Advanced Pulmonary Vascular Disease Research Articles

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.

Pathology of pulmonary hypertension

There are similarities in the pathological features of pulmonary hypertension of varying etiologies in infants and children. Abnormalities in growth and development of the peripheral pulmonary arteries related to abnormal extension of muscle into normally non-muscular peripheral arteries, medial hypertrophy of proximal normally muscular arteries and a reduction in the number of small arteries relative to alveoli occur in infants with congenital heart defects as well as lung parenchymal and hypoxia-induced lung disease. These features are also seen in infants with unexplained pulmonary hypertension. The pathology of thromboembolic pulmonary hypertension is usually distinguished by thrombi, recalanized vessels and lack of uniformity of pathological changes. In most cases of advanced pulmonary vascular disease as in the setting of a congenital heart defect, connective tissue disease, portal hypertension or when the etiology is unexplained, obliterative changes are prevalent and the ‘plexiform lesion’ is a common feature. Venous changes are prevalent with congenital heart defects causing left sided obstruction, and occlusive changes can occur primarily in veins in patients with unexplained pulmonary hypertension. The ability of continuous intravenous prostacyclin to arrest progression, and even induce regression of structurally advanced pulmonary vascular disease in some cases, has led to rethinking how pathological material can be useful in clinical decision making. The presence of occlusive changes and particularly plexiform lesions was thought to represent irreversible disease, but the observation that ongoing cellular proliferation and connective tissue synthesis occurs, even in advanced lesions thought to represent end stage ‘burnt-out’ diseases, led to re-evaluation of the potential of biologically reversing the disease process. Clinical material, cultured cells and studies in experimental animals provide insights into cellular mechanisms which lead to the progression of vascular changes. Our laboratory focused on the increased activity of an endogenous vascular elastase (EVE) and expression of the glycoproteins tenascin and fibronectin in the pathobiology of pulmonary hypertension. These studies suggested ways to prevent progression and induce regression of advanced pulmonary arterial changes.

Hemodynamic unloading leads to regression of pulmonary vascular disease in rats

Objective: Treatment options for patients with advanced pulmonary vascular disease caused by a congenital heart defect are still mainly limited to heart-lung transplantation or lung transplantation with repair of the cardiac lesion. Because we have previously shown that the structural changes associated with pulmonary hypertension can be reversed by stress unloading in an organ culture model, we now investigate whether hemodynamic unloading will lead to regression of pulmonary vascular disease in the intact animal. Methods: Right middle and lower lobectomy and monocrotaline injection were performed in Lewis rats (n = 22) to cause pulmonary vascular disease from a combined hemodynamic and toxic injury. Twenty-eight days later the left lungs were examined (n = 10) or exposed to normal pulmonary artery pressure for an additional 14 (n = 5) or 28 (n = 7) days by transplantation into healthy recipients. Pulmonary artery pressure, ventricular weight, and pulmonary artery morphology were evaluated in each group. Results: Pulmonary hypertension (50 vs 16 mm Hg; P <.001) and right ventricular hypertrophy (right ventricular/left ventricular weight 0.69 vs 0.32; P <.001) associated with pulmonary artery medial hypertrophy (28.2% vs 7.2% wall thickness; P <.001) and muscularization of small pulmonary arteries (92.3% vs 19.4%; P <.001) developed by day 28 (compared with untreated controls). However, transplantation into healthy recipients effectively unloaded the lungs (mean pulmonary artery pressure 17 and 24 mm Hg at 14 and 28 days after transplantation) and resulted in progressive normalization of medial hypertrophy (15.6% and 12.1% at 14 and 28 days) and muscularization (65.1% and 42.2% at 14 and 28 days) relative to nontransplanted controls (P <.005 in each case). Conclusions: Hemodynamic unloading of lungs with pulmonary vascular disease results in progressive normalization of pulmonary artery structure. These results are the first to provide a rationale for attempting to induce regression of pulmonary vascular disease by pressure unloading of the pulmonary circulation. Methods to mechanically unload the pulmonary circulation should be critically evaluated as a strategy for staged surgical repair of congenital heart defects despite presumed irreversible pulmonary hypertension. (J Thorac Cardiovasc Surg 2001;121:279-89)

Complete reversal of fatal pulmonary hypertension in rats by a serine elastase inhibitor.

