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Abnormal pulmonary vasoconstriction in the newborn


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failure with bidirectional shunting at the foramen ovale and ductal level together with pulmonary hypertension.6 7 Strangely, the initial observations on these complications were not to be expanded for many years and attention instead became directed towards the hemodynamic changes of the respiratory distress of the premature infant.@ More recently, the upgrading of neonatal care has resulted in fresh interest in the cardiovascular changes in the premature infant of low birth weight and has brought better understanding of the contribution to morbidity in these babies by a large left-to-right shunt through the ductus arteriosus.9 “¿

A parallel resurgence of interest has occurred for the term infant with cardiorespiratory distress. The group which first came under detailed scm tiny was that of term infants with marked cyanosis mimicking congenital heart disease. Some of these patients had polycythemia,12 and some had primary or secondary pulmonary paren chymal disorders which resulted in hypoxic pulmonary vasoconstriction, but in some theme was no obvious cause for what was termed “¿persistentfetal circulation.― “¿The characteristic feature of the latter type of disorder has been the presence of a low Pao2 value, generally with slightly higher values in arm or temporal artery samples than in those from the abdominal aorta and with variable change from increasing ambient oxygen concentrations. Hemodynamic data indicate the presence of a high pulmonary vascular resistance with right-to-left intracardiac shunting at both atrial and ductal levels but mainly at the latter site.

Another group of term infants with respiratory distress, where cyanosis was less conspicuous, emerged in the literature of the late 1960's and was variously described as type II respiratory distress syndrome, ‘¿4.


@ transient tachypnea of the

newborn,@6 and severe respiratory distress.'@ The characteristic feature of this group of patients was pulmonary hypertension or variable right-to-left or left-to-right shunting at atrial or ductal levels but without evidence of frank heart failure.

The heart size in both these groups was normal or only slightly enlarged on X-ray films and the lung vascular markings were either normal or slightly increased.'@ Attention paid to details in the electrocardiogram was limited in both types of presentation.

An added dimension has been given to the reports of cardiopulmonary distress in term infants since 1970 by the description of cases culminating in congestive heart failure.1926 In addition to respiratory distress, a large liver,

with selected comprehensive services. Pediatrics 55:176, 1975.

18. Roghmann KJ, Haggert@ RJ, Lorenz R: Anticipated and actual effects of Medicaid on the medical care

pattern of children. N EngI J Med 285:1053,


19. Schonfeld HK, Heston JF, Falk IS: Numbers of physi cians required for primary care. N EngI J Med 286:571,1972.

20. The Supply of Health Manpower. DHEW Publication No. (HRA) 75-38, 1974.

21. Swisher S: Oral communication, June 1 1, 1976.



the newborn

Since the classic perinatal lamb experiments of Dawes and associates' led to the description of a transitional circulation of the newborn, pediatri cians have responded by an increasing apprecia tion of this concept. Independent studies indicat ing both indirectly and directly the existence of this normal intermediate circulatory pattern for the human were reported shortly thereafter.24 These investigations were later supplemented by elegant studies@so that a very clear understanding of the usual and normal time sequence of the change over from fetal to adult circulatory path ways in the healthy term infant has been with us for over a decade. The essential part of this change is one of a reduction in tone of the pulmonary vascular bed during the first six hours after birth followed by an increase in tone of the ductus arteriosus. Within 24 hours of delivery the healthy term infant has a functionally closed ductus arteriosus and a mean pulmonary arterial pressure substantially below systemic arterial


It was early appreciated that term infants could deviate from this normal change-over through such apparently innocuous events as whether the cord was clamped early or late. More importantly it was recognized that hypoxia could create intense cyanosis due to a return to fetal character istics of the pulmonary vascular bed and the ductus arteriosus or produce congestive heart

318 PEDIATRICSVol. 59 No. 3 March 1977

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gallop rhythm, and frequently blowing murmurs of atrioventricular valve regurgitation localized to the lower left sternal border were noted. Sometimes the clinical picture is even more serious. Infants may appear in grave heart failure with hypotension and poor arterial pulse ampli tude and so simulate the late presentation of .patients with the hypoplastic left heart syndrome.

In this variety, echocardiography has proved useful in establishing normal architectural anato my and by indicating poor left ventricular func tion. The heart will usually show enlargement and vascular markings are often increased and show pulmonary venous congestion. At cardiac cathe terization pulmonary hypertension is usual but the systolic blood pressure varies according to the degree of left ventricular involvement. Shunts are extremely difficult to evaluate but are usually bidirectional at both atrial and ductal levels. Angiocardiography shows poor left ventricular ftinction2o 24 and tricuspid and/or mitral regurgi tation.20,26 It has been suggested that the cause of the heart failure in these patients is subendocar dial ischemia. @°

An earlier indication from the same unit that the systolic murmurs were likely due to tricuspid regurgitation has been confirmed in an important study by Bucciarelli and associates in this issue of


@ Their description and that of others

suggest that disturbed function of the right ventricle is more often the cause of the heart failure. A great majority of patients will show changes in the electrocardiogram, in the S-T and T segments for example, which strongly suggest an ischemic basis for this development.

