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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© 2 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. 4 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. 6 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 8 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 9 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 10 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© 12 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 13 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© 14 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. 1. Thilenius OG, Nadas AS, Jockin H. Primary Pulmonary Vascular Obstruction in Children. Pediatrics. Jul 1965;36:75-87. 2. Barst RJ, Maislin G, Fishman AP. Vasodilator therapy for primary pulmonary hypertension in children. Circulation. Mar 9 1999;99(9):1197-1208. (Retrospective; 74 patients) 3. Sandoval J, Bauerle O, Gomez A, Palomar A, Martinez Guerra ML, Furuya ME. Primary pulmonary hypertension in children: clinical characterization and survival. J Am Coll Cardiol. Feb 1995;25(2):466474. (Prospective; 18 patients) *4. Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med. Mar 21 2002;346(12):896-903. (Prospective randomized double-blind placebo-controlled; 213 patients) *5. Humpl T, Reyes JT, Holtby H, Stephens D, Adatia I. Beneficial effect of oral sildenafil therapy on childhood pulmonary arterial hypertension: twelve-month clinical trial of a single-drug, open-label, pilot study. Circulation. Jun 21 2005;111(24):3274-3280. (Prospective; 14 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) *7. Rich S, Dantzker DR, Ayres SM, et al. Primary pulmonary hypertension. A national prospective study. Ann Intern Med. Aug 1987;107(2):216-223. (Prospective; 187 patients) 8. Tulloh RM. Congenital heart disease in relation to pulmonary hypertension in pediatric practice. Paediatr Respir Rev. Sep 2005;6(3):174180. (Review) *9. Simonneau G, Galie N, Rubin LJ, et al. Clinical classification of pulmonary hypertension. J Am Coll Cardiol. Jun 16 2004;43(12 Suppl S):5S-12S. (Review, expert consensus opinion) 10. Hoffman JI. Congenital heart disease: incidence and inheritance. Pediatr Clin North Am. Feb 1990;37(1):25-43. (Review) 11. Friedman WF. Proceedings of National Heart, Lung, and Blood Institute pediatric cardiology workshop: pulmonary hypertension. Pediatr Res. Sep 1986;20(9):811-824. (Expert consensus opinion) 12. Haworth SG. Development of the normal and hypertensive pulmonary vasculature. Exp Physiol. Sep 1995;80(5):843-853. (Review) 13. Bando K, Turrentine MW, Sharp TG, et al. Pulmonary hypertension after operations for congenital heart disease: analysis of risk factors and management. J Thorac Cardiovasc Surg. Dec 1996;112(6):1600-1607; discussion 1607-1609. (Retrospective; 880 patients) 14. Kumar A, Taylor GP, Sandor GG, Patterson MW. Pulmonary vascular disease in neonates with transposition of the great arteries and intact ventricular septum. Br Heart J. May 1993;69(5):442-445. (Case series; 3 patients) 15. Widlitz A, Barst RJ. Pulmonary arterial hypertension in children. Eur Respir J. Jan 2003;21(1):155-176. (Review) 16. Rosenzweig EB, Barst RJ. Idiopathic pulmonary arterial hypertension in children. Curr Opin Pediatr. Jun 2005;17(3):372-380. (Review) 17. Rosenzweig EB, Widlitz AC, Barst RJ. Pulmonary arterial hypertension in children. Pediatr Pulmonol. Jul 2004;38(1):2-22. (Review) 18. Rubin LJ. Primary pulmonary hypertension. N Engl J Med. Jan 9 1997;336(2):111-117. (Review) *19. D’Alonzo GE, Barst RJ, Ayres SM, et al. Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. Ann Intern Med. Sep 1 1991;115(5):343-349. (Prospective; 194 patients) 20. Fuster V, Steele PM, Edwards WD, Gersh BJ, McGoon MD, Frye RL. Primary pulmonary hypertension: natural history and the importance of thrombosis. Circulation. Oct 1984;70(4):580-587. (Retrospective, 120 patients) 21. Hopkins WE, Ochoa LL, Richardson GW, Trulock EP. Comparison of the hemodynamics and survival of adults with severe primary pulmonary hypertension or Eisenmenger syndrome. J Heart Lung Transplant. Jan 1996;15(1 Pt 1):100-105. (Prospective; 100 patients) 22. Roos A. Poiseuille’s law and its limitations in vascular systems. Med Thorac. 1962;19:224-238. References Evidence-based medicine requires a critical appraisal of the literature based upon study methodology and number of subjects. Not all references are equally robust. The findings of a large, EBMedicine.net • January 2008 17 Pediatric Emergency Medicine Practice© 23. Caro CG. Mechanics of the pulmonary circulation. In: Caro CG, ed. Advances in Pulmonary Physiology. London: Edwin Arnold; 1966. 24. Prandtl L, Tietjens OG. Applied Hydro- and Aeromechanics. New York: Dover Publications; 1957. 25. Fineman JR, Heymann MA, Soifer SJ. N omega-nitro-L-arginine attenuates endothelium-dependent pulmonary vasodilation in lambs. Am J Physiol. Apr 1991;260(4 Pt 2):H1299-1306. (Animal based study) 26. Moncada S, Higgs A. The L-arginine-nitric oxide pathway. N Engl J Med. Dec 30 1993;329(27):2002-2012. (Review) 27. Dinh-Xuan AT. Endothelial modulation of pulmonary vascular tone. Eur Respir J. Jun 1992;5(6):757-762. (Review) 28. Garg UC, Hassid A. Nitric oxide-generating vasodilators and 8bromo-cyclic guanosine monophosphate inhibit mitogenesis and proliferation of cultured rat vascular smooth muscle cells. J Clin Invest. May 1989;83(5):1774-1777. (Animal based study) 29. Fineman JR, Chang R, Soifer SJ. EDRF inhibition augments pulmonary hypertension in intact newborn lambs. Am J Physiol. May 1992;262(5 Pt 2):H1365-1371. (Animal based study) 30. Fineman JR, Crowley MR, Heymann MA, Soifer SJ. In vivo attenuation of endothelium-dependent pulmonary vasodilation by methylene blue. J Appl Physiol. Aug 1991;71(2):735-741. (Animal based study) 31. Braner DA, Fineman JR, Chang R, Soifer SJ. M&B 22948, a cGMP phosphodiesterase inhibitor, is a pulmonary vasodilator in lambs. Am J Physiol. Jan 1993;264(1 Pt 2):H252-258. (Animal based study) 32. Kourembanas S, McQuillan LP, Leung GK, Faller DV. Nitric oxide regulates the expression of vasoconstrictors and growth factors by vascular endothelium under both normoxia and hypoxia. J Clin Invest. Jul 1993;92(1):99-104. (Animal based study) 33. Budhiraja R, Tuder RM, Hassoun PM. Endothelial dysfunction in pulmonary hypertension. Circulation. Jan 20 2004;109(2):159-165. (Review) 34. Matsuura A, Kawashima S, Yamochi W, et al. Vascular endothelial growth factor increases endothelin-converting enzyme expression in vascular endothelial cells. Biochem Biophys Res Commun. Jun 27 1997;235(3):713-716. (Animal based study) 35. Cassin S, Kristova V, Davis T, Kadowitz P, Gause G. Tone-dependent responses to endothelin in the isolated perfused fetal sheep pulmonary circulation in situ. J Appl Physiol. Mar 1991;70(3):12281234. (Animal based study) 36. Wong J, Vanderford PA, Fineman JR, Chang R, Soifer SJ. Endothelin-1 produces pulmonary vasodilation in the intact newborn lamb. Am J Physiol. Oct 1993;265(4 Pt 2):H1318-1325. (Animal based study) 37. Wong J, Vanderford PA, Fineman JR, Soifer SJ. Developmental effects of endothelin-1 on the pulmonary circulation in sheep. Pediatr Res. Sep 1994;36(3):394-401. (Animal based study) 38. Bradley LM, Czaja JF, Goldstein RE. Circulatory effects of endothelin in newborn piglets. Am J Physiol. Nov 1990;259(5 Pt 