Advanced Pulmonary Hypertension Research Articles

Management of pulmonary hypertension: physiological and pharmacological considerations for anesthesiologists.

For decades the pulmonary circulation was not considered as important as the systemic (“greater”) circulation. However, pulmonary hypertension can arise because of many diseases of the heart and lung. Therefore, increasing efforts in research have been undertaken leading to a profound increase in un

Response of the right ventricle to acute pulmonary vasodilation predicts the outcome in patients with advanced heart failure and pulmonary hypertension

Objectives This study was designed to assess whether testing of potential reversibility of pulmonary hypertension (PHT) may be a useful means of defining the short-term prognosis of patients with advanced heart failure and elevated pulmonary artery pressure. In such patients, the reversibility of PHT after acute vasodilator administration is associated with a low early mortality rate after heart transplantation. However, its short-term prognostic value has not yet been determined. Methods and Results Between 1994 and 1998, 76 patients with advanced heart failure and PHT underwent right heart cathetherization. The hemodynamic measurements, including thermodilution-derived right ventricular ejection fraction, were repeated after an intravenous bolus of nitroglycerin (NTG). During a median follow-up period of 8.2 months (25% and 75% centiles, 3.3 and 18.9 months), 47 patients had a cardiac event (death or urgent heart transplantation). With Cox survival analysis, a multivariate model that included the New York Heart Association class and the hemodynamic variables obtained after NTG administration allowed a better assessement of the short-term prognosis of the patients than a model including the baseline variables. The evaluation of right ventricular function during the acute NTG-induced pulmonary vasodilation was of critical importance in obtaining such a refinement in the prognostic stratification. Conclusions The prognostic evaluation of patients with advanced heart failure and PHT should include the assessment of the changes of right ventricular ejection fraction after acute afterload reduction. (Am Heart J 2003;145:310-6.)

Inhaled iloprost as a bridge to transplant in advanced pulmonary fibrosis and secondary pulmonary hypertension

The development of secondary pulmonary hypertension is a poor prognostic factor in patients with pulmonary fibrosis. An acute challenge of inhaled iloprost, a chemically stable derivative of prostacyclin, has previously been shown to cause selective pulmonary vasodilatation in secondary pulmonary hypertension. We assessed its short-term efficacy in patients with advanced pulmonary fibrosis and secondary pulmonary hypertension as a bridge to transplantation. We studied seven patients (4 with UIP, and 3 with advanced sarcoidosis) all in New York Heart Association functional class IV. Iloprost was nebulized using a Schill multisonic nebulizer, and administered 3 hourly in increasing daily doses to a maintenance of 90mcg/day. The effects of inhaled iloprost were assessed by echocardiography, shuttle walk test and right heart catheterization (n 2). Inhalation of iloprost was well tolerated, and administered for a mean (SEM) of 2.4 (0.9) months. Two of 4 UIP patients and 1 of 2 sarcoid patients died during the follow up. There was a fall in pulmonary artery pressure, 73mmHg (19) before iloprost, versus 40mmHg (9) after iloprost therapy (p 0.26). There was a non significant improvement in pulmonary artery pressure when assessed by echo, 60mmHg (8) before versus 48mmHg (7) after iloprost therapy (p 0.28). Shuttle walk distance improved, but not significantly, 86m (34) before, versus 104m (48) after iloprost therapy (p 0.77). Inhaled iloprost therapy with terminal pulmonary fibrosis may only benefit selected (sarcoid) patients.

Alterations in nitric oxide production in 8-week-old lambs with increased pulmonary blood flow.

