ORIGINAL ARTICLE
Survey of intravitreal injection techniques and treatment protocols among retina specialists in Canada Lin Xing, MD, Stephen J. Dorrepaal, MD, FRCSC, Jeffrey Gale, MD, FRCSC ABSTRACT ● RÉSUMÉ Objective: To describe intravitreal injection (IVI) techniques and treatment protocols by retina specialists in Canada from August 1, 2012, to October 1, 2012. Design: Cross-sectional survey. Participants: All fellowship-trained retina specialists across Canada, as identified from the Canadian Ophthalmological Society directory and the Canadian Retina and Vitreous Society directory. Methods: An anonymous 28-question survey was sent to 125 retina specialists across Canada by email. Reminder letters were sent by email, mail, and fax as necessary. Results: A total of 75 (63%) retina specialists responded to the survey. Most IVIs were performed in the office. Most surgeons did not use gloves (61%), sterile draping (91%), or surgical mask (71%). Antisepsis was used on conjunctiva by 100% and on periocular skin by 48%. Nearly all specialists used a sterile lid speculum (91%). Common anaesthetics included topical proparacaine or lidocaine drops (90%), topical lidocaine gel (25%), topical pledget (23%), and subconjunctival lidocaine injections (23%). Most (83%) dilate the pupil before IVI. Prophylactic topical antibiotics were used by 43%; 50% of these were started immediately after IVI. Injection location was estimated by visualization by 45%. A majority (63%) inject inferotemporally. Anterior chamber paracentesis was performed routinely by 5%. Optic nerve perfusion was formally assessed by 48%. The most common treatment protocol for age-related macular degeneration was treat and extend. For both diabetic and retinal vein occlusion–related macular edema, the most common protocol was 3 initial monthly injections with PRN follow-up. Conclusions: A wide variety of IVI practice patterns exist in terms of aseptic technique, anaesthetics, prophylactic antibiotics, postinjection monitoring, and treatment protocol. Objet : Description des techniques d’injection intravitréenne (IIV) et des protocoles de traitement par les spécialises de la rétine du Canada, du 1er août 2012 au 1er octobre 2012. Nature : Sondage transversal. Participants : Tous les spécialistes formés à cet effet au Canada et identifiés par le directoire de la Société canadienne d’Ophtalmologie et celui de la Société canadienne de la rétine et du vitré. Méthodes : Un sondage anonyme de 28 questions a été envoyé par courriel à 125 spécialistes de la rétine du Canada. Des lettres de rappel ont été envoyées par courriel, la poste et télécopie au besoin. Résultats : En tout, 75 spécialistes de la rétine (63 %) ont répondu au sondage. Les IIV ont pour la plupart été administrées au bureau. La plupart des chirurgiens n’ont pas utilisé de gants (61 %), de drap stérile (91 %) ni de masque chirurgical (71 %). Tous ont utilisé l’antisepsie sur la conjonctive et 48 % sur les zones périoculaires. Presque tous ont utilisé un spéculum à paupière stérile (91 %). Les anesthésiques les plus utilisés comprenaient les goutes de proparacaïne ou de lidocaïne topique (90 %), le gel de lidocaïne topique (25 %), le pledget topique (23 %) et les injections sous-conjonctivales de lidocaïne (23 %). La plupart (83 %) dilatent la pupille avant l’IIV. 43 % ont utilisé les antibiotiques topiques prophylactiques; 50 % d’entre eux ont commencé immédiatement après l’IIV. 45 % ont estimé l’endroit de l’injection par visualisation. La majorité (63 %) injectent au site inférotemporal. 5 % ont effectué la paracentèse de la chambre antérieure de façon routinière. 48 % ont évalué formellement la perfusion du nerf optique. Le protocole de traitement le plus utilisé pour la dégénérescence maculaire liée à l’âge était celui de Traitement et Extension. Pour l’œdème maculaire associé au diabète et à l’occlusion de la veine rétinienne, le protocole le plus répandu était trois injections mensuelles initiales avec suivi PRN. Conclusions : Il y a une grande variété de modes de pratique d’IIV concernant la technique antiseptique, l’anesthésie, les antibiotiques prophylactiques, le suivi post-injection et le protocole de traitement.
