Risk of Cataract among Interventional Cardiologists and Catheterization Lab Staff: A Systematic Review

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1 Catheterization and Cardiovascular Interventions 00:00 00 (2017) Original Studies Risk of Cataract among Interventional Cardiologists and Catheterization Lab Staff: A Systematic Review and Meta-Analysis Ahmed Elmaraezy, 1,2 Mostafa Ebraheem Morra, 1 Abdelrhman Tarek Mohammed, 1 Ahmed AL-HABAA, 3 Ahmed Elgebaly, 1 Ahmed Abdelmotaleb Ghazy, 4 Adham M. Khalil, 5 Nguyen Tien Huy, 6,7 * and Kenji Hirayama 8 Objectives: We performed a systematic review and meta-analysis to assess the risk of developing a radiation-induced cataract in interventional cardiologists (ICs). Background: ICs are forced to radiation exposure during cardiac catheterization procedures. Since the eye lens is one of the most radiosensitive organs in the body, ICs are highly susceptible to develop a radiation-induced cataract. Method: We performed a systematic literature search of nine electronic databases to retrieve studies that report cataract among interventional cardiologists. Records were screened for eligibility and data were extracted and analyzed using review manager (RevMan) for windows. Results: Eight studies involving 2559 subjects (exposed ICs ) were included. Posterior lens opacity was significantly higher in ICs relative to the control group (RR5 3.21, 95% CI [2.14, 4.83], P < ). In contrast, there was no significant difference between both groups in cortical lens opacity (RR5 0.69, 95% CI [0.46, 1.06], P ) and nuclear opacity (RR5 0.85, 95% CI [0.71, 1.02], P ). Conclusion: Interventional cardiologists are at high risk of developing radiation-induced cataract; therefore, protective measures with high safety rates should be implied. VC 2017 Wiley Periodicals, Inc. Key words: interventional cardiologists; radiation; cataract; meta-analysis Additional Supporting Information may be found in the online version of this article. 1 Faculty of Medicine, Al-Azhar University, Cairo, 11884, Egypt 2 Online Research Club, Nagasaki University, Nagasaki, Japan 3 Department of Cardiology, Faculty of Medicine, Al-Azhar University, Cairo, Egypt 4 Department of Cadiology, Shebin El-Kom Teaching Hospital, 31515, Egypt Menofia 5 Faculty of Medicine, Zagazig University, Zagazig, 44519, Egypt 6 Evidence Based Medicine Research Group & Faculty of Applied Sciences, Ton Duc Thang University, Ho Chi Minh City, Vietnam 7 Department of Clinical Product Development, Institute of Tropical Medicine (NEKKEN), Leading Graduate School Program, and Graduate School of Biomedical Sciences, Nagasaki University, Sakamoto, Nagasaki, , Japan 8 Department of Immunogenetics, Institute of Tropical Medicine (NEKKEN), Leading Graduate School Program, and Graduate School of Biomedical Sciences, Nagasaki University, Sakamoto, Nagasaki, , Japan Ahmed Elmaraezy and Mostafa Ebraheem Morra contributed equally to this work. Conflict of interest: Nothing to report. Contract grant sponsor: Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan; Contract grant number: 16H05844, Contract grant sponsor: Japan Initiative for Global Research Network on Infectious Diseases. *Correspondence to: Nguyen Tien Huy, Evidence Based Medicine Research Group & Faculty of Applied Sciences, Ton Duc Thang University, Ho Chi Minh City, Vietnam. nguyentienhuy@ tdt.edu.vn Received 7 September 2016; Revision accepted 8 April 2017 DOI: /ccd Published online 00 Month 2017 in Wiley Online Library (wileyonlinelibrary.com) VC 2017 Wiley Periodicals, Inc.

