Adverse reactions to radiopharmaceuticals.

SPECIAL

ARTICLE

Adverse Reactions to Radiopharmaceuticals Jashovam Shani, Harold L. Atkins, and Walter Wolf

This review covers the side effects and adverse reactions to radiopharmaceuticals that were reported in the literature over the past 25 years. The information published prior to 1970 is sporadic, but due to the increased utilization of nuclear medicine procedures and the recognition that radiopharmaceuticals may have pharmacologic side effects, a registry has existed since 1971 to tabulate information on such effects. This survey is medical, rather than pharmaceutical in emphasis and so the adverse reactions are classified

according to the target-organ systems involved rather than according to the specific radionuclides or to pharmaceuticals. If any of the radiopharmaceuticals of present or past use are not mentioned in this review, it is because no reports on their side effects were retrieved by us. Hopefully, the organized registry system suggested by the Society of Nuclear Medicine (SNM) will enable a more complete recording of side effects from radiopharmaceuticals in the future.

H E F I R S T R E P O R T from the registry system for adverse reactions to radiopharmaceuticals was published in 1972, ~ and further discussions have been published in the Journal o f Nuclear Medicine 2 and elsewhere) ,4 The present review does not include cases in which the wrong dose was administered to the patient or the wrong patient received a radiopharmaceutical, 5 except for very few cases from which medical conclusions may be drawn. It also does not include reports on incorrect administration of the drug (too quickly, demonstrating radioactive embolus at autopsy, i.e., following intravenous administration of macroaggregated human serum albumin), on failure to block the thyroid when necessary, or on mistakes that resulted from lack o f calibration or improper pH. 6 Adverse reactions in animals, reactions from industrial or commercial uses (i.e., tritium-luminous dial painting), and reactions to sealed sources, applied externally or implanted internally, are also purposely excluded. Prior to a description of the specific problems in nuclear medicine, it may be in order to attempt to define an adverse reaction. The situation is somewhat more straightforward for radiopharmaceuticals than for therapeutic drugs, since no therapeutic effect is expected with these diagnostic agents. An adverse

T

From the Radiopharmacy Program, School of Pharmacy, University of Southern California, Los Angeles, Calif. and the Medical Department, Brookhaven National Laboratory, Upton, N. Y. Supported in part by the Energy Research and Development Administration and the International Atomic Energy Agency. Jashovam Shani, Ph.D.: Senior Lecturer, Radiopharmacy Laboratory, School of Pharmacy, The Hebrew University, Jerusalem, Israel, and IAEA Fellow. Harold L. Atkins, M.D.: Senior Scientist, Medical Department, Brookhaven National Laboratory, Upton, N.Y. Walter Wolf, Ph.D.: Professor and Director, Radiopharmacy Program, School of Pharmacy, University of Southern California, Los Angeles, Calif. Reprint requests should be addressed to Harold L. Atkins, M.D., Medical Department, Brookhaven National Laboratory, Upton, N. Y. 11973 | 1976 by Grune & Stratton, Inc. Seminars in Nuclear Medicine, Vol. 6, No. 3 (July), 1976

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SHANI, ATKINS, AND WOLF

reaction may be defined as an unanticipated physiologic response of the patient to the vehicle carrying the radiation, not to the radiation itself. It may be further categorized as not due to overdose or an exaggerated response to a normal action of a drug, or a known side effect of the drug (for nonradiopharmaceutical therapeutic drugs). A special problem with radiopharmaceuticals might be radiation effects, but those again, are more properly categorized as overdose problems. Examples of adverse reactions would be hives, bronchospasm or other allergic phenomena, fever, infection, shock-like state, etc. An exception to the above definition may be those reactions encountered on occasions following administration of lung-imaging agents. In these cases diminished respiratory reserve of the patient may establish a condition in which the normal dose constitutes an overload for that particular patient. LUNGS

The major perfusion lung-imaging agents used today are macroaggregates of 131I- and 99mTc-human serum albumin (13~I-MAA and 99mTc-MAA, respectively). These agents accumulate as labeled microemboli in those pulmonary capillaries where active flow occurs, thus enabling imaging of their regional distribution. Although the possibility of adverse reactions to ~3~I-MAA was described over l0 years ago (namely, antigenic reaction, vascular obstruction, and overexposure to radiation), 7-9 those aggregates were considered safe and reliable in the diagnosis of pulmonary vascular occlusive diseases, I~ including pulmonary blood flow studies in cases of suspected pulmonary emboli. They are easily fragmented and biodegraded and occlude the small pulmonary capillaries only temporarily (their biologic half-life in lung is about 6 hr). Iodine-131-MAA and 99mTc-MAA scans were shown to correlate closely with pulmonary angiography, pulmonary function studies, and postmortem findings,7 with rare adverse reactions. During the past II years the following complications were reported: Wagner 7 described urticaria following administration of ~3~I-MAA and Lugol's solution in a patient with known iodine sensitivity, but at that time did not observe any deleterious effects in another 200 patients H receiving the same drug. Dworkin t2,~3reported an adverse reaction in a patient with severe occlusive disease of the pulmonary vascular bed due to widespread tumor emboli to the lungs after 300 #Ci of ~3JI-MAA (containing 11 mg albumin). The reaction consisted of faintness, cyanosis, tachypnea, agitation, and diaphoresis progressing to sinus tachycardia and death. In 1967, Fraimow ~4 noted a fall in pulmonary diffusion after pulmonary scanning in more than half of his patients, and more markedly on the day following the injection. A year later Vincent t5 reported a reaction in a patient with pulmonary occlusive phenomena due to intimal fibrosis of pulmonary arteries, immediately following the administration of 800 #Ci 99~Tc-MAA (3.8 mg albumin), with n o thrombi found in the heart or in the pulmonary vessels, but related this reaction to the patient's advanced pulmonary vascular disease and stated that this case was the only known fatality in over 50,000 administrations of MAA, up to that time.

