Common
pulmonary
vein
atresia
Marion K. Ledbetter, M.D.* David H. Wells, M.D.“” Dean M. Connors, M.D.““* Madison,
Wise.
Atresia of the common pulmonary vein (CPVA) occurs rarely; to our knowledge this condition has been previously reported in only eleven infants.“-6 The number of cases is larger if one includes those having a minor accessory pulmonary vein which drains into the systemic circulation.‘, s Two additional babies with a premortem diagnosis of isolated CPVA, and a third example of CPVA associated with the asplenia syndrome and other cardiac anomalies form the basis of this report. One baby had histological evidence of acute pericarditis, probably a fortuitous perinatal event unrelated to pathogenesis of the cardiac anomaly. These three infants had been admitted to the Intensive Care Nursery of St. Marys Hospital Medical Center, Madison, Wisconsin, where they underwent cardiac catheterization, and subsequently postmortem examination. This report emphasizes: (1) the developmental relationship of the pulmonary and bronchial venous circulations together with the manner in which the collateral circulation may help to sustain life for a brief period, (2) clinical and laboratory features upon which the diagnosis of atresia of the common pulmonary vein may be based, and (3) clinical implications of pathophysiology which must be considered so that diagnostic, medical, and surgical measures may be From the Departments Marys Hospital Medical University of Wisconsin,
of Pediatric Cardiology and Pathology, Center, and the Department of Neonatology, Madison, W&c.
Received
for publication
Nov.
11, 1977.
Accepted
for publication
Jan.
16, 1978.
Reprint requests: Cardiology, Nicolet *Dept. **Fellow, address: ***Dept.
580
of Pediatric
Marion Clinic,
K. Ledbetter, M.D., Dept. of Pediatric 411 Lincoln St., Neenah, Wise. 54956.
Cardiology,
St. Marys
Neonatology, University Greenville Hospital System, of Pathology,
November,
St.
St. Marys
1978,
Vol.
Hospital
of Wisconsin, Greenville, Hospital
Medical
96, NO.
Medical Madison; S. C.
5
Center.
Center. present
pursued, Despite the fact that our patients and all other reported infants with atresia of the common pulmonary vein have not survived, a successful result of medical and surgical treatment is considered feasible. Case reports Case 1. A 24-hour term son of a 19-year-old primigravid mother weighed 3.2 kilograms when admitted to the intensive care nursery from, a nearby hospital. The gestational history had been uneventful. The one minute Apgar score of 9 had declined to 5 at the five minute evaluation. Cyanosis and distressed breathing had persisted since shortly after birth. Aspiration of a profuse amount of mucus from the airways and ventilation with 100 per cent oxygen did not diminish the cyanosis. The chest had a wide anterior-posterior diameter. Respirations were shallow at a rate of 88 per minute. The heart rate was 165 per minute; both heart sounds were loud and single without murmurs. The peripheral pulses were normal and the liver was not palpable. Initial arterial blood gases with the infant breathing 100 per cent oxygen on the respirator were: pH, 7.19; PO?, 13 mm.; and PCO,, 52 mm. Hg. Dextrose water and bicarbonate were administered intravenously. The electrocardiogram was abnormal for age 24 hours with evidence of right ventricular hypertrophy: the QRS axis was deviated far rightward to 180 degrees, a high voltage QR pattern occurred in Lead V,, and the rS ratio in V, was 0.7. The chest roentgenogram revealed diffuse pulmonary congestion with an indistinct cardiac border (Fig. 1,a). Cardiac catheterization was performed while the infant breathed 100 per cent oxygen in a vinyl hood (Table I). Venous pressure was at the upper
0002-8703/78/110580
+ 07$00.70/O
0 1978
The
C. V. Mosby
Co.
range 01’ -normai; venous oxygen saturations were depressed and there was a step-up in oxygen saturation in the right atrium. During the latter part of the procedure the oxygen saturations became increased and were similar in both ventricles, in the pulmonary artery, and in the ascending aorta. Pulmonary arterial systplic pressure was 30 mm. g higher than aortic systolic pressure. Cineangiocardiograms revealed bidirectional shunting at the atrial level, shunting from the pulmonary artery to the aorta via a large ductus arteriosus, and persistent filling of pulmonary veins for 9 seconds after the pulmonary artery injection. Neither the left atrium nor other channels of venous drainage opacified. The diagnosis was pulmonary venous obstruction, probably due to common pulmonary vein atresia. The infant was maintained on a respirator with 100 per cent oxygen, but he developed severe bradycardia and died nine hours later. GROSS.The lungs were normally located and well aera The pericardial sac contained a small am t of clear yellow fluid. The heart, examined with the lungs intact, was slightly enlarged but the external configuration was not otherwise remarkable. The right atrium and right ventricle were normal. A patent ductus arteriosus measuring 3 mm. in diameter arose from the pulmonary artery of the same size, and communicated with the distal segment of the aortic arch. Two pulmonary veins drained each lung and formed a common thin-walled channel of 2 mm. internal diameter which ended blindly near the right wall. No accessory pulmonary veins were fied. Radiographic examination with contrast injection confirmed that the small channel formed a cul-de-sac and did not connect with either the rigbt or left atrium, and that there was no other connection of pulmonary veins. The left atrium was abnormally small and the mitral valve, the left ventricle, and the aorta were normal. MICROSCOPE. Significant microscopic findings were found only in the lungs. Pulmonary tissue was mature, but with the alveolar spaces incompanded, and some areas revealed ateleccapillary congestion. There were no areas of i~~ammatio~ or hyalme membrane. The lymphatic vessels were dilated, but apparently only to the extent as is usually seen in the lungs of stillborn infants.
cy to a q~ad~gravid, quadriparous 33 y woman. A first cousin had died with co transposition of the great arteries. A nuch was present, Apgar scores on the ini’ant were 7 at one minute and 10 at three rn~~~~e~, Xo resuscitative measures were necessary ; however, at eight minutes the infant quickly cyanosis persisted despite o two days he was admi nursery by transfer another b.~s~~t,al~ Despite oxygen and bit blood gaseson admission were: pI3, ‘7.14; base excess -16, ppeared rno~~~~ ations at a. rate of 84 per minute. There wa however, the bead and face we te, the nuchal cord. The preco m was overactive, the first and second sounds were single and a murmur was not audible. A!1 peripheral pulses were bounding in type and the Ever edge was 3 cm. below the rig& costal margin. The chest r~e~tgenogram revealed a bell configuration, ~~~rn5nary vascular c~~~est~o~ with miid raeration, and a normal heart size (Fig. electrocardiogram was abnormal; signs ML of right yper~~o~b~ ~~~~l~ded2 axis of 165 degrees, a high v&age q
sions of dextrose water and sodium bicarbonate were continued. An abb~ev~ate~~cardiac catbeterization was performed (Table I); he was resusci-
Ledbetter,
Table
Wells, and Connors
I. Cardiac catheterization Case 1 (age 1 day)?
Site
PH
svc
7.30 7.32 -
IVC RA LA RV LV PA Ao
7.33 7.33
Oxygen saturation, % 53 55 70 60 61,881 8% 91$ 931
Case 2 (age 3 days)?
