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Pulmonary thromboendartectomy (PTE) for chronic thromboembolic pulmonary hypertension may be complicated by reperfusion lung injury. This has previously been demonstrated to be neutrophil-mediated. We postulated that blocking selectin-mediated adhesion of neutrophils to the endothelium with Cylexin (CY-1503) would prevent reperfusion lung injury in this patient population. In this double-blind, randomized, placebo-controlled, parallel study, 26 patients received Cylexin the day of surgery and 25 received placebo. Significantly fewer patients in the treated group (31%) compared with the placebo group (60%) developed lung injury (p = 0.036). However, the average number of days of mechanical ventilation, days in the intensive care unit (ICU) and hospital, as well as mortality were not significantly different between the treatment groups. Those with reperfusion lung injury had significantly elevated percent neutrophils, total protein, and soluble P-selectin in bronchoalveolar lavage fluid compared with those without lung injury. We conclude that reperfusion lung injury after PTE is a high-permeability lung injury and its incidence can be reduced by the administration of Cylexin on the day of surgery.

Objective: To test the hypothesis that reperfusion of the canine lung after 1 week of vascular occlusion results in acute injury of the reperfused lung with concurrent impairment in gas exchange. Methodology: In 11 conditioned dogs, the left pulmonary artery was completely occluded by a vascular clip placed at thoracotomy. One week later, at repeat thoracotomy, the clip was removed in six animals (reperfused group) but left in place in five (sham group). Bronchoalveolar lavage fluid (BAL) components, gas exchange, haemodynamics and histological alterations were examined. Results: During occlusion, the mean pulmonary artery pressure and pulmonary vascular resistance increased significantly, and after 6 days there was a significant increase in ventilation to high ventilation perfusion ratio (V/Q) areas. With reperfusion, the previously occluded lung demonstrated, in comparison to the contralateral lung, a significant increase in BAL cellularity and neutrophil fraction, gross and histological evidence of oedema, and impaired surfactant activity. Shunt fraction, measured by the inert gas technique, also increased only after reperfusion, although mild hypoxaemia occurred in both groups. Endothelial abnormalities and perivascular oedema were noted in both groups, but were more marked in the reperfused lungs. Conclusion: Reperfusion of the canine lung after 1 week of complete occlusion resulted in evidence of mild acute lung injury. The aetiology of this injury was multifactorial.

Study objectives The aims of this study were: to evaluate the performance of a novel arterial biopsy catheter in obtaining pulmonary endovascular samples in hypertensive dogs; to compare the results of pulmonary endoarterial biopsy in hypertensive vs normotensive dogs; and to assess the histologic changes in the hypertensive model. Design and interventions Thirty-four dogs (27 with normal pulmonary arterial pressures and seven with pulmonary hypertension) were catheterized through an external jugular vein to obtain endovascular biopsy samples from distal pulmonary arteries 2 to 3 mm in luminal diameter. To induce pulmonary hypertension, seven dogs were given repeated infusions of 0.6- to 0.9-mm ceramic microspheres into the superior vena cava. Endoarterial samples were obtained at pulmonary systolic arterial pressures ranging from 10 to 110 mm Hg. Measurements and results Sixty-two biopsy catheterization procedures were performed in the 34 dogs. After 12 initial procedures of technique refinement, endoarterial samples were obtained in each of the last 50 procedures (21 in normotensive dogs and 29 in hypertensive dogs). The average number of endovascular biopsy samples retrieved was 7.1 (range, 2 to 12) from a mean of 8.6 (range, 2 to 15) biopsy attempts per catheterization (success rate=83%). The average biopsy piece measured 1.13 mm in length, 0.33 mm in depth, and up to 1.0 mm in width. The biopsy success rates and endoarterial sample sizes were similar in normotensive and hypertensive dogs. Smooth muscle cells and endothelial cells were grown from the biopsy samples. There were no significant procedural complications, except for one self-limited hemorrhage. Histologically, samples obtained from dogs with pulmonary hypertension showed characteristic changes when compared with biopsies from normotensive dogs. Conclusion This new endoarterial biopsy catheter was safe and effective when used to obtain pulmonary endoarterial samples in dogs with normal and experimentally elevated pulmonary arterial pressures. The quality and quantity of the biopsy samples allowed identification of pathologic changes.

Patients with sickle cell disease have been reported to have an increased risk of thromboembolism and pulmonary hypertension. Some of these patients may benefit from pulmonary thromboendarterectomy (PTE), a procedure that requires profound hypothermia, cardiopulmonary bypass, and periods of circulatory arrest, factors that may potentially increase the risk of sickling. Two patients with sickle cell disease (sickle-thalassemia [Hb S/beta+] and Hb SS) presented to the Pulmonary Vascular Center of UCSD Medical Center with significant shortness of breath and limitation of daily activities. Both of these patients were found to have surgically accessible chronic thromboembolic disease with pulmonary hypertension. PTE was performed in both patients using exchange transfusion, with avoidance of anemia, hypoxia, and acidosis. A successful outcome with resolution of pulmonary hypertension was achieved in both cases. To our knowledge this is the first report of patients with sickle cell disease who successfully underwent PTE for chronic thromboembolic pulmonary hypertension.

Purpose The purpose of this consensus report was to address clinically relevant questions related to the diagnosis and management of acute pulmonary embolism and deep venous thrombosis. Background Physicians are often forced to make decisions about the diagnosis and management of pulmonary thromboembolism even though there are only limited data to guide them. Methods We assessed the relevant literature regarding clinical trials according to levels of evidence. The data on which the opinions of the committee were made were sparse. The consensus opinions, therefore, were often based on experience or intuition, rather than firm data. Results Consensus opinions were given in regard to eight clinically relevant questions. Conclusion We hope that the consensus opinions of this committee will assist others in making clinical decisions while we all await prospective investigations.

