Right ventricular pathology in chronic pulmonary hypertension.

Right ventricular free wall biopsy specimens in 40 patients undergoing surgery for relief of chronic thromboembolic pulmonary hypertension were normal in 5%, disclosed only myocyte hypertrophy in 80%, mild focal fibrosis in 12.5%, and myocarditis in 2.5%. There was no relation between postsurgical functional or hemodynamic outcomes and the presence of focal fibrosis.

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 patents 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/m2 and the mean systemic oxygen transport increased from 268 to 317 ml/min/m2. 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.

Inhaled nitric oxide reverses hypoxic pulmonary vasoconstriction in dogs. A practical nitric oxide delivery and monitoring system.

Nitric oxide (NO) is a potent dilator of vascular smooth muscle that likely represents an important endothelium-dependent relaxing factor. Recent interest has focused on inhaled NO as a pulmonary vasodilator. The purpose of this study was to design a reliable NO delivery system with on-line monitoring of NO and nitrogen dioxide (NO2) concentrations, and to test the effects of inhaled NO in a dog model of acute hypoxic pulmonary vasoconstriction (HPV). Six canines were studied. Marked HPV was induced using a hypoxic gas mixture. Using a standard blender. NO was delivered through a volume-cycled ventilator. We were able to rapidly adjust the delivered NO concentration using this system. An on-line chemoluminescence analyzer was used to continuously measure NO and NO2 concentrations. Inhaled NO at 40 and 80 ppm for 30 min rapidly reversed HPV in all animals (PVR 502 +/- 154 dynes.s.cm-5 with hypoxia, 244 +/- 52 with 40 ppm NO, 227 +/- 47 with 80 ppm NO). No significant NO2 or methemoglobin production was noted during the study. We conclude that inhaled NO can be easily delivered through a ventilator and the dose rapidly adjusted, NO and NO2 concentrations can be monitored continuously on-line, inhaled NO rapidly reverses HPV in dogs, and with short-term NO inhalation, there is no significant NO2 or methemoglobin formation. Inhaled NO may, therefore, have a future clinical role as a new agent in the diagnosis and treatment of other forms of pulmonary hypertension.

Experience and results with 150 pulmonary thromboendarterectomy operations over a 29-month period.

A program to alleviate chronic, major vessel thromboembolic pulmonary hypertension by pulmonary thromboendarterectomy was initiated at this institution in 1970. Multiple evolutionary changes in the diagnostic evaluation, surgical approach, and postoperative management have been implemented over the series of 323 thromboendarterectomies performed through March 1992. A sequence of five surgeons at the University of California at San Diego have performed these procedures, with the last 150 having been performed by one surgeon. We report here the changes in surgical approach developed over the last 150 cases and the results obtained. The operation involves a median sternotomy incision, the institution of cardiopulmonary bypass, and deep hypothermia with circulatory arrest periods. Incisions are made in both pulmonary arteries into the lower lobe branches. Pulmonary thromboendarterectomy is always bilateral, with removal of both organized thrombus and an endarterectomy plane from all involved vessels. The right atrium is routinely explored for atrial septal defects. Current techniques appear to allow more thorough revascularization and shorter circulatory arrest times. The surgical mortality of 8.7% over this span is below that previously reported from this and other institutions. Among survivors, the hemodynamic and functional results have been excellent. Surgically correctable chronic thromboembolic pulmonary hypertension likely remains underdiagnosed. The diagnostic, surgical, and postoperative management evolution provided by the coordinated team involved at this institution has established that pulmonary thromboendarterectomy can be performed with an acceptable risk and good hemodynamic and symptomatic results.

Pulsed delivery of inhaled nitric oxide to patients with primary pulmonary hypertension: an ambulatory delivery system and initial clinical tests.