Pressure (mm. Hd S/D*
Mean
PH
6/l 6/4
3 5
-
-
S/D*
7/3 8/O 88/O 62/O 87/27
5 4 65
6.83 6.95 7.12 -
19 27 21 32 -
16/9 21/12 62/O -
54/34
46
-
-
39/25
-
hood,
II. Clinical features of common pulmonary vein atresia Table
History & physical examination 1. Usually term infants 2. Immediate condition at birth may be good 3. Cyanosis and distressed breathing ensue quickly 4. No cardiac murmur 5. Severe acidosis 6. Congestive heart failure Electrocardiogram Right ventricular hypertrophy Roentgenogram I. Heart size normal, border may be indistinct 2. Severe pulmonary congestion Cardiac Catheterization 1. Oxygen saturation low and similar in all chambers 2. Pulmonary artery pressure suprasystemic 3. Elevated venous pressure Angiocardiogram 1. Right to left shunting via foramen ovale and ductus arteriosus 2. Pulmonary veins opacify, but not other structures of venous drainage
tated throughout breathing 100 per cent oxygen via an endotracheal tube on a respirator. Venous pressure was severely elevated and blood in all chambers was hypoxemic. He was hypotensive; right ventricular systolic pressure exceeded aortic pressure. Cineangiocardiograms in the right and left atria and right ventricle revealed bidirectional shunting across the atria1 septum, tricuspid regurgitation, filling of the descending aorta from
582
Pressure (mm. Hi?..
Oxygen saturation, %
*Abbreviations: S/D = Systolic, diastolic; e.d. = end-diastolic. ?A11 infants breathed 100 per cent oxygen, Cases 1 and 3 by a vinyl $Saturations were obtained near the end of procedure. All peak venous pulses were “a” waves.
Case 3 (age 2 days)?
and
Case
Mean
PH -
12 16 e.d. = 12 -
Oxygen saturation, %
7.44 -
59
7.40
Pressure (mm. Hg) S/D*
Mean 1
84 -
3/o 4/2 5/o -
82
87/O
e.d. = 5
79
88/57
69
3 2
70
2 by a respirator.
the pulmonary artery via a large ductus arteriosus, a small left atrium, and a small left ventricle. Pulmonary veins opacified distinctly behind the heart, but continued filming for 6.5 seconds revealed no opacification of the left atrium or any anomalous venous channels. The diagnosis was common pulmonary vein atresia. Surgical correction was planned but he died three hours later. Autopsy findings GROSS. Both lungs were moderately emphysematous and blebs were seen over the external surfaces. The left lung was partially collapsed. There was no excess of pleural fluid. The pericardial sac contained 5 ml. of blood-tinged fluid. The epicardial surface was smooth and glistening without abnormal openings or hemorrhage. The heart chambers and arteries were normally oriented. A huge pulmonary artery arose from a dilated and hypertrophied right ventricle. The aortic arch was approximately one-third the size of the pulmonary artery and the aortic isthmus was hypoplastic. The ductus arteriosus was approximately equal in size to the pulmonary artery and communicated with a large descending aorta. An oval atria1 septal defect just above a normal foramen ovale measured 2 x 1 cm. The tricuspid valve was structually normal but dilated. The left atrium and left ventricle were small. Small pulmonary veins drained all lobes of the lungs but did not join the left atrium at any point. They formed a closed, tube-like blind venous chamber measuring 3 x 1 cm. No accesso-
November,
1978,
Vol.
96,
No. 5
Fig. Fig.
Ib. Chest radiograph.
Case 2. See text for description.
ry puhnonary vems were present. Bronchial vessels were identified but were not abnormally prominent and communicated normally. MICROSCOPIC. Evidence of an active pericarditis was a conspicuous feature. The serosa was thickened, edematous, and infiltrated with numerous ~olymor~ho~uclear leukocytes and lesser numbers of eosinophils and lymphocytes. Some of the sections revealed a small amount of granular lipid material associated with this inflammatory lesion. The infiltrate was confined to the outer aspects of the myocardium and did not involve the endocardium at any point. Special stains for lipid infiltration of the heart and for fungi and bacteria were negative. The blebs noted over the external surfaces of the lungs were dilated lymphatic vessels. Case 3. A 3.9 kilogram girl was delivered uneventfully to a primigravid 19-year-old mother after an uncomplicated 40 week gestation. The one minute Apgar score was 8 and the five minute score was 9, At three hours the baby became cyanotic, The heart sounds were most prominent in the right hemithorax, the first and second sounds were single, and ,a murmur was not audible. Roentgenograms (Fig. 1,~) revealed dextrocardia and indistinct cardiac borders, but not severe pulmonary congestion. Many Howell-Jolly bodies were seen in the peripheral blood smear. The e~ectr~card~ogran~ was compatible with
American
Hear% Journal
Ic.
Chest rairiograph.
