulmonary vascular resistance. 

However, excessive PEEP will increase FRC above optimal 

values, and result in an increase in pulmonary vascular 

resistance. The effect of tidal volume on pulmonary vascular 

resistance may similarly be bimodal. At low tidal volumes 

increased resistance occurs due to alveolar hypoxia and 

hypercarbia. At high tidal volumes lung volume intermittently 

exceeds normal FRC, resulting in compression of 

intra-alveolar vessels and increased pulmonary vascular 

resistance. Therefore, ventilation of the patient with pulmonary 

hypertension should use high concentrations of oxygen, 

moderate tidal volumes, rates sufficient to achieve 

hypocarbia, and low levels of PEEP (5-10 cm H 2 

O). Highfrequency 

ventilation has been advocated as a means of 

achieving adequate gas exchange, while maintaining lung 

volume continuously at normal FRC. 

Management of emergence from anesthesia requires 

maintaining hemodynamic stability and adequate alveolar 

ventilation. The major factor responsible for hemodynamic 

stability is the ratio of pulmonary to systemic vascular tone. 

Extubation in a deep plane of anesthesia to avoid pulmonary 

vasoconstriction may be complicated by decreased systemic 

vascular resistance, decreased contractility, and inadequate 

ventilation (producing hypoxemia or hypercarbia and exacerbating 

pulmonary hypertension). In addition, reductions in 

FRC can increase pulmonary vascular resistance. Extubation 

in a light plane of anesthesia can result in marked sympathetic 

tone and severe pulmonary vasoconstriction. The 

addition of narcotics to a primarily inhalational technique 

may allow extubation in a light plane of anesthesia without 

increasing sympathetic tone. A narcotic-oxygen anesthetic 

technique followed by postoperative mechanical ventilation 

appears to be the safest technique for major surgery. 

Pulmonary hypertension patients have limited ability to 

tolerate any further increase in pulmonary vascular resistance 

and it is important to avoid introduction of air or particulate 

matter (eg, precipitated drugs) into the venous system. 

In patients with anatomic shunting, such venous 


Table 1. Hemodynamic Patterns of Four 

Etiologies of Systemic Hypertension. 

Etiology CVP PAP PAOP CO 

Decreased preload ↓↓ ↓ ↓ ↓ 

Decreased contractility ≠ ↓ ≠ ↓ 

Decreased SVR → → → or ↓ ≠ or → 

Increased PVR ≠ ≠ ↓ ↓ 

CO = cardiac output; CVP = central venous pressure; PAOP = pulmonary 

artery occlusion pressure; PAP = pulmonary artery pressure; PVR = pulmonary 

vascular resistance; SVR = systemic vascular resistance. 

embolization may result in systemic embolization, as well as 

provoking hemodynamic decompensation. 

Treatment of Perioperative Hypotension 

Pulmonary hypertension patients should have hemodynamic 

therapy aimed at maintaining blood pressure, cardiac output, 

and low pulmonary vascular resistance. When inotropic 

therapy is required agents such as dobutamine and milrinone, 

which increase cardiac output, maintain systemic 

blood pressure, and decrease pulmonary vascular resistance, 

are indicated. The management of systemic hypotension in 

the patient with pulmonary hypertension is based on principles 

of hemodynamic management. As shown in Table 1, 

systemic hypotension may result from four etiologies, each 

of which has a specific hemodynamic pattern. 

Pulmonary artery catheterization allows differentiation 

among these etiologies. Decreased preload is the only etiology 

that decreases central venous pressure; volume therapy 

is the appropriate treatment. But volume loading of a failing 

right ventricle can result in further distention and progressive 

dysfunction and therefore must be monitored closely. 

Decreased contractility is the only condition that results in 

an increase in central venous pressure with a decrease in 

pulmonary artery pressure; inotropic therapy is indicated. 

Decreased systemic vascular resistance is the only condition 

in which cardiac output is maintained. Appropriate therapy 

may be a combination of systemic vasoconstrictors, inotropic 

agents, and pulmonary vasodilators. The use of vasopressin 

as a systemic vasoconstrictor has been recommended 

in some reports. 23,24 A combined inotropic-vasopressor 

agent such as epinephrine or norepinephrine may be useful. 

Finally, if pulmonary artery pressure has increased or 

remained the same during systemic hypotension, then the 

elevated pulmonary vascular resistance is preventing generation 

of adequate cardiac output. The initial approach 

should be to detect any correctable causes of increased pulmonary 

vascular resistance such as hypoxia, hypercarbia, 

acidosis, increased sympathetic tone, and endogenous or 

exogenous vasoconstrictors. Patients without correctable 

factors should be considered candidates for acute pulmonary 

vasodilator therapy. Therefore, arterial blood gases 

should be measured and acid-base status corrected to baseline. 

When systemic hypotension occurs without a decrease 

in pulmonary artery pressure, cardiac output measurement 

will differentiate between a primary fall in systemic resistance 

(cardiac output increased or unchanged with no 

change in pulmonary vascular resistance) and worsened pulmonary 

hypertension (cardiac output decreased with 

increased pulmonary vascular resistance). A primary fall in 

systemic vascular resistance may be treated by either 

increasing cardiac output with inotropic agents or by achieving 

selective systemic vasoconstriction with phenylephrine, 

norepinephrine, or vasopressin. 

When an increase in pulmonary vascular resistance produces 

decreased cardiac output and systemic hypotension, 

pulmonary vasodilator therapy is required to interrupt the 

cycle of pulmonary hypertension. This cycle is characterized 

by low cardiac output, systemic hypotension, and decreased 

right ventricular coronary perfusion with a further decrease 

in cardiac output; similarly, low cardiac output produces 

desaturation of mixed venous blood and acidosis, which 

result in increased pulmonary vasoconstriction. The goals of 

pulmonary vasodilator therapy are twofold: first, to reduce 

pulmonary vascular resistance and thereby decrease pulmonary 

artery pressure and/or increase cardiac output, and, 

second, to reduce the PVR/SVR ratio so that the increase in 

cardiac output will prevent hypotension by compensating for 

any reduction in systemic vascular resistance. Essentially all 

agents with systemic vasodilator activity (alpha-blockers, 

beta-agonists, acetylcholine, direct smooth muscle vasodilators, 

calcium channel blockers, prostacyclin, prostaglandin 

E 1 

) are capable of producing pulmonary vasodilation. 

However, use of these agents as pulmonary vasodilators has 

frequently resulted in systemic hypotension. In pulmonary 

hypertension, cardiac output varies with right heart function. 

Both the pulmonary and systemic vasodilator effects of 

drugs are dose-dependent. For the majority of drugs, systemic 

vasodilator effects occur at doses that do not produce 

pulmonary vasodilation. Thus, with a decrease in systemic 

and no change in pulmonary vascular resistance, cardiac 

output cannot rise and systemic blood pressure must fall 

(BP = CO x SVR). 

Pulmonary vasodilators include direct-acting nitro 

vasodilators such as hydralazine, nitroglycerin, and nitroprusside; 

alpha-adrenergic blockers such as tolazoline and 

phentolamine; beta-adrenergic agents such as isoproterenol; 

calcium blockers such as nifedipine and diltiazem; 

prostaglandins such as prostaglandin E 1 

and prostacyclin; 

adenosine; and indirect-acting vasodilators such as acetylcholine 

which cause nitric oxide release. The ideal pulmonary 

vasodilator for the perioperative setting should produce 

preferential pulmonary vasodilation without other 

direct hemodynamic effects; in addition, the drug should be 

short-acting when used for acute treatment. A major principle 

of acute vasodilator drug therapy is that short-acting 

titratable agents should be used and the effects should be 

assessed at each dose before increasing to a higher dose. 

For severe perioperative pulmonary hypertension resulting 

in right ventricular failure inhaled vasodilator therapy is 

the treatment of choice. This approach was first developed 

with inhaled nitric oxide, 23,25-27 which diffuses from the 

alveoli to the adjacent pulmonary vascular smooth muscle 

cells to produce pulmonary vasodilation. Inhaled nitric oxide 


does not produce systemic vasodilation because any nitric 

oxide that is absorbed into the pulmonary circulation is inactivated 

by binding to hemoglobin. In addition, inhaled nitric 

oxide may improve ventilation-perfusion matching in lung 

disease. Unlike intravenous vasodilators, which may 

increase blood flow to poorly ventilated alveoli, inhaled 

vasodilators are preferentially distributed to ventilated alveoli. 

By increasing blood flow to ventilated alveoli, there is an 

improvement in ventilation-perfusion matching and gas 

exchange. Inhaled nitric oxide effectively decreases perioperative 

pulmonary hypertension in multiple settings, particularly 

following cardiopulmonary bypass when pulmonary 

vascular resistance may be elevated due to pulmonary 

endothelial dysfunction. Inhaled nitric oxide may be useful 

in patients with allograft dysfunction following lung transplantation 

since nitric oxide may decrease pulmonary hypertension, 

improve ventilation-perfusion mismatch, and 

decrease ischemia-reperfusion lung injury. Inhaled nitric 

oxide improves outcome in neonatal pulmonary hypertension 

with hypoxic respiratory failure as judged by a decreased frequency 

of death or extracorporeal membrane oxygenation 

use. Although inhaled nitric oxide improves oxygenation and 

decreases pulmonary hypertension in the acute respiratory 

distress syndrome, randomized studies have not demonstrated 

sustained improvement or improved outcome. 

Patients with hypoxemia may not improve oxygenation with 

inhaled nitric oxide if the vascular tone in well-ventilated 

segments is not increased above basal levels. In such cases, 

combination of inhaled nitric oxide with almitrine bis mesylate 

or possibly phenylephrine may improve hypoxemia without 

producing excessive pulmonary hypertension. 

In general, the inhaled nitric oxide dose-response curve 

in patients with pulmonary hypertension demonstrates maximal 

responses at doses of 10 ppm or less and, in the perioperative 

setting, a trial of 20 ppm inhaled nitric oxide is 

usually sufficient to determine if the patient will have a beneficial 

response. Discontinuation of inhaled nitric oxide may 

produce rebound pulmonary hypertension, which limits its 

utility in the perioperative setting. Rebound pulmonary 

hypertension may be due to progression of underlying pulmonary 

hypertension, decreased endogenous nitric oxide 

synthesis, downregulation of guanylyl cyclase, or activation 

of endogenous vasoconstrictor pathways such as endothelin. 

Approximately one third of pulmonary hypertension patients 

have little or no response to inhaled nitric oxide. Possible 

explanations include an unreactive pulmonary circulation, 

rapid inactivation of nitric oxide, abnormalities in the guanylyl 

cyclase system, or rapid metabolism of cGMP. Inhibition 

of cGMP phosphodiesterase with sildenafil can increase the 

frequency, the magnitude, and the duration of response to 

inhaled nitric oxide. 

Other inhaled vasodilators may also produce selective 

pulmonary vasodilation. 28-32 These include nitro vasodilators 

(nitroglycerin, nitroprusside) and prostaglandin derivatives 

such as prostacyclin, prostaglandin E 1 

, and iloprost. The use 

of a combination of agents that affect different mechanisms 

of vasodilation (eg, nitric oxide, which increases cGMP and 

prostacyclin, which increases cAMP) may produce additive 

pulmonary vasodilation. 33 Patients undergoing cardiac surgery 

who develop intractable right ventricular failure due to 

pulmonary hypertension may be candidates for a right ventricular 

assist device, either on a temporary basis until right 

ventricular function recovers or as a bridge to transplantation. 

Postoperative Management 

Although the focus in the literature has been on intraoperative 

management of pulmonary hypertension, most patients 

who die in the perioperative period do so several days after 

surgery. Causes of death include progressive increases in 

pulmonary vascular resistance, progressive decreases in 

myocardial function, and sudden death. Patients should 

therefore be monitored in an appropriate setting. Deepening 

of the level of sedation/anesthesia may be effective in 

selected patients. 12 The use of epidural narcotics, limited 

thoracic epidural local anesthetics, continuous regional 

anesthesia, and non-narcotic analgesic adjuvant should be 

considered for pain management when appropriate. 

In summary, pulmonary hypertension patients have 

markedly increased morbidity and mortality during anesthesia 

and surgery. However, management based on physiologic 

principles can allow the majority of patients to safely 

undergo required surgical procedures. 

References 

1. Krowka MJ, Mandell MS, Ramsay MA, Kawut SM, Fallon MB, 

Manzarbeitia C, Pardo M Jr, Marotta P, Uemoto S, Stoffel MP, Benson 

JT. Hepatopulmonary syndrome and portopulmonary hypertension: a 

report of the multicenter liver transplant database. Liver Transpl. 

2004;10:174-82. 

2. Martin JT, Tautz TJ, Antognini JF. Safety of regional anesthesia in 

Eisenmenger’s syndrome. Reg Anesth Pain Med. 2002;27:509-13. 

