LX aque ena, ie lead A o a ' i173 Cy owaritad Ay “ry TO FR GO ITT ATE (WOR RST tele 2STLOWI wee EEE Sizth Baxter-Travenol Lecture of the International Anesthesia Research Society VIRGINIA APGAR, M.D., ALP.H. New York, New Yerk* ee THE operating room or intensive care . unit, we tend to take for granted the-de- pendable quality of the fluids we administer io our patients. Jf the label on the bottle reads Baxter-Travenol, we know we have an extra margin of safety. It is a pleasure to thank thern publicly for providing anesthesi- ologists with this peace of mind, a com- modity often in short supply in the operat- ing room. We thank them also for less tan- gible contributions, such as their support of lectureships and symposia. I have been permitted to select a topic only remotely related to anesthesiology, though less so in pediatric surgery, in which the large majority of your patients have birth defects. There is little likelihood that this number of patients will decrease. Rather, it will almost surely increase. In a recent study at Johns Hopkins, the children of parents who themselves were operated on for congenital heart disease have been fol- lowed. Whereas the estimate of this condi- tion in the general population was 0.3 per cent, those children who had one parent. with a history of successful heart surgery in childhood had congenital heart lesions at the rate of 1.8 per cent, a six-fold increase. There was no apparent relationship between the type of heart defect in the parent and in the child. In this particular category of congenital anomalies, the eternal, nagging problem of classification comes up. I personally think that the diagnosis patent ductus arteriosus should always be separated clearly from other cardiac diagnoses. It is not a develop-. mental defect, unless accompanied by an aneurysm of the ductus, but a physiologic defect. Its continued patency is not the re- sult of hereditary factors, nor of environ- mental effects before birth, but, in all prob- ability, of environmental effects after birth. *Vico-President for Medical Affairs, The National Foundation-March of Dimes, New York, New York 10017. Read at the 42nd Congress‘of the International Anesthesia Research Society, March 17-21, Francisco, Califomia, Anesthesia & Analgesia...Current Researches 1268, San 4 . > Vol. 47, No. July-August 1968 326 ANESTHESIA AND ANALGESIA .. « Importance of Pharmacogenetics — Also related more closely to anesthesiology is the specialty’ of pharmacogenetics. Errors in the construction of protein molecules are as much birth defects as cleft lip or palate, which themselves probably occur because of molecular mistakes. After Garrod’s pres- cient work at the turn of the last century, the saga of pseudocholinesterase aberration started pharmacogenetics on its merry way. Understanding of the relationship of barbi- turates to acute porphyria followed shortly thereafter. G-6-PD deficiency was quickly identified as being related to primaquine sensitivity, Intolerance to certain sulfa drugs and fava beans — even to the smoke arising frorn burning bean pods. A delightful essay by Louis Lasagna. “The Diseases Drugs Cause,” in the Summer, 1964, issue of Per- spectives in Biology and Medicine is highly recommended. I think it likely that most drug reactions will be found due to some enzymatic quirk, often heritable in nature. Back in 1960, shortly after I joined the research staff of the National Foundation- March of Dimes, I was coaxed by Dr. Ed- win Gold to write an article, “Congenital Anomalies, 1960.” Its rereading gives ‘me cause for both optimism and pessimism. At that time, the proposed structure of the DNA molecule had been before the public for 6 years, and for 4 years it was known that human cells contained 46 chromosomes, not 48. At scientific meetings, there was hot discussion about the transcription of the hereditary message via RNA to the forma- tion of proteins. Was it a triplet or doublet code? Was it degenerate? Were there non- sense triplets? Was ribosomal RNA specific? These particular..questions have all been answered. a OMe 2 a Wann ort een Pew owner me ty ‘Seema NN RSG AT IEE AE CEP Current Researches . be x Vircinta Apcar, M.D., M.P.H. is the former Chairman of the Department of Anesthesiology, the first Professor of Anesthesiology, and the first woman physician to have been awarded a full professorship at her alma mater, the College of Physicians and Surgeons of Columbia Uni- versity, New York City. Since 1959 she has been Head of the Division of Congenital Malformations of the National | Foundation and was recently appointed Vice-President — for Medical Affairs. The International Anesthesia Re- search Society was honored to have Dr. Apgar accept its invitation to present the Sixth Annual Baxter-Travenol Lecture March 20, 1968, at its 42nd Congress in San Francisco, California. SiN De ERAN ERE OR PERE TE. OE TET RT RS ETS DBRT IC Vou. 47, No. 4, Juty-Aucust, 1968 It is a triplet code; it is degenerate; all amino acids are coded by two or more trip-. lets. There are no nonsense triplets. All 64 possible combinations of the four