Rapidly progressing pulmonary vascular obstructive disease: Association with ventricular septal defects during early childhood∗

Case Reports

Rapidly Progressing Pulmonary Vascular

Obstructive Disease

Association with Ventricular Septal Defects During

Early Childhood*

RICHARD A. ANDERSON, M.D.,? ARTHUR M. LEW, M.D.,$ RICHARD L. NAEYE, M.D. and BURTON S. TABAKIN, M.D.

Burlington, Vermont

T HE natural history of isolated ventricular septal defect has been the subject of many

reports. l -lr The occurrence of associated pulmonary artery hypertension with pulmonary vascular obstructive disease has been well established, especially in older children and adults, and termed “Eisenmenger’s syndrome.“‘-t’s18 How- ever, the development of progressive pulmonary vascular obstruction in early childhood has only recently been documented by serial cardiac catheterizations.rO-17 Despite this evidence, many authors in the recent past have minimized the significance of this entity3-9sls or questioned its existence altogether, leaving a general impression that until adolescence there need be no concern about the development of pulmonary vascular obstruction in patients with ventricular septal defect. Because of the ominous clinical implications of advancing pulmonary vascular lesions, 19--21 an understanding of this type of course, including the rapidity with which this complication can appear, is necessary to develop a rational schedule of observation in children with ventricular septal defect.

The following case documents the abrupt and dramatic development of severe obstructive pulmonary vascular disease during the second year of life in a child with a high flow ventricular septal defect and pulmonary vascular resistance at

the upper limits of normal when first studied. This course, observed clinically and proved by serial cardiac catheterization and lung biopsy, represents one of the most fulminating cases of rapidly progressive pulmonary hypertension yet reported in patients with ventricular septal defect when the rapidity and degree of change as well as the age of onset are considered. This case underlines the importance of close follow-up and continual awareness of this perhaps uncommon but malignant course in the natural history of ventricular septal defect in childhood.

CASE REPORT

The patient, who is now 4 years of age, was referred to us at age 8 months for evaluation of a heart murmur noted at age 1 month. Her foster mother related a history of tachypnea, increased sweating, pallor and poor gain in weight. No cyanosis had been noted. Physical examination revealed a small but well de- veloped white female infant in no distress. There was an active apical cardiac impulse. A grade 4/6 pansystolic murmur was heard at the lower left sternal border. The electrocardiogram was interpreted as showing combined ventricular hypertrophy. Chest roentgenograms showed cardiac enlargement with increased pulmonary vascular markings. Because of a respiratory tract infection, cardiac catheterization was postponed.

At q”ge 75 months, the child was readmitted. She had

* From the Departments of Medicine and Pathology, University of Vermont College of Medicine, Burlington, Vt. t Trainee in Cardiology (U. S. Public Health Service Postgraduate Training Grant, 5-TI-HE-5286-07). $ Teaching Scholar of the American Heart Association and The Vermont Heart Association.

854 THE AMERICAN JOURNAL OF CARDIOLOGY

Pulmonary Vascular Disease in childhood

Fro. 1. Serial e~~c~~~ayd~og~a~s taken at an intervaiof 10 months. A, Aug. f&1963, age 15 months. B, June 25, 1964, age 25 months.

855

gained three pounds in the past six months. There was no change in history except that she was now walking. Active right and left ventricular impulses were felt. The grade 4/6 pansystolic murmur was still present at the lower left sternal border, with an associated thrill. The first heart sound was normal. The second heart sound split normally and moved with respiration, but the pulmonic component was accentuated. A short diastolic rumble was heard at the apex. The electrocardiogram continued to show bi- ventricular hypertrophy (Fig. IA), and the chest ro-

VOLUME 19, JUNE 1967

entgenograms showed significant cardiac emargement and increased pulmonary vascular markings (Fig. ZA).

