Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Cardiac contractility modulation wikipedia , lookup
Heart failure wikipedia , lookup
Mitral insufficiency wikipedia , lookup
Management of acute coronary syndrome wikipedia , lookup
Coronary artery disease wikipedia , lookup
Cardiac surgery wikipedia , lookup
Arrhythmogenic right ventricular dysplasia wikipedia , lookup
Antihypertensive drug wikipedia , lookup
Atrial septal defect wikipedia , lookup
Quantium Medical Cardiac Output wikipedia , lookup
Dextro-Transposition of the great arteries wikipedia , lookup
accp consensus statement Primary Pulmonary Chairman: LewisJ. Rubin, M.D., 1993; 104:236-50) (Chest PPH = primary pulmonary veno-ocelusive disease; PVOD hypertension; RAP right DEFINITIONS AND Primary pulmonary ferred to as unexplained atrial Hypertension* F.C.C.P the population ofpatients with pressure (PPH), also is a disease reor and syn- with this disease. The vast clinical PPH has a pulmonary are arteriopathy, logic evidence editorial see page 5 for PPH characteristic pulmonary pertension, , arteriopathy because ofpatients hypertension toxin-induced similar is not pathogno- changes are with congenital associated pulmonary of PPH pulmonary subsets PPH have Subsets been iden- heart disease, with portal hyhypertension, HIV-related pulmonary hypertension. For practical management, a clinical definition of PPH is sufficient for most patients. A useful clinical definition is the presence of pulmonary hypertension (mean pulmonary artery pressure >25 mm Hg at rest, In was distinct entities. the past, plexogenic considered hypertension, to be ofcritical the hallmark and plexogenic diagnostic and pathogenetic significance. The grading system developed by Heath and Edwards5 to assess the reversibility of hypertensive vascular lesions in biopsies heart disease was extrapolated congenital unproven assumption that of patients to PPH the pathogenesis and evolution ofplexogenic pulmonary arteriopathy would be identical regardless ofcause. Several recent studies in large series of patients with clinical PPH have shown also arteriopathy of primary pulmonary lesions were considered on the although a few patients will have pathoof other diseases or even normal lung Pulmonary monic comment three felt at present to represent Pulmonary Arteriopathy: with For of Pathologic tified pathologically. However, pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis ETIOLOGY hypertension or idiopathic, and Description Historically, pulmonary constellation of diseases described at both clinical pathologic levels. However, neither the clinical drome nor the pathologic changes independently define majority Definition that primary a spectrum pulmonary arteriopathy of histopathologic classic plexogenic nonplexogenic, includes lesions artenopathy forms. The three ranging from to microthrombotic, major types of pul- and or >30 artery causes 5Consensus mm Hg wedge (Table during exercise), pressure, 1). Conference F.C.C.P (Chairman), and Critical Care and normal absence pulmonary of secondary Lung C Professor Medicine, Lewis J. Rubin, M.D., 1 -Secondary ofPulmonary Causes Hypertension disease Parenchymal lung disease . Disorders of ventilation . Congenital anomalies . Hypoxia-induced, le, altitude Heart Participants: and Head, Division of Pulmonary University of Maryland School of Medicine, Baltimore; Robyn j Barst, M.D., Associate Professor of Clinical Pediatrics, Columbia University, New York; Larry R. Kaiser, M.D. , F.C.C.P, Chief, General Thoracic Surgery, Associate Professor of Surgery, University of Pennsylvania, Philadelphia; Spencer K. Koernet; M.D. , EC.C.P, Director, Pulmonary Division, Cedars-Sinai Medical Center, Professor of Medicine, UCLA School of Medicine, Los Angeles; James E. Lyd, M.D., F.C.C.P, Associate Professor, Division of Pulmonary and Critical Care Medicine, Vanderbilt University, Nashville, Tenn; Michael D. McGoon, M.D. , Associate Professor of Medicine and Consultant in Cardiovascular Diseases, Mayo Clinic, Rochester, Minn; Giuseppe Pietra, M.D. , F.C.C.P, Professor of Pathology, University of Pennsylvania Medical School, Department of Pathology and Laboratory Medicine, Philadelphia; Stuart Rich, M.D., F.C.C.P, Professor of Medicine, Chief, Section of Cardiology, University of Illinois, Chicago; Melvyn Rubenfire, M.D., F.C.C.P, Professor of Internal Medicine, University of Michigan, Ann Arbor; James Theodore, M.D., F.C.C.P, Associate Professor of Medicine, Division ofPulmonary and Critical Care Medicine, Stanford University School of Medicine, Palo Alto, Calif. Reprint requests: ACCI 3300 Dundee Road, Northbrook, IL 60062 236 Table . disease Disorders ofleft C Congenital Thromboembolic . heart systemic disease Pulmonary C Mediastinal . Congenital . Foreign filling - to - pulmonary or obstruction shunts of pulmonary vessels thromboembolism fibrosis stenosis ie, talc bodies, . Tumor C Hemoglobinopathies . Schistosome Collagen eggs vascular Conditions associated Exogenous substances . Anorexic Portal with and pulmonary pulmonary vasculitides hypertension agents . Toxic rapeseed . L-tryptophan . Crack cocaine HIV diseases oil infection hypertension Primary Pulmonary Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21673/ on 05/02/2017 Hypertension (Lewis J. Rubin et a!) monary are arteriopathy as follow: medial involving (1) isolated hypertrophy the muscular medial and concentric tosis, which may or may plexiform lesions, angiomatoid sis, and necrotizing arteritis; arteries Clinical hypertrophy; laminar (2) fibroelas- soon not be associated with lesions, fibrinoid necroand (3) medial hypertro- the Heath-Edwards with hemodynamic grading indices PPH: after the Families different the NIH between PPH do Histopathologic changes timal fibrosis of muscular veno-occlusive of pulmonary would be pulmonary occlusive similar capillaries pulmonary disease preferable to call angiopathy rather disease. Although and this than its arteries suggests in cases that it entity obstructive pulmonary venocause is unknown, cases have histopathologic presence of pulmonary hallmark organized veins and and of this disease recanalized venules. These thrombi rence thrombi are often pads not only arteries. The arterialization, the alveolar capillaries are extremely pleural and peribronchial-perivascular dilated, the pulmonary and pleural congested, lymphatics centric and the alveoli macrophages. the are interstitium contain Medial numerous hypertrophy, is ec- concentric nonlaminar intimal fibrosis, and fibrinoid necrosis of pulmonary arteries are also present. Pulmonary is a rare Capi&iry condition of thin-walled chial-perivascular the affected elastic muscular characterized microvessels interstitium, and the walls of pulmonary expansion Hemangiomatosis 1 infiltrating the peribronthe lung parenchyma, These microvessels veins of different infiltrate diameter, ofthe media, fibrous luminal vessels, and destruction fibers. There arteries and The proliferating to bleeding, by the is also medial muscularization macrophages the with hypertrophy ofthe arterioles. are prone accumulation in alveolar spaces. of patients, not and has analysis by incomplete transmitted is manifest to predisposfeatures, is complex The genetic is confounded the gene ex- was diagnosed probably due the disease. by A few reported and for generations, . both capillary A is familial occur- pulmonary veno- hemangiomatosis.’ 10.16 in Children the histopathologic differences appear children. Syncope, findings to be most with in children presenting symptom often effort-related patients younger with PPH. children, over 10 years Childhood ratio with occurs of symptoms in children severe, with long-standing equal 4 frequency and time of diagnosis than in adults, particularly to the 2- to 3-year median patients. The age at diagnosis most important useful PPH of survival (mean pressures and hemodynamics and responses significantly.’7 lator predictor parameters PPH. to male between is usually in those for PPH, diagnosis as survival appears in adult to be the in children. The pulmonary cardiac index) artery that are in predicting survival in adult patients with may not be applicable to the pediatric population. Baseline younger a in female to 1.7:1 female The interval PPH and right atnal is children and than in adult children who present with syncope. Prior to the era of vasodilator treatment most children died within 1 year of hemodynamic younger seizures, in young in children male children as opposed seen in adult onset shorter in the without Right heart failure is rare in the occurring most often in children of age PPH apparent or frequent is more opposed obstruction of of the medial thin-walled microvessels resulting in hemoptysis and of hemosiderin-laden (PCH): This proliferation transmission established. The not with PPH are often the same as those in adult patients with PPH, the clinical presentation, natural history, and factors influencing survival may differ. These and hemo- and been disease Although associated with eccentric fibrous intimal in venous vessels but also in muscular veins show medial hypertrophy and edematous, siderin-laden has PPH is the in recognized sporadic of onset is younger in subsequent present in many families with PPH occlusive have been observed in patients treated chemotherapeutic agents,7’8 and familial been reported.9”#{176} As the name indicates, by documented instances of father to son transmission of the gene suggested it is not x-linked. An interesting phenomenon, genetic anticipation, in which the age lesions with certain the in the alveolar arteries were considered to be secondary obstructions. The frequent presence of eccentric and concentric nonlaminar in- and PPH Although the gene appears to have dominant who