Abraham Morris Rudolph: An Appreciation

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HISTORY

Abraham Morris Rudolph: An Appreciation

Julien I. E. Hoffman, MD

ABSTRACT. Dr Abraham Rudolph is one of the most

distinguished pediatric cardiologists in the world. He entered pediatric cardiology (almost by accident) when the subject was still in its infancy and was present at— and indeed contributed to—most of its advances. He is best known for his studies on the pathophysiology of congenital heart diseases and for imaginative studies of fetal cardiovascular development and the transition to postnatal life.Pediatrics2002;110:622– 626; pathophysiol-ogy of congenital heart disease, fetal circulation, neonatal circulation, patent ductus arteriosus, radioactive micro-sphere method.

I

n October 2001, Dr Abraham M. Rudolph

re-ceived the Founders Award of the Cardiology section of the American Academy of Pediatrics. The presenter of the award remarked that Dr Ru-dolph was responsible for much of what we know about congenital heart diseases. That is certainly true, but it occurred to me that the younger pedia-tricians might not know exactly what his contribu-tions were and might be interested in learning about his career. As a colleague of Dr Rudolph, who has been my mentor and friend for most of my profes-sional life, I offer this brief discussion of his career.

Abraham Morris Rudolph was born in Johannes-burg, South Africa, in 1924. He entered the medical school at the University of the Witwatersrand in Johannesburg in 1941. During medical school, he won almost all of the prizes that students could be awarded, and he graduated summa cum laude and received his MB, BCh degree in 1946. The South African Medical Council had a regulation that for-bade medical graduates from practicing medicine in or outside a hospital until they were 22 years old, so Dr Rudolph became an instructor in the Department of Anatomy until he was able to start his internship. After the required internships of 6 months of internal medicine and 6 months of surgery, he decided to become a pediatrician, and did the equivalent of his residency training at the Transvaal Memorial Hospi-tal for Children under 2 superb clinical pediatricians, Dr Samuel Javett and Dr Seymour Heymann.

In 1949, Dr Rudolph spent almost a year in the

United Kingdom, and in that time he passed the examinations for Membership of the Royal College of Physicians of London and also the Royal College of Physicians of Edinburgh. The pass rate for first-time takers of these examinations was at that first-time 15%. He also spent 6 weeks with the great Scandina-vian pediatric cardiologist Edgar Mannheimer.

He returned to South Africa, where, in addition to gaining experience in pediatrics, he wrote a thesis on hemophilia to obtain his MD degree. For personal and professional reasons, he then decided to move to the United States, and he wrote to the heads of the Departments of Pediatrics at Yale and Johns Hopkins Medical Schools and at Boston Children’s Hospital to explore the possibility of receiving additional train-ing there. The first 2 institutions had nothtrain-ing to offer him, but Dr Charles Janeway in Boston informed him that he could work either in hematology with Dr Louis K. Diamond or in cardiology with Dr Alex-ander S. Nadas. With Dr Rudolph’s interest in hema-tology, Dr Diamond was well known to him, but he had never heard of Dr Nadas. Unfortunately, neither position carried any salary. A few weeks later, Dr Janeway wrote to let Dr Rudolph know that he would be able to pay him $3000 annually to work in pediatric cardiology, so Dr Rudolph accepted this opportunity, and he and his family moved to Boston in 1951. Seldom has an investment of $3000 paid off so well.

Dr Rudolph soon became head of the cardiac cath-eterization laboratory that, until his arrival, had only had a part-time head, Dr Walter Goodale, an adult cardiologist with an interest in congenital heart dis-ease. He spent some time with the great physiologist Dr Clifford Barger at Harvard Medical School, and their studies of renal function in congestive heart failure resulted in several important publications on fluid retention and congestive heart failure1,2 _{and 1} on chronic catheterization of the renal artery in dogs. Dr Rudolph also set up his own experimental animal laboratory.

