Several physiological fields are a matter of daily importance in our clinical management of the perinate -- energy metabolism, renal function, nutrition and cardiopulmonary function. Each of these has had an extremely rich history of development within, first, basic physiology and, later, clinical medicine. Each has developed under the initial driving influence of brilliantly inquiring minds in physiology and the subsequent stimulation of aware clinicians astute enough to see the applications of the theory thus developed to the evaluation and management of many of their most difficult patients. Each topic alone could fill a chapter but I shall confine myself to an overview of three of them, before focusing, finally, on one. In each case it is possible to link the development of principles and practice with a number of well-known investigators who have, over the years, represented a most productive mixture of bedside and bench physiologists.
The need for more basic knowledge in the field of clinical energy metabolism was, perhaps, first recognized among premature infants by Budin around the turn of the century. He recognized, but could not well measure, the degree to which the premature infant was subjected to thermal stress, to his peril. The technology of the day available for examination of clinical energy metabolism in that era of Howland, Benedict and Talbot, was the accurate but extremely cumbersome direct calorimeter. The later development of indirect calorimetry by Lusk and DuBois put simpler, yet accurate, measurements in the hands of clinicians. By 1920 Wilson, Blackfan and Hess were laying the groundwork for the classic and definitive studies of (well) premature infants conducted just prior to World War II by Levine, Gordon and Day (at Cornell) who also recognized and began to measure the role of insensible water loss in overall energy balance. Following the war, Karlberg, Cross and Bruck began to delineate the concept of "neutral temperature," while subsequently, Oliver, Silverman, Sinclair, Scopes and Stern documented in human infants the biochemically fueled "non-shivering thermogenesis" previously identified among newborn animals. These investigators and others, including Hey and Hull, were able to find physiologic evidence for the existence and use of "brown fat" in the generation of chemical heat by infants subjected to the thermal stress of ambient temperatures less than "neutral." All of these fundamental developments are now a matter of daily clinical encounter in our nurseries in the form of double-walled incubators, servo-controlled radiant heaters-and even that most recent of thermal innovations, the rediscovery of the usefulness of clothing as insulation against heat loss among premature infants.
Much the same sort of developmental history can be traced in renal physiology from the laboratories of Van Slyke, Smith (Homer) and Pitts of 40 years ago, where the basic concepts of renal clearance, glomerular filtration rate, renal plasma flow and tubular maxima were developed, to the nurseries of Henry Barnett and others (again at Cornell), where the limited urinary concentrating ability of the newborn infant was first documented. This work proceeded through the 50's and 60's under the hands of McCance and Widdowson in England, along with McCrory, Rubin and Calcagno in this country. By the 1960's, Edelman, Kildeberg, Oh, Lind and Winters were demonstrating that the newborn's kidney is a medullary organ regarding its degree of enzyme maturation, that the infant possesses a low renal threshold for bicarbonate ion and that, initially, the rate of renal perfusion in the developing animal (and, presumably in the developing human) is diminished for the very good reason that renal vascular resistance, like pulmonary vascular resistance, is higher in the newborn period than it subsequently will be. We daily experience the fruits of these labors in the formulation of sensible homeostatic limits for parenteral fluid therapy and are still, apparently, in the process of learning that exceeding these limits may lead to the development or exacerbation of patent ductus arteriosus and bronchopulmonary dysplasia, as well as outright hemodilution.
Time and my own ignorance will prevent adequate treatment of the topic of nutrition. Moreover, I am personally unable to identify the physiological engines of change, equivalent to a Homer Smith or Eugene DuBois, who may have driven this field. In any case, even we, the uninitiated, can trace in clinical terms the trail that Drs. Gordon, Levine, Holt, Snyderman and Kretchmer left through the 1940's in elucidating for us the role of low protein milk in infant feeding, the mutually supportive roles of tyrosine and vitamin C, the usefulness (and possible advisability) of vegetable, as opposed to animal, fats in infant formulae and, finally, the nutritional requirements among human infants for the several essential amino acids. It is particularly notable, in contrast to the topics previously touched upon, that this work was conducted nearly exclusively among human rather than animal newborns. These nutritional banners were carried into the 1950's by Drs. Barness and Winters and brought to the point of major practical clinical advance by the surgeon Dudrick. Subsequent important refinements have been contributed by, among others, Drs. Heird and Gaull, and, as a result, reasonably safe and very effective total parenteral nutrition is now a daily and often lifesaving clinical occurrence among patients of all ages.