3. Ramakrishna G, Sprung J, Ravi BS, Chandrasekaran K, McGoon MD. 

Impact of pulmonary hypertension on the outcomes of noncardiac surgery: 

predictors of perioperative morbidity and mortality. J Am Coll 

Cardiol. 2005;45:1691-9. 

4. Roberts NV, Keast PJ. Pulmonary hypertension and pregnancy—a 

lethal combination. Anaesth Intensive Care. 1990;18:366-74 

5. Tan HP, Markowitz JS, Montgomery RA, Merritt WT, Klein AS, 

Thuluvath PJ, Poordad FF, Maley WR, Winters B, Akinci SB, Gaine SP. 

Liver transplantation in patients with severe portopulmonary hypertension 

treated with preoperative chronic intravenous epoprostenol. Liver 

Transpl. 2001;7:745-9. 

6. Weiss BM, Atanassoff PG. Cyanotic congenital heart disease and 

pregnancy: natural selection, pulmonary hypertension, and anesthesia. 

J Clin Anesth. 1993;5:332-41. 

7. Blaise G, Langleben D, Hubert B. Pulmonary arterial hypertension: 

pathophysiology and anesthetic approach. Anesthesiology. 2003;99: 

1415-32. 

8. Burrows FA, Klinck JR, Rabinovitch M, Bohn DJ. Pulmonary hypertension 

in children: perioperative management. Can Anaesth Soc J. 

1986; 33:606-28. 

9. Fischer LG, Van Aken H, Burkle H. Management of pulmonary 

hypertension: physiological and pharmacological considerations for 

anesthesiologists. Anesth Analg. 2003;96:1603-16. 

10. Kaul TK, Fields BL. Postoperative acute refractory right ventricular 

failure: incidence, pathogenesis, management and prognosis. 

Cardiovasc Surg. 2000;8:1-9. 

11. Riedel B. The pathophysiology and management of perioperative 

pulmonary hypertension with specific emphasis on the period following 

cardiac surgery. Int Anesthesiol Clin. 1999;37:55-79. 

12. Rodriguez RM, Pearl RG. Pulmonary hypertension and major surgery. 

Anesth Analg. 1998;87:812-5. 


13. Via G, Braschi A. Pathophysiology of severe pulmonary hypertension 

in the critically ill patient. Minerva Anestesiol. 2004;70:233-7. 

14. Kahn ML. Eisenmenger’s syndrome in pregnancy. N Engl J Med. 

1993; 329:887. 

15. Armstrong P. Thoracic epidural anaesthesia and primary pulmonary 

hypertension. Anaesthesia. 1992; 47:496-9. 

16. Hohn L, Schweizer A, Morel DR, Spiliopoulos A, Licker M. 

Circulatory failure after anesthesia induction in a patient with severe 

primary pulmonary hypertension. Anesthesiology. 1999;91:1943-5. 

17. Davies MJ, Beavis RE. Epidural anaesthesia for vascular surgery 

in a patient with primary pulmonary hypertension. Anaesth Intens 

Care. 1984;12:115-7. 

18. Mallampati SR. Low thoracic epidural anaesthesia for elective 

cholecystectomy in a patient with congenital heart disease and pulmonary 

hypertension. Can Anaesth Soc J. 1993;2:159-68. 

19. Slomka F, Salmeron S, Zetlaoui P, et al. Primary pulmonary hypertension 

and pregnancy: anesthetic management for delivery. 

Anesthesiol. 1988;69:959-61. 

20. Stoddart P, O’Sullivan G. Eisenmenger’s syndrome in pregnancy: 

a case report and review of the literature. Int J Obstet Anaesth. 1993; 

2:159-68. 

21. Minder S, Fischler M, Muellhaupt B, Zalunardo MP, Jenni R, 

Clavien PA, Speich R. Intravenous iloprost bridging to orthotopic liver 

transplantation in portopulmonary hypertension. Eur Respir J. 2004; 

24:703-7. 

22. Rich S, Seidlitz M, Dodin E, Osimani D, Judd D, Genthner D, 

McLaughlin V, Francis G. The short-term effects of digoxin in patients 

with right ventricular dysfunction from pulmonary hypertension. Chest. 

1998;114:787-92. 

23. Oz MC, Ardehali A. Collective review: perioperative uses of inhaled 

nitric oxide in adults. Heart Surg Forum. 2004;7:E584-9. 

24. Braun EB, Palin CA, Hogue CW. Vasopressin during spinal anesthesia 

in a patient with primary pulmonary hypertension treated with 

intravenous epoprostenol. Anesth Analg. 2004;99:36-7. 

25. Ichinose F, Roberts JD Jr, Zapol WM. Inhaled nitric oxide: a selective 

pulmonary vasodilator: current uses and therapeutic potential. 

Circulation. 2004;109:3106-11. 

26. Kavanagh BP, Pearl RG. Inhaled nitric oxide in anesthesia and critical 

care medicine. Int Anesthesiol Clin. 1995;33:181210. 

27. Kawakami H, Ichinose F. Inhaled nitric oxide in pediatric cardiac 

surgery. Int Anesthesiol Clin. 2004;42:93-100. 

28. Bildirici I, Shumway JB. Intravenous and inhaled epoprostenol for 

primary pulmonary hypertension during pregnancy and delivery. Obstet 

Gynecol. 2004;103:1102-5. 

29. De Wet CJ, Affleck DG, Jacobsohn E, Avidan MS, Tymkew H, Hill 

LL, Zanaboni PB, Moazami N, Smith JR. Inhaled prostacyclin is safe, 

effective, and affordable in patients with pulmonary hypertension, right 

heart dysfunction, and refractory hypoxemia after cardiothoracic surgery. 

J Thorac Cardiovasc Surg. 2004;127:1058-67. 

30. Fattouch K, Sbraga F, Bianco G, Speziale G, Gucciardo M, 

Sampognaro R, Ruvolo G. Inhaled prostacyclin, nitric oxide, and nitroprusside 

in pulmonary hypertension after mitral valve replacement. J 

Card Surg. 2005;20:171-6. 

31. Lowson SM. Inhaled alternatives to nitric oxide. Crit Care Med. 

2005;33:S188-95. 

32. Siobal M. Aerosolized prostacyclins. Respir Care. 2004;49:640- 

52. 

33. Hill LL, Pearl RG. Combined inhaled nitric oxide and inhaled 

prostacyclin during experimental chronic pulmonary hypertension. J 

Appl Physiol. 1999;86:1160-4. 


Managing Right Ventricular Failure in PAH: 

An Algorithmic Approach 

Teresa De Marco, MD 

Professor of Clinical Medicine 

Director, Heart Failure and 

Pulmonary Hypertension Program 

Medical Director, Heart Transplantation 


San Francisco Medical Center 

San Francisco, California 

Dana McGlothin, MD 

Assistant Clinical 

Professor of Medicine 

Associate Director, Pulmonary 



San Francisco Medical Center 

San Francisco, California 

Pulmonary arterial hypertension (PAH) is a disorder characterized 

by progressive elevation of pulmonary artery pressure (PAP) 

and vascular resistance in the absence of left-sided cardiac disease, 

pulmonary vein compression, respiratory disorders, or 

thromboembolic disease. It is defined by a mean PAP over 25 

mmHg at rest or over 30 mmHg with exercise and a pulmonary 

artery occlusion pressure (PAOP) of less than 15 mmHg. PAH 

is associated with a poor prognosis. The estimated median survival 

from diagnosis is 2.8 years and the 1-year and 5-year survival 

rates are only 68% and 34%, respectively. 1,2 More than 

70% of PAH patients will die as a result of right ventricular failure 

and most of the remainder from dysrhythmia. Predictors of 

a poor prognosis in PAH are related to the development of right 

ventricular failure. 1,3,4 The objectives of this review are to 

examine the pathophysiologic mechanisms leading to the development 

of right ventricular failure due to PAH, the diagnostic 

features of right ventricular failure, and the management of 

chronic right ventricular failure with emphasis on acute decompensation 

in this setting. 

Pathophysiology 

Clinical Manifestations and Hemodynamic Derangements 

The normal right ventricle is a thin-walled (less than 0.6 

cm), trabeculated, roughly triangular structure that weighs 

less than 65 g in men and less than 50 g in women. 5,6 It is 

designed to empty its volume into a low-impedance, highcapacitance, 

pulmonary circulation by contracting sequentially 

from inflow to outflow. The pulmonary circulation can 

tolerate three- to fourfold increases in right-sided cardiac 

output without significant increases in PAP. In healthy individuals, 

pulmonary vascular resistance (PVR) decreases as 

the cardiac output rises with exercise. 7 In the setting of 

PAH, PVR does not sufficiently decrease with exercise, 

resulting in dyspnea and poor exercise capacity. 

Progressive PAH presents a pressure overload state to the 

right ventricle, increasing right ventricular workload leading 

to concentric hypertrophy (Figure 1). The right ventricle 

compensates: the walls hypertrophy while maintaining a normal 

or smaller chamber size, resulting in normal or reduced 

right ventricular wall stress. During this compensated phase 

of adaptive hypertrophy and normal to reduced wall stress, 

the ventricle is able to eject blood against the high PVR 

while maintaining an adequate right-sided cardiac output 

and normal right atrial pressure. During this phase patients 

exhibit few symptoms. 

The right ventricle can compensate only so long, initiating 

the symptomatic/declining phase (Figure 1). During this 

phase, with marked, maladaptive right ventricular hypertrophy 

and variable degrees of interstitial fibrosis, diastolic 

function may be impaired, altering the right ventricular diastolic 

pressure-volume relationship and leading to increases 

in right ventricular end-diastolic and right atrial pressures. 

With persistent pressure overload, the right ventricle undergoes 

a remodeling process eventually leading to right ventricular 

failure. The right ventricular chamber dilates and the 

concentric hypertrophy transitions to eccentric hypertrophy, 

resulting in increased wall stress and systolic dysfunction. 

Increased heart rate and right ventricular wall stress lead to 

significant increases in right ventricular myocardial oxygen 

consumption. This, in combination with reduced right ventricular 

endomyocardial coronary perfusion (due to reduced 

right coronary artery pressure, rising right ventricular enddiastolic 

pressure, and increased right ventricular mass), 

leads to right ventricular ischemia and worsening right ventricular 

diastolic and systolic function. The right ventricular 

ischemia may be clinically manifest as chest pain. As the 

right ventricle and the tricuspid valve annulus dilate, functional 

tricuspid regurgitation progressively worsens. 

Tricuspid regurgitation further compromises right ventricular 

forward output, and ultimately, left ventricular filling. During 

this phase of right ventricular remodeling, cardiac output 

does not meet peripheral demands and right atrial pressure 

rises further as reflected clinically by exercise intolerance, 

progressive dyspnea, elevated jugular venous pressure, and 

fluid retention with edema (the hallmarks of right ventricular 

failure). These clinical signs reflect both a low cardiac 

output and the detrimental activation of neurohormones and 

other mediators. 2,8,9 Natriuretic peptide levels become significantly 

elevated in patients with right heart failure even in 

the absence of left ventricular dysfunction. B-type natriuret- 


Pulmonary hypertension 

RV pressure overload 

Adaptive concentric RV hypertrophy 

RV chamber size normal or ↓ 

Decreased wall stress 

Compensated phase 

Normal CO, RAP 

Neurohormonal and other 

mediator activation 

RV remodeling 

Maladaptive RV hypertrophy, fibrosis 

RV diastolic dysfunction 

Symptomatic/declining phase 

Rising RAP 

Inadequate CO with exercise 

RV diastolic and systolic failure 

RV dilation: 

≠ Wall stress + ≠ heart rate 

+ ↓ endomyocardial perfusion 

Tricuspid regurgitation 

RV ischemia 

Decompensated phase 

↓ CO, ≠ RAP 

≠ A-VDO 2 

Hypoxia 

Acidosis 

Life-threatening dysrhythmias 

RV dilation (DVI): 

Interventricular septal shift to left 

≠ Intrapericardial pressure 

↓ Distending LV transmural pressure 

↓ LV compliance 

↓ LV preload 

↓ CO 

Figure 1.—Progressive PAH presents a pressure overload state to the right ventricle, increasing right ventricular 

workload leading to concentric hypertrophy. 

ic peptide (BNP) levels increase in proportion to the extent 

of right ventricular dysfunction in PAH and are predictive of 

mortality in right ventricular failure. 10,11 

Progressive right ventricular dilation in the setting of 

pericardial constraint and diastolic ventricular interdependence 

compromise left ventricular filling via several mechanisms. 