In his first few years in Boston, Dr Rudolph par-ticipated in a number of important clinical studies, now classics in the field, involving the use of digitalis in infants and children,3 _{pulmonic stenosis, atrial} septal defect, aortic stenosis, patent ductus arterio-sus, ventricular septal defect,4_complete atrioventric-ular block, tetralogy of Fallot, and transposition of the great arteries.5_{In subsequent years, his interest in} different aspects of congenital heart diseases contin-ued, and he published many articles that have

con-From the Department of Pediatrics (Emeritus) and Cardiovascular Research Institute, University of California, San Francisco, California.

Received for publication Mar 3, 2002; accepted May 8, 2002.

Reprint requests to (J.I.E.H.) Cardiovascular Research Institute, Box 0544, Rm M1331, University of California, 505 Parnassus Ave, San Francisco, CA 94143. E-mail: jhoffman@pedcard.ucsf.edu

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tributed to our modern understanding of these le-sions. Much of his insight into congenital heart disease formed the basis of his unique book Congen-ital Diseases of the Heart: Clinical-Physiologic Consider-ations, first published in 1974 and revised in 2001.6

The techniques of studying conscious animals that he learned from Dr Barger were initially put to use when Dr Rudolph and Dr Milton H. Paul described chronic catheterization of the pulmonary and sys-temic circulations,7_{a technique that avoided the} ex-tensive artifacts inevitable in the study of anesthe-tized animals. At this time, cardiovascular studies of conscious animals were rarely done; the only notable scientists involved in this field were Dr Robert F. Rushmer at the University of Washington in Seattle and Dr Edward Hawthorne at Howard University in Washington, DC.

In the late 1950s, too, Dr Rudolph also began his work on pulmonary hypertension, both in its clinical form in congenital heart disease and in a number of animal studies that examined the effect of a variety of agonists and antagonists on pulmonary vasomo-tion.8,9 _{Later, he made many other contributions in} this area.10 –15

Before effective treatment of congenital heart le-sions, the vast majority of deaths occurred in the first few months after birth. This convinced Dr Rudolph of the need to catheterize infants, and he began to do this in 1956. Dr Rudolph and Dr Glen Cayler de-scribed their techniques that were soon copied by other pediatric cardiologists.16_{Perhaps the only} oth-ers interested in catheterization of small infants at that time were Dr Richard Rowe and Dr Stanley James at Babies and Children’s Hospital, Columbia University, in New York.

Dr Rudolph’s interests also extended to prema-turely born infants, and Dr Rudolph pursued this vigorously. His interest was facilitated by the close

friendship of Dr Alexander Nadas with Dr Clement Smith, the head of the neonatal service at the Boston Lying-In Hospital, just across the road from the Chil-dren’s Hospital. At that time, the mortality rate from respiratory distress syndrome was very high; ade-quate ventilatory support had not yet been devel-oped. Dr Rudolph was the first to perform cardiac catheterization on these tiny infants. I can remember clearly how confused I was when Dr Rudolph told me that premature infants with respiratory distress syndrome and completely opaque lung fields on chest radiograph had large left-to-right shunts through a patent ductus arteriosus.17 _{The belief at} that time was that they would have a high pulmo-nary vascular resistance from hypoxic pulmopulmo-nary vasoconstriction and therefore would not have had significant left-to-right shunts.

In 1961, Dr Rudolph moved to Albert Einstein College of Medicine in New York City, where he continued his clinical and experimental work. Addi-tional studies on pulmonary vascular reactivity were published in this period, and Dr Rudolph’s interest in pulmonary vascular adjustments after birth began. He also published many clinical studies about treat-ment, mechanisms of disease, and diagnostic meth-ods.

