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Pediatric Pulmonary
Hypertension: Diagnosis And
Management In The Acute
Care Setting
A 10-year-old girl is brought to the pediatric emergency department after collapsing at school during her physical education class. She is well known to the
emergency physicians, having been treated in the ED on multiple occasions over
the past year for asthma exacerbations. Most recently, she was admitted for
inpatient treatment and was discharged after 24 hours with nebulized
bronchodilators.
As the paramedics transfer her to the ED staff, the patient’s mother reports
that her daughter has experienced increasing shortness of breath with exercise
over the past few days - even with walking up stairs at home - and, in general,
has appeared to be fatigued. The patient has been using her prescribed inhaler
frequently, without clear relief. The mother also mentions that on the evening
prior to this event, her daughter complained of abdominal pain.
P
ediatric pulmonary hypertension is a relatively rare, often
rapidly progressive disease with varied etiologies that is associated with significant morbidity and mortality. In fact, until
recently, virtually all patients with this condition died within a
few years of diagnosis.1-3 Fortunately, fundamental advances in
vascular biology over the last several decades have translated
into a vast expansion of our understanding about pulmonary
hypertension, and an increasing number of promising therapies
have emerged to treat this condition.2,4-6
Even today, however, the care of these patients remains highly
specialized, often requiring referral to regional tertiary academic
AAP Sponsor
Martin I. Herman, MD, FAAP,
FACEP
Professor of Pediatrics, UT
College of Medicine, Assistant
Director of Emergency
Services, Lebonheur Children’s
Medical Center, Memphis, TN
Editorial Board
Jeffrey R. Avner, MD, FAAP
Professor of Clinical Pediatrics,
Co-Director of Medical Student
Education in Pediatrics, Albert
Einstein College of Medicine;
Chief, Pediatric Emergency
Medicine, Children’s Hospital
at Montefiore, Bronx, NY
T. Kent Denmark, MD, FAAP,
FACEP
Residency Director, Pediatric
Emergency Medicine; Assistant
Professor of Emergency
Medicine and Pediatrics, Loma
Linda University Medical
Center and Children’s Hospital,
Loma Linda, CA
Michael J. Gerardi, MD, FAAP,
FACEP
Clinical Assistant Professor,
Medicine, University of
Medicine and Dentistry of New
Jersey; Director, Pediatric
Emergency Medicine,
Children’s Medical Center,
Atlantic Health System;
Department of Emergency
Medicine, Morristown Memorial
Hospital, Morristown, NJ
Ran D. Goldman, MD
Associate Professor,
Department of Pediatrics,
University of Toronto; Division
of Pediatric Emergency
Medicine and Clinical
Pharmacology and Toxicology,
The Hospital for Sick Children,
Toronto, ON
Mark A. Hostetler, MD, MPH
Associate Professor,
Department of Pediatrics;
Chief, Section of Emergency
Medicine; Medical Director,
Pediatric Emergency
Department, The University of
Chicago, Pritzker School of
Medicine, Chicago, IL
Alson S. Inaba, MD, FAAP,
PALS-NF
Pediatric Emergency Medicine
Attending Physician, Kapiolani
Medical Center for Women &
Children; Associate Professor
of Pediatrics, University of
Hawaii John A. Burns School
of Medicine, Honolulu, HI;
Pediatric Advanced Life
Support National Faculty
Representative, American
Heart Association, Hawaii &
Pacific Island Region
Andy Jagoda, MD, FACEP
Vice-Chair of Academic Affairs,
Department of Emergency
Medicine; Residency Program
Director; Director, International
Studies Program, Mount Sinai
School of Medicine, New York,
NY
Tommy Y. Kim, MD, FAAP
Attending Physician, Pediatric
Emergency Department;
Assistant Professor of
January 2008
Volume 5, Number 1
Authors
Peter E. Oishi, MD
Assistant Professor of Pediatrics, Division of Critical
Care Medicine, University of California San Francisco,
San Francisco, CA
Jeffrey R. Fineman, MD
Professor of Pediatrics, Division of Critical Care
Medicine, Investigator, Cardiovascular Research
Institute, University of California San Francisco, San
Francisco, CA
Peer Reviewers
Dolores Hoey, MD
Attending Physician, Emergency Medicine Department,
Our Lady of Lourdes Medical Center, Camden, NJ
Ghazala Q. Sharieff, MD, FAAP, FACEP, FAAEM
Associate Clinical Professor, Children’s Hospital and
Health Center/University of California, San Diego;
Director of Pediatric Emergency Medicine, California
Emergency Physicians, San Diego, CA
CME Objectives
Upon completing this article, you should be able to:
1. Describe pediatric patients at risk for developing
pulmonary hypertension.
2. Describe the pathophysiology of pulmonary
hypertension and a pulmonary hypertensive crisis.
3. Identify the symptoms and physical signs that are
associated with pulmonary hypertension.
4. Identify the diagnostic and laboratory tests that
assist in the diagnosis of pulmonary hypertension.
5. Describe the acute management of pulmonary
hypertension, specifically therapies to acutely
decrease pulmonary arterial pressure and therapies
that support right ventricular function.
Date of original release: January 1, 2008
Date of most recent review: December 1, 2007
Termination date: January 1, 2011
Time to complete activity: 4 hours
Medium: Print & online
Method of participation: Print or online answer form
and evaluation
Prior to beginning this activity, see “Physician CME
Information” on back page.
Emergency Medicine and
Pediatrics, Loma Linda Medical
Center and Children’s Hospital,
Loma Linda, CA
Brent R. King, MD, FACEP,
FAAP, FAAEM
Professor of Emergency
Medicine and Pediatrics;
Chairman, Department of
Emergency Medicine, The
University of Texas Houston
Medical School, Houston, TX
Robert Luten, MD
Professor, Pediatrics and
Emergency Medicine,
University of Florida,
Jacksonville, FL
Ghazala Q. Sharieff, MD, FAAP,
FACEP, FAAEM
Associate Clinical Professor,
Children’s Hospital and Health
Center/University of California,
San Diego; Director of
Pediatric Emergency Medicine,
California Emergency
Physicians, San Diego, CA
Gary R. Strange, MD, MA,
FACEP
Professor and Head,
Department of Emergency
Medicine, University of Illinois,
Chicago, IL
Adam Vella, MD, FAAP
Assistant Professor of
Emergency Medicine, Pediatric
EM Fellowship Director, Mount
Sinai School of Medicine, New
York
Michael Witt, MD, MPH, FAAP
Attending Physician, Division of
Emergency Medicine,
Children’s Hospital Boston;
Instructor of Pediatrics,
Harvard Medical School,
Boston, MA
Research Editor
Christopher Strother, MD
Fellow, Pediatric Emergency
Medicine, Mt. Sinai School of
Medicine; Chair, AAP Section
on Residents, New York, NY
Accreditation: This activity has been planned and implemented in accordance with the Essentials and Standards of the Accreditation Council for Continuing Medical Education
(ACCME) through the joint sponsorship of Mount Sinai School of Medicine and Pediatric Emergency Medicine Practice. The Mount Sinai School of Medicine is accredited by the
ACCME to provide continuing medical education for physicians. Faculty Disclosure: Dr. Oishi, Dr. Fineman, Dr. Hoey, and Dr. Sharieff report no significant financial interest or
other relationship with the manufacturer(s) of any commercial product(s) discussed in this educational presentation. Commercial Support: Pediatric Emergency Medicine does not
accept any commercial support.
centers with dedicated pediatric pulmonary hypertension programs. Such concentrated expertise carries many advantages but also bespeaks an inadequate permeation of knowledge about pulmonary
hypertension amongst the larger healthcare community. Referrals to such centers are possible only after
the diagnosis has been considered, placing the onus
on local providers to correctly identify patients in
need of further evaluation and care. In addition,
therapies for pulmonary hypertension are generally
chronic and are often associated with morbidities
that are likely to manifest when patients are at
home. Furthermore, the initial presentation of pulmonary hypertension in infancy or childhood often
mimics other more common, less dangerous diseases, and correctly identifying these patients
requires a high index of suspicion.
Emergency medicine physicians and acute care
providers face a daunting challenge when
knowingly or unknowingly faced with these
patients. Failing to recognize the initial presentation
of pulmonary hypertension can result in a lifethreatening delay in the initiation of specific therapies. Furthermore, an inadequate understanding of
the basic pathophysiology associated with
pulmonary hypertension - and acute pulmonary
hypertensive crises in particular - will retard the
institution of appropriately directed therapies, even
in patients already diagnosed with this condition,
with potentially devastating consequences.
Because the potential consequences can be so
devastating, this issue of Pediatric Emergency Medicine Practice will provide a comprehensive overview
of pediatric pulmonary hypertension, with particular attention to diagnosis and acute management.
An understanding of the pathophysiology of pulmonary hypertension is fundamental to the ability
to recognize and treat these patients and will be
reviewed in great detail.
V/Q: Ventilation-Perfusion
Critical Appraisal of the Literature
A literature review was conducted using the MEDLINE and PubMed databases. The terms hypertension and pulmonary were used. The search was limited to studies conducted between 1980 and 2007
that concerned human subjects, were written in the
English language, and had an available abstract.
The Cochrane Database of Systematic Reviews was
searched for reviews pertinent to pulmonary hypertension. The recent evidence-based clinical practice
guidelines for the diagnosis and management of
pulmonary arterial hypertension from the American
College of Chest Physicians were reviewed as well.
The search was then further limited to studies concerning subjects from birth to 18 years of age. Older
studies and pertinent basic science as well as
animal-based studies referenced in the above studies were also reviewed.
The review of the literature indicated a recent
surge in available therapies for pulmonary hypertension. The evidence for these newer therapies
often includes randomized placebo-controlled trials.
However, many of the recommendations contained
within the literature, particularly for the proper
diagnostic approach, are based upon uncontrolled
studies or expert opinion. Additionally, far fewer
data are available for pediatric patients as compared
to the adult population.