ADVERSE REACTIONS TO RADIOPHARMACEUTICALS

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Dully 16 reported in 1968 that two patients, each injected with 300 #Ci ~3~I-MAA developed enlarged and delayed embolism of the lungs due to incorporation of the aggregates into blood clots, resulting from the fact that blood was mixed with ~3~I-MAA in the syringe before injection. A second type of radioactive embolism was noted in both cases following the injection of the admixture, thus resulting in immediate embolization of small radioactive blood clots to pulmonary arteries. This type of embolism remains within the lungs longer than 24 hr, with a biologic half-life of 3-5 days. It seems, therefore, that the demonstration of a radioactive embolus must be considered a complication of the procedure and that any ~3~I-MAA preparation that has been mixed with blood should be immediately discarded. Using 216 #Ci of ~3~I-MAA, Roberts reported in 197017 a fatal hemoptysis in pulmonary embolism, probably precipitated by the pulmonary scanning agent. This was a patient with chronic recurrent pulmonary embolism who developed massive and ultimately fatal hemoptysis within minutes after the scan. Bliek, 18suspecting the 300-#Ci doses of the tagged ~3q-MAA to be too high, described a patient with idiopathic pulmonary hemosiderosis who, after being administered 250 uCi 1311-MAA (0.65 mg albumin), demonstrated anaphylactic response with shock and bilateral pulmonary consolidation and a delayed reaction with superficial mucocutaneous lesions (but no bronchospasm). As much as it is obvious that larger aggregates will block the lung capillaries, T o w 19 calculated that 0.65 mg of MAA of 7.5 # and above contains about 165,000 macroaggregates, which could not occlude more than 0.003~ of the total pulmonary vascular bed, well below the maximum safe level of albumin. Such calculations are estimates from particle counting per unit volume, and suggest that there are 250,000-1,000,000 particles per milligram, varying with the particle size. Weibel reported 2~ that in the normal lung there are 200-300 million precapiUary segments, with diameters in excess of 10 t~, capable of trapping most of the MAA particles. Particles of 7-10 t~ lodge in the more distal capillary segments (200-300 billion) while particles below 7.5 ~ in diameter (which is about the diameter of RBC) pass through the pulmonary capillary bed. Only in a disease process, when the pulmonary capillary bed is diminished, will larger pulmonary vessels be reduced to a size that will entrap MAA, and thus the number of vessels occluded may be higher. It seems possible that both the immediate and delayed reactions described by Bliek, were due to the Lugol's solution, which was administered immediately after the scan, rather than to the MAA particles. In a report on hemodynamics and gas exchange following injection of 200 #Ci ~31I-MAA particles (0.7-1.2 mg albumin) to 12 patients with restrictive lung disorders, Konietzko 2~ observed the following adverse reactions: decrease of stroke volume, increase of heart rate, decrease of cardiac output, increase of peripheral blood oxygen utilization and decrease of blood pressure. In spite of these side effects, no practical criteria with a view to patient hazards were elaborated. Williams 22 recently reported a case in which a severe reaction occurred immediately after the injection of 1 mCi of 99mTc-MAA particles (1.5 mg albumin), followed by death 6 hr later. As in the cases previously reported, it occurred in a patient with severe pulmonary hypertension.

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Nondetailed information on adverse reactions to 150-300 #Ci ~3EI-MAA is given by Taplinfl3 who reported "seven fatal cases" out of 500 patients studied between 1964 and 1967. It is not stated whether any of those fatal cases were connected to any extent with the scanning procedure or with the pulmonary embolism per se. More nonspecific fatal cases were reported in 1971 by the SNM Registry: 11 of the 142 adverse reactions reported were due to 99mTCand 13~I-MAA. In a later report by SNM, circulated in 1974, the number of adverse reactions due to MAA preparations was much lower. A single case report by Child et a134 concerns a young woman with pulmonary hypertension who died immediately following the injection of 99mTc-MAA. The British Institute of Radiology (BIR) reported in that year ~5 that one of every 36 patients scanned with MAA demonstrates adverse reactions. The incidence (2.8Y/o) of adverse reactions to this specific agent (MAA) for lung scanning is the highest incidence of adverse reactions recorded for any radiopharmaceutical. The reporter, E. S. Williams, comments on this high incidence saying that regardless of this figure the use of MAA is generally considered to be safe, assuming that centers using MAA for many years without adverse reactions did not feel it worthwhile to report a fact that they considered well known. Analyzing those cases it seems that in addition to mechanical obstruction to blood flow, other possible causes of this reaction may include anaphylaxis, pharmacologic effect of the suspension (e.g., ferric chloride left in the suspension from the labeling procedure, causing pulmonary vasoconstriction and therefore a further increase in pulmonary vascular resistance) or a primary cardiac or cerebral reaction from MAA particles that reached the systemic circulation. Vincent ~5suggests that fatal cases after administration of MAA might continue to be rare and might be predictable on the basis of clinical and laboratory evidence of pulmonary hypertension. One should remember that the lung is an effective filter that prevents MAA from reaching the leR heart and the coronary circulation, and therefore the size of those particles passing through should not exceed 30 # in order to avoid blockage of larger vessels and should be injected very slowly in order to assure uniform distribution. Particles are moved onward by cellular bombardment, so that a particle that initially blocks a small artery may become fragmented and move into smaller vessels36 This phenomenon may explain the period of apparent recovery seen in some of the patients who suffered such adverse reactions to MAA particles during their scans.

One new macroaggregate of albumin is ~ T c - S n - M A A . Only a few reports on its effects on humans have been published so far. The acute toxicity in dogs of this agent was reported recentlyY The advantage of this preparation is that Sn-MAA is stable in a kit form and may instantly be used for scanning by addition of pertechnetate.28 A dose-response curve of toxicity was evaluated in those healthy dogs, but their first signs occurred when approximately 100 times the usual lung scan dose was given. Additional studies in dogs with experimental pulmonary hypertension revealed no significant effect after a single injection of a human equivalent dose. A single case of an adverse reaction to ~ T c - h u m a n albumin microspheres (HAM) was reported lately.29 A pyrogen-, endotoxin-, and bacteria-free HAM


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preparation caused a severe anaphylactoid reaction within 15-20 sec after its i.v. administration (dose: 3 mCi, 0.6 mg albumin, 90,000 particles) for pulmonary scanning. The patient experienced severe bronchospasm, unobtainable blood pressure, rapid but weak pulsations and histamine-like cutaneous flushing, followed by cyanosis. Those symptoms were relieved by benadryl and hydrocortisone. A few more adverse reactions to 99mTc-HAM were reported to the registry during 1975 (see Table 1). Another group of radiopharmaceuticals for lung scanning that is known for its numerous adverse reactions is the iron hydroxide precipitates. First suggested by Stern 3~in 1966, with its easy method of production, 3~ iron hydroxide (ferric) labeled with "3rain was utilized for pulmonary perfusion studies and for lung scanning until a few years ago, when the former U.S. Atomic Energy Commission (May 1973) and the BIR (July 1973) advised discontinuing the use of radiopharmaceuticals containing iron, particularly for lung scanning. T a b l e 1. A d v e r s e R e a c t i o n s to R a d i o p h a r m a c e u t i c a l s

as R e p o r t e d to t h e

Adverse Reactions Registry of the Society of Nuclear Medicine Year

Radiopharmaceutical

1967 1311-Hippuran 99mTc-Sn-colloid 131t'RISA 113min-Fe(OH)3 N01311 32p

Reaction Local pain Pyrogenic Aseptic meningitis Allergic AIJergic Pulmonary

Number I 10 2 7 3 I

Year

Rodiopharmoceuticol

Reaction

Number

1971 1311-RISA 131I-Hippuran 131I-MAA 99mTc-pertechnetate 99mTc-Fe(OH)2 19eAu-colioid

Aseptic meningitis Urticaria Anaphylaxis Anaphylaxis Flushing Allergic

3O 1 1 2 22 1 57

1972 1311-RISA

Aseptic meningitis, one fatal Allerglc Aseptic meningitis Flush, three deaths Allergic

23 1 2 5 1 32

Hypotension Allergic Hypotension

1 4 7 9 2 1 1 25

24 1968 99mTc-Sn-colloid 9emTc-Sn-colleid 1311-RISA 1|3eln-Fe(OH)3 32p 19gAu-colioid 99mTc-rnicrospheres 131I-MAA No 1311 87msr

Pyrogenic Allergic Aseptic meningitis Allergic, free iron Pulmonary Allergic Allergic Allergic Idiosyncratic Pyrogenic

9 7 2 27 2

Allergic; idiosyncratic Vaso-vagal Aseptic meningitis Respiratory Allergic Allergic Allergic Allergic Allergic Allergic Allergic

1970 1311-Hippuron 131bRISA 99mTc-pertechnetate 99| 131I-MAA 99mTc-DTPA Na 1 3 1 1 Na 1311 83Sr

Vaso-vagal Pyrogenic Allergic Flushing Cardiovascular Pyrogenic Thrombophlebitis Heart failure Malaise