BACKGROUND: Inhaled nitric oxide (NO) has been shown to be a selective pulmonary vasodilator in certain patients with primary pulmonary hypertension (PPH). OBJECTIVES: The purpose of this study was to design and test a system for delivery of NO to awaken, ambulatory patients with PPH and to evaluate this system in the home setting. METHODS: The ambulatory delivery system consisted of a tank of 80 ppm of NO (balance N2), a modified gas-pulsing device, and nasal cannulas. The pulsing device was set to deliver NO for 0.1 s at the beginning of each inspiration. RESULTS: Using this system, eight patients with PPH were studied with pulmonary artery catheters in place. Inhalation of NO led to significant reductions in both mean pulmonary arterial pressure (PAPm) (51 +/-12 to 43 +/- 10 mm Hg; p=0.001) and pulmonary vascular resistance (PVR) (790 +/- 285 to 620 +/- 208 dyne x s x cm-5; p=0.01). Three of the eight patients had both greater than 20% and greater than 30% decreases in PAPm and PVR, respectively. No exhaled NO or N02 was detectable in any of the eight patients. One patient was discharged home from the hospital on a regimen of inhaled NO. At 9 months, no adverse effects were noted and the system was working well. CONCLUSIONS: Pulsed delivery of inhaled NO to ambulatory patients with PPH, via nasal prongs, is feasible and, in some patients, leads to significant improvement in pulmonary hypertension. Inhaled 09NO, therefore, may have a role in the long-term treatment of patients with PPH.

Parenchymal scarring is associated with restrictive spirometric defects in patients with chronic thromboembolic pulmonary hypertension.

UNLABELLED: The finding of a restrictive pulmonary defect may divert clinicians from considering the diagnosis of chronic thromboembolic pulmonary hypertension because lung volumes are usually normal in this disorder. We have, however, encountered a significant number of these patients with reduced lung volumes. Furthermore, we have observed many patients who have developed parenchymal scars and/or pleural thickening. To determine whether such findings are associated with lung volume restriction, we analyzed patients evaluated at our institution for chronic thromboembolic pulmonary hypertension over a 20-month period in whom thoracic high-resolution CT scans and pulmonary function testing had been performed. Patients with obstructive or restrictive lung disease from another cause were excluded. We compared the presence of lung restriction (total lung capacity below 80% of predicted) with the extent of parenchymal scarring, pleural thickening, and pulmonary artery diameter on CT scans. Of 191 patients evaluated, 51 met criteria for entry. Eleven patients (22%) had lung restriction. Parenchymal scarring was highly associated with lung restriction (p = 0.01). Neither pleural thickening (p = 0.08) nor pulmonary artery diameter (p = 0.80) was associated with lung restriction. CONCLUSIONS: A significant number of patients with chronic thromboembolic pulmonary hypertension may have restrictive lung defects. The restriction may be due to parenchymal scarring.

Outpatient inhaled nitric oxide in a patient with idiopathic pulmonary fibrosis: a bridge to lung transplantation.

Inhaled nitric oxide (INO) has been shown to improve oxygenation and decrease intrapulmonary shunt and pulmonary hypertension in various lung diseases. In this study we report a patient with end-stage idiopathic pulmonary fibrosis and pulmonary hypertension who received INO after coronary artery bypass surgery, with significant improvement in arterial oxygenation and pulmonary arterial pressure. Using a pulsing delivery system, the patient continued to receive outpatient INO for 30 months while waiting for lung transplantation. Exercise study and two-dimensional echocardiogram, after 3 months of inhaled NO, demonstrated continued benefits of INO for improvement of arterial oxygenation, pulmonary arterial pressure and exercise tolerance.

Reoperative pulmonary thromboendarterectomy.