Epidemiology, Etiology, And Pathophysiology
Definition, Classification, Etiology And
Epidemiology
Pulmonary hypertension is defined as a mean pulmonary artery pressure of greater than 25 mmHg at
rest or greater than 30 mmHg during exercise.7
Echocardiography, rather than right heart catheterization, is increasingly used to estimate pulmonary
artery pressures. Clinicians often employ a practical
definition for pulmonary hypertension of a systolic
pulmonary artery pressure that exceeds 50% of the
systolic systemic arterial pressure, although the formal definition is used for most clinical studies.8
In 2003, the Third World Symposium on
Pulmonary Arterial Hypertension was convened by
the World Health Organization, and a new classification system was created (Table 1).9 This system
divided pulmonary hypertension into pulmonary
arterial hypertension, pulmonary venous hypertension, pulmonary hypertension associated with
hypoxemia or disordered respiratory function, pulmonary hypertension associated with thrombotic or
embolic disease, and pulmonary hypertension secondary to miscellaneous diseases. This system
Abbreviations Used In This Article
BMPR2: Bone Morphogenetic Protein Receptor II
ECLS: Extracorporeal Life Support
EPCs: Endothelial Progenitor Cells
FPAH: Familial Pulmonary Arterial Hypertension
IPAH: Idiopathic Pulmonary Arterial Hypertension
NO: Nitric Oxide
NOS: Nitric Oxide Synthase
PCPA: Partial Cavopulmonary Anastomosis
PDEs: Phosphodiesterases
PPHN: Persistent Pulmonary Hypertension of the
Newborn
PHTN: Pulmonary Hypertension
RAP: Right Atrial Pressure
RVSP: Right Ventricular Systolic Pressure
sPAP: Systolic Pulmonary Arterial Pressure
TCPA: Total Cavopulmonary Anastomosis
Pediatric Emergency Medicine Practice©
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January 2008 • EBMedicine.net
discarded the term “primary pulmonary hypertension” in favor of “sporadic or idiopathic pulmonary
arterial hypertension” (IPAH) since it is a diagnosis
of exclusion.
In neonates, the most common etiology results
from a failure to undergo the normal fall in
pulmonary vascular resistance at birth (persistent
pulmonary hypertension of the newborn, PPHN),
with an incidence of < 1 per 1000 live births. Other
pulmonary abnormalities, such as congenital diaphragmatic hernia, respiratory distress syndrome,
and bronchopulmonary dysplasia, may also result
in neonatal pulmonary hypertension.
Beyond the neonatal period, the majority of
pediatric pulmonary hypertension is due to congenital heart defects or IPAH. Congenital heart disease
occurs in approximately 1% of live births.10 Without
surgical palliation or repair, one-third of these
patients die from pulmonary hypertension.11 In this
population, risk factors for developing pulmonary
hypertension include systemic to pulmonary (leftto-right) shunts, transposition of the great arteries,
and pulmonary venous hypertension.8,12-14
The true incidence of IPAH is unknown, but
experts believe that it has been under-diagnosed in
years past.15-17 At present, the best available estimates suggest an incidence of 1-2 cases per million
people.18 The disease is more common in adult
women, with a reported ratio of 1.7:1, which
appears to be similar to the pediatric population.7,17
Currently, the prognosis for patients with IPAH
is unknown, since long-term outcomes for patients
receiving newer therapies are not yet available. If
untreated, however, the prognosis is dismal, with
reported one-, three-, and five-year survival rates in
adult patients with IPAH ranging from 68% to 77%,
40% to 56%, and 22% to 38%, respectively.19-21
Although less data are available regarding the prognosis of children with untreated IPAH, the available
evidence indicates similar poor outcomes.2
Other, less common causes of pediatric pulmonary vascular disease include hypoxia-induced pulmonary vascular disease, rheumatologic disorders,
sickle cell disease, portal hypertension, chronic
thromboembolic disease, HIV disease, and drugtoxin induced disease.
Table 1. Clinical Classification of Pulmonary
Hypertension
Pulmonary Arterial Hypertension (PAH)
Idiopathic (IPAH)
Familial (FPAH)
Related to risk factors or associated conditions (APAH)
Collagen vascular disease
Congenital systemic-to-pulmonary shunts
Portal hypertension
HIV infection
Drugs and toxins
Other: thyroid disorders, glycogen storage disease,
Gaucher disease, hereditary hemorrhagic
telangiectasia, hemoglobinopathies,
myeloproliferative disorders, splenectomy
Associated with venous or capillary involvement
Pulmonary veno-occlusive disease
Pulmonary capillary hemangiomatosis
Persistent Pulmonary Hypertension of the Newborn
Pathophysiology
Pulmonary vascular resistance changes throughout
gestation and after birth. Shortly after birth, the
pulmonary vasculature of healthy individuals is
actively maintained in a relaxed state and provides
minimal resistance as blood flows through the pulmonary circulation. A complex interplay between
vasoactive substances produced by pulmonary vascular endothelial cells and the surrounding smooth
muscle cells regulates this process. Thus, aberrant
pulmonary vascular endothelial and/or smooth
muscle cell function can result in the loss of vascular
relaxation and may ultimately allow resistance and
pressure to rise to pathologic levels. Unchecked,
this process results in progressive hypoxemia, right
ventricular failure, diminished cardiac output, and
ultimately death. An appreciation of the basic
molecular mechanisms that regulate vascular tone
in health and disease will facilitate an understanding of the various available therapies for patients
presenting acutely with pulmonary hypertension.
The reader is referred to the addendum on page 15
for a more complete discussion.
Pulmonary Hypertension With Left Heart Disease
Left-sided atrial or ventricular heart disease
Left-sided valvular heart disease
Pulmonary Hypertension Associated With Lung Disease
And/Or Hypoxemia
Chronic obstructive pulmonary disease
Interstitial lung disease
Sleep-disordered breathing
Alveolar hypoventilation disorders
Chronic exposure to high altitude
Developmental abnormalities
Pulmonary Hypertension Due To Chronic Thrombotic And/Or
Embolic Disease
Proximal pulmonary arteries
Distal pulmonary arteries
Non-thrombotic embolism (tumor, parasites, foreign material)
Miscellaneous
Sarcoidosis, histiocytosis X, lymphangiomatosis, compression
of pulmonary vessels
Adapted from Simonneau G, Galie N, Rubin LJ, Langleben D,
Seeger W, Domenighetti G, Gibbs S, Lebrec D, Speich R,
Beghetti M, Rich S, and Fishman A. Clinical classification of
pulmonary hypertension. J Am Coll Cardiol. 43:5S-12S,2004.
Reprinted with permission.
EBMedicine.net • January 2008
Pulmonary Hypertensive Crisis
Most commonly observed in susceptible patients
after cardiac surgery, pulmonary hypertensive crises
3
Pediatric Emergency Medicine Practice©
are life-threatening events that involve acute elevations in pulmonary vascular resistance and pressure,
with subsequent hypoxemia, acidosis, and right
heart failure. Increasing hypoxia and acidosis compounds the pulmonary vascular constriction, resulting in a vicious cycle. Without treatment, these
crises result in rapid cardiovascular collapse and
death.79-83
The pathophysiology of such a crisis is outlined
in Figure 1. Following an acute increase in pulmonary arterial pressure, there is an acute increase in
right ventricular afterload that leads to right ventricular ischemia and, ultimately, failure.84,85 The
resulting increase in right ventricular end diastolic
volume shifts the intraventricular septum to the left,
decreasing left ventricular volume and cardiac output. Decreased cardiac output results in decreased
systemic perfusion and metabolic acidosis.
Increased pulmonary vascular resistance and right
ventricular failure also decrease pulmonary blood
flow, increasing dead space ventilation. Distention
of the pulmonary arteries and perivascular edema
produce large and small airway obstruction, respectively, which impairs ventilation-perfusion matching
and decreases lung compliance. In fact, the decrease
in lung compliance can be so dramatic that chest
wall movement is impaired, even with manual
ventilation. The ensuing hypoxemia, hypercapnia,
and acidosis (metabolic and/or respiratory) further
increase pulmonary vascular resistance and perpetuate this cascade.
Differential Diagnosis
Patients diagnosed with new onset pulmonary
hypertension require expeditious evaluation in
order to address potential etiologies and treatment
plans. The differential diagnosis for pulmonary
hypertension follows the recent classification
scheme shown in Table 1 on page 3.
The primary challenge for the emergency physician comes in identifying the patient with pulmonary hypertension rather than the disease causing it.
To this end, physicians must keep pulmonary
hypertension in the differential diagnosis for pediatric patients presenting with the nonspecific findings of dyspnea, fatigue, abdominal pain, abdominal fullness, weakness, palpitations, lower extremity
swelling, dizziness, syncope, or angina. An awareness of the various diseases that are associated with
the development of pulmonary hypertension may
help consolidate seemingly unrelated symptoms
into a diagnosis.
Figure 1. A Schematic Of A Pulmonary
Hypertensive Crisis
Prehospital Care
Prehospital management of acutely symptomatic
pulmonary hypertension mandates recognition of
the process and the immediate initiation of aggressive therapies. (See “Treatment” on page 8.)
Patients will likely require a period of inpatient
management, and arrangements for transport to a
facility with pediatric intensive care services should
be made promptly. The transport should be
conducted by a pediatric team with advanced life
support training.
ED Evaluation
An acute increase in pulmonary arterial pressure (PAP) results in a
decrease in pulmonary blood flow (PBF) and airway obstruction due
to distention of the pulmonary arteries proximal to the maximally
constricted resistance arterioles and perivascular edema. This
results in an increase in dead space ventilation and ventilation-perfusion (V/Q) mismatch, both of which contribute to respiratory acidosis. In addition, right ventricular end-diastolic pressure (RVEDP) and
volume (RVEDV) increase, which can result in failure of the right
ventricle (RV) and movement of the intraventricular septum leftward,
with compromise of left ventricular filling (decreased left ventricular
end-diastolic volume [LVEDV]). This can impair cardiac output,
resulting in metabolic acidosis. The resultant hypoxia (via hypoxic
pulmonary vasoconstriction) and respiratory and metabolic acidosis
can further increase PAP, causing a downward cycle. Reprinted
with kind permission of Springer Science and Business Media from
Peter Oishi and Jeffrey Fineman, Diseases of the Pulmonary Vascular System. In: Wheeler, DS, Wang HR, Shanley TP eds. Pediatric
Critical Care Medicine, Basic Science & Clinical Evidence, New York:
Springer; 2007:570-590.