Progression of pulmonary hypertension is associated with increased serine elastase activity and the proteinase-dependent deposition of the extracellular matrix smooth muscle cell survival factor tenascin-C (refs. 1,2). Tenascin-C amplifies the response of smooth muscle cells to growth factors, which are also liberated through matrix proteolysis. Recent organ culture studies using hypertrophied rat pulmonary arteries have shown that elastase inhibitors suppress tenascin-C and induce smooth muscle cell apoptosis. This initiates complete regression of the hypertrophied vessel wall by a coordinated loss of cellularity and extracellular matrix. We now report that elastase inhibitors can reverse advanced pulmonary vascular disease produced in rats by injecting monocrotaline, an endothelial toxin. We began oral administration of the peptidyl trifluoromethylketone serine elastase inhibitors M249314 or ZD0892 21 days after injection of monocrotaline. A 1-week treatment resulted in 92% survival, compared with 39% survival in untreated or vehicle-treated rats. Pulmonary artery pressure and muscularization were reduced by myocyte apoptosis and loss of extracellular matrix, specifically elastin and tenascin-C. After 2 weeks, pulmonary artery pressure and structure normalized, and survival was 86%, compared with 0% in untreated or vehicle-treated rats. Although concomitant treatment with various agents can reduce pulmonary hypertension, we have documented complete regression after establishment of malignant monocrotaline-induced disease.

Pathobiology of pulmonary hypertension: Impact on clinical management.

Our previous studies showed how analysis of pulmonary vascular changes on lung biopsy tissue and on angiography added to the hemodynamic assessment of pulmonary vascular resistance in predicting the success of a surgical repair. Both the potential for heightened vasoreactivity in the early postoperative period and for reversibility of pulmonary vascular disease at later follow-up were correlated with qualitative and quantitative evaluation of arterial changes. The ability of continuous intravenous prostacylin to arrest progression and even induce regression of structurally advanced pulmonary vascular disease in some cases has led to rethinking how pathological material can be useful in clinical decision making. The presence of occlusive changes and particularly plexiform lesions was thought to represent irreversible disease, but the observation that ongoing cellular proliferation and connective tissue synthesis occurs even in advanced lesions thought to represent end stage 'burnt-out' lesions, led to re-evaluation of the potential of biologically reversing the disease process. Our laboratory has used clinical material, cultured cells, and studies in experimental animals to gain new insights into some of the mechanisms which lead to the progression of vascular changes, and has used this information in strategies aimed at arresting progression and, more recently, inducing regression of pulmonary hypertension and associated vascular lesions. Specifically, we have focused on the increased activity of an endogenous vascular elastase (EVE) and expression of the glycoproteins tenascin and fibronectin in the pathobiology of pulmonary hypertension. This report will first review our studies in children with congenital heart defects, assessment of reversibility of pulmonary hypertension, and then discuss more recent work addressing cellular and molecular mechanisms aimed at developing newer therapeutic strategies. Copyright 2000 by W.B. Saunders Company

Morphology of the elastic pulmonary arteries in pulmonary hypertension: a quantitative study.

Recent studies of intravascular ultrasound of the pulmonary arteries suggest that the technique can detect intimal and medial thickening in patients with pulmonary hypertension, potentially providing a method of assessing severity of pulmonary vascular disease in life. A major drawback of the technique is that only the elastic pulmonary arteries are accessible to current ultrasound catheters. The aim of this study was to determine whether morphological changes in vessels accessible to intravascular imaging reflect severity of pulmonary vascular disease and are of a sufficient degree to be detectable by current ultrasound catheters. Morphometric studies of the elastic pulmonary arteries were performed in specimens of lungs from 24 patients who had died with pulmonary hypertension (aged 3 weeks-9 years) and compared with measurements from infants who had died from sudden infant death syndrome. Morphological changes evident in the elastic pulmonary arteries in pulmonary hypertension included luminal dilation and medial thickening but these changes were too variable to be predictive of the severity of peripheral pulmonary vascular disease. Intimal thickening and atherosclerosis were present only in those with advanced pulmonary hypertensive disease. The changes of medial thickening and luminal dilation, nonetheless, are too variable to be predictive of the severity of peripheral pulmonary vascular disease. Thus, imaging by intravascular ultrasound may help confirm advanced pulmonary vascular disease, but is unlikely to differentiate less severe pulmonary vascular disease when the patient may still potentially be operable.