purine or pyrimidine bases have been assigned to specific amino acids or to “start” or “stop” positions in the reading of the DNA code. Ribosomal RNA is not specific. Even E. coli ribosomes can be made to make hemoglobin if fed the right RNA message. But, as expected, new questions have arisen in geo- metric proportions. Jacob. and Monod gave birth to a theory of genetic control involving regulator genes, repressors and derepressors, operator and structural genes, derived from their work with bacteria. It is a brilliant theory, which has given a great impetus to research in this field. Whether or not it applies to mam- malian cells remains to be proven. White- house recently has divided living organisms into two major divisions, “. . . a chromone- mal kingdom, in which the DNA is not associated with basic protein and no nuclear membrane encloses the DNA (bacteria and blue-green algae),” while all the rest is .a chromosomal kingdom in which the ‘DONA is associated with basic protein and a nuclear membrane encloses the DNP ex- cept during cell division.” There is much discussion about extra-nuclear DNA, found in mitochondria, with a different nucleotide coding than chromosomal DNA. The elusive hereditary particles of Men- del, named ‘‘genes” by Johannsen over 40 years later, have finally been translated into chemical terms. “It is estimated that a gene consists of about 1000 nucleotide pairs. The smallest known organism, the virus X174,. which has a single helical DNA molecule, SP ht NEE EE ARPES TIE iy Bg LET RELY RE DA APSE EERIE ESN Human Congenital Anomalies ... 1968... Apgar has five genes or 5000 nucleotide pairs. The lambda virus has 50 genes, T phage 20,000 and .Drosophila 500,000 genes on eight chromosomes, only 0.1 per cent of which have been mapped. In human beings with 46 chromosomes, no gene locus has definitely been mapped though a number of linkage groups have becn discovered. In 1960, I mentioned some 35 different human conditions in which chromosomal abnormalities had been identified. This number is now well over 100 and, in fact, is limited only by methods of chromosome study. The commonly used technics of count- ing the total number of chromosomes, ar- ranging them in order by size and ratio of short and long arms, and their ingestion of tritiated thymidine by autoradiography, are responsible for the increase in positive di- agnoses but leave much to be desired. New technics are needed to study human chro- mosomes, especially in. meiosis. Electron microscopic photographs of the synaptimal | protein in meiotic chromosomes of corn (Mea zea) give hope that this technic will pay off with mammalian chromosome stud- jes. - Does one chromosome have one DNA molecule, or does it have many? There is evidence on both sides. Is the repressor substance indeed a histone, though nonspe- cific itself, attached to a specific repressor RNA? Chromosome “Breuks’ —- Chromosome “breaks” are much under discussion, prompt- ed by their discovery in leukocytes of people using LSD, and their offspring as well. The offspring,. though only a small group are under study, seem to be doing well, without birth defects or learning disabilities. In the leukocytes of children recovering from ru- beola infection, chromosome breaks are fre- quently found. In fact, in 3 to 6 per cent of controls, such breaks are found. Are they really “breaks”? Tijio thinks not, if they are aligned. One strand of the DNA chain, though presently invisible, is probably in- tact and can reproduce the other strand without difficulty, as has been known for some time in the case of radiation effect on chromosomes. Only occasionally do inver- sions, translocations, or deletions occur. Chromosome breaks in leukocytes have been reported after the use of many common drugs, such as caffeine, aspirin, and tran- guilizers, but as far as the genetic implica- tions are concerned, chromosome breaks in meiotic cells must be studied. To date, only streptonigrin has been identified as a drug 327 which causes meiotic chromosomal breaks in human oocytes. It comes as no real surprise that the chro- mosome complement of fetal cells in a quar- ter to a half of successful cultures from spontaneous abortion specimens have been found to be abnormal. Trisomies of all seven autosomal groups have been found, as well as several triploid and tetraploid fetuses. It is a surprise that the most common sex chromosome aberration in abortion speci- _mens is the deletion of one sex chromosome, a condition which is offen compatible. with life and even normal mentality. It is ob- vious in genetic counseling that it is im- portant to obtain an accurate history of spontaneous abortions. Whenever possible, such specimens should be examined for chromosome analysis. Only about half of attempted cultiires are presently successful, probably because of contamination and de- lay in reaching a cytogenetics laboratory. Problems of Mongolism —- Those working especially with sex chromosomes report an estimated incidence of sex chromosome ano- malies to be as high as one in 200 births, or 0.6 per cent. Living but abnormal chil- dren