Intravitreal injection (IVI) of medication through the pars plana has become essential to the treatment of several retinal diseases, and it is among the most common medical procedures in North America. First described in 1911, this safe and effective method is commonly used to deliver vascular endothelial growth factor inhibitors, corticosteroids, and other medications to the posterior segment.1–3 Despite the rapid increase in both the indications and the number of procedures performed,
and several published guidelines for IVI technique, a wide variety of practice patterns still exist.4–10 Anijeet et al.11 previously conducted a survey to show intravitreal triamcinolone injection techniques adopted by U.K. surgeons in 2004. A similar study was performed by Green-Simms et al.12 in the United States in 2010. To our knowledge, there have been no published accounts detailing the practice patterns of retina specialists in Canada. This study aims to demonstrate the IVI practice patterns used
From the Department of Ophthalmology, Queen’s University, Kingston, ON
Can J Ophthalmol 2014;49:261–266 0008-4182/14/$-see front matter & 2014 Canadian Ophthalmological Society. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jcjo.2014.03.009
Originally received Oct. 16, 2013. Final revision Mar. 2, 2014. Accepted Mar. 16, 2014 Correspondence to Stephen J. Dorrepaal, MD, Clarity Eye Institute, 8800 Dufferin St., Suite #105, Vaughan, ON; [email protected]
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Survey of intravitreal injection techniques—Xing et al. by retina specialists in Canada from August 1, 2012, to October 1, 2012, with respect to preinjection care, injection technique, postinjection care, and treatment protocol.
METHODS In August 2012, 120 practicing members of the Canadian Ophthalmological Society who self-categorized as having retina fellowship training and members of the Canada Retina and Vitreous Society were contacted with a confidential, 28question survey through their listed contact method. Nonresponders were sent repeat emails, faxed surveys, and mailed a copy of the survey along with a prepaid return envelope. A minimum of 4 attempts was made to contact each nonresponder before the study concluded on October 1, 2012. Data from the web-based survey distributed via email was collected using Survey Methods, which is an U.S.based, secure, and independent survey software application. Final results were compiled on October 1, 2012.
RESULTS There were 80 respondents, giving a response rate of 64%. The response rate was lower in Quebec with 9 of 20 (45%) responding. Five of the respondents indicated they were no longer practicing ophthalmology; they were therefore excluded from further analysis. Demographics: Forty-four percent of respondents had both an academic and a community practice, 27% had academic only, and 30% had community only. The majority (55%) practiced both medical and surgical retina, whereas 45% practiced medical retina only. The mean number of years with a retina practice was 21 ⫾ 14. Frequency and setting: The mean number of IVIs performed in a typical week was 43 ⫾ 21. The majority (57%) of respondents routinely performed simultaneous bilateral IVIs when necessary, whereas 21% did so on occasion and 21% never did. Most surgeons performed IVIs in their office (72%), whereas 28% performed them in a hospital clinic setting. Aseptic technique: Thirty-nine percent of respondents routinely used gloves, and 61% did not. With use of gloves, 72% were sterile and 28% were nonsterile. Nine percent of surgeons used sterile draping during IVIs, whereas the remainder used no draping. Twenty-nine percent of surgeons used a mask, 97% of which did so routinely, and 3% did so for select patients only. Povidone-iodine antisepsis was used on the conjunctiva by all surgeons and on the periocular skin as well by 48%. A sterile lid speculum was used by 91%. Anaesthetics: Whereas 90% of retina specialists routinely used topical proparacaine, lidocaine, or tetracaine drops in preparation for IVI, only 29% used these exclusively. Twenty-five percent routinely used topical lidocaine gel, and 16% used it infrequently. Twenty-three percent
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routinely used a pledget soaked with tetracaine or proparacaine, and 28% used pledgets infrequently. Twentythree percent routinely used subconjunctival lidocaine injection, and 43% used this technique infrequently. Prophylactic topical antibiotics: Fifty-seven percent of specialists used no peri-injection antibiotics, 40% used peri-injection antibiotics with all patients, and 3% did so with select patients only. Of the 32 surgeons who prescribed antibiotics either always or sometimes, 47% favoured gatifloxacin, 22% favoured moxifloxacin, and 31% preferred other topical antibiotics. Thirty of the 32 surgeons who used antibiotics provided detailed regimens. Half of these surgeons started antibiotics after IVI, 40% started immediately before IVI, 3% started 1 day before IVI, and 7% started 2 days before IVI. Of the same 30 surgeons, 50% used only a single drop of antibiotic in the peri-injection period. Three percent prescribed topical