Card& ca~~~~izu~ju~ demonstrated a ventricular septal defect. The pulmonary blood flow was 7.8 L./ min./M.2, while systemic flow was 2.8 (Qp/Qs = 2.8/l). Pulmonary artery pressure was 45/11 mm. Hg, and pulmonary vascular resistance was calculated to be 3.3 units (Table I, column 1). The moderate pulmonary hypertension (pulmonary resistance being at upper limits of normal) was thought to be secondary to increased pulmonary blood flow, and it was

856 Anderson et a!.

TABLE 1

Serial Cardiac Catheterization Data*

Pressures (mm. Hg) Pulmonary artery 45/l 1 (26) 75/32 (57) 59128 (41) Left ventricular 75/2 Femoral artery 81/56 (69) R7/53 (70)

P~~lmonary/systemic sys-

tolic ratio 0.6 0.9 0.7 Systemic arterial O2 sat. 94%, 91 yc 907: Blood Row (L./‘min.!M.2)

Pulmonary 78 6.2 3.5 Systemic 2.8 39 3.5 Pulmonary/syslemir

rddn 2.8/1.0 l.h/l.il 1.011 .o Resistance

(resistance tmits) Pulmonary vascular 3.3 8.7 11.9 Systemic vascular 17.7 22.9 Fu~m~n~ry/systemic

rado 0.5 0.5

*Assumed 01 uptake 180 ct./min./M.” Patient premeditated in all instances with a mixture of meperidine, 25 mg.; chlorpromazine, 6.25 mg.; and prometharine, 6.25 mg./cc.; dosage = 1 cc./30 Ih.

Prnmp. = postoperative; sat. = saturation.

elected to follow up the patient at six month intervals. When seen at 27 months of age (6 montkr later), she had

gained another three pounds. There was no change in history or in the physical findings. The electrocardiogram continued to show a pattern of combined ventricular hypertrophy, but rightward forces had increased in amplitude, with the R/S in lead Vt increasing from 16/l 3 to 12/l. Three months later at age 2 years, she had gained 2 more pounds. At this visit, the parents gave a history of recent onset of digital and perioral cyanosis with crying. This change, as well as several others, was noted by the exammer. The thrill was of diminished intensity. The previously noted pansystolic murmur was now a grade 3/6 systolic ejection murmur, and the diastolic rumble was no longer audible. The electrocardiogram showed a pattern of increasing right ventricular hypertrophy (Fig. 1B). Chest films showed less cardiomegaly, with a dilated pulmonary artery seg- ment and diminished pulmonary vascular markings at the periphery (Fig. 2B). In order to investigate the obviously increasing pulmonary hypertension, the child was scheduled for cardiac catheterization.

Repeat catheterization was done at the age of 27 months (Table I, column 2). A decrease in the left-to-right shunt was noted (Qp/Qs decreased from 2.8/l to 1.6,’ 1 with mild systemic arterial desaturation at rest [91%]). Pulmonary artery pressure had risen to 751 32 mm. Hg, with a simultaneous femoral artery pressure of 811’56. Pulmonary artery resistance had risen from 3.3 to 8.7 units and was half the systemic resistance. Thus, within 12 months, this patient had progressed to an advanced stage of pulmonary hypertension.

Operative F~n~~~gs: Surgical closure of the ventricular septal defect was recommended and performed un-

eventfully at age 31 months. In lung biopsy taken at the time of the operation, advanced intimal proliferative lesions were visible in muscular and elastic arteries, especially at points of branching (Fig. 3.~). A residual clot was visible in a number of these lesions, and suggested a possible thrombotic origin (Fig. 3B). Many of the lesions completely occluded the arterial lumina (Fig. 3C). Arteries proximal to these occlu- sive sites often showed a marked medial muscular hy pertrophy, that suggested a severe pulmonary arterial hypertension (Fig. 3A). At a few points, early plexiform structures were visible within smaller muscular arteries, i.e., the artery had enlarged and its lumina and walls were replaced by proliferated cells through which passed many tiny vascular channels (Fig. 3D). Skip sections showed that these tiny channels emptied into one or more dilated branches of the muscular arterial system distally; the media of these distal arteries was usually atrophic, suggesting that the proximal lesions had been present for some time.“’ According to the classification of Heath and Edwardsm the ap- pearance of these plexiform structures gives the lesions in this case a grade of 4.