Case 3. See ‘,t;xt ‘0~ :iesaq~~um.
mxror-image inversion of the atrra and sinus rhythm. High voltage con~~lexes in right precordial leads, and a co~~gt.~rati~r~ from Leads V, through V, indicated right ventricular hypertrophy. The fmdlngs were diagnostic for the asplenia syndrome. Cardiac catheterization was performed while the baby breathed 400 per cent oxygen (Table I). The inferior vena cava jomed the cardiac silhouette at the usual location in the right paravertebral area, an there was a iieft superior vena cava. The righ atrium in a mid”beart location was arteriaiized. Right v~~~r~c~~a~ and aortic systolic pressures were equat. A ~~~a~~~ right ventricle on the right heart ‘border gave origin to a large transposed aorta in the levoposiCon. Pulmonary arteries smaller than the aorta were filled only from a patent ductus arteriosus. Pulmonary venous drainage was not identified, although tine filming was c~~~~~~e~ secondsafter the pulmonary a~t~r~e~opaci lal.ock shunt was perform. anastomosis of the right subclaviaa arkry to de right pulmonary artery, but the b&y was not improved and died the foollowing day, Autopsy findings GROSS. The spleen was absent. The car atria were inverted with the ~~rnb~~of the fossa ovale identified in the left-sided chamber. Anomalies consisted of a large atrial septal. defect of the ostium secundum type, a dilat.ed and heavily trabeculated single anatomic right ventricle
Ledbetter,
Wells,
and
Connors
which gave rise to a large levotransposed aorta, pulmonary valve atresia, and a patent ductus arteriosus. The right lung with four lobes and a trilobed left lung drained into a verticle pulmonary vein which ended blindly; it did not communicate with the let atrium or any other chamber or vessel. The mid-line liver was predominantly left-sided. The inverted gastrointestinal tract revealed the stomach on the right and the cecum and appendix on the left. Stenosis of the ureters at the bladder junction had caused bilateral hydronephrosis and hydroureter. MICROSCOPIC. The lungs revealed foamy macrophages and inflammatory cells, the features being those of aspiration pneumonitis. The lymphatic vessels were dilated and showed no significant morphologic alteration. Comments Developmental bronchial venous
relationship circulations.
of pulmonary
and
Lucas and colleagues1 described the common embryologic features of total anomalous connection of pulmonary veins (TACPV) and CPVA. Development of the pulmonary venous system is recounted briefly. The splanchnic plexus of the primordial lung buds drains into somatic veins (the cardinal system) and abdominal visceral veins (the umbilice-vitelline system). Pulmonary veins do not connect with the heart until the common pulmonary vein has formed as a diverticulum on the sinoatrial chamber of the heart. As the left atrium grows it incorporates the common pulmonary vein, so the individual pulmonary veins connect separately with the left atrium. TACPV or CPVA results if the common pulmonary vein either fails to develop, undergoes involution, or becomes atretic. If one of these processes occurs at a time when connections of cardinal veins or umbilico-vitelline veins to the splanchnic plexus have persisted, there is TACPV. If all of these primitive venous channels have already undergone the normal involution process prior to failure of the common pulmonary vein to develop and join with the pulmonary veins, then the anomalous entity is CPVA. Developmental failure of the common pulmonary vein from whatever cause is a pathogenetic feature of both conditions. ShaneF and Marchand and co-workers’0 described the intimate developmental relation-
584
ship of the bronchial and pulmonary circulations. Bronchial veins also are formed from the splanchnit plexus and drain into cardinal veins. There are two groups of bronchial veins. The deep or true bronchial veins are intrapulmonary vessels related to the bronchi; they drain into the pulmonary veins or the left atrium. The other group is the pleurohilar veins which drain the subpleural and hilar structures of the lungs. They exist when the cardinal system breaks up, and drain into the azygous vein on the right, and into the accessory hemiazygous or innominate vein on the left. These pleurohilar veins communicate freely with the pulmonary veins and provide a decompression mechanism when pulmonary venous pressure is raised. In the first report of CPVA, Lucas and collaborators described the clinical and pathological features of three infants who survived for 28, 22, and three days. Their patient who died three days following surgery had a large bronchial vein originating in the right pulmonary hilus and entering the esophageal wall to connect with esophageal varices. However, their other two infants and most of the other cases reported did not have such grossly dilated bronchial venous channels. Bronchial-pulmonary vascular anastomoses are known to be present in health and in congenital and acquired disease states at the arterial, venous, and capillary levels.‘l Von Hayek’” estimated that under normal conditions the extensive anastomoses of bronchial and pulmonary arteries and veins are capable of conveying approximately one-tenth of the postnatal pulmonary circulation. This figure compares with the fraction of the right ventricular stroke volume which normally perfuses the fetal lung.‘” Therefore, the prenatal pulmonary circulation in CPVA may not have been compromised and there may have been little stimulus for retention of large fetal bronchopulmonary channels for collateral flow. However, survival of infants with CPVA for longer than several minutes indicates that a significant amount of arterialized blood must flow to the systemic circulation. The usual stimulus for growth and proliferation of bronchial arteries and dilation of bronchopulmonary anastomotic channels in congenital heart disease is pulmonary oligemia and hypotension, an effect of precapillary obstruction
November,
1978, Vol. 96, No. 5
such as m~.~rs in the tetralogy of Fallot. Conversely, the pulmonary circulation is engorged and the arterial pressure is elevated to a suprasystemic level when obstruction occurs beyond the pulmonary capillary bed as in CPVA and TACPV with obstruction. Histologic evidence indicates that there can be retrograde flow of capillary blood into the pulmonary arteries when the pulmonary veins are totally occluded. Wagenvoort and colleagues’” described dilated bronchopulmonary arteries and bronchopulmonary venous anastomoses in cases of aortic atresia with prematurely closed foramen ovale, a condition hemodynamically similar to CPVA. Mar&and and associates?’ found that the bronchial arteries in the full-term fetal lung and in the atelectatic lung of the stillborn infant have a calibre nearly equa.1 to that of adult vessels. Since the direction of flow in bronchopulmonary arterial anastomoses will depend upon the pressure relationship in the pulmonary and bronchial arteries, pulmonary capillary blood may enter the systemic circulation via bronchial arteries as well as bronchial veins. is for clinkal