BACKGROUND: Recurrent symptomatic pulmonary hypertension is uncommon after primary pulmonary thromboendarterectomy (PTE). We reviewed our experience with patients undergoing repeat PTE to determine the risk factors for recurrent disease, and the selection criteria, relative risks, and functional outcomes of reoperative PTE. METHODS: Since 1990, 13 of 870 (1.5%) patients underwent reoperative PTE at our institution. These 7 men and 6 women (mean age 38.6 years) were contrasted with the most recent 225 patients (111 men, 114 women, mean age 52.7 years) who underwent primary PTE for whom complete hemodynamic data are available. The preoperative evaluation of all patients was similar. Pulmonary hemodynamic data and outcome measures were compared between groups. RESULTS: Of 13 reoperated patients: 69% (9/13) had their primary operation at another institution, 54% (7/13) initially underwent unilateral PTE, 38% (5/13) had identifiable coagulation disorders, 38% (5/13) had ineffective caval filtration, 31% (4/13) had suboptimal anticoagulation management, and 31% (4/13) had complete unilateral pulmonary artery obstruction. The mean interval to reoperation was 5.2 years (range 0.7 to 10.9 years). All control patients underwent bilateral PTE using hypothermic circulatory arrest. Operative mortality was 7.7% (1/13) with reoperation vs 8.4% (19/225) in controls. No difference (p = NS) was observed between groups in the preoperative pulmonary artery pressure (PAP) or pulmonary vascular resistance; however, the control group had a significantly (p < 0.05) greater reduction in the postoperative PAP (46/19, mean 28 mm Hg vs 59/23, mean 35 mm Hg) and PVR (271 +/- 172 vs 399 +/- 154 dynes/s/cm(-5)) compared with the redo group. No substantial difference in morbidity or functional outcomes was observed between groups. CONCLUSIONS: Reoperative PTE can be performed with a perioperative risk comparable with primary PTE, although the improvement in pulmonary hemodynamics is not as favorable. Bilateral primary operation, effective caval filtration, and vigilant anticoagulant management would prevent the need for most reoperative PTEs.

New and experimental therapies for pulmonary hypertension.

Advances in the understanding of the molecular and cellular pathogeneses of PPH have led clinicians beyond simple pulmonary vasodilation as the only treatment for PPH and to a realization that what were previously believed to be irreversible vascular lesions may, in fact, be reversible. The development of agents that target the known endothelial and nonendothelial defects in patients with PPH is well underway. Clinicians are witnessing an exciting new era for physicians and patients dealing with this disease.

Chronic thromboembolic pulmonary hypertension.

Chronic, major-vessel thromboembolic disease represents a potentially correctable form of pulmonary hypertension. A thorough understanding of the unique problems associated with each aspect of care in these patients is essential to ensure a minimal perioperative mortality and satisfactory long-term outcome. This article reviews the cause, natural history, evaluation, surgical management, and postoperative course of patients with chronic thromboembolic pulmonary hypertension undergoing thromboendarterectomy.

Chronic thromboembolic pulmonary hypertension.