pulmonary to venous widespread for in recorded 15 individuals botic registry familial PPH which it was thromveins.6 were cept that in familial PPH, the disease earlier after the onset of symptoms, with in because PPH and heightened ing to familial obstructive venules and with disease in 12 (6 percent) of 187 patients.’4 manifestations and outcome of PPH were of families penetrance, so designated described of PPH 1984,’ hypertension, was were description familial clinical the mode of genetic not been definitively to be caused by a primary disorder of the pulmonary PPH clinical families Pulmonary Veno-occiusive Disease (PVOD): Venoocclusive disease, an uncommon cause of pulmonary thought with original Fourteen 1951.12 phy and eccentric and concentric nonlaminar fibrosis. Plexogenic pulmonary arteriopathy is a nonspecific pattern of response of the pulmonary vasculature to hemodynamic injury, and system does not correlate and prognosis.2 Subsets Familial older are children, as well as Histopathologic long-term studies CHEST Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21673/ on 05/02/2017 often although similar in chronic vasodi- the survival differ offer clues to I 104 I 1 I JULY, 1993 237 the findings. In the Wagenvoort,4 classic not only was studies by Wagenvoort medial hypertrophy and severe in patients the only reactive under 15 years ofage, but it was also often change in infants, suggesting a more vasopulmonary vascular bed in the youngest children. The youngest children long-term vasodilator kilogram) of calcium better to (per doses be needed with PPH to produce compared also tend to respond treatment. Higher channel blockers may a favorable to adult response in children for insomnia, More than Exogenous With Vasculopathy Pulmonary Hypertension: Pulmonary Drug-Induced Hypertension Pulmonary deaths. myalgia, disease syndromes infiltration, pleural sion. The Anorexic agents (aminorex, fenfluramine): An epidemic ofchronic pulmonary hypertension occurred in Switzerland, Austria, and Germany in the late 1960s in association with the use of aminorex (2-amino-S.. phenyl-2-oxazoline), an appetite suppressant with a chemical structure similar to adrenaline and ephedrifle.’9 This drug was released into the market in Switzerland in 1965 and was withdrawn in 1968. A 20-fold increase hypertension 1969, and ofaminorex timing, and mates suggest in ofchronic pulmonary 1967, peaked after 1972. The from 1968 association ofpulmonary is strong relative but stood, developed incidence started disappeared the epidemic and in the the the hypertension to geographic exact only is not remains 1 out of 1 ,000 pulmonary with the use distribution relationship mechanism that under- unsolved. users hypertension. Esti- ofaminorex However, the incidence of pulmonary hypertension also was increased in individuals who did not report the use of aminorex, and the disease syndrome could not be reproduced in animals, even after trials in several species in whom aminorex was administered for up to 2 years. pathologic pulmonary condition hypertension idiopathic pulmonary were characterized arteries laminar lesions, Four is diffuse hypertension methyl which of fenfluramine 3(trifluromethyl) An epidemic myalgia and in New syndrome L-tryptophan, 238 with progressive developed vasculitis, and veins. was also Mexico (EMS) characterized eosinophilia pulmonary The with that included pulmonary phenomena, of the patients hyper- and death. vasculitis was widearter- characterized by and transmural infiltrates eosinophils. In three patients, intimal arteries and was associated condition and of be- five patients showed vasculitis involving both fibromyxoid pulmonary of EMS embolic dense perivascular phocytes and few it is suspected thickening of lymthere of muscular veins. The vascular pathologic with mild interstitial pneu- interstitial accumulation of lymphocytes and eosinophils. (c) Chemotherapy-related pulmonary hypertension: Several therapy agents patients with PVOD developing after chemohave been reported. Some of the implicated include carmustine, bleomycin, cyclophospha- mide, etoposide and (d) Crack cocaine four young women hypertension pulmonary cocaine.m disease males. mitomycin-C.7’8 inhalation: who developed A recent clinical and hypertensive arteries in association The authors suspected in females, since changes in muscular with smoking crack a predisposition for the Pulmonary report cited pulmonary majority Hypertension: at risk were Toxins oil syndrome: The toxic oil syndrome disorder which was related to the from reported cases of muscular sumption of an oil in Spain in 1981.” More than 20,000 cases were and many deaths were related to pulmonary subsequent or dexfenfluramine benzene-ethanamine amine complex Both epidemics polyneuropathy, Lung biopsies from spread nonnecrotizing ies but pulmonary hyperten- (a) Toxic multisystem indistinguishable arteriopathy. The by medial hypertrophy drochloride), a sympathomimetic as an appetite suppressant. (b) L-tryptophan-associated sion: aminorex-associated and muscularization of arterioles, concentric intimal fibrosis, plexiform and angiomatoid fibrinoid necrosis, and siderosis. patients have been reported2#{176}’2’ with pulmo- the use and of to toxic byproduct or contaminant analogy has been suggested symptom oil syndrome. Exogenous The nary the is unknown, ofa An toxic monia to of have included diffuse effusion, and pulmonary mechanism tension, ( a) syndrome. reported for Disease Control, including several Common clinical manifestations have included arthralgia, dyspnea, and cough. Pulmonary to be the result L-tryptophan. 18 or premenstrual cases have been the Center tween Associated Conditions depression, 1,400 EMS reported, to distress and by a second developed hy- Pulmonary use this second scleroderma, hyperten- by a syndrome was first recognized marketed hypertension. The syndrome an early systemic syndrome (N-ethyl in current illegally of in 1989. The eosinophilia-myalgia was soon linked to consumption of which was available over the counter had several that included pulmonary infiltrates, stage in which one fever, was A later weight a common stage loss cooking stages, with respiratory which was followed third of the patients and neurologic myalgias, hypertension stage. with rapeseed is a con- symptoms. problem appeared similar and neuromuscular in to disorders. In 1986 and 1987, severe pulmonary hypertension was the leading cause of death from toxic oil syndrome.m The specific toxic agent has not been identified, but oleoanilides or toxic compounds derived from them The pathology or both are is unique Primary Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21673/ on 05/02/2017 believed to be important. but most closely resembles Pulmonary Hypertension (Lewis J. Rubin eta!) pulmonary veins are thelial thelial veno-occlusive involved. disease; both arteries consist of The initial lesions injury with marked cells and vasoformative proliferation reserve uisite and endo- pulmonary or of the vascular inflammatory infiltrates. The intimal lesions subsequently evolve into obliterative intimal and luminal fibrosis of arteries and veins. Medial hypentrophy of muscular arteries, musculanization of arterioles plexiform lesions have been (b) Portal Hypertension-Associated pertension: Although numerous reports four decades suggested with portal hypertension ship is sufficiently been an A large strated conclusively McDonnell et aP Hopkins from occurred in that reviewed 1944 to percent ofpatients clinical clinical patients prevalence during of pulmonary the relation- series 1981 and found of all patients, with cirrhosis with but (p’(O.OOl). biopsy-proven of PPH was prospective study incidence of pulmonary is real; at Johns be contributory. creased nhosis by finding with portal hospitalized mechanisms rather 10 (2 percent) that are than unclear, cirrhosis of 507 positive for hypertension, in 0.73 Of 2,459 HIV itself, appears / Endoth to be the been either type. material A recent from a cohort hypertension, reported of the to have plexogenic type Hypertenpatients with clinical syndrome Pulmonary described the on talc vascular obstruc- granulomatosis prospective of 1,200 study patients HIV. Six patients developed supporting an association may reported who were pulmonary of PPH and positivity. AND PATHOGENESIS PATHOPHYSIOLOGY Pat hogenesis the inin cm- The patients had PPH. hypertension, hypertension but portal embolic 74 patients PPH cirrhosis, the 0.61 percent substantiated hypertension portal that pulmonary concern tion from (p<0.001). A recent have HIV Infection-Associated Several case reports have infection who developed demon- that cirrhosis, arteniopathy micnothrombotic additional has first the relationship 17,901 autopsies 0. 