BACKGROUND Preliminary results of lung volume reduction surgery (LVRS) for patients with severe emphysema are promising, although many issues regarding the selection process for LVRS are still unaddressed. For example, it is unclear which patients should be referred for pulmonary rehabilitation, lung transplantation, or LVRS, and whether health-care providers are optimizing conservative treatment options before referral for surgical intervention. The purpose of this analysis is to describe preliminary results of the evaluation process for LVRS implemented as part of an integrated, programmatic approach to the evaluation, treatment, and rehabilitation of patients with advanced emphysema. METHODS The records of 105 consecutive patients with chronic obstructive pulmonary disease (COPD) referred for consideration for LVRS at the University of California San Diego Medical Center were reviewed. Results of prospective data collection pertaining to patient demographic, baseline dyspnea scores, and history of prior treatment, including pulmonary rehabilitation, were extracted. Patient disposition after the evaluation was noted. RESULTS One hundred five patients (mean age 65 years, range 40 to 84 years) completed evaluation. Fifty-eight had never before participated in pulmonary rehabilitation, and 47 of these patients were eventually referred to a rehabilitation program. Fourteen patients were referred for consideration of lung transplantation, 25 were considered eligible for LVRS, 13 were still undergoing rehabilitation and surgical eligibility had not yet been determined, and 53 were ineligible for LVRS because patients had other illnesses (n = 34), did not meet radiological or physiologic criteria (n = 5), were considered too ill (n = 5), or were too healthy (n = 9) after rehabilitation to warrant surgical intervention. CONCLUSIONS Lung volume reduction surgery is a surgical option to be considered within the framework of an integrated medical evaluation program that includes pulmonary rehabilitation. Pulmonary rehabilitation remains an often underused therapeutic alternative in patients with severe COPD. It has become the central component of our comprehensive management program for patients with severe dyspnea and deteriorating quality of life.

SummaryAccurate non-invasive diagnosis of deep venous thrombosis and pulmonary embolism remains an elusive goal. Radiolabeled antibodies specific for the epitope exposed on the β-chain of fibrin after fibrino- peptide B release (anti-β) enabled in situ imaging of thrombi in experimental subjects with nuclear medicine techniques. When used in patients anticoagulated for thrombo-embolic disease, however, the antibody was unable to reliably image the thrombi. We postulated that the neoepitope on the β-chain of fibrin is covered up as fibrin organizes into a polymer network and is therefore exposed to the antibody only during active incorporation of fibrin subunits. We determined the equilibrium binding kinetics of an anti-β monoclonal antibody to fibrin in various stages of organization. The concentration of exposed epitopes on immobilized fibrin monomers was equal to the molar concentration of fibrin β-chains. The percentage of β-chains exposed to the antibodies markedly decreased as the fibrin network was allowed to organize, a process catalyzed by calcium. Conclusions: The β-chain amino terminus of fibrin is exposed transiently as subunits are added to the enlarging fibrin network. Anti-β antibodies bind preferentially to actively enlarging fibrin polymers.

Background The presence of patent neovessels within vascular occlusions in chronic thromboembolic pulmonary hypertension suggests that local mechanisms exist to regulate the coagulation system. This study investigated the expression of a potent inhibitor of Factor IXa and Factor XIa (ie, protease nexin-2/amyloid β-protein precursor, AβPP) in the organized vascular occlusions harvested from patients with this disease. Methods and Results Immunohistochemical analysis revealed intense immunoreactivity for AβPP in the single layer of cells that line the neovessels. A positive signal was also detected by in situ hybridization analysis with the use of a 35 S-UTP–labeled antisense riboprobe that recognizes the various alternatively spliced mRNA forms of this molecule. To identify the forms of AβPP produced within the thrombi, total RNA was extracted from the thrombi, reverse transcribed, and subjected to amplification with the use of the polymerase chain reaction (PCR) and primers that flank the region encoding the alternatively spliced 56–amino acid Kunitz-type protease inhibitor (KPI) domain. The major PCR products consisted of 255 bp and 312 bp and corresponded to transcripts encoding this domain (ie, AβPP 751 and AβPP 770 ). In situ hybridization analysis with the use of a 35 S-UTP–labeled antisense riboprobe complementary to the region encoding the KPI domain confirmed the presence of these mRNA species in nucleated cells lining the neovessels. Conclusions The expression of KPI-containing isoforms of AβPP in thrombus endothelial cells may represent one mechanism utilized in this disease to shift the local hemostatic balance and preserve regional vessel patency.

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.

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 N 2 ), 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·s·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 NO 2 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.

Rationale and Objectives. We evaluated the accuracy of contrast-enhanced magnetic resonance (MR) angiography in demonstrating the findings of chronic pulmonary thromboembolism (CPTE) compared with conventional pulmonary angiography. Methods. We examined 18 patients with CPTE proved by conventional pulmonary angiography and 16 healthy control patients. T1-weighted and single-breathhold, two-dimensional multiplanar spoiled gradient-recalled pulmonary images were obtained after injection of gadopentetate dimeglumine. Images were interpreted independently by two radiologists. Results. All patients with CPTE were identified on MR angiography images by both readers. Sensitivity and specificity for MR angiography in diagnosing abnormal segments were 76% and 95% for reader 1 and 68% and 93% for reader 2, respectively. Sensitivity and specificity for MR angiography in depicting abnormal lobes were 83% and 96% for reader 1 and 82% and 93% for reader 2, respectively. Interobserver agreement was high; kappas for abnormal segments and abnormal lobes were .72 and .84, respectively. The T1-weighted spin-echo images demonstrated a mosaic signal intensity pattern in all patients with CPTE. Conclusion. Contrast-enhanced MR angiography accurately depicts abnormal segments and lobes in occlusive vascular disease and clearly distinguishes between patients with CPTE and those with healthy lungs.