and laboratory
features
of
ardiorespiratory function is severely altered immediately after birth in infants with CPVA, and causes their early death. Thus it is urgent to establish the diagnosis quickly. Clinical and laboratory findings are summarized in Table II. Obstructed pulmonary venous drainage may be suspected in infants who do not require resuscitation at birth but who quickly develop cyanosis and severe respiratory distress. They have e1ectrocardiographj.c evidence of right ventricular hypertrophy. The roentgenographic appearance of severe pulmonary congestion is similar in CPVA, TACPV with obstruction, and idiopathic pulmonary lymphangiectasis. The heart size is normal radiographically but the borders may be obscured. Dilated pulmonary lymphatic5 have been demonstrated in all previous casesof CPVA. They are more abundant in the connective tissue containing perilo!>ular tissues than in the lobules.” The elevated pulmonary venous pressure causes this pulmonary lymphangiectasis, and much edema fluid is conveyed by these channels into the systemic circulation. Rywlin and Fojaco’ postulated that the lymphangiectasis is a retained lymphatic pattern of the fetal lung. This massive dilation of pulmonary lymphatic
vesselswas appreciated histo~ogica!:y X&Y !n WI Case 2, the ir,fank with severely elevated venous pressure. ulmonary artery pressure has 5een elevated to auprasystemic levels in all patients with CPVA upon whom cardiac catheterization was performed. However, in our case three systolic pressures in the right ventricle and aorta -were equal. The oxygen saturation is severely depressed and usually is similar in all heart chambers. Tbe fetal pattern of blood flow persists with right-to-left shunting through the foramen ot?ale and the ductus arteriosus. A~~oca~di~gr~~by reveals persistent filling of pulmonary veins after the puimonary artery injection; but the left atrium, and any other cardiac chamber or veins do not opacifY* The anomalies of pulmonary artery atresia and TACPV occur commonly in tbe c~~~~~~i~alasplenia syndrome as described by uttenberg and colleagues.‘” Our Case 3 bad both ~~~rno~ar~ artery and pulmonary vein atresia: so that blood flowed to and from the lungs vrla the ductus arteriosus and intrapulmonary co&t essels. She could not have benefited from l&3& shunt. Most reported casesof GPVA have not bad other anomalies: and the gestational age has been 40 or more weeks existence of infants indicates that surgical anastomosis of the verticle pulmonary vein to the left atrium should be performed immediately after dia~~~st~c studies have been completed. A surgical procedure utilizing extracorporeal circulation may allow some correction of tbe severe acidosis and hypoxemia.‘” Deep bypoth~rmia and ci~c~~ato~y arrest may be necessary for the surgery to be accomplished. Despite postmortem evidence or” an adequate anast.omosisfor pulmonary venous flow into the left atrium, no in is problem f&XiQSCS ’ or when it was left patent7 Factors compromising pulmonary ve~~ila~~o~ and perfusion would be expected to persist following surgery. Wypoperfusion of the lungs and sev-ere acidosis will have suppressed ~~r~~~ti~~ of surfactant.17, I8 Deficiency of this antiatelectatic factor, in addition to residual pulmonary congestion and lymphangiectasis, will limit venti4ation1” Hypoxemia and acidosis are stimuli for persistent
Ledbetter,
Wells,
and
Connors
constriction of small pulmonary arteries.20 Physiologic involution of the muscle coat surrounding these vessels, as in those of normal infants, can occur only gradually after hypoxemia has been alleviated. Despite these remarks of pessimism, early recognition of CPVA followed by aggressive medical and surgical treatment may result in a successful outcome. Presumably the pathophysiologic changes occur only postnatally.
8.
9.
10.
Il. 12. 13.
REFERENCES 1.
2.
3.
4.
5.
6.
7.
586
Lucas, R. V., Jr., Woolfrey, B. F., Anderson, R. C., Lester, R. G., and Edwards, J. E.: Atresia of the common pulmonary vein, Pediatrics 29:729, 1962. Nakib, A., Moller, J. H., Kanjuh, V. I., Edwards, J. E.: Anomalies of the pulmonary veins, Am. J. Cardiol. 20:77, 1967. Levine, M. A., Moller, J. H., Amplatz, K., and Edwards, J. E.: Atresia of the common pulmonary vein; Case report and differential diagnosis, Am. J. Roentgenol. 100:322, 1967. Rywlin, A. M., and Fojaco, R. M.: Congenital pulmonary lymphangiectasis associated with a blind cbmmon pulmonary vein, Pediatrics 41:931, 1968. Hawker, R. E., Celefrmajer, Gengos, D. C., Cartmill, T. B., and Bowdler, M. B.: Common pulmonary vein atresia. Premortem diagnosis in two infants, Circulation 46:368, 1972. Delisle, G., Ando, M., Calder, A. L., Zuberbuhler, J. R., Rochenmacher, S., Alday, L. E., Mangini, O., Van Praagh, S., and Van Praagh, R.: Total anomalous pulmonary venous connection: Report of 93 autopsied cases with emphasis on diagnostic and surgical considerations, AM. HEART J. 91:99, 1976. Mody, G. T., and Folger, G. M., Jr.: Atresia of the common pulmonary vein: Report of one case, Pediatrics 54:62, 1974.
14.
15.
16.
17.
18.
19.
20.
Hastreiter, A. R., Paul, M. H., Molthan, M. E., and Miller, R. A.: Total anomalous pulmonary venous connection with severe pulmonary venous obstruction, Circulation 25:916, 1962. Shaner, R. F.: The development of the bronchial veins, with special reference to anomalies of the pulmonary veins, Anatomical Record 140:159, 1961. Marchand, P., Gilbroy, J. C., and Wilson, V. H.: An anatomical study of the bronchial vascular system and its variations in disease, Thorax 5:207, 1950. Harris, P., and Heath, D.: Human pulmonary circulation, Baltimore, 1962, The Williams & Wilkins Co. Von Hayek, H.: The human lung, N. Y., 1960, Hafner Publishing Co. Rudolph, A.: The changes in the circulation after birth; their importance in congenital heart disease, Circulation 41:343, 1970. Wagenvoort, C. A., Wagenvoort, N., and Becker, E. A.: The effect of obstructed pulmonary venous blood flow on the development of alternative pathways in the lung, J. Pathol. 107:21, 1971. Ruttenberg, H. D., Neufeld, H. N., Cucus, R. V., Jr., Carey, L. S., Adams, P., Jr., Anderson, R. C., and Edwards, J. E.: Syndrome of congenital cardiac disease with asplenia, Am. J. Cardiol. 13:387, 1964. Boncheck, L. II, Anderson, R. P., Wood, J. A., Chapman, R. D., and Starr, A.: Intracardiac surgery with extracorporeal circulation in infants, Ann. Thorac. Surg. 17:280, 1974. Chu, J., Clements, J. A., Cotton, E. K., Klaus, M. H., Sweet, A. Y., and Tooley, W. H.: Neonatal pulmonary ischemia 1. Clinical and physiological studies, Pediatrics 40:709, 1967. Merritt, T. A., and Farrell, P. M.: Diminished pulmonary lecethin synthesis in acidosis: Experimental findings as related to the respiratory distress syndrome, Pediatrics 67:32, 1976. France, N. E., and Brown, R. J. D.: Congenital pulmonary lymphangiectasis. Report of 11 examples with special reference to cardiovascular findings, Arch. Dis. Child. 46:528, 1971. Naeye, R. L.: Arterial changes during the perinatal period, Arch. Pathol. 71:121, 1961.
