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Fluorescein Angiography Complication Survey
Fluorescein Angiography Complication Survey LAWRENCE A. YANNUZZI, MD, KATHLEEN T. ROHRER, MA, LORI J. TINDEL, MD, RUSSELL S. SOBEL, MS, MARCELLE A. COSTANZA, BA, WILLIAM SHIELDS, MA, EDITH ZANG, PhD
Abstract: This is a report on the results of a national survey designed to study the nature and frequency of moderate and severe complications of intravenous fluorescein angiography. In this survey, 2434 responding ophthalmologists reported on 221,781 fluorescein angiograms performed in the year 1984. Adverse reactions were classified as mild, moderate, severe, and death, depending on the duration of the effect, the necessity for medical intervention, the time required for its resolution, and the final outcome. The frequency rate for a moderate reaction was (1:63), for a severe reaction (1:1900), and for death (1:222,000). A review of previous studies on adverse reactions to the drug, a compilation of suggested methods for the amelioration and prevention of the complications, and a comparison of the responses of the general ophthalmic public to the members of The Macula Society are also reported. [Key words: adverse reactions, complications, fluorescein angiography, intravenous fluorescein.] Ophthalmology 93:611-617, 1986
For more than 20 years, intravenous fluorescein has been used to study the ocular fundus in a variety of chorioretinal disorders. Originally introduced as an investigative procedure, fluorescein angiography rapidly evolved as a valuable diagnostic adjunct to investigate pathophysiological mechanisms and as a therapeutic guide to laser photocoagulation treatment for several retinal vascular and pigment epithelial-choroidal diseases. The procedure has been regarded as relatively safe, although numerous side effects have been recorded in the ophthalmic literature. Previous studies on the complications of fluorescein angiography indicate that the most frequent adverse side effects are mild reactions such as nausea and vomiting. 1- 14 It is believed that moderate and severe reactions seldom occur. The frequency rates of these less commonly encountered adverse reactions have not been clearly established in the literature. 1•2 The purpose of this
From the LuEsther T. Mertz Retinal Research Laboratory of The Manhattan Eye, Ear and Throat Hospital, New York, and the Edward S. Harkness Eye Institute of the Columbia University School of Medicine, New York. Presented at an Annual Meeting of the American Academy of Ophthal· mology. Supported by Akorn, Inc., Abita Springs, Louisiana and the Macula Foundation, Inc., New York, New York. Reprints requests to Lawrence A. Yannuzzi, MD, 519 E. 72nd Street, New York, NY 10021.
paper is ( l) to review the available information on adverse reactions to intravenous fluorescein; (2) to establish an acceptable classification of complications of the drug; (3) to report on the results of a large-scale national survey, the Fluorescein Angiography Complication Survey (FACS), designed to provide information on the nature and frequency of moderate and severe complications; and (4) to assess the methodology employed by the ophthalmic community and the members of The Macula Society to ameliorate or prevent these reactions.
MATERIALS AND METHODS The Fluorescein Angiography Complication Survey
(FACS) was a survey of practicing ophthalmologists in
the United States and Puerto Rico. The American Medical Association list of 14,864 ophthalmologists was used for the mailing. AllllO members of The Macula Society were· surveyed. The study was designed primarily to document complications of intravenous fluorescein angiography noted during the year 1984. Specifically, the survey asked responders to indicate the number of fluorescein angiograms performed, the frequency and nature of complications noted, the type and percent of fluorescein solution employed, and the method of injection used in the technique. Other questions were directed at special considerations in angiography, including the need for informed 611
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Macula Society
Non-Macula Society
Overall
23% 56% 21% 0%
45% 43% 10% 2%
44% 43% 10% 2%
consent, the identity ofthe person performing the injection, the method of injection, the use of contradindications to the procedure such as pregnancy, renal failure, and severe allergic history, and the repetition of angiography in a patient exhibiting a previous reaction. Open comments and suggestions were also invited to assess other methods used in office and hospital practices to ameliorate or prevent complications. Adverse reactions were classified as mild, moderate, severe, and death, depending on the duration of the effect, the necessity for medical intervention, the time required for its resolution, and the final outcome. CLASSIFICATION OF ADVERSE REACTIONS
Mild adverse reaction. A mild reaction was characterized as a transient effect which did not require treatment. It is also a reaction that has a rapid and complete resolution with no sequelae. Nausea, vomiting, extravasation, sneezing, pruritis, and inadvertent arterial injection were classified as mild. Moderate adverse reaction. A moderate adverse reaction was also defined as a transient effect. With this type of complication, some form of medical treatment may be required. This reaction has a complete but gradual resolution with no sequelae nor threat to the patient's safety. Urticaria, syncope, other skin eruptions, thrombophlebitis, pyrexia, local tissue necrosis, and nerve palsy were categorized as moderate adverse reactions. Severe adverse reaction. A severe adverse reaction was defined as one exhibiting prolonged effects which required intense treatment. It also posed as a threat to the patient's safety, and it resulted in a variable recovery. A severe adverse reaction involved the respiratory, cardiac or neurological systems. Respiratory adverse reactions included laryngeal edema, bronchospasm, and anaphylaxis. Cardiac adverse reactions included circulatory shock, myocardial infarction and arrest. A tonic-clonic seizure was classified as an adverse neurological reaction. Death. Death was attributed to the use of intravenous fluorescein if symptoms were noted within 24 hours and the event occurred within 48 hours of the procedure. Respondents were asked to report the estimated frequency of mild reactions in four categories (less than 1%, 1-5%, 6-10%, and greater than 10%). Because of their anticipated low frequency, moderate and severe adverse reactions and death were recorded on the questionnaire as absolute frequencies, which were divided by the total number of angiograms performed to establish a rate. Some complications not listed on the questionnaire were also 612
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reported on the survey. These included sneezing, pruritis, and nerve palsy.
Table 1. Frequency of Mild Adverse Reactions
1% 1-5% 6-10% 10%
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STATISTICAL ANALYSIS
All responses to the survey questions were initially analyzed as a whole, and then in two groups, one composed of members of The Macula Society (MS) and the other composed of nonmembers ofThe Macula Society (NMS). Categorical variables, such as the frequency of complications, the use of various procedures, or Macula Society membership, were correlated using contingency table analysis. The statistical significance of observed differences in relative frequencies was evaluated through the chisquare test of association. An alpha error of 5% or lower was considered significant.