7,12,13 A shift of the ventricular septum during diastole 

toward the left ventricle reduces left ventricular compliance 

and diastolic filling. As the right ventricle dilates in association 

with increases in right ventricular and right atrial diastolic 

pressure, a marked rise in intrapericardial pressure 

ensues. The transmural left ventricular end-diastolic pressure 

(end-diastolic pressure minus intrapericardial pressure), 

the true preload of the left ventricle, is reduced and 

by the Frank-Starling relationship results in low systemic 

cardiac output. Furthermore, with marked elevation in right 

atrial pressure the coronary sinus pressure also rises, resulting 

in left ventricular myocardial congestion and wall dimensions 

that limit left ventricular compliance. This mechanism 

appears to act independently of diastolic ventricular interaction 

due to pericardial constraint. 14 As a consequence of 

decreased left ventricular preload, systemic cardiac output 

is further compromised, first with exercise only but eventually 

even at rest. It should be noted that with extreme right 

ventricular failure and dilation, left ventricular compliance 

can be so severely impaired that at a certain point the left 

ventricular end-diastolic pressure (LVEDP) and PAOP may 

rise due to a shift of the left ventricular diastolic pressure 

volume relationship upward and to the left such that even 

with low left ventricular volume the left ventricular pressure 

is increased. 

The decompensated phase of right ventricular systolic 

failure is manifest as symptoms with minimal activity or at 

rest. It is marked by elevation in right atrial pressure and 

systemic venous hypertension leading to hepatic congestion, 

which combined with tricuspid regurgitation, leads to an 

enlarged, pulsatile liver and ascites. A right ventricular S 3 

gallop may be audible and renal and splanchnic congestion 

can cause diuretic resistance. Renal venous congestion 

combined with decreased renal arterial perfusion will be 

exhibited as diuretic resistance, reduced urine output, and 

prerenal azotemia. 15 Also evident is a low cardiac output 

state resulting in fatigue and syncope or pre-syncope. In 

acute decompensated right ventricular failure (ADRVF) 

reduced cardiac output is evident by a narrow pulse pressure 

and hypotension with peripheral tissue and vital organ 

hypoperfusion. The latter increases the arterio-venous oxygen 

difference. Hypoxemia may also be the consequence of 

right to left shunting in PAH patients with a patent foramen 

ovale and elevated right atrial pressure. Further, the destruction 

of the cross-sectional pulmonary vascular bed (a pathologic 

consequence of protracted PAH) also contributes to 


Roadmap 

To A Cure 

The Pulmonary Hypertension Association’s 

SEVENTH INTERNATIONAL 

PULMONARY HYPERTENSION CONFERENCE 

AND SCIENTIFIC SESSIONS 

June 23 to 25, 2006 • Hilton Minneapolis Hotel • Minneapolis, Minnesota 

PHA’s biennial Scientific Sessions and International Conference is unique 

in serving the pulmonary hypertension patient and medical communities. 

Over 900 attended in 2004. 

Medical Professionals and Researchers, 

Begin with the Scientific Sessions: June 23 

A full day devoted to presentations from nationally and internationally 

renowned PH experts, accompanied by poster sessions with 

presentations of abstracts. 

Presentations include: 

• Inflammation in Systemic Vascular Disease: What can we learn? 

Paul M. Ridker, M.D., M.P.H., F.A.C.C., Harvard Medical School, 

Brigham & Women’s Hospital 

• Inflammation in Pulmonary Arterial Hypertension 

Marc Humbert, M.D., Ph.D., Service de Pneumologie, Centre des 

Maladies Vasculaires Pulmonaires, Hôpital Antoine Béclère 

• MR Imaging in Pulmonary Arterial Hypertension 

Valentin Fuster, M.D., Ph.D., Zena and Michael A. Wiener 

Cardiovascular Institute, Marie-Josée and Henry R. Kravis 

Center for Cardiovascular Health, Mount Sinai Medical Center 

• Current Experiences with Stress Echocardiography in 

Pulmonary Arterial Hypertension 

Ekkehard Grünig, M.D., University of Heidelberg 

• Genetics of Pulmonary Arterial Hypertension 

John Newman, M.D., Vanderbilt Medical School 

For more information on Conference 2006, 

visit: www.phassociation.org/Conference 

or call 301-565-3004. 

CALL FOR ABSTRACTS 

Abstracts are invited for the poster 

session in the areas of clinical science 

(including treatment) and basic science. 

Five abstracts will be selected for oral 

presentation and an award will be given 

for the top presentation in both the 

Clinical and the Basic categories. 

Summaries of top presentations will be 

published in a future issue of Advances 

in Pulmonary Hypertension. 

An award will be given for top presentation 

in both Clinical and Basic category. 

Although PHA encourages the submission 

of original abstracts, abstracts 

submitted for this Conference do not 

need to be original work. 

Submission Deadline: February 15, 2006 

Notification Date: March 15, 2006 

For more information and for the 

Abstract Sample Form, visit: 

www.phassociation.org/Conference/ 

2006/Scientific-Sessions.asp#call

Patients, Caregivers and Medical Professionals, 

Experience the International Conference: 

June 23 – 25 

Medically-led and patient-led sessions for the pulmonary hypertension 

community of patients, family members, caregivers and medical professionals. 

Featuring over 50 medical and patient sessions (including several 

sessions in Spanish), an exhibits area, a variety of patient and caregiver 

support groups, special sessions for international attendees and more… 

Keynote Address: Empathy Unites Caregivers, Investigators, 

Patients and Medical Professionals, by Barbara Mossberg, Ph.D., 

President Emerita, Goddard College 

Presentations include: 

• The Latest in PH Therapies for Children (including 

secondary PH) 

• Associated Conditions: Liver Disease, Sleep Disorders, ILD, 

COPD, Thyroid Disease, 

• Emergency Situations 

• Scleroderma, Connective Tissue Diseases & PH: the problems 

and how to diagnose them 

• Investigational Agents (Ambrisentan, Cialis, Statins, Pulmolar) 

• Anti-coagulation, Drug-Drug Interactions, New studies 

• Surgical and Interventional Options and Future Trends in the 

Treatment of Pulmonary Hypertension 

• Thromboembolic Disease: Diagnosis and Treatment 

• Epoprostenol/Flolan: New Concepts in Dosing, Prevention & 

Management of Catheter-Related Infections 

• Prostanoids (Flolan, Remodulin, Iloprost) 

• PDE-5 Inhibitors (Viagra) and the Nitric Oxide Pathway 

• Changing to Different PH Medications: Important Things for 

Patients to Know Before, During and After The Switch 

• An Overview of Medical Therapies for PAH (Spanish) 

Attendees of the 2004 Conference have said… 

“The conference exceeded my 

expectations. The Scientific Sessions 

were outstanding. The level of 

expertise was superb. The interaction 

of patients, family members, and 

health care providers was a 

remarkable benefit.” 

“Very well organized 

sessions and 

exceptional presenters. 

I thought all physicians 

did a great job speaking 

in a language all patients 

could relate to.” 

“PHA and its staff and volunteers 

have done an amazing 

job organizing this event and 

we are very glad we made 

the trip down from Canada to 

attend! We can't wait to come 

back to Minnesota in 2006 

and bring our children 

as well!” 

For more information on Conference 2006, 

visit: www.phassociation.org/Conference 

or call 301-565-3004. 

Meet some of the brightest 

minds in the field of PH! 

These are just some of the 

doctors and nurses invited to 

present at Conference: 

David Badesch, MD 

Robyn Barst, MD 

Joy Beckmann, RN, MSN 

Raymond Benza, MD 

Bruce Brundage, MD 

Richard Channick, MD 


Gregory Elliott, MD 

Karen Fagan, MD 

Adaani Frost, MD 

Sean Gaine, MD 

Nazzareno Galie, MD 

Stephanie Harris, RN, BSN 

Nicholas Hill, MD 

Traci Housten-Harris, RN, MSN 

Marc Humbert, MD 

Abby Krichman, RRT 

Michael Krowka, MD 

David Langleben, MD 

James Loyd, MD 

Michael McGoon, MD 

Vallerie McLaughlin, MD 

John Newman, MD 

Ronald Oudiz, MD 

Tomas Pulido, MD 

Marlene Rabinovitch, MD 

Ivan Robbins, MD 

Lewis Rubin, MD 

Julio Sandoval, MD 

Cathy Severson, RN, BSN 

James Siebold, MD 

Karen Swanson, MD 

Lisa Wheeler, MT

hypoxemia and with reduction in peripheral oxygen delivery, 

acidosis, which can lead to life-threatening dysrhythmias, 

may ensue. 

Diagnostic Findings in 

Right Ventricular Failure in PAH 

Chest radiographs typically show enlarged pulmonary arteries 

and distal tapering of the peripheral vessels and on lateral 

view an enlarged right ventricular can be visualized by 

filling of the retrosternal space. The electrocardiogram in 

advanced stages of pulmonary hypertension and right ventricular 

failure may reveal right axis deviation, RBBB, p wave 

amplitude of more than 2.5 mm, and/or S 1 

Q 3 

T 3 

pattern 

reflective of pressure overload state on the right ventricle. 

The R wave will be prominent in V 1 

with deep S waves in the 

lateral precordial leads indicating right ventricular hypertrophy. 

Increased p wave amplitude in lead II, qR pattern in 

lead V 1 

, and right ventricular hypertrophy are associated 

with an increased risk of death. 16 

Transthoracic echocardiography is the most useful and readily 

available noninvasive tool to evaluate right ventricular failure 

due to PAH. Typically the right ventricle is hypertrophied and 

dilated with poor systolic function and the right atrium is 

enlarged while the left ventricle is small and underfilled. In a 

cross-sectional view, the left ventricle appears “D” or crescent 

shaped as the ventricular septum displaces or “flattens” toward 

the left ventricle. Septal flattening during systole suggests right 

ventricular pressure overload, whereas septal flattening during 

diastole occurs with volume overload (tricuspid regurgitation). 

Typically in right ventricular failure, septal flattening occurs 

throughout the cardiac cycle due to both right ventricular pressure 

and volume overload. The left ventricle contracts normally 

or is hyperdynamic. However, the diastolic transmitral filling 

characteristics are abnormal due to reduced left ventricular 

compliance. Patients with right ventricular failure have Doppler 

evidence of significant tricuspid regurgitation and moderately 

to severely elevated pulmonary artery systolic pressure (PAPs). 

The PAPs is estimated from the peak tricuspid regurgitant 

velocity and an estimate of right atrial pressure based on inferior 

vena cava size and respiratory dynamics. In right ventricular 

failure, the inferior vena cava is plethoric and does not collapse 

with inspiration, indicative of high right atrial pressure. 

Pulse wave Doppler in the right ventricular outflow tract typically 

reveals a reduced velocity-time integral suggestive of low 

forward output. Agitated saline contrast not only will aid in the 

diagnosis of some congenital systemic-to-pulmonary shunts, 

but may also detect a patent foramen ovale in one third of 

patients. Echocardiographic predictors of a poor prognosis 

include an enlarged right atrium, the presence of a pericardial 

effusion, and a higher Doppler global right ventricular 

index. 3,4,17 

Pulmonary Artery Catheterization 

In right ventricular failure associated with PAH pulmonary 

artery catheterization will reveal high right atrial, right ventricular, 

and pulmonary arterial pressures with a PAOP of 

greater than 15 mmHg. The cardiac and stroke volume 

indices are reduced and the mixed venous oxygen saturation 

is generally markedly reduced. With end-stage right ventricular 

failure, paradoxically the PAP may not be severely elevated 

and may actually fall as right ventricular ejection and 

the cardiac output are so compromised that the right ventricle 

cannot generate a high pulmonary pressure in the setting 

of high PVR. 18 Ultimately in the throes of severe right ventricular 

dilation and failure, the PAOP may be elevated as 

left ventricular compliance is severely compromised with 

perturbation of the left ventricular diastolic-pressure volume 

relationship. 

Pulmonary artery catheterization is useful not only for the 

diagnosis of right ventricular failure due to PAH but also for 

its management. In the case of systemic hypoperfusion and 

hypotension, catheterization can often identify the hemodynamic 

mechanism for the hypotension. Blood pressure is the 

product of cardiac output and SVR and hypotension in 

patients with PAH may be a result of either low cardiac output 

from right ventricular failure or reduced SVR from overvasodilation 

or infection. Precise identification of the operative 

hemodynamic derangement will guide therapy in right 

ventricular failure due to PAH. 