13 percent Hythe last Pulmonary that its existence autopsy HIV hypertension. with of PPH. One early report11 described five patients with hemophiliawho developed PPH; all had received intravenous factor VIII for several years and tested positive for HIV In individuals who develop HIV infection related to intravenous drug use, there is reported. association hypertension, infrequent debated. (c) sion: ofpulmonary patients with or without of myoendocells and pen- and even for development Pathologically, The prereq- pathogenesis of PPH remains speculative. Fig- ure 1 shows the for the pathogenesis accepted proposed suggested mechanisms responsible of this disease. The most widely mechanism for the pathogenesis of PPH-pulmonary vasoconstriction is based on histo- Ivury and Pu Vasoconstricon in Suscep8ble Indvis CoagtMtion I7m Pracoegulallon Damaged Pulmanaiy VascularBed with Loss PulmanyArriolea of PI-Ende1i C / lnons Throinbosas m aftu Abnormal Vascular A Vascular Pulmonaty Response Iniu,y with VIcious Cycle Hyperlension T Perpe’ua8gPu1monary + Crass-.ectlonalAre. of Pulmonary VascularBed Plexc and ThrOmbedc PuknonaryMedopathy FIGURE 1. Possible pathogenesis CHEST/104/1/JULY,1993 Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21673/ on 05/02/2017 of PPH. 239 pathologic studies therapy.4”8’’#{176} disease stimuli clinical responses studies suggest of predisposed may initiate the istic vascular is the primary lesions. event an important sible and These triggers individuals, development in whom various of the character- ofpulmonary include (high altitude) vasoconstrictor endothelium, balance between boxane versus derived factors. initiating occur, vascular vasoactive ments surface For example, not also activate between the and may contribute injury.49’5#{176} Migration of smooth to of vasocon- aggregation. and cellular The ele- injured endothelial cell ofthe pulmonary vascular the process in situ, muscle cells in the cell surface and transforming the pulmonary of in the pathogenesis that treatment also resulted in of PPH comes with anticoagincreased sun- the to the hypertension with a normal ventricular right prolonged filling without cardiac pressure exercise. With prolonged an anatomic decrease in and distensibility of pulmonary occurs in addition to vasoconstricresistance vessels. Initially, the output remains appropriately pressures becomes overload normal at nest but does not with exercise, despite an in- and ischemia. decreased develops to increasing heart rate, Eventually, producing the cardiac at rest. Right ventricular with tricuspid regurgitation, right uting to failure. also affects left ventricular wall stress right output volume leading and contrib- Severe right ventricular hypertension ventricular diastolic function, incneas- ing left ventricular end diastolic pressure and decneasing left ventricular filling. The pulmonary capillary wedge and left ventricular filling pressures may be increased episodes in this setting. in PPH are usually effort-related to a limitation in cardiac output. Other including sympathetic and parasympa- alterations, may also play Based on the pathogenesis PPH, the two most frequent progressive right ventricular a role. and pathophysiology of mechanisms ofdeath are failure and sudden death, with the former occurring more often.M sive right ventricular failure, the scenario With pnogresas described above leads to dyspnea, hypoxemia, and a progressive decrease in cardiac output. Pneumonia commonly is fatal due to alveolar hypoxia causing further pulmonary vasoconstriction, with an inability to maintain adequate cardiac and death. occur, vival. return crease in right ventricular filling pressure. Right ventricular myocandial blood flow may be compnomised by increases in right ventricular systolic and thetic vas- in response right to venous in filling pressures. artery hypertension, a normal area accommodates systemic Pulmonary failure occurs vessels pulmonary cardiac increase that in at rest as well as during pulmonary hypertension, and are due mechanisms, pulmonary that in situ thrombosis is occurring. Further support for the role of coagulation abnormalities at the endothelial output Syncopal cular bed from its usual anticoagulant state (due to release of prostacycin and plasmmnogen activator inhibitors) to a procoagulant state.52 Fibrinopeptide A levels are elevated in patients with PPH suggesting from the demonstration ulation therapy has pressure overload. right ventricular modestly of vascular occurs with release ofan unidentified chemagent from injured pulmonary endothelial Endothelial cell damage can also produce thrombosis hypentrophies ventricular levels pulmonary platelet humoral an bed elevated only ventricle diastolic endothelial- Coagulation abnormalities may or further exacerbating the pulmonary promote but other large changes pulmonary tion studies pump variations without With resistance the pulin the Several muscular considerable cross-sectional blood shear tone Many of an imbalance including throm- and of the blood and result in remodeling arterioles otactic cells.5’ mediators. possible role mediators disease.47’ stniction, interactions can damage in alterations prostacyclin, thromboxane pulmonary pressure and sympathetic injury.’ stimuli resulting have looked at the favoring vasoconstrictor it is Pos- vasoconstriction in suscepthe following: normobaric or hypoxia, autoimmune disor- dens, drugs and toxins, increased flow with or without increased stress, lung injury, and increased resulting in catecholamine-induced of these monary is a in its pathophysiology. tible individuals hypobaric PPH Whether or not vasoconstriction in the pathogenesis of PPH, component distensible to vasodilator that output When and resulting in cardiogenic arterial hypoxemia and life-threatening arnhythmias may also shock acidosis develop. Postulated Pat hophysiology The normal pulmonary low resistance, circulation. nary blood flow increases resistance decreases due opened blood marked circulation is a high During exercise, and pulmonary to both recruitment vessels and distension vessels. These two normal increases in pulmonary of patent pulmonary adaptations prevent artery pressure even when pulmonary blood flow increases by threefivefold. The normal right ventricle is a thin-walled, 240 flow, pulmovascular of un- to mechanisms for sudden death with PPH include the following: bnadyarrhythmias and tachyarrhythmias, acute pulmonary embolus, massive pulmonary hemorrhage, and sudden right ventricular ischemia. DIAGNOsIS Although the diagnosis it can be made with is taken to exclude thorough and detailed of PPH history Primary Pulmonary Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21673/ on 05/02/2017 is one of exclusion, a high degree of accuracy if care all likely secondary causes. A and physical Hypertension (Lewis examinaJ. Rubin eta!) Table 2-Evaluation ofUnexplained Mmonary HypertensiOn Information Data Obtained Riskt Secondary Quality Causes Detectable Screen History Dyspnea, Physical Exam P,, CXR angina, RV lift, Heart syncope clubbing size, lung parenchyma, vascular 0 + + + + PE, CHD, 0 + + + + Lung disease, CHD 0 + + Lung disease, PVOD, 0 ++ CHD 0 + + + + CHD, 0 + + + Chronic lung disease, LV dysfunction LV dysfunction pattern ECG RVH Diagnose Echo WQ scan Shunts, valves, LV function, Lobar, segmental perfusion PETs Lung ABG Po,, PA pressure function Pco, valve disease, LV dysfunction thromboembolism 0 + + + Parenchymal + + + + Hypoxemia, disease hypoventilation Confirm/Refine Catheterization Pressures, Pulmonary shunts, Vascular angiography cr/Mm + + + + + PVOD, + + + + PE, 0 + + + Proximal PE, lung + + + + + Proximal PE + + + + Vasculitis, PVOD + Vasculitis, collagen flow anatomy Central pulmonary vascular anatomy, CHD pulmonary stenoses disease parenchyma Angioscopy Intraluminal Lung Histopathology biopsy Serologies ANA, anatomy 1W, CH,, 0 vascular disease Management Catheterization Dose-response + + + + + Drug efficacy & safety, Echo RV size, 0 + + Drug efficacy treatment + + + Treatment Exercise Study *Abbretions: Quantitate PE RV=right function pulmonary RVH ventricle; exercise embolism; right tolerance CHD=congenital ventricle hypertrophy; heart disease; PA=pulmonary PVOD artery; =pulmonary response response venocclusive CT=computerized prognosis disease; LVleft ventricle; Mill magnetic resonance tomography; imaging. tNote: risk ofperformance and information quality are rated on a scale ofO to 4+. lion, as well as appropriate tests, must be performed to uncover potential causative on contributing factors, many of which In the National an algorithm secondary patient may not be readily apparent Institutes of Health registry Echo developed listing essential tests and diagnoses to be excluded’4 (Fig 2). No with a secondary cause of pulmonary Presenting PPH / No secondaly caisa registry Norn common symptom of PPH initial symptom in 60 percent leer prok with population. no curs greaten Angina Edema is generally failune and advanced that suggests Raynaud’s phenomenon frequency than is also common a reflection is more likely disease. The time symptom until diagnosis in 2.03 ± 4.9 years,’4 indicating generally made late. of right The PFTs- No PE Distal PE Wntiledon disease No significant ventilation cflseue + Serology PPH Exercise. lfctnical suspicion vasculitis to be associated with of onset from the first of patients assessment fUncOn ventricular registry diagnosis Cath Suspect was is PVOO with PPH are \ Drug study / \ Thorac biopsy Confirm Algorithm for diagnosis perfusion; PVFs pulmonary function gas determinations; and CKfH = right findings Pros PE ____e \ V oc- Examination physical detect ABOs Semiogy Ficuns Physical I Segment rio9raPhY in the general (47 percent). the NIH that the > is dyspnea, of patients and is eventually present in virtually all patients. Syncope may also be an early symptom of PPH (8 percent). In contrast to the olden literature, current experience Shunt. vthes c&omyopaIhy wo Symptoims most is the PH NOPH hyper- in the No suspicion /\ was tension was diagnosed as having when this algorithm was followed. The which Suspidon (Table 2). on PPH, 2. PH of PPH. V/Q=ventilation/ tests; ABCs =arterial blood heart hemodynamic catheri- zation. CHEST Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21673/ on 05/02/2017 I 104 I 1 1 JULY, 1993 241 typical of any patient with An increase in the pulmonic heart sound and early findings. pulmonary a right-sided may be heard of the second fourth Tricuspid heart regurgitation common. A right ventricular third erally reflects advanced disease. ciency hypertension. component and usually sound is also are very can heart sound genPulmonic insuffirelates and should suggest an alternative also be used pressure.tm Pulmonic valve seen, and