RESULTS The Fluorescein Angiography Complication Survey (FACS) received a total of 2434 completed forms, representing a 16% response rate. Only 1077 (44%) of the respondents performed at least one fluorescein angiogram in 1984. Of the 110 members of The Macula Society surveyed, 98 (89%) responded to the FACS. Overall, the survey reported on an estimated total of 221,781 fluorescein angiograms. The members of The Macula Society represented 57,267 (26%) of this total. FREQUENCY OF ADVERSE REACTIONS
Mild adverse reactions. The frequencies of mild adverse reactions as noted in the FACS are listed in Table 1. Overall, 44% of all respondents estimated a frequency of nausea and vomiting in less than 1% of their patients. A frequency of 1 to 5% was reported by 43% of all respondents. Thus, 87% of all respondents estimated the frequency of mild adverse reactions to be 5% or less. Another 10% of the overall responders reported an incidence of 6 to 10% of mild adverse reactions, and the remaining 2% indicated a rate greater than 10%. In the NMS group a frequency ofless than 1% for mild adverse reaction was reported by 45% of the respondents. An additional43% of the NMS indicated an incidence of 1 to 5%. Thus, a total of 88% of the NMS respondents estimated the frequency of nausea and vomiting to occur in 5% of patients or less. The NMS group reported a frequency rate of 6 to 10%, and 2% indicated a rate greater than 10%. In MS group, 23% of its members reported a rate of less than 1% for mild adverse reactions, and 56% of its members reported an incidence in 1 to 5% of their patients. This indicated that 79% of all MS respondents to this question estimated a mild adverse reaction frequency of 5% or less. The remaining 21% reported an incidence of 6 to 10%. A rate of greater than 10% was not reported by any Macula Society member. The only significant difference in the reported rates between the MS and NMS groups was in the greater than
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10% category (0% for MS and 2% for NMS). This difference was significant at P < 0.04. Moderate adverse reactions. The frequencies of moderate adverse reactions are listed in Table 2. The overall incidence ofthese reactions per angiogram was 1:63. The NMS group had a frequency of 1:58, and the MS had a frequency of 1:77 cases. There was no significant difference noted in the frequency of moderate reactions between the two groups. Urticaria was the most common moderate adverse reaction in the FACS, occurring in 1:75 angiograms. It was less commonly documented by the MS group ( 1: 115 cases), as compared to the NMS group (1 :77 cases) and this difference was statistically significant P < 0.0001). Overall, urticaria comprised 74% of all moderate reactions, syncope 18% and the others combined for a total of 8%. Syncope was reported with equal frequency ( 1:337 cases) by the two groups. The overall incidence of all other moderate adverse reactions was 1:769 cases. The NMS reported a slightly lower incidence ( 1:820) than the MS ( 1:637). This difference was not statistically significant. Severe adverse reactions. The frequency rates of severe adverse reactions are also summarized in Table 2. The overall frequency of these reactions in the FACS was 1: 1900 angiograms. The frequency for the NMS was 1: 1800 and for the NMS 1:2000. The overall rate of occurrence of tonic-clonic seizures was 1: 13,900 angiograms: 1:14,300 for the MS and 1:13,700 for the NMS. Respiratory adverse reactions were seen with an overall frequency of 1:3800 angiograms, with the MS reporting a lower rate of 1:5200 compared to the NMS, which had a rate of 1:3400. In contrast, the NMS reported a lower incidence of cardiac adverse reactions of 1:5700 compared to a 1:4400 frequency rate reported by the MS. The overall frequency for cardiac reactions was 1:5300 angiograms. No significant differences were found between the NS and NMS groups with respect to neurological, respiratory and cardiac severe adverse reactions. Death. One death was reported in the FACS, which suggests a death-risk rate of 1:222,000. THE FLUORESCEIN ANGIOGRAPHY TECHNIQUE
In reviewing the practices of respondents, the FACS indicated that there was a slight preference for Alcon's intravenous fluorescein dye by both groups (51% forMS and 43% for NMS). Overall, 22% of respondents indicated that they used Cooper Vision fluorescein; however, the MS members were significantly more likely to use this brand than the NMS group (P < 0.0003). A total of 33% of the respondents to this question used Akom intravenous fluorescein while 3% of the respondents did not use the Alcon, CooperVision or Akom fluorescein solutions. Instead, these ophthalomologists used a product that presumably was formulated by their institution or by a nonspecified pharmaceutical company. The majority of respondents (67%) indicated a preference for 10% fluorescein solution. Similarly, both groups preferred the butterfly needle injection method of administration (82% ), with 11% reporting use of a conventional needle and only 1% indicating use of a catheter. Only a
Table 2. Frequency of Moderate and Severe Adverse Reactions* Macula Society
Non-Macula Society
Overall
Moderate Urticaria Syncope Othert Any
1:115 1:337 1:637 1:77
1:75 1:337 1:820 1:58
1:82 1:337 1:769 1:63
Severe Respiratory reactions Cardiac reactions Tonic-clonic seizure Any
1:5,200 1:4,400 1:14,300 1:2,000
1:3,400 1:5,700 1:13,700 1:1 ,800
1:3,800 1:5,300 1:13,900 1:1,900
* Frequencies based on 221 ,781 angiograms performed in 1984 by 2434 respondents. t Thrombophlebitis, pyrexia, tissue necrosis and nerve palsy.
few respondents ( 17%) used prepacked fluorescein syringes, preinjection medication (3%) or a preinjection NPO state (3%). Overall, 16% of ophthalmologists responding to the survey indicated the use of oral fluorescein. Concerning this issue, respondents commented that they would occasionally use oral fluorescein to document cystoid macular edema or to evaluate children. No significant differences were noted between the NMS and MS groups with regard to these particular fluorescein angiographic practices. The respondents were equally divided with respect to their preferred need for informed consent prior to performing fluorescein angiography. Within each group, 48% did not use an informed consent, whereas 49% of the MS and 51% of the NMS felt it was prudent to obtain such a document. The survey asked respondents to indicate the identify of the primary injector of the fluorescein dye in their practices. The majority (69%) responded that they themselves administer the injection. The NMS group was more likely to do the injection themselves (72%) compared to the MS group (40% ). The MS was significantly more likely to use a nurse, another physician, and in particular a photographer to administer the dye (P < 0.001). The survey also asked responders to indicate whether they performed fluorescein angiography on pregnant women, on patients undergoing renal dialysis or on patients exhibiting mild or moderate adverse reactions to a previous study. The majority of ophthalmologists sur, veyed indicated that they would not perform a fluorescein angiogram on a pregnant patient (79% ofMS and 83% of NMS). This slight numerical difference between the two groups was statistically significant (P < 0.007). The two groups differed in their opinions regarding patients undergoing renal dialysis. Most of the MS members (80%) reported that they would perform fluorescein angiography on renal dialysis patients as compared to 56% of NMS members (P < 0.0001 ). Overall, the groups agreed that it was safe to repeat an angiogram in· a patient who had 613
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previously reacted with nausea or vomiting (99% of MS and 84% of NMS). Some repsonders used an antiemetic for premedication in these patients. Agreement did not exist with respect to urticaria. While 65% of the MS members reported that they would repeat an angiogram in a patient who previously developed urticaria, only 33% of the NMS group indicated that they would do this. This difference was statistically significant (P < 0.0001 ). In this section of the survey, there were a number of comments regarding patients with a history of severe allergies or asthmatic bronchitis. Several respondents viewed such histories as a relative contraindication for intravenous fluorescein angiography. Only a few respondents considered severe cardiovascular disease to be a relative contraindication to fluorescein angiography. CORRELATIONS
The most frequent side effects of intravenous fluorescein (nausea, vomiting, urticaria, and extravasation) were correlated with the studied angiographic methods. No significant correlation was found between the concentration of the fluorescein solutions (5%, IO% or 25%) and the frequency of these mild adverse reactions. Curiously, the use ofpreinjection medications was significantly associated with an increased frequency of nausea and vomiting (P < 0.04). No correlation was noted between the use of an informed consent and the frequency of these adverse reactions. This relationship was predicted in the comments section of the questionnaire by several respondents. No correlations were seen between the occurrence of urticaria and the various angiographic methods studied in the survey.