Nitric oxide (NO) is an important mediator of pulmonary vascular reactivity, and decreased NO synthase expression has been demonstrated in children with advanced pulmonary hypertension secondary to congenital heart disease and increased pulmonary blood flow. Using aortopulmonary vascular graft placement in the fetal lamb, we have established a unique animal model of pulmonary hypertension with increased pulmonary blood flow. At 4 wk of age, these lambs display an early, selective impairment in agonist-induced NO responses, but an up-regulation of basal NO activity and gene expression. We hypothesized that further exposure to increased flow and/or pressure results in progressive endothelial dysfunction and a subsequent decrease in basal NO production. The objective of this study was to characterize potential later alterations in agonist-induced NO responses and basal NO activity and gene expression induced by 8 wk of increased pulmonary blood flow and pulmonary hypertension. Twenty-two fetal lambs underwent in utero placement of an aortopulmonary vascular graft (shunt), and were studied 8 wk after delivery. Both in vivo and in isolated pulmonary arteries, the pulmonary vasodilating response to endothelium-dependent agents was attenuated in shunted lambs (p < 0.05), whereas the response to endothelium-independent agents was unchanged. The pulmonary vasoconstricting responses to Nomega-nitro-L-arginine, and lung tissue endothelial NO synthase mRNA, endothelial NO synthase protein, NO synthase activity, and NO(X) levels were all unchanged. These data suggest that the increase in basal NO activity demonstrated after 4 wk of increased pulmonary blood flow is lost by 8 wk of age, whereas the attenuation of agonist-induced responses persists. We speculate that the progressive decrease in basal NO activity participates in the development of pulmonary hypertension secondary to increased pulmonary blood flow.

Alterations in Nitric Oxide Production in 8-Week-Old Lambs with Increased Pulmonary Blood Flow

Nitric oxide (NO) is an important mediator of pulmonary vascular reactivity, and decreased NO synthase expression has been demonstrated in children with advanced pulmonary hypertension secondary to congenital heart disease and increased pulmonary blood flow. Using aortopulmonary vascular graft placement in the fetal lamb, we have established a unique animal model of pulmonary hypertension with increased pulmonary blood flow. At 4 wk of age, these lambs display an early, selective impairment in agonist-induced NO responses, but an up-regulation of basal NO activity and gene expression. We hypothesized that further exposure to increased flow and/or pressure results in progressive endothelial dysfunction and a subsequent decrease in basal NO production. The objective of this study was to characterize potential later alterations in agonist-induced NO responses and basal NO activity and gene expression induced by 8 wk of increased pulmonary blood flow and pulmonary hypertension. Twenty-two fetal lambs underwent in utero placement of an aortopulmonary vascular graft (shunt), and were studied 8 wk after delivery. Both in vivo and in isolated pulmonary arteries, the pulmonary vasodilating response to endothelium-dependent agents was attenuated in shunted lambs (p < 0.05), whereas the response to endothelium-independent agents was unchanged. The pulmonary vasoconstricting responses to Nω-nitro-l-arginine, and lung tissue endothelial NO synthase mRNA, endothelial NO synthase protein, NO synthase activity, and NOX levels were all unchanged. These data suggest that the increase in basal NO activity demonstrated after 4 wk of increased pulmonary blood flow is lost by 8 wk of age, whereas the attenuation of agonist-induced responses persists. We speculate that the progressive decrease in basal NO activity participates in the development of pulmonary hypertension secondary to increased pulmonary blood flow.

Nocturnal periodic breathing in primary pulmonary hypertension.

Cheyne-Stokes respiration is frequently observed in congestive heart failure. Among other factors, prolongation of circulation time, hypocapnia and hypoxia are thought to underlie this sleep-related breathing disorder. Primary pulmonary hypertension (PPH) is also characterized by reduced cardiac output and blood gas alterations. Therefore, the aim of the present study was to determine whether a nocturnal periodic breathing (PB) occurs in PPH. A total of 20 consecutive patients with PPH who had been admitted for pharmacological investigation of pulmonary vasoreactivity were investigated by lung function testing, right heart catheterization and full-night attended polysomnography. PB was detected in six patients (30%) (mean +/- SEM: apnoea/hypopnoea index 37 +/- 5 h(-1); arterial oxygen saturation was <90% during 56 +/- 6.5% of total sleep time). The patients with PB had more severe haemodynamic impairment than those without. They also had a more marked reduction in the pulmonary diffusion capacity and greater arterial hypoxia. PB was markedly improved or even eradicated by nasal oxygen during the night. Periodic breathing occurs in patients with advanced primary pulmonary hypertension and can be reversed by nocturnal nasal oxygen. The clinical and prognostic significance of periodic breathing in primary pulmonary hypertension needs to be determined by further studies.