2):H1613-1617. (Animal based study) 39. Perreault T, De Marte J. Maturational changes in endotheliumderived relaxations in newborn piglet pulmonary circulation. Am J Physiol. Feb 1993;264(2 Pt 2):H302-309. (Animal based study) 40. Bush PA, Gonzalez NE, Ignarro LJ. Biosynthesis of nitric oxide and citrulline from L-arginine by constitutive nitric oxide synthase present in rabbit corpus cavernosum. Biochem Biophys Res Commun. Jul 15 1992;186(1):308-314. (Animal based study) 41. Ignarro LJ, Byrns RE, Buga GM, Wood KS. Endothelium-derived relaxing factor from pulmonary artery and vein possesses pharmacologic and chemical properties identical to those of nitric oxide radical. Circ Res. Dec 1987;61(6):866-879. (Animal based study) 42. Ignarro LJ, Ross G, Tillisch J. Pharmacology of endothelium-derived nitric oxide and nitrovasodilators. West J Med. Jan 1991;154(1):51-62. (Animal based study) 43. Ignarro LJ, Harbison RG, Wood KS, Kadowitz PJ. Activation of purified soluble guanylate cyclase by endothelium-derived relaxing factor from intrapulmonary artery and vein: stimulation by acetylcholine, bradykinin and arachidonic acid. J Pharmacol Exp Ther. Jun 1986;237(3):893-900. (Animal based study) 44. Murad F. Cyclic guanosine monophosphate as a mediator of vasodilation. J Clin Invest. Jul 1986;78(1):1-5. (Review) 45. Mulsch A, Bassenge E, Busse R. Nitric oxide synthesis in endothelial cytosol: evidence for a calcium-dependent and a calcium-independent mechanism. Naunyn Schmiedebergs Arch Pharmacol. Dec 1989;340(6 Pt 2):767-770. (Animal based study) 46. Rubanyi GM, Romero JC, Vanhoutte PM. Flow-induced release of endothelium-derived relaxing factor. Am J Physiol. Jun 1986;250(6 Pt 2):H1145-1149. (Animal based study) 47. Brashers VL, Peach MJ, Rose CE, Jr. Augmentation of hypoxic pulmonary vasoconstriction in the isolated perfused rat lung by in vitro antagonists of endothelium-dependent relaxation. J Clin Invest. Nov 1988;82(5):1495-1502. (Animal based study) 48. Fineman JR, Soifer SJ, Heymann MA. Regulation of pulmonary vascular tone in the perinatal period. Annu Rev Physiol. 1995;57:115-134. (Animal based study) Pediatric Emergency Medicine Practice© *49. Giaid A, Saleh D. Reduced expression of endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension. N Engl J Med. Jul 27 1995;333(4):214-221. (Retrospective; 69 patients) 50. Black SM, Bekker JM, McMullan DM, et al. Alterations in nitric oxide production in 8-week-old lambs with increased pulmonary blood flow. Pediatr Res. Aug 2002;52(2):233-244. (Animal based study) 51. Black SM, Fineman JR, Steinhorn RH, Bristow J, Soifer SJ. Increased endothelial NOS in lambs with increased pulmonary blood flow and pulmonary hypertension. Am J Physiol. Nov 1998;275(5 Pt 2):H16431651. (Animal based study) 52. Fineman JR, Wong J, Mikhailov T, Vanderford PA, Jerome HE, Soifer SJ. Altered endothelial function in lambs with pulmonary hypertension and acute lung injury. Pediatr Pulmonol. Mar 1999;27(3):147-156. (Animal based study) 53. Reddy VM, Wong J, Liddicoat JR, Johengen M, Chang R, Fineman JR. Altered endothelium-dependent responses in lambs with pulmonary hypertension and increased pulmonary blood flow. Am J Physiol. Aug 1996;271(2 Pt 2):H562-570. (Animal based study) 54. Steinhorn RH, Fineman JR. The pathophysiology of pulmonary hypertension in congenital heart disease. Artif Organs. Nov 1999;23(11):970-974. (Review) 55. Yanagisawa M, Kurihara H, Kimura S, et al. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature. Mar 31 1988;332(6163):411-415. (Animal based study) 56. Arai H, Hori S, Aramori I, Ohkubo H, Nakanishi S. Cloning and expression of a cDNA encoding an endothelin receptor. Nature. Dec 20-27 1990;348(6303):730-732. (Animal based study) 57. Sakurai T, Yanagisawa M, Takuwa Y, et al. Cloning of a cDNA encoding a non-isopeptide-selective subtype of the endothelin receptor. Nature. Dec 20-27 1990;348(6303):732-735. (Animal based study) 58. Rubanyi GM, ed. Endothelin. New York: Oxford University Press for the American Physiological Society; 1992. (Review) 59. Vane JR, Anggard EE, Botting RM. Regulatory functions of the vascular endothelium. N Engl J Med. Jul 5 1990;323(1):27-36. (Review) 60. Rosenberg AA, Kennaugh J, Koppenhafer SL, Loomis M, Chatfield BA, Abman SH. Elevated immunoreactive endothelin-1 levels in newborn infants with persistent pulmonary hypertension. J Pediatr. Jul 1993;123(1):109-114. (Prospective; 44 patients) 61. Wong J, Reddy VM, Hendricks-Munoz K, Liddicoat JR, Gerrets R, Fineman JR. Endothelin-1 vasoactive responses in lambs with pulmonary hypertension and increased pulmonary blood flow. Am J Physiol. Dec 1995;269(6 Pt 2):H1965-1972. (Animal based study) *62. Giaid A, Yanagisawa M, Langleben D, et al. Expression of endothelin1 in the lungs of patients with pulmonary hypertension. N Engl J Med. Jun 17 1993;328(24):1732-1739. (Prospective; 43 patients) *63. Adatia I, Barrow SE, Stratton PD, Miall-Allen VM, Ritter JM, Haworth SG. Thromboxane A2 and prostacyclin biosynthesis in children and adolescents with pulmonary vascular disease. Circulation. Nov 1993;88(5 Pt 1):2117-2122. (Prospective; 65 patients) 64. Rabinovitch M, Bothwell T, Hayakawa BN, et al. Pulmonary artery endothelial abnormalities in patients with congenital heart defects and pulmonary hypertension. A correlation of light with scanning electron microscopy and transmission electron microscopy. Lab Invest. Dec 1986;55(6):632-653. *65. Celermajer DS, Cullen S, Deanfield JE. Impairment of endotheliumdependent pulmonary artery relaxation in children with congenital heart disease and abnormal pulmonary hemodynamics. Circulation. Feb 1993;87(2):440-446. (Prospective; 25 patients) 66. Dinh Xuan AT, Higenbottam TW, Clelland C, Pepke-Zaba J, Cremona G, Wallwork J. Impairment of pulmonary endothelium-dependent relaxation in patients with Eisenmenger’s syndrome. Br J Pharmacol. Jan 1990;99(1):9-10. (Prospective; 8 patients) 67. Adnot S, Raffestin B, Eddahibi S, Braquet P, Chabrier PE. Loss of endothelium-dependent relaxant activity in the pulmonary circulation of rats exposed to chronic hypoxia. J Clin Invest. Jan 1991;87(1):155-162. (Animal based study) 68. Meyrick B, Gamble W, Reid L. Development of Crotalaria pulmonary hypertension: hemodynamic and structural study. Am J Physiol. Nov 1980;239(5):H692-702. (Animal based study) 69. Yoshibayashi M, Nishioka K, Nakao K, et al. Plasma endothelin concentrations in patients with pulmonary hypertension associated with congenital heart defects. Evidence for increased production of endothelin in pulmonary circulation. Circulation. Dec 1991;84(6):22802285. (Prospective; 45 patients) *70. Christman BW, McPherson CD, Newman JH, et al. An imbalance between the excretion of thromboxane and prostacyclin metabolites in pulmonary hypertension. N Engl J Med. Jul 9 1992;327(2):70-75. (Prospective; 66 patients) *71. Lane KB, Machado RD, Pauciulo MW, et al. Heterozygous germline mutations in BMPR2, encoding a TGF-beta receptor, cause familial primary pulmonary hypertension. The International PPH Consortium. Nat Genet. Sep 2000;26(1):81-84. (Prospective; 50 patients) 18 January 2008 • EBMedicine.net 72. Thomson JR, Machado RD, Pauciulo MW, et al. Sporadic primary pulmonary hypertension is associated with germline mutations of the gene encoding BMPR-II, a receptor member of the TGF-beta family. J Med Genet. Oct 