DISCUSSION In 1940, Gifford first remarked on the relative safety of intravenous fluorescein. 15 He had been using the dye to assess aqueous flow time in various anterior segment abnormalities. On the basis of his studies, he predicted that fluorescein could be useful in the study of diseases associated with altered vascular permeability such as hypertension and toxemia of pregnancy. Adverse reactions associated with the use of intravenous fluorescein were also reported in this period in the non ophthalmic literature by investigators who used the dye to study circulation times and peripheral vascular perfusion. 16·17 Twenty years later, Novotny and Alvis introduced fluorescein angiography of the ocular fundus. 18 The procedure soon became extensively used as a valuable aid to the study and treatment of various chorioretinal diseases. On the basis of the reports from the three principal manufacturers of the product in the United States (Alcon Laboratories, CooperVision Laboratories, and Akom, Inc.), approximately 650,000 fluorescein angiograms were performed in the United States in 1984. In this respect, fluorescein angiography rivals cataract surgery as the most frequently performed ophthalmologic procedure. 614
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Complications of this intravenous dye have been investigated in numerous studies over the past 25 years. 1- 14·19- 45 The adverse reactions associated with the dye have been reported to be mild consisting principally of nausea and vomiting at an incidence ranging from 0.6 to 18%. 1- 14 Nausea has consistently been the predominant reaction occurring in 3.3 to 15.25% of patients and vomiting has been reported to occur between 0 to 7% of the time. 3·6 •11 •12 The next most frequent adverse reaction according to previous reports is urticaria, occurring in approximately 0.5% of the patients. 12 Because of their infrequent occurrence, most moderate adverse reactions and all severe adverse reactions have been documented almost exclusively as case reports. Therefore, their exact incidence is unclear. Althot1gh there are several case reports of severe reaction involving anaphylaxis and even cardiac arrest, death has been previously reported in the ophthalmic literature in only two patients.1,13,23,35,36 Data analysis for the Fluorescein Angiographic Complication Survey (FACS) was based on a simple and logical classification for adverse reactions. The methods for categorizing these reactions appear to be rational and practical for documenting complications in the FACS as well as in future studies. The results ofthe FACS confirm previous observations that most reactions associated with the use of intravenous fluorescein are mild. The F ACS also provides for the first time information regarding the frequency of moderate to severe reactions as well as the death rate associated with the use of the drug. An overall rate of 1: 63 for a moderate adverse reaction was estimated by the survey. It is no surprise that urticaria was the principle moderate reaction and syncope the second most frequent. An overall rate of 1: 1900 for a severe reaction is supportive of the relative safety of the intravenous drug. In this category of adverse reactions, the complications are primarily of a cardio-pulmonary nature, with respiratory difficulties occurring in 1:3800 of the cases, cardiac disturbances in 1:5300 of the cases and the neurological abnormality of tonic-clonic seizures occurring in I: I3,900 procedures. The F ACS also established an intravenous fluoresceinrelated death risk of 1:222,000. When compared to other intravenous solutions used commonly in diagnostic studies, intravenous fluorescein again appears to be an extremely safe drug. For example, the death risk for radio opaque dye used in intravenous pyelograms is 1:40,000. 28 Furthermore, the Collaborative Study of Coronary Artery Surgery (CASS) reported an overall mortality rate associated with coronary arteriography to be I :500. 46 The National Registry of Drug-Induced Side Effects has kept a ledger of reported intravenous fluorescein related deaths in the United States since I976. The Registry reveals only one fatality per year associated with the use of the drug. 28 These infrequent reports further support the relative safety of intravenous fluorescein. There are essentially two ways to reduce or eliminate complications of a diagnostic intravenous drug. The first is to identify and modify the pathophysiologic mechanisms of the adverse reactions, and the second is to alter the procedure in order to avoid or reduce reactions re-
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gardless of their exact cause. For most adverse side effects, it would be most appropriate to employ measures which modify the basic mechanisms of these reactions. This approach is still not possible for intravenous fluorescein since the precise pathogenic mechanisms of its adverse reactions are not clearly understood. Some proposed mechanisms include the following: ( 1) a vaso-vagal phenomenon resulting in bradycardia, hypotension, and reduced cardiovascular perfusion; 10•18·23 ·31 (2) a drug allergy of the immediate hypersensitivity type (immunological response to a hapten-protein configuration); 1·18 (3) a histamine release of a non-allergic nature in the absence of an antigenantibody reaction; 1 (4) an anxiety-related medullary sympathetic discharge, eliciting tachycardia and myocardial stress; 10•21 (5) a direct vasospastic toxic effect of the intravenous injection; 10 ( 6) an effect of a contaminant in the formulation of the drug; 43 (7) a direct systemic effect of the topical mydriatics, particularly phenylephrine;45 A8·49 and (8) any combination of the above potential factors. The F ACS was able to assess certain practices used in the fluorescein angiographic technique to minimize adverse reactions. An NPO state by patients to minimize nausea and vomiting proved to be utilized by only 3% of responding ophthalmologists. Several respondents recommended the use ofpremedications such as Phenergan®, Compazine®, or Tigan® prior to the injection of the dye to prevent nausea and vomiting. Curiously, the FACS noted a higher frequency of nausea and vomiting in premedicated patients which casts considerable doubt on the efficacy of this approach to minimizing mild, adverse reactions. The use of these drugs might amplify a patient's anxiety. The patient's emotional status, rather than the medication itself may be responsible for the increased frequency of side effects in these patients. In the comments section of the survey, several respondents predicted that the informed consent might also serve to heighten a patient's anxiety state, and induce mild adverse reactions, but this did not prove to be the case. Patients signing informed consents were no more likely to experience adverse reactions than those who did not. The type and percentage of fluorescein used in the technique have been frequent variables in the assessment of adverse reactions. The F ACS indicated no difference in adverse reaction rates relative to the concentration (5%, 10%, and 25%) of fluorescein used. This concurs with a previous report. 47 The F ACS also has provided information on the practical management of patients with a pregnancy, renal failure, severe allergies, asthmatic bronchitis, severe cardiovascular disease, and a previous history of nausea, vomiting or urticaria following intravenous fluorescein. In spite of animal studies revealing no teratogenicity and human experience indicating no fetal or maternal morbidity, the ophthalmic community felt that fluorescein angiography should generillly not be carried out in a pregnant patient.27·33·50 A few indicated that the procedure should be considered only if there was a threat to vision such as juxtafoveal s11bretinal neovascularization, preferably during the late second or third trimester of the pregnancy. Most responders perform fluorescein angiography in
patients undergoing renal dialysis or angiography in patients who previously exhibited nausea or even vomiting. With respect to patients previously exhibiting urticaria, a number of responders felt that fluorescein angiography could be carried oqt in these patients only under certain urgent situations such as juxtafoveal subretinal neovascularization. Many respondents also indicated that additional precautions such as premedication with Benadryl or another antihistamine and the presence of a medicalanesthesiological team were advisable. The F ACS recorded 29 cases of anaphylaxis and 58 episodes of bronchospasm in 1984. The ophthalmic literature documents several cases of such reactions, leading to life threatening situations. Numerous respondents to the FACS believed that patients with a history of allergies or asthmatic bronchitis were predisposed to this severe adverse reaction. A few respondents suggested certain restrictions in people with a history of severe cardio-vascular disease. There was also considerable caution regarding the use of topical phenylephrine as a mydriatic, in all patients, particularly those with cardiovascular disease. In the evaluation of severe cardiopulmonary adverse reactions secondary to intravenous fluorescein, it is important to keep in mind that the use of topical phenylephrine alone and even mere venopuncture have been reported to be associated with severe adverse reactions, including myocardial infarction and arrest. 48·49·51 - 54 One responder to the survey described a patient who suffered a fatal myocardial infarction while having routine fundus photography. The authors are aware of a fatal myocardial infarction in a patient who was waiting to be registered in an ophthalmic reception area. It is therefore reasonable to assume that some severe adverse reactions following intravenous fluorescein are not due to the drug, but to the procedure or to coincidence. Furthermore, the cardiovascular safety of intravenous fluorescein is also supported by one study which found no cardio-toxic effect of fluorescein angiography when an electrocardiogram was taken before, during, and after the procedure. 31 It is still prudent, however, to insure that the necessary medical equipment for the treatment of severe adverse reactions is immediately available to manage cardiopulmonary complications during fluorescein angiography. These include standby oxygen, epinephrine, steroids, and a resuscitative crash cart at immediate disposal. The equipment required in the office or hospital setting to handle such severe adverse reactions has been covered in the ophthalmic literature. 55 Based on the findings in the FACS, a commonly !!mployed practice guideline for fluorescein angiography can be derived. Ophthalmologists in the USA generally use· one of the 10% solutions available through the three leading manufacturers. The dye is injected with a butterfly needle by a physician or the delegated and trained assistant. No specific premedication is usually required; nor is the NPO state. Fluorescein angiograms are not routinely carried out in patients who are pregnant. Similarly, patients with severe allergies, asthmatic bronchitis or a history of urticaria following a previous injection, should have a repeat fluorescein angiogram only with good reason and possibly with premedication. Patients on renal di615