PURPOSE : An increased occurrence of thrombotic events has been described in patients exhibiting a lupus anticoagulant (LA). In patients with chronic, major vessel thromboembolic pulmonary hypertension, not only has there been a relatively high frequency of the LA, but also an unexpected association with heparin-related thrombocytopenia. This retrospective report emphasizes the frequency of this association. PATIENTS AND METHODS : We retrospectively reviewed the medical records of 216 patients admitted to the University of California, San Diego, Medical Center who were being considered for surgical correction of their chronic thromboembolic pulmonary hypertension. For each patient, the following information was sought : presence of an LA, variation in platelet numbers during the preoperative evaluation, and determination of whether an observed thrombocytopenia was related to heparin use. RESULTS : An LA was found in 23 of the 216 patients (10.6%). Of the remaining patients, sufficient platelet data for comparison were available for 68 patients. These 68 patients constituted the control group. Within the LA group, platelet counts during the preoperative evaluation declined to 51.6% ± 16.7% of baseline counts, a highly significant difference (P

Bleomycin-induced lung injury is an established murine model of human pulmonary fibrosis. Although procoagulant molecules (e.g., tissue factor [TF]) and fibrinolytic components (e.g., urokinase [u-PA] and type 1 plasminogen activator inhibitor [PAI-1]) have been detected in alveolar fluid from injured lungs, the origin of these molecules remains unknown. We therefore examined the expression of procoagulant and fibrinolytic components in relation to the distribution of parenchymal fibrin in bleomycin-injured lungs. Extravascular fibrin localized to the alveolar and extracellular matrix in injured lung tissue. Injured lung tissue extracts contained elevated levels of PAI-1 activity and decreased levels of u-PA activity. Whole lung PAI-1 and TF mRNAs were dramatically induced by lung injury. In situ hybridization of injured lungs revealed that PAI-1, u-PA, and TF mRNAs were induced within the fibrin-rich fibroproliferative lesions, primarily in fibroblast-like and macrophagelike cells, respectively, while TF mRNA was also induced in perilesional alveolar cells. Taken together, these observations suggest that the induction of PAI-1 and TF gene expression plays and important role in the formation and persistence of extracellular fibrin in bleomycin injured murine lungs.

Background Distinguishing chronic major vessel thromboembolic pulmonary hypertension from primary pulmonary hypertension is critical because the treatment options differ markedly. Surgical thromboendarterectomy is potentially curative in the former condition, whereas oxygen, vasodilators, perhaps anticoagulation, and lung transplantation are the options for the latter. The development of large thrombi in the main, right, or left pulmonary arteries has not been previously described in patients with primary pulmonary hypertension. Methods and Results Three pulmonary hypertensive patients with massive thrombi in the central pulmonary arteries are described. The data indicate that the large central thrombi in these three patients were not hemodynamically significant. In none did perfusion lung scans demonstrate segmental or larger defects. Conclusions Large central thrombi can develop in patients with primary pulmonary hypertension. Perfusion lung scans that do not demonstrate segmental or larger defects should alert physicians to this possibility. Chest computed tomography and other studies identifying such thrombi are not adequate in distinguishing such a development from operable chronic major vessel thromboembolic hypertension. Careful review of lobar and segmental artery findings and the pulmonary angiogram, angioscopy, and cardiac catheterization data demonstrating the hemodynamic significance (or lack thereof) of these thrombi are essential in making this important distinction. Furthermore, these observations may constitute an additional indication for anticoagulant therapy in primary pulmonary hypertension.

Background The decreased morbidity and rapid recovery after thoracoscopic lung biopsy compared with open lung biopsy by thoracotomy is increasingly recognized, as is the ability to obtain satisfactory diagnostic material thoracoscopically. To our knowledge, however, there has been no systematic comparison of specimen quality using different thoracoscopic biopsy techniques. The purpose of this study was to compare histologic features of lung parenchyma obtained by videothoracoscopic forceps and wedge biopsy techniques. Methods Five adult swine were anesthetized, intubated, and ventilated. Sequential left and right videothoracoscopies were performed to obtain biopsy specimens of lung parenchyma using 5-mm endoscopic cupped forceps. Specimens were obtained from fully inflated lung and from partially atelectatic (deflated) lung. Electrosurgery was applied during forceps biopsy for airleak closure. Limited wedge biopsy specimens were obtained using an endoscopic stapler. One hundred thirteen forceps biopsy specimens (55 inflated, 58 deflated) and 24 sections from 8 wedge biopsy specimens were examined. Specimens were assessed for overall histologic quality and ease of microscopic interpretation. Specific histologic features were then evaluated including presence of artifact, congestion and hemorrhage, degree of alveolar inflation, and number of bronchioles and vessels per cross-sectional area. Whole lungs from two animals were examined for extent and depth of lung injury at the areas of biopsy. Results No major differences in overall microscopic specimen quality were detected among the different techniques nor were significant differences noted between lung inflated and lung deflated forceps biopsy technique. Wedge sections contained more vessels per unit area (p Conclusions Multiple 5-mm forceps biopsy specimens were of comparable quality to single wedge biopsy specimens obtained by endoscopic stapling. Although greater numbers of vessels were present in endoscopic stapled wedge biopsy specimens, multiple forceps biopsy specimens in fact, contain amply sufficient vessels for histologic analysis.