characteristics flow velocity or changes profile across the pulmonic to estimate to dilatation patent diagnosis. foramen The Evaluation commonly shows triculan hypertrophy but does not The scintigraphy. right axis deviation with secondary necessarily parallel and right yenT-wave changes the severity of the underlying pulmonary hypertension. Atrial fibrillation is a particularly uncommon rhythm in PPH and may not be well-tolerated because of the dependence upon atrial Imaging: systole for ventricular Radiograph. Chest filling.m The chest with radiograph out chronic pulmonary thnomboemboli artery pressure. ventilation-perfusion Therefore, a normal rules out sion, and no further workup Pulmonary angiography. pletely diagnosis, exercised, dication with normal chest x-ray it should be noted PPH enrolled in the radiograph. Echocardiography. useful to look for film speaks that 6 percent NIH registry against the of patients had a normal echocardiogram dysfunction, disease, or congenital heart disease. The typical echocardiographic appearance ofthe patient with PPH shows right ventricular and right atrial enlargement with a normal to reduced left ventricular cavity. Pulmonic and tricuspid insufficiency is also easily detected normal with Doppler curvature septal interrogation. associated ular pressure overload disease. Hemodynamic pulmonary findings vascular reveal an ventricular internal with Reversal of the right ventric- states is seen correlations in advanced between the resistance and echocardiographic inverse relationship between the left dimension and pulmonary of left ventricular filling as a reflection of reduced ventricle.’ to noninvasively pressure. Most vascu- Doppler determine commonly, ultrasound the from early compliance can be to of used the pulmonary artery magnitude of the tri- 242 reproducible measurements of the right often probability pulmonary is necessary Ifthe lung thnomboembolism. pulmonary to pulmonary pulmonary two or lung hyperten- in this regard. scan shows one interpret. or magnetic While cane hypertension angiography. hypertension, into the and endothelialized mate the extent of the clots be resonance necessary imaging those centers with diagnostic evaluation are be actually pulmonary so the angiogram of obstruction or It may to should is not a contrainIn thromboem- the wall copy has had very limited in few centers. It should artery may undenestibe difficult to to employ angioscopy in these cases. Angios- application and not be performed is performed except in considerable experience in the of thnomboembolic pulmonary hypertension. Radionuclkk giography angiocardiography. can be utilized to assess function. However, in interpreting in the presence taken tions cuspid regurgitant flow velocity can be determined and enhanced using saline solution contrast to give relatively out ventricular left lan resistance, suggesting that underfilling of the left ventricle is a reflection ofthe severity ofthe pulmonary vascular disease. Doppler studies have also shown a redistribution late diastole rule bolic can be valvular small, patchy pulmonary at least one or more segmental, on greaten, ventilation-perfusion mismatches, an angiogram should be performed incorporated The myocardial mismatch, on low thnomboembolic shows evidence ofpulmonary hypertension in over 90 percent ofcases.’4 Prominence ofthe main pulmonary artery occurs in 90 percent, hilar vessel enlargement in 80 percent, and pruning of the vessels with hyperlucent lung periphery in 51 percent. While a com- undergo to rule as the cause ofthe elevated In PPH, the lung scan is normal on low probability with 14 Conversely, in thromboembolic hypertension, the lung scan demonstrates scan echof It is mandatory either major more. pnes- It has an of intnacardetection of a pulmonary hypertension lung scanning in order ventilation-perfusion electrocardiogram artery ovale. that patients Electrocardiogram: insufof the in the valve transesophageal in the evaluation patients with pulmonary hypertension.62 advantage of offering precise assessment diac defects and is very sensitive in the Ventilation-perfusion Diagnostic pulmonary sure noninvasively.6#{176}’6’ Recently, ocardiognaphy has been employed ofthe main pulmonary artery. Peripheral cyanosis and edema are often seen. Edema is a sign of right ventricular dysfunction. Clubbing is not a feature of PPH ventricular systolic ficiency is frequently pulmonic regungitant systolic flow velocity ular chambers, Radionuclide anboth left and right caution should be right ventniculan ejection fracof lange right atrial and ventric- as true isolation ofthe right ventricular blood pool can be difficult. Right ventricular ejection fraction has been shown to be inversely proportional to the pulmonary estimation of right ventricular MRI and artery pulmonary ejection and ultrafast CT scanners pressure, artery fraction CT As newer have evolved although pressure is difficult. direct from the generations of Mifi and software has improved, these imaging techniques have begun to offer great promise. Thnombi in proximal pulmonary arteries can be visualized without the necessity of an Primary Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21673/ on 05/02/2017 Pulmonary Hypertension (Lewis J. Rubin et a!) angiogram. In addition, motion can be evaluated left ventricular ejection ventricular and septal with calculation of right fractions. The sensitivity wall and of these tests for detection of central clots sufficient to cause pulmonary hypertension has not been determined, but this may become pant of the diagnostic algorithm for PPH in the near future. Pulmonary monary in the Testing: Function functional abnormalities may either the mechanical the lung, with changes prominent The include and reflect and (Dco), carbon in gas diffusing exchange as PPH dys- capacity reflected by studies registry performed disclosed on only Pul- the 187 pamild neduc- lung volumes and no evidence of airways 14 The presence of moderate or severe or obstructive physiologic defects should restrictive suggest described in small airways hypocapnia (alveolar hyperventilation), alveolar.arterial (A-a)O2 gradient. monary function tients in the PPH tion in greater. monoxide impaired hypoxemia, and increased derangements or gas exchanging properties of in the latter tending to be more disproportionately reduced of pul- in PPH, particularly of the disease. The functional abnormalities mild restrictive defects, function, cur Abnormalities function may be present more advanced stages another due in PPH, patent foramen output with diagnosis. Severe either to intracardiac ovale or a severely resultant mixed Cardiopulnwnary venous Tests: Exercise exercise tests are useful with nonapparent causes hypoxemia can shunting ocvia a Elevations in PPH in antinuclear collagen nuclear vascular antibodies associated with . antibodies As all of the imply are com- Lung in selected necessary factors that Biopsy: making Lung biopsy an accurate collagen vascular is not considered essendiagnosis of PPH. In patients, a lung biopsy may be desirable to establish a diagnosis when confounding make the diagnosis otherwise uncertain. respect, an accurate patient as having hypertension may primary be very diagnosis management. value Transbronchial in pulmonary hypertension blood vessels adequately the lung diagnosis because and may it also of hi- primary does not sample be risky due to elevated pulmonary artery pressure. Open lung hiopsy, possibly using a thoracoscope, would be preferred. Care should be taken in obtaining the tissues, preferably from right or left lower lobes during full lung inflation. difficult, and ferred vascular A correct to a pathologist disease. Cardiac with expertise Catheterization: be taken accurately with either determination to exclude It should terization. filling pressures is the diagnosis Particular care intracardiac shunting ventricular capillary with left be recognized rise modestly may be re- catheterization for confirming management. ascertain left a pulmonary or directly can be in pulmonary Cardiac an absolute requirement of PPH and for guiding should histologic diagnosis material should the pathologic filling wedge ventricular and pressure pressure cathe- that left ventricular in severe PPH due to diastolic dysfunction related to the pulmonary hypertension. Pulmonary veno-occiusive disease can result in a gradient between the wedge pressure and left ventricular wedge pressure elevated. Typical to the pressure, output, Although end-diastolic is usually ofveno-occlusive pressure the lung. accurate disease artery they direct although the only mildly or is variabil- determinations from various Particular attention should be measurement pulmonary since the pressure, normal of the pressure, specifically measurement right and atrial cardiac relate to prognosis. of cardiac output through the Fick method is preferred in low output states, a reasonably accurate assessment thermodilution can be obtained in most patients. cardiac using Flow- directed catheters for the right side of the heart an internal guidewine are commercially available have been particularly helpful in positioning catheter in the pulmonary artery. with and the an associated diseases have been associated with pulmonary hypertension, it is possible that some patients with PPH have a collagen vascular disease that is confined to the lung. tial no paid of patients there is a disease. No specific pattern of antior titer has been consistently PPH of hypoxemia. in the evaluation of dyspnea since and do not necessarily and is Cardiopulmonary cardiac ease.67 Since their sensitivity and specificity in the diagnosis of pulmonary hypertension are unknown, exercise testing is not considered essential in the evaluation