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alysis, exhibiting nausea or vomiting following a previous fluorescein angiogram or reporting a history of cardiovascular disease can be advised to undergo the procedure on a fairly routine basis. Numerous other factors not reviewed by the FACS have been previously implicated in the intravenous fluorescein complication rate. Factors such as speed and pressure of injection, temperature and purity of the solution, age, sex, and psychological or medical state of the patient were not addressed by the FACS since the authors did not believe that a retrospective determination of these variables could be carried out with reasonable accuracy. Greene et al found male patients to react adversely more frequently than females to the use of intravenous fluorescein. 5 Some respondents volunteered that the incidence of side effects decrease if the fluorescein solution was warmed prior to injection and if the room were kept cool. These suggestions are consistent with the management techniques outlined by Levacy and Justice. 6 Pacurariu has reported a higher complication rate in individuals ten years younger than the average patient undergoing fluorescein angiography. 11 Chazan et al noted that nausea was infrequent when injections were made at high pressure and speed, and these investigators recommended the use of an automatic injector. 3 This study also noted a higher incidence of nausea when patients were asked specifically if they experienced nausea. 3 Previous studies have also implicated the formulation of the solution as a factor affecting the complication rate. Yannuzzi et al reported a concentration-dependent effect related to adverse reactions in comparing different formulations.25 Jacob and co-workers implicated dimethyl formamide, a toxic contaminent of crude sodium fluorescein, with adverse reactions to intravenous dye. 44 Another possible complication of intravenous fluorescein not covered by the FACS is related to the "blue light hazard." This is the phenomenon of retinal damage from light exposure associated with the procedure rather than a reaction induced by the drug itself. In patients with chorioretinal diseases, light exposure during angiography represents a potential hazard to the retina relative to the spectral content of the light, the retinal irradiance, the exposure time, and the threshold for cellular damage. 56 The mechanisms of photochemical damage induced by these factors are still not clearly understood. It is certain, however, that retinal damage is wavelength dependent, notably the blue end of the visible spectrum and the ultraviolet range. This evidence is acknowledged by increasing and converging lines of clinical and experimental research. Undeniably, the majority oflight exposure during fluorescein angiography is in the 460 to 500 nm or blue range where retinal damage is produced by low levels of irradiance. However, Marshall has pointed out that fundus photography as well as fluorescein angiography pose as potential threats for retinal damage. 56 In fact, the potential hazard of fundus photography appears to be greater than that of fluorescein angiography because of its higher irradiance. The increased irradiance of fundus photography outweighs the wavelength dependency factor associated with fluorescein angiography. The recognition 616
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of this hazard has led retinal specialists to use faster color film which requires lower levels of irradiance. It is important to keep in mind that fundus photography, as well as fluorescein angiography, are still below the maximum permissible exposure levels with respect to retinal damage. Obviously, the whole concept of phototoxic damage to the retina or the so-called blue light hazard, warrants further research to elucidate the potentially damaging effects of fluorescein angiography fundus photography and all other forms of light exposure in the ophthalmic setting, including ophthalmoscopy and microsurgery. On the basis of the F ACS, ophthalmologists can once again be reassured that their important diagnostic aid, fluorescein angiography, is indeed a relatively safe procedure, particularly when compared to other diagnostic intravenous procedures in allied medical specialties. A simple and rational classification of adverse reactions to intravenous fluorescein has been proposed. More definitive values on the exact incidence of moderate to severe reactions are now available through the FACS. In addition, the absence of major differences between the reports of the members of the MS and the overall ophthalmic community indicates that the methods employed by members of the MS are fairly indicative of the procedures practiced in the ophthalmic community as a whole. This is an important consideration, since it is much easier and probably far more reliable to survey this small, highly responsive specialty group for the investigation of other aspects of the management of chorioretinal diseases in the future.
ACKNOWLEDGMENTS The authors thank Janet Kennaugh for typing the paper and The National Registry of Drug-induced Ocular Side Effects for its valuable assistance.
REFERENCES 1. Amalric P, Biau C, Fenies MT. Incidents et accidents au cours de l'angiographie fluoresceinique. Bull Soc Ophtalmol Fr 1968; 68:96872. 2. Stein MR, Parker CW. Reactions following intravenous fluorescein. Am J Ophthalmol 1971; 72:861-8. 3. Chazan Bl, Balodimos MC, Koncz L. Untoward effects of fluorescein retinal angiography in diabetic patients. Ann Ophthalmol 1971; 3:42-9. 4. Miki T, Sunada I, YoshidaS, et al. Side effects of intravenous sodium fluorescein in fluorescence fundus angiography with special reference to intracutaneous testing of the drug. Jpn J Clin Ophthalmol 1972; 26:693-6. 5. Greene GS, Bell LW, Hitching RA, Spaeth GL. Adverse reaction to intravenous fluorescein: evidence for sex difference. Ann Ophthalmol 1976; 8:533-6. 6. Levacy RA, Justice J Jr. Adverse reactions to intravenous fluorescein. lnt Ophthalmol Clin 1976; 16(2):53-61. 7. Marcus OF, Eitenee C. Clinical study of the adverse effects of sodium fluorescein as used in fluorescein angiography. Presented at Ocular Toxicology Symposium, Little Rock, Arkansas 1977. 8. Bloome MA. Fluorescein angiography: risks. Vision Res 1980; 20: 1083-97.
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9. Coscas G, Binaghi M, Faure M. Incidents et accidents au cours de l'angiographie en fluorescence. Conf Lyon Ophtalmol 1980; 145:522. 10. Heffner JE. Reactions to fluorescein. JAMA 1980; 243:2029-30. 11 . Pacurariu Rl. Low incidence of side effects following intravenous fluorescein angiography. Ann Ophthalmol1982; 14:32-6. 12. Butner RW, McPherson AR. Adverse reactions in intravenous fluorescein angiography. Ann Ophthalmol1983; 15:1084-6. 13. Zografos L. Enquete internationale sur !'incidence des accidents graves ou fatals pouvant survenir Iars d'une angiographie fluoresceinique. Klin Monatsbl Augenheilkd 1983; 182:460-2. 14. Marcus DF, Bovino JA, Williams D. Adverse reactions during intravenous fluorescein angiography. Arch Ophthalmol1984; 102:825. 15. Gifford H. Use of fluorescein intravenously as an aid to ophthalmic diagnosis and treatment. Arch Ophthalmol1940; 24:122-31. 16. Winsor T, Adolph W, Ralston W, Leiby GM. Fractional circulation times using fluorescent tracer substances. Am Heart J 1947; 34:80-6. 17. Lange K, Boyd LJ. Use of fluorescein method in establishment of diagnosis and prognosis of peripheral vascular diseases. Arch Intern Med 1944; 74:175-84. 18. Novotny HR, Alvis DL. A method of photographing fluorescence in circulating blood in the human retina. Circulation 1961; 24:82-6. 19. lngelstedt S, lvstarn B. Hypersensitivity to fluorescein; a case of anaphylactic reaction to the injection of fluorescein sodium. lnt Arch Allergy Appl lrnrnunol 1950; 1:157-9. 20. Maclean AC, Maumenee AE. Hemangioma of the choroid. Arn J Ophthalrnol 1960; 50:3-11. 21. Linhart JW, Mcintosh HD, Heyman A, Hart LM. Clinical experience with fluorescence retinal cinematography. Circulation 1964; 29:57782. 22. Scott DJ, Dollery CT, Hill DW, et al. Fluorescein studies of diabetic retinopathy. Br Med J 1964; 1:811-4. 23. LaPiana FG, Penner R. Anaphylactoid reaction to intravenously administered fluorescein. Arch Ophthalmol 1968; 79:161-2. 24. Krill AE. Annual ARO meeting. Am J Ophthalmol1969; 68:160-3. 25. Yannuzzi LA, Justice J, Baldwin HA. Effective differences in the formulation of intravenous fluorescein and related side effects. Am J Ophthalmol1974; 78:217-21. 26. Hayreh SS. Recent advances in fluorescein fundus angiography. Br J Ophthalmol1974; 58:391-412. 27. Shirai S, Majirna A. Effects of fluorescein-Na injected to mother mice on the embryo. Folia Ophthalmol J 1975; 26:132-7. 28. Fraunfelder FT, Meyer SM. National Registry of Drug-Induced Ocular Side Effects. 1976-1984. 29. Hess JB, Pacurariu Rl. Acute pulmonary edema following intravenous fluorescein angiography. Arn J Ophthalrnol1976; 82:567-70. 30. Deglin SM. Deglin EA. Chung EK. Acute myocardial infarction following fluorescein angiography. Heart Lung 1977; 6:505-9. 31. Byers NT, LaPiana FG. The electrocardiogram during fluorescein angiography. Arn J Ophthalrnol 1977; 83:928-9. 32. Tanaka M, Ozawa K, Majirna A, et al. An autopsy case of basilar artery stenosis following fluorescein fundus angiography. Jpn J Clin Ophthalmol1977; 31:1259-64. 33. McEnerney JK, Wong WP, Peyrnan GA. The evaluation of teratogenicity of fluorescein sodium. Am J Ophthalrnol1977; 84:847-50. 34. Schatz H. Sloughing of skin following fluorescein extravasation. Ann Ophthalrnol1978; 10:625.