antibiotics for 1 to 2 days, 33% prescribed them for 3 to 4 days, and 17% prescribed them for 1 full week. Preinjection considerations: Most retina specialists (83%) dilated the pupil before IVI, either to allow ocular examination (83%), to facilitate ocular coherence tomography (OCT, 17%), or both (15%). Injection technique: The most common quadrant for injection was inferotemporal (63%), followed by superotemporal (43%), and by inferonasal and superonasal at 7% each. These add up to greater than 100% because some retina specialists indicated a preference for more than 1 location. The location of injection relative to the limbus was estimated visually by 45% and measured using either a fixed caliper (36%) or the tip of a 1-mL syringe (20%) With respect to potential vitreous reflux after the needle was withdrawn, 40% did not use any methods of prevention. Forty-one percent applied direct pressure over the injection location using a cotton-tipped applicator, 11% used a cotton tip for conjunctival displacement, 7% used an angled scleral tunnel technique while injecting, and 1% used all 3 methods. Anterior chamber (AC) paracentesis was routinely performed by 5% of retina specialists, sometimes by 45% and not routinely by 50%. Of the specialists who performed AC paracentesis either routinely or sometimes, 34 responded with their indications, stating pre-existing glaucoma (60%), concerns about elevated intraocular pressure (IOP) not directly affecting vision (38%), and decreased vision postinjection because of elevated IOP (27%). Postinjection considerations: Fifty-two percent of retina specialists did not formally assess retinal or optic nerve perfusion postinjection routinely. Thirty-two percent always assessed perfusion, and 16% did so in select patients only. Of the 36 surgeons who assessed retinal or optic nerve perfusion either always or sometimes, direct visualization by ophthalmoscopy (67%), gross visual acuity assessment (44%), and IOP measurement (14%) were the methods used. Special patient populations: A majority of specialists (74%) used their preferred injection technique for all
Survey of intravitreal injection techniques—Xing et al. patients. Twenty-five percent did, however, report changing their routine practices for special patient populations. These changes included providing treatment of pre-existing severe blepharitis, uncontrolled IOP before performing IVI (58%), using more rigorous aseptic measures for immunocompromised patients (37%), and performing additional postinjection IOP checks in glaucomatous eyes (5%). Injection protocol: For patients with age-related macular degeneration (AMD), the most frequent protocol used was treat and extend (51%). For patients with diabetic macular edema (DME) involving the fovea and retinal vein occlusion–related edema, the most frequent treatment approach was 3 initial monthly injections, followed by PRN treatment. Table 1 outlines the frequency of each protocol used.
DISCUSSION Several suggested practices guidelines for IVIs have been discussed in recent years.4–10 Similar to other recent surveys of IVI technique, we report a wide range of practice patterns in terms of aseptic technique, anaesthetics, antibiotics, postinjection monitoring, and treatment protocol by Canadian retina specialists.11,12 Frequency and setting
In our study, 57% of surgeons routinely performed simultaneous bilateral IVIs when necessary. A 2011 survey of retina specialists in the United States reported that 46% performed simultaneous bilateral IVIs at that time.12 This may indicate a regional variation, or more ophthalmologists have become comfortable with simultaneous bilateral injections as their experience with IVIs has grown. Two recent studies have reported that performing simultaneous bilateral IVIs does not increase the rate of adverse events compared with unilateral injections.13,14 Patients in both of these studies preferred bilateral injections over alternating ones presumably for convenience reasons. Our survey indicated that most surgeons performed IVIs in an office setting (72%). Anijeet and associates11 reported that, in the United Kingdom, 76% of retina specialists primarily performed IVIs in an operating room (OR) setting. There is evidence that filtered air in the OR may decrease surgical infection rates; however, to our knowledge, this phenomenon has not been reported with respect to IVI in the ophthalmic literature.5 Many of the recent studies on incidence of endophthalmitis were based on IVIs done in an
office setting, quoting rates varying between 0.029% and 0.09%.15,16 We are not aware of any reports of endophthalmitis rates with IVIs done exclusively in the OR. Aseptic technique