I would, at this point, like to develop the story of the investigation of the fetal and neonatal cardiopulmonary systems, for I believe this to be the interface that has historically been the most conducive to multidisciplinary involvement of physiologists and physiologically-oriented clinicians, this time involving pediatricians, obstetricians and internists. In fact, I believe this interface to have been the true basis for the development of modern perinatal medicine.
During the first quarter of the century, the respiratory functions of the blood had been the subject of intense and successful scrutiny by the physiologists Henderson, Krogh, Hasselbalch, Haldane, Bohr and, most significant to our present theme, Sir Joseph Barcroft. Indeed, most of the fundamental aspects had been delineated in several classic monographs before, during and immediately after World War I -- the whole documenting that dull tools, such as those necessary for blood gas analysis in those days, need not impair sharp minds. Thus was documented the sigmoid shape of the O2-dissociation curve and its importance to O2 loading and unloading of hemoglobin.
During this period, Barcroft was interested in the problems of O2 transport posed by residence at high altitude-which may well have formed the basis for the analogy he drew of the fetus and his intervillous oxygen supply as that of "Mt. Everest in utero." In any case, post-World War I, he and his students began to study the distribution of cardiac output to the several organs and, sometime after he assumed the chair at Cambridge in 1925, especially to the uterus. This evidently led to the extension of his interest to the uterine contents, as well. While he had discovered the leftward shift of the fetal O2 -dissociation curve during the mid-1930's, few today may realize that the bulk of his fetal investigations were carried out after his retirement from Cambridge in 1937. Much of this was conducted in collaboration with a young American, Donald Barron, and together they developed many of the early techniques for management of that animal which has contributed so much to perinatal research-the pregnant sheep. [If Dr. McCance's animal diener could once remark that "rats are reagents -- pigs are people," what positively familial warmth must fetal researchers feel towards their ewes!] With relatively crude methods of blood oxygen analysis, they were able to apply the Fick principle for the estimation of placental and uterine blood flow. Together they stimulated Barclay, Franklin and Prichard at the Nuffield Institute in Oxford to apply the newly available technology of cineradiography to the study of the ductus venosus, the ductus arteriosus, the foramen ovale and their mode of closure post parturn. World War II brought these productive associations to a close and, when the lights finally did go on again, the stage was set for the multifocal development of the scientific base for perinatal medicine. The decade after the war saw the death of Barcroft, the publication of his Researches on Prenatal Life and his intellectual torch now being carried by physiologists on both sides of the Atlantic -- Geoffrey Dawes was shortly installed at the Nuffield Institute at Oxford and Donald Barron at Yale.
Of equal and necessary strategic importance for the incredible flowering of perinatal medicine from 1950-1960, however, was the placement of two clinicians -- Clement Smith in pediatrics at the Boston Lying-In and Nicholson Eastman in obstetrics at the Johns Hopkins. They (Smith and Eastman) were both evidently and understandably fascinated with the differences between O2 and CO2 carriage by the blood of mother and fetus, as detailed by Barcroft in sheep. And, as clinicians, they of course recognized that cord blood was one fetal material ethically available for their study. All could document, but none could explain, that the leftward shift of the fetal curve was just as true in humans as in farm animals. Smith and his biochemical colleagues at Harvard were able to dialyze away the difference, but it remained for Rheinhold Benesch at Columbia to show, many years later, that what they had dialyzed away was 2,3-diphosphoglycerate and that the fortunate failure of this compound's interaction with fetal hemoglobin explained the avidity of fetal cells for oxygen at low pressures. Apgar and James at Columbia were also realizing that excess organic acids in cord blood represented the fossil remains of transient intrauterine asphyxia among certain stressed babies who may have recovered normal blood oxygen content by the time of birth.
As Chief of Obstetrics at Hopkins and forceful editor of the Obstetrical and Gynecological Survey, Dr. Eastman was ideally placed to direct young academic obstetrical careers-and so he did, by sending many of them to work with Barron in New Haven: Prystowsky, Meschia, Helleghers, Bruns, Crenshaw, Makowski. They were occasionally joined by some from Boston -- Romney in Obstetrics, but often such interlopers as Huckabee and Metcalfe in Medicine, as well as Benirschke in Pathology and a brash Yale medical student of the early 50's and future pediatrician, Fred Battaglia, now at Colorado. The problem of their immediate focus at the time was the measurement of uterine blood flow by nitrous oxide and the newly available tracer for application in Fick principle studies, 4-aminoantipyrine. They were sometimes in courteous competition with Nicholas Assali, an obstetrician who had recently moved from Cincinnati to Los Angeles and was making equivalent direct measurements of uterine and placental blood flow with newly available electromagnetic flowmeters. During these years and into the early 60's, the Barron group perfected the techniques for chronic fetal vessel cannulation so necessary to the fetal metabolic studies still conducted by Battaglia and Simmons in Denver, as well as many others, including the fetal cardiovascular and pharmacologic investigations of Rudolf, Heymann and others in San Francisco.