BACKGROUND Chronic thromboembolic pulmonary hypertension is the result of nonresolving pulmonary emboli that lead to chronic obstruction of the central pulmonary arteries. METHODS AND RESULTS To determine if the failure to lyse pulmonary thromboemboli is caused by an abnormality in the endothelial cell (EC)-associated fibrinolytic system, conditions were established to culture ECs from patient main pulmonary arteries during surgical pulmonary thromboendarterectomies and to analyze the conditioned media for levels of tissue-type plasminogen activator (TPA) and type 1 plasminogen activator inhibitor (PAI-1). Our data indicate that the levels of TPA antigen and PAI-1 activity in media conditioned by primary ECs harvested from areas free of thrombus were not significantly different between patients with chronic thromboemboli and organ donors. In 13 consecutive patients, no correlation was obtained in either the TPA antigen or PAI-1 activity level in a patient's plasma and the respective levels in media conditioned by the patient's pulmonary ECs. Moreover, patient pulmonary arterial ECs were observed to increase the secretion of TPA and PAI-1 in response to thrombin in a fashion similar to donor pulmonary artery ECs. CONCLUSIONS The data suggest that an inherent EC-mediated fibrinolytic imbalance is not a generalized phenomenon observed in pulmonary arteries of patients with chronic pulmonary thromboemboli.

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 (NO 2 ) 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 NO 2 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 NO 2 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 NO 2 concentrations can be monitored continuously on-line, inhaled NO rapidly reverses HPV in dogs, and with short-term NO inhalation, there is no significant NO 2 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.

BACKGROUND Chronic thromboembolic pulmonary hypertension is the result of nonresolving pulmonary emboli that lead to chronic obstruction of the central pulmonary arteries. METHODS AND RESULTS To determine if the failure to lyse pulmonary thromboemboli is caused by the local expression of the primary inhibitor of tissue-type plasminogen activator (type 1 plasminogen activator inhibitor, PAI-1), levels of PAI-1 antigen and mRNA were analyzed by immunohistochemistry and in situ hybridization in specimens harvested from a series of patients during pulmonary thromboendarterectomies. Red, fibrin-rich thrombi within the thromboendarterectomy specimens were lined with a single layer of endothelial cells exhibiting high levels of PAI-1 antigen. Quantitation of the in situ hybridization signal revealed that a significant increase in PAI-1 mRNA was present in the endothelial cells lining the fresh thrombi in comparison to the signal present in the endothelial cells from noninvolved areas of patients' pulmonary arteries (n = 16, P < .001). In contrast, tissue-type plasminogen activator antigen levels were low in all samples. Yellowish-white thrombi were composed of smooth muscle cells and endothelial cells in numerous vessels that stained prominently for PAI-1 antigen. Both types of cells within the highly organized tissues also exhibited elevated PAI-1 mRNA levels in comparison to patient pulmonary artery specimens that were free of thrombus (n = 16, P < .02). CONCLUSIONS The prevalence of PAI-1 expression within pulmonary thromboemboli suggests that this inhibitory may play a role in the stabilization of vascular thrombi.

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.

Data from a number of laboratories indicate that human platelets contain type I plasminogen activator inhibitor (PAI-1) primarily in a latent form; however, one report (Biochemistry 28:5773, 1989) indicated that it is predominantly the active form of PAI-1 that is present in and can be purified from an ammonium sulfate precipitate of porcine platelets. To clarify this situation, we investigated and compared the status of PAI-1 in porcine and human platelets. Immunologic analysis of the ability of PAI-1 to form complexes with immobilized t-PA indicated that porcine and human platelets contained 3.7 +/- 0.4 and 1.7 +/- 0.3 U of PAI activity per 10(8) platelets (n = 6; +/- SD), respectively; sodium dodecyl sulfate (SDS)-activation of the lysates increased PAI-1 activity to 10.8 +/- 3.0 and 3.8 +/- 0.5 U per 10(8) platelets. Platelet lysates were also treated with an excess of soluble t-PA, which formed complexes with active PAI-1, whereas the latent form was detected by SDS-polyacrylamide gel electrophoresis and reverse fibrin autography. Furthermore, immobilized t-PA was able to deplete active PAI-1 from the platelet extracts, and the latent form remaining in the absorbed extract could be quantitated by activation with 4 mol/L guanidine. To investigate the differences between our observations and the published data, porcine platelets were extracted, and PAI-1 was partially purified as described in the literature. For quantitative analysis, porcine platelet PAI-1 was also purified to homogeneity using standard chromatographic procedures optimized in our laboratory for endothelial PAI-1, and the purified protein was used to develop an enzyme-linked immunoabsorbent assay for porcine PAI-1 antigen. Our results indicate that: (1) latent PAI-1 in concentrated ammonium sulfate precipitates of porcine platelet lysates cannot be detected unless the precipitates are diluted before treatment with denaturants; and (2) active and latent porcine platelet PAI-1 can be separated by gel filtration over molecular sieving columns. In summary, this report documents that PAI-1 in porcine platelets is present in both an active and a latent form.