In 1964, Dr Michael Heymann joined the pediatric cardiology group, and his interests in fetal and neo-natal problems led him to join Dr Rudolph in study-ing the fetal circulation. It was difficult to study because its many interconnected pathways made it hard to use conventional methods of measuring flow, such as indicator dilution curves or the Fick principle. Furthermore, most studies of the fetal cir-culation relied on exteriorized fetuses that remained attached to the placenta but were in fact deteriorat-ing preparations from the onset. One day, Dr Ru-dolph was sitting in a dentist’s waiting room and reading a magazine. He came across an advertise-ment placed by the 3M Corporation to seek uses for its newly developed radioactive plastic micro-spheres. The company had originally developed these to treat tumors, the idea being to inject the microspheres into the blood supply to the tumor, where they would be trapped and deliver a high radiation dose locally. Unfortunately, many tumors had large arteriovenous shunts that placed the pa-tients at risk of systemic embolism, so clinical appli-cation of the microspheres was abandoned. Dr Ru-dolph realized that these microspheres might be used to measure organ blood flows, and he and Dr Heymann began preliminary experiments to use these microspheres. They offered a great advantage over existing methods of measuring flow. The micro-spheres could be injected into conscious animals af-ter implanting a catheaf-ter into an appropriate blood vessel; they would travel to each organ and each part of each organ in proportion to the blood flow to that organ or organ part, so if one could measure the total cardiac output, then multiplying that output by the proportion of microspheres in an organ would give that organ’s blood flow. Because different radionu-clides could be placed in the microspheres, it was possible to measure several different sets of flows at

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different times in each animal. Initially, cardiac out-put was measured by a separate technique, but sub-sequently Drs Rudolph and Heymann adopted a method introduced by Drs Giovanni Meschia and Frederick Battaglia of drawing a reference sample of blood and measuring the proportion of microspheres in this sample.

In 1966, Dr Rudolph, Dr Heymann, and I, together with some of the fellows, moved to the University of California, San Francisco, where we became mem-bers of the Department of Pediatrics, under the chair-manship of Dr Melvin M. Grumbach, and the Car-diovascular Research Institute, then under the inspired guidance of Dr Julius H. Comroe, Jr. Drs Rudolph and Heymann perfected their microsphere method and made the first studies of cardiac output and organ blood flow in undisturbed, healthy, con-scious fetal lambs.18,19 _{This was one of the major} advances in cardiovascular techniques, and it has remained, with variations, one of the most used methods for measuring total and regional blood flows.

Dr Rudolph and his colleagues exploited the mi-crosphere method in several ways. They used it to study the development of total and regional flows throughout fetal development and, by measuring pressures as well, also assessed the changes in total and regional vascular resistances.20,21 _{They showed,} too, how abnormal the flows measured in anesthe-tized and exteriorized fetal lambs were. In other studies, they examined changes in distribution of blood flow with hemorrhage22 _{and also with} endo-toxin.

Soon after Dr Rudolph moved to San Francisco, there was a major change in the methods of treating respiratory distress syndrome when Drs George Gregory and William Tooley introduced continuous positive airway pressure for ventilating these infants. This was a revolution in treatment that resulted in greatly increased survival of these preterm infants. It also introduced a new epidemic disease, clinically significant patent ductus in preterm infants. I can recall Dr Rudolph’s asking me to see a premature infant, the son of one of our residents, to confirm his diagnosis, but he would not tell me what it was. My findings agreed with his: the child had a typical large patent ductus arteriosus. We persuaded the cardiac surgeon, Dr Henry Edmunds, to ligate the ductus, and the child improved. That was probably one of the first, if not the first, successful ligation of a ductus arteriosus in a premature infant to treat respiratory distress. (In fact, approximately 5 years earlier in Boston, Dr Rudolph had persuaded Dr Robert Gross to ligate the ductus arteriosus in a very sick prema-ture infant, but the infant died after a few days.)