ofa patient with suspected PPH. Connective flssue (Collagen Vascular) Serologic Studies: opsy ity in wedge sites within depressed characteristic pattern of ventilatory and circulatory response in the presence of pulmonary vascular dis- mon prognosis distinguishing or In the or secondary pulmonary important with respect to THERAPY There approach However, is no cure for PPH, nor is there which is uniformly accepted treatment for this disease a therapeutic or successful. has improved dramatically over the past decade, resulting in sustamed clinical improvement and prolongation of life in a substantial percent of patients. This section will address the management General Measures of PPH. Because PPH is a rare disease whose complexity poses tremendous challenges to the treating physician, it is recommended that patients be referred to a center with experience in management of this disease. The referring physician must, nevertheless, play a major CHEST Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21673/ on 05/02/2017 I 104 I 1 I JULY, 1993 243 role in the day ongoing dialogue crucial. Patients to day care between with substances PPH which of these patients, and the treating physicians should may avoid aggravate or However, preload, the and For excessive diunesis circumstances the disease state. exposure hypertension pulmonary by producing vasoconstriction. generally safe, alveolar While supplemental hypoxia-induced airplane travel oxygen when flying therapy may advisable, particularly cabins or hypoxemic when patients are mildly or moderately at sealevel. Additionally, pregnancy should should be monitoring in nonpressunized hypoxia frequently parenchymal lung pulmonary vasoconstriction occurs in the setting of disease, and hypoxic contributes genesis of pulmonary Supplemental low-flow vascular oxygen to the patho- disease in this setting. alleviates arterial hy- right-sided in these patients congestion heart ventricle is highly care should be volume status failure. dependent taken to on avoid this lead since by physical laboratory data. Patients of funosemide of greaten treated with can potassium necessary risk low doses of as needed, examination and who are refractory than 120 mg/day metolazone as an adjunct. to doses may be Meticulous of serum electrolytes is mandatory, and on magnesium supplementation may be when these agents are used. monitoring Therapy Alveolar long-term right great and hepatic with therapy may be instituted with (20 to 40 mg/d) and increased Anticoagulant Oxygen volume in patients to a fall in cardiac output and can compromise the use of other pharmacologic measures such as vasodilators. Diuretic furosemide be used. Supplemental occur is be avoided since this is poorly tolerated in the setting of PPH. Since oral contraceptives may worsen pulmonary hypertension, other effective methods of birth control intravascular which exercise should be guided by symptoms, and to high altitude may worsen pulmonary example, increased an is Therapy Patients with severe pulmonary for thrombotic events due hypertension are at to their sedentary venous insufficiency, dilated right-sided heart chambers, and sluggish pulmonary blood flow. Even a small pulmonary vascular obstruction by thrombus can be life-threatening in apatient with a compromised lifestyle, poxemia and attenuates pulmonary hypertension in patients with these disorders; in contrast, most patients with PPH do not exhibit resting hypoxemia and derive little hemodynamic benefit from supplemental pulmonary vascular bed which possesses little ability to dilate or recruit unused vessels. Indeed, patients with PPH frequenfly die suddenly, and fresh intrapulmonary clot may be found at post-mortem exami- oxygen rience nation. therapy. arterial Some patients, oxygen desatunation to increased oxygen oxygen delivery, and extraction in these patients ambulatory supplemental right-sided heart failure sulting from a markedly even at nest, therapy. arterial Patients to-left should shunt Cardiac useful the face of fixed may benefit from oxygen. Patients with severe and resting hypoxemia, reincreased oxygen extraction be treated through with a patent do not improve to an appreciable The will expeactivity, due continuous oxygen The goal of oxygen therapy is to maintain an oxygen saturation above 90 to 92 percent. with hypoxemia solely resulting from a right- teristically known. however, with degree foramen ovale charac- their level of oxygenation with supplemental oxygen. function associated with chronic thenmore, the risk ofdigitalis toxicity if hypoxemia and diuretic-induced in PPH is unthese drugs are ventricular dys- lung disease.m Fun- may be enhanced hypokalemia are also present. Some authors have advocated digitalis concomitant with calcium channel in PPH in order to counteract the potentially inotropic effects of the latter.x the use of blockers negative Diuretics Diuretics 244 can be quite useful in reducing the may be as a prophylaxis justified in patients who received anticoagulants survival when compared with treated with anticoagulants.7#{176} for with manifested improved those who were not Recently, Rich et aF’’ demonstrated in a small prospective study coagulation was associated with significant ment in survival rates. The preferred approach to anticoagulation administer prothrombin Patients efficacy of cardiac glycosides There is little evidence that in patients with isolated right anticoagulation PPH. A retrospective study from the Mayo Clinic provided support for this concept. Patients with PPH control Glycosides Thus, thromboembolism in doses sufficient to approximately warfarin time (international should normalized be advised could heart ratio therapy on any alter the effects of warfarin. failure may impair hepatic of the anticoagulant effects must be done with greater Adjusted-dose heparin, is to to prolong the 1.3 to 1.5 times of 2.0 regarding dangers of anticoagulation using nonsteroidal agents that antiimprove- the to 3.0). risks and should medication Since function, of warfanin frequency. using doses and avoid which right-sided monitoring in this which setting prolong the partial thromboplastin time to 1.3 to 1.5 times control, is a suitable alternative to warfanin, although its use is more cumbersome. This approach may be considered in patients who have a greater risk for hemorrhagic events, such as prior episodes of hemoptysis, on who have had Primary Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21673/ on 05/02/2017 adverse Pulmonary effects Hypertension with warfann, (Lewis J. Aubin eta!) such Table 3-Dose Half-Lives as alopecia. Ranges, Route Frequently OJMOSt ofAdministration, Used Vasodilators and Vasodilators Drug The rationale treat pulmonary that fon the use hypertension pulmonary degrees, in right vasoconstriction in right supported by ofthe hypertnophy early is pnesent, to varying in this disease, and that even small ventricular aftenload will produce improvement is of vasodilator agents to is based on the premise and selective ventricular consistent feature stnated to experimental The of PPH vasodilaton vasodilators agent, although a have been demon- produce pulmonary vascular and clinical conditions (Table effects 3). in goal ofvasodilaton therapy for PPH is to reduce pressure and increase cardiac output symptomatic systemic hypotension. This ef- pulmonary artery without 120-900 mg/day 2-24 ng/kg/min may is no be E, Intravenous 5-30 release preparations (Procardia given once range tolerance increased listed over time, for adverse The potent, immediate lators will increase and right these cardiac output without afFecting patients, unknown. the long-term Furthermore, for prolonged In the remaining one sustained either reduce monary artery pulmonary increased “fixed” systemic pressure artery output. vascular effects whether on this periods of time fourth ofpatients, pressure without or cardiac output, pressure These disease, commensurate patients are and vasodilator survival effect are can be is unclear. vasodilators Patients with pulmonary veno-occlusive life-threatening pulmonary edema to vasodilator ofincreasing persistent There administration, pulmonary downstream are blood vascular with an to have therapy is no hemodynamic disease may in response presumably as a result flow in the presence obstruction.’ on demographic of varia- bles which predict vasoreactivity. Patients with symptoms for several years suggestive of severe pulmonary vascular compromise, such as syncope, may manifest nearcomplete reversibility others with irreversible a brief disease. with vasodilators, duration of symptoms may This observation underscores while have the infusion its short CD) to conventional nontitratable of pnostacyclin of prostacycin half-life cardiac in this vasodilator, (3 to 5 min). output, (pros- heart catheterization magnitude of vasoreacsetting its titrataProstacyclin doses from 1 to 12 ng/ and pulmonary hemoand arterial saturation. The responses to prostacyclin have been useful in determining which patients may respond to oral therapy. 