The pulmonary angiograms of 250 patients evaluated for chronic thromboembolic pulmonary hypertension were reviewed. Pulmonary thromboendarterectomy was performed in each of these individuals, and the surgical findings were correlated with abnormal angiographic patterns. The pulmonary angiographic findings suggestive of chronic thromboembolic disease included "pouching" defects, webs or bands, intimal irregularities, abrupt vascular narrowing, and complete vascular obstruction. Pouching is reported by the authors to be a previously undescribed angiographic feature of this disease. Carefully obtained and properly interpreted pulmonary angiograms are necessary to confirm the diagnosis of operable chronic thromboembolic disease. Differential diagnostic possibilities should be considered prior to a decision to perform surgical correction.

Pulmonary thromboendarterectomy is being performed with increasing frequency for incapacitating pulmonary hypertension caused by chronic large-vessel pulmonary embolism. However, patient-related risk factors and procedural complications associated with morbidity and mortality have not been fully defined. From Oct. 1, 1984, to April 10, 1989, we performed pulmonary thromboendarterectomy using deep hypothermia and circulatory arrest in 127 consecutive patients (62.2% male, mean age 50 ± 16 [standard deviation], range 20 to 82 years) in whom the exposure and dissection of the pulmonary arteries and methods for myocardial protection have been standardized. End points for univariate and multivariate analyses of risk factors were reperfusion pulmonary edema leading to respiratory insufficiency as defined by ventilator dependency (≥5 days) (31.5%, 39/124) and hospital mortality (12.6%, 16/127). Multivariate analyses showed that ascites and need for 4 units of blood or more predicted ventilator dependency (p

This study evaluated long-term outcome of pulmonary thromboendarterectomy (PTE) in patients with chronic thromboembolic pulmonary hypertension (CTEPH). Survival, functional status, quality of life, health care utilization, and relationships between these parameters and postoperative pulmonary hemodynamics were assessed. Questionnaires were mailed to 420 patients who were more than 1 yr post-PTE; 308 responded (mean age, 56 yr [range, 19-89 yr]; mean years since PTE, 3.3 [range, 1- 16]). Survival after PTE was 75% at > 6 yr. After surgery, symptoms were markedly reduced. Median distance walked was 5,280 ft; 56 patients could walk "indefinitely." Of the working population, 62% of patients unemployed before PTE returned to work. Post-PTE patients scored several quality of life components of the Rand SF-36 slightly lower than reported normals but significantly higher than did pre-PTE patients. Ten percent of patients used oxygen. Ninety-three percent were in NYHA Class I or II. Disease-related hospitalizations/ER visits were minimal. A relationship was shown between 48 h postoperative pulmonary vascular resistance (PVR) and walking and stair-climbing ability, NYHA class, dyspnea scores, and the physical function and general health quality of life components. These data indicate that PTE offers most CTEPH patients substantial improvement in survival, function, and quality of life, with minimal disease-related health care utilization.

Abstract —Information is lacking on the mechanisms involved in the organization, resolution, and repair of the vascular lumen after acute pulmonary thromboembolism. Because recent data suggest that the balance between plasminogen activators (PAs) and type 1 plasminogen activator inhibitor (PAI-1) plays a role in regulating cell migration within the extracellular matrix, we investigated the expression of these molecules by immunohistochemical and in situ hybridization analysis of pulmonary artery specimens from patients suffering fatal pulmonary embolism. The data were compared with the expression of these molecules in both patients’ noninvolved pulmonary arteries and organ donor pulmonary arteries. Regions of initial organization and vascular remodeling were identified by a modified trichrome stain and by the presence of proliferating cell nuclear antigen (PCNA), a cell marker of proliferation. Staining for tissue-type PA antigen was low to undetectable in endothelial cells directly in contact with the fibrin-platelet thromboembolus and in areas in which the endothelial cell lining was replaced by cell growth into the thrombus. Urokinase-like PA (u-PA) expression was detected in mononuclear cells within the thrombus in the initial phase of thromboembolism and within cells migrating into the thrombus during the later stages of organization. PAI-1 expression was elevated in the monolayer of endothelial cells underlying the fresh platelet-fibrin thromboembolus and in a PCNA-positive cell population present between the pulmonary arterial intima and the thromboembolus that represents early organization. Increased expression of PAI-1 may play a role in inhibiting proteolysis and fostering the localization of the acute fibrin-platelet thrombus to the vascular wall, which is followed by the upregulation of u-PA in migrating cells during the reorganization process.

A reduced diffusing capacity for carbon monoxide (DCO) is common among patients with chronic thromboembolic pulmonary hypertension (CTEPH) and often persists for more than a year following successful pulmonary thromboendarterectomy (PTE). To determine the relative contribution the pulmonary membrane diffusing capacity (DM) and pulmonary capillary blood volume (VC) make to the reduction in DCO, we measured both in 29 patients with CTEPH before and approximately 3 weeks after PTE. Mean preoperative DM was reduced in patients with CTEPH (28 mL min-1 mm Hg-1 vs 43 mL min-1 mm Hg-1 in control subjects; p0.001) and dropped significantly following PTE (21 mL min-1 mm Hg-1; p0.001). Mean preoperative VC was mildly reduced in the CTEPH group compared with healthy control subjects (57 vs 67 mL; p = 0.044) and did not rise following PTE (57 mL pre-PTE vs 54 mL post-PTE; p0.05) despite substantial reduction in mean pulmonary artery pressure and increase in cardiac output after surgery. We conclude that the low DCO observed in patients with CTEPH before and after PTE is principally caused by a reduced DM and to a lesser extent by a low VC. The mechanisms responsible remain speculative but may reflect pathophysiologic changes in the pulmonary microcirculation caused by chronic pulmonary hypertension that did not improve in the postoperative period studied.