Thirty-nine percent of retina specialists used gloves while performing IVI. Among those who wore gloves, 72% used sterile ones. The overall use of gloves was similar to the 42% of U.S. surgeons in 2011, although only 58% of these surgeons wore sterile gloves.12 In the U. K. survey, 86% of surgeons donned gloves, likely related to increased percentage of IVIs done in the OR.11 In our study, the majority of specialists (71%) did not wear a mask during the IVI procedure. Recent studies of microbes implicated in endophthalmitis have found common oral flora.10,17 It is uncertain whether these were introduced by the surgeon or the patient, and whether prevention of contamination would lead to fewer cases of endophthalmitis. Nevertheless, measures to prevent airborne contamination with either masks or a “no speak” policy has been suggested as reasonable practice.4,18 Povidone-iodine was used by all surgeons on the conjunctiva and by 48% on the periocular skin as well. Nearly all of U.K. and U.S. surgeons also used povidine-iodine.11,12 The application of povidone-iodine has been shown to reduce bacterial load.19 Excessive eyelid scrubbing, however, has been reported to actually increase the conjunctival bacterial load and, therefore, should be avoided.4,20 For those who apply periocular povidone-iodine before IVI, a balance should be struck between eyelid antisepsis and inadvertently increasing bacterial dispersion. An eyelid speculum was used by almost all surgeons (91%). Again, this is similar to the 92% usage rate by U.S. surgeons.12 The use of a sterile lid speculum was strongly recommended on the basis that it would help prevent needle contamination by the lashes during IVI.4,9 Anaesthetics
The anaesthetic most frequently used was topical drops (90%), followed by topical gel (25%), pledget (23%), and subconjunctival injection (23%). It appears that the surveyed surgeons favoured methods that were least invasive and most convenient. Previous studies have showed no significant difference in pain score between pledget and subconjunctival injection,21 and between subconjunctival injection, topical drops, and pledget.22 Topical gel was demonstrated to be superior in pain scores to topical drops
Table 1—Intravitreal injection treatment protocols used by surgeons (N ¼ 75) for each indication Treatment Protocol
Indication AMD DME RVO
Monthly IVIs
3 Initial IVIs, Then PRN with Regular Follow-up
PRN, with Follow-up
3 Monthly IVIs (initial and retreatment) with Regular Follow-up
Treat and Extend
Other
4 (5%) 4 (5%) 10 (13%)
19 (25%) 38 (51%) 25 (33%)
0 (0%) 8 (11%) 10 (13%)
14 (19%) 12 (16%) 18 (24%)
38 (51%) 12 (16%) 11 (15)
0 (0%) 1 (1%) 1 (1%)
IVI, intravitreal injection; PRN, pro re nata (as needed); AMD, age-related macular degeneration; DME, diabetic macular edema; RVO, retinal vein occlusion–related edema.
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Survey of intravitreal injection techniques—Xing et al. in 1 study, but there was debate on whether the gel may affect the efficacy of the antisepsis if not applied correctly.10 Antibiotics
In our study, 57% of surgeons did not prescribe periinjection antibiotics at all, and the remaining 43% did so using a variety of regimens. In comparison, 81% of U.S. surgeons used prophylactic antibiotics postinjection in 2010.12 Antibiotic use before or after IVI has been a controversial topic, as reflected in the varying practice patterns of the surveyed retina specialists. Because postinjection endophthalmitis has a low incidence, definitive evidence of the efficacy of peri-injection antibiotics in reducing the rate of infection would be very difficult to obtain.23,24 Recent studies suggests that it is safe to perform IVIs without topical antibiotic prophylaxis, and that even short-term use of prophylactic peri-injection antibiotics can induce significant antibiotic resistance in treatment-naïve patients.24–28 It is our experience that the proportion of ophthalmologists using peri-injection antibiotics has been decreasing in recent years, which may account for our lower rate of peri-injection antibiotics usage than in the previous studies from the United Kingdom and United States in 2004 and 2010, respectively. Preinjection considerations
The majority of specialists (83%) routinely dilated the pupil with each IVI. Previous guidelines have recommended routine dilation with IVI for adequate visualization postinjection; however, no data exist on whether dilation affects complication rates.4,9
the 41% of Canadian surgeons who reported using direct pressure as their method of preventing reflux, which was not addressed in the U.S. study, our rate would be 19%. This is likely the reason for such discrepancy in our data compared with Green-Simms et al.12 (Table 2). AC paracentesis was sometimes performed by 51% of respondents, and only 10% did so in all patients.9 This is comparable with the 45% of U.K. surgeons.11 Short-term IOP elevation after IVI has been well described, typically resolving in less than 30 to 120 minutes.32–36 Decreased vision immediately postinjection may be secondary to decreased retinal perfusion if IOP is elevated beyond diastolic arterial pressure at the optic nerve. In patients whose vision is decreased immediately postinjection, we recommend funduscopy to assess retinal perfusion, as well as to rule out retinal detachment or vitreous hemorrhage. Postinjection considerations