The exact incidence of severe forms of cardio respiratory distress in term infants is not yet clear. It is quite uncertain, in view of the overall improvements in obstetrical and newborn care, why we now seem to find this disorder in its various forms more frequently. There has been obvious merit to descriptive papers for they represent developmental steps in the documenta tion of a full clinical profile. Knowledge of the full spectrum of the disorder may still be incomplete, but it is probably reasonable at this stage to speculate on pathogenesis and etiologic factors for the condition.

The influence of polycythemia, hypoglycemia, and hypocalcemia is uncertain because these factors have not been constantly observed in all descriptions.

@ The background of fetal distress,

maternal diabetes, the presence of hyaline membranes, and abnormal degrees of musculari zation of the small pulmonary vascular bed27 have not yet been placed into a consistent pattern

within such patients. Most observers could probably agree that hypoxia is the primary stim ulus for the development of pulmonary vasocon striction and severe pulmonary hypertension, though the presentation of the disorder will be greatly influenced by other variables. The dura tion and intensity of the hypoxic stimulus, the tone of the pulmonary vascular bed and the duct, the state of myocardial integrity, and the extent of the collateral coronary circulation could contrib ute to the final clinical picture. Using such considerations a working classification of these disorders could best relate to pulmonary vasocon striction in the newborn infant.

The commonest type would be acute. In the

simple form there would be vasoconstriction with

normal myocardial function. The background of this variety would be the idiopathic form (pos sibly an overreaction of the lung vascular bed to hypoxia), or a form secondary to birth asphyxia, pneumothorax, aspiration, polycythemia, dia phragmatic hernia,29 or pulmonary infection. The other acute form would be complex, i.e., pulmo nary vasoconstriction with myocardial dysfunc tion. Disadvantageous supply-to-demand ratios for myocardial flow or energy substrate could result in subendocardial ischemia.20 Finally, a chronic form of the disorder could be identified. This is usually of the simple variety with normal myocardial function. It is characterized by per sistent severe hypoxia secondary to chronic pulmonary vasoconstriction. Examples persisting beyond the first month of life have now been described in several papers. The explanation of most is unknown and only rarely is the picture secondary to disorders of the pulmonary paren chyma such as the Hamman-Rich syndrome, cystic fibrosis, or bronchopulmonary dysplasia.

Additionally, mild posterior papillary muscle dysfunction of the left ventricle has been ob served transiently at this age in term infants. When these facts are examined with the observa tions on tricuspid valve dysfunction cited by Buc ciarelli and colleagues,2― an interesting possibility arises—that the transient valve dysfunction of term infants may conceivably be the origin of some mitral and tricuspid valve prolapse or arrhythmias in older subjects.

The management of most affected babies is relatively straightforward. For those with the simple form of the disorder increasing ambient oxygen and the use of buffers, glucose, or calcium where appropriate usually improves the patient. When there is more intense cyanosis which fails to respond to increasing concentrations of oxygen, management becomes more complicated. In this


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type of patient the use of vasodilators such as tolazoline or curare under the precautions suggested recentIy@ becomes important. Nonspe cific influences on the puliiionarv vascular bed such as those which follow angiocardiographv and the effect of vasodilators on the systemic circuit niake it difficult to evaluate such therapy, but for the nioiiient in the resistant cases this is the only approach available. Whether exception all@ severe cases warrant the use of temporary whole-body oxygenation deserves further exam i nation. ‘¿For those babies with the con@plex

disturbance and congestive heart failure, addi

tional anticongestive nieasures are indicated. \Vhile noninvasive techniques can be helpful in diagnosis, there are many situations in both forn@s of the disorder where frank congenital heart malformation cannot be excluded without cardiac catheterization and angiocardiographv. An added advantage in these patients is that systemic effects of infused vasodilator drugs can be assessed while both pulmonary and systemic pressures are being monitored. How necessary it is to do this for the simple type of disorder is being debated.

Though there have been varying reports on the iirnrtality rate in these disorders, most patients survive. Even those with the very severe form of complex disturbance and gross left heart failure can i)e brought through by adequate supportive therapy to a situation of apparently complete cure. Among those with a bad outlook are infants

@vith either a late or chronic simple form of the

disorder who appear unresponsive to most measures, though there have been some spectac ular survivors even in this group.