2000;37(10):741-745. (Prospective; 50 patients) 73. Newman JH, Wheeler L, Lane KB, et al. Mutation in the gene for bone morphogenetic protein receptor II as a cause of primary pulmonary hypertension in a large kindred. N Engl J Med. Aug 2 2001;345(5):319-324. (Retrospective; 394 patients) 74. Humbert M, Deng Z, Simonneau G, et al. BMPR2 germline mutations in pulmonary hypertension associated with fenfluramine derivatives. Eur Respir J. Sep 2002;20(3):518-523. (Prospective; 168 patients) 75. Rabinovitch M, Haworth SG, Castaneda AR, Nadas AS, Reid LM. Lung biopsy in congenital heart disease: a morphometric approach to pulmonary vascular disease. Circulation. Dec 1978;58(6):1107-1122. (Prospective; 50 patients) 76. Meyrick B, Reid L. Ultrastructural findings in lung biopsy material from children with congenital heart defects. Am J Pathol. Dec 1980;101(3):527-542. (Case series; 6 patients) 77. Hislop A, Haworth SG, Shinebourne EA, Reid L. Quantitative structural analysis of pulmonary vessels in isolated ventricular septal defect in infancy. Br Heart J. Oct 1975;37(10):1014-1021. (Prospective; 5 patients) 78. Haworth SG. Pulmonary vascular disease in different types of congenital heart disease. Implications for interpretation of lung biopsy findings in early childhood. Br Heart J. Nov 1984;52(5):557-571. (Prospective; 16 patients) 79. Scott JP, Higenbottam TW, Smyth RL, Wallwork J. Acute pulmonary hypertensive crisis in a patient with primary pulmonary hypertension treated by both epoprostenol (prostacyclin) and nitroprusside. Chest. May 1991;99(5):1284-1285. (Case report) 80. Pelech AN, Neish SR. Sudden death in congenital heart disease. Pediatr Clin North Am. Oct 2004;51(5):1257-1271. (Review) 81. Allman KG, Young JD, Stevens JE, Archer LN. Nitric oxide treatment for fulminant pulmonary hypertension. Arch Dis Child. Oct 1993;69(4):449-450. (Case report) 82. Hopkins RA, Bull C, Haworth SG, de Leval MR, Stark J. Pulmonary hypertensive crises following surgery for congenital heart defects in young children. Eur J Cardiothorac Surg. 1991;5(12):628-634. (Prospective; 20 patients) 83. Wheller J, George BL, Mulder DG, Jarmakani JM. Diagnosis and management of postoperative pulmonary hypertensive crisis. Circulation. Dec 1979;60(7):1640-1644. (Case series; 3 patients) 84. Rowe RD, Hoffman T. Transient myocardial ischemia of the newborn infant: a form of severe cardiorespiratory distress in full-term infants. J Pediatr. Aug 1972;81(2):243-250. 85. Turner-Gomes SO, Izukawa T, Rowe RD. Persistence of atrioventricular valve regurgitation and electrocardiographic abnormalities following transient myocardial ischemia of the newborn. Pediatr Cardiol. Fall 1989;10(4):191-194. (Retrospective; 59 patients) 86. McGoon M, Gutterman D, Steen V, et al. Screening, early detection, and diagnosis of pulmonary arterial hypertension: ACCP evidencebased clinical practice guidelines. Chest. Jul 2004;126(1 Suppl):14S34S. (Review, expert consensus opinion) 87. Abenhaim L, Moride Y, Brenot F, et al. Appetite-suppressant drugs and the risk of primary pulmonary hypertension. International Primary Pulmonary Hypertension Study Group. N Engl J Med. Aug 29 1996;335(9):609-616. (Prospective; 95 patients) 88. Machado RD, Pauciulo MW, Thomson JR, et al. BMPR2 haploinsufficiency as the inherited molecular mechanism for primary pulmonary hypertension. American Journal of Human Genetics. Jan 2001;68(1):92102. 89. Loyd JE, Butler MG, Foroud TM, Conneally PM, Phillips JA, 3rd, Newman JH. Genetic anticipation and abnormal gender ratio at birth in familial primary pulmonary hypertension. Am J Respir Crit Care Med. Jul 1995;152(1):93-97. (Prospective; 429 patients) 90. Lupi E, Dumont C, Tejada VM, Horwitz S, Galland F. A radiologic index of pulmonary arterial hypertension. Chest. Jul 1975;68(1):28-31. (Retrospective; 250 patients) 91. Ahearn GS, Tapson VF, Rebeiz A, Greenfield JC, Jr. Electrocardiography to define clinical status in primary pulmonary hypertension and pulmonary arterial hypertension secondary to collagen vascular disease. Chest. Aug 2002;122(2):524-527. (Retrospective; 61 patients) 92. Battle RW, Davitt MA, Cooper SM, et al. Prevalence of pulmonary hypertension in limited and diffuse scleroderma. Chest. Dec 1996;110(6):1515-1519. (Prospective; 34 patients) 93. Grunig E, Janssen B, Mereles D, et al. Abnormal pulmonary artery pressure response in asymptomatic carriers of primary pulmonary hypertension gene. Circulation. Sep 5 2000;102(10):1145-1150. (Prospective; 52 patients) 94. Chan KL, Currie PJ, Seward JB, Hagler DJ, Mair DD, Tajik AJ. Comparison of three Doppler ultrasound methods in the prediction of pulmonary artery pressure. J Am Coll Cardiol. Mar 1987;9(3):549-554. (Prospective; 50 patients) EBMedicine.net • January 2008 95. Currie PJ, Seward JB, Chan KL, et al. Continuous wave Doppler determination of right ventricular pressure: a simultaneous Dopplercatheterization study in 127 patients. J Am Coll Cardiol. Oct 1985;6(4):750-756. (Prospective; 127 patients) 96. Denton CP, Cailes JB, Phillips GD, Wells AU, Black CM, Bois RM. Comparison of Doppler echocardiography and right heart catheterization to assess pulmonary hypertension in systemic sclerosis. Br J Rheumatol. Feb 1997;36(2):239-243. (Retrospective; 33 patients) 97. Hinderliter AL, Willis PWt, Barst RJ, et al. Effects of long-term infusion of prostacyclin (epoprostenol) on echocardiographic measures of right ventricular structure and function in primary pulmonary hypertension. Primary Pulmonary Hypertension Study Group. Circulation. Mar 18 1997;95(6):1479-1486. (Prospective; 81 patients) 98. Kim WR, Krowka MJ, Plevak DJ, et al. Accuracy of Doppler echocardiography in the assessment of pulmonary hypertension in liver transplant candidates. Liver Transpl. Jul 2000;6(4):453-458. (Prospective; 74 patients) 99. Shapiro SM, Oudiz RJ, Cao T, et al. Primary pulmonary hypertension: improved long-term effects and survival with continuous intravenous epoprostenol infusion. J Am Coll Cardiol. Aug 1997;30(2):343349. (Prospective; 69 patients) 100. Shen JY, Chen SL, Wu YX, et al. Pulmonary hypertension in systemic lupus erythematosus. Rheumatol Int. 1999;18(4):147-151. (Prospective; 84 patients) 101. Yock PG, Popp RL. Noninvasive estimation of right ventricular systolic pressure by Doppler ultrasound in patients with tricuspid regurgitation. Circulation. Oct 1984;70(4):657-662. (Prospective; 62 patients) 102. Chotivittayatarakorn P, Pathmanand C, Thisyakorn C, Sueblinvong V. Doppler echocardiographic predictions of pulmonary artery pressure in children with congenital heart disease. J Med Assoc Thai. Feb 1992;75(2):79-84. 103. Fernandes R, Bjorkhem G, Lundstrom NR. Echocardiographic estimation of pulmonary artery pressure in infants and children with congenital heart disease. Eur J Cardiol. 