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.

Profile of paediatric patients with pulmonary hypertension judged by responsiveness to vasodilators.

To describe the demographic and haemodynamic variables of children presenting with primary pulmonary hypertension or pulmonary hypertension appearing or persisting after surgical correction of congenital heart defects and to assess the acute effect of vasodilator drugs on their pulmonary vascular bed. Retrospective review. Paediatric cardiology department and intensive care unit of a large tertiary centre. Fourteen consecutive patients presenting with primary pulmonary hypertension (group 1) or pulmonary hypertension persisting or appearing late after complete surgical repair (group 2). Baseline haemodynamic measurements were taken in room air at rest and repeated in 100% oxygen. With constant monitoring of heart rate and pulmonary and systemic arterial pressures, patients were given serial intravenous, sublingual, or oral incremental doses of vasodilators (mean 4.1 trials per patient). The maximum effect of the drug was charted. A positive response to acute vasodilator tests was defined as a decrease in mean pulmonary or mean systemic arterial pressure > 15% with the mean pulmonary artery pressure not reaching the systemic level and either no change or an increase in mean systemic arterial pressure. Haemodynamic variables between groups (1 v 2, responders v non-responders, patients experiencing or not experiencing adverse effects to vasodilators) were compared by a two tailed unpaired Student's t test, and their survival curves were compared by the log rank statistic. Groups are small and definitive conclusions are difficult to draw, but the baseline haemodynamic assessments were not significantly different between group 1 and 2 or between responders and non-responders to vasodilators. Patients experiencing adverse effects had a higher pulmonary vascular resistance (p = 0.04) and wedge pressure (p = 0.02) than those without adverse effects. Of the vasodilators used, tolazoline, hydralazine, salbutamol, phentolamine, and phenoxybenzamine were ineffective. A positive response was seen in five of 13 patients given oxygen, in one of eight given prostacyclin, four of 12 given nifedipine, four of eight given diltiazem, one of six given captopril, and two of seven given glyceryl trinitrate. Estimates of survival of the population with primary pulmonary hypertension were 37% at one year and 12% at 2.5 years. Survival was significantly shorter in the non-responders than in the responders (p = 0.005). Children with primary pulmonary hypertension present to the cardiologist at a young age (five of eight were younger than 7 years) but with advanced pulmonary vascular disease and have a poor prognosis. 64% of group 1 and group 2 patients had a positive response to acute treatment with at least one vasodilator. Calcium channel blockers were the most effective agents. There was a positive response to drugs despite a negative response to acute treatment with oxygen. The survival of non-responders was shorter than that of the responders.

Thromboxane A2 and prostacyclin biosynthesis in children and adolescents with pulmonary vascular disease.