35. Madowitz JS, Schweiger MJ. Severe anaphylactoid reaction to radiographic contrast media; recurrence despite premedication with diphenhydramine and prednisone. JAMA 1979; 241:2313-5. 36. Cunningham EE, Venkataraman B. Cardiac arrest following fluorescein angiography. JAMA 1979; 242:2431. 37. Kratz RP, Mazzocco TR, Davidson B. A case report of skin necrosis following infiltration with I.V. fluorescein. Ann Ophthalrnol 1980; 12: 654-6. 38. Pinto G, Motolese E, Malagola R, Vilardi V. Effetti secondari indesiderati in corso di fluoroangiografia. Ann Ottalrnol 1980; 106:435-40. 39. Ansell G, Tweedie MCK, West CR, et al. The current status of reactions to intravenous contrast media. Invest Radiol1980; 15(Suppi):S32-9. 40. McAllister RG Jr. Hypertensive crisis and myocardial infarction after fluorescein angiography. South Med J 1981; 74:508-9. 41. Feigelman MJ, Fine SL, Yannuzzi LA, et al. Skin necrosis following fluorescein extravasation. Presented to the Macula Society Meeting, 1984. 42. Bovino JA, Marcus DF. Accidental intra-arterial injection of fluorescein dye. Ophthalmic Surg 1984; 15:983-4. 43. Jacob JSH, Rosen ES, Young E. Report on the presence of a toxic substance, dimethyl forrnarnide, in sodium fluorescein used for fluorescein angiography. Br J Ophthalmol1982; 66:567-8. 44. Arroyave CM, Wolbers R, Ellis PP. Plasma complement and histamine changes after intravenous administration of sodium fluorescein. Am J Ophthalrnol1979; 87:474-9. 45. Wesley RE, Blount WC, Arterberry JF. Acute myocardial infarction after fluorescein angiography. Am J Ophthalrnol1979; 87:834-5. 46. Davis K, Kennedy JW, Kemp HG Jr, et al. Complications of coronary arteriography from the collaborative study of coronary artery surgery (CASS). Circulation 1979; 59:1105-12. 47. Justice J Jr, Paton D, Beyrer CR, Seddon GG. Clinical comparison of 10% and 25% intravenous sodium fluorescein solutions. Arch Ophthalrnol1977; 95:2015-6. 48. Vaughan RW. Ventricular arrhythmias after topical vasoconstrictors. Anesth Analg 1973; 52:161-5. 49. Tizes R. Cardiac arrest vs extreme bradycardia. JAMA 1978; 240: 213. 50. Soubrane G, Canivet J, Coscas G. Influence of pregnancy on the evolution of background retinopathy: preliminary results of a prospective fluorescein angiography study. In: Ryan SJ, Dawson AK, Little HL, eds. Retinal Diseases. Orlando FL: Grune & Stratton, 1985; 15-20. 51. Fraunfelder FT, Scafidi AF. Possible adverse effects from topical ocular 10% phenylephrine. Arn J Ophthalmol1978; 85:447-53. 52. Robertson D. Contraindication to the use of ocular phenylephrine in idiopathic orthostatic hypotension. Arn J Ophthalmol 1979; 87:81922. 53. Raghuprasad PK. Venipuncture and cardiac arrest. JAMA 1979; 241: 134-5. 54. Wesley RE. Phenylephrine eyedrops and cardiovascular accidents after fluorescein angiography. JOcular Ther Surg 1983; 2:212-4. 55. Schatz H, Burton TC, Yannuzzi LA, Raab MF. Interpretation of Fundus Fluorescein Angiography. St Louis: CV Mosby, 1978. 56. Marshall J. Light damage and the practice of ophthalmology. In: Rosel'1 ES, Haining WM, Arnott EJ, eds. Intraocular Lens Implantation. St Louis: CV Mosby, 1984; 182-207.
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Abstract: This is a report on the results of a national survey designed to study the nature and frequency of moderate and severe complications of intravenous fluorescein angiography. In this survey, 2434 responding ophthalmologists reported on 221,781 fluorescein angiograms performed in the year 1984. Adverse reactions were classified as mild, moderate, severe, and death, depending on the duration of the effect, the necessity for medical intervention, the time required for its resolution, and the final outcome. The frequency rate for a moderate reaction was (1:63), for a severe reaction (1:1900), and for death (1:222,000). A review of previous studies on adverse reactions to the drug, a compilation of suggested methods for the amelioration and prevention of the complications, and a comparison of the responses of the general ophthalmic public to the members of The Macula Society are also reported. [Key words: adverse reactions, complications, fluorescein angiography, intravenous fluorescein.] Ophthalmology 93:611-617, 1986
For more than 20 years, intravenous fluorescein has been used to study the ocular fundus in a variety of chorioretinal disorders. Originally introduced as an investigative procedure, fluorescein angiography rapidly evolved as a valuable diagnostic adjunct to investigate pathophysiological mechanisms and as a therapeutic guide to laser photocoagulation treatment for several retinal vascular and pigment epithelial-choroidal diseases. The procedure has been regarded as relatively safe, although numerous side effects have been recorded in the ophthalmic literature. Previous studies on the complications of fluorescein angiography indicate that the most frequent adverse side effects are mild reactions such as nausea and vomiting. 1- 14 It is believed that moderate and severe reactions seldom occur. The frequency rates of these less commonly encountered adverse reactions have not been clearly established in the literature. 1•2 The purpose of this
From the LuEsther T. Mertz Retinal Research Laboratory of The Manhattan Eye, Ear and Throat Hospital, New York, and the Edward S. Harkness Eye Institute of the Columbia University School of Medicine, New York. Presented at an Annual Meeting of the American Academy of Ophthal· mology. Supported by Akorn, Inc., Abita Springs, Louisiana and the Macula Foundation, Inc., New York, New York. Reprints requests to Lawrence A. Yannuzzi, MD, 519 E. 72nd Street, New York, NY 10021.
paper is ( l) to review the available information on adverse reactions to intravenous fluorescein; (2) to establish an acceptable classification of complications of the drug; (3) to report on the results of a large-scale national survey, the Fluorescein Angiography Complication Survey (FACS), designed to provide information on the nature and frequency of moderate and severe complications; and (4) to assess the methodology employed by the ophthalmic community and the members of The Macula Society to ameliorate or prevent these reactions.