Obviously, the search for an effective pulmo iiar@' vasodilator has pressing inlportance. More

research into the contribution of the several

variables to the picture is crucial if we are to rise al)ove an enipirical nianagenient program for these patients. An increasing emphasis on deter

minants of mvocardial function in this age group

can be expected to lead to a clearer understand ing of the spectrum of the disease as well as to aid

Ill its treatment. The more iniportant goal

oI)viously lies in a search for prenatal influences

@vhich might eventually lead to intervention therapy oi at the very least to anticipation and earI@' postnatal treatment.

RICHARD D. ROWE, M.D., F.R.C.P.(C) The Hospital for Sick Children

Toivn to, On t(lriO, Ga iiada


1. Born GVR, Dawes GS, Mott JC, \Viddiconibe JG: Changes in the heart and lungs at birth. Cold Spring

Harbor Svmp Qtiant Biol 19: 102, 1954.

2@ Prec KJ. Cassels DE: Dye dilution curves and cardiac output in newborn infants. Circulation 9:789, 1955.

:3. Rowe RD, James LS: The Iu)rlnal ptilinoiiarv arterial pressure during the first @earof life. J Pediatr 51:1, 1957.

4. Adams FH, Lind J: Physiologic studies on the cardiovas cular status of nori@@alnewborn infants (with special reference to the ductus arteriosus). Pediatrics 19:431, 1957.

5. @%IossAJ. Emiiianouilides C, Diiffie ER Jr: Closure of the ductus arteriosus in the neWl)Orn infant .

32:25, 1963.

6. Ro@veRD: Clinical observations of transitional circula tion. In, Oliver TK ed): .\claI)tatioll to Extrauterine Life: Report of the :31st Ross Conference on Pedi atric Research . Colitinbus. Ohio. Ross Laboratories. 1959. p :36.

7. James LS. Rowe RD: The pattern of response of

pulmonary and svstei@iic arterial pressures in

ne\Vl)orn and older infants to short periods of hypoxia. I Pediatr 51:5. 1957.

8. Rudolph .-@M,Drorbaugh JE. .-@tildP.-@N1.(‘ta!: Studies on the circulation in the neonatal I)eriod: The circulation ii@ the respirator@ distress svndrouie.

Pediatrics 27:551, 1961.

9. Stahlman NI, Blankenship \VJ. Shepard FM, (‘ta!: Circulator@ studies in clinical hyaline ii@e@nbrane disease. Biol Neonate 20:3(X), 1972.

10. Moss AJ, Enimanouilides CC. Rettori 0. (‘ta!: Postnatal circulator@ and nletal)olic adjustments in normal and distressed pre1@@att1re infants. Biol Neonate 8:177, 1965.

11. Nadas AS: Patent ductus revisited. N Engl J Med

295:563, 1976.

12. Gatti RA, Muster AJ. Cole RB. Paul MH: Neonatal polvcvthemia with transient cyanosis and cardiores piratorv abnormalities. J Pediatr 69: 1063. 1966. 1:3. Cersoiiv \VM, Due CV, Sinclair jC: “¿PFC―svndro,,@e

(Persistet@ce of fetal circulation), al)stracted. Circi,— lation 39(suppl :3)87, 1969.

14. Prod'hom LS. Levison H, Cherry RB, Smith C.@: Adjust

inent of ventilation, intrapuliiionarv gas exchange

and acid balance during the first day of life.

Pediatrics :35:662. 1965.

15. Sundell H, Garrott J, Blankensliip \VJ, et a!: Studies on infants with tV))e II respirator@ distress syndrome.

I Pediatr 78:754. 1971.

16. Avers ME, Gatewood 0G. Brui@@lev C: Transient tachvpnea of the newborn. .@ni J Dis Child :3:380, 1966.

17. Roberton NRC, Hallidie-Smith K.@, Davis JA: Severe respirator\ distress syndrome mimicking cyanotic heart disease in term babies. Lancet 2: 1 108, 1967. 18 Baiter CR, Tsipuras D, Fletcher BD: Syndrome of

I)ersistent pulmonary vascular obstruction of the newborn: Roentgen findings. .\m J Roentgenol Radium Ther NucI Med 120:285, 1974.

19. Amatavakul 0. Cumming CR. Ilaworth JC: .\ssociation of h@poglvcaeniia with cardiac enlargement and heart failure in newborn infants. Arch Dis Child 45:717, 1970.