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.

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.

A case of digital clubbing in a patient with pulmonary artery sarcoma and severe pulmonary hypertension is presented. The differential diagnosis of clubbing and clinical features of pulmonary artery sarcoma are reviewed with emphasis on the possible association of clubbing with pulmonary artery sarcoma.

Activation of endothelial cells occurs in response to numerous physiological stimuli and results in the concerted expression of endothelial cell proteins that change the nonthrombogenic intimal surface of a vessel into a thrombogenic surface, with the subsequent development of local thrombosis. For example, both type 1 plasminogen activator inhibitor and tissue factor expression are mediated by endothelial cell stimulation in vitro; however, in contrast to type 1 plasminogen activator inhibitor, it has been difficult to detect tissue factor associated with endothelial cells in vivo. This case study describes the presence of both type 1 plasminogen activator inhibitor and tissue factor antigen associated with pulmonary arterial endothelial cells of a patient exhibiting a mycobacterial infection. The disease was associated with chronic hemoptysis and characterized by extensive tissue destruction and local thrombosis within the pulmonary artery. The data show that conditions occur in vivo in which local thrombosis is associated with increased levels of type 1 plasminogen activator inhibitor and tissue factor.

Chronic obstruction of pulmonary arteries can be due to a variety of disease processes, including chronic thromboembolic disease, fibrosing mediastinitis, or neoplasia. Large vessel arteritis is another unusual cause of pulmonary artery obstruction and can be difficult to distinguish from the above-listed etiologies. We present four patients referred to our institution with the provisional diagnosis of chronic thromboembolic pulmonary hypertension who were subsequently diagnosed with Takayasu's arteritis involving the pulmonary arteries. We review the historical, physical examination, and radiologic characteristics that help distinguish Takayasu's arteritis from chronic thromboembolic disease.

All doctors with patients suspected of having an acute deep venous thrombosis or a pulmonary embolism would love a diagnostic magic bullet. They long for a test that would rule in or rule out the diagnosis of venous thromboembolism with a high degree of certainty. Ideally, such a test would be rapid, non-invasive, and widely available. The search for a reliable test has continued because the clinical diagnosis of thromboembolism is neither sensitive nor specific. Neither symptoms nor examination of the legs are reliable; nor can clinical signs or symptoms define the presence or absence of pulmonary embolism. Clinical signs and symptoms can only suggest these diagnoses—and asymptomatic venous thrombosis and pulmonary embolism are both fairly common. Not surprisingly, then, over the years a succession of simple, relatively non-invasive tests has been explored. Blood tests have included measurement of the “diagnostic” triad of lactic dehydrogenase, bilirubin, and glutamic oxaloacetic transaminase; immunoglobulin E1; …

BACKGROUND The brisk fibrinolytic response of canines has impaired efforts to develop a canine model of chronic thromboembolic pulmonary hypertension. Difficulties in retaining chronic embolic residuals were partially overcome by administration of tranexamic acid (TXA) (Circulation. 1991;83:1272-1279.). In this study, we used type 1 plasminogen activator inhibitor (PAI-1), a major inhibitor of the endogenous fibrinolytic system, to determine its efficacy in the suppression of thrombolysis in canines. METHODS AND RESULTS Thrombus was induced in the inferior vena cava of anesthetized mongrel dogs with thrombin and a special double-balloon catheter; 2 hours later, the thrombus was embolized. In one group of dogs, activated type 1 plasminogen activator inhibitor (PAI-1) (130 micrograms) was delivered directly into the forming thrombus; in another, TXA (110 mg/kg) was given intravenously before thrombus formation; in controls, thrombus was induced without inhibitors. Cross-linked fibrin degradation product (D-dimer) appeared in the blood of control animals within 1 hour of thrombus induction (176 +/- 62.5 versus 1.02 +/- 0.39 ng/mL baseline; mean +/- SEM), was maximal by 4 hours (413 +/- 110 ng/mL) and remained elevated at 24 hours (90.8 +/- 19.5 ng/mL). Compared with controls, PAI-1 and TXA suppressed D-dimer release by 80% and 85%, respectively, over the first 24 hours. One week later, animals were killed, and residual emboli were harvested. Perfusion scan defects persisted in all animals at this time, but there were no scan defect differences among groups. However, emboli recovered from animals receiving PAI-1 still harbored immunoreactive PAI-1 and were, on average, more than twofold greater in mass (393 +/- 56 mg) than emboli recovered from either controls (183 +/- 76 mg) or animals receiving TXA (180 +/- 80 mg). CONCLUSIONS Intravenous TXA and intrathrombus PAI-1 effectively suppress thrombolysis for 24 hours in canines. Thromboemboli enriched with PAI-1 appear to resist lysis for longer periods of time (up to 1 week). These findings are consistent with the hypothesis that PAI-1 remains associated with the embolus, where it continues to inhibit lysis, whereas TXA eventually diffuses out of the embolus, allowing lysis to ensue.

PURPOSE: To study the relationship of regional hypoperfusion and areas of decreased lung attenuation on computed tomographic (CT) scans of patients with chronic pulmonary thromboembolism. MATERIALS AND METHODS: Preoperative CT scans of five patients (four men and one woman, aged 29-72 years) with chronic pulmonary thromboembolism were reviewed and compared with axial single photon emission CT (SPECT) perfusion scans obtained at similar levels. Regions of varying attenuation and perfusion were scored on a three-point scale. RESULTS: In the five patients, 198 regions were identified. Of 176 abnormal regions at SPECT, 133 were abnormal at CT (sensitivity, 75.6%). Eleven of 22 regions interpreted as normal at SPECT were judged to have normal attenuation at CT (specificity, 50%). The overall accuracy of CT for detecting areas of hypoperfusion was 72.7% (P = .011). CONCLUSION: A mosaic pattern of lung attenuation at CT is a sign of variable regional perfusion and may suggest chronic pulmonary thromboembolism as...

