Patent ductus arteriosus

Pathologic obstruction of the proximal lumen and secondary atrophy of the media of the peripheral small pulmonary arteries were absolute operative contraindications in cases of VSD and/or PDA with severe pulmonary hypertension. Such patients who were operated on died with no decrease in pulmonary arterial pressure. The index of pulmonary vascular disease (IPVD), a composite and quantitative evaluation of the severity of pulmonary vascular disease, was introduced to determine the operability of other patients. An IPVD rating of 2.2 in Down's syndrome and 2.1 without the syndrome were regarded as the upper permissible limits for surgical intervention based on results of 23 autopsies and 26 lung biopsies of patients operated on before 1981. Open lung biopsy was performed in 51 patients to determine applicability of our operative indications. Twenty-nine cases were considered operable by our criteria, and 28 underwent surgical correction without operative or late death. Twenty-two cases thought inoperable remain under observation. Comparative analysis of the pathology and preoperative hemodynamic data suggested that lung biopsy should be carried out to determine operability in cases with pulmonary vascular resistance greater than 8 units*[m.sup.2].

(Chest 1989; 96:31-39)

Even today there are problems involved in the hemodynamic determination of operability in cases of congenital heart disease with severe pulmonary hypertension. The Heath-Edwards (HE) classification,[1] histopathologic criteria in widespread clinical use, can provide only qualitative information about plexogenic pulmonary arteriopathy and consequently has limitations for use in determining operability.

We previously developed our own histopathologic criteria for determining operability in cases of transposition of the great arteries (TGA) and secundum atrial septal defect (ASD), based on open lung biopsy findings.[2,3] The present study was undertaken to establish similar criteria for ventricular septal defect (VSD) and patent ductus arteriosus (PDA), using the same lung biopsy technique. We also focus on operative and late postoperative results of cases in whom diagnosis was based on open lung biopsy and on the relationship between pathologic findings and conventional hemodynamic measures.

Patients and Methods

Patients

Clinical subjects included 100 cases of PDA and/or VSD with severe pulmonary hypertension, 49 of whom underwent surgery before 1981, and 51 of whom experienced lung biopsy or lung biopsy and surgery between 1981 and 1988. Of the total 100 cases, 31 also exhibited Down's syndrome. There were 63 cases of VSD, 16 cases of PDA, and 21 cases of VSD in conjunction with PDA. Ages ranged from 2 months to 61 years, with a mean age of 8.2 years.

Among the 49 pre-1981 cases, in 26 lung biopsy was performed during corrective surgery, which the patients survived (Table 1). There were 19 operative deaths and four late deaths due to plexogenic pulmonary arteriopathy; autopsies were performed in all cases (Table 2). The criteria for operative indications were determined on the basis of the results of these 49 cases.

In the 51 cases between 1981 and 1988, operability was determined based on open lung biopsy findings using the previously determined criteria (Table 3).

Histopathologic Sections

As a rule, a 2 x 1 x 1.5-cm specimen of lung tissue was obtained from the right median lobe in both cases of biopsy and autopsy and fixed in 10 percent formalin. The tissue was then divided into three parts and embedded in paraffin. Step sections of each block were made at 50-[mu] intervals, yielding a total of about 60 histologic sections per case. Staining was done using the Elastica-Goldner method.

Determination of the Severity of Plexogenic Pulmonary Arteriopathy

Determination of the severity of plexogenic pulmonary arteriopathy was made using the index of pulmonary vascular disease (IPVD).[4,5] That is, pulmonary vascular disease in the small pulmonary arteries was measured for each histologic section and classified into one of four grades. A rating of 1 to 4 was assigned to each small pulmonary artery and a mean rating obtained for each case. These ratings corresponded to the following pathologic findings: (1) no [TABULAR DATA OMITTED] hypertrophy of the intima of small pulmonary arteries; (2) cellular proliferation of the intima of small pulmonary arteries; (3) fibrous thickening of the intima of small pulmonary arteries; and (4) destruction of the media of small pulmonary arteries. Evaluation of the lesions was also made using the HE classification, and this was compared with the IPVD results. [TABULAR DATA OMITTED]

Results

Establishing Criteria for Lung Biopsy Diagnosis

Criteria for lung biopsy diagnosis were established on the basis of the 49 cases experienced prior to 1981. Of the 19 cases of operative death, nine showed no significant decreases in postoperative pulmonary arterial pressure. In these cases, there was nearly total obstruction of the vascular lumen of pulmonary arteries with diameters of 100-200 [mu] due to intimal proliferation, and more peripherally located small pulmonary arteries showed thinner media, ie, secondary atrophy of the peripheral media (Fig 1). These findings strongly suggested that pulmonary arterial pressure was high at locations proximal to the region of obstruction, but that more peripherally there was a decrease in pulmonary blood flow and pressure.