P~sto~~ative Course: At 34 months of age (three months postoperatively) she was readmitted for a third catheterization, The pulmonary artery pressure was found to have dropped to 59/‘28 mm. Fig (simultaneous brachial artery pressure 87/53). How- ever, pulmonary vascular resistance remained at half systemic level, although pulmonary blood flow had decreased to normal levels (Table t, column 3).

When last seen at age 4 years (21 months postoperatively), the child was developing well and was free of symptoms. Cardiac findings were within normal limits except for a persistently accentuated pulmonic component of the second heart sound. Serial electro- cardiograms have shown a progressive decrease in signs of right ventricular hypertrophy following operation.

DISCUSSION

Natural History of Ventricular Seeptal Defects. Pulmonary Vascular Resistance: From the initial published reports of large numbers of cathe- terized patients with ventricular septal defects, an outline of the natural history of the patients with this lesion was constructed. It was ac- knowledged that most patients with ventricular septal defect had a benign course in infancy and childhood provided that two early complications did not occur: (1) severe congestive cardiac failure in infants with large left to right shunts or (2) pulmonary hypertension with right to left shunting thought to be present from birth and postuIated as being secondary to a persistence of fetal pulmonary arterial changes. It also be- came apparent that the incidence of pulmonary hypertension increased with age after the onset of adolescence. The majority of children with

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Pulmonary Vascular Disease in C~hildhoocl

ventricular scptal defect enjoyed a relatively benign period between infancy and adolescence. Consequently-. the recommendation that fol- lowed frown this general picture of the natural histor?-of\-elttricular scptal defects was that a cor- rrctivc operation coIlId be performed before the

VOI.t!MI’ I’)> ,JL’NE 1967

late teens without fear of progressive pulmon; vascular obstructive disease that might rent these patients inoperable.

When enough cases with serial catheterizatia had accumulated, it was again found that most instances pulmonary vascular resistance

3ry der

3ns in

re-

858 Anderson et al.

mained constant or decreased during childhood. In 1961, however, Lucas et al.10 reported on 4 patients ranging in age from 6 months to 111/Z years in whom pulmonary vascular resistance was observed to increase from near-normal levels. It was assumed that in these patients normal pulmonary vascular maturation had occurred with disappearance of fetal pulmonary hypertension prior to the first catheterization. In 1 of these patients (Case 30) the extraordinary rise in pulmonary vascular resistance during the first year of life was of proportions similar to the case reported here. In 1963, Auld et al.” and Weidman et a1.12 published reports of progressive pulmonary vascular obstruction occurring in infants and young children and suggested that pulmonary vascular obstruction could develop in patients with ventricular septal defect with in- itially normal or only slightly elevated pulmonary vascular resistance and large left to right shunts. They cautioned that the possible development of this lesion in a group of patients generally considered to have a good prognosis, i.e., having survived infancy and without initial pulmonary hypertension, should influence the decision to operate and necessitate close patient observation.

Despite the publication of these well documented cases, there was little acceptance of this concept of progressive pulmonary hypertension during this period, as illustrated by the following quotations; “Fear of progression of pulmonary vascular disease should not be a deciding factor in timing surgery.“a “I agree . . . that fear of progression of pulmonary vascular disease should not be a deciding factor in timing surgery.“s “In patients with normal or only slightly increased pulmonary artery pressure, there is no justification for early surgery because of fear of progressive changes. There is no evidence for rapidly progressive and irreversible pulmonary hypertension in early childhood. The point is important in relation to surgical intervention.“7 “The therapeutic implications of these findings is that a conservative approach to the infant or child with a ventricular septal defect is possible without undue risk or fear of progressive pulmonary hypertension.“6 While some of the authors quoted no longer hold this view, the impression remains in the literature.

In 1965, reports by Kidd et a1.i3J4 Farrar and Dunlop’5 and Ritter et al.16 further documented the occurrence of progressive pulmonary hypertension and indicate an increased concern within the medical professsion about this entity.