18.75 Prostacyclin is not commercially United at the present time; alternatives for testing acute reactivity States be suitable prostaglandin Patients who manifest sponse to acute vasodilaton a reduction in pulmonary available E,, and in the which include adenosine. a potentially beneficial rechallenge defined as either artery pressure with no change on an increase in cardiac output, or an increased cardiac output with an unchanged pulmonary artery pressure, may be treated with oral calcium channel blockers. A common strategy is to titrate with hourly doses until maximal hemodynamic on adverse nifedipine effects (Procardia are achieved. XL) in doses nifedipine effects Sustained release of 120 to 240 mg/ day is often used. In some patients who either have a resting tachycardia or develop unacceptable systemic hypotension with nifedipine, diltiazem, in doses up to 900 mg daily, is a suitable alternative. The heart rate and monitored PR interval in patients on electrocardiogram receiving diltiazem, ycardia and atrioventricular mil is not recommended greaten propensity fects. Additionally, with any vasodilator patients elevated blocker as an risk refers a long-acting as a pulmonary great variability in the course ofthis disease and serves to emphasize the need to individualize the approach to therapy for each patient. The experience from the NIH registry on PPH has suggested, however, that with right-sided heart failure, defined right atnial pressure, are at the greatest when advantages acetylchohne, contraindicated. develop The and may altering pulon increase felt tivity.74 dynamics, artery mm Cardizem 50 to 100 ng/kgfmin. is administered in incremental kg/mm, monitoring systemic pnessure. While exercise tolerance ventricular function may be improved in pulmonary exceeding intravenous bility, regression 2-4 XL and infusions; dose requirements long-term infusions have taglandin I,) during right-sided to determine the potential and and pressure ag/kg/min shown h 3 mm is administered immediately.72 approach taken in many centers is to use a short acting, titratable vasodilator such as vasodilaton ductions artery often events are its potency hypentrophy in such patients. one half of PPH patients, vasodi- half-life is for immediate patients receiving in one fourth of reported that sustained re- in pulmonary daily; 2-4.5 preparation. tDose and fect may be achievable in approximately patients. Rich and Brundage have calcium channel blockers can produce of right ventricular In approximately 2-5 h 30-240 Oral Intravenous 55usimned There .‘ mg/day Oral Prostaglandin concept Half-Life Diltiazem5 Prostacyclint reductions This Range Dose Nifedipine* substantial the pathologic finding of medial muscular pulmonary arteries as an pulmonary of systemic variety output. Route The due major to the block may occur. for use in PPH since to produce unmonitoned is strongly adverse therapy effects in PPH negative inotropic Verapait has a negative inotropic efempiric treatment discouraged. of calcium are reduction CHEST Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21673/ on 05/02/2017 should be since brad- effects, channel in cardiac output systemic hypo- I 104 I 1 I JULY, 1993 245 tension, When and edema calcium edema due to salt and water develops in a PPH patient channel blocker therapy, patent retention. receiving is important it to differentiate between the effects which these agents have on renal salt and water reabsorption and right heart failure due to negative inotropy. Vasodilators can also produce arterial hypoxemia through the following three mechanisms: ventilated lung creasing right units increasing (decreasing to left shunting blood flow to poorly V/Q matching); in- through a patent occurs more hypertension lung disease, left shunting through a patent foramen only in more severe forms ofpulmonary A similar phenomenon may occur Eisenmenger’s Nitrates, treat some with these agents, as hydralazine and diazoxide, angiotensin converting disappointing, been enzyme and their may is be have not have and colleagues76 ous intravenous infusion onstrating ance with first reported ofprostacyclin using recomcontinu- in PPH, in hemodynamics in a series of PPH to live prognosis balloon atnal with advanced Kerstein et septostomy pulmonary al81 reported longer than in 15 patients than PPH patients septum.79 of symptoms with with syncope and heart-lung transplantation has been expertise to perform patients, and the Additional organs. the procedure and limited availability problems have incidence (25 to 40 percent) in transplanted lungs, organ istic infections. Recently, single ofbronchiolitis rejection, and and double performed lung successfully artery has tion, Dose of the indwelling or interruption requirements catheter, of the infusion tend to increase gesting tachyphylaxis, maintained responses although for periods years. bridge whom may This approach to transplantation oral vasodilator pump and than lung 246 for combined transplantation drug or malfunc- Patients several patients have extending beyond 5 be particularly useful as a in seriously ill patients in therapy is either contraindiexperisurvival and IV atomegaly, suitable with severe PPH in whom the foramen ovale is in whom right-sided impaired. There right-sided heart hyperbilirubinemia, and candidates for transplantation an excessively few high mortality rate heart is no or double failure, ascites since in this hepare not there is group. The timing of transplantation is controversial and dependent, in part, on the individual patient’s wishes. In general, for patients functional consideration for transplantation is advised who fall into New York Heart class III or IV who are refractory Association to medical management. AND The clinical course inexorable progression Septostomy with yen- in the heart-lung transplantation. may be the surgical proce- dune of choice for patients function is not irreversibly PRoGNosIs Patients right dramatically . patients. Atrial has PPH. patients evaluated to date Although rejection, infection, and bronchiolitis may occur with lung transplantation as well, it is likely that there should be a greater availability ofsuitable donor organs for lung transplan- for other reasons. over time, sug- cated or of no demonstrable benefit. Recent ence suggests that prostacyclin may improve in New York Heart Association class III obliterans opportun- with fallen, has improved for these transplantation in patients pressure function care of suitable donor included the high uniform census on the preference of single lung transplantation for PPH at present. infection per- formed successfully on patients with PPH for nearly a decade. The major limitations to its widespread use include the limited number of centers with the cations delivery to the thrombosis heart investigational. triculan has been recently patients who were attributable included a blade right-sided tation Thus, been have who has been reported in patients vascular disease.#{176} Recently, improvement with sept05- treated with long-term continuous intravenous prostacyclin.73 The drug is delivered by a portable infusion pump which is connected to a Hickman catheter inserted into the jugular or subclavian vein. Complihave generally system and those failure. Thus, blade balloon septostomy may serve as adjunct palliative therapy in selected patients with severe PPH and intractable right-sided heart failure. It should be emphasized that this invasive approach is Pulmonary dem- sustained improvement in exercise toterthis aggressive approach.76 Sustained improvement demonstrated a better interatrial palliation been mended. J ones reported foramen ovale.78 Additionally, patients syndrome due to an atnal septal have an intact Successful Combined reactivity, but utility. Results inhibitors use been Transplantation physiology who are given vasodilators. either oral or topical, have been used to patients with PPH, although the experience agents to date is limited. Direct acting such with commonly in secondary to while right-toovale is present hypertension. in patients with useful in select patients with marked systemic hypotension has limited their defect tomy foramen ovale if a greater degree of systemic vasodilation than pulmonary vasodilation is produced, and decreasing mixed venous oxygen content ifcardiac output actually falls. The first scenario patients with pulmonary underlying parenchymal have without a patent with Eisenmenger’s ral history studies Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21673/ on 05/02/2017 HISTORY of PPH is generally toward death. However, vary Primary NATURAL in Pulmonary reporting Hypertension and (Lewis one of natuin J. Rubin case eta!) ascertainment, and utilize survival duration (eg, the symptoms on the consensus has been interval different interval since definitions since onset diagnosis), 0.8 of of so that Among percent; percent; actuarial 2 years, 4 years, survival at 1 year 52 to 58 percent; 30 to 43 percent; is 68 to 77 Despite the survival overall ranges up dismal to 10 .l 3 years, 40 to 56 and 5 years, 22 to 38 percent.TM70M The usual mechanisms of death right ventricular failure (63 percent), pneumonia percent), and sudden death (7 percent).TM’7#{176} prognosis, years or (1) Higher between studies Vascular the have 0 0.3 was Some degree cause despite resistance . 4 5 Years ca’e341ss 0.8 Pres- 0.7 0.6 0 for pressure 0.4 2 a- of 85 be that in these patients, the 0.2 2 1 3 Years caieasiesoi 0.9 finding failed to identify as a predictor of a correlation with U 0.8 ‘% pulmonary MPAP RAP CI 60 10 3.3 60 10 1.3 . A *% response Response to vasodilaton to therapy has long as being predictive ofsurvival. components to this predictor. demonstrate reduced acute longer, pulmonary : 2 a. treatment with vasodilators hance survival.’73 Preliminary data randomized survival study of PPH prolonged intravenous prostacyclin . 0.4 0.3 . N .__ 0.2 tend of may 1 , to en- from a 12-week patients treated also N . resis- administration of vasodilators and this may be independent treatment status. Second, in addition role of vasodilators, there is suggestive that __ .N .l05 There First, vascular .N 0.6 0 Vasodilator of the pulmonary vasculature to respond to agents may identify patients in a more (earlier) phase ofthe disease. Thus, those subsequent the predictive with 5 correlation to 12 months arterial of Favorable The evidence 4 0.3 may been recognized are two potential tance with to survive 3 !0.7 (2) Absence who 2 of mortality. mortality, the ability vasodilator vasoreactive 2.3 abnormality compared studies, however, have of pulmonary hypertension Therapy: 2.3 10 .