ATRIAL SEPTOSTOMY FOR PULMONARY HYPERTENSION

Atrial septostomy represents an additional, promising strategy in the treatment of severe PPH. Experience with this procedure still is limited; however, based on analyses of the worldwide experience, several general conclusions and recommendations can be made. 1. Atrial septostomy can be performed successfully in selected patients with advanced pulmonary vascular disease. 2. Patients with primary pulmonary hypertension who have undergone successful AS have shown: a significant clinical improvement beneficial and long-lasting hemodynamic effects at rest a trend toward improved survival 3. The procedure-related mortality of the collective experience is high (16%). Several recommendations can be made to minimize the risk: [figure: see text] Atrial septostomy should be attempted only in institutions with an established track record in the treatment of advanced pulmonary hypertension, where septostomy is performed with low morbidity. Atrial septostomy should not be performed in patients in whom death is impending or who have severe right ventricular failure and are on maximal cardiorespiratory support. An mRAP greater than 20 mm Hg, PVR index greater than 55 u/m2, and a predicted 1-year survival less than 40% are significant predictors of procedure-related death. Before cardiac catheterization, patients should have an acceptable baseline systemic oxygen saturation (> 90% in room air) and optimized cardiac function (adequate right heart filling pressure, additional inotropic support if necessary). During cardiac catheterization, the following are mandatory: Supplemental oxygen Mild sedation to prevent anxiety Careful monitoring of variables (left atrial pressure, SaO2, and mRAP) Step by step procedure After AS, it is important to optimize oxygen delivery. Transfusion of packed red blood cells or erythropoietin (before and following the procedure, if needed) may be necessary to increase oxygen content. 4. Because the disease process in PPH is unaffected by the procedure (late deaths), the long-term effects of an AS must be considered to be palliative. 5. Despite its risk, AS may represent a viable alternative for selected patients with severe PPH. Indications for the procedure may include: Recurrent syncope or right ventricular failure, despite maximal medical therapy, including oral calcium-channel blockers or continuous intravenous prostacyclin (Fig. 11) As a bridge to transplantation When no other option exists.

Myocardial revascularization as a therapeutic strategy in the patient with advanced ventricular dysfunction.

The number of patients with severe ventricular dysfunction from coronary artery disease is constantly increasing. Although the medical management of these patients with angiotensin-converting enzyme inhibitors and beta-blockers has favorable impact on the morbidity and mortality the overall prognosis is still poor. Historically many of these patients have been referred for transplantation. In the past few years there has been an increasing amount of information about the utility of surgical revascularization in patients with low ejection fraction. Careful patient selection and optimal perioperative management is of critical importance for good outcome. Coronary artery bypass grafting (CABG) can be performed relatively safely despite the advanced level of left ventricular dysfunction. Quality of life is improved by CABG with elimination of angina and enhanced functional capacity. Improvement in the ejection fraction and increased survival after the operation has been objectively demonstrated. However patients with advanced right ventricular dysfunction, pulmonary hypertension, redo bypass and ungraftable coronaries should be considered for heart transplantation. In this review we describe our experience and focus on pertinent issues in patient selection, perioperative management and long term outcome after coronary artery bypass grafting.

Continuous intravenous prostacyclin for advanced primary pulmonary hypertension.

This article discusses the use of prostacyclin therapy for patients with advanced primary pulmonary hypertension, from patient selection through initiation, dosing, outpatient management, and outcomes. Advanced practice nurses are key to helping patients adapt to this complex medical therapy.

Altered regulation of the ET-1 cascade in lambs with increased pulmonary blood flow and pulmonary hypertension.