1980;11(6):473-481. (Prospective; 20 patients) 104. Kosturakis D, Goldberg SJ, Allen HD, Loeber C. Doppler echocardiographic prediction of pulmonary arterial hypertension in congenital heart disease. Am J Cardiol. Apr 1 1984;53(8):1110-1115. (Retrospective; 32 patients) 105. Mirrakhimov MM, Tenenbaum AM, Moldotashev IK, Niazova ZA, Zlatkovsky ML. New approaches to noninvasive assessment of pulmonary artery pressure. Clin Cardiol. Nov 1992;15(11):811-816. (Prospective; 36 patients) 106. Brecker SJ, Gibbs JS, Fox KM, Yacoub MH, Gibson DG. Comparison of Doppler derived haemodynamic variables and simultaneous high fidelity pressure measurements in severe pulmonary hypertension. Br Heart J. Oct 1994;72(4):384-389. (Prospective; 10 patients) 107. Naeije R, Torbicki A. More on the noninvasive diagnosis of pulmonary hypertension: Doppler echocardiography revisited. Eur Respir J. Sep 1995;8(9):1445-1449. (Editorial) 108. Penning S, Robinson KD, Major CA, Garite TJ. A comparison of echocardiography and pulmonary artery catheterization for evaluation of pulmonary artery pressures in pregnant patients with suspected pulmonary hypertension. Am J Obstet Gynecol. Jun 2001;184(7):1568-1570. (Retrospective; 27 patients) 109. D’Alonzo GE, Bower JS, Dantzker DR. Differentiation of patients with primary and thromboembolic pulmonary hypertension. Chest. Apr 1984;85(4):457-461. (Retrospective; 25 patients) 110. Bergin CJ, Hauschildt J, Rios G, Belezzuoli EV, Huynh T, Channick RN. Accuracy of MR angiography compared with radionuclide scanning in identifying the cause of pulmonary arterial hypertension. AJR Am J Roentgenol. Jun 1997;168(6):1549-1555. (Prospective; 53 patients) 111. Worsley DF, Palevsky HI, Alavi A. Ventilation-perfusion lung scanning in the evaluation of pulmonary hypertension. J Nucl Med. May 1994;35(5):793-796. (Retrospective; 75 patients) 112. Bergin CJ, Sirlin CB, Hauschildt JP, et al. Chronic thromboembolism: diagnosis with helical CT and MR imaging with angiographic and surgical correlation. Radiology. Sep 1997;204(3):695-702. (Retrospective; 55 patients) 113. Bergin CJ, Hauschildt JP, Brown MA, Channick RN, Fedullo PF. Identifying the cause of unilateral hypoperfusion in patients suspected to have chronic pulmonary thromboembolism: diagnostic accuracy of helical CT and conventional angiography. Radiology. Dec 1999;213(3):743-749. (Retrospective; 410 patients) 114. Choe KO, Hong YK, Kim HJ, et al. The use of high-resolution computed tomography in the evaluation of pulmonary hemodynamics in patients with congenital heart disease: in pulmonary vessels larger than 1 mm in diameter. Pediatr Cardiol. May-Jun 2000;21(3):202-210. (Prospective; 36 patients) 115. Kuriyama K, Gamsu G, Stern RG, Cann CE, Herfkens RJ, Brundage BH. CT-determined pulmonary artery diameters in predicting pulmonary hypertension. Invest Radiol. Jan-Feb 1984;19(1):16-22. (Retrospective; 58 patients) 19 Pediatric Emergency Medicine Practice© 116. Ng CS, Wells AU, Padley SP. A CT sign of chronic pulmonary arterial hypertension: the ratio of main pulmonary artery to aortic diameter. J Thorac Imaging. Oct 1999;14(4):270-278. (Retrospective; 50 patients) 117. Tan RT, Kuzo R, Goodman LR, Siegel R, Haasler GB, Presberg KW. Utility of CT scan evaluation for predicting pulmonary hypertension in patients with parenchymal lung disease. Medical College of Wisconsin Lung Transplant Group. Chest. May 1998;113(5):1250-1256. (Retrospective; 45 patients) 118. Boxt LM, Katz J, Kolb T, Czegledy FP, Barst RJ. Direct quantitation of right and left ventricular volumes with nuclear magnetic resonance imaging in patients with primary pulmonary hypertension. J Am Coll Cardiol. Jun 1992;19(7):1508-1515. (Prospective; 21 patients) 119. Katz J, Whang J, Boxt LM, Barst RJ. Estimation of right ventricular mass in normal subjects and in patients with primary pulmonary hypertension by nuclear magnetic resonance imaging. J Am Coll Cardiol. May 1993;21(6):1475-1481. (Prospective; 23 patients) 120. Murray TI, Boxt LM, Katz J, Reagan K, Barst RJ. Estimation of pulmonary artery pressure in patients with primary pulmonary hypertension by quantitative analysis of magnetic resonance images. J Thorac Imaging. Summer 1994;9(3):198-204. (Prospective; 20 patients) 121. Sun XG, Hansen JE, Oudiz RJ, Wasserman K. Pulmonary function in primary pulmonary hypertension. J Am Coll Cardiol. Mar 19 2003;41(6):1028-1035. (Prospective 79 patients) 122. Owens GR, Fino GJ, Herbert DL, et al. Pulmonary function in progressive systemic sclerosis. Comparison of CREST syndrome variant with diffuse scleroderma. Chest. Nov 1983;84(5):546-550. (Retrospective; 165 patients) 123. Steenhuis LH, Groen HJ, Koeter GH, van der Mark TW. Diffusion capacity and haemodynamics in primary and chronic thromboembolic pulmonary hypertension. Eur Respir J. Aug 2000;16(2):276-281. (Prospective; 27 patients) 124. Rich S, Kaufmann E, Levy PS. The effect of high doses of calciumchannel blockers on survival in primary pulmonary hypertension. N Engl J Med. Jul 9 1992;327(2):76-81. (Prospective; 64 patients) 125. Packer M, Greenberg B, Massie B, Dash H. Deleterious effects of hydralazine in patients with pulmonary hypertension. N Engl J Med. Jun 3 1982;306(22):1326-1331. (Prospective; 13 patients) 126. Nagaya N, Nishikimi T, Uematsu M, et al. Plasma brain natriuretic peptide as a prognostic indicator in patients with primary pulmonary hypertension. Circulation. Aug 22 2000;102(8):865-870. (Prospective; 60 patients) 127. Nagaya N, Nishikimi T, Uematsu M, et al. Secretion patterns of brain natriuretic peptide and atrial natriuretic peptide in patients with or without pulmonary hypertension complicating atrial septal defect. Am Heart J. Aug 1998;136(2):297-301. (Prospective; 42 patients) 128. Reynolds EW, Ellington JG, Vranicar M, Bada HS. Brain-type natriuretic peptide in the diagnosis and management of persistent pulmonary hypertension of the newborn. Pediatrics. Nov 2004;114(5):1297-1304. (Prospective; 47 patients) 129. Suda K, Matsumura M, Matsumoto M. Clinical implication of plasma natriuretic peptides in children with ventricular septal defect. Pediatr Int. Jun 2003;45(3):249-254. (Prospective; 59 patients) 130. Hoffman JI, Rudolph AM, Heymann MA. Pulmonary vascular disease with congenital heart lesions: pathologic features and causes. Circulation. Nov 1981;64(5):873-877. (Review) 131. Burrows FA, Klinck JR, Rabinovitch M, Bohn DJ. Pulmonary hypertension in children: perioperative management. Can Anaesth Soc J. Sep 1986;33(5):606-628. (Review) 132. Bancalari E, Jesse MJ, Gelband H, Garcia O. Lung mechanics in congenital heart disease with increased and decreased pulmonary blood flow. J Pediatr. Feb 1977;90(2):192-195. (Prospective; 25 patients) 133. Whittenberger JL, Mc GM, Berglund E, Borst HG. Influence of state of inflation of the lung on pulmonary vascular resistance. J Appl Physiol. Sep 1960;15:878-882. (Animal based study) 134. Day RW, Allen EM, Witte MK. A randomized, controlled study of the 1-hour and 24-hour effects of inhaled nitric oxide therapy in children with acute hypoxemic respiratory failure. Chest. Nov 5 1997;112(5):1324-1331. (Prospective randomized; 12 patients) *135. Inhaled nitric oxide in full-term and nearly full-term infants with hypoxic respiratory failure. The Neonatal Inhaled Nitric Oxide Study Group. N Engl J Med. Feb 27 1997;336(9):597-604. (Prospective randomized; 235 patients) 136. Atz AM, Wessel DL. Inhaled nitric oxide in the neonate with cardiac disease. Semin Perinatol. Oct 1997;21(5):441-455. (Review) *137. Clark RH, Kueser TJ, Walker MW, et al. Low-dose nitric oxide therapy for persistent pulmonary hypertension of the newborn. Clinical Inhaled Nitric Oxide Research Group. N Engl J Med. Feb 17 2000;342(7):469-474. (Prospective randomized; 248 patients) 138. Dellinger RP, Zimmerman JL, Taylor RW, et al. Effects of inhaled nitric oxide in patients with acute respiratory distress syndrome: results of a randomized phase II trial. Inhaled Nitric