MATERIALS AND METHODS The Fluorescein Angiography Complication Survey
(FACS) was a survey of practicing ophthalmologists in
the United States and Puerto Rico. The American Medical Association list of 14,864 ophthalmologists was used for the mailing. AllllO members of The Macula Society were· surveyed. The study was designed primarily to document complications of intravenous fluorescein angiography noted during the year 1984. Specifically, the survey asked responders to indicate the number of fluorescein angiograms performed, the frequency and nature of complications noted, the type and percent of fluorescein solution employed, and the method of injection used in the technique. Other questions were directed at special considerations in angiography, including the need for informed 611
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Macula Society
Non-Macula Society
Overall
23% 56% 21% 0%
45% 43% 10% 2%
44% 43% 10% 2%
consent, the identity ofthe person performing the injection, the method of injection, the use of contradindications to the procedure such as pregnancy, renal failure, and severe allergic history, and the repetition of angiography in a patient exhibiting a previous reaction. Open comments and suggestions were also invited to assess other methods used in office and hospital practices to ameliorate or prevent complications. Adverse reactions were classified as mild, moderate, severe, and death, depending on the duration of the effect, the necessity for medical intervention, the time required for its resolution, and the final outcome. CLASSIFICATION OF ADVERSE REACTIONS
Mild adverse reaction. A mild reaction was characterized as a transient effect which did not require treatment. It is also a reaction that has a rapid and complete resolution with no sequelae. Nausea, vomiting, extravasation, sneezing, pruritis, and inadvertent arterial injection were classified as mild. Moderate adverse reaction. A moderate adverse reaction was also defined as a transient effect. With this type of complication, some form of medical treatment may be required. This reaction has a complete but gradual resolution with no sequelae nor threat to the patient's safety. Urticaria, syncope, other skin eruptions, thrombophlebitis, pyrexia, local tissue necrosis, and nerve palsy were categorized as moderate adverse reactions. Severe adverse reaction. A severe adverse reaction was defined as one exhibiting prolonged effects which required intense treatment. It also posed as a threat to the patient's safety, and it resulted in a variable recovery. A severe adverse reaction involved the respiratory, cardiac or neurological systems. Respiratory adverse reactions included laryngeal edema, bronchospasm, and anaphylaxis. Cardiac adverse reactions included circulatory shock, myocardial infarction and arrest. A tonic-clonic seizure was classified as an adverse neurological reaction. Death. Death was attributed to the use of intravenous fluorescein if symptoms were noted within 24 hours and the event occurred within 48 hours of the procedure. Respondents were asked to report the estimated frequency of mild reactions in four categories (less than 1%, 1-5%, 6-10%, and greater than 10%). Because of their anticipated low frequency, moderate and severe adverse reactions and death were recorded on the questionnaire as absolute frequencies, which were divided by the total number of angiograms performed to establish a rate. Some complications not listed on the questionnaire were also 612
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reported on the survey. These included sneezing, pruritis, and nerve palsy.
Table 1. Frequency of Mild Adverse Reactions
1% 1-5% 6-10% 10%
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STATISTICAL ANALYSIS
All responses to the survey questions were initially analyzed as a whole, and then in two groups, one composed of members of The Macula Society (MS) and the other composed of nonmembers ofThe Macula Society (NMS). Categorical variables, such as the frequency of complications, the use of various procedures, or Macula Society membership, were correlated using contingency table analysis. The statistical significance of observed differences in relative frequencies was evaluated through the chisquare test of association. An alpha error of 5% or lower was considered significant.
RESULTS The Fluorescein Angiography Complication Survey (FACS) received a total of 2434 completed forms, representing a 16% response rate. Only 1077 (44%) of the respondents performed at least one fluorescein angiogram in 1984. Of the 110 members of The Macula Society surveyed, 98 (89%) responded to the FACS. Overall, the survey reported on an estimated total of 221,781 fluorescein angiograms. The members of The Macula Society represented 57,267 (26%) of this total. FREQUENCY OF ADVERSE REACTIONS
Mild adverse reactions. The frequencies of mild adverse reactions as noted in the FACS are listed in Table 1. Overall, 44% of all respondents estimated a frequency of nausea and vomiting in less than 1% of their patients. A frequency of 1 to 5% was reported by 43% of all respondents. Thus, 87% of all respondents estimated the frequency of mild adverse reactions to be 5% or less. Another 10% of the overall responders reported an incidence of 6 to 10% of mild adverse reactions, and the remaining 2% indicated a rate greater than 10%. In the NMS group a frequency ofless than 1% for mild adverse reaction was reported by 45% of the respondents. An additional43% of the NMS indicated an incidence of 1 to 5%. Thus, a total of 88% of the NMS respondents estimated the frequency of nausea and vomiting to occur in 5% of patients or less. The NMS group reported a frequency rate of 6 to 10%, and 2% indicated a rate greater than 10%. In MS group, 23% of its members reported a rate of less than 1% for mild adverse reactions, and 56% of its members reported an incidence in 1 to 5% of their patients. This indicated that 79% of all MS respondents to this question estimated a mild adverse reaction frequency of 5% or less. The remaining 21% reported an incidence of 6 to 10%. A rate of greater than 10% was not reported by any Macula Society member. The only significant difference in the reported rates between the MS and NMS groups was in the greater than
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10% category (0% for MS and 2% for NMS). This difference was significant at P < 0.04. Moderate adverse reactions. The frequencies of moderate adverse reactions are listed in Table 2. The overall incidence ofthese reactions per angiogram was 1:63. The NMS group had a frequency of 1:58, and the MS had a frequency of 1:77 cases. There was no significant difference noted in the frequency of moderate reactions between the two groups. Urticaria was the most common moderate adverse reaction in the FACS, occurring in 1:75 angiograms. It was less commonly documented by the MS group ( 1: 115 cases), as compared to the NMS group (1 :77 cases) and this difference was statistically significant P < 0.0001). Overall, urticaria comprised 74% of all moderate reactions, syncope 18% and the others combined for a total of 8%. Syncope was reported with equal frequency ( 1:337 cases) by the two groups. The overall incidence of all other moderate adverse reactions was 1:769 cases. The NMS reported a slightly lower incidence ( 1:820) than the MS ( 1:637). This difference was not statistically significant. Severe adverse reactions. The frequency rates of severe adverse reactions are also summarized in Table 2. The overall frequency of these reactions in the FACS was 1: 1900 angiograms. The frequency for the NMS was 1: 1800 and for the NMS 1:2000. The overall rate of occurrence of tonic-clonic seizures was 1: 13,900 angiograms: 1:14,300 for the MS and 1:13,700 for the NMS. Respiratory adverse reactions were seen with an overall frequency of 1:3800 angiograms, with the MS reporting a lower rate of 1:5200 compared to the NMS, which had a rate of 1:3400. In contrast, the NMS reported a lower incidence of cardiac adverse reactions of 1:5700 compared to a 1:4400 frequency rate reported by the MS. The overall frequency for cardiac reactions was 1:5300 angiograms. No significant differences were found between the NS and NMS groups with respect to neurological, respiratory and cardiac severe adverse reactions. Death. One death was reported in the FACS, which suggests a death-risk rate of 1:222,000. THE FLUORESCEIN ANGIOGRAPHY TECHNIQUE
In reviewing the practices of respondents, the FACS indicated that there was a slight preference for Alcon's intravenous fluorescein dye by both groups (51% forMS and 43% for NMS). Overall, 22% of respondents indicated that they used Cooper Vision fluorescein; however, the MS members were significantly more likely to use this brand than the NMS group (P < 0.0003). A total of 33% of the respondents to this question used Akom intravenous fluorescein while 3% of the respondents did not use the Alcon, CooperVision or Akom fluorescein solutions. Instead, these ophthalomologists used a product that presumably was formulated by their institution or by a nonspecified pharmaceutical company. The majority of respondents (67%) indicated a preference for 10% fluorescein solution. Similarly, both groups preferred the butterfly needle injection method of administration (82% ), with 11% reporting use of a conventional needle and only 1% indicating use of a catheter. Only a
Table 2. Frequency of Moderate and Severe Adverse Reactions* Macula Society
Non-Macula Society
Overall
Moderate Urticaria Syncope Othert Any
1:115 1:337 1:637 1:77
1:75 1:337 1:820 1:58
1:82 1:337 1:769 1:63
Severe Respiratory reactions Cardiac reactions Tonic-clonic seizure Any
1:5,200 1:4,400 1:14,300 1:2,000
1:3,400 1:5,700 1:13,700 1:1 ,800
1:3,800 1:5,300 1:13,900 1:1,900
* Frequencies based on 221 ,781 angiograms performed in 1984 by 2434 respondents. t Thrombophlebitis, pyrexia, tissue necrosis and nerve palsy.