Remarkable advances have occurred over the past 2 decades in the diagnostic approach, surgical management, and postoperative care of patients afflicted with chronic thromboembolic pulmonary hypertension. Despite these advances, a great deal needs to be achieved if the morbidity and mortality of the disease process are to be reduced further. First, the preliminary insights that have been achieved into the natural history of the disease must be defined further. The level of pulmonary hypertension encountered in most patients with chronic thromboembolic pulmonary hypertension at the time of initial clinical recognition cannot be reached on an acute basis. Gradual hemodynamic progression, therefore, must occur over time. The basis for this progression, why it occurs in certain patients and not others, following an acute thromboembolic event and why it seems to occur over months in certain patients and over decades in others, remain entirely speculative. It is possible that the overall extent of central pulmonary vascular obstruction represents the primary pathophysiologic determinant of disease progression. Given the lack of correlation between the degree of central thromboembolic obstruction and hemodynamic impairment in certain patients, however, it is also possible that other factors, such as the circulating vasoconstrictors, the development of a hypertensive pulmonary arteriopathy, an individual genetic predisposition to pulmonary hypertension, or the compensatory adaptations of the right ventricle, contribute to the extent and rate of disease progression. By identifying and sequentially evaluating patients with persistent pulmonary vascular obstruction or pulmonary hypertension following an acute thromboembolic event, valuable insights into the natural history of thromboembolic pulmonary hypertension and other variants of pulmonary hypertension might be achieved. It is also important to recognize that the development of chronic thromboembolic pulmonary hypertension represents a failure in the long-term management or follow-up surveillance of those with documented acute thromboembolic disease. Recent insights into the recurrent nature of acute thromboembolic disease and its potential for only partial resolution in a number of afflicted individuals suggest that a repeat perfusion scan and, if abnormal, an echocardiogram be performed at the time of anticipated discontinuation of anticoagulation in patients with documented pulmonary embolic disease. Although the cost-effectiveness of this approach has been questioned in the past, recent data suggest that doing so would help identify that subset of patients with unresolved embolism, provide additional information regarding the optimal duration of anticoagulation, and provide a new baseline study for patients in whom anticoagulation is discontinued and who subsequently present with suspected embolic recurrence. Improved diagnostic techniques are also necessary if the mortal risk of thromboendarterectomy is to be reduced. Even in the setting of a broad experiential base, prognostic uncertainty exists in approximately 10% of patients before operative intervention. Because many of these patients will benefit from the procedure, and because many are ineligible for transplantation for reason of age or other restriction, it has been the authors' practice to offer surgery to these patients, although at an assumed higher risk. To not do so would be to deny a potentially lifesaving procedure to many who would benefit and who might be left without an effective therapeutic alternative. The ability to better define the group of patients who will not benefit from surgery, however, would spare those patients the morbid and mortal risks of the procedure and provide a basis for the investigation of other therapeutic alternatives such as pulmonary vasodilating agents. Finally, this patient population offers a unique opportunity to enhance understanding of the pathophysiologic mechanisms involved in acute lung injury. The population involved is uniform, the predisposing event is consistent, the time of onset is predictable, and, compared with other populations at risk for acute lung injury, the presence of confounding variables is negligible. It also provides a unique opportunity to evaluate pharmacologic interventions designed to prevent or diminish the occurrence of acute lung injury and postoperative management strategies designed to minimize its impact.

Evaluation of patients with suspected chronic thromboembolic pulmonary hypertension.

Chronic thromboembolic pulmonary hypertension (CTEPH) can be a difficult diagnosis to establish, typically requiring a high index of suspicion on the part of the clinician when challenged by a patient reporting exertional dyspnea. The importance of this diagnosis is heightened by the appreciation that it is a potentially curable form of pulmonary hypertension, by a surgical procedure called pulmonary thromboendarterectomy. This article highlights the clinical presentation, evaluation, and criteria for surgical candidacy of those patients suspected of having CTEPH.

Rituximab treatment of pulmonary arterial hypertension associated with systemic lupus erythematosus: a case report.

Pulmonary hypertension is a common but underdiagnosed complication of systemic lupus erythematosus, which can be associated with significant morbidity and early mortality. Although often associated with anti-phospholipid antibodies, the etiology remains poorly understood. In case reports and small open trials, the anti-CD20, B-cell targeted therapeutic antibody, rituximab, has been reported to provide benefits for systemic lupus erythematosus patients with glomerulonephritis, anti-phospholipid antibody syndrome, vasculitis, arthritis, and refractory skin disease. However, the outcome of rituximab treatment of pulmonary arterial hypertension associated with systemic lupus erythematosus has not been described. We, therefore, present a case of a young systemic lupus erythematosus patient with early onset of pulmonary arterial hypertension during the disease course, refractory to multiple treatment modalities, who had significant improvement with rituximab therapy.

Improvement in pulmonary hypertension and hypoxemia during nitric oxide inhalation in a patient with end-stage pulmonary fibrosis.