BACKGROUND Numerous investigators have observed that pulmonary emboli are rapidly lysed in a canine model system. This study was undertaken to delineate the unique mechanism that accounts for the rapid dissolution of pulmonary emboli in mongrel dogs. METHODS AND RESULTS Canine plasminogen activator (PA) activity (2.6 +/- 1.1 IU/mL acidified platelet-poor plasma [PPP], < 0.3 IU/mL acidified whole blood serum [WBS], mean +/- SD; n = 6) and PA inhibitor activity (6.1 +/- 2.6 U/mL PPP, 35.4 +/- 7.8 U/mL WBS; n = 6) were determined in standard plasminogen-based chromogenic assays. Analysis of canine PPP, WBS, platelet lysates, and primary canine endothelial cell (EC) cultures by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and fibrin autography revealed a plasminogen-dependent lytic zone at 45-kd relative molecular mass that was shown to be related to urokinase-type PA (u-PA) by its selective inhibition through amiloride. Analysis of canine platelets on standard 125I fibrin plate assays revealed a net fibrinolytic activity. In a clot lysis assay system, canine platelets were able to stimulate fibrinolysis when layered on the outside of fibrin clots containing autologous PPP. Moreover, net fibrinolytic activity of primary canine pulmonary artery endothelial cells was higher than the activities expressed by canine aortic or carotid artery endothelial cells. CONCLUSIONS Rapid lysis of pulmonary emboli in mongrel dogs appears to be a result of 1) the high u-PA activity in canine PPP and 2) the predominant association of u-PA activity with canine platelets and canine pulmonary artery endothelial cells.

The status of small pulmonary arteries may influence diagnosis, surgical selection and postoperative outcome of patients with chronic major vessel thromboembolic pulmonary hypertension (CTEPH). Therefore, in patients with the established diagnosis of CTEPH, lung tissue was obtained by biopsy (15 patients) or at autopsy (16 patients) to assess the histopathologic composition of small pulmonary arteries. Pathologic examination disclosed the full range of pulmonary hypertensive lesions in the small arteries, including plexogenic lesions. The type and extent of hypertensive lesions did not relate to preoperative hemodynamic values, to patient age, or to symptom duration. The findings indicate that primary pulmonary hypertension cannot be differentiated from potentially correctable CTEPH on the basis of histopathologic findings in small pulmonary arteries. Furthermore, none of the histologic findings preclude a positive hemodynamic and clinical result from pulmonary thromboendarterectomy. However, development of these hypertensive changes may explain the deterioration which these patients experience preoperatively over time.

BACKGROUND Chronic thromboembolic pulmonary hypertension (CTEPH) is a disorder characterized by pulmonary arterial hypertension as a consequence of organized thrombotic material in the central pulmonary arteries. Incomplete resolution of acute pulmonary emboli is believed to be pathogenically important; however, the mechanism for poor thrombus dissolution remains to be explained. We undertook this study to assess the major determinants of plasma fibrinolysis in patients with CTEPH (n = 32). METHODS AND RESULTS Immunological and functional levels of tissue-type plasminogen activator (t-PA) and type 1 plasminogen activator inhibitor (PAI-1) were quantified in platelet-poor plasma (PPP) from patients with CTEPH as well as age-matched controls. Although basal PPP t-PA antigen levels (CTEPH mean, 29.5 ng/ml; control mean, 2.7 ng/ml) and PAI-1 antigen levels (CTEPH mean, 55.8 ng/ml; control mean, 21.0 ng/ml) were higher in the CTEPH group, no between-group differences were detected in the enzymatic activities of these two molecules. The CTEPH group demonstrated a greater rise in t-PA antigen (CTEPH mean rise, 53.0 ng/ml; control mean rise, 5.6 ng/ml) and PA activity (CTEPH mean rise, 10.5 IU/ml; control mean rise, 1.2 IU/ml) than controls in response to an experimentally induced venous occlusion. Immunoprecipitation and fibrin autography of PPP from two patients with markedly elevated basal t-PA antigen levels demonstrate that the t-PA antigen was present in PPP primarily in complex with PAI-1. CONCLUSIONS Although abnormalities of the fibrinolytic system were detected, neither a high resting plasma PAI-1 activity nor a blunted response of t-PA to venous occlusion can be invoked as an etiology for CTEPH

While bronchoalveolar lavage has been shown to be more sensitive than brush biopsy (BB) for the diagnosis of Pneumocystis carinii pneumonia in AIDS patients, some have reported that BB occasionally is positive in spite of a negative BAL. Many bronchoscopists, therefore, continue to perform routine BB when doing bronchoscopy on AIDS patients. We performed a retrospective study of all fiberoptic bronchoscopies done on human immunodeficiency virus-infected patients over a one-year period at our institution to determine if the use of BB added to the diagnostic yield of bronchoscopy over that of BAL alone. Of 84 bronchoscopies in which BB was performed in addition to BAL, BB yielded no diagnoses that were not obtained by BAL. Brush biopsy added approximately $400 to the cost of bronchoscopy. We conclude that BB should not be routinely done when performing bronchoscopy on HIV-infected patients.