November,
1978, Vol. 96, No. 5
pulmonary
vein
atresia
Marion K. Ledbetter, M.D.* David H. Wells, M.D.“” Dean M. Connors, M.D.““* Madison,
Wise.
Atresia of the common pulmonary vein (CPVA) occurs rarely; to our knowledge this condition has been previously reported in only eleven infants.“-6 The number of cases is larger if one includes those having a minor accessory pulmonary vein which drains into the systemic circulation.‘, s Two additional babies with a premortem diagnosis of isolated CPVA, and a third example of CPVA associated with the asplenia syndrome and other cardiac anomalies form the basis of this report. One baby had histological evidence of acute pericarditis, probably a fortuitous perinatal event unrelated to pathogenesis of the cardiac anomaly. These three infants had been admitted to the Intensive Care Nursery of St. Marys Hospital Medical Center, Madison, Wisconsin, where they underwent cardiac catheterization, and subsequently postmortem examination. This report emphasizes: (1) the developmental relationship of the pulmonary and bronchial venous circulations together with the manner in which the collateral circulation may help to sustain life for a brief period, (2) clinical and laboratory features upon which the diagnosis of atresia of the common pulmonary vein may be based, and (3) clinical implications of pathophysiology which must be considered so that diagnostic, medical, and surgical measures may be From the Departments Marys Hospital Medical University of Wisconsin,
of Pediatric Cardiology and Pathology, Center, and the Department of Neonatology, Madison, W&c.
Received
for publication
Nov.
11, 1977.
Accepted
for publication
Jan.
16, 1978.
Reprint requests: Cardiology, Nicolet *Dept. **Fellow, address: ***Dept.
580
of Pediatric
Marion Clinic,
K. Ledbetter, M.D., Dept. of Pediatric 411 Lincoln St., Neenah, Wise. 54956.
Cardiology,
St. Marys
Neonatology, University Greenville Hospital System, of Pathology,
November,
St.
St. Marys
1978,
Vol.
Hospital
of Wisconsin, Greenville, Hospital
Medical
96, NO.
Medical Madison; S. C.
5
Center.
Center. present
pursued, Despite the fact that our patients and all other reported infants with atresia of the common pulmonary vein have not survived, a successful result of medical and surgical treatment is considered feasible. Case reports Case 1. A 24-hour term son of a 19-year-old primigravid mother weighed 3.2 kilograms when admitted to the intensive care nursery from, a nearby hospital. The gestational history had been uneventful. The one minute Apgar score of 9 had declined to 5 at the five minute evaluation. Cyanosis and distressed breathing had persisted since shortly after birth. Aspiration of a profuse amount of mucus from the airways and ventilation with 100 per cent oxygen did not diminish the cyanosis. The chest had a wide anterior-posterior diameter. Respirations were shallow at a rate of 88 per minute. The heart rate was 165 per minute; both heart sounds were loud and single without murmurs. The peripheral pulses were normal and the liver was not palpable. Initial arterial blood gases with the infant breathing 100 per cent oxygen on the respirator were: pH, 7.19; PO?, 13 mm.; and PCO,, 52 mm. Hg. Dextrose water and bicarbonate were administered intravenously. The electrocardiogram was abnormal for age 24 hours with evidence of right ventricular hypertrophy: the QRS axis was deviated far rightward to 180 degrees, a high voltage QR pattern occurred in Lead V,, and the rS ratio in V, was 0.7. The chest roentgenogram revealed diffuse pulmonary congestion with an indistinct cardiac border (Fig. 1,a). Cardiac catheterization was performed while the infant breathed 100 per cent oxygen in a vinyl hood (Table I). Venous pressure was at the upper
0002-8703/78/110580
+ 07$00.70/O
0 1978
The
C. V. Mosby
Co.
range 01’ -normai; venous oxygen saturations were depressed and there was a step-up in oxygen saturation in the right atrium. During the latter part of the procedure the oxygen saturations became increased and were similar in both ventricles, in the pulmonary artery, and in the ascending aorta. Pulmonary arterial systplic pressure was 30 mm. g higher than aortic systolic pressure. Cineangiocardiograms revealed bidirectional shunting at the atrial level, shunting from the pulmonary artery to the aorta via a large ductus arteriosus, and persistent filling of pulmonary veins for 9 seconds after the pulmonary artery injection. Neither the left atrium nor other channels of venous drainage opacified. The diagnosis was pulmonary venous obstruction, probably due to common pulmonary vein atresia. The infant was maintained on a respirator with 100 per cent oxygen, but he developed severe bradycardia and died nine hours later. GROSS.The lungs were normally located and well aera The pericardial sac contained a small am t of clear yellow fluid. The heart, examined with the lungs intact, was slightly enlarged but the external configuration was not otherwise remarkable. The right atrium and right ventricle were normal. A patent ductus arteriosus measuring 3 mm. in diameter arose from the pulmonary artery of the same size, and communicated with the distal segment of the aortic arch. Two pulmonary veins drained each lung and formed a common thin-walled channel of 2 mm. internal diameter which ended blindly near the right wall. No accessory pulmonary veins were fied. Radiographic examination with contrast injection confirmed that the small channel formed a cul-de-sac and did not connect with either the rigbt or left atrium, and that there was no other connection of pulmonary veins. The left atrium was abnormally small and the mitral valve, the left ventricle, and the aorta were normal. MICROSCOPE. Significant microscopic findings were found only in the lungs. Pulmonary tissue was mature, but with the alveolar spaces incompanded, and some areas revealed ateleccapillary congestion. There were no areas of i~~ammatio~ or hyalme membrane. The lymphatic vessels were dilated, but apparently only to the extent as is usually seen in the lungs of stillborn infants.
cy to a q~ad~gravid, quadriparous 33 y woman. A first cousin had died with co transposition of the great arteries. A nuch was present, Apgar scores on the ini’ant were 7 at one minute and 10 at three rn~~~~e~, Xo resuscitative measures were necessary ; however, at eight minutes the infant quickly cyanosis persisted despite o two days he was admi nursery by transfer another b.~s~~t,al~ Despite oxygen and bit blood gaseson admission were: pI3, ‘7.14; base excess -16, ppeared rno~~~~ ations at a. rate of 84 per minute. There wa however, the bead and face we te, the nuchal cord. The preco m was overactive, the first and second sounds were single and a murmur was not audible. A!1 peripheral pulses were bounding in type and the Ever edge was 3 cm. below the rig& costal margin. The chest r~e~tgenogram revealed a bell configuration, ~~~rn5nary vascular c~~~est~o~ with miid raeration, and a normal heart size (Fig. electrocardiogram was abnormal; signs ML of right yper~~o~b~ ~~~~l~ded2 axis of 165 degrees, a high v&age q
sions of dextrose water and sodium bicarbonate were continued. An abb~ev~ate~~cardiac catbeterization was performed (Table I); he was resusci-
Ledbetter,
Table
Wells, and Connors
I. Cardiac catheterization Case 1 (age 1 day)?
Site
PH
svc
7.30 7.32 -
IVC RA LA RV LV PA Ao
7.33 7.33
Oxygen saturation, % 53 55 70 60 61,881 8% 91$ 931
Case 2 (age 3 days)?