A patient with severe interstitial pulmonary fibrosis, hypoxemia, pulmonary hypertension, and cor pulmonale was given inhaled nitric oxide (NO) followed by intravenous PGE1 to assess the reversibility of pulmonary hypertension. During NO inhalation, there was marked reduction in pulmonary vascular resistance, increased cardiac output, and dramatic improvement in arterial oxygenation. There was no effect on systemic vascular resistance. In contrast, intravenous PGE1 led to rapid arterial oxygen desaturation and worsened dyspnea. The beneficial responses to inhaled NO in this patient suggest that, even in severe chronic lung disease, reversible pulmonary vasoconstriction is present. Inhaled NO thus has a potential therapeutic role as a selective pulmonary vasodilator in patients with interstitial pulmonary fibrosis and cor pulmonale.

Accuracy of MR angiography compared with radionuclide scanning in identifying the cause of pulmonary arterial hypertension.

OBJECTIVE: MR imaging has proven accurate in identifying patients with chronic thromboembolic pulmonary hypertension (CTEPH). However, we know of no attempt to distinguish patients with CTEPH from patients with other causes of pulmonary arterial hypertension (PAH). Primary pulmonary hypertension (PPH) is the disease most frequently confused with CTEPH. We examined patients with CTEPH or PPH and control subjects to identify MR imaging features that might distinguish CTEPH from PPH, to compare the accuracy of MR angiography (MRA) with that of radionuclide scanning, and to determine the cardiac and pulmonary vascular measurements in these groups. SUBJECTS AND METHODS: T1-weighted and two-dimensional multiplanar spoiled gradient-recalled scans were obtained in 30 patients with CTEPH who had undergone conventional pulmonary angiography, 10 patients with PPH, and 13 control subjects with no known vascular disease. Ventilation-perfusion scans were available in all patients with CTEPH and in six of the 10 patients with PPH. The MR scans were assessed independently by two radiologists who evaluated the appearance of segmental vessels and noted the presence of mosaic perfusion. Cardiac chambers and pulmonary vessels were measured on T1-weighted spin-echo scans. RESULTS: The two radiologists used MR angiograms to reliably distinguish between patients with CTEPH and those with PPH. The accuracy of MR angiograms matched that of ventilation-perfusion scans (92%). On T1-weighted scans, the two radiologists used cardiac and pulmonary vascular measurements to distinguish patients with PAH from control subjects but failed to distinguish between patients with CTEPH and those with PPH. CONCLUSION: MRA is useful in distinguishing patients with CTEPH from those with PPH. In this population, MRA had an accuracy that was identical to that of radionuclide scanning. Vascular and cardiac measurements made on MR scans reliably identified patients with PAH but did not distinguish between patients with CTEPH and those with PPH.

Unilateral pulmonary artery thrombotic occlusion: is distal arteriopathy a consequence?

The characteristics and postoperative outcomes of a unique group of eleven patients with total unilateral pulmonary artery (PA) thromboembolic occlusion were compared with those of some 400 patients who underwent bilateral thromboendarterectomies during the same time period. Preoperative historical, physical, and laboratory features and postoperative outcomes of these two groups were analyzed. The unilateral group had no distinct historical features. However, they were younger (32 +/- 10 yr) than the bilateral group (51 +/- 15 yr), dominantly female (10 of 11) versus a male predominance (62%) in the bilateral group; had significantly lower preoperative PA mean pressures (30 +/- 12 versus 46 +/- 12 mm Hg) and calculated pulmonary vascular resistance (360 +/- 293 versus 901 +/- 467 dynes/s/cm-5); and small lung by chest radiograph was common (8 of 11). Postoperatively, four unilateral patients developed unilateral rethrombosis (two immediate; two late, at several years postsurgery); this occurred in only one bilateral patient. Furthermore, of six patients with unilateral occlusion present more than 1 yr, reperfusion was poor in four despite an adequate thromboendarterectomy in all. Postoperative pulmonary angiograms in two of these disclosed apparent atrophy of central and distal pulmonary arteries. Prior animal investigation models indicate that unilateral PA occlusion is followed by development of a postobstructive arteriopathy in the resistance arteries of the occluded lung. The unusual outcomes in these 11 patients suggest that they may develop a similar arteriopathy which requires special management considerations at surgery and postoperatively.