Chronic and Acute RV Failure in PAH 

Goals of Therapy 

The goals of treating chronic right ventricular failure due to 

PAH are to 1) relieve symptoms, improve exercise capacity, 

and quality of life; 2) reduce morbidity and mortality; and 3) 

improve cardiopulmonary hemodynamics to prevent worsening 

of right heart failure (ie, delay disease progression). The 

immediate goals of treating acute decompensated right ventricular 

failure (ADRVF), especially with hemodynamic compromise, 

are to 1) restore oxygenation; 2) treat volume overload; 

and 3) restore vital organ perfusion. The intermediate 

and long-term goals are to optimize the medical regimen to 

alleviate symptoms, prevent further disease progression, 

reduce morbidity and mortality, and successfully bridge the 

patient to lung or heart-lung transplantation in appropriate 

individuals. 7,8 

Chronic RV Failure: Medical Therapies 

The long-term goals of managing chronic right ventricular failure 

in PAH can be reached by applying the approaches delineated 

in Table 1 that have been reviewed elsewhere. 8,19-21 

Strategies to prevent and treat chronic right ventricular failure 

are aimed at reducing right ventricular wall stress, thereby minimizing 

myocardial oxygen consumption and ischemia, and to 

improve the inotropic state of the right ventricle. To reduce wall 

stress, one must lower right ventricular afterload. This is 

accomplished with chronic pulmonary arterial vasodilators: O 2 

therapy, endothelin receptor antagonists, prostanoids, and 

phosphodiesterase V inhibitors as described in recent 

reviews. 19,20 Calcium channel blockers should be avoided in 

patients with marginal blood pressure and significant right 

heart failure as manifest by right atrial pressures greater than15 

mmHg and low cardiac index (less than 2.0 L/min/m 2 ). Chronic 

anticoagulation is recommended to prevent pulmonary arterial 

thrombosis in situ, which contributes to narrowing and remodeling 

of the pulmonary arterial bed, consequently increasing 

right ventricular outflow impedance. 22 

Reduction in right ventricular preload and tricuspid regurgi- 


Table 1. Management of Chronic 

Right Ventricular Failure in 

Pulmonary Arterial Hypertension. 

Diet and lifestyle considerations 

• Sodium restriction 

• Smoking cessation 

• Weight loss 

• Avoidance of physical exertion in setting of pre or frank 

syncope 

• Avoidance of pregnancy 

• Avoidance of high altitude 

Interventions for treatment of pulmonary arterial hypertension 

• Pulmonary vasodilators (endothelial receptor antagonists, 

prostanoids, PDE-5 inhibitors) 

• Supplemental oxygen 

• Anticoagulation (maintain INR 2-3) 

Pharmacologic interventions for right ventricular failure 

• Reduction of wall stress by decreasing excessive preload 

–Diuretics: loop, thiazide, and aldosterone antagonists 

• Improve inotropy and reduce neurohormonal activation 

–Digitalis glycosides 

Invasive interventions 

• Lung transplantation 

• Heart-lung transplantation for complex congenital heart 

disease 

• Percutaneous blade-balloon atrial septostomy 

tation to reduce right ventricular wall stress can be accomplished 

with diuretics. Chronic therapy with loop diuretics 

(furosemide, bumetanide, torsemide) alone or in combination 

with intermittent potent thiazide diuretics (ie, metolazone) 

and/or aldosterone antagonists (spironolactone, eplerenone) are 

effective at controlling volume overload. Right ventricular failure 

and hepatic congestion are associated with aldosterone 

activation. Use of aldosterone antagonists in appropriate doses 

and with close monitoring of electrolytes can potentiate diuresis 

in patients treated with loop diuretics. As aldosterone activation 

is associated with sodium/fluid retention, potassium/ 

magnesium wasting, increases in ventricular mass and fibrosis, 

and endothelial dysfunction, even nondiuretic neurohormonal 

blocking doses of the aldosterone antagonists (spironolactone 

or eplerenone at 12.5 to 50 mg daily) often exert beneficial 

effects in patients with right ventricular failure due to PAH. 23 

When attempts to decrease right ventricular wall stress by 

pharmacologically manipulating right ventricular preload and 

afterload are inadequate, an alternative strategy is to improve 

right ventricular inotropy. In chronic right ventricular failure, 

low dose digoxin (0.125 mg daily) may be useful. Digoxin can 

produce a modest increase in cardiac output and it has been 

shown to decrease circulating catecholamine levels. 24 

Attenuation of neurohormonal activation may ultimately slow 

progression of right ventricular failure in patients with PAH. 

There is a paucity of outcome data utilizing digoxin in right ventricular 

failure due to PAH. 

Chronic RV Failure: Surgical and Interventional Therapies 

Atrial septostomy. It is well known that patients with PAH and 

a patent foramen ovale have a better prognosis compared to 

those without a patent foramen ovale. 25 The interatrial communication 

allows right to left shunting, thus reducing right 

atrial pressure and improving left ventricular filling and cardiac 

output, delaying progression of right ventricular failure. 

Percutaneous blade-balloon atrial septostomy is a catheterbased 

technique that allows the creation of a perforation in the 

atrial septum allowing shunting of blood from right to left. It 

has been utilized in select patients with right ventricular failure 

and syncope. 21,26 Atrial septostomy has been shown to improve 

clinical status and produce beneficial long-lasting hemodynamic 

effects. 26 The procedure is limited by systemic arterial oxygen 

desaturation, spontaneous closure of the atrial septal aperture, 

the potential for paradoxical embolic events, and a high 

procedure-related mortality. This investigational procedure 

should be performed only by experienced operators. It should 

not be performed in moribund patients or in those who have 

severe right ventricular failure and are on maximal cardiorespiratory 

support. A right atrial pressure greater than 20 mmHg, 

a PVR index greater than 55 u/m 2 and a predicted 1-year survival 

less than 40% are significant predictors of procedure– 

related death. Furthermore, patients should have an acceptable 

baseline systemic oxygen saturation (greater than 90% on room 

air). The procedure is indicated for recurrent syncope or right 

ventricular failure, despite maximal medical therapy, when no 

other options exist and/or as a bridge to lung transplantation. 27 

Extracorporeal membrane oxygenator systems in conjunction 

with atrial septostomy in a low cardiac output patient with 

hypoxemia have not been studied, but could theoretically be of 

value. 

Transplantation. Bilateral lung transplantation or heart-lung 

transplantation for patients with complex congenital heart disease 

may be indicated for suitable candidates with chronic right 

ventricular failure who continue to deteriorate with poor quality 

of life despite aggressive pharmacologic therapy. With bilateral 

lung transplantation, survival is 70%, 45%, and 20%; with 

heart-lung transplantation, it is 65%, 40%, and 25% at 1 year, 

5 years, and 10 years, respectively. 21 Long-term survival is predominantly 

limited by the development of post-transplant bronchiolitis 

obliterans. 

ADRVF: Identification and Correction of Precipitating Factors 

Factors that may precipitate ADRVF in patients with chronic 

right ventricular failure must be sought and corrected (Figure 

2). These include dietary indiscretion, intercurrent infection, 

anemia/erythrocytosis, thyroid disorders, concomitant pulmonary 

embolus, and dysrhythmias. Infection must be considered 

in patients presenting with decompensated right ventricular 

failure and hemodynamic compromise, especially in 

patients with an indwelling central venous catheter for 

epoprostenol infusion. Infection is poorly tolerated in patients 

with right ventricular failure and limited right ventricular contractile 

reserve. The increase in right ventricular work associated 

with reduction in SVR will result in systemic hypotension. In 

this scenario, beta- and alpha- agonists such as dopamine or 

norepinephrine are indicated as initial therapy to stabilize 

hemodynamics. Anemia also increases right ventricular work 

and it has been shown to be associated with worse quality of 

life and increased mortality in patients with PAH. 2,29 


• Dietary indiscretion 

• Infection 

Identify and treat underlying precipitating factors 

• Anemia/erythrocytosis 

• Dysrhythmia 

• Thyroid disorders 

• Pulmonary embolus 

Restore oxygenation 

• Supplemental O 2 

• Vapotherm 

• Mechanical ventilation 

-Avoid acidemia 

Restore vital organ perfusion 

• Pulmonary vasodilators: 

• VInhaled NO/epoprostenol 

• IV epoprostenol 

• Combination therapy 

• Inotropes and vasopressors: 

• Adrenergic agonists 

• Add or Δ to IV epoprostenol 

Treat volume overload 

• IV bolus + IV infusion loop diuretic 

• IV or oral thiazide diuretic 

• Oral aldosterone antagonist 

• Addition of β-adrenergic inotropic agent 

• Mechanical fluid removal 

Stabilization achieved 

Transition to chronic therapy 

• Wean NO with IV epoprostenol 

• Wean IV inotropic agents 

• Optimize chronic therapies (Table 1) 

Unstable and/or refractory cases 

(not candidates for lung transplantation) 

• Palliation of symptoms 

• Oxygen supplementation 

• Diuretics 

• Continuous infusion inotropes 

• Liberal use narcotic analgesics 

• Hospice care 

Bridge to lung transplantation (suitable candidates) 

• IV epoprostenol + other pulmonary vasodilators 

• Inotropic support (digoxin, β-adrenergic agonists) 

• Diuretic therapy 

• Percutaneous atrial septostomy 

Figure 2.—Factors that may precipitate ADRVF in patients with chronic right ventricular failure 

must be sought and corrected. 

Erythrocytosis is associated with higher viscosity and more cardiovascular 

events in patients with Eisenmenger syndrome and 

cor pulmonale from respiratory disorders. 8 Specifically, higher 

hemoglobin levels are associated with worse cardiopulmonary 

hemodynamics. 28 Pulmonary embolism as a precipitating factor 

for ADRVF should be excluded in the appropriate clinical setting 

in patients who are not receiving anticoagulation or are 

receiving subtherapeutic doses. 

Atrial tachyarrhythmias should be slowed with digoxin, 

amiodarone, or diltiazem. The use of beta-blockers or the calcium 

blocker verapamil should be avoided as their negative 

inotropic effects may exacerbate the low cardiac output state 

while vasodilatory effects may reduce the SVR and cause 

hypotension. Amiodarone is relatively safe in this setting and is 

useful for the management of atrial fibrillation with rapid ventricular 

response to slow the rate as well as to facilitate electrical 

or chemical cardioversion to sinus rhythm. With symptomatic 

bradydysrhythmias, temporary and/or permanent pacemaker 

insertion should be considered in the appropriate situation. 

Ventricular dysrhythmias usually occur in end-stage right 

ventricular failure. 

ADRVF: Restoration of Oxygenation and 

Prevention of Acidemia 

Oxygen is a pulmonary vasodilator and maintenance of adequate 

oxygenation in right ventricular failure due to PAH is of 

paramount importance. High-flow oxygen has been shown to 

reduce PVR and increase cardiac index even in normoxic 

patients with pulmonary hypertension 30 and should be applied 

liberally in patients with right ventricular failure or hypoxemia. 

Vapotherm is a high-flow oxygen delivery device that heats and 

humidifies oxygen for use with a nasal cannula, face mask, 

or tracheostomy mask at flow rates of 6 to 14 L/min that may 

provide adequate oxygen delivery without having to use positive 

pressure. 31 Mechanical ventilation may be required 

for cardiorespiratory collapse due to ADRVF in order to maintain 

adequate oxygenation. However, by increasing transpulmonary 

pressures, especially with positive end expiratory pressure 

(PEEP), mechanical ventilation may increase right 

ventricular afterload and decrease right ventricular stroke 

volume, aggravating right ventricular failure and potentially 

exacerbating hepatic, splanchnic, and renal congestion. 7 

The ventilator should be set to the lowest possible PEEP and 

acidemia, a potent pulmonary vasoconstrictor, should be 


COMMUNICATION 

EDUCATION 

RESOURCES 

NETWORKS 

PH 


Clinicians and Researchers (PHCR) 

(formerly PH Doctor) 


A professional section within the Pulmonary 

Hypertension Association for physicians and 

MD/PhD level researchers interested in 

pulmonary hypertension 

Why join… 

PHCR is the professional membership section 

for physicians and researchers within PHA, 

providing: 

• membership in the first professional organization 

of pulmonary hypertension professionals 

• opportunities to interact with other pulmonary 

hypertension colleagues throughout the year 

• regular updates on pulmonary hypertension 

developments 

Benefits of membership include: 

• Listing in the Find a Doctor section of the 

PHA website 

• Quarterly medical journal subscription 

• PHCR listserv 

• Educational Material Discounts 

• Discount for International Conferences 

• Representation in Washington 

• And much more! 

“ ” 

“ 

” 

PHCR has been invaluable in strengthening the 

network between physicians and patients. It allows 

physicians to interact with other physicians as well as 

with patients. This is a very unique opportunity not 

seen in any other organization. 

Fernando Torres, MD 

Director Pulmonary Hypertension Clinic 

UT Southwestern Medical Center- Dallas 

We are often confronted with treatment issues with 

no clear answers. Those of us who practice in this 

field find ourselves navigating through uncharted 

territories, with the decisions we make on behalf of 

our patients impacting their outcome. It is so imperative 

to have a community of colleagues who you can 

rely on for sound and trusted advice and opinions— 

that’s where PHCR comes in. 