few respondents ( 17%) used prepacked fluorescein syringes, preinjection medication (3%) or a preinjection NPO state (3%). Overall, 16% of ophthalmologists responding to the survey indicated the use of oral fluorescein. Concerning this issue, respondents commented that they would occasionally use oral fluorescein to document cystoid macular edema or to evaluate children. No significant differences were noted between the NMS and MS groups with regard to these particular fluorescein angiographic practices. The respondents were equally divided with respect to their preferred need for informed consent prior to performing fluorescein angiography. Within each group, 48% did not use an informed consent, whereas 49% of the MS and 51% of the NMS felt it was prudent to obtain such a document. The survey asked respondents to indicate the identify of the primary injector of the fluorescein dye in their practices. The majority (69%) responded that they themselves administer the injection. The NMS group was more likely to do the injection themselves (72%) compared to the MS group (40% ). The MS was significantly more likely to use a nurse, another physician, and in particular a photographer to administer the dye (P < 0.001). The survey also asked responders to indicate whether they performed fluorescein angiography on pregnant women, on patients undergoing renal dialysis or on patients exhibiting mild or moderate adverse reactions to a previous study. The majority of ophthalmologists sur, veyed indicated that they would not perform a fluorescein angiogram on a pregnant patient (79% ofMS and 83% of NMS). This slight numerical difference between the two groups was statistically significant (P < 0.007). The two groups differed in their opinions regarding patients undergoing renal dialysis. Most of the MS members (80%) reported that they would perform fluorescein angiography on renal dialysis patients as compared to 56% of NMS members (P < 0.0001 ). Overall, the groups agreed that it was safe to repeat an angiogram in· a patient who had 613
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previously reacted with nausea or vomiting (99% of MS and 84% of NMS). Some repsonders used an antiemetic for premedication in these patients. Agreement did not exist with respect to urticaria. While 65% of the MS members reported that they would repeat an angiogram in a patient who previously developed urticaria, only 33% of the NMS group indicated that they would do this. This difference was statistically significant (P < 0.0001 ). In this section of the survey, there were a number of comments regarding patients with a history of severe allergies or asthmatic bronchitis. Several respondents viewed such histories as a relative contraindication for intravenous fluorescein angiography. Only a few respondents considered severe cardiovascular disease to be a relative contraindication to fluorescein angiography. CORRELATIONS
The most frequent side effects of intravenous fluorescein (nausea, vomiting, urticaria, and extravasation) were correlated with the studied angiographic methods. No significant correlation was found between the concentration of the fluorescein solutions (5%, IO% or 25%) and the frequency of these mild adverse reactions. Curiously, the use ofpreinjection medications was significantly associated with an increased frequency of nausea and vomiting (P < 0.04). No correlation was noted between the use of an informed consent and the frequency of these adverse reactions. This relationship was predicted in the comments section of the questionnaire by several respondents. No correlations were seen between the occurrence of urticaria and the various angiographic methods studied in the survey.
DISCUSSION In 1940, Gifford first remarked on the relative safety of intravenous fluorescein. 15 He had been using the dye to assess aqueous flow time in various anterior segment abnormalities. On the basis of his studies, he predicted that fluorescein could be useful in the study of diseases associated with altered vascular permeability such as hypertension and toxemia of pregnancy. Adverse reactions associated with the use of intravenous fluorescein were also reported in this period in the non ophthalmic literature by investigators who used the dye to study circulation times and peripheral vascular perfusion. 16·17 Twenty years later, Novotny and Alvis introduced fluorescein angiography of the ocular fundus. 18 The procedure soon became extensively used as a valuable aid to the study and treatment of various chorioretinal diseases. On the basis of the reports from the three principal manufacturers of the product in the United States (Alcon Laboratories, CooperVision Laboratories, and Akom, Inc.), approximately 650,000 fluorescein angiograms were performed in the United States in 1984. In this respect, fluorescein angiography rivals cataract surgery as the most frequently performed ophthalmologic procedure. 614
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Complications of this intravenous dye have been investigated in numerous studies over the past 25 years. 1- 14·19- 45 The adverse reactions associated with the dye have been reported to be mild consisting principally of nausea and vomiting at an incidence ranging from 0.6 to 18%. 1- 14 Nausea has consistently been the predominant reaction occurring in 3.3 to 15.25% of patients and vomiting has been reported to occur between 0 to 7% of the time. 3·6 •11 •12 The next most frequent adverse reaction according to previous reports is urticaria, occurring in approximately 0.5% of the patients. 12 Because of their infrequent occurrence, most moderate adverse reactions and all severe adverse reactions have been documented almost exclusively as case reports. Therefore, their exact incidence is unclear. Althot1gh there are several case reports of severe reaction involving anaphylaxis and even cardiac arrest, death has been previously reported in the ophthalmic literature in only two patients.1,13,23,35,36 Data analysis for the Fluorescein Angiographic Complication Survey (FACS) was based on a simple and logical classification for adverse reactions. The methods for categorizing these reactions appear to be rational and practical for documenting complications in the FACS as well as in future studies. The results ofthe FACS confirm previous observations that most reactions associated with the use of intravenous fluorescein are mild. The F ACS also provides for the first time information regarding the frequency of moderate to severe reactions as well as the death rate associated with the use of the drug. An overall rate of 1: 63 for a moderate adverse reaction was estimated by the survey. It is no surprise that urticaria was the principle moderate reaction and syncope the second most frequent. An overall rate of 1: 1900 for a severe reaction is supportive of the relative safety of the intravenous drug. In this category of adverse reactions, the complications are primarily of a cardio-pulmonary nature, with respiratory difficulties occurring in 1:3800 of the cases, cardiac disturbances in 1:5300 of the cases and the neurological abnormality of tonic-clonic seizures occurring in I: I3,900 procedures. The F ACS also established an intravenous fluoresceinrelated death risk of 1:222,000. When compared to other intravenous solutions used commonly in diagnostic studies, intravenous fluorescein again appears to be an extremely safe drug. For example, the death risk for radio opaque dye used in intravenous pyelograms is 1:40,000. 28 Furthermore, the Collaborative Study of Coronary Artery Surgery (CASS) reported an overall mortality rate associated with coronary arteriography to be I :500. 46 The National Registry of Drug-Induced Side Effects has kept a ledger of reported intravenous fluorescein related deaths in the United States since I976. The Registry reveals only one fatality per year associated with the use of the drug. 28 These infrequent reports further support the relative safety of intravenous fluorescein. There are essentially two ways to reduce or eliminate complications of a diagnostic intravenous drug. The first is to identify and modify the pathophysiologic mechanisms of the adverse reactions, and the second is to alter the procedure in order to avoid or reduce reactions re-
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gardless of their exact cause. For most adverse side effects, it would be most appropriate to employ measures which modify the basic mechanisms of these reactions. This approach is still not possible for intravenous fluorescein since the precise pathogenic mechanisms of its adverse reactions are not clearly understood. Some proposed mechanisms include the following: ( 1) a vaso-vagal phenomenon resulting in bradycardia, hypotension, and reduced cardiovascular perfusion; 10•18·23 ·31 (2) a drug allergy of the immediate hypersensitivity type (immunological response to a hapten-protein configuration); 1·18 (3) a histamine release of a non-allergic nature in the absence of an antigenantibody reaction; 1 (4) an anxiety-related medullary sympathetic discharge, eliciting tachycardia and myocardial stress; 10•21 (5) a direct vasospastic toxic effect of the intravenous injection; 10 ( 6) an effect of a contaminant in the formulation of the drug; 43 (7) a direct systemic effect of the topical mydriatics, particularly phenylephrine;45 A8·49 and (8) any combination of the above potential factors. The F ACS was able to assess certain practices used in the fluorescein angiographic technique to minimize adverse reactions. An NPO state by patients to minimize nausea and vomiting proved to be utilized by only 3% of responding ophthalmologists. Several respondents recommended the use ofpremedications such as Phenergan®, Compazine®, or Tigan® prior to the injection of the dye to prevent nausea and vomiting. Curiously, the FACS noted a higher frequency of nausea and vomiting in premedicated patients which casts considerable doubt on the efficacy of this approach to minimizing mild, adverse reactions. The use of these drugs might amplify a patient's anxiety. The patient's emotional status, rather than the medication itself may be responsible for the increased frequency of side effects in these patients. In the comments section of the survey, several respondents predicted that the informed consent might also serve to heighten a patient's anxiety state, and induce mild adverse reactions, but this did not prove to be the case. Patients signing informed consents were no more likely to experience adverse reactions than those who did not. The type and percentage of fluorescein used in the technique have been frequent variables in the assessment of adverse reactions. The F ACS indicated no difference in adverse reaction rates relative to the concentration (5%, 10%, and 25%) of fluorescein used. This concurs with a previous report. 