Pressure (mm. Hd S/D*
Mean
PH
6/l 6/4
3 5
-
-
S/D*
7/3 8/O 88/O 62/O 87/27
5 4 65
6.83 6.95 7.12 -
19 27 21 32 -
16/9 21/12 62/O -
54/34
46
-
-
39/25
-
hood,
II. Clinical features of common pulmonary vein atresia Table
History & physical examination 1. Usually term infants 2. Immediate condition at birth may be good 3. Cyanosis and distressed breathing ensue quickly 4. No cardiac murmur 5. Severe acidosis 6. Congestive heart failure Electrocardiogram Right ventricular hypertrophy Roentgenogram I. Heart size normal, border may be indistinct 2. Severe pulmonary congestion Cardiac Catheterization 1. Oxygen saturation low and similar in all chambers 2. Pulmonary artery pressure suprasystemic 3. Elevated venous pressure Angiocardiogram 1. Right to left shunting via foramen ovale and ductus arteriosus 2. Pulmonary veins opacify, but not other structures of venous drainage
tated throughout breathing 100 per cent oxygen via an endotracheal tube on a respirator. Venous pressure was severely elevated and blood in all chambers was hypoxemic. He was hypotensive; right ventricular systolic pressure exceeded aortic pressure. Cineangiocardiograms in the right and left atria and right ventricle revealed bidirectional shunting across the atria1 septum, tricuspid regurgitation, filling of the descending aorta from
582
Pressure (mm. Hi?..
Oxygen saturation, %
*Abbreviations: S/D = Systolic, diastolic; e.d. = end-diastolic. ?A11 infants breathed 100 per cent oxygen, Cases 1 and 3 by a vinyl $Saturations were obtained near the end of procedure. All peak venous pulses were “a” waves.
Case 3 (age 2 days)?
and
Case
Mean
PH -
12 16 e.d. = 12 -
Oxygen saturation, %
7.44 -
59
7.40
Pressure (mm. Hg) S/D*
Mean 1
84 -
3/o 4/2 5/o -
82
87/O
e.d. = 5
79
88/57
69
3 2
70
2 by a respirator.
the pulmonary artery via a large ductus arteriosus, a small left atrium, and a small left ventricle. Pulmonary veins opacified distinctly behind the heart, but continued filming for 6.5 seconds revealed no opacification of the left atrium or any anomalous venous channels. The diagnosis was common pulmonary vein atresia. Surgical correction was planned but he died three hours later. Autopsy findings GROSS. Both lungs were moderately emphysematous and blebs were seen over the external surfaces. The left lung was partially collapsed. There was no excess of pleural fluid. The pericardial sac contained 5 ml. of blood-tinged fluid. The epicardial surface was smooth and glistening without abnormal openings or hemorrhage. The heart chambers and arteries were normally oriented. A huge pulmonary artery arose from a dilated and hypertrophied right ventricle. The aortic arch was approximately one-third the size of the pulmonary artery and the aortic isthmus was hypoplastic. The ductus arteriosus was approximately equal in size to the pulmonary artery and communicated with a large descending aorta. An oval atria1 septal defect just above a normal foramen ovale measured 2 x 1 cm. The tricuspid valve was structually normal but dilated. The left atrium and left ventricle were small. Small pulmonary veins drained all lobes of the lungs but did not join the left atrium at any point. They formed a closed, tube-like blind venous chamber measuring 3 x 1 cm. No accesso-
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1978,
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96,
No. 5
Fig. Fig.
Ib. Chest radiograph.
Case 2. See text for description.
ry puhnonary vems were present. Bronchial vessels were identified but were not abnormally prominent and communicated normally. MICROSCOPIC. Evidence of an active pericarditis was a conspicuous feature. The serosa was thickened, edematous, and infiltrated with numerous ~olymor~ho~uclear leukocytes and lesser numbers of eosinophils and lymphocytes. Some of the sections revealed a small amount of granular lipid material associated with this inflammatory lesion. The infiltrate was confined to the outer aspects of the myocardium and did not involve the endocardium at any point. Special stains for lipid infiltration of the heart and for fungi and bacteria were negative. The blebs noted over the external surfaces of the lungs were dilated lymphatic vessels. Case 3. A 3.9 kilogram girl was delivered uneventfully to a primigravid 19-year-old mother after an uncomplicated 40 week gestation. The one minute Apgar score was 8 and the five minute score was 9, At three hours the baby became cyanotic, The heart sounds were most prominent in the right hemithorax, the first and second sounds were single, and ,a murmur was not audible. Roentgenograms (Fig. 1,~) revealed dextrocardia and indistinct cardiac borders, but not severe pulmonary congestion. Many Howell-Jolly bodies were seen in the peripheral blood smear. The e~ectr~card~ogran~ was compatible with
American
Hear% Journal
Ic.
Chest rairiograph.