Myung H. Park, MD, FACC 

Director, Pulmonary Hypertension Vascular 

Disease Program 


University of Maryland School of Medicine 

Baltimore, Maryland 

Apply for PHCR membership on-line at 

www.phassociation.org/PHCR 

or call 301-565-3004 for more information. 

Allied Health Professionals… please go to page 29 for 

information on PH Resource Network, PHA’s membership 

section for non-physician medical professionals.

avoided. Small degrees of alkalemia may be beneficial. 32 

ADRVF: Restoration of Vital Organ Perfusion 

In the setting of ADRVF with hypotension once emergent measures 

have been applied to stabilize the patient, pulmonary arterial 

catheterization should be considered to identify the hemodynamic 

mechanism for the hypotension and to guide therapy. 

Pharmacologic therapy to reduce right ventricular afterload 

and/or increase inotropy should be promptly and aggressively 

administered to avoid vital organ damage. Inhaled nitric oxide 

(via endotracheal tube or by face mask) up to 40 ppm can be 

administered. 33,34 Inhaled nitric oxide is a selective pulmonary 

vasodilator that reduces the PVR via the cyclic guanosine 

monophosphate system without affecting the SVR as it is quickly 

inactivated by hemoglobin. 33 With the reduction in pulmonary 

afterload the cardiac output increases and the blood 

pressure can stabilize. 34 Alternatively, inhaled epoprostenol or 

iloprost may be considered, but unlike inhaled nitric oxide, 

these agents can exert systemic vascular effects. 35-37 Once stabilized 

patients can be transitioned to intravenous epoprostenol 

which has pulmonary vasodilator properties and may exert 

inotropic effects on right ventricular function. 38 Continuous 

intravenous infusion of epoprostenol should be started at 1 

ng/kg/min and titrated by 0.5 to1 ng/kg/min every 30 minutes 

while maintaining a systolic blood pressure of greater than 80 

mmHg, until a maximum tolerated dose is reached. This point 

is usually marked by the development of hypotension or other 

dose-limiting side effects such as headache, nausea/vomiting, 

diarrhea, myalgias, arthralgias, and trismus. If the patient 

maintains an adequate systemic blood pressure and cardiac 

output, inhaled nitric oxide can be weaned slowly by 5 ppm 

increments until a dose of 5 ppm is reached. Thereafter, nitric 

oxide should be weaned by 1 ppm increments until off to prevent 

rebound increases in pulmonary hypertension. While 

administering nitric oxide, methemoglobin levels must be monitored 

every 6 hours and maintained at less than 5% of hemoglobin 

to avoid methemoglobin toxicity. 39 

Nitric oxide and epoprostenol may be used together in 

refractory cases, given that the combination may be additive as 

they exert their effects via different cyclic nucleoside pathways. 

It must be emphasized that if an acute effect to epoprostenol 

is not apparent, the therapy should not be abandoned (provided 

multiorgan failure has not occurred) as its benefits may be 

delayed. The effects of epoprostenol on the pulmonary circulation 

will take time (weeks) and prove to be effective while the 

cardiac output and blood pressure are supported with inotropic 

agents to avoid vital organ hypoperfusion. In addition to its pulmonary 

vasodilator effects epoprostenol may exert positive right 

ventricular inotropic effects via activation of the cyclic adenosine 

monophosphate pathway. 38 It should replace or be added 

to any chronic oral or inhalational pulmonary vasodilator agent 

the patient may already be receiving for PAH when ADRVF 

supervenes. Intravenous epoprostenol can assist with the weaning 

process from inhaled nitric oxide and beta-adrenergic 

inotropes in severe right ventricular failure. 

In ADRVF, low dose beta-adrenergic agents such as dobutamine 

or dopamine at 1 to 2 mcg/kg/min may improve cardiac 

output and restore vital organ perfusion. 7 In the initial treatment 

of hypotension/hypoperfusion, dopamine or norepinephrine 

should be considered to restore right ventricular function, 

systemic hemodynamics and coronary perfusion. These agents 

may be more beneficial than phenylephrine alone, which is a 

selective alpha-agonist. 40 Phenylephrine with low-dose dobutamine 

is a combination that may be desirable in tachycardic 

patients with vital organ hypoperfusion. Manipulating these 

drugs separately will allow the clinician to attain specific hemodynamic 

effects. The institution of inotropic and vasopressor 

agents is a double-edged sword as they can increase right ventricular 

work and exert vasopressor effects on the pulmonary circulation. 

However, in the appropriate clinical situation they are 

essential to restore and maintain systemic perfusion. The lowest 

possible dose of these drugs should be utilized to minimize 

tachycardia, proarrhythmia, myocardial oxygen consumption 

and ischemia, and pulmonary vasoconstriction. 

In patients with ADRVF, central venous congestion, and 

hypotension volume infusion should not be employed. The 

failing right ventricle is operating on the flat to descending 

portion of its Frank-Starling curve and further increase in 

right ventricular preload will not improve cardiac output and 

blood pressure. Volume loading will further dilate the right 

ventricle, resulting in worsening tricuspid regurgitation and 

right ventricular wall stress. In addition, as a result of diastolic 

ventricular interdependence imposed by pericardial 

constraint, volume loading will exacerbate the low systemic 

cardiac output state due to compromised left ventricular filling 

as previously discussed. 41,42 

The phosphodiesterase-3 inhibitor, milrinone, is an intravenous 

inodilator that should be avoided in right ventricular 

failure from PAH as its vasodilatory properties may overwhelm 

its inotropic effect. Milrinone may reduce the SVR without 

affecting the PVR in this patient population and may exacerbate 

systemic hypotension. By the same token, nitric oxide donors 

such as nitroprusside or nitrates should not be used in ADRVF 

due to PAH as they can exacerbate systemic hypotension. 15 

Although the recombinant B-type natriuretic peptide 

nesiritide is effective in pulmonary hypertension due to leftsided 

heart failure, it has not been shown to decrease PVR 

when administered acutely in patients with PAH with or 

without right ventricular failure. 43 Data are lacking for this 

agent in PAH and concerns for systemic hypotension do not 

support use of nesiritide in this patient population at this 

time. 

ADRVF: Treatment of Volume Overload 

In severe right heart failure when diuretic resistance is operative, 

aggressive intravenous and combination diuretic therapy 

should be instituted. Diuretic resistance may result from 1) 

poor intestinal absorption of oral diuretic secondary to bowel 

wall edema; 2) pre-existing renal disease; 3) low cardiac output 

with renal arterial hypoperfusion and inadequate delivery of 

solute to the distal renal tubule; 4) renal arterial hypoperfusion 

combined with renal venous congestion resulting in reduced 

glomerular filtration; 5) tubular cell hypertrophy due to chronic 

diuretic use; 6) intense neurohormonal activation; and/or 7) 

concomitant administration of nonsteroidal anti-inflammatory 

agents or COX-2 inhibitors. 44,45 Intravenous bolus loop diuretic 

therapy or a continuous infusion of loop diuretic (furosemide 

5 to 20 mg/h, bumetanide 0.5 to 1 mg/h, and torsemide 5 to 


10 mg/h) after a priming bolus dose often overcomes the diuretic 

resistance. 45 The constant infusion strategy will maintain a 

continuous renal threshold of drug without the peak and valleys 

of the higher dose intermittent bolus administration and effect 

a constant diuresis with less ototoxicity. If loop diuretic drip 

alone is ineffective, then intermittent intravenous chlorothiazide 

(not to exceed 2 gm over a 24 hour period) can be instituted. 

Intermittent metolazone can also be administered provided 

that absorption of the oral drug is felt to be adequate. The 

use of an aldosterone antagonist in conjunction with loop or thiazide 

diuretics will often be effective. Aldosterone antagonists 

should be avoided in patients with hyperkalemia and significantly 

compromised renal function. Electrolytes should be 

monitored closely with these agents. 

In the patient who is markedly volume overloaded and not 

responding adequately to aggressive diuresis, or in whom the 

blood urea nitrogen and creatinine are rising, low dose dobutamine 

and dopamine should improve renal perfusion and potentiate 

diuresis. If diuretic manipulation with inotrope assistance 

fails to adequately deal with the volume overload, mechanical 

fluid removal usually with continuous venous-venous hemodialysis 

or other methods of ultrafiltration should be promptly 

employed to decompress the right ventricle, improve right ventricular 

performance and left ventricular preload, and reduce 

vital organ congestion. 

Once hemodynamic stabilization has been achieved with 

the maneuvers delineated above, optimization of chronic therapy 

should be instituted. For patients who are suitable candidates 

for lung or heart-lung transplantation, strategies should 

be put in place to successfully bridge them to surgery. For those 

who are unstable and/or have refractory right ventricular failure 

and are not candidates for transplantation, the emphasis of 

care should shift to palliation of symptoms and hospice care 

when appropriate. 

Conclusions 

In patients with PAH, right ventricular failure is associated 

with a poor prognosis. Established therapies for PAH should 

be instituted early and optimized to prevent right ventricular 

failure. Diuretics are the mainstay of therapy for right ventricular 

failure and should be optimized. For patients who 

present with ADRF an aggressive approach should be undertaken. 

Pharmacologic therapy including oxygen, inhalational 

nitric oxide, epoprostenol, and inotropic support must be 

instituted rapidly to prevent vital organ hypoperfusion. 

Volume overload must be treated promptly to decompress 

the right ventricle and promote left ventricular filling. 

Sequential nephron blockade with intravenous loop and thiazide 

diuretics as well as aldosterone antagonists should be 

instituted. Mechanical fluid removal should be applied if 

diuretic therapy fails. In suitable patients who continue to 

deteriorate despite optimal medical therapy, prompt evaluation 

and listing for lung or lung-transplantation is indicated. 

At specialized centers, atrial septostomy should be considered 

for severe right ventricular failure, recurrent syncope, or 

as a bridge to lung transplantation. Intravenous epoprostenol 

and beta-adrenergic inotropic agents may be utilized in 

combination as a bridge to transplantation. For end-stage 

right ventricular failure, when all treatment options are 

exhausted or are inappropriate, the focus of management 

should transition to palliative care. 

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bridge to lung transplantation in patients with severe pulmonary hypertension. 

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arterial hypertension. Circulation. 2004;110(17):III-558. 

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predictor of mortality in patients with pulmonary hypertension. 

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30. Roberts D, Lepore J, Maroo A, et al. Oxygen therapy improves cardiac 

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hypertension. Chest. 2001;120(5):1547-55. 

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Crit Care Med. 1999;159(2):571-9. 

35. Lowson S. Inhaled alternatives to nitric oxide. Anesthesiology. 

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of inhaled nitric oxide and aerosolized prostacyclin in acute respiratory 

distress syndrome. Am J Resp Crit Care Med. 1996;153(3):991-6. 

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acute hemodynamic effects of inhaled nitric oxide and aerosolized iloprost 

in primary pulmonary hypertension. German PPH study group. J 

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39. Hermon M, Burda G, Golej J, et al. Methemoglobin formation in 

children with congenital heart disease treated with inhaled nitric oxide 

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effects on right ventricular function in experimental canine pulmonary 

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loading compared with dobutamine in severe right ventricular infarction. 

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approach. J Intensive Care Med. 1996;11:121-48. 


Cases from the Pulmonary Hypertension Service 


Director, Pulmonary 







Medical Director, Lung and 

Heart-Lung Transplantation 

Co-Director, Vera M. Wall Center for 




CASE 1: 

A 42-year-old woman with HIV-related pulmonary arterial 

hypertension (WHO class II) presented to the emergency 

room with a 2-day history of fever, dysuria, lightheadedness, 

and increased abdominal girth. Her medications at home 

included continuous intravenous epoprostenol at a rate of 

25 ng/kg/min, furosemide 80 mg po qd, and co-trimoxazole 

for PCP prophylaxis. Her heart rate (HR) was 140/min regular, 

blood pressure (BP) was 72/45 mmHg, she had an oxygen 

saturation of 95% on 3L/min nasal cannula and a temperature 

of 38 Celsius degrees. Her mucous membranes 

were moist; she had elevated jugular venous pressure and 

evidence of ascites. Cardiac examination revealed a right 

ventricular heave, loud P2, murmur of tricuspid regurgitation, 

and right-sided gallop. Lungs were clear to auscultation 

bilaterally, the liver was slightly enlarged, and she had 

suprapubic tenderness. Hickman line insertion site had no 

evidence of erythema or discharge. Electrocardiographic 

examination showed sinus tachycardia at a rate of 138/min, 

right axis deviation, and incomplete right bundle branch 

block. Chest radiography demonstrated cardiomegaly, but 

neither lung parenchymal infiltrates nor pleural effusions. 