The pathogenesis of pulmonary vascular disease in children with congenital heart disease is incompletely understood. Thromboxane (TX) A2 and prostacyclin (PGI2) have opposing effects on platelet aggregation and pulmonary vascular smooth muscle. An imbalance in their biosynthesis could contribute to the progressive increase in pulmonary vascular resistance seen in older untreated patients with pulmonary hypertensive congenital heart disease and the thrombotic complications they may develop. We investigated TXA2 and PGI2 biosynthesis in 15 young children (0.2 to 2.25 years old) with congenital heart disease with increased pulmonary blood flow and potentially reversible pulmonary vascular disease by measuring urinary excretion of 2,3-dinor-TXB2 and 2,3-dinor-6-oxoprostaglandin (PG) F1 alpha and compared the findings with those in 16 healthy children (0.5 to 2.8 years old). 2,3-Dinor-TXB2 excretion was greater in the patients than in control subjects (1253 +/- 161 versus 592 +/- 122 ng/g creatinine; P < .001). Excretion of 2,3-dinor-6-oxo-PGF1 alpha was 452 +/- 54 compared with 589 +/- 95 ng/g creatinine in control subjects. In 5 patients who underwent successful cardiac surgery > or = 1 year later excretion of 2,3-dinor-TXB2 decreased from 1100 +/- 298 to 609 +/- 131 ng/g creatinine (P < .05), a value comparable to those in 5 healthy children of similar age (749 +/- 226 ng/g creatinine). We also compared 15 patients (11 to 23 years old) with advanced irreversible pulmonary vascular disease with 19 healthy control subjects (10 to 23 years old). The ratio of TX to PGI2 metabolite excretion was greater in the patients than in control subjects (3.5 +/- 0.6 versus 2.0 +/- 0.3; P < .05). There is increased 2,3-dinor-TXB2 excretion in children with congenital heart disease and a high pulmonary blood flow that may reflect an imbalance in biosynthesis of TXA2 and PGI2 in the pulmonary vascular bed. The imbalance may contribute to the progressive development of increased pulmonary vascular resistance and persists in older patients whose heart defects are uncorrected.

Lung and Heart-Lung Transplantation

Heart-lung transplantation (HLT) and lung transplantation (LT) are effective treatment modalities for patients with advanced pulmonary parenchymal or vascular disease. Lung transplantation offers potential advantages over HLT, including reduced pretransplant waiting time and improved efficiency of organ utilization, and is currently being offered to patients formerly treated by HLT. To explore the relative merits of these procedures, the authors examined the results in 44 procedures (23 HLT and 21 LT) in 42 patients transplanted at their institution. Heart-lung transplant recipients included 20 adults and three children (ages 5,5 and 3). Most HLT patients had primary pulmonary hypertension (PPH) (n = 9) or Eisenmenger's syndrome (ES) (n = 8). Twenty-two of twenty-three patients have been long-term survivors (mean follow-up = 17.8 months, Kapaln-Meier survival at 12 months = 85%). Obliterative bronchiolitis (OB) has occurred in five patients (22%), and all have died. Of 21 LTs in 19 patients, nine had obstructive and eight had restrictive lung diseases. Three single-LT (SLT) patients had PPH, and one had ES secondary to a ventricular septal defect. Mean pulmonary artery pressures fell from 55 +/- 6 mm Hg before SLT to 21 +/- 3 mm Hg after SLT; p less than 0.001. Three pediatric patients (ages 4, 10, 17, and 17[re-transplant]) have undergone four SLTs. With mean follow-up of 6.4 months, LT patients have survival at 12 months of 80% (Kaplan-Meier). Lung transplant patients wait a far shorter time for their transplant than do HLT patients (166 vs. 384 days, p less than 0.03). Three patients (19%) have evidence of OB after SLT, with one death. By virtue of equal intermediate-term outcomes, shorter waiting times, and better use of donor organs in comparison with HLT, LT should be offered whenever possible to patients with end-stage pulmonary parenchymal or vascular disease. The authors' pediatric LT and HLT experience (7 treatments in 6 patients) is the largest reported to date and demonstrates the utility of these procedures in this group. Chronic rejection (OB) remains the greatest impediment to long-term survival in both LT and HLT pts.

Pulmonary vascular damage and the development of cor pulmonale following hyaline membrane disease

Light microscopic morphometric techniques have been used to study the lungs in 17 infants and young children aged 2 weeks to 3.5 years who were born prematurely, developed hyaline membrane disease (HMD), and died with chronic lung disease. They were divided into three groups. In group 1 the babies died without recovering from their initial illness at age 2-13 weeks. In group 2 they died, aged 4-15 months, having recovered from the neonatal illness. Neither group showed clinical or pathological evidence of cor pulmonale (CP). In group 3 children died aged 6 months to 3.5 years with CP. None of the 17 patients had classical fibrotic bronchopulmonary dysplasia (BPD) but all had a reduced alveolar number and an increase in bronchial smooth muscle in small airways. All three groups showed an increase in pulmonary arterial medial thickness (P less than 0.001). In group 1 the appearance of the arteries suggested persistance of the fetal state. In group 2 and 3 the vessels had a more mature structure; in group 3 a marked secondary increase in muscularity was found, approaching the thickness seen in fetal life. In groups 2 and 3 muscle extended into smaller arteries than normal. Vein wall thickness was increased. The alveolar to arterial ratio was normal, the alveolar number was reduced, therefore the total number of arteries was reduced in all three groups. Thus, babies who recover from HMD may have significant vascular abnormalities in the absence of CP; conversely, CP if present, does not mean advanced obliterative pulmonary vascular disease. Thus, pulmonary vascular morphology does not correlate with the presence or absence of CP.