Pediatric Emergency Medicine Practice©
Important Historical Questions
The initial historical questions should focus on
understanding the nature of the presenting symptoms. In general, symptoms related to pulmonary
hypertension are attributable to impaired oxygen
delivery and cardiac output (Table 2). Dyspnea is
the most common presenting symptom; since virtually every patient with pulmonary hypertension
eventually develops dyspnea, knowing the onset,
duration, trigger, and number of prior episodes is
important.7 Other common early symptoms that
should be investigated include fatigue, weakness,
and exercise intolerance.
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January 2008 • EBMedicine.net
Angina and chest pain, which are relatively
common complaints seen in emergency departments, were reported in 40% of patients with pulmonary hypertension.7 More advanced stages of
pulmonary hypertension are associated with
anorexia, leg swelling, abdominal fullness, pain, and
distension.86 Dyspnea at rest and syncope are particularly ominous signs.86
The age at onset of pulmonary hypertension is
quite variable, and symptoms will differ depending
on the age of the patient. In infants, failure to
thrive, lethargy, diaphoresis (especially with feeding), and irritability may be prominent. Toddlers or
children who have an atrial communication that
allows a right-to-left shunt may manifest cyanosis,
particularly with exercise. Hypoxia may result in
hypoxic seizures or seizure-like activity at any age.
As seen in Table 1 on page 3, a host of diseases
are now known to be potential causes of pulmonary
hypertension. Therefore, the medical history should
be evaluated for symptoms that may be related to
congenital heart disease, collagen vascular disease,
liver disease, HIV disease, thyroid disorders, hemoglobinopathies, and thrombotic disease. Specific
questions might inquire about arthralgias, swollen
extremities or joints, Raynaud’s phenomenon, and
frequent illnesses. In addition, inquire about a history of snoring or obstructive sleep apnea.
Obtain a birth and neonatal history. A history of
left-to-right cardiac shunts, bronchopulmonary dysplasia, or congenital diaphragmatic hernia is particularly relevant. Ask patients and their families
about frequent respiratory infections or problems
related to bleeding or clotting. A travel history with
attention to high-altitude locations should also be
elicited.
Exposures to medications or potential toxins
should also be included in the history. Appetite
suppressants have received significant attention as a
cause of pulmonary hypertension, but other toxins
(such as chemotherapeutic agents and rapeseed oil)
have also been linked to pulmonary vascular
disease.86,87
Finally, a careful family history is essential, especially probing for early unexplained deaths. Recent
discoveries indicate that mutations in the BMPR2
gene occur in up to 50% of patients with familial
pulmonary arterial hypertension (FPAH) and in as
many as 25% of patients thought to have
IPAH.71,72,88 The onset of pulmonary hypertension
tends to occur earlier in life in each generation of
family members with FPAH; this is termed genetic
anticipation.89 In addition, inquire about a family
history of connective tissue diseases.86
Important Physical Findings
Signs of pulmonary hypertension can range from
mild to severe. No studies are available to quantify
the predictive value of any particular clinical sign in
the setting of pulmonary hypertension. However,
the pathophysiology of pulmonary hypertension is
associated with distinct clinical findings (Table 3).
Findings on cardiac auscultation may include an
accentuated pulmonary component of the second
heart sound, an early systolic ejection click, a midsystolic ejection murmur due to turbulence across
the pulmonary valve, a palpable parasternal heave
due to right ventricular hypertrophy, an S4 gallop,
and a prominent jugular “a” wave that is consistent
with elevated central venous pressures. One study
reported that an accentuated second heart sound
and an S4 gallop were present in over 90% and 38%
Table 3. Physical Findings Of Pulmonary
Hypertension
Table 2. Symptoms Of Pulmonary
Hypertension
Early Findings
Accentuated pulmonary component of the second heart sound
Early ejection click
Midsystolic ejection murmur
Parasternal heave
S4 gallop
Prominent jugular “a” wave
Early Symptoms
Dyspnea
Fatigue
Exercise intolerance
Late Symptoms
Cyanosis with exertion
Chest pain
Leg swelling
Abdominal fullness/pain
Anorexia
Seizures
Syncope
Dyspnea at rest
Late Findings
Diastolic pulmonary regurgitation murmur
Holosystolic tricuspid regurgitation murmur
Jugular venous distention
Prominent “V” wave
S3 ventricular gallop
Pulsatile hepatomegaly
Peripheral edema
Ascites
Symptoms In Infants
Failure to thrive
Lethargy
Diaphoresis
Irritability
EBMedicine.net • January 2008
Findings Related To Various Etiologies
Cyanosis
Rash
Obesity
5
Pediatric Emergency Medicine Practice©
of patients with pulmonary hypertension, respectively.7,86
In later stages of disease, physical findings may
include a diastolic pulmonary regurgitation murmur, a holosystolic tricuspid regurgitation murmur,
jugular venous distention with prominent “V”
waves which is indicative of tricuspid regurgitation,
and a hepatojugular reflex. The findings of an S3
ventricular gallop, pulsatile hepatomegaly, peripheral edema, and ascites suggest the beginning of
right ventricle failure.86
In addition, the physical examination should
include inspection for stigmata of diseases consistent with pulmonary hypertension. For example,
cyanosis may be seen with congenital cardiac
defects due to right-to-left shunting, skin findings
may suggest connective tissue disease, and obesity
may cause obstructive sleep apnea.
Most importantly, patients with pulmonary
hypertension who present in shock are at extreme
risk for imminent cardiopulmonary collapse. Tachycardia, tachypnea, altered mental status, peripheral
vasoconstriction, oliguria, and hypotension herald
imminent cardiovascular collapse and death.
Beyond routine resuscitation, these patients require
immediate and aggressive therapy aimed at acutely
decreasing pulmonary vascular resistance and supporting the failing right ventricle. (See “Treatment.”)
associated with pulmonary hypertension measured
by right heart catheterization; a radiographic index
is obtained by measuring the horizontal distances
from the midline to the first divisions of the right
and left pulmonary arteries and dividing the sum of
these distances by the maximum transverse diameter
of the thorax.90 While an index of > 0.38 was found
to be abnormal, there was no correlation with disease severity.90 Right ventricular enlargement, a less
common finding, may also be noted by chest
radiography.
Chest radiography may also indicate processes
that contribute to the symptoms of pulmonary
hypertension or its etiology, such as scoliosis leading to restrictive lung disease, pulmonary congestion (suggestive of pulmonary venous disease), or
effusions that may be a part of congenital heart disease or chronic thromboembolic disease. However,
it should be noted that the absence of abnormalities
on chest radiography does not exclude the diagnosis
of pulmonary hypertension.
ECG
The chief finding of interest on an ECG is evidence
of right ventricular hypertrophy (Figure 3). The
ECG findings associated with pulmonary hypertension are right axis deviation (noted in 79% of
patients in one study), an R/S ratio of > 1 in lead
V1, qR complex in V1, an rSR’ pattern in V1, a R/S
Diagnostic Studies
A summary of the diagnostic studies that should be
performed in the emergency department is shown
in Table 4.
Figure 2. Representative Chest Radiograph Of
A Child With Pulmonary Hypertension
Chest Radiography
The classic findings on chest radiography are enlargement of the main pulmonary arterial shadow
and attenuation of the peripheral pulmonary vascular markings, also termed “pruning” 7,86 (Figure 2).
A prospective study of 187 patients reported these
findings in the majority of patients with IPAH.7 An
older study defined a radiographic index that was
Table 4. Diagnostic Studies For Pulmonary
Hypotension
Initial Studies
Chest radiography
Electrocardiogram
Echocardiography
Later Studies
Ventilation-perfusion scan
CT scan
MRI
Sleep-study; nocturnal oximetry
Six-minute walk test
Pulmonary function test
Right-heart catheterization
Pediatric Emergency Medicine Practice©
This chest radiograph was taken of a 13-year-old with a six-month
history of exercise intolerance, presenting with a syncopal episode.
The significant findings include an enlarged right atrium, right ventricle, prominent main pulmonary artery, dilated central pulmonary
arteries, and “pruned” distal vessels.
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January 2008 • EBMedicine.net
ratio < 1 in leads V5 or V6, or an S1, S2, S3 pattern.86
A P wave greater than 2.5 mm in leads II, III, and
aVF with a frontal P-axis of greater than 75 degrees
indicates right atrial enlargement.86
Findings on ECG provide important objective
data as a part of the work-up for pulmonary
hypertension, but studies of patients with known
pulmonary hypertension have demonstrated that
ECG alone lacks adequate sensitivity and
specificity.91,92
equation is used to estimate the RVSP: RVSP= 4ν2 +
RAP, where ν is the velocity of the TR jet in meters
per second, and RAP is the right atrial pressure that
is ether standardized or estimated by echocardiography. Multiple studies have validated estimates of
sPAP determined by echocardiography using rightheart catheterization as confirmation.93-101 In the
absence of a measurable TR jet, parameters related
to right ventricular outflow patterns and time intervals might be assessed by Doppler echocardiography with demonstrated accuracy compared to rightheart catheterization.102-105
The use of Doppler echocardiography is well
studied. However, when used as a screen for a rare
disease (such as pulmonary hypertension), its sensitivity, specificity, positive predictive value, and negative predictive value will not be perfect. In fact, as
expected, studies indicate underestimates of sPAP in
patients with severe pulmonary hypertension and
overestimates in normal patients.106-108 However,
expert consensus supports the recommendation that
all patients suspected of having pulmonary hypertension undergo cardiac echocardiography in order
to estimate sPAP and to evaluate for anatomic
abnormalities, intracardiac shunting, and cardiac
function.86
Echocardiography
Although cardiac catheterization is the “gold standard” for the measurement of pulmonary arterial
pressure and vascular resistance, it is invasive and
not readily available in most situations. Thus,
echocardiography is the single best diagnostic tool
for the diagnosis of pulmonary hypertension in an
acute care setting.