Even when surgery is performed in such cases, a decrease in pulmonary arterial pressure cannot be anticipated if the obstructed portion is left untouched. Moreover, if a decrease somehow occurs, there is a danger that peripheral pulmonary circulation cannot be maintained. Consequently, we consider that corrective surgery is absolutely contraindicated in cases with such histopathology. The IPVD ratings of these nine cases were high, ranging between 2.2 and 4.0 (with a mean of 3.0).

Quantitative analysis of pulmonary vascular disease was possible using the IPVD ratings obtained from the 26 survivors of corrective surgery and the ten operative deaths, excluding the cases of absolute contraindication.

No distinct differences in diagnostic criteria between the cases of VSD and cases of PDA were found, but a difference was seen between Down's syndrome and the non-Down cases (Fig 2). Among the non-Down cases, the IPVD ratings of the six cases in whom the cause of death was thought to have been pulmonary vascular disease ranged from 2.2 to 2.7, whereas those of the 18 operative survivors ranged from 1.0 to 2.1. In contrast, among the Down cases, in the four cases in whom the cause of death was pulmonary vascular disease, the IPVD ratings were concentrated around 2.3 to 2.6, while the ratings of the eight surviving Down cases ranged from 1.0 to 2.3. There were two Down cases with IPVD scores of 2.3; one died and one survived. On the basis of these results, it was decided that an IPVD rating of 2.1 or lower in the non-Down cases and of 2.2 or lower in the Down cases is an indication for surgical correction.

There were four late deaths among the cases of PDA despite IPVD ratings between 1.3 and 1.9, well within the limits for surgical indication. In a seven-month-old patient (case 46), there was severe septitis and pulmonary emphysema, as well as hypoplasia of small pulmonary arteries and abnormal branching of the pulmonary lobes. Preoperative pulmonary arterial oxygen saturation was 52 percent, indicating severe hypoxia. One 16-month-old Down patient (case 47) showed grade 4 septitis,[6] interstitial emphysema, and dilatation of the peripheral respiratory tract, all of which are characteristic of the Down syndrome.[7] Moreover, grade 3 alveolar hypoplasia[7] was also found. Preoperatively, these two cases of late death had suffered pneumonia and severe hypoplasia of the alveolar and pulmonary arterial systems, which causes hypoxia. In autopsy studies, it was found that pulmonary vascular disease, especially medial hypertrophy, had progressed postoperatively,[8] strongly suggesting that the late deaths were due to further progression of pulmonary vascular disease attributable to postoperative hypoxia. Therefore, although the IPVD ratings fell within the limits of surgical correction, surgery was considered to be contraindicated in these cases. In addition, there were two cases (cases 48 and 49, 19- and 24-month-old infants) in whom plexogenic pulmonary arteriopathy due to fibrous thickening of the vascular lumen was already present. There was also thinning of the peripheral pulmonary arterial walls in these cases. Despite the fact that they did not have high IPVD ratings, they were classified as being absolutely inoperable.

Open Lung Biopsy and Operative Results

Between 1981 and 1988, open lung biopsy was performed in a total of 51 cases in whom it was difficult to determine operative indications from hemodynamic measurements alone. Based on the above criteria, 29 cases were diagnosed as suitable for corrective surgery. Twenty-eight of these cases underwent total correction, and one is currently awaiting surgery. The operative results have been favorable, with no operative deaths and no late deaths. Including those for whom surgery was absolutely contraindicated, a total of 22 cases were diagnosed as inappropriate for surgical correction. Surgical intervention has not been employed and these patients have been treated medically. Thus far, there has been only one late death following lung biopsy among patients in this group not surgically treated (case 91).