2 2 Elmaraezy et al. INTRODUCTION Biological hazards of ionizing radiation are welldocumented. The increased carcinogenic risk is observed on exposure to an acute radiation dose of msv, whereas long-term exposure demands higher accumulated dose ( msv) to induce carcinogenesis [1]. Tissues with direct exposure to radiation, such as skin and eyes, are more liable to radiation-induced pathologies. Direct exposure to radiation at a dose of 2-3 Gy is associated with skin erythema within a few hours and cataract at approximately 6 months post exposure [2]. Moreover, previous data have shown that direct radiation exposure is correlated with a marked decline in the lymphocytic count [3]. Being directly exposed to radiation, the eye lens is one of the most radiosensitive tissues in the body [4,5]. A characteristic, dose-dependent progressive lens opacification usually occurs as a result of ocular exposure to ionizing radiation [6,7]. Anatomically, clinical cataract presents at three main forms: posterior subcapsular (PSC), cortical, and nuclear. Although it is the least common type, PSC cataract results in a significant impairment of vision owing to its location along the vertical axis of the lens [5]. Furthermore, PSC cataract is the most prevalent radiation-induced type. Medical radiation forms a considerable portion of artificial radiation exposure [8]. The wider use of medical imaging as a diagnostic and intervention-guiding tool has led to increasing exposure to ionizing radiation among medical staff [9]. Interventional cardiologists (ICs) are among the most intensive users of fluoroscopy during imaging guided procedures [9]. It is postulated that occupational exposures in the interventional cardiology theater are the highest doses received by health professionals [9 11]. The dramatic rise of occupational X- ray exposure among ICs over the past 30 years has led to increased risk of radiation injury [12,13]. Lack of training on radiation protection and not using or unavailability of protective measures largely boosts such harmful effects and results in accumulation of large doses of radiation sufficient to induce cataract [14]. It is well-known that exposure to large doses of ionizing radiation induces lens opacification [15]. However, the current disagreement includes lower occupational doses which are expected to be within the accepted range of annual exposure limits [16,17]. Since 2010, several studies have investigated the association between cataract and occupational radiation exposure among ICs. Several methodological shortcomings were addressed and inconsistency was observed among the findings of these studies. Therefore, the current comprehensive systematic review and meta-analysis aimed to provide a thorough view of the current evidence regarding the association between lens opacification and radiation exposure in interventional cardiologists. MATERIALS AND METHODS Sources Nine medical electronic databases (PubMed, Scopus, ISI Web of Science, POPLINE, Virtual Health Library (VHL), System for Information on Grey Literature in Europe (SIGLE), Global Health Library (GHL), The New York Academy of Medicine (NYAM), and google scholar) were searched from inception to October, The following search queries were used independently or in combination according to the medical subject heading (MESH) terms: interventional cardiologists, cardiologist, lens opacification, cataract, lens opacity, ionizing radiation, radiation, X-ray, fluoroscopy, and medical imaging. For google scholar, the advanced search option was used. The reference lists of relevant reviews and articles were further scanned for additional relevant studies. Study Selection Records retrieved from the searches were imported into Endnote X7. Endnote software was used for references managing, omitting duplicates, and screening. Duplicated articles were removed and abstracts of the remaining references were screened by two independent reviewers for eligibility in our review. The full-text articles of potentially relevant abstracts were retrieved for further scrutiny. We included case-control, cohort, and cross-sectional studies addressing the association between radiation exposure and cataract in ICs. Case reports, animal studies, and uncontrolled studies were excluded. Reviews were retrieved for the purpose of screening the reference lists for potentially eligible studies but did not contribute to the final number of included studies. There was no restriction with respect to language, date, country, or ethnic group. Measures of Radiation Exposure Effect The primary outcome that measured the effect of radiation exposure on the eye of ICs, was that the posterior lens opacity was defined as characteristic radiationinduced lens changes, examined by slit lamp examination, and evaluated by at least two independent observers under the supervision of an expert. We also considered cortical, nuclear, and all types of lens opacity as secondary outcomes. Data Extraction Data extraction was carried out using a custom data extraction form designed specifically for this review.