The important data that may be obtained by
echocardiography include an estimate of systolic
pulmonary arterial pressure (sPAP), right and left
ventricular function, and cardiac anatomy, including
determinations of chamber sizes, valvular function,
and intracardiac shunts. In general, the sPAP is considered equivalent to the right ventricular systolic
pressure (RVSP), unless there is right ventricular
outflow tract obstruction or pulmonary valve stenosis. With the use of Doppler echocardiography,
RVSP is estimated by determining the velocity of
flow across the tricuspid valve during systole (tricuspid [TR] jet). A modification of the Bernoulli
Second Tier Evaluation
Once the diagnosis of pulmonary hypertension has
been made or is strongly suspected, a number of
further tests are warranted. These evaluations are
better suited to an inpatient setting, outside of the
emergency department. However, emergency
physicians may be called upon to organize these
tests and certainly would benefit their patients by
preparing them for the evaluation ahead.
Figure 3. Representative Electrocardiogram
Of A Child With Pulmonary Hypertension
Ventilation-Perfusion (V/Q) Scan
Thromboembolic disease may present with pulmonary hypertension and can be evaluated by V/Q
scan. Several studies found that V/Q scanning was
both highly sensitive and specific in differentiating
between idiopathic pulmonary hypertension and
thromboembolic disease.109-111 Recent expert opinion guidelines state that pulmonary angiography is
the study of choice for the definitive diagnosis of
thromboembolic disease in the setting of a positive
V/Q scan.86
An ECG from a 13-year-old child shows severe right atrial enlargement, right axis deviation, abnormal R wave progression with severe
right ventricular hypertrophy (the R-wave in V1 is off the scale), and
ventricular strain. Note the ST segment depression in V6 suggesting
impaired left ventricular output due to compression by the enlarged
right ventricle. At cardiac catheterization, the child had suprasystemic pulmonary artery pressures with a pulmonary vascular resistance index of 55 WU m2 and depressed cardiac output. In addition,
there are premature atrial ectopic beats. The paper speed is 25
mm/sec and the scale is 10 mV/mm.
EBMedicine.net • January 2008
CT Scan and MRI
Contrast-enhanced CT scan and/or MRI can help
identify causes of pulmonary hypertension. Thromboembolic disease may be visualized by both
modalities.112 In addition, both imaging techniques
can identify other pulmonary pathology, such as
masses or vasculitis.113 Findings on CT scan, such
as pulmonary artery size, may contribute to the
7
Pediatric Emergency Medicine Practice©
diagnosis of pulmonary hypertension, but a CT scan
does not replace Doppler echocardiography.114-117
MRI can better delineate the cardiac anatomy,
particularly chamber sizes and wall thickness, and
MRI measurements can detect pulmonary hypertension.118-120 However, like CT, it is not clear that MRI
offers any advantages for diagnosis when compared
to Doppler echocardiography.
assess oxygen delivery and cardiac output. In this
regard, an arterial blood gas provides considerable
data. For example, mild respiratory acidosis with
evidence of chronic metabolic alkalosis indicates
that the patient’s homeostatic mechanisms are compensating for the disease, whereas severe respiratory or metabolic acidosis heralds imminent cardiopulmonary collapse. Likewise, serum lactate levels
increase with inadequate oxygen delivery, and central venous oxyhemoglobin saturations decrease
with diminished cardiac output. Plasma B-type
natriuretic peptide levels, which increase with
myocardial stress, may also be helpful in distinguishing pulmonary hypertension from respiratory
illnesses and may give an indication of right ventricular stress.126-129
Pulmonary Function Testing And Oximetry
Studies have indicated abnormalities detected by
pulmonary function testing in patients with
pulmonary hypertension from multiple etiologies,
including thromboembolic disease and collagen vascular disease.121-123 Nocturnal oximetry and oximetry during exercise may also provide important
information, as sleep disordered breathing is a
known cause of pulmonary hypertension that may
be amenable to treatment.
Treatment
The basic management of patients presenting with
pulmonary hypertension follows standard
emergency medicine practice, including an assessment and stabilization of the airway, control of
breathing, and support of circulation. As outlined
in the preceding sections, it may be challenging –
yet could be lifesaving – to promptly recognize that
the patient’s presenting condition is secondary to
pulmonary hypertension. Attention to the history
and a thoughtful analysis of the physical findings
should aid in this determination.
The decision to intubate a patient must be made
on an individual basis. Patients presenting with
signs of shock secondary to pulmonary hypertension require intubation and mechanical ventilation.
Right Heart Catheterization
Cardiac catheterization remains the “gold standard”
for the diagnosis of pulmonary hypertension. In
addition to measuring pulmonary artery pressures
and vascular resistance, cardiac catheterization can
assess for intracardiac and extracardiac shunts; it
can also measure intracardiac pressures and cardiac
output. Furthermore, pulmonary vascular reactivity
testing is essential in selecting appropriate therapy.
Indeed, children who are responsive to acute vasodilator testing (evoked by short acting agents such
as inhaled nitric oxide (NO) or iloprost and intravenous epoprostenol or adenosine), which is
defined as a decrease in pulmonary artery pressure
of more than 20% without a decrease in cardiac output, have been shown to have a favorable response
to long-term therapy with calcium channel blockers.2,124 Conversely, calcium channel blockers may
be deleterious to patients who are not responsive to
vasodilator therapy, highlighting the value of this
information.125
Table 5. Laboratory Studies For Pulmonary
Hypertension
Initial Screening Studies
Complete blood count with smear
Electrolyte panel
Ionized calcium
BUN
Creatinine
Glucose
Laboratory Screening
Laboratory tests are aimed at refining the differential diagnosis (Table 1 on page 3). Tests that should
be considered in the emergency department are
shown in Table 5. A complete blood count with
smear, electrolyte panel, BUN, creatinine, coagulation studies, and a liver function panel provides a
good first screen. Other studies that might be indicated are an HIV test, thyroid function studies, collagen vascular studies (such as antinuclear antibodies, rheumatoid factor, erythrocyte sedimentation
rate, and C-reactive protein), urinalysis, and a toxicology screen for stimulants, especially
methamphetamine.
Laboratory data are also important in order to
Pediatric Emergency Medicine Practice©
Laboratory Studies Aimed At Identifying Etiology
Liver transaminases
Coagulation studies
HIV
Thyroid function tests
Antinuclear antibodies
Rheumatoid factor
Erythrocyte sedimentation rate
C-reactive protein
Urinalysis; toxicology screen
Laboratory Results Aimed At Assessing Severity Of
Acute Illness
Arterial blood gas
Mixed venous oxyhemoglobin saturation
Lactate
B-type natriuretic peptide
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January 2008 • EBMedicine.net
In this way, physicians may deliver maximal
inspired oxygen concentrations, control minute
ventilation in order to achieve respiratory alkalosis,
sedate without fear of respiratory depression,
administer muscle relaxants, and deliver inhaled
NO. Keep in mind, however, that the transition
from spontaneous to positive pressure breathing,
particularly when combined with agents to induce
anesthesia, is dangerous. Great attention to hemodynamics, the maintenance of adequate preload,
and preparations for resuscitation are mandatory.
In critically ill patients, central venous and
arterial access are indicated to secure the administration of all intravenous therapies, central venous
pressure monitoring, determinations of central
venous oxyhemoglobin saturation, continuous
hemodynamic monitoring, and arterial blood gas
management.
Regardless of the underlying etiology, the general treatment approach is similar and can be subdivided into four major goals: (1) prevent and acutely
treat active pulmonary vasoconstriction; (2) support
the failing right ventricle; (3) treat the underlying
etiology; and (4) chronically promote, if possible,
the regression of pulmonary vascular remodeling.
The first two goals will be the primary focus in the
emergency department setting. Depending on individual circumstances, treatment directed at the
underlying etiology may also be crucial. Emergency
physicians are first to diagnose some patients with
pulmonary hypertension. Thus, starting the process
of halting – or potentially reversing – the disease
process will often begin with them. Treatments are
summarized in Table 6.
and pleural effusions, and the maintenance of the
hematocrit below 55%.132,133 In addition, selective
pulmonary vasodilator therapies are essential for the
treatment of pulmonary hypertensive crises.134-146
The mainstay of acute pulmonary vasodilator
therapy remains supplemental oxygen and moderate alkalosis, as these therapies have minimal effects
on the systemic vasculature. Interestingly, the dosedependent response of the pulmonary vasculature
to these agents has not been well established. Studies in newborn lambs demonstrate dose-dependent
pulmonary vasodilation in response to increasing
pH from 7.30 to 7.60 and a dose-dependent response
to increasing inspired oxygen concentrations from
0.21 to 0.5 with minimal effects at higher concentrations.147 Several intravenous agents have
been utilized to promote pulmonary vasodilation;
these include tolazoline, sodium nitroprusside,
Table 6. Therapies For Pulmonary
Hypertension
Therapies Aimed At Acutely Decreasing Pulmonary Vascular
Constriction
• Oxygen (100% FiO2)
• Alkalinization
• Inhaled nitric oxide (5-80 ppm)
• Inhaled prostacyclin (iloprost, ~ 2.5-5 mcg/dose)
• Intravenous prostacyclin (epoprostenol, ~ 20-80
nanog/kg/min, IV infusion)
• Analgesics
• Sedatives
• Muscle relaxants
Therapies Aimed At Supporting The Right Heart And
Improving Cardiac Output
• Intravenous PDE type III inhibitors – milrinone (0.25-1
mcg/kg/min, IV infusion)
• Dopamine (3-10 mcg/kg/min, IV infusion)
• Dobutamine (5-15 mcg/kg/min, IV infusion)
• Creation of right-left shunt
Atrial septostomy
Extracardiac shunt (e.g., left pulmonary artery to
descending aorta)
• Extracorporeal life support
1. Prevent And Acutely Treat Active Pulmonary
Vasoconstriction
In the acute care setting, the treatment of active pulmonary vasoconstriction must be the primary focus
of care for the symptomatic patient. It is well
known that these patients have augmented pulmonary vasoconstriction in response to such stimuli as
hypoxia, acidosis, catecholamine-mediated α1adrenergic stimulation associated with pain and/or
agitation, and increases in intrathoracic pressure.83,130,131 In fact, acute increases in pulmonary
vascular resistance can lead to significant cardiopulmonary compromise (i.e., a pulmonary hypertensive
crises).