Assessment and follow-up of patients with ventricular septal defect and elevated pulmonary vascular resistance

Cardiac catheterization was undertaken in 87 patients (for a total of 89 studies) with ventricular septal defects, including 58 patients with moderate or severe elevation of pulmonary arteriolar resistance. When resting resistance was ≤7.9 U · m 2, it always decreased with isoproterenol and no postoperative problems were experienced with pulmonary vascular obstructive disease. In 36 patients resting resistance measured ≥8 U · m 2. In 17 of these patients it decreased to <7 U · m 2 with isoproterenol. Fifteen patients were operated on and postoperative problems with pulmonary vascular disease were experienced only in the single patient whose repair broke down. Surgery was undertaken in 4 of 19 patients in whom resistance did not decrease to <7 U · m 2 with isoproterenol and advanced pulmonary vascular disease was evident in the 3 patients with follow-up observation. Correlation between measured resistance and other hemodynamic parameters was only fair. A pulmonary to systemic resistance ratio ≥0.75 always indicated high absolute resistance but resistance ratios <0.75 were found quite frequently in the group with limited response to isoproterenol. These data argue that a reliable estimate of resistance, <7 U · m 2, with a vasodilator predicts a good postoperative response regardless of measurements at rest or other hemodynamic parameters. Although observations on postoperative progress of patients with resistance >7 U · m 2 with a vasodilator are limited, a good postoperative course is unlikely unless resistance can Le lowered to a level close to 7 U · m 2.

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.

Postoperative changes of pulmonary vascular resistance in patients with complete atrioventricular canal defect. Relation to the age at primary repair.

The postoperative changes of pulmonary vascular resistance (PVR) of two age groups of children with complete atrioventricular canal (CAVC) were compared. Patients were divided by age at the time of primary repair; Group-1 (G-1, n = 4) with age below 2 years (average 13.8 mo.) and Group-2 (G-2, n = 5) with age over 2 years (average 44.0 mo.). All except one were Down's syndrome. Preoperatively, pulmonary to systemic resistance ratio (Rp/Rs) were 0.87 +/- 0.50 in G-1 and 0.41 +/- 0.13 in G-2 (n.s.), and postoperative study (average 6.5 mo.) showed no significant falls in Rp/Rs in both groups. However, G-2 showed significantly lower Rp/Rs postoperatively (0.79 +/- 0.19 in G-1 vs 0.27 +/- 0.12 in G-2, p less than 0.05). Mean pulmonary artery pressure (mPA) showed significant fall after surgery in only G-2 (66.8 +/- 6.6 to 31.8 +/- 11.6 mmHg, p less than 0.005). Anatomically, type-A showed better postoperative change in mPA compared to type-C. This study summarized the early progression of pulmonary vascular obstructive disease with poor postoperative improvement even the primary repair was done before 2 years of age. The less advanced pulmonary vascular disease in G-2 might have some relations to the natural selection of the disease.

Isolated Partial Anomalous Venous Connection: A Congenital Defect with Late and Serious Complications

The cases of 3 patients with partial anomalous pulmonary venous return with intact atrial septum are reported. The 2 adult patients had evidence of severe pulmonary artery hypertension with markedly increased pulmonary vascular resistance indicating advanced pulmonary vascular obstructive disease. This confirms earlier limited observations and emphasizes the potential for this congenital lesion to develop late, serious complications. In view of this potential, surgical repair of the anomaly should be considered whenever it is found. Descriptions of a successful operative approach are included.