Total white blood cell count was 14.5 x 1000/dL with 95% 

polymorhphonuclear cells, and urinalysis showed numerous 

white blood cells, positive leukocyte esterase and nitrite. 

Blood urea nitrogen (BUN) was 32 mg/dL and serum creatinine 

(Cr) 1.8 mg/dL (baseline BUN/Cr = 16/0.9). Blood and 

urine cultures were collected. She was immediately given 

one liter of crystalloid infusion over 90 minutes, followed by 

a continuous infusion of normal saline at 100 mL/h and one 

dose of intravenous Piperacillin-Tazobactam. HR remained 

elevated at 135/min and BP remained low at 70/45 mmHg; 

she had minimal urine output and complained of worsening 

shortness of breath. Her pulmonary hypertension physician 

was called, the patient was transferred to the CCU, and 

intravenous fluids were discontinued. Repeat BUN at 4 

hours was 38 mg/dL and Cr was 2.2 mg/dL. Urine Na was 

25 mEq/L, with a fractional excretion of sodium of 0.22. 

Bedside echocardiogram showed right ventricular dilatation 

and severe dysfunction, enlarged right atrium, and a small 

pericardial effusion without tamponade physiology. She 

received 80 mg of furosemide intravenously and continuous 

infusion of dopamine at 2 mcg/kg/min and dobutamine at 3 

mcg/kg/min. After 2 hours, BP increased to 85/55 mmHg, 

and she urinated 250 cc of urine. Dobutamine was 

increased in 1 mcg/kg/min increments to 5 mcg/kg/min over 

3 hours and the patient was initiated on standing dose of 

intravenous furosemide 80 mg intravenously every 12 hours. 

Upon urine culture results that showed growth of Klebsiella 

pneumoniae sensitive to fluoroquinolones, the patient was 

transitioned to oral ciprofloxacin, after receiving 48 hours of 

intravenous antibiotics. Blood cultures were negative. Over 

the next 3 days, her BP remained stable at 95-100 

mmHg/50-60 mmHg, HR of 95-110/min (sinus tachycardia), 

she was afebrile, and her respiratory status improved. 

She had good urine output, her oxygen supplementation 

requirement decreased and renal function returned to normal. 

Dopamine and dobutamine were tapered to off, intravenous 

furosemide converted to oral form, and she was discharged 

home on oral antibiotics after a 7-day hospital stay. 

Discussion: 

This case provides an example of acute right heart failure 

precipitated by an intercurrent urinary tract infection in a 

patient with pulmonary arterial hypertension who was relatively 

well controlled with intravenous epoprostenol. Patients 

with pulmonary arterial hypertension have little tolerance for 

any comorbidity, which can easily precipitate acutely 

decompensated right heart failure (ADRVF), particularly in 

cases with significant baseline right ventricular dysfunction. 

Even with another obvious source of infection (in this case, 

a urinary tract infection) patients receiving continuous intravenous 

prostacyclin through a central catheter who present 

with fever should have blood cultures done and receive 

empiric coverage for gram-positive organisms. Patients with 

ADRVF are usually hypotensive and tachycardic and in a low 

flow state. Any further increase in the right ventricular preload 

(such as with intravenous fluid administration) may 


exacerbate right ventricular dysfunction, as it did in this 

case. The systemic hypotension that follows is due to 

decreased left ventricular filling from interventricular septal 

shift and decreased right ventricular output. Intravenous 

fluid administration should be done with great caution in 

patients with pulmonary hypertension and requires clear evidence 

of true intravascular fluid depletion, such as a history 

of recent fluid loss, dry mucous membranes, or drenching 

sweats with large insensible fluid loss. Patients who present 

in septic shock, particularly if it is complicated by cardiogenic 

shock, may be extremely difficult to manage and likely 

will require pulmonary artery catheterization to guide 

management. Decreased urinary output and evidence of prerenal 

azotemia can be due to low cardiac output and cannot 

be considered evidence enough to begin intravenous fluid 

administration, as was the case in our patient. 

The goal of BP support is to decrease the right ventricular 

dilatation and to directly improve the right ventricular 

contractility. Right ventricular dilatation is primarily 

decreased by administration of intravenous loop diuretics. 

Because of bowel edema, orally administered diuretics may 

be ineffective. By decreasing the right atrial size and pressure 

diuretics improve right ventricular filling and contractility, 

and in some cases, may be the only intervention 

required to improve systemic hemodynamics. Most patients, 

however, will benefit from direct right ventricular inotropic 

support and vasopressors, as in this case where low-dose 

dopamine and dobutamine were used. In patients with right 

ventricular failure dobutamine is the inotropic agent of 

choice, despite some potential direct pulmonary hypertensive 

effect. Milrinone may be more beneficial as a pulmonary 

vasodilator, but the pronounced systemic hypotension 

induced by this agent has the potential to decrease 

venous return to the already insufficient right heart, worsening 

the right ventricular failure. All vasopressors may have a 

direct pulmonary vasoconstrictor effect, but low-dose 

dopamine, phenylephrine, norepinephrine, or vasopressin 

may be used to sustain the systemic blood pressure. 

Improved systemic hemodynamics are usually translated in 

improved renal function, increased diuresis, and further 

increased right ventricular contractility. In conclusion the 

mainstay of therapy in cases of hypotension from right ventricular 

failure in pulmonary arterial hypertension is not 

intravenous fluid administration, but rather inotropic support, 

diuretics, and vasopressors. 

CASE 2: 

A 58-year-old man with hepatitis C-cirrhosis (MELD = 32, 

refractory ascites, recurrent variceal bleeds, episodes of 

hepatic encephalopathy, and hepato-renal syndrome) and 

porto-pulmonary hypertension was called for cadaveric 

orthotopic liver transplantation (OLT). He had been deemed 

an appropriate candidate for OLT after 9 months of therapy 

with subcutaneous treprostinil. His initial cardiac catheterization 

at the time of diagnosis of porto-pulmonary hypertension 

revealed the following hemodynamics: mean pulmonary 

artery pressure (mPAP) of 55 mmHg, pulmonary artery 

occlusion pressure (PAOP) of 10 mmHg, cardiac output (CO) 

of 6 L/min and pulmonary vascular resistance (PVR) of 600 

dynes x s x cm -5 . He lived alone, was mildly encephalopathic, 

and his wife, who had multiple sclerosis, resided in 

a nursing home. With hemodynamics that posed a prohibitive 

operative risk for OLT, and an inappropriate social situation 

for intravenous epoprostenol therapy, treatment was 

initiated with subcutaneous treprostinil. Six months after 

initiation a follow-up right heart catheterization on 36 

ng/kg/min of treprostinil showed the following hemodynamics: 

mPAP of 33 mmHg, PAOP of 15 mmHg, CO of 8.7 

L/min, and PVR of 166 dynes x s x cm -5 . On the basis of 

these numbers he was listed for liver transplantation and 

because of rapidly progressing liver disease he received a 

graft after 3 months. 

Preoperatively his mPAP was 40 mmHg, his central 

venous pressure (CVP) was 18 mmHg, PAWP was 20 mmHg, 

and CO was 8.5 L/min, with a PVR of 188 dynes x s x cm -5 . 

During abdominal preparation the subcutaneous treprostinil 

administration was discontinued. Systemic blood pressure 

was 85/55 mmHg before induction of general anesthesia 

and decreased to 70/35 mmHg after induction. This fall in 

blood pressure responded to a phenylephrine bolus of 0.2 

mg. Approximately half an hour after treprostinil discontinuation 

a continuous intravenous epoprostenol infusion was 

started at 2 ng/kg/min and adjusted to keep mPAP = 30-40 

mmHg, with up-titration in 1-2 ng/kg/min increments every 

30 to 60 minutes. Cardiac output was constantly monitored 

and remained at 6.5-8.5 L/min. Inhaled nitric oxide (NO) 

was kept on stand-by for potential rebound pulmonary 

hypertensive episodes, but was not used. After removal of 

ascites, mPAP, PAOP, and CVP decreased by 10 mmHg. 

Intermittent boluses of phenylephrine (0.2 mg) and vasopressin 

(2-4 U) were used to maintain the mean systolic BP 

above 45-50 mmHg. During the procedure the patient 

received a total of 6 L crystalloid infusion, 10 U of fresh 

frozen plasma, and 5 units of packed red blood and he was 

placed on continuous veno-venous hemofiltration (CVVH). 

He remained stable hemodynamically throughout the transplant, 

including during the anhepatic phase. Upon graft 

revascularization during a 2 minute hypotensive episode 

(with a decrease in the mean systemic BP to 30 mmHg and 

a rebound mPAP to 45 mmHg) he received 4 U of vasopressin 

and this increased the mean systemic BP to 50 

mmHg, without significant change in mPAP. On completion 

of the transplant operation he was receiving 15 ng/kg/min of 

continuous intravenous epoprostenol. He was transferred to 

the surgical intensive care unit, where he remained hemodynamically 

stable. The next day subcutaneous treprostinil 

was reinitiated and up-titrated in 3-4 ng/kg/min increments, 

with simultaneous down-titration of intravenous 

epoprostenol in 1-2 ng/kg/min decrements, until a dose of 

30 ng/kg/min of treprostinil were reached. Prior to discontinuation 

of the pulmonary artery catheter the mPAP was 32 

mmHg, the CO was 7.5 L/min, the PAOP was 12 mmHg, and 

the calculated PVR was 213 dynes. 

Discussion: 

This case illustrates the strategy that may be employed for 

the perioperative hemodynamic management of patients 

with porto-pulmonary hypertension who require OLT. Porto- 


COMMUNICATION 

EDUCATION 

RESOURCES 

NETWORKS 

PH 


Resource Network (PHRN) 


A professional section with the Pulmonary 

Hypertension Association for nurses, nurse practitioners, 

physician assistants, pharmacists, respiratory 

therapists, technicians, and other allied health 

professionals 

Why Join… 

PH Resource Network is the professional membership 

section for non-physician healthcare 

professionals working within the field of pulmonary 

hypertension, providing: 

• membership in a unique organization dedicated to 

providing resources to allied health professionals 

working with PH patients 

• a chance to interact with other PH colleagues 

• regular updates on pulmonary hypertension 

developments 

• opportunities for professionals enhancement 

Benefits of Membership Include: 

• Quarterly Medical Journal Subscription 

• PH Resource Network listserv 

• Educational material discounts 

• Continuing Education Credits 

• Representation in Washington 

• General membership in PHA 

Join online at 

www.phassociation.org/PHRN 

or call 301-565-3004 for more information. 

“ ” 

“ ” 

There are many reasons to join this group, but the 

benefit I have truly enjoyed is being able to ‘tap’ into 

everyone’s collective knowledge with the listserv. 

Many changes are taking place in this field right now 

and it would be difficult for even the most seasoned 

veterans to have all the answers. With this, my 

patients and I can benefit from everyone else’s 

experiences and expertise. 

Ginger R. Ward, RN 



It is so reassuring to know that if I have a question 

that I can’t answer, I have many, many PH specialists 

(we nurse’s, of course!) right at my fingertips! 

Stephanie Harris 

University of Washington Medical Center 

Seattle, WA 

Physicians and Researchers… please go to page 23 for information 

on PH Clinicians and Researchers, the membership section 

for physicians and researchers.

pulmonary hypertension is a type of pulmonary arterial 

hypertension that develops in patients with end-stage liver 

disease, characterized by the presence of a true pulmonary 

arteriopathy (elevated PVR) and (potential for) right ventricular 

dysfunction. Perioperative mortality is significantly 

increased in the presence of moderate to severe pulmonary 

hypertension. These patients require chronic therapy for pulmonary 

hypertension for hemodynamic optimization prior to 

OLT, and case series in the literature support the use of continuous 

intravenous epoprostenol in these circumstances. 

This patient was treated with subcutaneous treprostinil 

instead because of the lack of social support and his own 

inability to manage the complexities of intravenous 

epoprostenol therapy. With the advent of alternative therapeutic 

options for pulmonary arterial hypertension, it is likely 

that physicians will use other forms of chronic prostacyclin 

therapy, ideally in the setting of organized clinical trials. 

This patient had a good hemodynamic response to treprostinil, 

rendering him an OLT candidate, but the particular 

challenge in his case was the timing of transition from subcutaneous 

to intravenous prostacyclin during the surgical 

procedure. Given the relative unpredictability of the time of 

OLT, it is not possible to transition these patients in 

advance. Liver transplantation surgery is associated with 

hemodynamic instability, rebound pulmonary hypertension, 

and precipitation of right ventricular failure, particularly 

after induction of general anesthesia, after graft revascularization, 

and during the first postoperative days. Transitioning 

from one to another form of prostacyclin therapy during OLT 

may increase the risk of hemodynamic instability. In this 

case, transition from subcutaneous treprostinil to prostacyclin 

infusion was successfully achieved with guidance from 

pulmonary artery catheterization. 