BACKGROUND Many questions remain regarding the pathogenesis, natural history, diagnosis, and treatment of chronic thromboembolic pulmonary hypertension in patients. To answer such questions, we developed an animal model of this disorder. The brisk thrombolytic response of canines to acute embolism has, previously, prevented the establishment of such a model. METHODS AND RESULTS The fibrinolytic inhibitor tranexamic acid was given orally to canines before, and for intervals after, pulmonary emboli were released from venous thrombi formed in vivo in femoral veins or the inferior vena cava. Preliminary studies disclosed that embolic residuals from femoral vein thrombi were not sufficient to cause significant, persistent pulmonary hypertension. With repetitive, larger thrombi embolized from the inferior vena cava, however, persistent pulmonary hypertension was achieved in most animals. CONCLUSIONS Resolution of emboli in the canine can be inhibited by tranexamic acid. As in humans, a spectrum of embolic residuals is encountered, and the perfusion lung scan consistently underestimates the extent of embolic residuals. Studies of this animal model continue.

Pulmonary thromboendarterectomy is now the treatment of choice for pulmonary hypertension due to chronic pulmonary thromboemboli. A precise assessment of location and extension of these thrombi is important because only proximal chronic pulmonary thromboemboli are accessible to surgery. Because intravascular ultrasound imaging can assess not only arterial luminal size, but also wall thickness, its value as a complement to angiography was assessed in 11 patients aged 35 to 64 years with severe pulmonary hypertension (systolic pulmonary artery pressure, mean ± standard deviation 70 ± 19 mm Hg; pulmonary artery resistance, 609 ± 297 dynes·s· cm −5 ). Intravascular ultrasound was obtained in 10 of 11 patients and no complication occurred. Intravascular ultrasound identified 10 segments with suspected chronic pulmonary thromboemboli in 7 patients, all confirmed at operation. Nine segments were considered normal, all of which (except 1) were free of chronic pulmonary thromboemboli at operation. Image quality was highly dependent on pulmonary artery size and position of the catheter. Therefore, intravascular ultrasound of pulmonary arteries is feasible and safe in patients with pulmonary hypertension. It may help to assess the location and extension of the pathologic process involving pulmonary arteries.

To map global epicardial repolarization patterns and test the "SI" model of T wave generation, the patterns of epicardial activation and repolarization in patients with chronic pulmonary thromboembolism and right ventricular hypertrophy were studied by computerized mapping techniques and monophasic action potential (MAP) recording. The ventricular activation patterns were characterized by delayed right ventricular activation and the absence of normal early epicardial ventricular breakthrough in some cases. The repolarization patterns were characterized by nonuniform distribution of T wave morphologies. The T waves were predominantly positive over the left ventricular epicardium and negative or biphasic over the right ventricular epicardium. The activation-recovery (A-R) intervals were measured from the local activation to the maximal dV/dt of the upstroke of the T waves (Wyatt method). The difference between the A-R intervals and the MAP from onset of activation to 90% repolarization (MAP90) varies according to T wave morphology and could be as high as 96 msec with positive T waves, despite significant correlations (r = 0.56-0.90) between MAP90 and A-R intervals for each morphology. Better overall correlations were found if the minimal dV/dt on the downslope of the positive T waves was chosen to estimate the time of local repolarization (alternative method). Using this method, the mean A-R intervals were the same over the right and left ventricles. Cardiopulmonary bypass significantly prolonged the action potential duration equally at all parts of the epicardium. We conclude that in patients with right ventricular hypertrophy, the time of local repolarization can be estimated by our alternative method; the right ventricle completes activation and repolarization later than the left ventricle, and the distribution of T wave morphologies is nonuniform, with predominantly positive T waves observed over the left ventricle and negative or biphasic T waves observed over the right ventricle. These findings are compatible with the SI model of the generation of T waves.

After pulmonary thromboendarterectomy, performed for relief of chronic thromboembolic pulmonary hypertension, perfusion lung scans have frequently disclosed new perfusion defects in segments served by undissected pulmonary arteries. Our hypotheses were that these new postoperative defects occurred with great frequency and did not represent postoperative vessel occlusion. We retrospectively reviewed the preoperative and postoperative perfusion scans of 33 consecutive patients undergoing pulmonary thromboendarterectomy. New postoperative perfusion defects were noted in 23 of 33 patients. The incidence of new defects was increased tenfold in segments that had (1) normal preoperative angiographic findings, (2) normal preoperative radionuclide perfusion, and (3) not been entered at the time of surgery. Postoperative angiograms, available in 15 of 33 patients, documented the nonembolic, nonocclusive nature of the new perfusion scan defects. The most plausible alternate explanation for this previously undescribed finding is a redistribution of pulmonary arterial resistance induced by the thromboendarterectomy, namely, a pulmonary vascular "steal."

Thromboendarterectomy is the treatment of choice for chronic large vessel thromboembolic pulmonary hypertension. To identify the mechanisms responsible for the improvement in gas exchange following thromboendarterectomy, we studied nine patients with chronic thromboembolic pulmonary hypertension before and eight to 18 months after surgery using the multiple inert gas elimination technique. Preoperatively, all subjects had pulmonary hypertension and were hypoxemic or had an elevated P(A-a)O 2 . The V · A / Q · distribution was widened with an elevated V D /V T and a low cardiac index. After thromboendarterectomy, significant improvement had occurred. The V · A / Q · distribution had narrowed to near normal, and the cardiac index increased. It was concluded that thromboendarterectomy improved gas exchange both by improving V · A / Q · relationships and by increasing cardiac output.