Myocardal infarction Allergic

111In-D~PA 99mToFe(OH)2 99mTc-DTPA

1

2 I

3 1

55 1969 99"Tc-Sn-colloid 131I-Hippuran 1311-RISA 113mIn-colloid 99mTopertechnetate 131I-MAA 99mTc-MAA 99mTc-HSA 99mTomicrospheres Na 1311 19gAu-colloid No 13|l therapy 2a3Hg-chlormerodrin

99mTc.Sn-colfoid

2 4 7 1 2 2 1 2 3 3 I 1

3 32 4 8

2 3 I

1 1 1

3 24

1973 ~mTc-Fe(OH)2 99mTc-polyphosphate 99mTc-Sn-colloid I 111n-DTPA 131I-Hippuran 99roTe-HAM No 123j

Vaso-vagal Diaphoresis, flush Vaso-vagal

1974 131I-Hippuron I~Au-colioid 99mTc-pob/phosphate 99mTc-diphosphonate 99mToSn-co|loid 99mToSn-colloid 99mTc-Sn-collold 99mTc-HAM 131I-MAA 99mTc-Fe(OH)2 99mTc-DMSA I 111n-DTPA

Voso-vagal Allergic Allergic Allergic Pyrogenic Allergic Vaso-vagal Hypotension Hypatension Flush Hypotension Aseptic meningitis

1 I 1 1 5 2 I 2 3 1 1 4 23

1975 99mTopyrophosphate 131I-cholesterol 99mTc-HAM 99mTc-Sn-colloid 1311-MAA

Flush,headache Cardiovascular Flush, allergic, opnea, shock I~ruritis Dyspnea, itching

1 1 8 1 1 12

Aseptic meningitis

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Heidenreich 32 was the first to report irreversible malfunction of the newly transplanted kidney after angiography with ,~3mln_Fe hydroxide, and Wright 33 reported a fatal case after administering "3mln-Fe-gelatin to a man suffering from pulmonary embolism. Wright indicated that this was the only such case out of more than 1000 successful lung scans. Gelatin in this preparation is a stabilizing agent and is recommended as such in the preparation of 113raincontaining radiopharmaceuticals, to prevent the precipitation of indium hydroxide in acidic pH.34 Brashear 35 measured pulmonary diffusing capacity in 14 patients before and after lung scanning, using about 220,000 particles of this preparation, but no change was demonstrated in their diffusion capacities. Due to the short half-life of 113rain, individual preparations of gelatin-stabilized indium-containing complexes could not be tested for pyrogenicity prior to administration, and consequently, some pyrogenic reactions were reported. 36'37 In one of those studies, 36 1~ of the patients injected with the gelatin-containing preparation exhibited a pyrogenic reaction, but no reactions were observed when the gelatin was omitted, although some patients have complained of "smarting eyes" immediately after the injection. This reaction is thought to result from the rapid intravenous injection of iron and can be prevented by diluting the reagent with twice its volume of blood before injection .36 Indium-ll3m eventually was replaced by 99~Tc, and 99mTc-Fe-gelatin was introduced for lung scans in a form of 99"Tc-ferrous-hydroxide macroaggregates. In a preliminary study during a 7-month trial period 38 of a commercial kit, out of 177 perfusion lung scans, three deaths occurred within 3 min of injec'tion of the agent: the ferrous hydroxide macroaggregates were prepared according to the general method of Davis, 39but with considerable modification, and when injected as particles of an average of 25-tz size, were not detected microscopically in the vascular lumens. Neither was free iron detected in the injected material. These preparations contained less than 200 mg gelatin and less than 100 ug iron per patient. No mechanism for those adverse reactions was proposed, but in a following experiment on mice, Davis 4~ reported a complete absence of pathologic lesions that could be attributed to the residence of 99mTc-ferrous-hydroxide-macroaggregate in the pulmonary capillaries. Nevertheless, it has been established that microgram quantities of free iron, especially in the ferric (Fe +3) form, have a toxic effect, probably due to their indirect vasoconstrictive activity, and two reports on pathologic changes after 99mTc-Fe-hydroxide may be attributed to its ferric (Fe § hydroxide contamination. 3s Silvester 4~ suggested that iron in solution, especially in the presence of citrate, can form polyions, which are not large enough particles to be colloidal, but could be present in the ferric hydroxide colloid preparations and may be responsible to the adverse reactions that had been reported. Rhodes 42 reported significant pathology caused by ferric hydroxide in 1969 and an article describing similar findings in mice was published more recently,43 both findings attributed to ferric (Fe § hydroxide intoxication. In a private communication by Cawsey,'4 the Australian Atomic Energy Commission reports only one adverse reaction out of 27,712 injections of locally produced labeled iron hydroxide preparation, thus suggesting that a


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quality control element may be an important one. Another internal document from Davis to the FDA lists a total of 25,000 injections since 1971 without a fatality. In the April 1974 report of the SNM, 28 out of the 110 adverse reactions reported from 1971 to 1973 were associated with iron hydroxide. This may still be a very low percentage of all iron hydroxide scans performed but is definitely a high value among other adverse reactions to radiopharmaceuticals. In the report of the BIR, one out of every 97 scans performed with iron precipitate demonstrated adverse reactions, while due to its high popularity this test accounts for the highest total number of adverse reactions reported in Britain. Although some fatal cases were reported, six of them occurring within a short time after the injection, in no case could a cause and effect relationship between the administration of the radiopharmaceutical and the death of the patients be established, since all the patients were already seriously ill when their scans were undertaken. In several cases allergic manifestations to the lung-imaging agent have been encountered. Taplin suggested that allergic phenomena are rare because of the rapid degradation of the aggregates in vivo. However, the biologic fate of the aggregates has not been clearly demonstrated. It can be shown that the label migrates from the lungs but this does not positively indicate that the albumin itself is no longer in the lung .23 CENTRAL NERVOUS SYSTEM

The second major organ system associated with adverse reactions to radiopharmaceuticals is the central nervous system, with cisternography as the procedure presenting the most problems. According to the SNM Registry, 93 ouC of 121 adverse reactions reported from 1971 to 1972 were associated with cisternography, with two albumin preparations, m I-RISA and 99mTc-HSA, responsible for most of them. It was only natural that the best agent for cisternography was albumin, which with its high molecular weight of about 70,000 is poorly resorbed along the CSF tract and, being a physiologic component, had the least chances of evoking adverse reactions. The first report on untoward reactions to intrathecal injections of m I-RISA was published by Bell in 1957,45 even before Di Chiro described the isotopic demonstration of the CSF pathway by scintigraphy of the head after intrathecal injection of 13~I_RISA. Detmer 46 was the first to report aseptic meningitis secondary to intrathecal injection of 131I.RISA (27 mg albumin) but could not prove the cause-effect relationship of any of the components of the injection (i.e., guanethidine or sodium phosphate): the spinal fluid cultures remained negative during the complete period of the hospitalization of the patient. The second documented case of aseptic meningitis following ~3~I-RISA cisternography was published by Nicoll in 1967.47 Both cases involved patients with rhinorrhea who developed the symptoms of meningitis 6 and 24 hr following intrathecal RISA. Nicoll suggested that the high protein content of the injection (100-130 mg) may be the cause of the meningeal reaction, although

