Document created: 19 September 03
Air University Review, January-February
1974
Lieutenant Colonel
William C. Harvey, USAF, MC
The medical specialty known as nuclear medicine is one of the youngest in modern science. It began in the early 1940s after the demonstration that the fission of uranium could be controlled and that the resulting fission products were both numerous and of biological interest. Many of the by-products of nuclear fission resulted in radioactive substances called radionuclides (the term radioisotopes is often incorrectly used). The detection of the radioactivity of these fission-produced radionuclides (and more recently certain accelerator-produced nuclides) forms the basis of nuclear medicine.
Biologists believe that ionizing radiation (such as that produced by a radionuclide) is fundamentally harmful if received in greater amounts than we are all exposed to by natural radiation, such as cosmic rays. The objective of nuclear medicine is to work within a radiation dose range that is considered safe in relation to natural radiation and that received from long-accepted X-ray examinations.
The unit of measurement of radioactivity, named for the famed French scientists, is the curie. One curie of a radioactive substance undergoes some 1012 potentially detectable events within the space of one minute. The ability to detect a minute fraction of these events—for example, 10,000 instead of the 1,000,000,000,000 events of a curie—enables nuclear medicine to perform meaningful tests. Thus, we give minute or tracer amounts of a radioactive substance to a patient in the expectation that the number of nuclear disintegrations will provide sufficient information to diagnose disease without harming him.
The concept of a tracer radionuclide is possible because radioactive substances emit such a great number of nuclear disintegrations that only a minuscule amount of a radioactive substance need be administered. For example, with iodine, an essential component of many body proteins and hormones, the substitution of a radioactive form of this element allows the detection of as little as one picogram of iodine (roughly one ten-thousandth of a millionth of an ounce). Tracer doses of radioactive materials are regularly employed in nuclear medicine to evaluate the function of the thyroid gland as well as other organs of internal secretion, such as the pituitary and adrenal glands. A tracer dose of iodine is so minute that it can be safely administered to patients who have had documented, severe, anaphylactic reactions to larger doses of iodine such as are found in agents used to visualize the gallbladder or the kidneys by X ray.
Nuclear medicine, then, exploits the observation that very numerous nuclear transformations can be not only detected but quantitated, thus leading to description of disease that is a quantum jump ahead of traditional methods. In this article I shall note particularly the unique benefits afforded by nuclear medicine, outline the physical and technical prerequisites for participation in this burgeoning field, explain the procedures currently performed at Wilford Hall USAF Medical Center, and finally consider the immediate future of nuclear medicine, particularly as it affects the Air Force.
in-vitro applications
Over a decade ago Dr. Solomon Berson and Dr. Rosalyn Yallow, working at the Bronx Veterans Administration Hospital in New York, developed a technique called radioimmunoassay (RIA), which ranks as one of the most significant advances of medicine in the twentieth century. The technique has universal applicability in clinical medicine and adds a new dimension to investigative medicine as well.
The theory of this technique is surprisingly simple. Small amounts of the material to be measured—for example, a hormone—are injected into an animal such as a rabbit. The rabbit makes antibodies against the hormone, and in several weeks these antibodies are harvested by collecting the rabbit’s blood. Analysis shows what happens when the patient’s blood, containing an unknown amount of the hormone, is introduced into a test tube containing the rabbit antibody together with a known amount of the hormone, which has been tagged with a radionuclide. The rabbit antibody does not distinguish between the patient’s hormone and the radioactive hormone. Depending on the amount of hormone present, a certain number of antibody molecules will bind to a number of radioactive and nonradioactive hormone molecules. The bound molecules can be separated from the unbound molecules. Furthermore, the number of bound and free hormone molecules has a direct relationship to the number of free molecules that were originally present. By counting the radioactivity of the bound (or free) radioactive hormone, one can extrapolate the amount of hormone that was originally present in the patient’s blood (or urine, saliva, or whatever). This is the technique that allows of quantitative detection of picogram amounts of a biological substance.
Although theoretically simple, radioimmunoassay entails a number of technical complexities that make it a demanding discipline. Nonetheless, careful quality control permits accurate and reliable estimations of a number of substances that have great medical importance. The equipment required is expensive, and radio-immunoassay generally requires the ability to handle rather large numbers of specimens. To this end, systems that permit of automated counting of specimens and automated calculations of data are required. For example, the accompanying photo shows a gamma counter for measuring radioactivity. It automatically changes samples and prints out the results on a paper tape for later calculation and conversion to final results. This instrument costs about $14,000, and the total investment required for a clinical radioimmunoassay service is approximately $50,000.