3 Risk of Cataract among in IC s 3 The following data were extracted from each study by three authors independently: title, authors, year, country, study design, number of participants in each group, mean age, gender, number of years working in interventional cardiology, lens equivalent dose (cumulative dose) of radiation, data for quality assessment, number of events and total number of participants in each group for PSC cataract, cortical cataract, nuclear cataract, and any type of opacification. Quality Assessment Methodological quality assessment of the included articles was performed according to the nine metrics recommended by Pai et al. [18] and Well et al. [19]. These metrics were as follows: study design, characteristics of the patient population, data collection, patient selection, inclusion and exclusion criteria, method quality, blinded interpretation of factors, and description of diagnosis. The quality of study methodology was described by the proportion of studies adhering to each of the nine criteria. abstract screening phase. The full-text articles of the remaining 42 references were screened for eligibility in our review and meta-analysis. Finally, eight studies [22 29] with a total of 2559 participants were included in this review; (Fig. 1; PRISMA flow diagram). Characteristics of Included Studies Included references consisted of four case-control studies, three prospective cohorts, and one crosssectional study. All studies were conducted between 2010 and A total of 2559 subjects (1224 exposed personnals and 1335 unexposed controls) were investigated upon in the included studies. Age ranged between 34 and 63 years and the total working years in interventional cardiology ranged between 5 and 21.9 years. Most of the studies used slit lamp examination for detection of lens opacities, and cataract was graded using the Merriam Focht scoring system [30] and LCOS III grading guidelines [31]. Summary of the included studies and baseline characteristics of their population are presented in (Table I). Data Synthesis Review manager (RevMan) -the Cochrane Collaboration tool for meta-analysis, quality assessment tables and figures generating- version 5.3 for windows was used for quantitative synthesis. Dichotomous data were pooled as relative risk (RR) bounded by their 95% confidence interval (CI) in a fixed effect meta-analysis model using the Mantel-Haenzel (M-H) method. Heterogeneity among studies was assessed by visual inspection and using the I-square and Chi-square tests. Chi-square P value of <0.1 indicated significant heterogeneity. In the case of significant heterogeneity (P <0.1), sensitivity analysis was performed and random effects model was adopted. According to Egger and colleagues [20,21], publication bias assessment is not reliable for less than 10 pooled studies. Therefore, in the present study, we could not assess the existence of publication bias by egger s test for funnel plot asymmetry. Subgroup Analysis We performed a subgroup analysis to test for the effect of radiation dose. Data from two subgroups (<1 Sv and 1 Sv) were pooled and common effect size was estimated. RESULTS Search Results Electronic search yielded 659 citations. Of them, 292 records were duplicates, and 325 were excluded in the Outcomes Prevalence of overall posterior lens opacities. Our analysis indicated that the pooled prevalence of overall posterior lens opacities among ICs was 33.4% (95% CI [19.6%, 50.9%]). The overall prevalence of any lens opacity was 36% (95% CI [6%, 84%]). Risk of posterior lens opacity among ICs. Data of PSC lens opacity was provided by five studies [22,24 26,29] including 556 participants. The studies were consistent in terms of statistical heterogeneity (I 2 5 0%, P ) and fixed effect model was adopted. Exposed ICs were shown to be at a higher risk of developing PSC cataract compared with unexposed controls (RR5 3.21, 95% CI [2.14, 4.83], P < ); (Fig. 2). Risk of cortical and nuclear lens opacities. Two hundred and forty-one participants were investigated for cortical and nuclear opacities in two studies [26,29]. No heterogeneity was noted between these studies (I 2 5 0%, P ) and fixed-effect model was used. The summary RR did not favor either of the two groups in terms of occurrence of cortical and nuclear opacification (RR5 0.69, 95% CI [0.46, 1.06], P ) and (RR5 0.85, 95% CI [0.71, 1.02], P ), respectively; (Fig.3 A and B). Risk of any lens opacity. Four studies (2129 participants) compared the risk of developing any type of lens opacity among ICs exposed to ionizing radiation and unexposed controls [23,26 28]. There was a substantial heterogeneity among these studies (I %, P < 0.001); therefore, the analysis was performed under the random effects model. The overall risk was higher