Once the working diagnosis has been made,
important basic therapies for the acute treatment of
pulmonary hypertension must be initiated. Therapies include supplemental oxygen, analgesics, sedatives, muscle relaxants (for patients requiring
mechanical ventilation), the maintenance of an alkalotic pH with the use of controlled ventilation and/
or buffer, aggressive evacuation of pneumothoraces
EBMedicine.net • January 2008
Chronic Therapies For Pulmonary Hypertension
• Endothelin receptor antagonists
Combined ETA and ETB: Bosentan
Selective ETA: Itaxsentan, Ambrisentan
• PDE type V inhibitors: sildenafil
• Prostacyclin analogues
Oral: Beraprost sodium
Subcutaneous: Treprostinil sodium
Novel Therapies In Development
• Cell-based therapy
• Gene therapy
• Antioxidants: superoxide dismutase
• Statins
• Rho kinase inhibitors
• Elastase inhibitors
• Platelet derived growth factor inhibitors
• Vasoactive intestinal peptide
• 5-HT transport inhibitors
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Pediatric Emergency Medicine Practice©
nitroglycerin, prostacyclin, prostaglandin E1,nifedipine, and alpha-adrenergic antagonists such as
phenoxybenzamine.148-155 The efficacy of these
agents is variable, at least in part due to their effects
on the systemic vasculature. Systemic afterload
reduction can be advantageous in the setting of left
ventricular dysfunction; however, significant reductions in pulmonary arterial pressure without unacceptable systemic hypotension are often not possible.156-158 In addition, intravenous vasodilators can
override intrinsic hypoxic pulmonary vasoconstriction, resulting in an increase in dead space ventilation that may not be tolerated in some patients.159-163
More recent treatment modalities, most notably
inhaled NO, deliver short-acting vasodilators
directly to the pulmonary vasculature via an inhalational route.134-146 When administered to the lung in
its natural gaseous form, NO diffuses through the
alveolar wall to reach small pulmonary arteries. It
then enters vascular smooth muscle cells, initiating
a cascade that results in pulmonary vasodilation via
increases in cGMP. After entering the blood vessel
lumen, NO is rapidly inactivated by hemoglobin
which confines its effects to the pulmonary vasculature. Because of these properties, inhaled NO has
several advantages over other vasodilators; these
include (1) selective pulmonary vasodilation due to
rapid inactivation by hemoglobin; (2) rapid onset
and elimination; and (3) an improvement in ventilation-perfusion matching due to the limitation of
delivery to well ventilated lung regions. Accordingly, inhaled NO (5-20 ppm) has become a mainstay of treatment for acute pulmonary hypertensive
disorders and the assessment of pulmonary vascular
reactivity. Although various noninvasive modalities
for delivering inhaled NO are under development,
the most common practice by far is delivery
through an endotracheal tube. Recent studies suggest that the combination of 100% oxygen and
inhaled NO (80 ppm) produces maximal pulmonary
vasodilation and should be used in combination in
emergency situations.164,165
Inhaled prostacyclin has similar pulmonary
selectivity, secondary to rapid inactivation by hemoglobin. Its vasodilating effects are due to increasing
cAMP concentrations. Currently, studies on the use
of inhaled prostacyclin for pediatric pulmonary
hypertension are sparse, and comparison studies
between inhaled NO and inhaled prostacyclin are
lacking.166-176
Inhibitors of phosphodiesterases (PDEs), a family of enzymes that hydrolyze the cyclic nucleotides
cAMP and cGMP, are a relatively new class of
agents that have potent vasodilating and inotropic
effects.177 Milrinone is a PDE 3 inhibitor that
increases cAMP concentrations. Animal and human
data demonstrate pulmonary vasodilation in
response to milrinone that can be in excess of its
Pediatric Emergency Medicine Practice©
systemic effects if the pulmonary vasculature is
constricted.178-181
Sildenafil, a PDE 5 inhibitor that increases cGMP
concentrations, also has potent pulmonary vasodilating effects.182 The oral formulation is currently
being investigated for chronic pulmonary hypertensive therapy, and recent short-term studies demonstrate beneficial effects in children with advanced
pulmonary vascular disease.5 The intravenous formulation is currently being investigated for acute
pediatric pulmonary hypertensive disorders.183,184
Increasing data implicate alterations in ET-1 in
the pathophysiology of pulmonary hypertension,
and suggest that ET receptor antagonism may be a
useful therapeutic strategy.53,60-62,185 In fact, bosentan, an oral combined ETA and ETB receptor antagonist, has demonstrated efficacy as a chronic therapy
for advanced pulmonary vascular disease.4,186
There have been no large studies on the use of ET
receptor antagonists for acute pulmonary hypertensive disorders to date. The use of selective ET
receptor antagonism is under investigation.
Patients with pulmonary arterial hypertension
have histological evidence of in situ pulmonary vascular thrombosis which can cause or contribute to
increased pulmonary arterial pressure and
resistance. Although several adult studies have
demonstrated efficacy for anticoagulation therapy,
pediatric studies are lacking.20,187 Warfarin is currently the treatment of choice in adult patients and
in large pediatric centers with significant experience
with pediatric pulmonary arterial hypertension.
Low molecular weight heparin is another alternative;188 aspirin does not have demonstrated efficacy.
2. Support The Failing Right Ventricle
A significant component of the pathophysiology of
both acute and chronic pulmonary hypertension is
the development of right ventricular dysfunction;
this often requires pharmacologic support. Maintenance of adequate preload is necessary to optimize
cardiac output in patients with pulmonary hypertension. Continuous central venous pressure monitoring may be helpful to guide volume therapy,
keeping in mind that patients with a poorly compliant right ventricle or increased right ventricular
afterload may require elevated central venous pressures to maintain an adequate cardiac output. Frequent clinical assessment of liver size can be helpful, particularly in infants.
Despite adequate preload, cardiac output may be
compromised secondary to elevated right ventricular
afterload and/or biventricular myocardial dysfunction, necessitating the use of inotropic agents.131,189
These agents increase stroke volume at a given preload and afterload by stimulating β1 adrenergic
receptors.190,191 However, some of these agents also
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January 2008 • EBMedicine.net
stimulate β2 or α1 adrenergic receptors, which are
found on the smooth muscle cells of both the
pulmonary and systemic arteries. Agents that stimulate β2 adrenergic receptors decrease both pulmonary and systemic vascular resistance and improve
right and left ventricular function.192,193 Agents that
stimulate α1 adrenergic receptors may increase both
systemic and pulmonary vascular resistance. Therefore, a rational approach to using inotropic agents in
the setting of pulmonary hypertension is to utilize
agents with beta selectivity and minimal α1 adrenergic stimulation, such as low dose dopamine (3-10
mcg/kg/min, continuous intravenous infusion) or
dobutamine (5-15 mcg/kg/min, continuous intravenous infusion). Although animal studies have
shown that high doses of dopamine increase pulmonary vascular resistance, human studies have shown
increased cardiac output with minimal effects on
pulmonary vascular resistance, making dopamine a
relatively safe choice.148,194 Milrinone (0.5-1
mcg/kg/min, continuous intravenous infusion) is
also a useful therapy for patients with pulmonary
hypertension and myocardial dysfunction, given its
vasodilatory and inotropic properties.195
In patients with refractory pulmonary hypertension, short-term extracorporeal life support (ECLS)
has been used successfully. However, its use should
be limited to support those patients in which the
underlying pulmonary vascular disease is deemed
reversible.
of prostacyclin (epoprostenol) has been the most
successful therapy to date.99,196-199 Several studies in
humans with advanced pulmonary vascular disease
demonstrated improved five-year survival and
improved exercise tolerance. Interestingly, even
those patients without an initial vasodilating
response to the infusion show significant long-term
benefit, suggesting that effects beyond vasodilation
(such as anti-platelet effects, cAMP-mediated inhibition of smooth muscle cell growth, or other
unknown mechanisms) may be responsible for the
treatment effect.2 Despite the impressive results,
several factors limit its utilization, including the
need for chronic intravascular access with the associated infectious and thrombotic risks and many
other untoward effects, including headache, flushing, and acute cardiopulmonary compromise with
disruption of the infusion.15
With the increasing appreciation for the role of
ET-1 in the pathophysiology of pulmonary vascular
disease, ET receptor antagonists have been developed as a potential treatment modality. To date,
bosentan, a combined ETA and ETB receptor antagonist, is the most widely studied agent, and it is
approved for the treatment of pulmonary hypertension.4,186 Recent studies in adults with primary pulmonary hypertension demonstrate similar improvements in survival and exercise tolerance as those
demonstrated with epoprostenol.200 The use of ET
receptor antagonists for pediatric pulmonary hypertensive disorders is currently under investigation.
Deficiencies in the NO-cGMP cascade in
pulmonary vascular disease are well documented.
In addition, the vasodilating effects, anti-platelet
effects, and anti-proliferative effects of augmenting
this cascade are well appreciated. Therefore, new
chronic therapies that augment NO-cGMP signaling,
which include chronic inhaled NO delivered by
nasal cannula and sildenafil, are currently under
investigation.15 In fact, the short-term benefit of
sildenafil in children with advanced pulmonary
hypertension has recently been reported.5
Data indicate that several of these new oral therapies, such as bosentan and sildenafil, may offer
additional benefit by virtue of their ability to inhibit
vascular smooth muscle growth and fibrosis.15 A
number of other treatment strategies, including
combination drug therapies, are currently under
investigation.