Oxide in ARDS Study Group. Crit Care Med. Jan 1998;26(1):15-23. (Prospective randomized; 177 patients) Pediatric Emergency Medicine Practice© 139. Dobyns EL, Cornfield DN, Anas NG, et al. Multicenter randomized controlled trial of the effects of inhaled nitric oxide therapy on gas exchange in children with acute hypoxemic respiratory failure. J Pediatr. Apr 1999;134(4):406-412. (Prospective randomized; 177 patients) 140. Fineman JR, Zwass MS. Inhaled nitric oxide therapy for persistent pulmonary hypertension of the newborn. Acta Paediatr Jpn. Aug 1995;37(4):425-430. (Review) 141. Karamanoukian HL, Glick PL, Zayek M, et al. Inhaled nitric oxide in congenital hypoplasia of the lungs due to diaphragmatic hernia or oligohydramnios. Pediatrics. Nov 1994;94(5):715-718. (Prospective; 9 patients) 142. Kinsella JP, Truog WE, Walsh WF, et al. Randomized, multicenter trial of inhaled nitric oxide and high-frequency oscillatory ventilation in severe, persistent pulmonary hypertension of the newborn. J Pediatr. Jul 1997;131(1 Pt 1):55-62. (Prospective randomized; 205 patients) 143. Lunn RJ. Inhaled nitric oxide therapy. Mayo Clin Proc. Mar 1995;70(3):247-255. (Review) *144. Roberts JD, Jr., Fineman JR, Morin FC, 3rd, et al. Inhaled nitric oxide and persistent pulmonary hypertension of the newborn. The Inhaled Nitric Oxide Study Group. N Engl J Med. Feb 27 1997;336(9):605-610. (Prospective randomized; 58 patients) 145. Russell IA, Zwass MS, Fineman JR, et al. The effects of inhaled nitric oxide on postoperative pulmonary hypertension in infants and children undergoing surgical repair of congenital heart disease. Anesth Analg. Jul 1998;87(1):46-51. (Prospective randomized; 40 patients) 146. Schreiber MD, Gin-Mestan K, Marks JD, Huo D, Lee G, Srisuparp P. Inhaled nitric oxide in premature infants with the respiratory distress syndrome. N Engl J Med. Nov 27 2003;349(22):2099-2107. (Prospective randomized double-blind placebo-placebo controlled; 207 patients) 147. Heidersbach RS, Johengen MJ, Bekker JM, Fineman JR. Inhaled nitric oxide, oxygen, and alkalosis: dose-response interactions in a lamb model of pulmonary hypertension. Pediatr Pulmonol. Jul 1999;28(1):311. (Animal based study) 148. Stephenson LW, Edmunds LH, Jr., Raphaely R, Morrison DF, Hoffman WS, Rubis LJ. Effects of nitroprusside and dopamine on pulmonary arterial vasculature in children after cardiac surgery. Circulation. Aug 1979;60(2 Pt 2):104-110. (Prospective; 28 patients) 149. Rubis LJ, Stephenson LW, Johnston MR, Nagaraj S, Edmunds LH, Jr. Comparison of effects of prostaglandin E1 and nitroprusside on pulmonary vascular resistance in children after open-heart surgery. Ann Thorac Surg. Dec 1981;32(6):563-570. (Prospective; 26 patients) 150. Wimmer M, Schlemmer M, Ebner F. Hemodynamic effects of nifedipine and oxygen in children with pulmonary hypertension. Cardiovasc Drugs Ther. Dec 1988;2(5):661-668. (Prospective; 14 patients) 151. Bush A, Busst C, Booth K, Knight WB, Shinebourne EA. Does prostacyclin enhance the selective pulmonary vasodilator effect of oxygen in children with congenital heart disease? Circulation. Jul 1986;74(1):135-144. (Prospective; 20 patients) 152. Uglov FG, Davydenko VV, Orlovskii PI, Grigor’ev EE, Bushmarin ON. [Intravascular hemolysis in patients with artificial heart valves]. Vestn Khir Im I I Grek. Apr 1986;136(4):135-141. (Review) 153. Weesner KM. Hemodynamic effects of prostaglandin E1 in patients with congenital heart disease and pulmonary hypertension. Cathet Cardiovasc Diagn. Sep 1991;24(1):10-15. (Prospective; 27 patients) 154. Kermode J, Butt W, Shann F. Comparison between prostaglandin E1 and epoprostenol (prostacyclin) in infants after heart surgery. Br Heart J. Aug 1991;66(2):175-178. (Prospective; 20 patients) 155. Brook MM, Fineman JR, Bolinger AM, Wong AF, Heymann MA, Soifer SJ. Use of ATP-MgCl2 in the evaluation and treatment of children with pulmonary hypertension secondary to congenital heart defects. Circulation. Sep 1994;90(3):1287-1293. (Prospective, 28 patients) 156. Stevenson DK, Kasting DS, Darnall RA, Jr., et al. Refractory hypoxemia associated with neonatal pulmonary disease: the use and limitations of tolazoline. J Pediatr. Oct 1979;95(4):595-599. (Prospective; 39 patients) 157. Tripp ME, Drummond WH, Heymann MA, Rudolph AM. Hemodynamic effects of pulmonary arterial infusion of vasodilators in newborn lambs. Pediatr Res. Dec 1980;14(12):1311-1315. (Animal based study) 158. Starling MB, Neutze JM, Elliott RL, Elliott RB. Comparative studies on the hemodynamic effects of prostaglandin E1 prostacyclin, and tolazoline upon elevated pulmonary vascular resistance in neonatal swine. Prostaglandins Med. Nov 1981;7(5):349-361. (Animal based study) 159. Radermacher P, Huet Y, Pluskwa F, et al. Comparison of ketanserin and sodium nitroprusside in patients with severe ARDS. Anesthesiology. Jan 1988;68(1):152-157. (Prospective; 10 patients) 160. Radermacher P, Santak B, Becker H, Falke KJ. Prostaglandin E1 and nitroglycerin reduce pulmonary capillary pressure but worsen ventilation-perfusion distributions in patients with adult respiratory distress syndrome. Anesthesiology. Apr 1989;70(4):601-606. (Prospective; 10 patients) 20 January 2008 • EBMedicine.net 161. Vlahakes GJ, Turley K, Hoffman JI. The pathophysiology of failure in acute right ventricular hypertension: hemodynamic and biochemical correlations. Circulation. Jan 1981;63(1):87-95. (Animal based study) 162. Melot C, Lejeune P, Leeman M, Moraine JJ, Naeije R. Prostaglandin E1 in the adult respiratory distress syndrome. Benefit for pulmonary hypertension and cost for pulmonary gas exchange. Am Rev Respir Dis. Jan 1989;139(1):106-110. (Prospective; 6 patients) 163. Radermacher P, Santak B, Wust HJ, Tarnow J, Falke KJ. Prostacyclin for the treatment of pulmonary hypertension in the adult respiratory distress syndrome: effects on pulmonary capillary pressure and ventilation-perfusion distributions. Anesthesiology. Feb 1990;72(2):238-244. (Prospective; 9 patients) *164. Atz AM, Adatia I, Lock JE, Wessel DL. Combined effects of nitric oxide and oxygen during acute pulmonary vasodilator testing. J Am Coll Cardiol. Mar 1999;33(3):813-819. (Prospective; 71 patients) 165. Balzer DT, Kort HW, Day RW, et al. Inhaled Nitric Oxide as a Preoperative Test (INOP Test I): the INOP Test Study Group. Circulation. Sep 24 2002;106(12 Suppl 1):I76-81. (Prospective; 124 patients) 166. De Wet CJ, Affleck DG, Jacobsohn E, et al. 