The ductus epidemic led Dr Rudolph to begin a detailed study of ductus physiology and pharmacol-ogy in fetal lambs. In 1972, he published an article with Drs Dorothy McMurphy, Michael Heymann, and the late Kenneth Melmon on the response of the fetal ductus to oxygen and vasoactive substances.23 There followed a series of articles on the regulation of patency of the fetal ductus arteriosus.24 –33_Parallel to these experimental studies was a series of clinical

studies on the diagnosis and treatment of the ductus arteriosus in prematurely born infants,34 –37 _starting with surgery and then progressing to treatment with the prostaglandin synthesis inhibitor indometha-cin.38_{It was natural to follow the successful closure} of the premature ductus with attempts to keep the ductus open in ductus-dependent congenital heart disease by infusing prostaglandin E1.39,40

While these studies were being done, Dr Rudolph continued to pursue his interests in fetal develop-ment and the transition from fetal to early postnatal life. Some of these studies concerned developmental aspects of the autonomic nervous system.41– 46_Other studies dealt with factors that affect congenital heart lesions before and after birth.47–50 _{Still others dealt} with the stresses that might be imposed on normal infants by the birth process and the early postnatal period.48 – 65

His interest in fetal development and response to stress led to collaborations with obstetricians, peri-natologists, and pharmacologists, and jointly they studied the uteroplacental circulation and the re-sponses of the fetus to a variety of stresses.48 – 68 Many of the insights derived from these studies can be applied to the stressed human fetus.

Dr Rudolph is best known for his experimental studies of developmental and postnatal physiology and pathophysiology and his application of the in-sights derived from these studies to the understand-ing and management of clinical disease. He has not, however, ignored pharmacology, as mentioned above, and has also investigated a variety of bio-chemical changes in the fetus and the newborn.69 –73 He has both initiated and collaborated in studies of hormonal development and function.74 –77_Although he has concentrated on the heart and circulatory system, he has also done important experiments on various regional circulations and functions.78 – 85 Even after his official retirement, he continued to do experiments and initiated studies of the effect of cortisol on myocardial development.86,87

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Francisco, and his editorship of the highly successful general pediatric text Rudolph’s Pediatrics as well as the companion Rudolph’s Fundamentals of Pediatrics.

Dr Rudolph’s career has been marked by imagina-tion and creativity and a devoimagina-tion to the care of children with heart disease. He has moved from careful consideration of the pathophysiology of con-genital heart disease to the experimental laboratory, from which he has obtained insights that have al-lowed him to return to the clinical arena with im-provements in clinical care. He has collaborated with investigators in several disciplines and with a large group of superb research fellows who came for train-ing and returned to become leaders in their respec-tive fields and countries. His selection to receive the Founders Award of the American Academy of Pedi-atrics is in recognition of his many invaluable con-tributions to the care of children with heart disease and to the ways in which research can be invoked to help them.

ACKNOWLEDGMENT

This study was supported, in part, by Program Project grant HL25847 from the National Heart, Lung, and Blood Institute and the National Institutes of Health.

REFERENCES

1. Barger AC, Rudolph AM, Yates FE. Observations on the pathogenesis of congestive heart failure.Bull NE Med Center.1954;16:24 –29

2. Barger AC, Yates FE, Rudolph AM. Renal hemodynamics and sodium excretion in dogs with graded valvular damage, and in congestive heart failure.Am J Physiol.1961;200:601– 608

3. Nadas AS, Rudolph AM, Reinhold JDL. The use of digitalis in infants and children.N Engl J Med.1953;248:98 –105

4. Fyler DC, Rudolph AM, Wittenborg MH, Nadas AS. Ventricular septal defect in infants and children.Circulation.1958;18:833– 851

5. Noonan JA, Nadas AS, Rudolph AM, Harris GBC. Transposition of the great arteries.N Engl J Med.1960;263:592–596

6. Rudolph AM.Congenital Diseases of the Heart: Clinical-Physiological Con-siderations.2nd ed. Armonk, NY: Futura Publishing Company, Inc; 2001:808

7. Rudolph AM, Paul MH. Chronic catheterization of pulmonary and systemic circulations: a technic for repeated measurement of cardiac output and pulmonary and systemic pressures in the unanesthetized dog.J Appl Physiol.1957;10:327–328