3. Treat The Underlying Etiology
Whenever possible, treatment of the underlying disorder must coincide with symptomatic treatment for
pulmonary hypertension if attenuation and/or
reversal of the disease are to be successful. For
example, in neonates, this may involve correction of
underlying metabolic disturbances, antibiotics for
infectious etiologies, and exchange transfusions for
polycythemia. For patients with congenital heart
disease, repair of the underlying defect after determining that the pulmonary vascular disease is
reversible (see below) is mandatory. For hypoxiainduced disease, tonsillectomy and adenoidectomy
may be required for sleep apnea, and a descent to
sea level may be needed for high-altitude-related
disease. Lastly, for rheumatologic disease, immunosuppression may be required.
4. Chronically Promote, If Possible, The
Regression Of Pulmonary Vascular Remodeling
Special Circumstances
The mainstay of chronic therapy has been aimed at
decreasing pulmonary vascular resistance, thereby
assisting right ventricular function and perhaps
attenuating the progression of vascular remodeling
by decreasing the pressure to which the vasculature
is exposed. In this regard, the continuous infusion
Acute Withdrawal Of Prostacyclin
EBMedicine.net • January 2008
The continuous infusion of prostacyclin (epoprostenol) has been the most successful therapy to
date for the chronic treatment of pulmonary hypertension.99,196-199 However, patients receiving this
11
Pediatric Emergency Medicine Practice©
therapy may suffer significant dyspnea with brief
interruptions of the infusion and, in fact, may die.201
In children, infusions are normally given
through a permanent indwelling central line by a
portable infusion pump. Any patient receiving continuous prostacyclin who presents to an urgent care
setting with symptoms that may be attributable to
pulmonary hypertension must have the entire system interrogated immediately. Indeed, making the
assumption that the infusion is not functioning
would be prudent. Possibilities for malfunction
include incorrect drug formulation, inoperative
pump, and central line malfunction. Resumption of
the infusion is the best therapy, but otherwise
aggressive therapies, as outlined previously, to
acutely decrease pulmonary vasoconstriction and
support the right ventricle are necessary.
ventricle in their recommendations for stepwise
management.202 These therapies include systemic
alkalinization, inhaled NO, type III phosphodiesterase inhibitors, and ECLS.
Congenital Heart Disease – Single Ventricle
Physiology
The most common treatment for neonates born with
single ventricular congenital heart disease is staged
surgical palliation, which is achieved through a
series of operations. The first stage is aimed at
ensuring adequate systemic blood flow and securing pulmonary blood flow through the creation of a
systemic to pulmonary shunt. The second and third
stage, which are partial cavopulmonary anastomosis
(PCPA) and total cavopulmonary anastomosis
(TCPA) respectively, transition to a circulation
wherein the single ventricle provides systemic blood
flow and passive venous return provides pulmonary blood flow. Importantly, the absence of a dedicated subpulmonary ventricle requires the single
ventricle to supply the total kinetic energy for pulmonary and systemic blood flow, making patients
extremely susceptible to elevations in pulmonary
vascular resistance. Even levels that do not meet
the definition of pulmonary hypertension may
greatly disrupt the circulation in these later stages.
For this reason, pulmonary vasoconstriction
must be considered as a potential problem when
patients with single ventricle congenital heart disease present to the emergency department. Even
with mild elevations in pulmonary vascular resistance, these patients may become hypoxic and cyanotic. Without treatment, their cardiac output may
decrease due to inadequate preload from impaired
pulmonary venous return. Treatment aimed at
Neonatal Sepsis
Newborns presenting to the emergency department
with septic shock are far more common than presentations of pulmonary hypertension. However, elevated pulmonary arterial pressures and vascular
resistance can complicate neonatal septic shock.
Normally, pulmonary vascular resistance and pressure decrease dramatically after birth, reaching
adult levels by six weeks of age. However, sepsis,
acidosis, and/or hypoxia can impair this transition,
maintaining high pulmonary arterial pressures and
vascular resistance, which can lead to right ventricular failure (Figure 1 on page 4).
In fact, recent clinical practice guidelines for
neonates with septic shock, put forth by a task force
of the American College of Critical Care Medicine,
include therapies aimed at altering pulmonary
vascular resistance and supporting the right
Key Points
• Pediatric pulmonary hypertension is a rare, often
rapidly progressive disease, with varied etiologies
and significant associated mortality.
hypertension.
• Symptoms of pulmonary hypertension are generally attributable to impaired cardiac output and
oxygen delivery.
• Failing to recognize the initial presentation of pulmonary hypertension can result in a life-threatening delay in the initiation of specific therapy.
• A pulmonary hypertensive crisis represents a
period of acutely increased pulmonary vascular
constriction that can result in right ventricular
failure and complete cardiopulmonary collapse.
• In neonates, the most common cause of
pulmonary hypertension results from a failure to
undergo the normal fall in pulmonary vascular
resistance at birth.
• Acute treatment of pulmonary hypertension combines routine emergency medicine practices with
specific therapies aimed at decreasing pulmonary
arterial pressure and supporting the right
ventricle.
• Beyond the neonatal period, the majority of pediatric pulmonary hypertension is due to congenital
heart disease or idiopathic pulmonary
Pediatric Emergency Medicine Practice©
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January 2008 • EBMedicine.net
Clinical Pathway For The Acute Management
Of Pediatric Pulmonary Hypertension
Pediatric patient presenting with symptoms suggestive
of, or consistent with, PHTN (Table 2 on page 5).
Evaluate and stabilize consistent with
Pediatric Advanced Life Support
(PALS) guidelines.
Known history
of PHTN?
YES
NO
Signs of PHTN
(Table 3 on
page 5)
Receiving PHTN
therapy?
Initiate initial diagnostic and laboratory studies (Table 4 and 5 on
pages 6 and 8): CXR, ECG (Class III) and echocardiography. (Class
II)
NO
Perform initial diagnostic and
laboratory studies (Table 4
and 5 on pages 6 and 8): CXR,
ECG (Class III) and
echocardiography (Class II).
Consider other diagnoses
NO
Initiate therapies for PHTN (Table 6 on page 9):
Acutely decrease PVR
Oxygen – FiO2 100% (Class I)
Alkalinization – pH > 7.4 (Class II)
Inhaled nitric oxide (5-80 ppm) (Class II) or
Inhaled prostacyclin (2.5-5 mcg/dose) (Class II) or
Intravenous prostacyclin (20-80 nanograms/kg/min)
(Class I)
Support the right heart
Dopamine 5-15 mcg/kg/min (Class III) and/or
Dobutamine 5-15 mcg/kg/min (Class III)
Consider milrinone 0.25-1 mcg/kg/min (Class III)
Supportive measures
Analgesics, sedatives, muscle relaxants (Class III)
YES
Restart
therapy
(Class II)
YES
Consider obtaining central venous and arterial access. (Class III)
NO
Therapy
interrupted?
YES
Studies suggest PHTN?
YES
Improved?
YES
Consider period of
inpatient monitoring.
Consult with
physician managing
PHTN prior to
discharge
(Indeterminate).
Continue therapy
YES
YES
Prompt referral to or
consultation with specialty
center for further diagnostic
studies and treatment. (Class II)
Improved?
NO
Escalate therapy by combining treatments
and consider ECLS (Indeterminate).
Obtain expert consultation.
The evidence for recommendations is graded using the following scale. For complete definitions, see back page. Class I: Definitely
recommended. Definitive, excellent evidence provides support. Class II: Acceptable and useful. Good evidence provides support. Class III:
May be acceptable, possibly useful. Fair-to-good evidence provides support. Indeterminate: Continuing area of research.
This clinical pathway is intended to supplement, rather than substitute for, professional judgment and may be changed depending upon a
patient’s individual needs. Failure to comply with this pathway does not represent a breach of the standard of care.
Copyright © 2008 EB Practice, LLC. 1-800-249-5770. No part of this publication may be reproduced in any format without written consent of
EB Practice, LLC.
EBMedicine.net • January 2008
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Pediatric Emergency Medicine Practice©
acutely decreasing pulmonary vascular resistance
(see “Treatment” on page 8) may provide valuable
time for a complete diagnostic assessment and more
definitive therapy.
pressures. Clearly, physicians caring for pediatric
patients with acute lung injury must include an
awareness of the pulmonary vascular aberrations
associated with the disease in their management
considerations.
Acute Lung Injury
Controversies/Cutting Edge
The pathophysiology of acute lung injury involves
damage to both the alveolar epithelium and pulmonary vascular endothelium. Vascular endothelial
injury accounts for key features of acute lung injury,
including intravascular thrombosis and capillary
permeability that increases alveolar fluid.203 In fact,
pulmonary vascular injury, in the setting of acute
lung injury, can lead to pulmonary arterial hypertension that results in increased intrapulmonary
shunting, hypoxia, pulmonary edema, and right
ventricular dysfunction.204-207 In children with acute
lung injury, persistently elevated pulmonary arterial
pressures have been associated with worse outcomes.208 Vasodilators have been utilized in the
management of these patients. However, intravenous vasodilators that dilate both the systemic
and pulmonary vasculature have significant problems; these include systemic hypotension, right ventricular ischemia, increased intrapulmonary shunting (i.e., increased V/Q mismatch), and increased
hypoxemia.159-163 Consequently, selective pulmonary vasodilation with inhaled NO has been
utilized, as it improves V/Q matching and oxygenation without untoward systemic effects.209,210 Unfortunately, improvements in oxygenation associated
with inhaled NO are transient, and large randomized trials have failed to demonstrate an improvement in mortality with its use.138,211,212 Therefore,
the routine use of inhaled NO in patients with acute
lung injury cannot be justified; however, it may be
indicated in individual patients, particularly those
with acute hemodynamic compromise and refractory hypoxemia due to elevated pulmonary arterial
In 1997, endothelial progenitor cells (EPCs) were
first isolated from human blood, and autologous
EPCs were shown to incorporate into vessels during
angiogenesis in animal models.213 Subsequently,
therapeutic administration of EPCs was shown to
ameliorate injury in animal models with improved
efficacy when EPCs were transduced with
eNOS.214-216 Recently, Wang and colleagues
performed a prospective, randomized trial to assess
the safety and efficacy of adding autologous EPCs
infusions to conventional therapy in 31 patients
with idiopathic pulmonary hypertension, with
encouraging results.217 Specifically, treated patients
demonstrated improved hemodynamics and exercise capacity and did not have increased adverse
events during the study period. Together, these
studies suggest that cell based therapy may become
an important part of treatment for patients with pulmonary hypertension.