4 4 Elmaraezy et al. Fig. 1. PRISMA flow diagram of studies screening and selection. among exposed ICs, but this result was not statistically significant (RR5 2.61, 95% CI [0.68, 10], P ); (Fig. 4). Sensitivity analysis was conducted to check for the effect of individual studies on the summary effect size. Neither of the included studies significantly changed the overall effect estimate except for Jacob et al. [26] which removal resulted in a significant higher risk of lens opacification among exposed ICs (RR5 3.76, 95% CI [1.35, 10.49], P5 0.01; (Supporting Information File 1). Association between lens opacity and other occupational factors. Jacob et al. [26] investigated the association between cataract and occupational factors related to the catheterization lab. Lens opacification was significantly correlated with the duration of work in catheterization lab and wearing protective lead eyeglasses. Doctors who performed cardiac catheterization for more than 25 years and those who used lead eyeglasses less than 75% of time had significantly higher prevalence of lens opacities (adjusted odds ratio (aor)5 5.94, 95% CI [1.08, 36.62] and (aor5 3.87, 95% CI [1.28, 11.68]), respectively. Subgroup analysis. Two studies [24,25] stratified participants according to the cumulative radiation dose (<1 Svor1 Sv) and provided data on PSC cataract in each dose stratum. Pooling data from these studies resulted in a significantly increased risk of PSC cataract in both groups compared to non-exposed controls (RR5 2.93, 95% CI [1.52, 5.67], P ) and (RR5 3.83, 95% CI [1.81, 8.09], P ) for the <1 Sv and 1 Sv, respectively. When the 1 Sv group was compared to <1 Sv, there was a non-significant increased risk (RR % CI [0.86, 1.86], P ); (Fig. 5). Nonetheless, this result should be interpreted cautiously since it may be compromised by the very limited sample size (53 participants in the 1 Sv group and 66 in the <1 Sv group). Furthermore, this non-significant difference is contradictory to the well-documented association between radiation dose and risk of cataract [26].

5 Risk of Cataract among in IC s 5 TABLE I. Summary of Included Studies and Baseline Characteristics Study population Years working in interventional cardiology, Age group: mean (SD) Author/year Case Control mean (SD) Case Control Main result Auvinen 2015 Radiologists:16 16 ND No increase in lens opacification between ICs: 3 Surgeons: 2 exposed and non-exposed Rajabi 2015 ICs: (8.5) (6.9) Risk of cataract is related to dose exposure Jacob 2013 ICs: (8.7) 51.1 (7.3) 49.6 (6.7) ICs are at high risk of PSC Vano 2013 With opacity 28 Case 16.6 (9.3) 47.7 (8.8) 43.3 (11.2) ICs and support staff are at high risk of ICs: 27 Control 12 (8.5) PSC lens changes Without opacity 41 Case 10.4 (8.9) 41.5 (9.5) 35.4 (8.8) ICs: 27 Control 8.4 (6.7) Ciraj-Bjelac 2012 ICs: (6) 43 (9) 40 (16) ICs and support staff are at high risk of Support staff: 22 5(4) 34 (9) 40 (16) PSC Lens changes Ciraj-Bjelac 2010 ICs: (6.9) 42 (7) 44 (9) ICs and support staff are at high risk Nurses: 11 6 (4.6) 38 (11) 44 (9) of cataract Vano 2010 ICs: (8) 46 (8) 41 (10) ICs are at high risk of cataract While less Paramedical: (5) 38 (7) 41 (10) common in paramedicals Yuan 2010 ICs: ND ND ND ICs are at higher risk of cataract than non-exposed ICs: Interventional Cardiologists, PSC: posterior sub scabular. Exploratory analysis: risk of PSC cataract among nurses and supporting staff. Date of PSC lens opacities among exposed nurses and supporting staff was provided by three [22,24,25] of the included studies. The overall RR indicated a higher risk of PSC cataract in nurses and technical workers when compared to unexposed controls (RR5 2.76, 95% CI [1.43, 5.31], P ). Heterogeneity was not found among studies (I 2 5 0%, P ); (Fig. 6). DISCUSSION Fig. 2. Forest plot of relative risk of posterior lens opacity in exposed versus control groups. M-H: Mantel-Haenzel, CI: confidence interval. [Color figure can be viewed at wileyonlinelibrary.com] Our analysis reveals that interventional cardiologists exposed to medical radiation during work conditions are more vulnerable to develop radiation-associated lens opacities. PSC cataract, which is the most frequent radiation-induced type, presents a significantly higher prevalence among ICs, whereas cortical and nuclear types do not differ between the exposed and control groups. Marked inconsistency is indicated among studies with respect to any type of lens opacity. This discrepancy might be explained by different backgrounds from which participants were driven and country-to-country variability in work practices and guidelines. As such, higher rates of lens opacities have been reported among the Asian and Latin population than among Europeans [32,33]. On the other hand, heterogeneity among studies is unlikely to be attributed to neither exposure to sunlight and UV-rays nor smoking habits, because the former is associated with superficial cortical cataract [34] while the latter correlates with nuclear lens opacities [34 36]. Considerable uncertainty regarding the dose-response relationship in low-exposure occupational conditions still exists. The results of this study could not indicate a