8. Cutler JG, Nadas AS, Goodale WT, et al. Pulmonary arterial hyperten-sion with markedly increased pulmonary resistance: the pulmonary vascular obstruction syndrome.Am J Med.1954;17:485– 498

9. Rudolph AM, Auld PAM. Physical factors affecting normal and sero-tonin-constricted pulmonary vessels.Am J Physiol.1960;198:864 – 872 10. Rudolph AM, Yuan S. Response of the pulmonary vasculature to

hyp-oxia and H⫹ion concentration changes.J Clin Invest.1966;45:399 – 411 11. Hoffman JI, Rudolph AM. Increasing pulmonary vascular resistance during infancy in association with ventricular septal defect.Pediatrics. 1966;38:220 –230

12. Levin DL, Rudolph AM, Heymann MA, Phibbs RH. Morphological development of the pulmonary vascular bed in fetal lambs.Circulation. 1976;53:144 –151

13. Lewis AB, Heymann MA, Rudolph AM. Gestational changes in pulmo-nary vascular responses in fetal lambs in utero.Circ Res. 1976;39: 536 –541

14. Rudolph AM. High pulmonary vascular resistance after birth: I. Patho-physiologic considerations and etiologic classification. Clin Pediatr (Phila).1980;19:585–590

15. Hoffman JI, Rudolph AM, Heymann MA. Pulmonary vascular disease with congenital heart lesions: pathologic features and causes. Circula-tion.1981;64:873– 877

16. Rudolph AM, Cayler GG. Cardiac catheterization in infants and chil-dren.Pediatr Clin North Am.1958;4:907–943

17. Rudolph AM, Drorbaugh JE, Auld PAM, et al. Studies on the circulation in the neonatal period. The circulation in the respiratory distress syn-drome.Pediatrics.1961;27:551–566

18. Rudolph AM, Heymann MA. The circulation of the fetus in utero. Methods for studying distribution of blood flow, cardiac output and organ blood flow.Circ Res.1967;21:163–184

19. Heymann MA, Payne BD, Hoffman JI, Rudolph AM. Blood flow mea-surements with radionuclide-labeled particles.Prog Cardiovasc Dis. 1977;20:55–79

20. Rudolph AM. The changes in the circulation after birth. Their impor-tance in congenital heart disease.Circulation.1970;41:343–359 21. Rudolph AM, Heymann MA. Circulatory changes during growth in the

fetal lamb.Circ Res.1970;26:289 –299

22. Neutze JM, Wyler F, Rudolph AM. Changes in distribution of cardiac output after hemorrhage in rabbits.Am J Physiol.1968;215:857– 864 23. McMurphy DM, Heymann MA, Rudolph AM, Melmon KL.

Develop-mental changes in constriction of the ductus arteriosus: responses to oxygen and vasoactive agents in the isolated ductus arteriosus of the fetal lamb.Pediatr Res.1972;6:231–238

24. Oberha¨nsli-Weiss I, Heymann MA, Rudolph AM, Melmon KL. The pattern and mechanisms of response to oxygen by the ductus arteriosus and umbilical artery.Pediatr Res.1972;6:693–700

25. Heymann MA, Rudolph AM. Effects of acetylsalicylic acid on the duc-tus arteriosus and circulation in fetal lambs in utero.Circ Res.1976;38: 418 – 422

26. Clyman RI, Heymann MA, Rudolph AM. Ductus arteriosus responses to prostaglandin E1 at high and low oxygen concentrations. Prostaglan-dins.1977;13:219 –223

27. Clyman RI, Wong L, Heymann MA, Rudolph AM. Responsiveness of the lamb ductus arteriosus to prostaglandins and their metabolites. Prostaglandins.1978;15:325–331

28. Clyman RI, Mauray F, Roman C, Rudolph AM. PGE2 is a more potent vasodilator of the lamb ductus arteriosus than is either PGI2 or 6 keto PGF1alpha.Prostaglandins.1978;16:259 –264