have been. identified with chromosomal errors in groups A, B, D, E, and G. Only one child has been found with a missing autosome, from group G. Trisomy of pair 21 is the most common error, estimated to occur once in 600 births (mongolism). The ’ causes for this nondisjunction are probably multiple. Heredity plays only a very minor role, if any, unlike its role in families with a translocated 21 chromosome. It has been noted from Australian evi- dence that mongolism occurs in neighbor- hoods and in epidemics. It is suggested that the births of mongoloid infants regularly follow —~ about 9 months later — epidemics of infectious hepatitis, as a result of ma- ternal infection early in pregnancy or pos- sibly just before conception. Four other studies in other parts of the world do not corroborate this idea. By 1969, a definite answer should be found, for there is at pres- ent an unusual amount of infectious hepati- tis in the State of Victoria, Australia. Another clue to the causes of mongolism has received reinforcement. In 1960, it was reported from Canada that the mothers of mongoloid children, had a history of x-ray exposure to the abdomen before conception four and one-half times greater than their neighborhood controls. Such an experience was not found in the followup of women and 328 ANESTHESIA AND ANALGESIA... their infants exposed to the atom bombs in Hiroshima and Nagasaki. Recently a much larger series of familiés“was examined in Baltimore in which it was found that fluros- copy and radiotherapy were present seven and one-half times as often in mothers of mongoloid children. ,Also, there was a hint of evidence that a greater percentage of the fathers had been in radar work in military service. The obvious preventive measure suggested by these findings is to protect, whenever possible, the future germ cells from the effects of x-ray at any age, both in intrauterine and extrauterine life for males and up to the age of genetic death in women. Another theory for the cause of mongo- lism is related to the sexual habits of mar- ried couples. Jt is well known that mongo- Joid children are born much more often to women nearing the end of their reproductive life. A woman of 25 has about 1:2500 chance of giving birth to such a baby. At age 40, these odds are nearer 1:40 or 1:50. (On the hopeful side, a woman of 40 has a 98 per cent chance of not having a mongoloid baby). Studies of reproductive biology in mammals all agree that the sooner an cgg is fertilized after. ovulation, the better the quality of the product. The quality of the mammalian egg and possibly the sperm, too, ‘begins to deteriorate after 24 to 36 hours and, by 48 hours, fertilization is not possi- ble. Ideally, the egg should be received in an environment of fresh, capacitated sperm. A study of the habits of long-married cou- ples shows that the frequency of intercourse, on the average, declines with the length of marriage. Prophylactic measures, if concep- tion is truly desired, are obvious. One im- portant question which has not: yet been answered, either in human beings or sub- human primates, is “when is ovulation?” Hopefully, future research will hold the answer. . Teratogenic Drugs — Thalidomide is the most teratogenic drug ever discovered. Its availability to women of reproductive age has very properly been made impossible. There is no real evidence why women be- yond menopausal age and men should not have access to it as a tranquilizer or seda- tive, but the unhappy habit of Americans of sharing prescriptions with one another indicates that the decision to remove it from the market was correct. The only other group of drugs which have been dcemon- strated to be occasionally teratogenic are the progestins, frequently given to mothers with bleeding in the first trimester. Over Current Reséarches Vou. 47, No. 4, dury-Aucust, 1968 200 instances of masculinization of the fe- male fetus have been reported. Fortunately, the changes in the external genitalia can be corrected by plastic surgery. A new con- cern has arisen recently about the use of these hormones and related steroids. There are rumblings on both sides of the Atlantic that the steroids used for certain pregnancy tests may be teratogenic. Likewise, a break in the prescribed routine of taking contra- ceptive pills may result in abnormality if pregnancy occurs during the break. The present prescription for a better-qual- ity baby with respect to steroids is to stay faithfully with the routine prescribed for contraceptive pills; when conception is de- sired, to stay off the pills entirely, have in- tercourse every 24 hours from the 10th to 25th day after the beginning of the last menstrual period, and avoid pregnancy tests which involve the use of ingested or injected steroids. There are very few prospective data about the habits of American women and _ their exposure to environmental teratogens. One teratologist considers that the teratogenic period in human pregnancy is the first 40 days, another suggests that it is 60 days. Originally, in the large Perinatal Study of the National Institute for Neurological Dis- eases