6 6 Elmaraezy et al. Fig. 3. A: Forest plot of relative risk of cortical lens opacities in exposed versus control groups. M-H: Mantel-Haenzel, CI: confidence interval. B: Forest plot of relative risk of nuclear lens opacities in exposed versus control groups. M-H: Mantel-Haenzel, CI: confidence interval. [Color figure can be viewed at wileyonlinelibrary.com] Fig. 4. Forest plot of relative risk of any lens opacity in exposed versus control groups. M-H: Mantel-Haenzel, CI: confidence interval. [Color figure can be viewed at wileyonlinelibrary.com] significant association between the cumulative dose of radiation and cataract development. However, several animal experiments and human epidemiological studies suggest progressively increased lens changes with elevated radiation dose [7,37,38]. In the same vein, Ciraji et al. and Vano et al. reported a marked association between radiation dose and cataract [22 24]. Moreover, in contrast to the U.S. National Council On Radiation Protection and Measurement (NCRP) and the International Council on Radiation Protection (ICRP) former guidelines [16,39], recent updates [17,40] along with several experiments [41,42] have indicated a higher radiosensitivity of the lens to subthreshold doses of ionizing radiation. The association between cataract and factors related to work conditions was addressed by one high-quality study. Jacob et al. [26] deduced that lens opacification was significantly correlated with the duration of work in catheterization lab. Length of professional activity was a significant predictor of increased risk of radiation induced cataract. However, the study could not detect a robust association between the cumulative number of procedures and lens opacities; ICs who performed 7800 procedures were at significant higher risk of developing cataract (Adjusted OR5 5.75) but cataract rates in those who performed ,500 and >12,500 procedures were similar to controls (P > 0.05) [26]. We, thus, urge further investigations of this variable to remove doubts and provide a clear-cut evidence. After control for potential confounders (such as BMI, smoking status, myopia, diabetes, and corticosteroid use), wearing lead eyeglasses conferred protection against radiation-

7 Risk of Cataract among in IC s 7 Fig. 5. Forest plot of relative risk of posterior subcapsular cataract in exposed versus control groups according to cumulative radiation dose. M-H: Mantel-Haenzel, CI: confidence interval. [Color figure can be viewed at wileyonlinelibrary.com] Fig. 6. Forest plot of relative risk of posterior subcapsular cataract among nurses and supporting staff. M-H: Mantel-Haenzel, CI: confidence interval. [Color figure can be viewed at wileyonlinelibrary.com] induced lens injury. Data from the International Atomic Energy Agency (IAEA) confirmed these findings [43,44]. It is postulated that the biological mechanism by which radiation might induce cataract involves disruption of the naturally rapid proliferation of endothelial and blood cells [27]. This pathogenic mechanism requires a low radiation dose to induce lens changes [27]. Therefore, utilizing radiation protection tools reduces the risk of injury. However, the majority of ICs reported nonuse of such protective measures. Only 18% used lead eyeglasses in Jacob et al. [26] report, and this ratio was reduced to 13% in Ciraji et al. study [24,25]. This may be because of lack of awareness about radiation protection, unavailability of protective means, or uncomfortable weight of lead glasses. The quality of included studies ranged from low to moderate. Two studies reported six of nine criteria, five fair references addressed five domains, and one lowquality report described only the characteristics of patients population and inclusion criteria. The risk of bias assessment is shown in (Table II). study was conducted in strict accordance with the Cochrane handbook of systematic reviews of interventions [45] and reported according to the guidelines of the MOOSE statement [46]. Limitations Owing to the paucity of data on relevant moderators and few number of included studies, we could not run a meta-regression analysis to adjust for potential confounders. Therefore, the P values presented in this study are not adjusted for multiplicity. However, two of the included studies [26,28] reported no significant change in the effect size after adjustment for confounding variables. Another limitation is the variability among studies in the control group; some studies used unexposed cardiologists while others used nurses and technicians as controls. Moreover, we were not able to assess the publication bias because of a small number of included studies. Despite the limitations of our study, we believe that it still reflects the actual trend that prevalence of cataract in exposed ICs is higher than in physicians who are not exposed to radiation at work. Strength Points This study is the first comprehensive systematic review and meta-analysis to address the association between cataract and radiation exposure in ICs. The Implications and Recommendations In view of the current evidence, we emphasize the urgent need of educational programs about radiation protection strategies for interventional medical personnel.