29. Clyman RI, Mauray F, Koerper MA, et al. Formation of prostacyclin (PGI2) by the ductus arteriosus of fetal lambs at different stages of gestation.Prostaglandins.1978;16:633– 642

30. Clyman RI, Mauray F, Demers LM, et al. Developmental response to indomethacin: a comparison of isometric tension with PGE2 formation in the lamb ductus arteriosus.Prostaglandins.1979;18:721–730 31. Clyman RI, Mauray F, Rudolph AM, Heymann MA. Age-dependent

sensitivity of the lamb ductus arteriosus to indomethacin and prosta-glandins.J Pediatr.1980;96:94 –98

32. Clyman RI, Mauray F, Demers LM, et al. Does oxygen regulate pros-taglandin-induced relaxation in the lamb ductus arteriosus? Prostaglan-dins.1980;19:489 – 498

33. Clyman RI, Mauray F, Roman C, et al. Circulating prostaglandin E2 concentrations and patent ductus arteriosus in fetal and neonatal lambs. J Pediatr.1980;97:455– 461

34. Kitterman JA, Edmunds LH Jr, Gregory GA, et al. Patent ducts arteri-osus in premature infants. Incidence, relation to pulmonary disease and management.N Engl J Med.1972;287:473– 477

35. Edmunds LH Jr, Gregory GA, Heymann MA, et al. Surgical closure of the ductus arteriosus in premature infants.Circulation.1973;48:856 – 863 36. Silverman NH, Lewis AB, Heymann M, Rudolph AM. Echocardio-graphic assessment of ductus arteriosus shunt in premature infants. Circulation.1974;50:821– 825

37. Rudolph AM, Heymann MA, Fishman Lakier JB. Formalin infiltration of the ductus arteriosus. A method for palliation of infants with selected congenital cardiac lesions.N Engl J Med.1975;292:1263–1268 38. Heymann MA, Rudolph A, Silverman NH. Closure of the ductus

arte-riosus in premature infants by inhibition of prostaglandin synthesis. N Engl J Med.1976;295:530 –533

39. Heymann M, Rudolph AM. Ductus arteriosus dilatation by prostaglan-din E1 in infants with pulmonary atresia.Pediatrics.1977;59:325–329 40. Heymann MA, Berman W Jr, Rudolph AM, Whitman V. Dilatation of

the ductus arteriosus by prostaglandin E1 in aortic arch abnormalities. Circulation.1979;59:169 –173

41. Shinebourne EA, Vapaavuori EK, Williams RL, et al. Development of baroreflex activity in unanesthetized fetal and neonatal lambs.Circ Res. 1972;31:710 –718

42. Barrett CT, Heymann MA, Rudolph AM. Alpha and beta adrenergic receptor activity in fetal sheep.Am J Obstet Gynecol.1972;112:1114 –1121 43. Lebowitz EA, Novick JS, Rudolph AM. Development of myocardial sympathetic innervation in the fetal lamb.Pediatr Res.1972;6:887– 893 44. Lipp JA, Rudolph AM. Sympathetic nerve development in the rat and

guinea-pig heart.Biol Neonate.1972;21:76 – 82

45. Llanos AJ, Green JR, Creasy RK, Rudolph AM. Increased heart rate response to parasympathetic and beta adrenergic blockade in growth-retarded fetal lambs.Am J Obstet Gynecol.1980;136:808 – 813

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circulation in chronically instrumented fetal lambs.Circ Res.1983;52: 589 –596

47. Sidi D, Kuipers JR, Heymann MA, Rudolph AM. Recovery of cardio-vascular function in newborn lambs after thoracotomy.Pediatr Res 1982;16:705–710