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. Apr 2004;127(4):1058-1067. (Retrospective; 126) 167. Hache M, Denault A, Belisle S, et al. Inhaled epoprostenol (prostacyclin) and pulmonary hypertension before cardiac surgery. J Thorac Cardiovasc Surg. Mar 2003;125(3):642-649. (Prospective randomized; 20 patients) 168. Kelly LK, Porta NF, Goodman DM, Carroll CL, Steinhorn RH. Inhaled prostacyclin for term infants with persistent pulmonary hypertension refractory to inhaled nitric oxide. J Pediatr. Dec 2002;141(6):830-832. (Case series; 4 patients) 169. Weston MW, Isaac BF, Crain C. The use of inhaled prostacyclin in nitroprusside-resistant pulmonary artery hypertension. J Heart Lung Transplant. Dec 2001;20(12):1340-1344. (Prospective; 6 patients) 170. Hache M, Denault AY, Belisle S, et al. Inhaled prostacyclin (PGI2) is an effective addition to the treatment of pulmonary hypertension and hypoxia in the operating room and intensive care unit. Can J Anaesth. Oct 2001;48(9):924-929. (Retrospective; 35 patients) 171. Fiser SM, Cope JT, Kron IL, et al. Aerosolized prostacyclin (epoprostenol) as an alternative to inhaled nitric oxide for patients with reperfusion injury after lung transplantation. J Thorac Cardiovasc Surg. May 2001;121(5):981-982. (Case report) 172. Della Rocca G, Coccia C, Costa MG, et al. Inhaled areosolized prostacyclin and pulmonary hypertension during anesthesia for lung transplantation. Transplant Proc. Feb-Mar 2001;33(1-2):1634-1636. (Prospective; 12 patients) 173. Abe Y, Tatsumi K, Sugito K, Ikeda Y, Kimura H, Kuriyama T. Effects of inhaled prostacyclin analogue on chronic hypoxic pulmonary hypertension. J Cardiovasc Pharmacol. Mar 2001;37(3):239-251. (Animal based study) 174. van Heerden PV, Barden A, Michalopoulos N, Bulsara MK, Roberts BL. Dose-response to inhaled aerosolized prostacyclin for hypoxemia due to ARDS. Chest. Mar 2000;117(3):819-827. (Prospective; 9 patients) 175. Max M, Rossaint R. Inhaled prostacyclin in the treatment of pulmonary hypertension. Eur J Pediatr. Dec 1999;158 Suppl 1:S23-26. (Review) 176. Olschewski H, Ghofrani HA, Walmrath D, et al. Inhaled prostacyclin and iloprost in severe pulmonary hypertension secondary to lung fibrosis. Am J Respir Crit Care Med. Aug 1999;160(2):600-607. (Prospective; 8 patients) 177. Beavo JA. Cyclic nucleotide phosphodiesterases: functional implications of multiple isoforms. Physiol Rev. Oct 1995;75(4):725-748. (Review) 178. Kato R, Sato J, Nishino T. Milrinone decreases both pulmonary arterial and venous resistances in the hypoxic dog. Br J Anaesth. Dec 1998;81(6):920-924. (Animal based study) 179. Chen EP, Bittner HB, Davis RD, Jr., Van Trigt P, 3rd. Milrinone improves pulmonary hemodynamics and right ventricular function in chronic pulmonary hypertension. Ann Thorac Surg. Mar 1997;63(3):814-821. (Animal based study) 180. Chen EP, Bittner HB, Davis RD, Van Trigt P. Hemodynamic and inotropic effects of milrinone after heart transplantation in the setting of recipient pulmonary hypertension. J Heart Lung Transplant. Jul 1998;17(7):669-678. (Animal based study) 181. Chang AC, Atz AM, Wernovsky G, Burke RP, Wessel DL. Milrinone: systemic and pulmonary hemodynamic effects in neonates after cardiac surgery. Crit Care Med. Nov 1995;23(11):1907-1914. (Prospective; 10 patients) 182. Watanabe H, Ohashi K, Takeuchi K, et al. Sildenafil for primary and secondary pulmonary hypertension. Clin Pharmacol Ther. May 2002;71(5):398-402. (Case report) EBMedicine.net • January 2008 183. Shekerdemian LS, Ravn HB, Penny DJ. Interaction between inhaled nitric oxide and intravenous sildenafil in a porcine model of meconium aspiration syndrome. Pediatr Res. Mar 2004;55(3):413-418. (Animal based study) 184. Stocker C, Penny DJ, Brizard CP, Cochrane AD, Soto R, Shekerdemian LS. Intravenous sildenafil and inhaled nitric oxide: a randomised trial in infants after cardiac surgery. Intensive Care Med. Nov 2003;29(11):1996-2003. (Prospective randomized; 16 patients) 185. Faraci FM, Heistad DD. Regulation of the cerebral circulation: role of endothelium and potassium channels. Physiol Rev. Jan 1998;78(1):5397. (Review) *186. Channick RN, Simonneau G, Sitbon O, et al. Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study. Lancet. Oct 6 2001;358(9288):1119-1123. (Prospective randomized double-blind placebo-controlled; 32 patients) 187. Frank H, Mlczoch J, Huber K, Schuster E, Gurtner HP, Kneussl M. The effect of anticoagulant therapy in primary and anorectic druginduced pulmonary hypertension. Chest. Sep 1997;112(3):714-721. (Retrospective 173 patients) 188. Thompson BT, Spence CR, Janssens SP, Joseph PM, Hales CA. Inhibition of hypoxic pulmonary hypertension by heparins of differing in vitro antiproliferative potency. Am J Respir Crit Care Med. Jun 1994;149(6):1512-1517. (Animal based study) 189. Kouchoukos NT, Blackstone EH, Kirklin JW. Surgical implications of pulmonary hypertension in congenital heart disease. Adv Cardiol. 1978(22):225-231. (Review) 190. Mentzer RM, Alegre CA, Nolan SP. The effects of dopamine and isoproterenol on the pulmonary circulation. J Thorac Cardiovasc Surg. Jun 1976;71(6):807-814. (Animal based study) 191. Holloway EL, Polumbo RA, Harrison DC. Acute circulatory effects of dopamine in patients with pulmonary hypertension. Br Heart J. May 1975;37(5):482-485. (Prospective; 21 patients) 192. Martinez AM, Padbury JF, Thio S. Dobutamine pharmacokinetics and cardiovascular responses in critically ill neonates. Pediatrics. Jan 1992;89(1):47-51. (Prospective; 13 patients) 193. Perkin RM, Levin DL, Webb R, Aquino A, Reedy J. Dobutamine: a hemodynamic evaluation in children with shock. J Pediatr. Jun 1982;100(6):977-983. (Prospective; 33 patients) 194. Crowley MR, Fineman JR, Soifer SJ. Effects of vasoactive drugs on thromboxane A2 mimetic-induced pulmonary hypertension in newborn lambs. Pediatr Res. Feb 1991;29(2):167-172. (Animal based study) 195. Hoffman TM, Wernovsky G, Atz AM, et al. Efficacy and safety of milrinone in preventing low cardiac output syndrome in infants and children after corrective surgery for congenital heart disease. Circulation. Feb 25 2003;107(7):996-1002. (Prospective randomized doubleblind placebo-controlled; 238 patients) 196. Higenbottam T, Wheeldon D, Wells F, Wallwork J. Long-term treatment of primary pulmonary hypertension with continuous intravenous epoprostenol (prostacyclin). Lancet. May 12 1984;1(8385):10461047. (Case report) 197. Barst RJ, Rubin LJ, McGoon MD, Caldwell EJ, Long WA, Levy PS. Survival in primary pulmonary hypertension with long-term continuous intravenous prostacyclin. Ann Intern Med. Sep 15 1994;121(6):409-415. (Prospective; 18 patients) *198. Barst RJ, Rubin LJ, Long WA, et al. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. The Primary Pulmonary Hypertension Study Group. N Engl J Med. Feb 1 1996;334(5):296-302. (Prospective randomized; 81 patients) *199. McLaughlin VV, Genthner DE, Panella MM, Rich S. Reduction in pulmonary vascular resistance with long-term epoprostenol (prostacyclin) therapy in primary pulmonary hypertension. N Engl J Med. Jan 29 1998;338(5):273-277. (Prospective; 27 patients) 200. McLaughlin VV, Sitbon O, Badesch DB, et al. Survival with first-line bosentan in patients with primary pulmonary hypertension. Eur Respir J. Feb 2005;25(2):244-249. (Prospective; 169 patients) 201. Rubin LJ, Mendoza J, Hood M, et al. Treatment of primary pulmonary hypertension with continuous intravenous prostacyclin (epoprostenol). Results of a randomized trial. Ann Intern Med. Apr 1 1990;112(7):485-491. (Prospective randomized; 24 patients) 202. Carcillo JA, Fields AI. Clinical practice parameters for hemodynamic support of pediatric and neonatal patients in septic shock. Crit Care Med. Jun 2002;30(6):1365-1378. (Review, expert consensus) 203. Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med. May 4 2000;342(18):1334-1349. (Review) 204. Zapol WM, Snider MT. Pulmonary hypertension in severe acute respiratory failure. N Engl J Med. Mar 3 1977;296(9):476-480. (Prospective; 30 patients) 205. Tomashefski JF, Jr., Davies P, Boggis C, Greene R, Zapol WM, Reid LM. The pulmonary vascular lesions of the adult respiratory distress syndrome. Am J Pathol. Jul 1983;112(1):112-126. (Retrospective; 22 patients) 21 Pediatric Emergency Medicine Practice© 206. Erdmann AJ, 3rd, Vaughan TR, Jr., Brigham KL, Woolverton WC, Staub NC. Effect of increased vascular pressure on lung fluid balance in unanesthetized sheep. Circ Res. Sep 1975;37(3):271-284. (Animal based study) 207. Sibbald WJ, Driedger AA, Myers ML, Short AI, Wells GA. Biventricular function in the adult respiratory distress syndrome. Chest. Aug 1983;84(2):126-134. (Prospective; 50 patients) 208. Katz R, Pollack M, Spady D. Cardiopulmonary abnormalities in severe acute respiratory failure. J Pediatr. Mar 1984;104(3):357-364. (Prospective; 23 patients) 209. Rossaint R, Falke KJ, Lopez F, Slama K, Pison U, Zapol WM. Inhaled 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 oxide to children with acute respiratory distress syndrome. Pediatr Crit Care Med. Sep 2004;5(5):469-474. (Retrospective; 39 patients) 211. Taylor RW, Zimmerman JL, Dellinger RP, et al. Low-dose inhaled nitric oxide in patients with acute lung injury: a randomized controlled trial. Jama. Apr 7 2004;291(13):1603-1609. (Prospective randomized placebo-controlled; 385 patients) 212. Lundin S, Mang H, Smithies M, Stenqvist O, Frostell C. Inhalation of nitric oxide in acute lung injury: results of a European multicentre study. The European Study Group of Inhaled Nitric Oxide. Intensive Care Med. Sep 1999;25(9):911-919. (Prospective randomized; 268 patients) 213. Asahara T, Murohara T, Sullivan A, et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science. Feb 14 1997;275(5302):964-967. (Animal based study) 214. Baber SR, Deng W, Master RG, et al. Intratracheal mesenchymal stem cell administration attenuates monocrotaline-induced pulmonary hypertension and endothelial dysfunction. Am J Physiol Heart Circ Physiol. Feb 2007;292(2):H1120-1128. (Animal based study) 215. Kanki-Horimoto S, Horimoto H, Mieno S, et al. Implantation of mesenchymal stem cells overexpressing endothelial nitric oxide synthase improves right ventricular impairments caused by pulmonary hypertension. Circulation. Jul 4 2006;114(1 Suppl):I181-185. (Animal based study) 216. Zhao YD, Courtman DW, Deng Y, Kugathasan L, Zhang Q, Stewart DJ. Rescue of monocrotaline-induced pulmonary arterial hypertension using bone marrow-derived endothelial-like progenitor cells: efficacy of combined cell and eNOS gene therapy in established disease. Circ Res. Mar 4 2005;96(4):442-450. (Animal based study) *217. Wang XX, Zhang FR, Shang YP, et al. Transplantation of autologous endothelial progenitor cells may be beneficial in patients with idiopathic pulmonary arterial hypertension: a pilot randomized controlled trial. J Am Coll Cardiol. Apr 10 2007;49(14):1566-1571. (Prospective randomized; 31 patients) 218. Rozkovec A, Montanes P, Oakley CM. Factors that influence the outcome of primary pulmonary hypertension. Br Heart J. May 1986;55(5):449-458. (Retrospective; 34 patients) 219. Rich S, Lam W. Atrial septostomy as palliative therapy for refractory primary pulmonary hypertension. Am J Cardiol. May 15 1983;51(9):1560-1561. (Case report) 220. Mullins CE, Nihill MR, Vick GW, 3rd, et al. Double balloon technique for dilation of valvular or vessel stenosis in congenital and acquired heart disease. J Am Coll Cardiol. Jul 1987;10(1):107-114. (Case series; 41 patients) 221. Hausknecht MJ, Sims RE, Nihill MR, Cashion WR. Successful palliation of primary pulmonary hypertension by atrial septostomy. Am J Cardiol. Apr 15 1990;65(15):1045-1046. (Case report) 222. Kerstein D, Levy PS, Hsu DT, Hordof AJ, Gersony WM, Barst RJ. Blade balloon atrial septostomy in patients with severe primary pulmonary hypertension. Circulation. Apr 1 1995;91(7):2028-2035. (Prospective; 15 patients) 223. Sandoval J, Gaspar J, Pulido T, et al. Graded balloon dilation atrial septostomy in severe primary pulmonary hypertension. A therapeutic alternative for patients nonresponsive to vasodilator treatment. J Am Coll Cardiol. Aug 1998;32(2):297-304. (Case series; 15 patients) 224. Barst RJ. Role of atrial septostomy in the treatment of pulmonary vascular disease. Thorax. Feb 2000;55(2):95-96. (Editorial) 225. Nagaoka T, Fagan KA, Gebb SA, et al. Inhaled Rho kinase inhibitors are potent and selective vasodilators in rat pulmonary hypertension. Am J Respir Crit Care Med. Mar 1 2005;171(5):494-499. (Animal based study) 226. Kao PN. Simvastatin treatment of pulmonary hypertension: an observational case series. Chest. Apr 2005;127(4):1446-1452. (Prospective; 16 patients) 227. Taraseviciene-Stewart L, Scerbavicius R, Choe KH, et al. Simvastatin causes endothelial cell apoptosis and attenuates severe pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol. Oct 2006;291(4):L668-676. (Animal based study) Pediatric Emergency Medicine Practice© 228. Jiang BH, Tawara S, Abe K, Takaki A, Fukumoto Y, Shimokawa H. Acute vasodilator effect of fasudil, a Rho-kinase inhibitor, in monocrotaline-induced pulmonary hypertension in rats. J Cardiovasc Pharmacol. Feb 2007;49(2):85-89. (Animal based study) 229. Steinhorn RH, Albert G, Swartz DD, Russell JA, Levine CR, Davis JM. Recombinant human superoxide dismutase enhances the effect of inhaled nitric oxide in persistent pulmonary hypertension. Am J Respir Crit Care Med. Sep 1 2001;164(5):834-839. (Animal based study) 230. Cowan KN, Heilbut A, Humpl T, Lam C, Ito S, Rabinovitch M. Complete reversal of fatal pulmonary hypertension in rats by a serine elastase inhibitor. Nat Med. Jun 2000;6(6):698-702. (Animal based study) 231. Cowan KN, Jones PL, Rabinovitch M. Elastase and matrix metalloproteinase inhibitors induce regression, and tenascin-C antisense prevents progression, of vascular disease. J Clin Invest. Jan 2000;105(1):21-34. (Animal based study) 232. Rubinstein I. Human VIP-alpha: an emerging biologic response modifier to treat primary pulmonary hypertension. Expert Rev Cardiovasc Ther. Jul 2005;3(4):565-569. (Review) 233. Guignabert C, Raffestin B, Benferhat R, et al. Serotonin transporter inhibition prevents and reverses monocrotaline-induced pulmonary hypertension in rats. Circulation. May 31 2005;111(21):2812-2819. (Animal based study) 234. Patterson KC, Weissmann A, Ahmadi T, Farber HW. Imatinib mesylate in the treatment of refractory idiopathic pulmonary arterial hypertension. Ann Intern Med. Jul 18 2006;145(2):152-153. (Case report) 235. Schermuly RT, Dony E, Ghofrani HA, et al. Reversal of experimental pulmonary hypertension by PDGF inhibition. J Clin Invest. Oct 2005;115(10):2811-2821. (Animal based study) 236. Mallory GB, Spray TL. Paediatric lung transplantation. Eur Respir J. Nov 2004;24(5):839-845. (Review) 237. Mendeloff EN, Meyers BF, Sundt TM, et al. Lung transplantation for pulmonary vascular disease. Ann Thorac Surg. Jan 2002;73(1):209-217; discussion 217-209. (Retrospective; 100 patients) 238. Boucek MM, Edwards LB, Keck BM, Trulock EP, Taylor DO, Hertz MI. Registry for the International Society for Heart and Lung Transplantation: seventh official pediatric report—2004. J Heart Lung Transplant. Aug 2004;23(8):933-947. 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 Free Report: “Evidence-Based Medicine: A Guide For Physicians” Date of Original Release: January 1, 2008. Date of most recent review: December 10, 2007. Termination date: January 1, 2011. 