Plasma concentrations of endothelin-1 (ET-1) are increased in children with congenital heart disease associated with increased pulmonary blood flow. However, the role of ET-1 in the pathophysiology of pulmonary hypertension remains unclear. Preproendothelin-1 gene expression is increased in adults with advanced pulmonary hypertension. To characterize potential early molecular alterations in the ET-1 cascade induced by increased pulmonary blood flow and pulmonary hypertension, fetal lambs underwent in utero placement of an aortopulmonary vascular graft (shunt). RNase protection assays and Western blot analysis were performed on lung tissue prepared from 4-wk-old shunt lambs and age-matched controls. Endothelin-converting enzyme-1 [the enzyme responsible for the production of active ET-1 from big ET-1, mRNA (411%, p<0.05)] and protein (170%, p<0.05) were increased in lung tissue prepared from shunt lambs, compared with age-matched controls. Endothelin type A receptor (the receptor that mediates vasoconstriction), mRNA (246%, p<0.05), and protein (176%, p<0.05) also were increased in lung tissue prepared from shunt lambs compared with age-matched controls. Conversely, endothelin type B receptor (the receptor that mediates vasodilation), mRNA (46%, p<0.05), and protein (65%, p<0.05) were decreased in shunt lambs. Both the mRNA and protein levels for preproendothelin-were unchanged. Thus we conclude that increased pulmonary blood flow and pulmonary hypertension induce early alterations in the ET-1 cascade that result in increased ET-1 production, increased ET-1-mediated vasoconstriction, and decreased vasodilation. These early alterations in gene expression may contribute to the development of pulmonary hypertension and its associated enhanced pulmonary vascular reactivity.

Atrial septostomy as a bridge to lung transplantation in patients with severe pulmonary hypertension

Long waiting times for lung transplantation have limited the survival of patients with advanced pulmonary hypertension. Atrial septostomy has been used in this group of patients in an attempt to prolong survival. We evaluated the results of atrial septostomy in 12 patients using the static graded balloon dilation technique. Between December 1990 and May 1998, 10 women and 2 men (ages 13 to 56 years, mean 37 years) underwent atrial septostomy. Nine patients had primary and 3 patients had secondary pulmonary hypertension. Five patients deteriorated despite long-term intravenous prostacyclin infusions. The atrial septum was crossed with a Brockenbrough needle, followed by an 0.035-J exchange wire and progressively larger catheter balloons for atrial septal dilation, until systemic oxygen saturation decreased 5% to 10%. An atrial septal defect was successfully created in each patient. The mean right atrial pressure decreased from 23 to 18 mm Hg and the mean systemic oxygen saturation decreased from 93% to 85%. The mean cardiac index increased from 1.7 to 2.1 L/min/m 2 and the mean systemic oxygen transport increased from 268 to 317 ml/min/m 2. Complications occurred in 3 patients: transient hypotension during transesophageal echocardiography, a femoral pseudoaneurysm, and a femoral arteriovenous fistula. After septostomy, 6 patients had clinical improvement (resolution of ascites, edema, and no further episodes of syncope); 5 of these 6 patients underwent lung transplantation a mean of 6.1 months after septostomy. Six patients did not have clinical improvement after septostomy. Atrial septostomy improves the hemodynamic status and may be useful as a bridge to lung transplantation in selected patients with pulmonary hypertension.

Continuous infusion of epoprostenol improves the net balance between pulmonary endothelin-1 clearance and release in primary pulmonary hypertension.

Primary pulmonary hypertension results from progressive narrowing of the precapillary pulmonary vasculature. A variety of endothelial abnormalities have been identified, including a net reduction in pulmonary clearance of the vasoconstrictor and smooth muscle mitogen endothelin-1. In many patients, net pulmonary release of endothelin-1 is observed. Chronic infusions of epoprostenol (prostacyclin) improve functional capacity, survival, and hemodynamics in patients with advanced primary pulmonary hypertension. We hypothesized that the epoprostenol infusions, as compared with conventional therapy, might alter the abnormal pulmonary endothelin-1 homeostasis. Using a subset of patients from a larger randomized study comparing epoprostenol plus conventional therapy (n=11 in the present study) with conventional therapy alone (n=7 in the present study), we determined the ratio of plasma endothelin-1 levels in systemic arterial blood leaving the lung to levels in mixed venous blood entering the lung both before randomization and after 88 days of continuous therapy. There were no differences between the 2 groups before therapy, but by day 88, the epoprostenol-treated group had a greater proportion of patients (82%) with an arterial/venous ratio <1 than did the conventional therapy group, in which only 29% of patients had a ratio <1 (P<0.05). These results suggest that continuous epoprostenol therapy may have a beneficial effect on the balance between endothelin-1 clearance and release in many patients with primary pulmonary hypertension and may provide one explanation for the salutary effect of epoprostenol in this disease.