As might be expected, radioimmunoassay requires specialized personnel. At present there are fewer than a dozen airmen qualified to perform radioimmunoassay, and the number of Air Force physicians so qualified is equally limited. Another important figure in radioimmunoassay is the radio-pharmacist, a qualified pharmacist who is also trained in nuclear medicine. There are perhaps 30 radio-pharmacists in the United States, and the Air Force is privileged to have one of them. She is in charge of the modest clinical radioimmunoassay service at Wilford Hall.
What can radioimmunoassay do? Why should any medical center expend $50,000 in scarce investment funds to establish this service? Why should efforts be expended to train specialized personnel?
Radioimmunoassay measures substances which are of considerable medical importance. They are of primal importance in human physiology as well as disease. A partial list of body hormones measurable by RIA includes cortisone, insulin, testosterone, thyroid stimulating hormone, estrogen, progesterone, human growth hormone, gastrin, angiotensin, renin, prostaglandin, erythropoietin, placental lactogen, prolactin, parathormone, and thyrocalcitonin.
The applications of radioimmunoassay and hormone assays are broad indeed, and some examples will be of interest:
The other example is the carcino-embryonic antigen (CEA). This is a substance elaborated by the body in minute amounts when bowel cancer develops. The exquisite sensitivity of RIA enables detection of the CEA frequently before the malignancy can be confirmed by any other technique. Conceivably the measurement of CEA as a screening test for bowel cancer will take its place alongside the famed Pap smear for cancer of the cervix.
Obviously the detection of hepatitis-associated antigen and the carcino-embryonic antigen will require both expensive equipment and additional trained personnel. The urgency of the matter may preclude any alternative considerations; the necessity is quite likely already upon us.
In addition to the assay of hormones, RIA can be applied to numerous other substances having medical import: digitalis, morphine, LSD, carcino-embryonic antigen (CEA), hepatitis-associated antigen (HAA), cyclic-adenosine monophosphate (AMP), barbiturates, folic acid, vitamin B-12, and rheumatoid factor. Intoxication with digitalis, which occurs in 20 percent of the heart patients treated with it, is detectable with RIA, and there is no other acceptable technique for detecting potentially fatal overdosage of this primary treatment for heart failure. A number of other pharmaceuticals that have potentially harmful side effects are also amenable to measurement by RIA. Assays for certain antibiotics also have been developed; the physician knows how much antibiotic he has given the patient, but only a direct blood measurement will tell how much is reaching the site of infection.
Some substances are abnormal if detected at all. Recently an assay has been developed to detect the hallucinogen LSD in the urine. Since RIA can be performed on large numbers of samples, and since the detection of LSD is of great importance in the Air Force drug screening program, again the protean utility of radioimmunoassay is evident. An unlimited number of substances, present in minute quantities and otherwise defying quantitation, can be measured by the technique of radioimmunoassay.
The greater part of the medical twentieth century has been spent in dealing with disease on organ and cellular levels. Radioimmunoassay is a quantum jump in our effort to comprehend, describe, and treat human disease on molecular and physiochemical bases.
other in-vitro applications
The in-vitro (in-glass or chemical) applications of nuclear medicine extend beyond radioimmunoassay. Many substances present in small quantities can be measured without the exquisite sensitivity of radioimmunoassay. The level of circulating thyroid hormone, for example, can be directly measured in the blood, and this test is the single most important screening determination of a patient’s metabolic state.
Radionuclides are also employed in the measurement of unknown spaces in biological systems. By use of a principle previously employed in biochemical analysis, the volume or space in which a given substance circulates can be measured accurately. For example, one can introduce radioactive water into a patient and, by applying isotope dilution principles, determine his total body water content. This determination is of inestimable value in clinical research and also has ready application to clinical medicine.
Often the physician needs to know the volume of a patient’s blood, and this is readily obtainable by injection of an appropriate radioactive tracer and the use of isotope dilution equations. (The use of this principle in in-vivo, or in-human studies, will be considered later.) The use of isotope dilution principles has provided invaluable investigative information, and again this is readily applicable to clinical study.
A third area of in-vitro radionuclide application involves the kinetics of biology. Traditionally, biology and medicine express themselves in two dimensions, length and breadth, on the one hand and in mass on the other; or, as these translate, in terms of volume and weight—cubic centimeters and milligrams. Nuclear medicine adds a third dimension, time. Nuclear medicine has done much to add time as a third dimension to clinical and investigative medicine. We are now learning to quantitate health and disease on a temporal as well as a conventional weight-length basis.
Nuclear medicine has revamped many “classical” theories of biology. For example, several years ago it was thought that growth hormone was high in youth and low in adulthood. We now know, from kinetic studies with radionuclides, that growth hormone is a very dynamic hormonal system and that its level rises and falls several times each day in the normal child and the normal adult. As a result of these kinetic studies, the process of growth and many other biologic functions have become better known.