312


he could not exclude pyrogenic or allergic phenomena. An additional case was reported by Abbott 4s in a patient with communicating hydrocephalus. Aliquots of that solution also produced aseptic meningitis in animals. Two more cases of aseptic meningitis following the introduction of 100 #Ci ~31I-RISA intrathecally (less than 2 mg albumin each) were reported by Oldham 49in 1970. The author indicates that those two cases are out of a series of 70 cisternograms and stresses the idea that "any foreign material may cause aseptic meningitis." He advised the use of higher specific activity ~31I.RISA, up to 500 #Ci/mg, which permits reduction of the amount of albumin to only a few milligrams. However, in his own cases in which 2 mg albumin were injected aseptic meningitis still occurred. Repeated lumbar punctures 24 hr after 13,I-RISA injection yielded perfectly clear fluid, indicating that the reaction did not appear subclinically in all patients. Barnes and Fish s~noted chemical meningitis in five (out of 50) patients after intrathecal injection of a combination of 2 mCi 99"Tc-HSA and 100-300 #Ci 1311-RISA (total of 3-11 mg albumin) or i~, I-RISA alone. The clinical syndrome was characterized by early onset of fever, malaise, and meningismus. All patients showed dramatic CSF changes, with an elevation of the cell count and of the protein level after injection, but no bacterial contamination could be detected in the extensive cultures performed. No further cases of meningitis occurred using 99mTc-HSA (2-ml dose) in over 60 patients. In 1971 Dramov sl described two additional cases of aseptic meningitis following intrathecal injection of 1311-RISA (14 and 3 mg albumin). In 1972 three reports on febrile responses to 131I-RISA administration were published: Banerji 52 retrospectively reviewed his experience with intrathecal procedures over a 4-year period with ,31I_RISA for cerebrospinal flow studies, a total of 88 patients. Of this group 36 patients (41~) had a febrile response according to his criteria and 28 patients had accompanying pneumoencephaiograms that increased the incidence of the febrile course in that group. Pyrogen-testing in rabbits proved to be negative. In another communication Messert and Rieder 53 reported a study on intrathecal RISA administration to 50 hospitalized male patients (100-200 ttCi; 4.5 mg albumin each). The spinal fluid was examined for cells, protein, and glucose, body temperature was recorded at 1-7 days after injection, and the side effects were evaluated. Twelve patients showed CSF abnormalities within 1 day, seven of which manifested clinical meningeal irritation symptoms, but all symptoms disappeared within 3 days. In a third report Jonas ~4 described a patient who developed a neurogenic bladder following intrathecal 1311-RISA administration for evaluating suspected hydrocephalus. Jonas noted that most of the radioactivity remained in the lower spinal area and postulated that the CSF findings of inflammation were a consequence of the onset of an irritative process, thus exceeding a critical "duration of exposure concentration" threshold for nerve root damage. The fact that all these meningeal processes were aseptic led Cooper and Harbert 55 to suspect that the sporadic incidents of aseptic meningitis following intrathecal injection of human serum albumin may be due to a pyrogenic chemical contaminant (for which the human theca is a more sensitive biologic


313

test) rather than to the concentration of albumin. They used the Limulus lysate test, which is specific and sensitive for bacterial endotoxin (pyrogen) to test some of the commercial radiopharmaceuticals that were used for radionuclide cisternography, and found all those that were checked from one specific supplier to be strongly positive for pyrogens. All batches produced by that supplier after this check were negative to the Limulus test. In a recent paper, Cooper and Harbert reported 56 39 reactions associated with radionuclide cisternography, which resulted in aseptic meningitis during a 15-month period. All samples reacted strongly positive to the Limulus test, and the less-sensitive rabbit pyrogen test was negative with these preparations when tested on a doseper-weight basis. These authors claim that endotoxin is at least 1000 times more toxic intrathecally than intravenously. Since the Limulus test is very useful for testing small-volume parenterals, especially products unsuitable for the rabbit pyrogen test, it is recommended that the USP pyrogen test be supplemented with the Limulus test, at least for intrathecal preparations. 57'5s Since 1971, chelated radiopharmaceuticals (rain and 169yb-DTPA) have become widely used for cisternography, this partially replacing the albumin preparations. There are three reports in the literature attributing aseptic meningitis to labeled chelates. A report by Alderson and Siegel 59 records three cases of aseptic meningitis after H~In-DTPA administration, out of over 130 patients who had been evaluated by them; the CSF cultures were sterile and the gram-strain showed no organisms. In reviewing their anamnesis it was discovered that two of the three patients had clinically recovered from bacterial meningitis before cisternography but developed signs of meningeal irritation within 8 hr after the "tln-DTPA injection. These three mild adverse reactions were the only ones of 3000 cisternographic procedures, which made the radiopharmaceutical compare favorably with 13q-RISA, in which symptomatic meningitis has been frequently encountered. A second report, published recently by Jayabalan et al. 6~ described aseptic meningitis after intrathecal instillation of "~In-DTPA in three patients out of 70 examinations. This report concludes that these meningitis cases were due to unknown cause, but in a recent note Rhodes 6~ suggests that they were most probably due to pyrogen contamination. In the consideration of 169yb for cisternography and ventriculography, Barbizet reported in 197262 that in 12 patients who were examined with this radiopharmaceutical, radioactivity could be monitored as long as 3 months after examination, due to fixation of the isotopic agent on meningoencephalic structures, thus delivering 1500 rads for 1 mCi, a dangerous dose for a radiologic diagnostic examination. This excludes ~69yb-DTPA as a practical agent in cisternography or ventriculography. The first note on pyrogen reactions after i.v. administration of H3mln chelate for brain scan was published by Wright. 6~His preparation did not contain gelatin, and no definite source for that reaction was suggested, except for a possible washout of some materials from the rubber cap. Another isotope associated with brain complications is 133Xe, after its injection into the carotid artery for regional cerebral blood flow (rCBF) measurements. The investigation was based on reports of rCBF measurements in close

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to 4000 patients. 64 The overall rate of complication was 1.3%, of which 16% had permanent neurologic sequelae. Almost all complications were reported in patients with arterial or intracranial disease. These rates are equal to corresponding rates following cerebral angiography with carotid puncture. The authors (Ingvar and Lassen) collected information from 18 centers in 12 countries and drew some clinical recommendations about the techniques and precautions of the test, but none of them were related to the radiopharmaceutical agent. It seems as if all cerebral complications reported from the use of '33Xe for rCBF can be attributed to the technique or the status of the patient (i.e., with intracranial hypertension) and not to the radiopharmaceutical itself. LIVER