Only 32% of respondents formally assessed retinal and optic nerve perfusion. This is lower than the 83% who dilate before injection. In comparison, a much higher number of U.S. surgeons (72%) formally assessed retinal and optic nerve perfusion postinjection.12 Because of the potential for ischemic damage and several reports of shortterm increases in IOP,32–36 it is recommended that patients with decreased vision immediately after IVI are assessed expediently.9 This may be done through direct visualization of the optic nerve, IOP testing, or gross visual acuity as reported by the patient. Injection protocol
Injection technique
Forty-five percent of specialists determined the site of injection by visual estimation. Similar data were reported by Green-Simms et al.12 in 2011. It has been recommended that IVIs should be made 3.5 to 4 mm from the limbus in the inferotemporal quadrant, although no clear consensus has been reached.4,29,30 The inferotemporal quadrant was the most commonly injected area, followed by the superotemporal quadrant. A potential advantage of an inferotemporal injection is avoiding drug deposition in the visual axis. Also, in the event that an IVI resulted in a retinal break near the injection site, an inferotemporal break may be less likely to rapidly lead to fovea-involving retinal detachment. The preference for injecting in the superotemporal quadrant may be related to the fact that a retinal break there is likely more amenable to pneumatic retinopexy. A majority (60%) of the respondents reported using at least 1 method of preventing vitreous reflux. The “vitreous wick syndrome” has been described and is thought to create an entry for bacteria into the globe, although there are no large studies demonstrating the relationship between vitreous leak and rates of endophthalmitis.31 Green-Simms et al.12 reported 20% of U.S. surgeons use methods to prevent vitreous reflux, specifically mentioning scleral tunnel and conjunctival displacement. If we exclude
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For patients with neovascular AMD, the most common treatment protocol was treat and extend (51%), in which patients were treated on a monthly basis until dry, after which the treatment interval would be extended on subsequent visits. Of the 44% that used 3 initial monthly treatments followed by PRN treatment, 58% used regular Table 2—Comparison of intravitreal injection practice pattern between this study and previous studies by Green-Simms et al.12 (United States) and Anijeet et al.11 (United Kingdom)
Survey response rate (%) IVI practice pattern (%) Office setting Bilateral IVI Gloves Sterile draping Mask Lid speculum Povidone-iodine Pupil dilatation Measured injection site Postinjection antibiotics Vitreous reflux prevention AC paracentesis (pre or post) Optic nerve perfusion
Canada: 2012
United States: 2010
United Kingdom: 2004
64
44
63
72 57 39 9 29 91 100 83 55 20 60
— 46 58 12 — 92 100 — 56 81 21
19 — 86 63 — — 94 78 — 58 —
51
—
64
48
72
—
IVI, intravitreal injection; AC, anterior chamber.
Survey of intravitreal injection techniques—Xing et al. follow-up when dry with a single injection each month if neovascular activity was noted clinically, angiographically, or on OCT, as in the PrONTO trial.37 The remaining 42% also followed patients regularly when dry, but would re-treat with 3 monthly injections if neovascular activity was noted, as in the IVAN trial.38 Five percent of respondents continued to prefer and use monthly treatment as in the MARINA/ANCHOR trials.39,40 For patients with diabetic clinically significant macular edema involving the fovea, 67% of respondents used 3 initial monthly injections followed by PRN treatment, with 76% of those treating with 1 injection for recurrences of edema (as in the RESOLVE and RESTORE studies), and 24% treating with 3 injections for each recurrence of edema.41,42 Less commonly used were a treat and extend protocol, PRN treatment (as per READ-2 study), and monthly injections (as per RISE/RIDE studies).43,44 For patients with macular edema secondary to retinal vein occlusion, 48% of respondents used 3 initial monthly injections followed by PRN treatment, with 69% of those treating with 1 injection for recurrences of edema, and 31% treating with 3 injections for each recurrence of edema. Less commonly used were a treat and extend protocol, monthly injections, and PRN only treatment. These protocols are largely similar, but not identical, to the BRAVO/CRUISE protocol of 6 initial injections followed by PRN treatment.45,46
CONCLUSION Our study had an overall response rate of 64%. This compares favourably with recent national surveys of Canadian ophthalmologists regarding DME treatment protocols and cataract surgery practices, as well as the recent U.S. IVI techniques survey.12,47,48 A possible limitation, as in any survey, is selection bias in the surgeons who chose to respond. We demonstrated there are various IVI practice patterns by retina specialists in Canada. Overall, Canadian surgeons’ practice patterns were similar to ones in the United States and United Kingdom, with some differences in aseptic technique, optic nerve perfusion assessment, and antibiotic use (Table 2). Further studies are needed to examine the evidence behind these practice patterns. It is our hope that our results will serve as a baseline for future studies to monitor changes over time and to allow comparison with techniques done elsewhere in the world.