Cancer has classically meant an uncontrolled growth of tissue in excess of the normal tissue growth rate. Radionuclide studies of lymphocytic leukemia in adults, however, have shown that the fundamental problem is not that too many white blood cells are born but that too few die. In other words, the presence of excessive circulating white blood cells is due not to excessive birth of these cells but to their failure to die after their normal life span. This observation of chronic lymphocytic leukemia illustrates again the phenomenal capabilities of clinical investigative and clinical nuclear medicine.
The importance of biokinetics in medicine cannot be overestimated. Classical measurements in biology have given rise to a concept of medicine that basically ignored time as a dimension. Measurements were made as if biokinetics did not exist. It is as if one were to sample the traffic on a highway by counting the number of vehicles between point A and point B at some instantaneous time. By this technique one does not determine the nature of the flow of traffic over an extended period of time but rather the number of vehicles on the road at the time the measurement is made.
in-vivo applications
Much effort in nuclear medicine is devoted to giving tracer amounts of radionuclides to the patient himself rather than to some extracorporeal patient product. The most dramatic use of radionuclides within patients has been in radionuclide organ scanning.
Basically, the object of organ scanning is to show an increase in radioactivity in an area of one body organ or a decrease in radioactivity in another. The photo shows an increase in radioactivity in a scan of the brain of a patient who was found to have a brain tumor. The isotope brain scan can detect and localize some 85 percent of brain tumors, thus vying in accuracy with classical techniques such as angiography. Moreover, unlike other classical techniques, it is quite safe; that is, there are virtually no side effects resulting from the simple injection of an isotope. Today the brain scan is the single most important screening test in the detection of diseases of the brain. A corollary study performed at the same time is the brain flow study. Here a sequence of pictures is made as the radionuclide is distributed throughout the brain. Thus the blood vessels of the brain can be visualized, and important judgments can be made on the competence and symmetry of blood flow in different areas. The study may, for example, show an area of inadequate blood supply before an actual stroke occurs.
The accompanying photo shows an area of decreased radioactivity in the liver of a patient who was shown to have cancer that had advanced to the liver. The liver scan can reveal cancerous deposits in the liver as small as one inch in diameter, before they are extensive enough to be detected by any chemical test. Furthermore, sequential liver scans provide the clinician with an objective measure of the anticancer therapy his patient is receiving. Physicians often request radionuclide organ scanning even when no indication of disease is present. The scans are then used as screening tests to detect disease demonstrable in no other way. The organs commonly scanned include the brain, thyroid, lungs, heart, liver, spleen, pancreas, bone, bone marrow, and kidney.
A screening procedure made generally available only within the past year is the whole-body radionuclide bone scan. Surgeons perform radical or extensive surgery only when there is reasonable hope of eradicating all of the malignancy. Radical surgery usually results in a definite disability of some degree, so there is no point in causing disability if the disease cannot be cured. Radionuclide bone scans are perhaps ten times as accurate in detecting early cancer spread to bone as conventional X rays. Thus we can identify more of these patients preoperatively and save them the pain and disability of radical surgery.
Body organ scanning requires very expensive and sophisticated equipment. The $35,000 Anger scintillation camera currently utilized at Wilford Hall is seen in the accompanying photograph. A “simple” device to record and retransmit data from this instrument for special statistical treatment, a video-tape storer, costs an additional $15,000. There is no doubt that this relatively simple data storage container adds a significant dimension to our ability to scan both healthy and diseased organs.
It should come as no surprise that computers have been successfully applied to the collection and analysis of data from patients given radionuclides. A case in point is the determination of cardiac output, a measurement of basic importance in the evaluation of heart disease. Traditionally, this measurement is made by meticulously threading a catheter through an arm or leg artery up into the patient’s heart. This measurement can now be made by the simple intravenous injection of radionuclides without the use of a catheter. The information obtained can be analyzed in compartmental fashion to ascertain the function of each individual chamber of the heart to determine whether or not any abnormal communication exists between chambers and, most critically, to show how much work the heart can do in a given period of time. The information gained from nuclear angiography augments traditional cardiology as well as developing techniques of cardiac surgery and the treatment of myocardial infarction.
In-vivo nuclear medicine has a number of other exciting applications. With the growing use of kidney transplants, nuclear medicine is showing increasing value in assessing the viability of a transplanted kidney. Before traditional methods are able to detect transplant failure, the radionuclide kidney study can often do so, thus alerting the transplant team of adversity before it can be detected by any other method.
The potential uses of radionuclides in studies of patients are virtually infinite. Many areas of clinical medicine, previously mysterious and inaccessible, lend themselves to radionuclide techniques. At Wilford Hall we have been interested in the radionuclide diagnosis of hidden infections and abscesses. Using an experimental radionuclide, gallium-67, we have been able to detect hidden abscesses not demonstrated by other diagnostic methods. We believe this can be a significant contribution to clinical medicine. The potential benefits of radionuclides are limited only by the tenacity and ingenuity of their users.