Colloids have been used for liver imaging for over 20 years, and they account for numerous adverse reactions that are most likely secondary to the stabilizers used in them. The main colloids used in nuclear medicine are colloids of 99mTc, llamIn, and 19SAu. Ever since colloidal materials were used for the treatment of infectious diseases, it was known that they may induce severe anaphylactoid reactions and even death. Today, most of the reports agree that the major source of hazard with those colloids, apart from possible pyrogens in pertechnetate, seems to be the gelatin, due to the ease with which it grows bacteria. Except for gelatin, there are two more additives that may be used as stabilizers, namely human serum albumin (HSA) and dextran, but while HSA must be used in minute amounts (maximum, 0.4~o), dextran may be added in higher concentrations [6~ (MW, 75,000) was suggested by Larson and Nelp, 65 while 10~ (MW, 40,000) was suggested by Ege,~ knowing that dextrans of high molecular weight are more antigenic in man than low molecular weight dextrans67]. Ege reported a 0.8~ incidence of minor side effects after administration of dextran-containing radiopharmaceuticals, and recently Larson and Bennett 6s reported that injections of several hundred patients produced three anaphylactoid reactions (flushing of the skin and hypotension), which subsequently were felt to be related to the dextran. In 1969, Hunter reported 69 ten anaphylactic reactions requiring full resuscitation during the use of dextran-stabilized sulfur colloid in 800 patients. In addition to HSA and dextran, carboxymethylcellulose, 25~o mannitol (with no reactions in 1100 cases), 25~ sorbitol, or a combination of 0.8 mg/ml PVP with 1.25 mg/ml gelatin were suggested as stabilizers. PVP has distinct advantages over gelatin due to its availability in sterile, nonpyrogenic solutions, and proven biologic usefulness. Because of the many side effects due to the stabilizers, some practitioners feel that the use of any stabilizer is not necessary if the colloid is to be injected very soon after its preparation. 7~ This conclusion was based on the absence of accumulation of activity of the nonstabilized freshly prepared colloid in other organs, such as the lung. This might require several fresh preparations each day. Adverse reactions after 99~Tc-sulfur colloid administrations for liver imaging were first reported by Stern et al. 72 and by Larson and Neip 65 in 1966, but the first survey of this radiopharmaceutical was published by Smith in a 1967 nuclear medicine symposium. 73 He reviewed cases of anaphylactoid reactions


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that had been detected in ten medical units after administration of 99mTc-sulfur colloid preparations (dextran-stabilized). These amounted to 0.9~ of 1300 patients. The number of adverse reactions observed in preparations without dextran (but including gelatin 74) in the radiopharmaceutical agents was much lower: 3 out of 3000 -- 0.1~, and the reactions that were encountered were milder. In one of the patients who developed an intense reaction, there also occurred a severe decrease of arterial blood pressure, which required prolonged medical assistance. The other suffered from a "histamine-type reaction," mainly flushing, subjective feeling of being hot and itching of both hands and feet. Similar reactions were published throughout the years. 75 Indium-ll3m-phosphate (or sulfate) colloids seem to be the cause of relatively few side effects by themselves. From a group of 770 patients studied with this agent, three developed anaphylactoid reactions with transient vascular shock within 20 min after an i.v. injection containing 1.6-2.0 mg iron. The state of shock lasted between 10 min and 1 hr. 76 The author of this report notes that the ll3mln preparation may cause a sensation of heat in the head and in the body, with flushing of the face during administration or immediately after it. The exact cause of the flushing has not yet been identified but is similar to reactions to technetium-iron hydroxide aggregates and is likely due to free iron in the preparation. Gold-198-colloid accounts for about 1~ of all side effects to radiopharmaceuticals as reported in the United States from 1971 to 1974 ~ and are classified as "very rare" in England. 25 Aplastic anemia secondary to i.v. therapy with 19SAu-colloid was reported as early as 1956 by Schoolman.77 The first reported instance of an accidental overdose with i.v. ~gSAu-colloid was described by Baron 7s in an elderly hepatosplenomegalic patient after 200 mCi of the colloid was administered instead of the intended dose of 200 #Ci. The radiation dose from the uptake of the ~gSAu-colloidin the reticulendothelial system was enormous, with an estimated 400-500 rads to the bone marrow and 7000-8000 rads to the liver, although liver functions did not deteriorate during the period of observation. The patient developed hematuria and purpura and suffered a terminal spontaneous intracerebral hemorrhage on the 69th day after injection. At postmortem, no specific changes could be detected in the liver, but there was evidence for serious hematopoietic insufficiency with patchy areas of granulocytic and erythroid marrow regeneration. Baron mentioned a personal communication with J. Brodsky, who had a similar experience with an overdose accident. In that case the patient survived a prolonged period of hematopoietic insufficiency with thrombocytopenia as a major failure, only to expire of hepatic insufficiency months later. It must be pointed out, however, that the exact nature of the hepatic pathology was not clear in Brodsky's case, and that hepatitis secondary to extensive blood product replacement during the hematopoietic failure phase may have been an important contributing factor. Moreover, in the discussion to Baron's presentation, Andrews reported on several patients who received rather "large total doses" of colloidal 198Au, who were studied at autopsy with no apparent liver damage that could be attributed to irradiation. In a paper by Lamoureux, two cases of colloidal gold embolism to the lungs

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were observed in a series of 1500 patients injected with tracer amounts of 198Au for the performance of liver scans. 79 A year later Raiciulescu 76 reported severe shivering in two out of 181 patients injected with this colloid (0.04-1.7 mg of colloidal gold), followed by changes in intravascular coagulation. Investigations carried out in the same laboratory on another group of patients have shown that administration of labeled colloids causes certain changes of blood coagulation. This group included 13 patients who received tl3mln and nine who received colloidal 198Au. The coagulation tests were carried out before administration of the colloidal substance as well as 1 and 5 days afterwards and revealed accelerated coagulation time within the first 24 hr, a decreased number of adhesive platelets and a decrease in the fibrinogen amount. These results are in agreement with toxicity studies in animals, revealing blood dyscrasias, delayed hepatic pathology, cystic changes, fibrosis, necrosis, and cirrhosis, ~82 and questions the traditional concept of hepatic radioresistance. Gold-198 is also known to be administered in Hodgkin's disease, mostly in combination with external radiation. In a first report Kaplan s3 observed cirrhosis and some marrow depletion, particularly thrombocytopenia, in the four patients each treated with a single i.v. dose of 60 mCi JgSAu. Due to those severe side effects only 25-40 mCi was administered in the following treatments, fractionated into 10-mCi doses at weekly intervals. In the next cumulative report s4 only one death (out of 21 patients) was directly attributed to the isotope, but the authors felt that thrombocytopenia, its most serious complication, might be prevented or lessened by adjusting the fractionated and total dose of the isotope. The common approach to liver imaging is by using radioactive colloidal particles that may be phagocytized by the reticuioendothelial system, 90% of which is in the liver. Thus, there seems to be a lack of effective methods for mobilization and metabolizing colloidal particles once they are retained by macrophages. Therefore, nuclides of shorter physical half-life and radiopharmaceuticals with shorter biologic half-life should always be preferable. BONE MARROW

Technetium-99m-sulfur colloid and ~9SAu-colioid have also been extensively employed to image bone marrow because of their localization in the RE elements in marrow. Botsford s5 reported four instances of hypoplasia of the vertebral bone marrow associated with the intraperitoneal administration of 19sAtl colloid for therapy ofascites due to metastatic implants. The cause-effect relationship was firmly established, since none of these patients had received x-ray therapy or any drug known to depress the bone marrow. The dose dependence was proven as well, since 11 patients who were given less than 50 mCi of 198Au showed no side effects, and their bone marrow at postmortem was found normal, while the 12 patients receiving 58-153 mCi t9SAu showed cellular depletion of bone marrow, and particulate material consistent with colloidal gold was demonstrated in their marrow. This suggests that intraperitoneal administration of 19SAumay be followed by rapid systemic uptake of the colloidal gold and subsequent deposition in the bone marrow. One of the patients was even suspected of having severe bone marrow depletion prior to death.