In the setting of pulmonary hypertension
secondary to congenital heart defects, an atrial communication can be beneficial in that it allows the
failing right ventricle to decompress when right
atrial pressure rises.218 The existence of an atrial
level communication decreases the risk of right ventricular failure and maintains left sided cardiac output. The resulting right-to-left shunt is generally
well tolerated, particularly if high hemoglobin concentrations are maintained. As right ventricular
function improves, right-to-left shunting decreases
and oxygenation improves. Thus, atrial septostomy
as a part of management for chronic pulmonary
Risk Management Pitfalls For Pediatric Pulmonary Hypotension
1. Failure to consider pulmonary hypertension in
the differential diagnosis.
hypertension on the physical examination.
6. Failure to appreciate signs of pulmonary hypertension on diagnostic studies.
2. Failure to recognize a pulmonary hypertensive
crisis.
7. Failure to link pulmonary hypertension to other
systemic illnesses.
3. Failure to add therapies to resuscitative efforts
that are aimed at decreasing pulmonary vascular
constriction and supporting the right ventricle.
8. Failure to obtain a thorough family history and
past medical history.
4. Assuming that previous diagnoses are correct.
9. Losing patients to follow-up.
5. Failure to appreciate signs of pulmonary
Pediatric Emergency Medicine Practice©
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January 2008 • EBMedicine.net
hypertension has been advocated.219-224 However,
atrial septostomy in the setting of an acute exacerbation of chronic pulmonary hypertension may lead to
unacceptable hypoxemia due to excess right-to-left
atrial shunting. In addition to atrial septostomy,
other palliative shunts, such as a shunt from the left
pulmonary artery to descending aorta, are currently
under investigation.
In addition, novel therapeutic agents targeting
various cascades that are now known to contribute
to pulmonary vascular disease under different conditions are at various levels of development. These
include antioxidants, statins, rho kinase inhibitors,
elastase inhibitors, platelet-derived growth factor
inhibitors, vasoactive intestinal peptide, and 5-HT
transport inhibitors.225-235
Finally, heart/lung, single lung, or bilateral lung
transplantation has been successful in pediatric patients with terminal pulmonary hypertension.236,237
The International Society for Heart and Lung Transplantation reported a survival of approximately 50%
at five years in pediatric patients.238 Consensus is
lacking as to the best type of transplant.
Genetic testing and family history subsequently confirmed a diagnosis of familial arterial pulmonary hypertension. The patient improved and was eventually discharged home on intravenous prostacyclin and bosentan.
Summary
Every day of practice, emergency physicians face
continuous challenges. A neonate, infant, or child
presenting with symptomatic pulmonary hypertension – a rare but deadly condition that may masquerade as a common benign condition and that
requires immediate and specific therapy – combines
multiple challenges together into a perfect storm
ripe with potential disaster. An awareness of this
disease entity, its various presentations, and effective first-line therapy is the single best resource for
emergency physicians finding themselves in this
unenviable situation.
Fortunately, over the past decade, an expanded
understanding of the vascular endothelium, vascular smooth muscle cells, and the role of their interactions in the pathophysiology of pulmonary vascular
disease have resulted in new effective treatments,
with additional potential therapies evolving rapidly.
In addition, accumulated experience and focused
research have uncovered a multitude of disease
processes that contribute directly or indirectly to the
development of pulmonary hypertension. Physicians caring for children must remain abreast of
these illnesses, the pathophysiology of pulmonary
hypertension, and the available treatment options in
order to translate these advances into improved
outcomes for patients.
Disposition
In general, patients presenting with acute symptoms
secondary to pulmonary hypertension warrant
admission to an inpatient setting. Patients with any
degree of instability should be transferred to a pediatric intensive care unit, if possible. Newly diagnosed patients almost certainly require admission,
whereas patients with a known diagnosis may be
managed with extended observation in the emergency department if the trigger for their acute presentation is well understood and adequately treated
(e.g., interruption of prostacyclin infusion). In such
patients, consultation with the physician managing
their chronic treatment would be prudent.
Addendum
Pathophysiology
Pulmonary vascular resistance changes throughout
gestation and after birth. The resistance of the pulmonary circulation at any one time is related to several factors and can be estimated by applying the
resistance equation and the Poiseuille-Hagen relationship.22 The resistance equation (the hydraulic
equivalent of Ohm’s law) states that the resistance
to flow between two points along a tube equals the
decrease in pressure between the two points
divided by the flow.23,24 For the pulmonary vascular bed, where Rp = pulmonary vascular resistance
and Qp = pulmonary blood flow, the decrease in
mean pressure is from the pulmonary artery (Ppa)
to the pulmonary vein (Ppv) or left atrium, where la
= mean left atrial pressure:
Case Conclusion
This patient was suffering from arterial pulmonary
hypertension, and her previous presentations to the ED
were incorrectly diagnosed as reactive airway disease. In
the ED, she had significant dyspnea that improved somewhat with 100% oxygen delivered by facemask. CXR
revealed clear lung fields with pruned distal pulmonary
vessels and dilated central pulmonary arteries. ECG
revealed right ventricular hypertrophy. Echocardiography revealed supra-systemic systolic pulmonary artery
pressures. She was intubated, and mechanical ventilation
was adjusted to achieve respiratory alkalosis. She was
maintained on an inspired oxygen concentration of 100%
and started on 20 ppm of inhaled nitric oxide and intermittent inhaled prostacyclin. The child was then transferred to the pediatric intensive care unit. A pulmonary
hypertension specialist was consulted and the patient was
scheduled for a diagnostic right heart catheterization.
EBMedicine.net • January 2008
Rp = (Ppa – Ppv or la [mean]/Qp
Therefore, the calculated pulmonary vascular resistance increases when pulmonary arterial pressure
increases or when pulmonary blood flow decreases.
15
Pediatric Emergency Medicine Practice©
Other factors that affect pulmonary vascular resistance can be defined by applying a modification of
the Poiseuille-Hagen relationship which describes
the resistance (R) to flow of a Newtonian fluid
through a system of round, straight glass tubes of
constant cross sectional area:
relaxation by increasing concentrations of guanosine
3’5’-monophosphate (cGMP) via the activation of
soluble guanylate cyclase.43,44 NO is released in
response to a variety of factors including shear
stress (flow) and the binding of certain
endothelium-dependent vasodilators (such as
acetylcholine, ATP, and bradykinin) to receptors on
the endothelial cell.45,45 Basal NO release is an
important mediator of both resting pulmonary and
systemic vascular tone in the fetus, newborn, and
adult, as well as a mediator of the normal fall in pulmonary vascular resistance that occurs immediately
after birth.41,47,48 In addition, aberrant NO-cGMP
signaling is integral to the pathophysiology of pulmonary hypertension.29,30,49-54
ET-1 is a 21 amino acid polypeptide also produced by vascular endothelial cells.55 The vasoactive properties of ET-1 are complex and studies have
shown varying hemodynamic effects on different
vascular beds.35-39 Its most striking property is its
sustained hypertensive action. In fact, ET-1 is the
most potent vasoconstricting agent discovered, with
a potency 10 times that of angiotensin II.
The hemodynamic effects of ET-1 are mediated
by at least two distinctive receptor populations: ETA
and ETB.56,57 The ETA receptors are located on vascular smooth muscle cells and mediate vasoconstriction. In contrast, the ETB receptors are located on
endothelial cells and smooth muscle cells and may
mediate both vasodilation and vasoconstriction,
respectively. Individual endothelins occur in low
levels in the plasma, generally below their vasoactive thresholds. This suggests that they are primarily effective at the local site of release. Even at
these levels, they may potentiate the effects of other
vasoconstrictors, such as norepinephrine and serotonin.58 The role of endogenous ET-1 in the regulation of normal vascular tone is unclear at present.59
Nevertheless, alterations in ET-1 have been implicated in the pathophysiology of pulmonary hypertensive disorders.53,60-62
The breakdown of phospholipids within vascular endothelial cells results in the production of the
important byproducts of arachidonic acid, including
prostacyclin (PGI2) and thromboxane (TXA2). PGI2
activates adenylate cyclase, resulting in increased
cAMP production and subsequent vasodilation,
whereas TXA2 results in vasoconstriction via phospholipase C signaling. Other prostaglandins and
leukotrienes also have potent vasoactive properties.
Evidence in patients with congenital heart disease
and pulmonary hypertension indicates that an
imbalance between TXA2 and PGI2 that favors
TXA2-mediated vasoconstriction contributes to the
development of pulmonary vascular disease in
these patients.63
Increasing evidence suggests that endothelial
injury and the resulting alteration in the balance of
Rp = 8·l·η/νπr4
Where l = length of the system of vessels, ν = vessel
number, r = the internal radius of the system of vessels, and η = the viscosity of the fluid. According to
this relationship, increasing the viscosity of blood
perfusing the lungs or decreasing the radius or
cross-sectional area (πr4) of the pulmonary vascular
bed increases pulmonary vascular resistance.