and Blindness, it was intended that women would be admitted to the Study only if they were in the eighth week of pregnancy or earlier. Now that 60,000 couples are under study, it is found that fewer than one third entered in the first 3 months of preg- nancy, or 90 days. There are almost no data about the first 40 to 60 days following conception. Two other studies, one in New York City and one in Oakland, California, are in prog- ress, but. only prescription drugs are. en- tered for analysis. It scems imperative to enlist.a group of women who are planning to have children in a prospective study which will involve daily reporting ofa number of parameters. Such a study is being planned by The National Foundation, which will be extended to a large group of couples if found to be feasible. Congenital Anomalies Not Remote from Anesthesiology Interests —- This subject of congenital anomalies is not so remote from anesthesiology in still another respect. No longer are birth defects thought of as condi- tions which are present and diagnosed only at birth. In over 57 per cent of the babies, Human Congenital Anomalies ... 1968 ... Apgar the condition is diagnosed long after the usual 48 hours after birth, when a birth cer- tificate must be filed. Between 85 and 95 per cent of significant birth defects are diag- nosed by the end of the first year of life. In the broader view of this field, many birth defects are “expressed”. in adolescents and adults, many of whom come under ‘your care. A recent paper surprisingly reported the occurrence of congenital pyloric stenosis in a man of 40 who had had gastrointestinal symptoms all his life. . Diabetes is probably the most common biochemical defect in man. One in four of us has one gene for diabetes, while one in 20 has two genes — one for each parent — and if we live long enough, we shall have this genetic. defect expressed. Yet, this con- dition is a most complex one. Recent tech- nics show that juvenile diabetes is quite different from the middle-aged type.- A true deficiency of insulin production seems to be present in the former, while hyperinsulinism may exist in the older age group. The anes- thetic management may be quite different in these two types of -diabetes. Congenital cerebral aneurysm is the most common diagnosis in strokes. occurring in young people. Polycystic kidneys and other urologic abnormalities, such as those pro- duced by vascular aberrations, are frequent in adults. Intestinal obstruction from a vari- ety. of gastrointestinal anomalies, colonic polyposis, and diverticula are all evidences of late expression of hereditary conditions. The classic book, “The Mendelian Inheri- tance of Man,” now in its second edition, catalogs 1487 inherited traits, many of which you are already treating as anesthesiologists. Fortunately, there are many advances on the therapeutic front. Augmenting the State Crippled Children’s Clinics, 100 Birth De- fects Centers have been established by The National Foundation-March of Dimes, where specialists In many disciplines are concentrated. The associated medical spe- cialties are represented in full force: physi- cal therapists, medical social workers, occu- 329 pational therapists, and clinical psycholo- gists. Medical students and nurses are ex- posed to this interdisciplinary approach. The individual patient and his family are offered all these services at one visit. This great number of patients offers an oppor- tunity to set up birth defects registries, spe- cial genetic and environmental studies, and a comparison of therapeutic measures. This review has touched only on the high spots in the field of human birth defects. No mention has been made of what has been learned from the recent rubella epidemic. Its occurrence has led to the identification of the virus, positive identification of anti- bodies and, shortly, to the production of an effective vaccine which will protect that 10 to 15 per cent of young women still suscep- tible to infection from the rubella virus. Neither has mention been made of the imminent eradication of erythroblastosis due to the Rh factor. Some 5000 deaths annually of liveborn infants, let alone many -thousands of stillborn infants, will soon be averted by administration of a special vac- cine to Rh-negative women with Rh-positive husbands at the time of the first delivery. Many dozens of other immunologic de- fects, most of them fatal to the child who inherits them, are under study. Recently, two conferences on immunology have been held at Sanibel Island in Florida, sponsored by the United States Public Health Service and The National Foundation-March of Dimes. You, as anesthesiologists, will, I am sure, keep abreast of the literature especially dealing with inborn errors of metabolism. You have my sympathy when you are called upon to determine someone “legally dead” for cardiac transplant. I trust your efforts to change the legal usage of ‘“‘death” from cardiac arrest to neurologic arrest will be ‘successful in the near future. May I assure you of my continuing in- terest and great optimism in new develop- ments in anesthesiology.