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Another complication to the bone marrow reported by Corwin et al, s6 was bone marrow depression and consequent anemia after 32p administration in a multiple course regimen, as reported for 20 patients with carcinoma of the prostate. Evaluation of anemia as a complication of 32p therapy in patients with extensive metastasis is difficult, since marrow destruction can result from tumor metastasis as well as from isotope therapy, but the fact that patients required transfusions after the second and third (but not the first) course of therapy speaks for the involvement of 32p in damaging the bone marrow, and consequently the hematopoietic system. When 198Au(4-8 mCi) was used for the treatment of persistent knee effusions in 18 patients, the main detectable side effect of that treatment was an increase in pain and effusion in five cases within 1 week after the injection, but this reaction was temporary and easily controlledY A serious disadvantage of intraarticular 198Aususpensions is that marked leakage may occur from the joint into which it was injected, followed by deposition in the regional lymph nodes, the liver, and the spleen. Such leakage was reported by Virkkunen ss in 36~o of his treated patients (156 applications to 90 patients, receiving 1-10 mCi each). In a report on the therapeutic effect of 5 mCi t9SAu-colloid in intraarticular infiltration into 13 patients, Cruz et al. reported s9 pain during the infiltration time in 12 instances, rise of local temperature, articular fluid growth and disability in 27 out of the 28 administrations. Three to four hours after the infiltrations, six patients had moderate fever, anorexia, muscular pain, and uneasiness for up to 12 hr. It seems that the hazard to the blood-forming tissues of the body should be borne in mind in the clinical use of radioactive tgSAu-colloid. This should be especially emphasized, since reports have been published of chromosome abnormalities in peripheral lymphocytes after intraarticular 198Auinjections,s~ Another agent that was found beneficial in the treatment of chronic knee effusions in patients with rheumatoid arthritis is colloidal soY injected into the knee joint as an alternative to surgical synovectomy. In the first report on adverse reactions to soY, Chapelle et al.91injected soY-resin colloid into 25 patients with rheumatoid arthritis and reported chromosome breaks. The percentage of chromosome rearrangement was higher in the nonimmobilized patients than in the immobilized ones, both values lower than those after 198Au treatment. In another study Jalava 92 reported inflammation of the knee 1 day after the injection, and a rise of temperature in two out of his 63 patients. In a later report by the same author, 93 6 mCi of 25-50 m/~ particles were injected into 49 patients, and chromosome damage was noticed in many of them within 1 week after administration of the drug. The authors report a four-fold increase in chromosome aberrations, from 0.379/0 incidence in their normal population to 1.429/o in the soY-treated populations. These figures for normal incidence are lower than those reported by Chapelle 91 and Stevenson.94 The fact that the range frequency of damaged cells in the literature is 0.13~o-1.32~ makes the significance of the four-fold increase reported by Jalava questionable. Similar doubts on the limitations of chromosome analysis as a method for biologic dosimetry of internal exposure to radionuclides have also been raised by Visfeldt.95 In a paper published in 1971, Bridgman et al.96 reported reactions in seven

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out of a series of 22 patients injected with 90y resin, with no statistical improvement between the experimental and control groups. The author recognizes that the 3-mCi dose ofg~ used might have been too low but has hesitated to use a larger dose because of the risk of severe local and general reactions, and because of the possibility of producing radionecrosis of the cartilage and malignant change in the synovia. This remark indicates the benefit of such a treatment to be doubtful when weighed against its possible damage. THYROID

For the sake of this review all adverse reactions that are related to radioiodine treatments will be described under this "thyroid" heading. On the other hand, histologic changes of the gland undergoing thyroid ablation by radioiodine are beyond the scope of this review. Radioiodine is increasingly being used for the treatment of thyrotoxicosis and is suggested as the treatment of choice for thyrocardiac patients. In a survey on hospital death in Scotland, a series of 36 patients dying primarily from thyrotoxicosis was studied 97and it was noted that over 21~ of the deaths occurred within 3 weeks after n3tI therapy. Reports of death from thyrotoxicosis in thyroid crisis have been published previously, and are still being published currently with mortality rates of 20~ and over. 98.99This should be noted in comparison with the mortality rate after surgery, which is reported to be less than 1~. This seems to be a controversial issue: while Sandier and Wilson '~176 found no side effects from mI therapy, Lamberg et al) ~ reported 20 patients with adverse reactions out of 144 that were treated for toxic nodular goiter. Nemec et al) ~ described a rise in the blood level of iodinated organic compounds and impending thyrotoxic crisis after administration of n3~i to treat pulmonary metastases of differentiated thyroid carcinoma. A thyrotoxic crisis is a very rare complication of radioiodide treatment of thyrotoxicosis, but mild thyrotoxic manifestations in an euthyroid patient after administration of a thyroid-ablating dose are not uncommon and are explained by the destruction of thyroid tissue. In a case report Freeman~~ described acute thyroiditis, thyroid crisis, and transient hypocalcemia 5 days after a therapeutic dose of 3.5 mCi 131I for treatment of hyperthyroidism. The hypocalcemia was thought to be caused by enhanced release of thyrocalcitonin from the injured thyroidal tissue or by inflammatory processes affecting parathyroid function. Radioactive iodine therapy effectively controls hyperthyroidism in the majority of patients treated. However, the subsequent appearance of hypothyroidism is of increasing concern, especially as the cumulative incidence of hypothyroidism may affect a large percentage of the patients 10 years after radiotherapy. This fact has induced certain authors to reduce the dosage. In reviewing 424 patients with hyperthyroidism 7-16 years after their last dose of radioiodine treatment (maximum 50 #Ci ~3~I per gram thyroid), 334 patients were reexamined. Of these, 9.6~ were hypothyroid, while 2.1 ~o remained hyperthyroid, with 88.3~o euthyroid. In one-third of the euthyroid patients, increased TSH levels were detected. According to Reinwein et al) ~ fractionated radioiodine treatment was superior to standard procedures in avoiding hypothyroidism; thus, late hypothyroidism or the development of hypothyroidism from


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a subclinical stage need not be an inevitable risk of radioiodine treatment. Similar figures with even lower radioiodine doses were published by Jackson ~~ giving less than 10 mCi to 91~ of his study group, the incidence of hypothyroidism was 11~, with only 3~ of the patients remaining hyperthyroid. A comparative study of large and small doses of mI in the treatment of patients with cardiac damage associated with thyrotoxicosis, was published by Felt et al., ~~ revealing that thyrotoxicosis recedes more rapidly after large doses of radioiodine but is associated with a high incidence of hypothyroidism in subsequent years. After small doses of radioiodine the incidence of hypothyroidism is lower with a higher percentage of persisting thyrotoxicosis, the same trend which is expected in noncardiac patients. In a 5-year follow-up published in 1974, Cevallos 1~ recorded only five hypothyroid cases after two courses of t3lI to each of 102 thyrotoxic patients. The authors indicate that lowering the dosage levels to 80 ~Ci ~3~I per gram tissue reduces the frequency of posttherapy hypothyroidism, especially in the first year. However, the yearly increment of hypothyroidism appears greater with lower than with higher doses. It seems, therefore, that the ultimate development of hypothyroidism following the use of radioactive iodine in the treatment of hyperthyroidism should be well understood by both physicians and patients. An infrequent adverse reaction to ~3~I treatment of thyrotoxicosis is hypoparathyroidism) ~176 Although the clinical presentation of patients with hypoparathyroidism after 131Iadministration is not common, more frequent evaluations of serum calcium levels might have uncovered more instances of transient hypoparathyroid states. Adams and Chalmers ~" reported that 10~ of their patients undergoing ~3~Itherapy were unable to restore their calcium levels after it had been artificially lowered, which indicated a reduced parathyroid reserve, but no subsequent hypoparathyroidism was developed. Determination of the calcium values before and after administration of 131I might be a helpful parameter in assessing potential hypoparathyroidism. Irradiation of the parathyroid gland with radioactive iodine in an abnormal situation may cause tetany in hyperthyroid patients. Chronic tetany after isotopic treatment is very rare; on the other hand, patients often suffer temporary neuromuscular disorders with significant abnormalities in their electromyogram and symptoms of tetany, probably related to an abnormal temporary secretion of thyrocalcitonin.H2 The dose-effect relationship in the therapeutic application of 13~Iis very poor; thus, only a narrow margin of efficacy for 131Iexists between 80 and 130 ~Ci/g. There is a low incidence of myxedema, with a slow response at one end of the spectrum and a therapeutically effective response with a high occurrence of myxedema at the other end. "3 An investigation of the use of 125I as a substitute for 1311 has been undertaken by a number of investigators in the hope that the incidence of late myxedema could be reduced. So far the number of therapeutic studies of diffuse goiter with ~25Iare limited. Weidinger et al. TM reported after 5 years' experience with 1251that there was the same wide variability in sensitivity to t25I radiation as previously observed with 131I therapy, and that ~25Itreatment seemed to be only slightly more beneficial than ~3~I, having fewer ocular symptoms and a stable antithyroglobulin titer.