Lung transplantation for pulmonary hypertension: patient selection and maintenance therapy while awaiting transplantation

Although lung transplantation is considered a definitive treatment of patients with advanced pulmonary vascular disease and pulmonary hypertension, advances in the success of the medical management of patients with pulmonary hypertension make it less clear as to when to refer a patient for transplantation. Coumadin anticoagulation is associated with improved survival in all patients, and calcium channel blockers therapy with improved survival in very select patients. Chronic prostacyclin represents a newer therapy that seems to have a dramatic impact on patients' functional class and survival. As improvements continue in the medical management in pulmonary hypertension, and in survival of patients undergoing lung transplantation, the guidelines for patient selection should be constantly evolving.

Lung transplantation for pulmonary hypertension: patient selection and maintenance therapy while awaiting transplantation.

Although lung transplantation is considered a definitive treatment of patients with advanced pulmonary vascular disease and pulmonary hypertension, advances in the success of the medical management of patients with pulmonary hypertension make it less clear as to when to refer a patient for transplantation. Coumadin anticoagulation is associated with improved survival in all patients, and calcium channel blockers therapy with improved survival in very select patients. Chronic prostacyclin represents a newer therapy that seems to have a dramatic impact on patients' functional class and survival. As improvements continue in the medical management in pulmonary hypertension, and in survival of patients undergoing lung transplantation, the guidelines for patient selection should be constantly evolving.

Usefulness of Atrial Septostomy as a Treatment for Primary Pulmonary Hypertension and Guidelines for its Application

We review our experience and that for 2 large series of atrial septostomy as a treatment for advanced pulmonary hypertension to better understand the hemodynamic changes that result. Atrial septostomy may be a useful procedure in patients with severe refractory pulmonary hypertension, but should not be used in patients who are critically ill.

963-19 Evidence for Complement Activation by Smooth Muscle Cells in Lesions of Advanced Pulmonary Hypertension (PH)

In PH and other vascular obstructive diseases, the mediators of intimal hyperplasia of arteries have been extensively studied. Little attention has been given to the pathogenesis of the more advanced pulmonary vascular lesions, such as fibrinoid necrosis and plexiform lesions. Recently, it was shown that the membrane attack complex of the complement (MAC) plays a role in pathologic processes chracterized by cell proliferation, including atherosclerosis. To contribute to the understanding of the development of the arterial obstructive lesions in PH, we studied the expression of MAC in lungs from 8 patients presenting advanced vascular disease: five with primary PH, two with PH secondary to Schistosomiasis and one secondary to a congenital heart defect (mean age 20; median 17.5 years), We characterized immunohistochemically the proliferative vascular lesions using antibodies that recognize the active form of MAC, α -actin and Factor VIII, in paraffin embedded tissue. The intimal lesions, including plexiform lesions, contained predominantly α -actin positive smooth muscle cells (SMC). Factor VIII strongly labelled the endothelial cells of arteries, including the vascular spaces within plexiform lesions. All 8 cases exhibited positive MAC reaction (mild to moderate) in the medial layer of arteries but not of veins, staining individual SMC and also lining the internal and/or external elastic membranes. MAC was constantly negative in the SMC of the plexiform lesions and in endothelial cells. In only 2 of 8 cases was MAC expressed (weakly) in intimal lesions. MAC was also positive focally in fibrinoid necrosis. We conclude that SMC are the main constituents of the intimal and plexiform lesions, and that MAC is always present in the medial SMC. Since MAC is known to induce cell proliferation, our findings may suggest that it participates in the pathogenesis of obstructive lesions in human PH, and that the fibrinoid necrosis of the arterial wall could be related to a complement attack which extends beyond the sublytic stage.