Hoffman and Rudolph17 also reported several cases of increasing pulmonary vascular resistance in infants with large ventricular septal defects. Their findings on recatheterization in Case 5 (D.V.) showed pulmonary hypertension developing rapidly in a manner resembling that in our case. Their resulting recommendation is recatheterization at six to nine months in infants with large ventricular septal defects, to detect rising pulmonary resistance before the appear- ance of clinical signs.

Pulmonary Vascular Proliferative Changes: Re- ferring to anatomic changes in the pulmonary vasculature, most investigators agree that in many infants with large ventricular septal defects, intimal proliferative and sclerotic lesions begin to appear in the pulmonary arteries after the first year of life.12,23J4 The finding of transi- tional stages between these intimal lesions and organizing thrombi raises the possibility that many of the lesions may have a thrombotic origin. More important, the lesions seem respon- sible for the progressive increase in pulmonary vascular resistance sometimes recorded in such infants. When the vascular lesions reach Heath and Edwards’20 grade 4, as in our case, pressure and resistance often fail to decrease to normal values after operative closure of the septal defect.20321 Although such advanced vascular changes have been regarded as rare in infancy, they have been recently reported in at least 4 infants less than 4 years of age.12t23J4 Less advanced intimal proliferative lesions have been observed with an even higher frequency in young infants with large ventricular septal defects who die.23,24

Clinical Implications: Our case, then, is presented as an example of the kind of rapidly accel- eratingpulmonary hypertension which can occur in young patients with ventricular septal defects and which, although uncommon, particularly at this age, must be continually watched for because it obviously will increase the hazards of operation. It is also important to stress, as illustrated in our case, that careful evaluation of auscultatory findings, combined with electrocar- diographic and x-ray studies at frequent intervals, will detect the changing hemodynamic situation. Close follow-up certainly should be recommended in all children with largeventricu- lar septal defects and with pulmonary hypertension secondary to high flow rates and probably also in those with large left to right shunts and essentially no pulmonary hypertension. The occurrence of advancing pulmonary hyperten-

7HE AMERICAN JOURNAL OF CARDIOLOGY

Pulmonary Vascular Disease in Childhood 85?

sion detected clinically should be documented at the earliest indication by repeated cardiac catheterization. Early surgical intervention in these cases may arrest the progression of the pulmonary vascular changes.

SUMMARY

A case of rapidly progressing pulmonary vascular obstructive disease occurring in a young child with an isolated ventricular septal defect is presented. Serial cardiac catheterizations at 15 and 27 months of age showed a rise in pulmonary artery pressure from 45/11 to 75/32 mm. Hg, a rise in pulmonary vascular resistance from 3.3 to 8.7 units and a decrease in pulmonary to systemic flow ratio (Qp/Qs) from 2.8/l to 1.6/l.

The clinical findings of (1) a heart murmur which changed from a holosystolic to an ejection type, (2) a disappearing diastolic flow rumble, (3) the onset of cyanosis on crying, (4) the ap- pearance of a decreasing cardiothoracic ratio and sparsity of peripheral pulmonary markings in the roentgenogram and (5) the development of increasing right ventricular hypertrophy as in- dicated by the electrocardiogram in less than one year led to recatheterization and the decision to operate. Far-advanced obstructive pulmonary arterial lesions were found on lung biopsy.

The significance of this entity is discussed in the light of the oft-repeated statement in the cur- rent literature that progressive pulmonaryhyper- tension need not be considered as a factor in planning surgical therapy. Because of the danger that this perhaps uncommon but severe complication may develop in high flow ventricular septal defects, frequent clinical observations should be made in such patients by physicians alert to the early clinical signs of pulmonary hypertension and aware of the rapidity with which advancing pulmonary vascular obstructive lesions can occur.

REFERENCES

1. BROTMAC~ER, L., and CAMPBELL, M. The natural history of ventricular septal defect. Brit. Heart J., 20: 97, 1958.

2. MUDD, J. G. et al. Untreated, low pressure ventricular septal defect. Arch. Swg., 89: 126 1964.

3. ASH, R. Natural history of ventricular septal defects in childhood lesions with predominant arteriovenous shunts. J. Pediat., 64: 45, 1964.