___ I is more advanced or has progressed to a more level relatively rapidly (1#{128}, by the time of diagnosis). The higher pressure imposes a workload on the right ventricle, contributing from right-sided heart failure, the most common 10 80 median survival for those arterial pressure less than 55 pulmonary implications disease severe correct greater to death and an inverse hemodynamic 48 months, those with mean mm Hg or more.M The 60 A 0.2 Among the 194 patients in the for the Characterization of Primary Pulmonary Hypertension, with a mean pulmonary Hg . of Isolated Resistance found pulmonary and survival.MM87 Patient Registry mm CI survival. Pulmonary Most sure: 2.3 0.5 2 (7 instances of survival up to 24 years have been reported, as have rare cases of apparent regression of the disease.ec A variety of indicators appear to have predictive for short 10 0.4 are duration more. RAP 40 . a about the rate of progression of the disease difficult to establish. patients who do not undergo heart-lung transplantation, value I MPAP support 2 3 4 5 Years FIGURE 3. Probability of survival for medically treated patients with PPH. Differences in survival probability are depicted based upon variation ofbaseline mean pulmonary artery pressure (MPAP, mm Hg) (upper); right atnal pressure (RAP, mm Hg) (center); and cardiac index (CI, L/minlm’) (lower). Adapted from D’Alonzo et al.’ CHEST Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21673/ on 05/02/2017 I 104 I 1 I JULY, 1993 247 this ACKNOWLEDGMENT: provided by Renata observation. (3) Worse with Functional PPH are Nevertheless, Classification: symptomatic Most at the symptoms are time presumably of hemodynamic patients, those decompensation dysfunction. exhibiting have shorter a late subsequent class and (4) Right months; Atrial measurable in class Pressure hemodynamic function, mean indices RAP elevation 2 Palevsky is highly 10 mm E, Schloo et structure, et al. qualitative and from S8patients output is associated by both high the pulmonary ure. Not correlates less than with 4 Wagenvoort ventricular sion: of reduced with reduced 2.0 IJminJm2 survival.M,70,87 is associated of 17 months; or more increases cardiac median (6) Low Pulmonary Desaturation: Low survival D, nary ation due to reduced low cardiac output. in from the an individual developed:TM registry, patient’s t= the pulmonary septal 11 12 z = cardiac The use 13 assessing of Loyd years 15 pressure clinically pulmo- The of structural reference 1958; pathology Archiv to 18:533-47 of pulmonary (A) 1974; 364:69-79 veno-occlusive disease after S. Pulmonary for malignant veno-occlusive neoplasms. 1987; Chest veno-occlusive study. disease Hum in siblings: Pathol 1982; 13:911- Familial ElemaJD. a case report. Beetsra A, Thorax Schultz 1978; M, and veno- 32:763-66 J. Capillary Spijker Histopathology pulmonary 1977; hemangioma- 2:401-06 Michtom Primary RJ. hemodynamic study. pulmonary J Med Am 1951; Primm Newman RK, clinical Familial JH. patterns. Am primary Rev pulmonary Respir Dis 1984; Rich 5, BH, Detre Dantzker DR. KM. prospective JE, Atkinson Loyd Ann Am in 1988; Hall EH, CC, Virmani Dis a 1987; 107:216-23 R, Newman Med in familial Respir Brundage hypertension: 1988; primary JH. pulmo- 138:952-57 JM, Batten AP, Wang NS, Fitch N, et al. Familial pulmonary capillary hemangio- RD, Med Intern lesions Rev Bergofsky pulmonary Heneghan resulting RJ, study. JB, Pietra hypertension. D, SM, Primary of pathologic Langleben Barst Ayres al. et JC, vasodilator pulmonary WM. Gersony with children primary hypertension. Ann 109:106-09 primary agents Factors influencing pulmonary [abstract]. survival hypertension Circulation treated 1988; 78(suppl 2):293 18 will of treatment be important in Barst different sets sion. 19 modalities, three 3 for 156 120:194-97 17 are shown hemodynamic Figure variables. hyperten- in special with A, Winokur clinical JE, matosis for which survival data of survival probability 248 CA, lung. DT, national such as lung transplantation, can be compared. Examples in 1989; 41:415-16 KuipersJRG, of and Chest young 1986; Gurtner HP AP, ed. The Philadelphia: 20 induced RJ. Pharmacologically in children appropriateness 1986; morphometnic disease: Intern an equation Institute pulmonary Circulation N. L. Pulmonary hypertension: index of such CG, Schlesinger arterial pressure Blood Circulation of hypertensive arteries therapy and ofthe nary pulmonary right atnial vessels 11:686-705 with mean mean and of six grades Vmrchows Churg P, Reid report Dresdale among = CM, Wagenvoort 1, 2, or 3 years x y B, a blood vessels pathology defects. Thorax hypertension: 16 t J, Schloo 42:1163-84 SJ. Pulmonary following Voordes tosis an equa- at vasodilator hypertension: Lung, lung 1970; Wagenvoort Capewell occlusive = of survival to registry. N. Primary The cardiac Heterogeneity chances JS, vascular 92:871-76 10 H(t)=[0.88-0.14t+0.01t211 A(x,y,z) = where: P(t) = a patient’s Heart, a description disease. DA, disease and chances K’!’, Janieki of pulmonary of the JE. CA, 8 Lombard pre- hypoxemia, study study disease: chemotherapy. 14 obtained tion to predict survival has been P(t) arterial 60:16- 15 of this factor is probably reflection ofpoor oxygen- capacity, Weber pulmonary hypertension Edwards changes case Oxygen SVO2 1985; hypertension: primary Circulation vascular 9 Davies to 43 months.M %nons) Proc responsiveness in the National cases. 5 Heath Llmin/m2 63 percent) GC, and CA, Wagenvoort diagnosed also survival of 17 percent, whereas a mean survival of 55 percent at 3 years.7#{176}The power derived from its cumulative on data of 4.0 (Mixed than output hypertension: Clin pulmonary of a pathologic 7 Ellis Cardiac index with a median index Arterial (less a mean 3-year SVO2 predicted Based cardiac Pietra quantitative veno-occlusive fixed resistance to blood flow through vasculature and right ventricular fail- survival dicted higher Decreased cardiac of PPH. It is caused unexpectedly, pulmonary Mayo 1989; 60:1207-21 WD, Kay JM, Rich 5, Kennis pulmonary 6 Wagenvoort Output: severity assistance &1198-1206 Hg.TM Cardioc cases. BL, Histopathology congenital (5) Depressed Primary of8O morphometry, primary predictive WD. Primary al. agents. Circulation 3 Pietra CC, Edwards survival. Mean RAP greater than 20 mm Hg corresponds to a median survival of 1 month, compared to 46 months survival for patients with mean RAP less than study HI, Rubin Among of right the 25 in New months; Elevation: Edwards a histopathologic IV, 6 months. (RAP) J, 1 Bjornsson survival. survival for patients class I or II was 58.6 31.5 appreciates ACCP staff. REFERENCES devel- Among symptomore symptomatic In the registry, median York Heart Association III, panel and the patients of diagnosis. opment in this disease, resulting mainly from endorgan (right ventricular) sequelae. Level of symptomatic deterioriation may be considered a global clinical index matic The Simonsen adults with pulmonary primary vasodilatation pulmonary hyperten- 98:497-503 Aminorex pulmonary University pulmonary hypertension. In: circulation: normal and ofPennsylvania Press, 1990; Fishman abnormal. 397-412 JG, Munro JF, Kitchin AH, Muir AL, Proudfoot AT. Pulmonary hypertension and fenfluramine. BMJ 1981; 283:881Douglas 83 Primary Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21673/ on 05/02/2017 Pulmonary Hypertension (Lewis J. Rubin eta!) 21 McMurray J, Bloornfield hypertension after P. Miller therapy HC. with Irreversible control pulmonary fenfluramine. BMJ Dis 1986; 43 202:239-40 22 HD, Tazelaar Colby induced TV. Russell 97:1032-36 1990; Spehlmann Dim de hypertension 25 with female M, crack prevents pulmonary mine pathology Pulmo- CA. [abstract]. Am Rev Mestre de Atauri due to toxic MJ, Comez-Pajuelo C, FJ. Pulmonary Juan MJ, 45 Martinez-Tello oil syndrome: Gomez-Sanchez MA, Saene 26 McDonnell PJ, hypertension Dis 27 Toye and 1983; de hi Calzada C, Gomez-Pajuelo C, 46 Coll PA, Cardiol 1991; Hutchins cirrhosis: nary hypertension relation they MK, Primary related? Lebrec D, splanchnic Rev Respir 47 Benhamou JR hypertension: Pulmo- prevalence GH, Baily RG, Brettler JO, Driscol TE, et al. Primary DB, Davidson pulmonary hemophilia. Ann 48 WRJ, Ballard hypertension Intern Med Speich R, Jenni R, Opravil M, Pfab M, pulmonary hypertension in HIV infection. 