Evidence for the association of unexplained pulmonary hypertension in children with the major histocompatibility complex.

A link between primary pulmonary hypertension (PPH) and autoimmune disorders has been postulated. To investigate this relation, we performed immunofluorescent antinuclear antibody tests (ANA) and serological human leukocyte antigen (HLA)-A, B, C, DR, and DQ typing on two groups of Caucasian children with unexplained pulmonary hypertension (PHT) and their parents. Group 1 consisted of 17 children with PPH including two patients with familial PPH and three patients with trivial congenital pulmonary to systemic communications. Group 2 consisted of 13 children with advanced PHT and anatomically large congenital pulmonary to systemic communications (PHT + shunt). Both groups had comparably severe pulmonary vascular disease documented by cardiac catheterization. The following statistically significant data (p less than 0.05) were obtained when the study groups were compared with those published for normal controls. Although positive ANAs and varying titers of autoantibodies were found in both groups of children and mothers (not fathers), +ANAs were only significant for the maternal groups. The PPH (group 1) children had increased frequencies of HLA-DR3, DRw52, and DQw2 and decreased DR5, whereas the group 2 (PHT + shunt) children (also their parents) had no statistically significant alterations in any of the DR or DQ alleles. The PPH mothers had decreased DQw3, an allele in linkage disequilibrium with DR5. These immunogenetic data suggest that childhood PPH appears to be associated with the major histocompatibility complex alleles HLA-DR3, DRw52, and DQw2. This newly found correlation of juvenile PPH with these alleles adds this disease to the DR3+ group of autoimmune diseases. Further studies are needed to determine whether there is also an immunological or autoimmune component in some children with PHT + shunt lesions because this group lacked an HLA association.

Patent Ductus Arteriosus in Arabs

Two hundred patients with patent ductus arteriosus (PDA) underwent sur gery for either triple ligation and transfixation (183 patients = 91.5%) or divi sion and suture (18 patients = 8.5%). The patent ductus arteriosus was an isolated lesion in 163 patients (81.5%) and combined with other cardiac anoma lies in 37 patients (18.5%). Advanced pulmonary hypertension (&gt; 50 mmHg), even in the pediatric age group, was seen in 70 patients (35%). Familial PDA occurred in 6 patients, and 38 patients were born at a high- altitude area (&gt; 4000 feet). Recanalization occurred in only 1 patient (0.5%) owing to initial faulty tech nique using umbilical tape instead of strong silk for ligation of the PDA. Only 2 patients with complex congenital anomalies died (mortality rate of 1%). The peculiarities, presentation forms, and surgical results in Arab patients with PDA are discussed in this paper.

Pulmonary function in advanced pulmonary hypertension: Burke CM, Glanville AR, Morris AJR, et al: Thorax 42:131–135, 1987

Pulmonary function in advanced pulmonary hypertension: Burke CM, Glanville AR, Morris AJR, et al: Thorax 42:131–135, 1987

Pulmonary function in advanced pulmonary hypertension.

Pulmonary mechanical function and gas exchange were studied in 33 patients with advanced pulmonary vascular disease, resulting from primary pulmonary hypertension in 18 cases and from Eisenmenger physiology in 15 cases. Evidence of airway obstruction was found in most patients. In addition, mean total lung capacity (TLC) was only 81.5% of predicted and 27% of our subjects had values of TLC less than one standard deviation below the mean predicted value. The mean value for transfer factor (TLCO) was 71.8% of predicted and appreciable arterial hypoxaemia was present, which was disproportionate to the mild derangements in pulmonary mechanics. Patients with Eisenmenger physiology had significantly lower values of arterial oxygen tension (PaO2) (p less than 0.05) and of maximum mid expiratory flow (p less than 0.05) and significantly higher pulmonary arterial pressure (p less than 0.05) than those with primary pulmonary hypertension, but no other variables were significantly different between the two subpopulations. It is concluded that advanced pulmonary vascular disease in patients with primary pulmonary hypertension and Eisenmenger physiology is associated not only with severe hypoxaemia but also with altered pulmonary mechanical function.