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According to Greig "5 30% of the 125I-treated patients became hypothyroid: doses of 400 ~Ci a2SI/g thyroid produced the best outcome 2 years after treatment, with 88~o being euthyroid, and only 10~ hypothyroid, and doses lower than 400 ttCi/g lowered the proportion of hypothyroid patients but increased the number who remained thyrotoxic and required retreatment. According to these authors, reduced hypothyroidism and lesser need for further retreatments make 1251somewhat superior to 131Iin treatment for hyperthyroidism. Similar initially favorable results were also reported by Siemsen et al. "6 Another adverse reaction to iodide therapy is the possible ablation of the thyroid of fetuses, whose mothers received millicurie doses of radioiodine during their pregnancies. Hypothyroidism, either congenital or of later onset, has been reported in at least six children whose mothers were treated with 131I during pregnancy.llT'l~s The risk of fetal radiochemical thyroidectomy increases with the onset of the iodine-concentrating ability of the fetal thyroid, at about the 74th gestational day. 117In a recent report by Jafek 119 a mother who had received 50 mCi of Na 131I at 14 weeks of gestation gave birth to a hypothyroid infant with hyperplasia in the region of the thyroid, with respiratory stridor, and tracheal stenosis at 2 days and respiratory obstruction at 5 months. A similar report was published by Exss 12~after 50 mCi Na 131I was administered to a 21-year-old woman bearing a 12-week-old fetus and should indicate a special alertness to the treatment of fertile women. The incidence of thyroid carcinoma formation after radioiodine therapy is a controversial issue. While epidemiologic surveys have shown that external radiation to the neck undoubtedly increases the incidence of carcinoma of the thyroid in children, 121 and an association between external radiation and thyroid neoplasia has also been shown to exist in adults, ~22by 1970 there were only ten cases of thyroid carcinoma following 131I therapy documented in the literature. 123,124 Many hundreds of thousands of patients have been treated with radioiodine, most commonly 1311and more recently 125I, but the low incidence of thyroid tumors found in patients treated with radioiodine is thus striking. A likely reason may be that only a small number of thyroids have been examined histologically after 131I therapy. Of 3770 thyrotoxic patients who had been treated with radioiodine in the Glasgow Royal Infirmary until October 1970, only one case of thyroid cancer was observed following radiotherapy. Nevertheless, there is a policy in Britain to restrict the use of radioactive iodine in the treatment of thyrotoxicosis to patients over 40 years of age.123 KIDNEY

Radiation dose to the kidney following the application of 2~ was published for animal experimentation in 1969.125 This drug caused distinct tubular damage, most probably as a result of both radiation and mercury poisoning. The disturbances in the permeability of the glomerular apparatus is interpreted as a result of the radiation damage. Further studies on 2~ and 197Hg-neohydrin in 45 patients who were subjected to scanning of the kidneys revealed suppression of the phagocytic reaction of neutrophils and monocytes, reduction of the metabolic intensity and aggravation of the pathologic processes of the kidney. The use of 197Hg-neohydrin caused fewer adverse reactions than 203Hg-neohydrin. 126


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In contrast to mercury-chlormerodrin, which is bound to the tubular cells of the kidney for several hours, orthoiodohippurate has a transit time in the normal kidney of a few minutes, and its side effects are expected to be minor. Surprisingly, in the 1971 SNM Registry, 14 adverse reactions to ~3q-o-iodohippurate were reported. These consisted of a feeling of weakness or dizziness at about the conclusion of the study. Most of the reactions were attributed to the emotional state of the patients or to antihypertensive medication, but pharmacologic effect of the radiopharmaceutical cannot be excluded. SKIN

The two published untoward reactions of radiopharmaceuticals to the skin were associated with improper injection of the drug. Patton ~27 described an ulcerated area in the forearm of a 62-year-old patient who received i.v. yttrium chloride-S~ (yttrium hydroxycitrate complex), a colloidal preparation administered at that time to attack certain neoplastic growths and for therapy of lymphatic leukemia. Some of the colloid particles apparently deposited in the perivascular tissues of the forearm and released 100,000 rads beta radiation in approximately 1 cu cm of tissue, during 8 weeks until dissected. Another case of local radiation damage to the skin caused by local colloid application was mentioned by Wolf in 1968.128 That was a skin ulceration after subcutaneous injection of colloidal radiogold. Two years later, Haas 129reported details of this case of chronic radiation damage to the skin at the injection site of colloidal 198Au for scintigraphy of retroperitoneal lymph nodes. The radiation dose to the patient from that injection was very high. Wright 63reported occasional reactions of an allergic type, with urticarial skin rash after sTmSr-citrate was administered. The number of those urticarial reactions was not large, and there was never a major incident. PERITONEUM

Gold-198 has been reported to cause adhesions of the abdomen after intraperitoneal administration of 120 mCi for therapeutic purposes. ~3~ Perhaps a smaller dose is sufficient. The use of chronic phosphate labeled with 32p results in a more superficial radiation distribution, perhaps lessening the chance of such a complication. In a retrospective analysis of 74 patients receiving intraperitoneal colloidal Cr32PO4 or colloidal 198Aufor treatment of ovarian cancer (stages I-III), minor complications (abdominal pain, ileus, fever or improper subcutaneous injection) occurred in ten patients (13.4~) and only one patient exhibited a major complication: a small bowel obstruction, which did not require surgery. ~3~The same major complication was reported by Decker, ~3~ who administered colloidal 198Au intraperitoneally as a supplementary treatment after operation to 142 patients with epithelial ovarian cancer. In 13 patients an obstruction of the small bowel was developed from 1-10 years after radiogold therapy. In one of them it was considered at laparotomy to be a result of a recurrent malignant lesion. These results confirm previous findings by Kettel et al., ~32who observed minor complications when 198Au-colloid was administered prophylactically into 209 ovarian cancer patients. This also confirms the first study by Rose 133 where the minor complications encountered following radiogold instillation were

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transient nausea in 42% and emesis in 30% of the patients. Diarrhea occurred in that study in 2% of the patients and transient low-grade fever in 30% of them. Serious complications, mainly due to improper injections, occurred in 4.3% of these cases, with no deaths, while the minor symptoms disappeared within 48-72 hr. PITUITARY