Case 3. See ‘,t;xt ‘0~ :iesaq~~um.
mxror-image inversion of the atrra and sinus rhythm. High voltage con~~lexes in right precordial leads, and a co~~gt.~rati~r~ from Leads V, through V, indicated right ventricular hypertrophy. The fmdlngs were diagnostic for the asplenia syndrome. Cardiac catheterization was performed while the baby breathed 400 per cent oxygen (Table I). The inferior vena cava jomed the cardiac silhouette at the usual location in the right paravertebral area, an there was a iieft superior vena cava. The righ atrium in a mid”beart location was arteriaiized. Right v~~~r~c~~a~ and aortic systolic pressures were equat. A ~~~a~~~ right ventricle on the right heart ‘border gave origin to a large transposed aorta in the levoposiCon. Pulmonary arteries smaller than the aorta were filled only from a patent ductus arteriosus. Pulmonary venous drainage was not identified, although tine filming was c~~~~~~e~ secondsafter the pulmonary a~t~r~e~opaci lal.ock shunt was perform. anastomosis of the right subclaviaa arkry to de right pulmonary artery, but the b&y was not improved and died the foollowing day, Autopsy findings GROSS. The spleen was absent. The car atria were inverted with the ~~rnb~~of the fossa ovale identified in the left-sided chamber. Anomalies consisted of a large atrial septal. defect of the ostium secundum type, a dilat.ed and heavily trabeculated single anatomic right ventricle
Ledbetter,
Wells,
and
Connors
which gave rise to a large levotransposed aorta, pulmonary valve atresia, and a patent ductus arteriosus. The right lung with four lobes and a trilobed left lung drained into a verticle pulmonary vein which ended blindly; it did not communicate with the let atrium or any other chamber or vessel. The mid-line liver was predominantly left-sided. The inverted gastrointestinal tract revealed the stomach on the right and the cecum and appendix on the left. Stenosis of the ureters at the bladder junction had caused bilateral hydronephrosis and hydroureter. MICROSCOPIC. The lungs revealed foamy macrophages and inflammatory cells, the features being those of aspiration pneumonitis. The lymphatic vessels were dilated and showed no significant morphologic alteration. Comments Developmental bronchial venous
relationship circulations.
of pulmonary
and
Lucas and colleagues1 described the common embryologic features of total anomalous connection of pulmonary veins (TACPV) and CPVA. Development of the pulmonary venous system is recounted briefly. The splanchnic plexus of the primordial lung buds drains into somatic veins (the cardinal system) and abdominal visceral veins (the umbilice-vitelline system). Pulmonary veins do not connect with the heart until the common pulmonary vein has formed as a diverticulum on the sinoatrial chamber of the heart. As the left atrium grows it incorporates the common pulmonary vein, so the individual pulmonary veins connect separately with the left atrium. TACPV or CPVA results if the common pulmonary vein either fails to develop, undergoes involution, or becomes atretic. If one of these processes occurs at a time when connections of cardinal veins or umbilico-vitelline veins to the splanchnic plexus have persisted, there is TACPV. If all of these primitive venous channels have already undergone the normal involution process prior to failure of the common pulmonary vein to develop and join with the pulmonary veins, then the anomalous entity is CPVA. Developmental failure of the common pulmonary vein from whatever cause is a pathogenetic feature of both conditions. ShaneF and Marchand and co-workers’0 described the intimate developmental relation-
584
ship of the bronchial and pulmonary circulations. Bronchial veins also are formed from the splanchnit plexus and drain into cardinal veins. There are two groups of bronchial veins. The deep or true bronchial veins are intrapulmonary vessels related to the bronchi; they drain into the pulmonary veins or the left atrium. The other group is the pleurohilar veins which drain the subpleural and hilar structures of the lungs. They exist when the cardinal system breaks up, and drain into the azygous vein on the right, and into the accessory hemiazygous or innominate vein on the left. These pleurohilar veins communicate freely with the pulmonary veins and provide a decompression mechanism when pulmonary venous pressure is raised. In the first report of CPVA, Lucas and collaborators described the clinical and pathological features of three infants who survived for 28, 22, and three days. Their patient who died three days following surgery had a large bronchial vein originating in the right pulmonary hilus and entering the esophageal wall to connect with esophageal varices. However, their other two infants and most of the other cases reported did not have such grossly dilated bronchial venous channels. Bronchial-pulmonary vascular anastomoses are known to be present in health and in congenital and acquired disease states at the arterial, venous, and capillary levels.‘l Von Hayek’” estimated that under normal conditions the extensive anastomoses of bronchial and pulmonary arteries and veins are capable of conveying approximately one-tenth of the postnatal pulmonary circulation. This figure compares with the fraction of the right ventricular stroke volume which normally perfuses the fetal lung.‘” Therefore, the prenatal pulmonary circulation in CPVA may not have been compromised and there may have been little stimulus for retention of large fetal bronchopulmonary channels for collateral flow. However, survival of infants with CPVA for longer than several minutes indicates that a significant amount of arterialized blood must flow to the systemic circulation. The usual stimulus for growth and proliferation of bronchial arteries and dilation of bronchopulmonary anastomotic channels in congenital heart disease is pulmonary oligemia and hypotension, an effect of precapillary obstruction
November,
1978, Vol. 96, No. 5
such as m~.~rs in the tetralogy of Fallot. Conversely, the pulmonary circulation is engorged and the arterial pressure is elevated to a suprasystemic level when obstruction occurs beyond the pulmonary capillary bed as in CPVA and TACPV with obstruction. Histologic evidence indicates that there can be retrograde flow of capillary blood into the pulmonary arteries when the pulmonary veins are totally occluded. Wagenvoort and colleagues’” described dilated bronchopulmonary arteries and bronchopulmonary venous anastomoses in cases of aortic atresia with prematurely closed foramen ovale, a condition hemodynamically similar to CPVA. Mar&and and associates?’ found that the bronchial arteries in the full-term fetal lung and in the atelectatic lung of the stillborn infant have a calibre nearly equa.1 to that of adult vessels. Since the direction of flow in bronchopulmonary arterial anastomoses will depend upon the pressure relationship in the pulmonary and bronchial arteries, pulmonary capillary blood may enter the systemic circulation via bronchial arteries as well as bronchial veins. is for clinkal
and laboratory
features