Figure 3 illustrates the IPVD ratings and status of the cases operated on and those not operated on based on lung biopsy diagnosis, with distinctions also being made between the cases with and without the Down syndrome. Correlation Between IPVD Scores and HE Classification

Figure 4 shows the correlation between the IPVD ratings and gradings obtained by HE classification for the entire group of 100 cases. Operative criteria based on the HE classification were not less reliable: most of the cases with an HE classification of 4 or higher, generally considered to be unsuitable for surgical intervention, had an IPVD rating of more than 2.2. However, even among those with HE classifications of 4 or higher, there were cases where surgery was indicated based on the IPVD ratings. Specifically, four cases had HE classifications of 4 and IPVD ratings of 1.6 (case 13), 2.1 (case 10), 2.1 (case 54), and 2.2 (case 24, Down). There were also two cases with HE classification of 6 whose IPVD ratings were 1.8 (case 58) and 1.9 (case 55). All six of these cases were judged suitable for surgical intervention based on the IPVD ratings and underwent total correction. The postoperative courses in all six cases have been uneventful thus far. Figure 5 shows the pulmonary vascular disease of case 55, in which the HE classification was 6 and the IPVD rating was 1.9.

Correlation Between IPVD Ratings and Age

In Figure 6, the correlation between age and IPVD ratings is shown for the 100 cases. The 55 cases in whom corrective surgery was indicated include 54 who survived the operation and one who is awaiting surgery. The 45 cases in whom surgery was contraindicated included 23 cases of absolute contraindication, 20 cases with IPVD ratings beyond the operative criteria, and two cases of late postoperative death.

Among the patients younger than two years, 31 cases had operative indications but only six contraindications. Among the patients between two and ten years of age, there were equal numbers of cases with and without surgical indications (18 each). Finally, five of 27 patients over the age of ten were diagnosed as being operable.

Hermodynamics in Cases with Surgical Indications and Those with Contraindications

Hemodynamics of the cases with surgical indications or contraindications based on histopathologic study are summarized in Figure 7. Significant differences were seen between the two groups with regard to pulmonary arterial systolic pressure (p<0.001) and pulmonary vascular resistance (PVR)(p<0.001). However, no significant differences between the groups were found in pulmonary to systemic pressure ratio (Pp/Ps), pulmonary to systemic flow ratio (Qp/Qs), or pulmonary to systemic resistance ratio (Rp/Rs). The most reliable hemodynamic value was PVR. Of the 25 cases with PVR of less than 8 unit*[m.sup.2], 23 cases have survived surgery. On the other hand, 17 of the 39 cases with PVR greater than 8 unit*[m.sup.2] have survived the operation. These results suggest that when a PVR greater than 8 unit*[m.sup.2] is obtained, operative indication should be determined on the basis of pathologic findings obtained at lung biopsy.

Discussion

Several researchers have reported methods for determining operative indications by means of lung biopsy in cases of congenital heart disease with severe pulmonary hypertension,[9,10] but there have been few detailed studies concerning VSD or PDA. We have previously reported that among the pulmonary vascular lesions in ASD, in addition to plexogenic pulmonary arteriopathy, thromboembolism and musculoelastosis also occur.[3] Wagenvoort et al[9,11] reported similar findings in cases of VSD. All of the lesions observed in the present study were of plexogenic pulmonary arteriopathy. It is generally held that surgical correction is not indicated in such cases, when irreversible lesions such as severe concentric laminar intimal fibrosis, fibrinoid necrosis of the media, and plexiform lesions are present. We have experienced several cases in which death immediately followed surgery without a fall in pulmonary arterial pressure and in which, at autopsy, occlusion of the vascular lumen of small pulmonary arteries was found together with thin media of peripheral small pulmonary arteries. We have therefore concluded that in cases exhibiting these two pathologies, surgical correction is absolutely contraindicated. Findings of medial thinning accompanying plexogenic lesions have been reported by Health and Edwards to be dilatation lesions.[1] Particularly among the youngest patients, however, we found that medial thinning of distal small pulmonary arteries can occur even when the proximal region does not include severe intimal lesions such as plexiform lesions or fibrinoid necrosis of the media. That is, when there is fibrous thickening in the region of the obstruction, there are few dilatation lesions such as granulomatous lesions and vein-like lesions of the peripheral wall, but rather only medial thinning without intimal lesions. Dilatation and elongation of the lamina elastica interna and externa, which are characteristic of dilatation lesions, were also absent. We believe that since there is a decrease in intra-arterial pressure and blood flow peripheral to the site of obstruction, secondary atrophy of the hypertrophied peripheral media occurs. Based on a bitter experience in which we noticed only this secondary atrophy and overlooked the more proximally located pulmonary vascular lesions, we have devised a procedure for obtaining more definitive diagnoses on the basis of serial histologic sectioning.