8 8 Elmaraezy et al. TABLE II. Methodological quality assessment of included studies Total score Cataract diagnosis (No full description 5 1) Interpretation of factors (Not blinded or no description of blinded method 5 1) Method quality (Not described50; described51) Assignment of patients. (Not consecutive or random or no consecutive or random 5 1) Exclusion criteria (No full description 5 1) Inclusion criteria (No full description 5 1) Data collection (Not consecutive or not random or no description5 0; consecutive or random5 1) Characteristic of patient population. No full description 5 1 Study design. Case or no descriptio n 5 0; all case 5 1 Author, year [reference] Auvinen Rajabi Jacob Vano Ciraj-Bjelac Ciraj-Bjelac Vano Yuan Wearing protective shields and lead glasses is imperative for protection against radiation harmful effects. Concerns raised about the current recommended doses are still unresolved. Thus, advisory and regulatory bodies should provide updated guidelines concerning the acceptable dose of ionizing radiation. Moreover, further large prospective well-designed studies with an extended follow-up period, adjustment for potential confounders, and valid and reliable quantification of cumulative radiation doses are warranted. CONCLUSION To recapitulate, interventional cardiologists and accompanying technical staff exposed to occupational ionizing radiation are more susceptible to cataract than unexposed controls. Using radiation protective measures is a must and further investigations are recommended for determining the threshold dose of radiation. AUTHOR CONTRIBUTIONS NTH, MEM, AAH, KH participated in the design of the study. AE, MEM, ATM, AAH, AE, AAG, AMK, NTH, KH carried out in the data collection and analysis. All authors wrote the manuscript, read and approved the final manuscript. ACKNOWLEDGMENTS This study was supported by the Japan Initiative for Global Research Network on Infectious Diseases (J- GRID). The funders had no role in the study design, data collection and analysis, decision to publish or preparation of the manuscript. REFERENCES 1. Brenner DJ, Doll R, Goodhead DT, Hall EJ, Land CE, Little JB, et al. Cancer risks attributable to low doses of ionizing radiation: Assessing what we really know. Proc Natl Acad Sci 2003 ;100: Nov Strauss HW, Dauer LT. Medical Effects of Ionizing Radiation. JAMA 2008 ;300:102. Jul 2 3. Kirillova EN, Muksinova KN, Skukovskaia TL. [Effect of prolonged continuous external irradiation on humoral immunity indices of mice]. Kosm Biol Aviakosm Med 1987;22: Ainsbury EA, Bouffler SD, D orr W, Graw J, Muirhead CR, Edwards AA, et al. Radiation cataractogenesis: A review of recent studies ;172:1 9. Jul 5. Brown NP. The lens is more sensitive to radiation than we had believed. Br J Ophthalmol 1997 ;April 181: Williams KM, Bentham GCG, Young IS, McGinty A, McKay GJ, Hogg R, et al. Association between myopia, ultraviolet b radiation exposure, serum vitamin D concentrations, and genetic polymorphisms in vitamin D metabolic pathways in a multicountry European study. JAMA Ophthalmol 2016; Dec 1; 1 7.

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