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46.
47. 48.
findings from the IVAN randomized trial. Ophthalmology. 2012; 119:1399-411. Rosenfeld PJ, Brown DM, Heier JS, et al. MARINA Study Group. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006;355:1419-31. Brown DM, Michels M, Kaiser, et al, ANCHOR Study Group. Ranibizumab versus verteporfin for neovascular age-related macular degeneration [ANCHOR study 1-year data]. N Engl J Med. 2006; 355:1432-44. Mitchell P, Bandello F, Schmidt-Erfurth U, et al. The RESTORE Study: ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edema. Ophthalmology. 2011;118:615-25. Massin P, Bandello F, Garweg JG, et al. Safety and efficacy of ranibizumab in diabetic macular edema (RESOLVE Study). Diabetes Care. 2010;33:2399-405. Nguyen QD, Shah SM, Khwaja AA, et al. Two-year outcomes of the ranibizumab for edema of the mAcula in diabetes (READ-2) study. Ophthalmology. 2010;117:2146-51. Nguyen QD, Brown DM, Marcus DM, et al. Ranibizumab for diabetic macular edema: results from 2 phase III randomized trials: RISE and RIDE. Ophthalmology. 2012;119:789-801. Campochiaro PA, Brown DM, Awh CC, et al. Sustained benefits from ranibizumab for macular edema following central retinal vein occlusion: twelve-month outcomes of a phase III study. Ophthalmology. 2011;118:2041-9. Brown DM, Campochiaro PA, Bhisitkul RB, et al. Sustained benefits from ranibizumab for macular edema following branch retinal vein occlusion: 12-month outcomes of a phase III study. Ophthalmology. 2011;118:1594-602. Ong-Tone L, Bell A, Tan YY. Practice patterns of Canadian Ophthalmological Society members in cataract surgery—2010 survey. Can J Ophthalmol. 2011;46:139-42. Schweitzer KD, Eneh A, Gale J. Practice patterns of Canadian vitreoretinal specialists in diabetic macular edema treatment. Can J Ophthalmol. 2011;46:227-31. http://dx.doi.org/10.1016/j.jcjo.2011. 05.013.
Survey of intravitreal injection techniques and treatment protocols among retina specialists in Canada Lin Xing, MD, Stephen J. Dorrepaal, MD, FRCSC, Jeffrey Gale, MD, FRCSC ABSTRACT ● RÉSUMÉ Objective: To describe intravitreal injection (IVI) techniques and treatment protocols by retina specialists in Canada from August 1, 2012, to October 1, 2012. Design: Cross-sectional survey. Participants: All fellowship-trained retina specialists across Canada, as identified from the Canadian Ophthalmological Society directory and the Canadian Retina and Vitreous Society directory. Methods: An anonymous 28-question survey was sent to 125 retina specialists across Canada by email. Reminder letters were sent by email, mail, and fax as necessary. Results: A total of 75 (63%) retina specialists responded to the survey. Most IVIs were performed in the office. Most surgeons did not use gloves (61%), sterile draping (91%), or surgical mask (71%). Antisepsis was used on conjunctiva by 100% and on periocular skin by 48%. Nearly all specialists used a sterile lid speculum (91%). Common anaesthetics included topical proparacaine or lidocaine drops (90%), topical lidocaine gel (25%), topical pledget (23%), and subconjunctival lidocaine injections (23%). Most (83%) dilate the pupil before IVI. Prophylactic topical antibiotics were used by 43%; 50% of these were started immediately after IVI. Injection location was estimated by visualization by 45%. A majority (63%) inject inferotemporally. Anterior chamber paracentesis was performed routinely by 5%. Optic nerve perfusion was formally assessed by 48%. The most common treatment protocol for age-related macular degeneration was treat and extend. For both diabetic and retinal vein occlusion–related macular edema, the most common protocol was 3 initial monthly injections with PRN follow-up. Conclusions: A wide variety of IVI practice patterns exist in terms of aseptic technique, anaesthetics, prophylactic antibiotics, postinjection monitoring, and treatment protocol. Objet : Description des techniques d’injection intravitréenne (IIV) et des protocoles de traitement par les spécialises de la rétine du Canada, du 1er août 2012 au 1er octobre 2012. Nature : Sondage transversal. Participants : Tous les spécialistes formés à cet effet au Canada et identifiés par le directoire de la Société canadienne d’Ophtalmologie et celui de la