Since the early 1950s various investigators used radioactive substances to destroy the pituitary, mainly for treatment of metastasizing, hormone-dependent prostatic and breast cancers. The three isotopes used mostly for that treatment were Cr32po4, 9oy, and 198Au, but only Cr32po4 is a nonsealed source, which precipitates on injection and remains at the injection site. Some of those nuclides, in seed form, are used for radiohypophysectomy,~ but their effects, morphological and physiologic, are beyond the scope of this review. BLOOD AND LYMPH

Phosphorus-32 is a major therapy for polycythemia vera, aiming to reduce the blood count and blood viscosity. It seems that most of the cases of acute leukemia complicating polycythemia vera occur in patients treated with 32p, with an incidence of about 10%. Due to longer survival of polycythemia vera patients so treated, leukemic complication of treatment is more prominent, and the late appearance of anemia nearly always heralds acute leukemia. ~35 In an intensive survey of about 1100 polycythemia patients treated with 32p or receiving no radiation treatment, Modan and Lilienfeldt36'~37tried to answer whether radiophosphorus should still be recommended as a therapeutic measure for polycythemia vera patients. They found that 11% of the polycythemia vera, ~2p-treated group and 16.7% of those who had received combined treatment of 32p plus x-rays had died of acute leukemia, compared to less than 1% in the control group, which consisted of patients who had not been subjected to treatment with ionizing radiation. These findings support the hypothesis that 3zp plays a major role in the development of acute leukemia in polycythemia vera patients. Moreover, the increase in the length of survival of 3zP-treated patients seems minimal, thus indicating that the increased risk of leukemia does not necessarily follow a prolonged survival. Phosphorus-32treated leukemia patients undergo significant cytogenetic damage, which becomes noticeable 2 months after their treatment and affects a variety of cells. In a study by Barnes ~38the cytogenetic damage was randomly distributed throughout the chromosome groups of all patients. Although chromosome damage is a recognized side effect of radiation in general, it should be kept in mind in any case where systemic treatment with radioisotopes is given and its risk benefit carefully evaluated before the treatment. Endolymphatic radiotherapy with radioisotopes was suggested by Chiappa in 1961~39 and has been used since then in a limited number of institutions. Between 1969 and 1972 Jentzseh t4~ treated 131 patients with 32p, 13tl, or tSSAu combined with an oily contrast medium administered lymphatically and observed mainly local reactions after disturbances of the lymphatic flow. In those cases, stenosis of the ureter, possible reversible amenorrhea and late lung and liver side effects must be taken into account.

ADVERSE REACTIONS 10 RADIOPHARMACEUTICALS

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MISCELLANEOUS

In addition to the major types of reactions listed above, there are a number of other reactions that have occurred that do not appear to fit into any particular pattern. These are allergic and anaphylactoid-type responses to a variety of agents including 99mTc-pertechnetate, 99mTc-polyphosphate and diphosphonate, and others. These are listed in reports of the Registry of Adverse Reactions of the Society of Nuclear Medicine IA4t (Table 1). ADVERSE REACTIONS REGISTRY

Due to the rapidly increasing utilization o f radiopharmaceuticals in clinical research, the Society of Nuclear Medicine had decided in 1969 to establish a Registry on Adverse Reactions to Radiopharmaceuticals. Several registries for adverse reactions of (nonradioactive) drugs have existed on a national and international basis, such as the A M A Registry on Adverse Drug Reactions, but experience has shown that such programs are carried out with extreme difficulty and data so obtained are very incomplete. The stimulation leading to the establishment of an adverse reaction registry by the Society of Nuclear Medicine was the reporting of reactions to gelatin use as a stabilizer of 99mTc-sulfur colloid preparations. 73,74 In a young and rapidly growing field utilizing materials that were thought to be unusually safe, it was felt to be imperative that a true picture be obtained of the risks involved in the administration of radiopharmaceuticals. An initial survey was carried out for the years 1967-1969, and then the registry was set up on a continuing basis in 1971. The purposes of the registry are as follows: (1) To obtain an accurate assessment of the scope and frequency o f adverse reactions to radiopharmaceuticals; to accumulate, record, and disseminate this information. (2) To alert the profession to potential or actual problems before they become widespread. (3) To provide a data base for rational regulation of production and utilization of radiopharmaceuticals and to backfeed that information to the manufacturers and appropriate authorities. Maintaining such a registry of adverse reactions is notoriously difficult. The busy practitioner is prone to forget or put off filing the appropriate information. There is also difficulty in establishing what actually constitutes an adverse reaction and to classify reactions should they occur. Naturally, there is fear o f litigation arising out of such events unless confidentiality can be maintained. In addition, many adverse drug reactions are not reported to a nuclear medicine department by the primary physician. As an example, Goodwin reported m that a retrospective audit of patients who had had radionuclide cisternography revealed 14 adverse drug reactions of which only one had been reported to the Society of Nuclear Medicine and was therefore the only one that has been included by their registry. A newly proposed registry of adverse reactions to radiopharmaceuticals combines the efforts of the United States Food and Drug Administration (FDA), the United States Pharmacopoiea (USP), and the Society of Nuclear Medicine

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( S N M ) . It seeks to o v e r c o m e these p r o b l e m s by f r e q u e n t mailings o f report forms to the S N M m e m b e r s a n d e v e r y o n e i n v o l v e d in the a d m i n i s t r a t i o n o f r a d i o p h a r m a c e u t i c a l s is invited to cooperate. T h e identity o f the p e r s o n rep o r t i n g a n d the p a t i e n t are strictly protected, thus o b s e r v i n g confidentiality, a n d u n d e r such c o n d i t i o n s it will e n a b l e p u b l i c a t i o n o f m a t e r i a l for e d u c a t i o n a l purposes. A n o t h e r significant aspect o f a registry is g e n e r a t i o n o f data o n the u t i l i z a t i o n o f r a d i o p h a r m a c e u t i c a l s to c o m p l e m e n t the d a t a o n adverse reactions, thus leading to i n f o r m a t i o n o n their incidence. W i t h such i n f o r m a t i o n , r e g u l a t i o n s can be b a s e d o n a c t u a l experience a n d therefore be n o t o n l y a p p r o p r i a t e to the p r o b l e m b u t help to m i n i m i z e the adverse reactions to r a d i o p h a r m a c e u t i c a l s . ACKNOWLEDGMENT

The authors are indebted to Drs. Michael A. Davis and Buck Rhodes for their valuable remarks. REFERENCES

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Prevalence of adverse events to radiopharmaceuticals from 2007 to 2011.

Adverse reactions to monosulfiram.

Adverse Reactions to Sulphasalazine.

Adverse reactions to Althesin.

Adverse reactions to diuretics.

Adverse reactions to alclofenac.

Adverse reactions to rifampicin.

Adverse reactions to intravenous anaesthetics.

Monitoring adverse reactions to drugs.

Adverse reactions to i.v. agents.

Adverse reactions to intravenous thiopentone.

Letter: Adverse reactions to prazosin.

Monitoring adverse reactions to drugs.

Monitoring adverse reactions to drugs.

Letter: Adverse reactions to prazosin.

Adverse reactions to carbamazepine (tegretol).

Letter: Adverse reactions to practolol.

Adverse reactions to alcohol and alcoholic beverages.

Letter: Adverse reactions to intravenous anaesthetic agents.

Adverse reactions to intravenous induction agents.

Adverse reactions to plasma volume expanders.

Imaging of adverse reactions to metal debris.

Adverse reactions to intravenous induction agents.

Adverse reactions to drugs in general practice.