4. ARCIL.LA, R. A. et al. Further observations on the natural history of isolated ventricular septal defects in infancy and childhood. Circulation, 28: 560, 1963.

5. NADAS, .4. S. Pediatric Cardiology, p. 419.

VOLUME 19. ,JUNE 1967

Philadelphia, 1963. \\.. B. Saundrrs Com- pany.

6. SYAN.I.ON, R. E:. and FYLER, D. C. The natural history of pulmonary hypertension in children with ventricular septal defects assessed by serial right-heart catheterization. Pedrntrics, 27 : 621. 1961.

7. LYNFIELD, J., GASUL, B. M., .~RCII.I.A, K. and LUAN, L. L. The natural history of ventricular septal defects in infancy and childhood. Am. J. Med., 30: 357,196l.

8. BLOOMFIELD, D. K. The natural history of ventricular septal defect in patients surviving infancy. Circulation, 29: 914,1964.

9. WALKER, W. J. et al. Interventricular septal defect. Circulation, 31: 54, 1965.

10. LUCAS, R. V. et al. The natural history of isolated ventricular septal defect. Clrculatio?z, 24: 1372, 1961.

11. AULD, P. 4. M., JOIINSON, A. L., GIBBONS, J. E. and MCGREGOR, M. Changes in pulmonary vascular resistance in infants and children with left-to-right intracardiac shunts. Circuln- tion, 27: 257, 1963.

12. WEIDMAN, W. H., DUSHANE, J. \\‘. and Kincaid, 0. W. Observations concerning- progressive pulmonary vascular obstruction in children with ventricular septal defects. Am. Heart J., 65: 148, 1963.

13. KIDD, L., ROSE, V., COLLINS, G. and KEITH, J. Ventricular septal defect in infancy. Am. Heart J., 69: 4, 1965.

14. KIDD, L., ROSE, V., COLLINS, G. and KEITI.II, J. The hemodynamics in ventricular septal defect inchildhood. rim. Heart J., 70: 732, 1965.

15. FARRAR, J. F. and DUNLOP, I. C. The natural history of children suffering from ventricular septal defect and pulmonary hypertension. Australasian Ann. Med., 14: 130, 1965.

16. RITTER, D. G., FELDT, R. H., WEIDMAN, W. I-I. and DUSHANE, J. ‘\V. Ventricular septal defects. Czrculation, 32 (Suppl. 3j: 42, 1965.

17. HOFFMAN, J. I. E. and RUDOLPH, A. M. The natural history of ventricular septal defect in infancy. Am. J. Cardiol., 16: 634, 1965.

18. NADAS, A. S., RUDOLPH, A. M. and GROSS, K. E. Pulmonary arterial hypertension in congenital heart disease. Circulation, 22: 1041, 1960.

19. KIRKLIN, J. W. and DUSHANE, J. W. Indications for repair of ventricular septal defects. .4m. J. Cardiol., 12: 75, 1963.

20. HEATH, D. and EDWARDS, J. E. The pathology of hypertensive pulmonary vascular disease. A description of six grades of structural changes in the pulmonary arteries with special reference to congenital cardiac septal defects. Circulo- tion, 18: 533, 1958.

21. HEAT~I, D. et al. Relation between structural changes in the small pulmonary arteries and the immediate reversibility of pulmonary hypertension following closure of ventricular and atria1 septal defects. Crrculation, 18: 1167, 1958.

22. NAEYE, R. L. and VENNART, G. P. Pulmonary plexiform structures, their structure and significance. Am. J. Path., 36: 593, 1960.

23. NAEYE, R. L. The pulmonary arterial bed in

860 Anderson et al.

ventricular septal defect, anatomic features in childhood. Cjrc~lQt~o~. 34: 962, 1966.

arterial tree in ventricular septal defect: A quantitative study of anatomic features in

24. WAGENVOORT, C. A., NE&QEZD, fi. N., DUSHANE, J. W. and EDWARDS, J. E. The pulmonary

f&uses, infants and children. C’irtuEution, 23: 740, 1961.

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Rapidly progressing pulmonary vascular obstructive disease: Association with ventricular septal defects during early childhood∗