Pulmonary vascular disease in transposition of the great vessels and intact ventricular septum.

Eight of 135 (6%) children with d-transposition of the great vessels and with intact ventricular septum and no patent ductus arteriosus had evidence of progressive pulmonary vascular disease. Seven of 101 (7%) patients for whom histologic data was available, had Heath-Edwards grades IV or V pulmonary vascular disease, six had grade II, and 88 had either normal or grade I findings. One of 34 patients for whom histologic data was not available had hemodynamic evidence of pulmonary vascular disease at cardiac catheterization after the Mustard operation. When infants younger than 3 months old were excluded, eight of 85 (9%) had advanced pulmonary vascular disease. Twenty-three patients had microthrombi in their pulmonary arteries and arterioles, and in one patient thrombi were observed before the development of pulmonary vascular disease. Clinically unrecognized pulmonary microthrombi are suggested as a possible etiologic agent in the development of pulmonary vascular disease in patients with transposition of the great vessels. Progressive pulmonary vascular disease can first be discovered after the Mustard operation, even in patients without preoperative evidence of pulmonary hypertension or elevated pulmonary vascular resistance.

Acute respiratory failure

Acute cardiorespiratory failure occurred in a patient with advanced bullous emphysema following perfusion photoscintigraphy with radiolabeled macroaggregated albumin. Complications of perfusion photoscintography are rare. However, in patients with advanced pulmonary vascular disease, special precautions may decrease the minimal hazard associated with perfusion photoscintigraphy.

Pulmonary vascular disease in complete atrioventricular canal defect

The incidence and time of occurrence of pulmonary vascular disease were studied in 67 children with the complete form of atrioventricular (A-V) canal defect. Advanced pulmonary vascular disease begins to develop during the first year of life, with intimal fibrosis (grade 3 cahnges) noted between age 6 months to 1 year. Vascular dilatation with plexiform lesions (grade 4 changes) can be found by age 1 year. These changes can be found in some patients in spite of hemodynamic findings usually considered to indicate lesser degrees of vascular disease. After age 2 years advanced pulmonary vascular disease is commonly found and may persist after surgical correction of the defects. A similar rapid progression of pulmonary vascular disease was noted in 40 children who had a large ventricular septal defect without A-V canal in whom systemic pressure was transmitted directly to the pulmonary vascular bed. Thirty-six of the 67 children had trisomy-21. No difference was noted in the speed of progression of pulmonary vascular disease between these children and those without trisomy 21. Palliative or corrective surgery should be performed in these patients by age 1 year to prevent development of advanced pulmonary vascular disease.

Pulmonary vascular disease after systemic-pulmonary arterial shunt operations

More than 1,100 patients underwent a systemic-pulmonary arterial shunt operation at the Children's Memorial Hospital, Chicago, from 1946 to 1974. Of these patients, 294 were studied to assess the presence of pulmonary vascular disease and the time of its occurrence after surgery. They were selected either because lung tissue was available for histologic grading of pulmonary vascular disease (114 patients) or because hemodynamic studies were performed after the shunt operation (180 patients). The shunts, all patent at the time of the study, ranged in duration from 1 month to 23 years. After a subclavan-pulmonary arterial shunt (75 patients) there was little evidence of advatients) pulmonary vascular disease in either histologic C2 of 25 patients) or hemodynamic (1 of 50 patients) studies. After an aortic-pulmonary arterial shunt (44 Waterston, 175 Potts) there was small likelikhood of advanced pulmonary vascular disease with a shunt duration of less than 5 years (1 of 35 histologic, 0 of 27 hemodynamic studies). With a shunt duration of more than 5 years the incidence of advanced pulmonary vascular disease increased significantly (15 of 54 histologic, 17 of 103 hemodynamic studies). A mean pulmonary arterial pressure of 50 mm Hg or greater strongly suggests the presence of advanced pulmonary vascular disease. When a systemic-pulmonary arterial shunt has provided effective palliation with decreased pulmonary pressure there is small likelihood that advanced pulmonary vascular disease will develop, even with a long shunt duration of 20 to 25 years.