The safety of radionuclides in medicine is the province of a small, elite corps of men mown as medical physicists. All of them are trained to the doctoral level and work closely with physicians, technicians, and patients in assuring radiation safety as well as in monitoring equipment, training the Air Force’s resident physicians and technicians, and designing research.
Most of the radionuclides used at Wilford Hall USAF Medical Center come in prepackaged form from commercial radiopharmaceutical houses. It is evident now that an on-site radiopharmacist can supervise the local preparation of a number of agents previously available only in kit form. Three advantages result from local preparation:
1. The quality of the radiopharmaceutical in many instances is superior to that of the prepackaged one.
2. The cost of preparing standard radiopharmaceuticals locally is considerably less, saving an estimated $15,000 annually.
3. The ability to compound radiopharmaceuticals locally gives the medical facility a virtually unlimited potential for tailoring clinical research to the individual patient. This ability confers upon a medical facility an advanced treatment capability that is available now only at university and research-oriented medical facilities.
Nuclear medicine has recently been organized in a conjoint alliance with the specialties of internal medicine, radiology, and pathology. We recognize that the benefits of radioactivity are universal in clinical and investigative medicine. To that end, the Wilford Hall Nuclear Medicine Service offers an ongoing course comprising 35 hours of didactic lectures and 16 hours of laboratories. The course is conducted six times a year and is open to any military physician. We are training, on a regular basis, physicians specializing in internal medicine, pathology, and radiology. Certain technologists as well attend selected portions of the curriculum.
current resources and the future
The regulatory body of American hospitals, namely the Joint Commission on Accreditation of Hospitals, has recently decreed that all accredited hospitals must offer their patients the benefits of nuclear medicine. Of the 75 Air Force CONUS in-patient medical facilities, nine have the capability of nuclear medicine: USAF Academy, Andrews, Keesler, Lackland, Maxwell, Scott, Sheppard, Travis, and Wright-Patterson, plus two overseas bases; Wiesbaden, Germany, and Clark AB, Philippines. Those AF hospitals that do not have this capability obtain it from the civilian sector at a considerable cost.
There is no doubt that the price of nuclear medicine is considerably less in Ail Force facilities than if this resource is obtained from a civilian medical source. The actual costs at Wilford Hall are currently being computed by our laboratory and should provide the Surgeon General with valuable information. Quite clearly, economics and good medical practice will dictate a large expansion of Air Force nuclear medicine in the near future.
The Air Force has begun to take steps to meet this clearly expanding need. In mid-1972 the Air Force Surgeon General allied the training of Air Force nuclear medicine technologists with the U.S. Navy training program at Bethesda, Maryland. In this program some twelve Air Force technology students per year receive four months of didactic training, after which they are dispersed to Air Force medical centers for eight months of practical experience. This will do much to relieve the supercritical technological shortage that had threatened to abort the development of nuclear medicine in the Air Force.
Radionuclides are assuming an increasingly important role in American medicine; so are they in the Air Force. Both chemical (in-glass) and imaging (in-body) applications of radioactive substances offer unique tools to the physician in clinical research as well as in the routine practice of medicine. The success of nuclear medicine in our service requires a definite commitment on the part of the local medical facility as well as the Air Force. This commitment will be costly, both in dollars and manpower, but the excellence of Air Force medicine cannot be maintained without it.
As mentioned previously, the investment cost of a radiopharmacy will be $50,000. Clinical imaging equipment will be more expensive. A l000-bed hospital, such as Wilford Hall, requires two gamma cameras (total cost $120,000) plus two rectilinear scanners ($55,000). Very shortly a small on-line computer will be essential (cost some $75,000). The establishment and maintenance of clinical nuclear medicine cannot be regarded as a luxury afforded to American civilians. It has become a medical and a medicolegal necessity.
Wilford Hall USAF Medical Center
Lieutenant Colonel William C. Harvey is a board-certified internist who is currently Chief of Nuclear Medicine, Wilford Hall USAF Medical Center, Lackland AFB, Texas. He attended Cornell University Medical College and completed internship and residency training at the Hartford Hospital, Connecticut. Following an assignment in Pakistan, Colonel Harvey served as Chief of Medicine and Chief of Professional Services, 58th USAF Hospital, Luke AFB, Arizona. He has published articles on internal and nuclear medicine.
Disclaimer
The conclusions and opinions expressed in this
document are those of the author cultivated in the freedom of expression,
academic environment of Air University. They do not reflect the official
position of the U.S. Government, Department of Defense, the United States Air
Force or the Air University.
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