As a general rule, prostacyclin deficiency may be associated 

with rebound pulmonary hypertension and prostacyclin 

excess with systemic hypotension. There is a difference in 

half-lives between epoprostenol and treprostinil (2 to 3 minutes 

and 2 to 4 hours, respectively) and anecdotal evidence 

suggests that approximately two to three times more treprostinil 

(in nanograms) is required for an equivalent effect. 

Inhaled NO may be used for the pulmonary vasodilator 

effect, particularly in cases with systemic hypotension, 

because of its selectivity for the pulmonary vasculature. 

Inotropic agents and vasopressors, as well as volume 

replacement or volume removal, may be used as needed for 

the hemodynamic management during liver transplantation. 


Pulmonary Hypertension Roundtable 

Managing the Critically Ill Patient 

by Translating Best-of-Care Principles 

into Clinical Practice 


James R. Klinger, MD 


Fernando Torres, MD 

This discussion was moderated by Roxana Sulica, 

MD, Assistant Professor of Medicine, Mount Sinai 

School of Medicine, and Director, Mount Sinai 

Pulmonary Hypertension Program, Mount Sinai 

Medical Center, New York, New York. The participants 

included James R. Klinger, MD, Pulmonary 

Hypertension Center, Rhode Island Hospital, 

Providence, and Associate Professor of Medicine, 

Brown University Medical School, Providence, Rhode 

Island; Ronald G. Pearl, PhD, MD, Professor and 

Chair, Department of Anesthesia, and Associate 

Director, Intensive Care Units, Stanford University 

Medical Center, Stanford, California; and Fernando 

Torres, MD, Director, Pulmonary Hypertension Clinic, 

University of Texas Southwestern Medical Center, 

Dallas, Texas. 

Dr Sulica: Thank you for joining us for this discussion 

today. I’ll start by asking how you would manage a 

patient with the following: recently diagnosed pulmonary 

hypertension, as suggested by an echocardiogram, 

with estimated right ventricular systolic pressure 

of 90 mmHg, right ventricular dilatation and 

severe dysfunction, pericardial effusion, and an 

enlarged right atrium. The patient has a systemic 

blood pressure of 80/50 mmHg with a heart rate of 

120 bpm and is very short of breath with activities of 

daily living. There are a few episodes of impending 

syncope with minimal exertion for the past two or 

three weeks. What would you do or what is your first 

choice of treatment? 

Dr Torres: The first thing I would try to find out is why 

the patient developed cor pulmonale. One of the first 

illnesses we will try to rule out is chronic pulmonary 

emboli. I would try to sort things out very quickly 

either by a ventilation perfusion scan or by a CT 

angiogram. I would get a chest x-ray and make sure 

the patient doesn’t have interstitial lung disease, etc, 

as an etiology of cor pulmonale. While I am waiting 

for other tests, obviously the patient seems to be in 

right ventricular failure, and in such patients we want 

to make sure to start diuretics fairly quickly. I usually 

use furosemide at about 10 to 20 mg per hour even 

though they are hypotensive. Most of the time, the 

right ventricle is able to compensate better and work 

more efficiently when the preload decreases. Another 

intervention that we tend to do fairly quickly is to try 

to get a right-sided catheterization to make sure the 

patient has cor pulmonale. This will help manage the 

patient. Obviously, with the heart rate of 120 bpm 

this may be somewhat challenging, but it is very 

important to monitor pulmonary pressures and right 

ventricular function in a patient who has hypotension 

and tachycardia. Most of the time when I use diuretics 

in these patients they seem to stabilize to the 

point where we can start epoprostenol therapy. 

Usually, when the patients seem to be decompensated, 

a challenge with epoprostenol, adenosine, or 

nitric oxide is not going to be useful given that their 

cardiac index is going to be so low that it would be 

inappropriate to consider them for calcium channel 

blocker therapy. A lot of times, fairly soon, for these 

patients treatment is going to be started with a 

prostacyclin, usually epoprostenol. 

Dr Sulica: And your choice is epoprostenol despite 

the current availability of other forms of prostacyclins? 

Dr Torres: You know, I don’t think there are enough 

data on patients with decompensated cor pulmonale, 

class IV, for me to feel comfortable enough to start 

using inhaled therapy at this point. At this point, the 

drug of choice for the decompensated phase of cor 

pulmonale is intravenous epoprostenol. Intravenous 

treprostinil is also available, but we do not have as 

much experience using it in acute right ventricular 

failure. 

Dr Sulica: Absolutely. Ron, do you see placement of 

a pulmonary artery catheter in critical care settings as 

riskier than in patients with no pulmonary hypertension? 

Dr Pearl: Certainly placing a central line in a decompensated 

patient who is hypoxemic, is very dyspneic, 

and may not tolerate lying flat may have increased 

risks. I don’t view the passage of a pulmonary artery 


catheter by itself as being particularly risky in a patient with 

pulmonary hypertension. It may be much more difficult to do 

with just pressure waveform guidance, but we have never had 

complications from passing the catheter itself. Obtaining a 

wedge pressure may not be feasible in many of these patients, 

but it may not be particularly important to measure the wedge 

pressure because with ventricular interdependence the wedge 

pressure may no longer reflect left ventricular filling. So, people 

just try to get into the pulmonary artery and are happy with 

looking at pulmonary artery pressures. I think that is being safely 

done. 

Dr Sulica: How about the reliability of cardiac output determinations? 

Do you confidently rely on thermodilution cardiac output, 

given the fact that frequently these patients have significant 

tricuspid regurgitation or maybe open PFOs? 

Dr Pearl: If there is no intracardiac shunting, and if we are not 

talking about a patent foramen ovale, but simply pulmonary 

hypertension, our experience has been that the cardiac output 

seems to be reliable, and it does provide a useful trend. We 

often supplement the cardiac output values by using a continuous 

cardiac output catheter with venous oximetry, or at least 

getting some intermittent mixed venous oxygen saturations to 

be sure that what we think cardiac output is doing seems to be 

reflected in the trend in mixed venous oxygen saturation. I 

would like to mention that as the cardiac output gets very low, 

thermodilution may be less reliable. 

Dr Sulica: Great point. What do you think about the role of 

transesophageal echocardiography and transthoracic echocardiography 

in the critical care area or intraoperatively? 

Dr Pearl: In the intensive care unit we have been extensively 

using portable transthoracic echocardiography for diagnosis, 

but we would use it in the patient you described to be sure that 

what we are dealing with is clearly right heart failure and not 

from the insult that has occurred, and that there are no major 

valvular abnormalities. We would want to see if there is shunting 

going on that we would want to know about. I think in the 

intensive care unit setting, transesophageal echocardiography 

is likely not all that useful in the nonintubated patient. I would 

be concerned about potentially decompensating a patient as 

described. In the operating room it is effective, because we are 

leaving a probe in for the entire duration of many of the marked 

changes that we might expect to occur. 

Dr Torres: Do you have vasovagal episodes during the procedure 

with transesophageal echocardiography? 

Dr Pearl: I think in the nonintubated patient who is already 

decompensating I would worry about it. In the operating room 

the patient would already be asleep and anesthetized. 

Dr Sulica: What do you think about the reliability of pulmonary 

artery catheterization determinations in patients with an acute 

lung injury or ARDS (acute respiratory distress syndrome) associated 

with signs of right heart dysfunction, low urine output, or 

systemic hypotension? How useful and reliable is the information 

obtained from placing a pulmonary artery catheter? 

Dr Klinger: I think I would approach it two ways. One is the person 

we don’t think has pulmonary hypertension and now has a 

Swan-Ganz catheter placed for acute lung injury and is found 

to have pulmonary hypertension. In that situation, what we 

need to stress is that an acute lung injury normally causes a 

certain degree of pulmonary hypertension, so that should be 

anticipated, not as pulmonary arterial hypertension, but as pulmonary 

hypertension secondary to the acute lung disease. This 

should resolve as the lung disease improves. The second situation 

is someone who has pulmonary arterial hypertension and 

then develops an acute lung injury, and has a Swan-Ganz 

catheter inserted. Now the pulmonary pressures may actually 

be less if the cardiac output is decreased compared to baseline. 

High levels of PEEP will decrease right-sided return and right 

ventricular filling, and decrease cardiac output. So the pulmonary 

arterial pressure may come down. Occasionally there 

will be patients who have high wedge pressure because they are 

being volume resuscitated or who have a lot of pressure transmitted 

from the airways, causing a falsely elevated wedge pressure 

with a true transmural left ventricular diastolic pressure 

that is normal. These patients may appear to have elevated pulmonary 

venous hypertension when they actually don’t. So, pulmonary 

artery pressure measurements may be confusing in 

someone that has established pulmonary hypertension who 

develops an acute lung injury, goes on mechanical ventilation 

and PEEP, and then has a Swan-Ganz catheter coming in. The 

other issue to consider is if patients have enough hypercapnea 

that they are acidotic. For any level of hypoxia, pulmonary vasoconstriction 

is increased in the presence of acute hypercapnea 

or acidosis. So there may be some degree of elevation in pulmonary 

arterial pressure in response to acute hypercapnea. I 

would add that in many of these settings one can administer 

inhaled nitric oxide diagnostically to see to what extent the 

acute pulmonary vasoconstriction is really contributing to any 

hemodynamic problems. Inhaled nitric oxide can be effective in 

blunting the increased pulmonary vascular resistance from 

acute hypercapnea. 

Dr Sulica: So, you would consider inhaled nitric oxide if the pulmonary 

vascular resistance is high? 

Dr Klinger: Well, it depends on the type of patient. There is the 

patient who, as a result of acute lung injury, has pulmonary 

hypertension. It is rarely important to treat pulmonary hypertension 

in that situation. Then there is the patient who has 

established pulmonary hypertension, who now has a superimposed 

acute lung injury and develops worsening of the pulmonary 

hypertension because of acute hypoxia, acidosis, or 

hypercapnea. This is a very different setting and it is often not 

easy to know how much of the pulmonary hypertension in these 

patients is actually a problem versus a normal response to acute 

lung injury. So, sometimes we debate whether we should treat 

the pulmonary hypertension or not. In this setting, we often use 

inhaled nitric oxide diagnostically to see if we can lower the pulmonary 

pressures. If it is effective in doing that and cardiac 

output increases, this can tell you that the pulmonary hypertension 

itself is a problem. 


Dr Sulica: And you also take into account the level of the right 

ventricular dysfunction. 

Dr Klinger: Definitely! 

Dr Sulica: Now, in patients already diagnosed with pulmonary 

hypertension who are presenting to the emergency room 

hypotensive and seeming septic, what will be the diagnostic 

and therapeutic maneuvers? 

Dr Pearl: It depends a bit on whether one believes that cardiac 

output has increased due to systemic vasodilation versus 

whether hypotension is due to a decrease in cardiac output 

related to very high pulmonary artery pressures. If the hypotension 

is directly related to worsened pulmonary hypertension, I 

would use an agent that is inotropic and has some pulmonary 

vasodilation, such as dobutamine. 

Dr Sulica: What do you think about milrinone? 

Dr Torres: If they have a fever, we get a urinalysis, CBC, 

chemistries, blood cultures, and a chest x-ray. If we do not identify 

the source of the infection fairly quickly, we are going to 

assume it is coming from the central line in a patient receiving 

intravenous epoprostenol and start intravenous antibiotics. 

Dr Sulica: How about giving intravenous fluids 

when patients come in septic? Sometimes they 

are febrile and possibly fluid depleted. We discussed 

that we actually diurese patients in right 

heart failure even though they are hypotensive. 

Dr Torres: For the most part, in patients with pulmonary 

hypertension, the right ventricle is not 

going to need more preload. We tend just to give 

them antibiotics, and we may even have to diurese 

them, as you are saying. We check their BUN and 

creatinine and it is usually higher than you think. 

You are right, even though they have a fever and 

their blood pressure is a little bit low, we tend not 

to give them any fluids. For the most part we continue 

giving them their diuretics or just cut back a 

little bit on the diuretics. 

Dr Sulica: And even though they are hypotensive, 

you do not interrupt the intravenous epoprostenol. 

Dr Torres: Exactly! We never interrupt the vasodilator 

therapy because then you may make the 

hypotension much worse. 

Dr Sulica: Jim, do you have the same strategy of managing 

these patients? 

Dr Klinger: Absolutely. I have very much the same strategy. We 

have done some laboratory studies showing that a lot of the 

catheters are infected with an organism called Micrococcus, 

which is a kind of Staphylococcus, that responds fairly well to 

treatment with antibiotics even though you might have to give 

treatment for a long period. While commonly considered a contaminant, 

Micrococcus should be treated as a real pathogen in 

these patients with indwelling lines. 