47 The F ACS also has provided information on the practical management of patients with a pregnancy, renal failure, severe allergies, asthmatic bronchitis, severe cardiovascular disease, and a previous history of nausea, vomiting or urticaria following intravenous fluorescein. In spite of animal studies revealing no teratogenicity and human experience indicating no fetal or maternal morbidity, the ophthalmic community felt that fluorescein angiography should generillly not be carried out in a pregnant patient.27·33·50 A few indicated that the procedure should be considered only if there was a threat to vision such as juxtafoveal s11bretinal neovascularization, preferably during the late second or third trimester of the pregnancy. Most responders perform fluorescein angiography in
patients undergoing renal dialysis or angiography in patients who previously exhibited nausea or even vomiting. With respect to patients previously exhibiting urticaria, a number of responders felt that fluorescein angiography could be carried oqt in these patients only under certain urgent situations such as juxtafoveal subretinal neovascularization. Many respondents also indicated that additional precautions such as premedication with Benadryl or another antihistamine and the presence of a medicalanesthesiological team were advisable. The F ACS recorded 29 cases of anaphylaxis and 58 episodes of bronchospasm in 1984. The ophthalmic literature documents several cases of such reactions, leading to life threatening situations. Numerous respondents to the FACS believed that patients with a history of allergies or asthmatic bronchitis were predisposed to this severe adverse reaction. A few respondents suggested certain restrictions in people with a history of severe cardio-vascular disease. There was also considerable caution regarding the use of topical phenylephrine as a mydriatic, in all patients, particularly those with cardiovascular disease. In the evaluation of severe cardiopulmonary adverse reactions secondary to intravenous fluorescein, it is important to keep in mind that the use of topical phenylephrine alone and even mere venopuncture have been reported to be associated with severe adverse reactions, including myocardial infarction and arrest. 48·49·51 - 54 One responder to the survey described a patient who suffered a fatal myocardial infarction while having routine fundus photography. The authors are aware of a fatal myocardial infarction in a patient who was waiting to be registered in an ophthalmic reception area. It is therefore reasonable to assume that some severe adverse reactions following intravenous fluorescein are not due to the drug, but to the procedure or to coincidence. Furthermore, the cardiovascular safety of intravenous fluorescein is also supported by one study which found no cardio-toxic effect of fluorescein angiography when an electrocardiogram was taken before, during, and after the procedure. 31 It is still prudent, however, to insure that the necessary medical equipment for the treatment of severe adverse reactions is immediately available to manage cardiopulmonary complications during fluorescein angiography. These include standby oxygen, epinephrine, steroids, and a resuscitative crash cart at immediate disposal. The equipment required in the office or hospital setting to handle such severe adverse reactions has been covered in the ophthalmic literature. 55 Based on the findings in the FACS, a commonly !!mployed practice guideline for fluorescein angiography can be derived. Ophthalmologists in the USA generally use· one of the 10% solutions available through the three leading manufacturers. The dye is injected with a butterfly needle by a physician or the delegated and trained assistant. No specific premedication is usually required; nor is the NPO state. Fluorescein angiograms are not routinely carried out in patients who are pregnant. Similarly, patients with severe allergies, asthmatic bronchitis or a history of urticaria following a previous injection, should have a repeat fluorescein angiogram only with good reason and possibly with premedication. Patients on renal di615
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alysis, exhibiting nausea or vomiting following a previous fluorescein angiogram or reporting a history of cardiovascular disease can be advised to undergo the procedure on a fairly routine basis. Numerous other factors not reviewed by the FACS have been previously implicated in the intravenous fluorescein complication rate. Factors such as speed and pressure of injection, temperature and purity of the solution, age, sex, and psychological or medical state of the patient were not addressed by the FACS since the authors did not believe that a retrospective determination of these variables could be carried out with reasonable accuracy. Greene et al found male patients to react adversely more frequently than females to the use of intravenous fluorescein. 5 Some respondents volunteered that the incidence of side effects decrease if the fluorescein solution was warmed prior to injection and if the room were kept cool. These suggestions are consistent with the management techniques outlined by Levacy and Justice. 6 Pacurariu has reported a higher complication rate in individuals ten years younger than the average patient undergoing fluorescein angiography. 11 Chazan et al noted that nausea was infrequent when injections were made at high pressure and speed, and these investigators recommended the use of an automatic injector. 3 This study also noted a higher incidence of nausea when patients were asked specifically if they experienced nausea. 3 Previous studies have also implicated the formulation of the solution as a factor affecting the complication rate. Yannuzzi et al reported a concentration-dependent effect related to adverse reactions in comparing different formulations.25 Jacob and co-workers implicated dimethyl formamide, a toxic contaminent of crude sodium fluorescein, with adverse reactions to intravenous dye. 44 Another possible complication of intravenous fluorescein not covered by the FACS is related to the "blue light hazard." This is the phenomenon of retinal damage from light exposure associated with the procedure rather than a reaction induced by the drug itself. In patients with chorioretinal diseases, light exposure during angiography represents a potential hazard to the retina relative to the spectral content of the light, the retinal irradiance, the exposure time, and the threshold for cellular damage. 56 The mechanisms of photochemical damage induced by these factors are still not clearly understood. It is certain, however, that retinal damage is wavelength dependent, notably the blue end of the visible spectrum and the ultraviolet range. This evidence is acknowledged by increasing and converging lines of clinical and experimental research. Undeniably, the majority oflight exposure during fluorescein angiography is in the 460 to 500 nm or blue range where retinal damage is produced by low levels of irradiance. However, Marshall has pointed out that fundus photography as well as fluorescein angiography pose as potential threats for retinal damage. 56 In fact, the potential hazard of fundus photography appears to be greater than that of fluorescein angiography because of its higher irradiance. The increased irradiance of fundus photography outweighs the wavelength dependency factor associated with fluorescein angiography. The recognition 616
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of this hazard has led retinal specialists to use faster color film which requires lower levels of irradiance. It is important to keep in mind that fundus photography, as well as fluorescein angiography, are still below the maximum permissible exposure levels with respect to retinal damage. Obviously, the whole concept of phototoxic damage to the retina or the so-called blue light hazard, warrants further research to elucidate the potentially damaging effects of fluorescein angiography fundus photography and all other forms of light exposure in the ophthalmic setting, including ophthalmoscopy and microsurgery. On the basis of the F ACS, ophthalmologists can once again be reassured that their important diagnostic aid, fluorescein angiography, is indeed a relatively safe procedure, particularly when compared to other diagnostic intravenous procedures in allied medical specialties. A simple and rational classification of adverse reactions to intravenous fluorescein has been proposed. More definitive values on the exact incidence of moderate to severe reactions are now available through the FACS. In addition, the absence of major differences between the reports of the members of the MS and the overall ophthalmic community indicates that the methods employed by members of the MS are fairly indicative of the procedures practiced in the ophthalmic community as a whole. This is an important consideration, since it is much easier and probably far more reliable to survey this small, highly responsive specialty group for the investigation of other aspects of the management of chorioretinal diseases in the future.
ACKNOWLEDGMENTS The authors thank Janet Kennaugh for typing the paper and The National Registry of Drug-induced Ocular Side Effects for its valuable assistance.
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