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. Credit Designation: The Mount Sinai School of Medicine designates this educational activity for a maximum of 48 AMA PRA Category 1 Credit(s)TM per year. Physicians should only claim credit commensurate with the extent of their participation in the activity. ACEP Accreditation: Pediatric Emergency Medicine Practice is also approved by the American College of Emergency Physicians for 48 hours of ACEP Category 1 credit per annual subscription. AAP Accreditation: This continuing medical education activity has been reviewed by the American Academy of Pediatrics and is acceptable for up to 44 AAP credits. These credits can be applied toward the AAP CME/CPD Award available to Fellows and Candidate Fellows of the American Academy of Pediatrics. Needs Assessment: The need for this educational activity was determined by a survey of medical staff, including the editorial board of this publication; review of morbidity and mortality data from the CDC, AHA, NCHS, and ACEP; and evaluation of prior activities for emergency physicians. Target Audience: This enduring material is designed for emergency medicine physicians, physician assistants, and nurse practitioners. Goals & Objectives: Upon completion of this article, you should be able to: (1) demonstrate medical decision-making based on the strongest clinical evidence; (2) cost-effectively diagnose and treat the most critical ED presentations; and (3) describe the most common medicolegal pitfalls for each topic covered. Discussion of Investigational Information: As part of the newsletter, faculty may be presenting investigational information about pharmaceutical products that is outside Food and Drug Administration approved labeling. Information presented as part of this activity is intended solely as continuing medical education and is not intended to promote off-label use of any pharmaceutical product. Disclosure of Off-Label Usage: This issue of Pediatric Emergency Medicine Practice discusses no off-label use of any pharmaceutical product. Faculty Disclosure: It is the policy of Mount Sinai School of Medicine to ensure objectivity, balance, independence, transparency, and scientific rigor in all CME-sponsored educational activities. All faculty participating in the planning or implementation of a sponsored activity are expected to disclose to the audience any relevant financial relationships and to assist in resolving any conflict of interest that may arise from the relationship. Presenters must also make a meaningful disclosure to the audience of their discussions of unlabeled or unapproved drugs or devices. In compliance with all ACCME Essentials, Standards, and Guidelines, all faculty for this CME activity were asked to complete a full disclosure statement. The information received is as follows: 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. Method of Participation: • Print Subscription Semester Program: Paid subscribers with current and valid licenses in the United States who read all CME articles during each Pediatric Emergency Medicine Practice six-month testing period, complete the post-test and the CME Evaluation Form distributed with the June and December issues, and return it according to the published instructions are eligible for up to 4 hours of CME credit for each issue. You must complete both the post test and CME Evaluation Form to receive credit. Results will be kept confidential. CME certificates will be delivered to each participant scoring higher than 70%. • Online Single-Issue Program: Current, paid subscribers with current and valid licenses in the United States who read this Pediatric Emergency Medicine Practice CME article and complete the online post-test and CME Evaluation Form at EBMedicine.net are eligible for up to 4 hours of Category 1 credit toward the AMA Physician’s Recognition Award (PRA). You must complete both the post-test and CME Evaluation Form to receive credit. Results will be kept confidential. CME certificates may be printed directly from the Web site to each participant scoring higher than 70%. Hardware/Software Requirements: You will need a Macintosh or PC with internet capabilities to access the website. Adobe reader is required to download archived articles. Learn how practicing evidence-based medicine can empower you to provide better patient care in this free report. Send an email to [email protected] with the subject “FREE E-NEWS” to sign up for our free email newsletter and we’ll email you a copy of “Evidence-Based Medicine: A Guide For Physicians.” Your free e-newsletter will be delivered to your email twice per month and includes case studies, medico-legal pitfalls to avoid, conference updates, job listings, and more. You can easily opt out at anytime. Best Of All: It’s Free! Class Of Evidence Definitions Each action in the clinical pathways section of Pediatric Emergency Medicine Practice receives a score based on the following definitions. Class I • Always acceptable, safe • Definitely useful • Proven in both efficacy and effectiveness Level of Evidence: • One or more large prospective studies are present (with rare exceptions) • High-quality meta-analyses • Study results consistently positive and compelling Class II • Safe, acceptable • Probably useful Level of Evidence: • Generally higher levels of evidence • Non-randomized or retrospective studies: historic, cohort, or case control studies • Less robust RCTs • Results consistently positive Class III • May be acceptable • Possibly useful • Considered optional or alternative treatments Level of Evidence: • Generally lower or intermediate levels of evidence • Case series, animal studies, consensus panels • Occasionally positive results Indeterminate • Continuing area of research • No recommendations until further research Level of Evidence: • Evidence not available • Higher studies in progress • Results inconsistent, contradictory • Results not compelling 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. Pediatric Emergency Medicine Practice is not affiliated with any pharmaceutical firm or medical device manufacturer. CEO: Robert Williford President and Publisher: Stephanie Williford Director of Member Services: Liz Alvarez Direct all editorial or subscription-related questions to EB Medicine: 1-800-249-5770 • Fax: 1-770-500-1316 • Non-U.S. subscribers, call: 1-678-366-7933 EB Medicine • 5550 Triangle Pkwy, STE 150 • Norcross, GA 30092 E-mail: [email protected] • Web Site: EBMedicine.net Pediatric Emergency Medicine Practice (ISSN Print: 1549-9650, ISSN Online: 1549-9669) is published monthly (12 times per year) by EB Practice, 5550 Triangle Pkwy, Ste. 150, Norcross, GA 30092. Opinions expressed are not necessarily those of this publication. Mention of products or services does not constitute endorsement. This publication is intended as a general guide and is intended to supplement, rather than substitute, professional judgment. It covers a highly technical and complex subject and should not be used for making specific medical decisions. The materials contained herein are not intended to establish policy, procedure, or standard of care. Pediatric Emergency Medicine Practice is a trademark of EB Practice, LLC. Copyright © 2008 EB Practice, LLC. All rights reserved. No part of this publication may be reproduced in any format without written consent of EB Practice, LLC. Individual subscription price: $299, Institutional/library/hospital price: $899, U.S. funds. (Call for international shipping prices.) Pediatric Emergency Medicine Practice© 24 January 2008 • EBMedicine.net