20. Rowe RD, lloffnian T: Transient irtyocardial ischeinia of the fleWl)Orn infant: A form of severe cardiorespira tor@ distress in full-term infants. J Pediatr 81:243, 1972.


and delivery. They were breast-fed and appeared normal until 6 and 1 1 weeks, respectively, when, over a period of one to two days, each became unable to suck and swallow and was generally weak. When referred to the University of Califor nia, San Francisco, for evaluation, one to two weeks after the onset of symptoms, they were profoundly weak, without head control, and had a feeble cry. Each infant had ptosis, pupils that reacted sluggishly to light, reduced facial move ment, and a depressed gag reflex. Muscle tone was

severely decreased and stretch reflexes were


In the first patient, small, short motor unit potentials were found, suggesting an abnormality in the distal motor-axon branches, neuromuscular junctions, or niuscle fibers. These findings have been reported in botulism and other conditions. In the second case, small CMAP amplitudes and a two-fold increase in CMAP amplitude after 50 Hz stimulation were found. These findings suggested a defect in acetylcholine release at the neuromus cular junction, as has been reported in botulism, Lambert-Eaton syndrome, antibiotic toxicity, excess magnesium or manganese levels, decreased calcium level, or snakebite.' The blood levels of calciuni, magnesium, and manganese were all normal and there was no history of significant drug exposure or snakebite. Blood and fecal specimens were obtained in a search for botulinal toxin.

Although no botulinal toxin was identified in the serum of the two patients, botulinal toxin type A was identified in fecal specimens of the first patient and botulinal toxin type B was found in fecal specimens of the second. Clostridium botti lin,,m organisms were recovered froni the stools of both patients. The two infants were given supportive care, and because the clinical course in each case was at a plateau, it was elected not to give antitoxin. Each recovered completely over a period of weeks. The botulinal toxin was recov ered from fecal specimens of the first patient until eight weeks following the onset of symptoms, although the patient was clinically normal at the


Two separate reports of infants diagnosed as having acute infantile polyneuropathy were reviewed.2 The findings noted were so similar to those of the infants with botulism that we suggested to the California State Department of Health that they investigate the four infants in

southern California who had been recently

reported. At that time, two additional infants with similar clinical findings were in hospitals in southern California; botulinal toxin and C boti,

21. Brown B, Pickering D: Persistent transitional circula tioii. Arch Dis Child 49:88.3, 1974.

22. Ei,@manouilides CC, Siassi B: Neonatal cardiopulmonary distress without congenital heart disease. Paediatri cian 4:270, 1975.

2:3. Riemenschneider TA, Nielsen HG, Ruttenberg HD, Jaffe RD: Disturbances of the transitional circula tion: Spectrum of ptilnionarv h@pertension and mvocardial dysfunction. J Pediatr 89:622, 1976. 24. Nielson hG, Rienieusclmeider TA, Jaffe RB: Persistent

transitional circulation. Roentgenographic findings in thirteen infants. Radiolog@' 120:649, 1976. 25 Levin l)L, llevmann M.@, Ketterman JA, et a!: Persis

tent pulmonary hypertension of the newt)orn infant. J Pediatr 89:626, 1976.

26. Bucciarelli RL, Nelson RM, Egan EA, et a!: Transient tricuspid insufficiency of the newborn: A form of iiivocardial d@sfunction in stressed newborns. Pedi atri(.s 59:330. 1977.

27. Goldberg SJ, Levy RA, Sias.siB, Betten J: The effects of maternal hypoxia and lwperoxia upon the neonatal pulmonary vasculature. Pediatrics 48:528, 1971. 28. Haworth SC, Reid L: Persistent fetal circulation: Newly

recognized structural features. J Pediatr 88:614, 1976.

29. Dibbins A\V: Neonatal diaphragmatic hernia: A ph@si ologic challenge. Am J Surg 131:408, 1976.

30. Korones SB, Eyal FG: Successful treatment of @‘¿persist ent fetal circulationS' with tolazoline. Pediatr Res 9:367, 1975.

:31. \Vhite JJ. .-@ndrews HG, Risemberg H, et al: Prolonged respirator\ support in newborn infants with a Ineml)ranoils oxygenator. Surgery 70:288, 1971. :32. Levin DL, Gates L, Newfeld EA, et a!: Persistence of

fetal cardiopulmonary circulation pathway: Surviv al of an infant after a prolonged course. Pediatrics 56:58,1975.

:3:3. Cersony \\TM. Morishinia HO, Daniel SS, et a!: The hemodvnamic effects of intrauterine hypoxia: An experiniental model in newborn lambs. J Pediatr 89:631,1976.

Syndromeof infantbotulism

Since the initial recognition of infant botulism,'

seven additional patients have been identified in

California and there are documented reports from other regions of the United States. The syndrome of infant botulisn@ appears to be more common than is recognized, and the attention of physicians who attend patients should be directed to this syndrome of acute weakness.

Each of the first two cases reported was a product of a normal, full-term gestation, labor,

PEDIATRICS Vol. 59 No. 3 March 1977 321

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Richard D. Rowe

Abnormal pulmonary vasoconstriction in the newborn


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Richard D. Rowe

Abnormal pulmonary vasoconstriction in the newborn


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