Société canadienne de la rétine et du vitré. Méthodes : Un sondage anonyme de 28 questions a été envoyé par courriel à 125 spécialistes de la rétine du Canada. Des lettres de rappel ont été envoyées par courriel, la poste et télécopie au besoin. Résultats : En tout, 75 spécialistes de la rétine (63 %) ont répondu au sondage. Les IIV ont pour la plupart été administrées au bureau. La plupart des chirurgiens n’ont pas utilisé de gants (61 %), de drap stérile (91 %) ni de masque chirurgical (71 %). Tous ont utilisé l’antisepsie sur la conjonctive et 48 % sur les zones périoculaires. Presque tous ont utilisé un spéculum à paupière stérile (91 %). Les anesthésiques les plus utilisés comprenaient les goutes de proparacaïne ou de lidocaïne topique (90 %), le gel de lidocaïne topique (25 %), le pledget topique (23 %) et les injections sous-conjonctivales de lidocaïne (23 %). La plupart (83 %) dilatent la pupille avant l’IIV. 43 % ont utilisé les antibiotiques topiques prophylactiques; 50 % d’entre eux ont commencé immédiatement après l’IIV. 45 % ont estimé l’endroit de l’injection par visualisation. La majorité (63 %) injectent au site inférotemporal. 5 % ont effectué la paracentèse de la chambre antérieure de façon routinière. 48 % ont évalué formellement la perfusion du nerf optique. Le protocole de traitement le plus utilisé pour la dégénérescence maculaire liée à l’âge était celui de Traitement et Extension. Pour l’œdème maculaire associé au diabète et à l’occlusion de la veine rétinienne, le protocole le plus répandu était trois injections mensuelles initiales avec suivi PRN. Conclusions : Il y a une grande variété de modes de pratique d’IIV concernant la technique antiseptique, l’anesthésie, les antibiotiques prophylactiques, le suivi post-injection et le protocole de traitement.
Intravitreal injection (IVI) of medication through the pars plana has become essential to the treatment of several retinal diseases, and it is among the most common medical procedures in North America. First described in 1911, this safe and effective method is commonly used to deliver vascular endothelial growth factor inhibitors, corticosteroids, and other medications to the posterior segment.1–3 Despite the rapid increase in both the indications and the number of procedures performed,
and several published guidelines for IVI technique, a wide variety of practice patterns still exist.4–10 Anijeet et al.11 previously conducted a survey to show intravitreal triamcinolone injection techniques adopted by U.K. surgeons in 2004. A similar study was performed by Green-Simms et al.12 in the United States in 2010. To our knowledge, there have been no published accounts detailing the practice patterns of retina specialists in Canada. This study aims to demonstrate the IVI practice patterns used
From the Department of Ophthalmology, Queen’s University, Kingston, ON
Can J Ophthalmol 2014;49:261–266 0008-4182/14/$-see front matter & 2014 Canadian Ophthalmological Society. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jcjo.2014.03.009
Originally received Oct. 16, 2013. Final revision Mar. 2, 2014. Accepted Mar. 16, 2014 Correspondence to Stephen J. Dorrepaal, MD, Clarity Eye Institute, 8800 Dufferin St., Suite #105, Vaughan, ON; [email protected]
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Survey of intravitreal injection techniques—Xing et al. by retina specialists in Canada from August 1, 2012, to October 1, 2012, with respect to preinjection care, injection technique, postinjection care, and treatment protocol.
METHODS In August 2012, 120 practicing members of the Canadian Ophthalmological Society who self-categorized as having retina fellowship training and members of the Canada Retina and Vitreous Society were contacted with a confidential, 28question survey through their listed contact method. Nonresponders were sent repeat emails, faxed surveys, and mailed a copy of the survey along with a prepaid return envelope. A minimum of 4 attempts was made to contact each nonresponder before the study concluded on October 1, 2012. Data from the web-based survey distributed via email was collected using Survey Methods, which is an U.S.based, secure, and independent survey software application. Final results were compiled on October 1, 2012.