48. Sidi D, Kuipers JR, Heymann MA, Rudolph AM. Effects of ambient temperature on oxygen consumption and the circulation in newborn lambs at rest and during hypoxemia.Pediatr Res.1983;17:254 –258 49. Sidi D, Kuipers JR, Teitel D, et al. Developmental changes in

oxygen-ation and circulatory responses to hypoxemia in lambs.Am J Physiol. 1983;245:H674 –H682

50. Rudolph AM. The fetal circulation and its response to stress.J Dev Physiol.1984;6:11–19

51. Rudolph AM, Heymann MA. Cardiac output in the fetal lamb: the effects of spontaneous and induced changes of heart rate on right and left ventricular output.Am J Obstet Gynecol.1976;124:183–192 52. Klopfenstein HS, Rudolph AM. Postnatal changes in the circulation and

responses to volume loading in sheep.Circ Res.1978;42:839 – 845 53. Berman W Jr, Goodlin RC, Heymann MA, Rudolph AM. Effects of

pharmacologic agents on umbilical blood flow in fetal lambs in utero. Biol Neonate.1978;33:225–235

54. Lister G, Walter TK, Versmold HT, et al. Oxygen delivery in lambs: cardiovascular and hematologic development.Am J Physiol.1979;237: H668 –H675

55. Edelstone DI, Rudolph AM, Heymann MA. Effects of hypoxemia and decreasing umbilical flow liver and ductus venosus blood flows in fetal lambs.Am J Physiol.1980;238:H656 –H663

56. Reuss ML, Rudolph AM. Distribution and recirculation of umbilical and systemic venous blood flow in fetal lambs during hypoxia.J Dev Physiol. 1980;2:71– 84

57. Rudolph AM, Itskovitz J, Iwamoto H, et al. Fetal cardiovascular re-sponses to stress.Semin Perinatol.1981;5:109 –121

58. Itskovitz J, Goetzman BW, Rudolph AM. The mechanism of late decel-eration of the heart rate and its relationship to oxygenation in normox-emic and chronically hypoxnormox-emic fetal lambs.Am J Obstet Gynecol.1982; 142:66 –73

59. Itskovitz J, La Gamma EF, Rudolph AM. The effect of reducing umbil-ical blood flow on fetal oxygenation.Am J Obstet Gynecol.1983;145: 813– 818

60. Itskovitz J, La Gamma EF, Rudolph AM. Heart rate and blood pressure responses to umbilical cord compression in fetal lambs with special reference to the mechanism of variable deceleration.Am J Obstet Gy-necol.1983;147:451– 457

61. Itskovitz J, Goetzman BW, Roman C, Rudolph AM. Effects of fetal-maternal exchange transfusion on fetal oxygenation and blood flow distribution.Am J Physiol.1984;247:H655–H660

62. Teitel DF, Sidi D, Chin T, et al. Developmental changes in myocardial contractile reserve in the lamb.Pediatr Res.1985;19:948 –955

63. Teitel D, Sidi D, Bernstein D, et al. Chronic hypoxemia in the newborn lamb: cardiovascular, hematopoietic, and growth adaptations.Pediatr Res.1985;19:1004 –1010

64. Iwamoto HS, Teitel D, Rudolph AM. Effects of birth-related events on blood flow distribution.Pediatr Res.1987;22:634 – 640

65. Teitel DF, Iwamoto HS, Rudolph AM. Changes in the pulmonary cir-culation during birth-related events.Pediatr Res.1990;27:372–378 66. Teitel D, Rudolph AM. Perinatal oxygen delivery and cardiac function.