Because some cases with grade 4 HE classification survive surgery,[12,13] it has recently been realized that quantitative assessment of the frequency and severity of lesions, determined by lung biopsy, is more important than qualitative indications.[14,15] Our IPVD method is designed to allow for an overall evaluation of the plexogenic vascular lesions of all small pulmonary arteries observed in histologic sections. Use of this method allows a quantitative measurement of the severity of the vascular lesions.[4,5] We have found six cases in which, although the HE classifications were 4 or greater, surgical correction was performed and the postoperative courses were uneventful. In other words, this diagnostic technique is thought to expand the dimensions of surgical indications to include such cases.

Operative indications as per the IPVD rating in cases of VSD and/or PDA with Down syndrome were found to be similar to that previously reported for TGA, but for cases without Down syndrome the IPVD rating indicating surgery was lower. This difference is thought to be due to the fact that, in comparison with cases without Down syndrome, in cases of TGA or Down syndrome the media is thinner,[4,14] suggesting that even if slightly more advanced intimal lesions exist, such patients can more easily withstand the surgical procedure.

There have been reports of late death due to postoperative progression of pulmonary vascular disease caused by hypoxia,[16,17] and we have also experienced two cases of this kind. We believe, however, that such progressive pulmonary vascular disease can be predicted preoperatively by evaluating the vascular disease and hypoplasia of small pulmonary arteries and the respiratory tract using lung biopsy sections.[18]

Various criteria for determining operative indication based on hemodynamics in cases of VSD and PDA with severe pulmonary hypertension have been reported previously, and Qp/Qs, Rp/Rs, and PVR have been used as indices.[19-21] In studying the hemodynamics in our cases in which surgery was histologically indicated or contraindicated, we found that the Qp/Qs and Rp/Rs ratios were not useful in determining operative indications, whereas PVR proved to be the most reliable index of hemodynamics.

In 1973, DuShane and Kirklin[19] reported that a PVR of 14 unit*[m.sup.2] or less was an indication for surgery, and in 1976 Kirklin et al[20] reported that a value of 10 or less was an indication among older children. More recently, Momma et al[21] have reported a PVR of 8 unit*[m.sup.2] or less to be an operative indication. In light of the fact that we had both an operative death and an operative survivor with PVRs of more than 8 unit*[m.sup.2], we believe that lung biopsy is an appropriate tool for diagnosis in cases with such PVR values. Since there were patients younger than two years of age for whom surgical correction was contraindicated, we conclude that, regardless of the patient's age, when pulmonary vascular resistance of 8 unit*[m.sup.2] or more is obtained, operative indications should be determined on the basis of lung biopsy. However, based on study regarding pulmonary vascular reactivity, some such patients might be excluded from lung biopsy diagnosis.

ACKNOWLEDGMENTS: We thank the following institutions for supplying us with materials: Sapporo Medical College, Hirosaki University School of Medicine, Aomori Prefectural Central Hospital, Hachinohe City Hospital, Iwate Prefectural Central Hospital, Akita University School of Medicine, Yuri Hospital, Yamagata University School of Medicine, Yamagata Prefectural Central Hospital, Sendai National Hospital, Fukushima Medical College, Iwaki City Hospital, Mito National Hospital, Niigata University School of Medicine, The Heart Institute of Japan, Sakakibara Heart Institute, National Children's Hospital, Mitsui Memorial Hospital, Sizuoka Children's Hospital, Nagoya Eisei University, Nara Medical College, Yamaguchi University School of Medicine, Ehime University School of Medicine and Fukuoka Children's Hospital. We also thank Mr. Thomas Mandeville for his help in preparing the manuscript.

References

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