A schematic of some of the vasoactive factors
produced by the pulmonary vascular endothelium
is shown in Figure 4 on page 16. These substances,
such as nitric oxide (NO), endothelin-1 (ET-1), and
prostacyclin are capable of producing vascular
relaxation and/or constriction, modulating the
propensity of the blood to clot and inducing and/or
inhibiting smooth muscle cell migration and replication.25-39 NO is a labile humoral factor produced by
nitric oxide synthase (NOS) from L-arginine in the
vascular endothelial cell.40-42 NO diffuses into the
smooth muscle cell and produces vascular
Figure 4. A Schematic Of Some EndothelialDerived Factors
Endothelial derived factors may cause smooth muscle cell relaxation (LEFT) and/or constriction (RIGHT). EDHF = endothelial
derived hyperpolarizing factor, PGI2 = prostaglandin I2, PLA2 =
phospholipase A2, AA = arachidonic acid, COX1 = cyclooxygenase-1, COX2 = cyclooxygenase-2, TXA2= thromboxane A2, PLC
= phospholipase C, IP3 = inositol triphosphate, DAG = diacylglycerol, L-Arg = L-arginine, L-Cit = L-citrulline, NOS = endothelial nitric oxide synthase, ET-1 = endothelin-1, ETA = endothelin A
receptor, ETB = endothelin B receptor, NO = nitric oxide, sGC =
soluble guanylate cyclase, GTP = guanosine 5’-triphosphate,
cGMP = guanosine 3’-5’cyclic monophosphate, GMP = guanosine monophosphate, PKG = phosphokinase G, AC = adenylate
cyclase, ATP = adenosine 5’-triphosphate, cAMP = adenosine
3’-5’-monophosphate, AMP = adenosine monophosphate, PKA
= phosphokinase A, K+ = potassium channels.
Pediatric Emergency Medicine Practice©
16
January 2008 • EBMedicine.net
these and other vasoactive substances has a significant role in the development of pulmonary hypertension and increased vascular reactivity.64-66 Support for this hypothesis is strengthened by
observations that endothelial injury precedes pulmonary hypertension and its associated vascular
remodeling in several animal models of pulmonary
hypertension.67,68 In humans, endothelial dysfunction, including histological abnormalities of the
endothelium, impairment of endothelium-dependent pulmonary vasodilation, and increased plasma
ET-1 concentrations, have been described in children
with congenital heart defects and pulmonary hypertension before the development of significant vascular remodeling.64,65,69 In addition, neonates with
PPHN and adults with advanced pulmonary vascular disease have evidence of endothelial dysfunction, as manifested by impaired endotheliumdependent pulmonary vasodilation, increased
plasma ET-1 concentrations, and decreased prostacyclin production.49,62,66,70 The mechanism of injury
to the vascular endothelium is unclear, but it is
likely multi-factorial and dependent in part upon
the etiology of the pulmonary hypertension. For
example, in children with congenital heart disease
and increased pulmonary blood flow, the initiating
endothelial injury is likely mediated by increased
shear stress. However, once pulmonary arterial
pressure is elevated, shear stress-mediated endothelial injury appears to promote the progression of the
disease, independent of the underlying etiology.
Finally, a genetic disposition appears to be important in some subtypes of pulmonary vascular disease and remains an area of active research. For
example, up to 50% of patients with familial pulmonary hypertension have mutations resulting in the
loss of function of bone morphogenetic protein
receptor II (BMPR2).71-74
Following an initial endothelial injury, smooth
muscle proliferation and progressive structural
remodeling occurs. The progression of anatomic
changes is best characterized in congenital heart disease.75-78 However, regardless of the etiology,
advanced disease is characterized by medial hypertrophy, intimal hyperplasia, angiomatoid formation,
in situ thrombi, and eventual vascular obliteration.
Untreated, these structural changes progress to the
point of becoming functionally “fixed,” or irreversible. An important goal of therapy is to halt this
progression and reverse the early vascular remodeling, when possible.
prospective, randomized, and blinded trial should
carry more weight than a case report.
To help the reader judge the strength of each reference, pertinent information about the study, such
as the type of study and the number of patients in
the study, will be included in bold type following
the reference, where available. In addition, the most
informative references cited in this paper, as determined by the authors, will be noted by an asterisk
(*) next to the number of the reference.
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Obstruction in Children. Pediatrics. Jul 1965;36:75-87.
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pulmonary hypertension in children. Circulation. Mar 9
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*5. Humpl T, Reyes JT, Holtby H, Stephens D, Adatia I. Beneficial effect
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patients)
6. Beghetti M. Current treatment options in children with pulmonary
arterial hypertension and experiences with oral bosentan. Eur J Clin
Invest. Sep 2006;36 Suppl 3:16-24. (Review)
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1987;107(2):216-223. (Prospective; 187 patients)
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Staub NC. Effect of increased vascular pressure on lung fluid balance
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208. Katz R, Pollack M, Spady D. Cardiopulmonary abnormalities in
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(Prospective; 23 patients)
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nitric oxide for the adult respiratory distress syndrome. N Engl J Med.
Feb 11 1993;328(6):399-405. (Prospective; 9 patients)
210. Fioretto JR, de Moraes MA, Bonatto RC, Ricchetti SM, Carpi MF.
Acute and sustained effects of early administration of inhaled nitric
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CME Questions
1. Pulmonary hypertension is defined as:
a. A systolic pulmonary artery pressure of 25
mmHg at rest or greater than 30 mmHg
during exercise
b. A mean pulmonary artery pressure of 25
mmHg at rest or greater than 30 mmHg
during exercise
c. Right ventricular hypertrophy with signs
of impaired cardiac output and oxygen
delivery
d. An acute increase in pulmonary arterial
pressure, resulting in right ventricular
failure and cardiopulmonary collapse
2. The most common cause of pulmonary hypertension in neonates is:
a. Congenital heart disease
b. Connective tissue disease
c. Persistent pulmonary hypertension of the
newborn
d. Familial pulmonary hypertension
3. Nitric oxide is:
a. An anesthetic agent
b. A gas produced by vascular endothelial
cells that results in smooth muscle cell
relaxation through cGMP signaling
c. A potent vasoconstricting factor produced
by vascular endothelial cells
22
January 2008 • EBMedicine.net
d. Increased in patients with pulmonary
hypertension
b. Endothelin receptor antagonism
c. Inhaled nitric oxide
d. Oxygen
4. When treating a pulmonary hypertensive
crisis, the most important goals are:
a. To decrease pulmonary arterial pressure
and support right ventricular function
b. To reverse pulmonary vascular remodeling
c. To increase systemic oxygen saturation
d. To maintain systemic blood pressure
12. The drug(s) of choice for supporting the right
ventricle in the setting of pulmonary hypertension is/are:
a. Epinephrine
b. Norepinephrine
c. Vasopressin
d. Dopamine and/or dobutamine
5. Which disease is associated with pulmonary
hypertension?
a. HIV
b. Asthma
c. Cerebral palsy
d. Hypertension
13. The acute withdrawal of intravenous prostacyclin may be associated with:
a. A pulmonary hypertensive crisis
b. Infection
c. The ability to restart at a lower dose after a
“drug holiday”
d. Depression
6. A key physical finding in patients with pulmonary hypertension is:
a. Difficulty palpating the liver edge
b. A loud second heart sound
c. Bounding pulses
d. Carotid bruit
14. Pulmonary hypertension may complicate
neonatal sepsis because:
a. HIV disease is a common cause of neonatal
sepsis
b. Septic neonates often have hypothyroidism
c. Sepsis, acidosis, and/or hypoxia may
impair the fall in pulmonary vascular
resistance that occurs over the first few
weeks of life
d. Congenital heart disease is a common
cause of sepsis in neonates
7. The key findings on ECG are:
a. S-T segment changes consistent with
ischemia
b. Evidence of right ventricular hypertrophy
c. Heart block
d. Atrial flutter or fibrillation
8. Estimates of pulmonary artery pressure are
made with echocardiography by:
a. Measuring the main pulmonary artery
diameter
b. Right ventricular wall thickness
c. Tricuspid regurgitation jet velocity
d. Pulmonary valve regurgitation jet velocity
15. Which patient with congenital heart disease
may be most affected by an increase in pulmonary arterial pressure and vascular resistance?
a. A neonate with un-repaired hypoplastic
left heart syndrome (HLHS)
b. An infant with an un-repaired ventricular
septal defect (VSD)
c. A child with an un-repaired atrial septal
defect (ASD)
d. An infant with a partial cavopulmonary
anastomosis (PCPA)
9. Children with pulmonary hypertension may
be considered for therapy with calcium channel blockers if:
a. They do not have systemic hypotension
b. They do not have known allergies to
calcium channel blockers
c. They demonstrate an acute decrease in
pulmonary vascular resistance without
decreased cardiac output in response to
vasodilator testing during right heart
catheterization
d. They fail other therapies
16. Pediatric patients presenting to an acute care
setting with pulmonary hypertension should:
a. Be immediately transferred to a pediatric
facility
b. Have pulmonary vasodilator therapy initiated immediately
c. Undergo right-heart catheterization immediately
d. Be referred to a tertiary center with a dedicated pediatric pulmonary hypertension
program
10. Which of the following laboratory studies aid
in the assessment of cardiac output?
a. Complete blood count
b. Coagulation studies
c. Central venous oxyhemoglobin saturation
d. C-reactive protein
11. The best first-line therapy for decreasing pulmonary arterial pressure is:
a. Prostacyclin
EBMedicine.net • January 2008
23
Pediatric Emergency Medicine Practice©
Physician CME Information
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Medicine Practice receives a score based on the following
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Significantly modified from: The
Emergency Cardiovascular Care
Committees of the American
Heart Association and representatives from the resuscitation
councils of ILCOR: How to
Develop Evidence-Based Guidelines for Emergency Cardiac
Care: Quality of Evidence and
Classes of Recommendations;
also: Anonymous. Guidelines for
cardiopulmonary resuscitation
and emergency cardiac care.
Emergency Cardiac Care Committee and Subcommittees,
American Heart Association. Part
IX. Ensuring effectiveness of
community-wide emergency
cardiac care. JAMA
1992;268(16):2289-2295.
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