In this same period at New Haven, and possibly stimulated by their burgeoning knowledge of the depths of fetal bypoxia (or heights of Everest!) in utero, made possible by polarographic measurements of amniotic fluid, Quilligan and Hon began to develop instrumentation for the measurement of the fetal heart rate, and Caldeyro-Barcia was doing the same in South America. This groundwork has now culminated in oxytocin stress tests and, equally important, this early breaching of the amniotic fetal inner sanctum emotionally prepared us for diagnostic amniocentesis of all kinds.
At Oxford, Dawes was documenting that the apparently hypoxic fetus had in fact, thanks to the fortunate anatomic arrangement of the via(s) dextra and sinistra, excellent oxygenation of those organs most important to him, the heart and brain. He and Strang elucidated the reduction in pulmonary vascular resistance that accompanies the onset of respiration in the newborn and its essential role in the transition of the fetal into an effective neonatal circulation.
In Stockholm, Lind and an impressive array of young North American pediatric associates (Stern, Usher, Oh, Arcilla, Oliver) were eclectically pursuing in human infants the closure of the ductus venosus, the placental transfusion and its consequences, as well as thermal balance in the perinatal period.
Meantime, Dr. Smith's group at the Boston Lying-In took fruitful advantage of their intellectual and geographic proximity to the pulmonary physiology group at the Harvard School of Public Health (principally Jere Mead) as Cook, Karlberg, Cherry, Lucey, Sutherland, Auld and many others made most of the measurements of newborn pulmonary function which still stand today. The reverberations of Avery and Mead's 1959 notation of the missing surfactant in hyaline membrane disease are, of course, still being felt.
With most of the requisite scientific information for rational intervention in the affairs of the ill newborn thus in place as the 1960's began, all that remained was the documentation that such intervention was acceptable, otherwise it could never be fruitful. To be sure, Allen and Diamond were actively curing erythroblastosis fetalis in a Hess bed at the Lying-In, but this was a matter for robust, if somewhat edematous, babies at term or nearly so. The fragile premature was mostly left to gasp oxygen on his own under the hopeful gaze oŁ his concerned but inactive attendants.
The fluid and electrolyte supports introduced by Usher and the respiratory supports introduced by Stahlman, Sawyer, Tooley, James and others, not to mention the freer use of diagnostic catheters by cardiologists, all brought the sick premature newborn infant to his present status of respectability as a patient to be cared for, rather than an object to be pitied.
These successes in improving the status of the newborn ex utero by pediatricians, added to the preceding scientific communication among pediatricians and obstetricians, fostered by such physiologists as Barcroft, Barron, Dawes and Mead, virtually dictated the eventual daily clinical collaboration that is modern perinatal medicine.
Since, apart from the resistant mysteries of the origins of labor and the genetic dictates of imperfect development, most of the requisite scientific information is now in place for the consistent conduct of a healthy gestational period for all women and their infants, we may now need to enlist economists, priests and politicians into an enlarged collaboration for a more perfect distribution of these benefits.
1. Barness L. A., Connely D. A., Valyasevi A. et al.: Comparisons of prematures fed high and low protein diets. Am. J. Dis. Child. 94:480, 1957.
2. Dudrick S. J., Wilmore D. W., Vars H. M., et al.: Long-term total parenteral nutrition with growth, development, and positive nitrogen balance. Surgery 64:134-142, 1968.
3. Strang L. B.: Uptake of liquid from the lungs at the start of breathing. In de Reuck A. V. S. and Porter R. (eds.): Development of the Lung. London: J & A Churchill Ltd., p. 348, 1967.
4. Lind, J., Wegelius C.: Human fetal circulation: Changes in the cardiovascular system at birth and disturbances in the postnatal closure of the foramen ovale and ductus arteriosus. In Cold Spring Harbor Symposia on Quantitative Biology, Vol. XIX, p. 109, New York, 1954.
5. Avery M. E., Mead J.: Surface properties in relation to atelectasis and hyaline membrane disease. Am. J. Dis. Child. 97:517, 1959.