Identifying the cause of unilateral hypoperfusion in patients suspected to have chronic pulmonary thromboembolism: diagnostic accuracy of helical CT and conventional angiography.

PURPOSE: To determine the prevalence of unilateral hypoperfusion in patients suspected to have chronic thromboembolism (CTE), to identify the most common cause of hypoperfusion, and to compare the accuracy of helical computed tomographic (CT) angiography with that of conventional angiography in helping to determine the cause. MATERIALS AND METHODS: Radionuclide lung scan reports showed asymmetric hypoperfusion in 47 of 410 consecutive patients referred because of suspected CTE. Twenty-seven patients had unilateral or predominantly unilateral perfusion abnormalities. Each pulmonary angiogram and CT angiogram in these patients was interpreted independently by two readers blinded to clinical information and surgical outcome. Surgical confirmation of the diagnosis was available in 39 of the 47 patients with asymmetric hypoperfusion. RESULTS: Unilateral (n = 11) or predominantly unilateral hypoperfusion (n = 16) was found in 6.6% (27 of 410 patients) of patients referred, and CTE was the most common cause. The accuracies of CT angiogram readers (reader 1, 83%; reader 2, 89%) were greater than those of conventional angiogram readers (reader 1, 73%; reader 2, 65%) for distinguishing CTE from other causes. CONCLUSION: Unilateral hypoperfusion occurred in 6.6% of our study population, most frequently because of CTE. CT angiography is an excellent diagnostic alternative to conventional angiography for distinguishing patients with CTE from those with other causes.

Pulmonary vascular remodeling distal to pulmonary artery ligation is accompanied by upregulation of endothelin receptors and nitric oxide synthase.

There is increasing evidence that the pathogenesis and progression of many forms of pulmonary vasculopathy are related to abnormalities in endothelial mediators, including endothelin-1 (ET-1) and nitric oxide (NO). Using a rat model of chronic unilateral pulmonary artery ligation, we investigated the role of ET-1 and NO in postobstructive pulmonary vasculopathy (POPV). Eight months after a left thoracotomy with either left main pulmonary artery ligation (ligated group) or no ligation (sham group), rat lungs, including those contralateral to the ligation (hyperperfused group), were fixed and mounted for histologic sectioning. Morphometric measurements were carried out by computer-assisted image analysis and immunohistochemical staining was performed using specific antibodies against ET-1, ETA, and EBB receptors, and endothelial NO synthase (eNOS). Compared to sham lungs, the ligated lungs showed (1) an increase in muscular, adventitial, and intimal thickness of pulmonary artery; (2) increase in external diameter of the bronchial artery (39.8 +/- 2.2 microns vs. 16.8 +/- 0.9 microns in sham group; P < .005) and number of bronchial arteries per bronchiole (3.21 +/- mu 0.26 vs. 1.86 +/- mu 0.21 in sham group; P < .001); and (3) increase in the intensity of eNOS and ETA, B receptor immunoreactivity. No morphometric or immunohistochemical differences were observed between the hyperperfused and sham lungs. These findings suggest that increased synthesis of endothelial NO may serve as a compensatory mediator in ET-1-mediated vascular remodeling.

"High probability" perfusion lung scans in pulmonary venoocclusive disease.

"High-probability" ventilation/perfusion (V/Q) lung scans generally indicate proximal pulmonary arterial occlusion by thromboemboli or, rarely, other processes such as tumors, fibrosing mediastinitis, or vasculitis. In this report we describe three patients with high probability V/Q scans in whom pulmonary angiography failed to demonstrate arterial occlusion. All three patients were determined to have pulmonary venoocclusive disease (PVOD). In two patients, a tissue diagnosis of PVOD was made, in one case with explanted tissue taken after a successful heart-lung transplant and in the other case with tissue taken at autopsy. PVOD in the third patient was diagnosed with pulmonary venography. A potential explanation for the discrepancy between perfusion lung scan and pulmonary angiographic findings in PVOD is discussed.