Adv Pediatr.1985;32:321–347

67. Wang LH, Rudolph AM, Benet LZ. Pharmacokinetic studies of the disposition of acetaminophen in the sheep maternal-placental-fetal unit. J Pharmacol Exp Ther.1986;238:198 –205

68. Wang LH, Rudolph AM, Benet LZ. Distribution and fate of acetamin-ophen conjugates in fetal lambs in utero.J Pharmacol Exp Ther.1985;235: 302–307

69. Wood CE, Rudolph AM. Can maternal stress alter fetal adrenocortico-tropin secretion?Endocrinology.1984;115:298 –301

70. Gleason CA, Rudolph AM. Gluconeogenesis by the fetal sheep liver in vivo.J Dev Physiol.1985;7:185–194

71. Gleason CA, Roman C, Rudolph AM. Hepatic oxygen consumption, lactate uptake, and glucose production in neonatal lambs.Pediatr Res. 1985;19:1235–1239

72. Rudolph CD, Roman C, Rudolph AM. Effect of acute umbilical cord compression on hepatic carbohydrate metabolism in the fetal lamb. Pediatr Res.1989;25:228 –233

73. Townsend SF, Rudolph CD, Wood CE, Rudolph AM. Perinatal onset of hepatic gluconeogenesis in the lamb.J Dev Physiol.1989;12:329 –335 74. Gluckman PD, Mueller PL, Kaplan SL, et al. Hormone ontogeny in the

ovine fetus. I. Circulating growth hormone in mid and late gestation. Endocrinology.1979;104:162–168

75. Drummond WH, Rudolph AM, Keil LC, et al. Arginine vasopressin and prolactin after hemorrhage in the fetal lamb.Am J Physiol.1980;238: E214 –E219

76. Breall JA, Rudolph AM, Heymann MA. Role of thyroid hormone in postnatal circulatory and metabolic adjustments.J Clin Invest.1984;73: 1418 –1424

77. Birk E, Tyndall MR, Erickson LC, et al. Effects of thyroid hormone on myocardial adrenergic beta-receptor responsiveness and function dur-ing late gestation.Pediatr Res.1992;31:468 – 473

78. Goodlin RC, Rudolph AM. Tracheal fluid flow and function in fetuses in utero.Am J Obstet Gynecol.1970;106:597– 606

79. Berman W Jr, Goodlin RC, Heymann MA, Rudolph AM. Measurement of umbilical blood flow in fetal lambs in utero.J Appl Physiol.1975;39: 1056 –1059

80. Edelstone DI, Rudolph AM, Heymann MA. Liver and ductus venosus blood flows in fetal lambs in utero.Circ Res.1978;42:426 – 433 81. Papile LA, Rudolph AM, Heymann MA. Autoregulation of cerebral

blood flow in the preterm fetal lamb.Pediatr Res.1985;19:159 –161 82. Iwamoto HS, Rudolph AM. Metabolic responses of the kidney in fetal

sheep: effect of acute and spontaneous hypoxemia.Am J Physiol.1985; 249:F836 –F841

83. van Bel F, Roman C, Klautz RJ, et al. Relationship between brain blood flow and carotid arterial flow in the sheep fetus.Pediatr Res.1994;35: 329 –333

84. van Bel F, Sola A, Roman C, Rudolph AM. Role of nitric oxide in the regulation of the cerebral circulation in the lamb fetus during normox-emia and hypoxnormox-emia.Biol Neonate.1995;68:200 –210

85. van Bel F, Sola A, Roman C, Rudolph AM. Perinatal regulation of the cerebral circulation: role of nitric oxide and prostaglandins.Pediatr Res. 1997;42:299 –304

86. Rudolph AM, Roman C, Gournay V. Perinatal myocardial DNA and protein changes in the lamb: effect of cortisol in the fetus.Pediatr Res. 1999;46:141–146

87. Rudolph AM. Myocardial growth before and after birth: clinical impli-cations.Acta Paediatr.2000;89:129 –133

HOUSE CALLS REDISCOVERED

“. . . Three former residents worried that the grueling demands of residency training were creating a breed of callous, angry physicians. The three brainstormed for solutions and decided on a month of house calls in the training program to remind residents that their patients are people, not biochemical analyses.”

Epstein RH. House calls: how physicians heal themselves.New York Times. June 4, 2002

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DOI: 10.1542/peds.110.3.622

2002;110;622

Pediatrics

Julien I.E. Hoffman