Dr Sulica: What if the patient becomes hemodynamically unstable? 

What would be your favorite inotropic drug and favorite 

vasopressor, and what do you think would be the best management 

strategy for these patients with pulmonary hypertension in 

the operating room? 

I think we are relatively 

liberal in allowing pulmonary 

hypertension 

when they have a compensated 

right ventricle. 

We are doing something 

that will eventually improve 

the outcome. We 

may have to temporarily 

support the right and left 

ventricle with pharmacologic 

and mechanical 

means, but normally 

when the cardiac problem 

is repaired, over 

time we will see things 

improve. Those are the 

patients in whom we 

may postoperatively use 

inhaled nitric oxide and 

transition to a phosphodiesterase-5 

inhibitor such 

as sildenafil. 

Dr Pearl: I think it is a great drug. However, it is difficult to start 

it in a hypotensive patient because of its systemic vasodilation. 

You cannot titrate it well. We use it more when we think we have 

several hours of treatment time for careful titration. 

Dr Torres: I would echo your comments. I think 

your preferred therapy depends on where you 

were trained or what your subspecialty might be. 

If you are a pulmonologist, you tend to use a little 

bit more dopamine and if you are a cardiologist, 

then you tend to use more dobutamine. As a 

pulmonologist I tend to use a little bit more 

dopamine, especially in the hypotensive patient. 

Obviously, I use dopamine at the expense of 

patients developing tachycardia. I still go back 

and forth between dopamine and dobutamine, 

especially in the patient with hypotension. 

Dobutamine can still worsen the hypotension and 

the patient may not tolerate it. 

Dr Pearl: The other setting is your sepsis 

patients, as you mentioned a little bit before. It 

is probably a good example. What has occurred 

often is not that cardiac output has fallen from 

exacerbation of the pulmonary hypertension, but 

that there has been some systemic vasodilation 

and they are not able to increase cardiac output 

because of the pulmonary hypertension. In those 

settings I am much more likely to use something 

that has the ability to give some inotropic effect 

and some systemic vasoconstriction, like dopamine. I am not as 

worried about adding on pulmonary vasodilation. 

Dr Sulica: How about norepinephrine? What is your opinion 

about this? 

Dr Klinger: I think Ron is right. The difficulty is really not so 

much treating the pulmonary hypertension as it is decreasing 

the drop in afterload on the systemic side. You need to do what 

you need to do to keep up that blood pressure. We do this sometimes 

in septic patients as well. When we think their volume is 

expanded to the maximum, we try to get away from volume 

expansion and go toward vasopressors. I think people get concerned 

that when they use vasopressors they are going to have 

pulmonary vasoconstrictive effects as well, but this is really very 

mild. As a result, once you have tried the inotropic route, and 

you fail, vasopressors would be the next thing to use. I would 

probably use Levophed. I don’t know anyone who has tried 

vasopressin. Are there some case reports of it now? 


Dr Sulica: Yes, although the effect of vasopressin in experimental 

pulmonary hypertension is controversial, there are few 

human case reports showing that low-dose vasopressin may be 

used to treat systemic hypotension with minimal consequences 

on pulmonary hemodynamics. How about combining those 

drugs with direct pulmonary vasodilator effect, such as inhaled 

nitric oxide or inhaled epoprostenol? 

Dr Klinger: We have tried that infrequently, but if patients are 

going to die of hemodynamic collapse due to sepsis while they 

have pulmonary hypertension, I would like to see them treated 

with pretty high doses of epoprostenol intravenously, along with 

dobutamine. Then, if they are still hypotensive, I would add 

other pressors such as Levophed or vasopressin. I think that is 

probably the best approach that we have right now. Years ago, 

I would try nitric oxide for some of these patients, 

but I do not think it has any more vasodilatory 

effects than epoprostenol, and it doesn’t have 

some of the inotropic effects that epoprostenol 

has. So, those would be my three drugs of choice 

to have on even if the patient does not survive. 

Dr Pearl: I do not think there is any advantage to 

using inhaled prostacyclin when you have someone 

with cardiogenic shock or other kinds of compromise. 

The area where we have seen advantages 

possibly with the drug’s performance is when we 

are trying to avoid hypotension. I don’t think it is 

going to contribute in sepsis. Just to clarify, when 

the patient is acutely hypotensive it is a pretty difficult 

setting to start intravenous epoprostenol. I 

would think about using an inhaled pulmonary 

vasodilator transiently. They usually don’t work in 

that setting more than anything else in terms of 

giving acute pulmonary vasodilation. I think in a 

hypotensive patient it is hard to initially and 

quickly get to high doses of prostacyclin. Once you get other 

pressors and inotropic agents on, it may be much easier. 

Dr Sulica: And how would you look at the response of therapy? 

Would you place a pulmonary artery catheter in that situation? 

Dr Pearl: I think you probably have to. If you can’t, then you 

would be looking at as much epoprostenol as you can start without 

the patient becoming hypotensive. It depends on the situation. 

If you start epoprostenol therapy, and as you go up, the 

blood pressure starts to drop, then you have defined the maximum 

dose the patient can tolerate. 

Dr Sulica: Perioperatively, how would you manage a patient, 

let’s say, after having surgery for valvular heart disease, who still 

has elevated pulmonary vascular resistance? 

Dr Pearl: I think in the intraoperative and perioperative setting, 

a lot of treatment has to be based on defining what goals you 

are trying to achieve. Many patients have pulmonary hypertension 

after cardiac surgery but do not have problems from the 

pulmonary hypertension. You have to figure out if the problem 

is they are hypotensive because of low cardiac output or if there 

34 Advances in Pulmonary Hypertension 

The preoperative testing 

concern is that the 

pulmonary vasodilation 

allows the right heart to 

overload the left heart 

because the patient is 

already in a volume overloaded 

state. In essence, 

the pulmonary hypertension 

is a protective mechanism. 

Our experience 

has been that there is less 

concern in the outpatient 

setting for the heart 

failure patient than in 

past years because these 

patients are so much 

better managed clinically 

now than they used to be. 

is some gas exchange problem going on. Where people run into 

problems is when they treat the pulmonary artery pressures 

themselves as the problem. If the issue is one of low cardiac 

output without systemic hypotension, one can often treat that 

the same way we would commonly treat low cardiac output, 

using inotropes and vasodilators and optimizing the degree of 

volume. When we have pulmonary hypertension itself that is 

clearly resulting in hypotension, then choices become fairly limited. 

In the postcardiac surgery setting, inhaled nitric oxide has 

sometimes been useful where we will decrease pulmonary vascular 

resistance with the inhaled nitric oxide and then use additional 

agents to support both the right and the left ventricle. 

Sometimes the severe pulmonary hypertension is associated 

with left-sided problems, and you may have to go to an intraaortic 

balloon pump, left ventricular assist device, or sometimes a 

right ventricular assist device. It is hard to make 

broad generalizations on how to treat the perioperative 

pulmonary hypertension. The point I 

would emphasize is that often people get into 

trouble trying to treat it, when in fact it doesn’t 

need to be treated. We need to be sure that we 

identify what we are trying to improve. 

Dr Sulica: How about preoperatively, for example, 

in patients with valvular disease or patients 

evaluated for heart transplantation? Do you have 

a cut-off of the preoperative pulmonary vascular 

resistance to proceed with surgery? Do you test 

for so-called reversibility? 

Dr Pearl: If you are now talking about cardiac 

surgery, there are two very different settings, the 

patient who is having definitive repair of mitral 

valve disease or coronary disease, versus the 

patient who is having a heart transplant. In 

patients who are having corrective cardiac surgery, 

I think we are relatively liberal in allowing pulmonary 

hypertension when they have a compensated right ventricle. We 

are doing something that will eventually improve the outcome. 

We may have to temporarily support the right and left ventricle 

with pharmacologic and mechanical means, but normally when 

the cardiac problem is repaired, over time we will see things 

improve. Those are the patients in whom we may postoperatively 

use inhaled nitric oxide and transition to a phosphodiesterase-5 

inhibitor such as sildenafil. In contrast are the 

patients who are having heart transplants where there is a high 

resistance pulmonary circulation, and we are putting in a donor 

heart that has no right ventricular compensatory mechanisms, 

and so for those patients, yes, we do consider pulmonary hypertension 

to be a contraindication to the surgery. In terms of the 

exact numbers, I think it is a combination of the pulmonary 

artery pressure, the gradient between mean pulmonary artery 

pressure and wedge pressure, the pulmonary vascular resistance, 

and the reversibility with pulmonary vasodilator therapy. I 

hesitate to give exact numbers because it is often the combination 

of them that we decide on, rather than using one specific 

number. 

Dr Sulica: In terms of testing the vasoreactivity and reversibili-

ty, what agents are you using? In the catheterization lab when 

you test for vasoreactivity, if we have a patient with high wedge 

pressure we are reluctant to use inhaled nitric oxide or 

epoprostenol, being mindful of pulmonary edema. 

Dr Klinger: We are always concerned. We actually had two 

patients whose cases we published years ago who developed 

acute pulmonary edema in a response to inhaled nitric oxide. 

They had wedge pressures that were pretty normal. They both 

had scleroderma, and we think they just had stiff ventricles and 

couldn’t handle it. On the other hand, we have a plethora of 

patients with long-standing congestive heart failure and diastolic 

dysfunction who we are called to see because they have 

pulmonary hypertension that appears to be out of proportion to 

their wedge pressure. In some cases, I have actually done 

vasodilator trials and have seen improved pulmonary pressure 

without an increase in the wedge pressure. What we generally 

try to do is to get as much diuresis as possible and get the 

wedge as low as possible. Then after that we will try to add a 

pulmonary vasodilator. In that situation, I think nitric oxide is 

really the best because, if we do see a rise in wedge pressure, 

we can turn it off pretty quickly and resolve the problem. 

Dr Sulica: Although there are reports of pulmonary edema in 

patients with underlying left heart dysfunction, even with 

inhaled nitric oxide, it has a much shorter action, so you hope 

it is going to reverse faster. 

Dr Klinger: I think it is a very interesting area of pulmonary 

hypertension that we don’t have a lot of data on. There are some 

people with elevated wedge pressure in whom we are hesitant 

to do vasodilator trials, yet other patients seem to tolerate it 

fairly well, and I don’t currently have a good way to differentiate 

what is going to happen. 

Dr Torres: At the same time, should we be doing a vasodilator 

challenge in a patient with a high wedge, or should we measure 

a left ventricular end diastolic pressure to confirm that this was 

an accurate wedge? 

Dr Sulica: Absolutely! It might sometimes be impossible to 

determine an accurate wedge in patients with pulmonary hypertension, 

at least severe pulmonary hypertension. Ron, are these 

issues still valid for the patient we were just discussing with 

high pulmonary vascular resistance? Presuming that there is a 

left heart failure so the wedge is high, are you concerned about 

putting the patient in pulmonary edema with the vasodilator 

challenge? 

Dr Pearl: The preoperative testing concern is that the pulmonary 

vasodilation allows the right heart to overload the left 

heart because the patient is already in a volume overloaded 

state. In essence, the pulmonary hypertension is a protective 

mechanism. Our experience has been that there is less concern 

in the outpatient setting for the heart failure patient than in 

past years because these patients are so much better managed 

clinically now than they used to be. They have less volume overload 

and we don’t precipitate a lot of pulmonary edema with the 

challenge. In the acute intraoperative and postoperative setting 

we are normally very actively titrating volume, and although it 

is conceivable that the nitric oxide would produce the same 

effect of producing pulmonary edema, I think it is less likely to 

occur because we are often very focused on maintaining the 

appropriate volume status. 

Dr Sulica: Great. Thank you Ron, Jim, and Fernando. I really 

appreciate your time. 


The Pulmonary Hypertension Association 

announces the 

2006 Postdoctoral Fellowship Awards 

Application Process 

$30,000 stipend support per year for two years/ 

$4,000 project support per year for two years/ 

$2,000 to attend PHA’s biennial conference in June 2008 

Application Deadline: January 20th, 2006 

Award Activation: July 2006 

Suggested investigational topics include, 

but are not limited to: 

• Genetics 

• Molecular biology of pulmonary vascular endothelium 

• Development of new pharmacologic agents to treat PH 

• Development of innovative techniques for early diagnosis 

• Pathophysiology of right heart failure 

• Epidemiology of risk factors for developing PH 

Congratulations to the 

2005 grant winners: 

George El Ferzli, MD 


Cristhiaan Ochoa, MD 

Massachusetts General Hospital 

University of Massachusetts 

For more information visit 

www.phassociation.org/support/fellowships.asp 

Advances in 



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To order additional copies, call or contact PHA at 1-866-474-4742 or www.phassociation.org.

Pulmonary Hypertension in the Critical Care Setting, Winter 2005

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