of
ardiorespiratory function is severely altered immediately after birth in infants with CPVA, and causes their early death. Thus it is urgent to establish the diagnosis quickly. Clinical and laboratory findings are summarized in Table II. Obstructed pulmonary venous drainage may be suspected in infants who do not require resuscitation at birth but who quickly develop cyanosis and severe respiratory distress. They have e1ectrocardiographj.c evidence of right ventricular hypertrophy. The roentgenographic appearance of severe pulmonary congestion is similar in CPVA, TACPV with obstruction, and idiopathic pulmonary lymphangiectasis. The heart size is normal radiographically but the borders may be obscured. Dilated pulmonary lymphatic5 have been demonstrated in all previous casesof CPVA. They are more abundant in the connective tissue containing perilo!>ular tissues than in the lobules.” The elevated pulmonary venous pressure causes this pulmonary lymphangiectasis, and much edema fluid is conveyed by these channels into the systemic circulation. Rywlin and Fojaco’ postulated that the lymphangiectasis is a retained lymphatic pattern of the fetal lung. This massive dilation of pulmonary lymphatic
vesselswas appreciated histo~ogica!:y X&Y !n WI Case 2, the ir,fank with severely elevated venous pressure. ulmonary artery pressure has 5een elevated to auprasystemic levels in all patients with CPVA upon whom cardiac catheterization was performed. However, in our case three systolic pressures in the right ventricle and aorta -were equal. The oxygen saturation is severely depressed and usually is similar in all heart chambers. Tbe fetal pattern of blood flow persists with right-to-left shunting through the foramen ot?ale and the ductus arteriosus. A~~oca~di~gr~~by reveals persistent filling of pulmonary veins after the puimonary artery injection; but the left atrium, and any other cardiac chamber or veins do not opacifY* The anomalies of pulmonary artery atresia and TACPV occur commonly in tbe c~~~~~~i~alasplenia syndrome as described by uttenberg and colleagues.‘” Our Case 3 bad both ~~~rno~ar~ artery and pulmonary vein atresia: so that blood flowed to and from the lungs vrla the ductus arteriosus and intrapulmonary co&t essels. She could not have benefited from l&3& shunt. Most reported casesof GPVA have not bad other anomalies: and the gestational age has been 40 or more weeks existence of infants indicates that surgical anastomosis of the verticle pulmonary vein to the left atrium should be performed immediately after dia~~~st~c studies have been completed. A surgical procedure utilizing extracorporeal circulation may allow some correction of tbe severe acidosis and hypoxemia.‘” Deep bypoth~rmia and ci~c~~ato~y arrest may be necessary for the surgery to be accomplished. Despite postmortem evidence or” an adequate anast.omosisfor pulmonary venous flow into the left atrium, no in is problem f&XiQSCS ’ or when it was left patent7 Factors compromising pulmonary ve~~ila~~o~ and perfusion would be expected to persist following surgery. Wypoperfusion of the lungs and sev-ere acidosis will have suppressed ~~r~~~ti~~ of surfactant.17, I8 Deficiency of this antiatelectatic factor, in addition to residual pulmonary congestion and lymphangiectasis, will limit venti4ation1” Hypoxemia and acidosis are stimuli for persistent
Ledbetter,
Wells,
and
Connors
constriction of small pulmonary arteries.20 Physiologic involution of the muscle coat surrounding these vessels, as in those of normal infants, can occur only gradually after hypoxemia has been alleviated. Despite these remarks of pessimism, early recognition of CPVA followed by aggressive medical and surgical treatment may result in a successful outcome. Presumably the pathophysiologic changes occur only postnatally.
8.
9.
10.
Il. 12. 13.
REFERENCES 1.
2.
3.
4.
5.
6.
7.
586
Lucas, R. V., Jr., Woolfrey, B. F., Anderson, R. C., Lester, R. G., and Edwards, J. E.: Atresia of the common pulmonary vein, Pediatrics 29:729, 1962. Nakib, A., Moller, J. H., Kanjuh, V. I., Edwards, J. E.: Anomalies of the pulmonary veins, Am. J. Cardiol. 20:77, 1967. Levine, M. A., Moller, J. H., Amplatz, K., and Edwards, J. E.: Atresia of the common pulmonary vein; Case report and differential diagnosis, Am. J. Roentgenol. 100:322, 1967. Rywlin, A. M., and Fojaco, R. M.: Congenital pulmonary lymphangiectasis associated with a blind cbmmon pulmonary vein, Pediatrics 41:931, 1968. Hawker, R. E., Celefrmajer, Gengos, D. C., Cartmill, T. B., and Bowdler, M. B.: Common pulmonary vein atresia. Premortem diagnosis in two infants, Circulation 46:368, 1972. Delisle, G., Ando, M., Calder, A. L., Zuberbuhler, J. R., Rochenmacher, S., Alday, L. E., Mangini, O., Van Praagh, S., and Van Praagh, R.: Total anomalous pulmonary venous connection: Report of 93 autopsied cases with emphasis on diagnostic and surgical considerations, AM. HEART J. 91:99, 1976. Mody, G. T., and Folger, G. M., Jr.: Atresia of the common pulmonary vein: Report of one case, Pediatrics 54:62, 1974.
14.
15.
16.
17.
18.
19.
20.
Hastreiter, A. R., Paul, M. H., Molthan, M. E., and Miller, R. A.: Total anomalous pulmonary venous connection with severe pulmonary venous obstruction, Circulation 25:916, 1962. Shaner, R. F.: The development of the bronchial veins, with special reference to anomalies of the pulmonary veins, Anatomical Record 140:159, 1961. Marchand, P., Gilbroy, J. C., and Wilson, V. H.: An anatomical study of the bronchial vascular system and its variations in disease, Thorax 5:207, 1950. Harris, P., and Heath, D.: Human pulmonary circulation, Baltimore, 1962, The Williams & Wilkins Co. Von Hayek, H.: The human lung, N. Y., 1960, Hafner Publishing Co. Rudolph, A.: The changes in the circulation after birth; their importance in congenital heart disease, Circulation 41:343, 1970. Wagenvoort, C. A., Wagenvoort, N., and Becker, E. A.: The effect of obstructed pulmonary venous blood flow on the development of alternative pathways in the lung, J. Pathol. 107:21, 1971. Ruttenberg, H. D., Neufeld, H. N., Cucus, R. V., Jr., Carey, L. S., Adams, P., Jr., Anderson, R. C., and Edwards, J. E.: Syndrome of congenital cardiac disease with asplenia, Am. J. Cardiol. 13:387, 1964. Boncheck, L. II, Anderson, R. P., Wood, J. A., Chapman, R. D., and Starr, A.: Intracardiac surgery with extracorporeal circulation in infants, Ann. Thorac. Surg. 17:280, 1974. Chu, J., Clements, J. A., Cotton, E. K., Klaus, M. H., Sweet, A. Y., and Tooley, W. H.: Neonatal pulmonary ischemia 1. Clinical and physiological studies, Pediatrics 40:709, 1967. Merritt, T. A., and Farrell, P. M.: Diminished pulmonary lecethin synthesis in acidosis: Experimental findings as related to the respiratory distress syndrome, Pediatrics 67:32, 1976. France, N. E., and Brown, R. J. D.: Congenital pulmonary lymphangiectasis. Report of 11 examples with special reference to cardiovascular findings, Arch. Dis. Child. 46:528, 1971. Naeye, R. L.: Arterial changes during the perinatal period, Arch. Pathol. 71:121, 1961.
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1978, Vol. 96, No. 5