1988; tension: 31 Yamald Edwards three pathologic 32 Reeves J1 Russi EW. Chest Respir Rich 5, Dis 49 108:797- Primary 1991; 100: 50 Rich 5, 35 36 37 Heath E, Whitaker ease. Circulation Rich 5, BH. Antinuclear J Am Barst RJ, Flaster the 1992; with ER, 52 53 channel blocking evidence for long- and regression effect of high primary in doses of 54 PF. pulmonary vascular Notes Physiol Guazzi MD, Hypersensitivity BM, Stodo in primary and Miura JD, Stone D, pulmonary 1991; 338: HC, reactivity in pulmonary A, Fotino 56 hyperten- pulmonary JH. pulmonary Cor M, Suzuki Y, Ishizawa in secundum atrial Chest do vascular endothelial Sci 1989; 4:22-5 Alimeato M, Fiorentini vessels 1986; 57 Vasa E, Takahashi septal defect respond Pepi to catecholamines M, Rabinovitch H, Trusler endothelial do- in pul- CA, factor Williams VIII and congenital associ- heart defects. LW, Reid LM. von Willebrand pulmonary hypertension. M. Endothelial monocrotaline injury pulmonary L, progressive Johnson Am and vascular hypertension. DJ, elastin pulmonary a biochemical Smith P, Heath Banger and collagen J Am P Keeley synthesis hypertension and study. FW, associated induced ultrastructural Pathol 1990; US. Proc 1986; by monocro- Lab Invest 1988; M, Madden J, A, Gosney pulmonary arteriopathy. endothelial surface and responses to injury. Fed E, BE, AS, 45:101-08 PR, Lucore C, Kaufmann 5, et al. ibrinopeptide A levels throm’bosis in patients tension. Circulation 1990; D’Alonzo GG, Detre Barst KM. Ann with RJ, Ayres et Intern al SM, EK, Rich Med 5, 1991; J Am J, Harrison ofprimary pulmonary hyper- EH, patients from a Brundage with natural primary prospective 115:343-49 in primary Brundage BH. left pressure Goodman pulmonary pulmonary hyper- 1980; 12:181-93 of impaired ventricular Jaffe of pulmonary Bergofsky in results J Cardiol primary Survival N. Electrocardiogram Eur Sobel indicative 82:841-47 hypertension: Kanemoto Louie B, Caslin of plexogenic vascular Coll Doppler ventricular overload Cardiol DC, due RL. echocardiographic filling in patients to primary 1986; Popp with pulmonary 8:1307-11 Echocardiographic hypertension. J Am Shimada R, Takeshita A, Nakamura of ventricular systolic right 1984; A. in systemic BMJ 1986; 293:291-94 Barst RJ, Stalcup SA, Steeg CN, Hall JC, Frosolono MF, Cato AE, et al. Relation of arachinodate metabolites to abnormal Yacoub 160:111-21 The Eisenberg septum to flow? Polese D, ultrastructure Ryan analysis 59 C, heart features Cardiol 1974; 33:438- 43 89:694-98 cells congenital with 1987; 135:294-99 M. Altered hypertension. in Circulation hypertension. M, in patients of endothelin Thom hypertension Todorovich-Hunter right Evidence hypertension complex. Y, Matsumura 1988; 255:H1484-91 assessment M, Morse K, Sarto 1991; 84:2280-85 M, in primary Dis Rosenberg tension. Brundage 8:1307-11 disease of lung AT, Lancet with 1987; 76:1043-52 RL, Carvalho CA, Hoyer registry. dis55 Groves hypertension. How Ber- pulmonary ofselective production et al. Abnormal pulmonary pulmonary 327:76-81 58 pulmonary in concentrations associated Andrew RD. Respir BH, pulmonary 27:160-71 Davies GA, the excretion Dinh-Xuan K, Nakao endothein abnormalities Rich 1987; 76:135-41 histocompatibility HP Aminorex hypertension. 42 with Geggel J of Am 88:249-58 Yama.ki 5, HoriuchiT, T. Pulmonary vascular 41 1992; of unexplained 39 with The survival 1986; the major Gurtner 40 K, Menom 38 1985; PS. Hypertensive Cardiol between as a cause Circulation M, et al. The for treatment pressure Circulation antibodies Coil 51 84:428-34 25:323-43 Hart King 58:184-95 hypertension. calcium arterial Med W. K, association children dose on J EM, blockade 82:1765-77 JH, hypertension. Nishioka circulation. taline: plexogenic 1985; case hypertension: Levy 1956; Kieras sion. for High blockers N Engl D, D. The hypertrophy. Kaufmann hypertension. J hyper- 56:884-88 of primary Br Heart pulmonary in pulmonary calcium-channel 1977; Comparison children. pulmonary ventricular Green heparmn-prota- metabolites oxide for increased Babinovitch 134:342-46 BH. reduction pulmonary Circulation primary 1986; for primary ofright 34 with Brundage therapy term CA. and primary BM , Turkevich Groves patients Rev Clinical types. in adults selected 33 JE. 5, Wagenvoort arteriopathy Respir 327:70-5 TW, nitric hypertension Rowe Rev in M, Rabinovitch with WD, prostacyclin Higgenboftam evidence Physiol Edwards by 1990; Newman J Med 1992; T, et al. Plasma Circulation Castroenterology 1268-71 30 ML, An imbalance in pulmonary Yoshibayashi ated 99 29 J, factor classic and Inhaled monary pulmonary Am hemodynamics. Goldsmith with Rev receptor Circulation CD, etal. N EngI Pepke-Zaba fects: 100:520-28 patients BM, WallworkJ. Ogletree induced sheep. McPherson Groves pulmonary 18:1539-45 GM. are complicatingportal to E, hypertension thromboxane WG, A, Behayoun and GR, Ueda 127:43741 Hadengue 1991; 28 J Am oil syndrome. Am 1173-74 Martinez-Tello FJ, Mestre de Juan MJ, James TN. Clinical and pathologic manifestation of pulmonary vascular disease in the toxic BW, vasodilatation a clinicopathologic in a child. K, et al. Thromboxane in awake hypertension. 1989; 95:325-31 Chest Christman of Hartl reactions nard circulation Lowenstein and Lillington users G, L-tryptophan- 5, 44 Clarke Montalevscot DR. Jr. Aguayo clinical pulmonary 131:171-77 Robinson TE 145:A717 MA, JI, King syndrome: JE, in 1992; Gomez-Sanchez study. associated Chest hypertension Lopez disease myalgia Bespmr Dis 24 CW, Pulmonary LA, nary JL, Drage eosinophilic features. 23 Myers of the 1985; the end-systolic by two-dimensional Noninvasive in atrial configuration of echocardiography. assessment septal the defect: ventricular J Am Cardiol 53:1117-23 Berger M, Haimowitz Quan titative with tricuspid ultrasound. 60 of M. pressure Masuyama A, Van Tosh assessment of pulmonary regurgitation J Am CoU T, Kodama M. Continuous-wave Cardiol using 1985; K, Kitabatake Doppler Goldberg hypertension continuous E. in patients wave Doppler 6:359-65 A, Sato H, Nanto 5, Inoue echocardiographic detection I 104 1993 CHEST Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21673/ on 05/02/2017 A, BerdoffRL, 1 1 I JULY. of 249 pulmonary regurgitation and estimation of artery pulmonary its application to pressure. noninvasive Circulation 74 1986; 74:484-94 61 J, elevated Torres A, M, Trugeda et al. pulmonary at cardiac DG, arterial pulmonary echocardiographic Chen WJ, ovale by contrast Kuan 76 77 Chest 1992; Moser KM, scans provide GT, Ashburn a guide pulmonary WL, to which hypertension Fedullo patients merit PF. with Perfusion lung apparent angiography. Med Posteraro Am 66 J Sostman HD, Spritzer CE, MR imaging of central RH, Roentgen Debatin AJ, et comparing 67 79 MR K, ger, Hansen and JM, Morgan Mathur PN, blood Imaging DY, 80 RE, pool BJ. Principles 1991; 99:551-56 Powles RCP, Pugsley of digoxin on airflow obstruction. PM, RL. Primary importance Wagenvoort 72 Weir of Detre KM. The pulmonary PPH. Am U, tinuous Rev Treatment intravenous Intern and SM, 1989; Hood of primary prostacyclin M, 83 1981; 95:283-88 BJ, 1984; 85 and 86 the registry 1993 on (pros- of treatment survival in PPH [ab- (in press) P. Oaldey 88 on Fate C. Factors that hypertension. of the 1971; influence the J Br Heart 1986; patient Wallwork Oyer PE, et al. Heart-lung patients with 306:557-64 Pasque MK, SA, vascular Circulation CM, JL, Billingham JD. J Med Single three lung he- month 84:2275-79 J, ED. Robin of survival Chest ME, therapy N Engl Cooper Theodore idiopathic 145:A717 successful 1991; length pulmonary 1992; disease. LD, pulmo- RJ. Efficacy Dis hypertension: transplantation. 1973; Respir balloon cor Barst Pennock Kaiser and advanced transplantation: ER Burke Benign in Rev for pulmonary hypertension: Burdillon HardofAJ, pulmonary Trulock AR, E. DT, Hunt follow-up. Glanville Trell JL, Blade 60(suppl):1 Am BA, Eisenmenger’s for terminal septostomy Reitz 1982; CE. 1987; lIP, Hsu [abstract]. with 65:655.69 J Cardiol atnial disease Primary in patients referred 1987; 91:675-81 pulmonary hypertension. Med Acta 193:137-43 PD, CM. Oakley J Br Heart Kanemoto mary BH, in primary NIH Dis H. balloon hypertension. 87 Brundage of primary epoprostenol M. Influence prostacyclin D, Garofano blade Scand in 22:535-46 EH, from history in primary J. Treatment RJ, McGoon J Cardiol Am for heart-lung MD, hypertrophy ofvasodilators N, Sasamoto pulmonary Regression 1976; H. Pulmonary hypertension. Roskovic A, Montanes outcome of primary of primary pulmonary 38:264-70 Jpn P. Oakley hemodynamics J Heart CM. Factors pulmonary hypertension. BH, PS. in pri- 20:395-405 1979; that influence Br Heart the J 1986; 55:449-58 140:1623-30 McCoon pulmonary Kerstein pulmonary 70:580-87 medial 1960; 84 severe McGoon Comparable 110:1200-04 intravenous pulmonary Mark Am transplantation Campbell in natural Bergofsky experience Dis J, MP, function Med Gersh Circulation administration Respir Mendoza McEwan Circulation acute pulmonary hypertension: Ayres hypertension: Rubin WB. D, modynamic WD, Vasoconstriction U, pulmonary primary Barst Respir [abstractj. for Febi- Hypoxic and SO, Ann ofthrombosis. Rubin KM. ventricular Edwards hypertension. EK, right pulmonary CA. pulmonary Bois Wallwork with A, Montanes vascular 82 and TW, 1985; Nihill MR. O’Laughlin MP, Muffins atnial septostomy is effective palliation of imaging, 2:135-42 Lea 81 study 1992; Whipp sclerosis Chest V, Steele 71 250 Coleman phantom Philadelphia: M, du Fuster 1990; Sue systemic chronic Frye 73 Reson interpretation. in EJ. Effect the HD, fraction: radionucide JE, Grilliths hypertension. 70 emboli. 1987 vasoconstriction 69 imaging, J Magn testing RJ. Cine- JF, Sostman ejection Heart infusion ofprimary Young nale Paolini Cardiac ventriculography. Wasserman Herikens pulmonary 152:465-68 SN, al. cine exercise 68 1989; JF, Nadel Evans and Rozkovec syndrome. gradient-refocused U, Rev J Am MF. hydralazmne J 1987; 57:270-78 Br Heart Am and primary 66:334-38 Frosolono ofprostacycin hypertension continuous 1982; JT, F, Cato in 55:449-58 1988; 148:167-70 65 Reeves M, Handel vasodilation Circulation U, effects outcome primary J West Rubin Long W, Rubin JT, Frosolono pulmonary hypertension. stract]. 78 Page Reeves DK, Higgenbottam Jones with foramen echocardiography. BM, tacyclin). 85:1414-22 ofpatent BM, hypertension. Groves pul monary in severe transesoph- 1992; FY. Detection transesophageal 75 pulmonary 101:1515-20 64 Groves hemodynamic 57:859-63 adaptation Circulation W, Un JA, measured an intraoperative study. P. Lien pressure 1986; Pericardial hypertension: ageal with J Cardiol HC. de Prada of Doppler-determined pressure Am Dittrich A, Vazquez Comparison catheterization. Blanchard chronic 63 U, Prostacycin-induced pulmonary R, Larman Martin-Duran Ruane 62 Rubin AE. M, Barst hypertension (epoprostenol). Ann R, Williams with Intern 89 Rich 5, con- therapy Med pulmonary Brundage on the clinical hypertension. Levy outcome Circulation The of effect patients of vasodilator with primary 1985; 71:1191-96 112:485-91 Primary Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21673/ on 05/02/2017 Pulmonary Hypertension (Lewis J. Rubin et a!)