RESULTS There were 80 respondents, giving a response rate of 64%. The response rate was lower in Quebec with 9 of 20 (45%) responding. Five of the respondents indicated they were no longer practicing ophthalmology; they were therefore excluded from further analysis. Demographics: Forty-four percent of respondents had both an academic and a community practice, 27% had academic only, and 30% had community only. The majority (55%) practiced both medical and surgical retina, whereas 45% practiced medical retina only. The mean number of years with a retina practice was 21 ⫾ 14. Frequency and setting: The mean number of IVIs performed in a typical week was 43 ⫾ 21. The majority (57%) of respondents routinely performed simultaneous bilateral IVIs when necessary, whereas 21% did so on occasion and 21% never did. Most surgeons performed IVIs in their office (72%), whereas 28% performed them in a hospital clinic setting. Aseptic technique: Thirty-nine percent of respondents routinely used gloves, and 61% did not. With use of gloves, 72% were sterile and 28% were nonsterile. Nine percent of surgeons used sterile draping during IVIs, whereas the remainder used no draping. Twenty-nine percent of surgeons used a mask, 97% of which did so routinely, and 3% did so for select patients only. Povidone-iodine antisepsis was used on the conjunctiva by all surgeons and on the periocular skin as well by 48%. A sterile lid speculum was used by 91%. Anaesthetics: Whereas 90% of retina specialists routinely used topical proparacaine, lidocaine, or tetracaine drops in preparation for IVI, only 29% used these exclusively. Twenty-five percent routinely used topical lidocaine gel, and 16% used it infrequently. Twenty-three percent
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routinely used a pledget soaked with tetracaine or proparacaine, and 28% used pledgets infrequently. Twentythree percent routinely used subconjunctival lidocaine injection, and 43% used this technique infrequently. Prophylactic topical antibiotics: Fifty-seven percent of specialists used no peri-injection antibiotics, 40% used peri-injection antibiotics with all patients, and 3% did so with select patients only. Of the 32 surgeons who prescribed antibiotics either always or sometimes, 47% favoured gatifloxacin, 22% favoured moxifloxacin, and 31% preferred other topical antibiotics. Thirty of the 32 surgeons who used antibiotics provided detailed regimens. Half of these surgeons started antibiotics after IVI, 40% started immediately before IVI, 3% started 1 day before IVI, and 7% started 2 days before IVI. Of the same 30 surgeons, 50% used only a single drop of antibiotic in the peri-injection period. Three percent prescribed topical antibiotics for 1 to 2 days, 33% prescribed them for 3 to 4 days, and 17% prescribed them for 1 full week. Preinjection considerations: Most retina specialists (83%) dilated the pupil before IVI, either to allow ocular examination (83%), to facilitate ocular coherence tomography (OCT, 17%), or both (15%). Injection technique: The most common quadrant for injection was inferotemporal (63%), followed by superotemporal (43%), and by inferonasal and superonasal at 7% each. These add up to greater than 100% because some retina specialists indicated a preference for more than 1 location. The location of injection relative to the limbus was estimated visually by 45% and measured using either a fixed caliper (36%) or the tip of a 1-mL syringe (20%) With respect to potential vitreous reflux after the needle was withdrawn, 40% did not use any methods of prevention. Forty-one percent applied direct pressure over the injection location using a cotton-tipped applicator, 11% used a cotton tip for conjunctival displacement, 7% used an angled scleral tunnel technique while injecting, and 1% used all 3 methods. Anterior chamber (AC) paracentesis was routinely performed by 5% of retina specialists, sometimes by 45% and not routinely by 50%. Of the specialists who performed AC paracentesis either routinely or sometimes, 34 responded with their indications, stating pre-existing glaucoma (60%), concerns about elevated intraocular pressure (IOP) not directly affecting vision (38%), and decreased vision postinjection because of elevated IOP (27%). Postinjection considerations: Fifty-two percent of retina specialists did not formally assess retinal or optic nerve perfusion postinjection routinely. Thirty-two percent always assessed perfusion, and 16% did so in select patients only. Of the 36 surgeons who assessed retinal or optic nerve perfusion either always or sometimes, direct visualization by ophthalmoscopy (67%), gross visual acuity assessment (44%), and IOP measurement (14%) were the methods used. Special patient populations: A majority of specialists (74%) used their preferred injection technique for all
Survey of intravitreal injection techniques—Xing et al. patients. Twenty-five percent did, however, report changing their routine practices for special patient populations. These changes included providing treatment of pre-existing severe blepharitis, uncontrolled IOP before performing IVI (58%), using more rigorous aseptic measures for immunocompromised patients (37%), and performing additional postinjection IOP checks in glaucomatous eyes (5%). Injection protocol: For patients with age-related macular degeneration (AMD), the most frequent protocol used was treat and extend (51%). For patients with diabetic macular edema (DME) involving the fovea and retinal vein occlusion–related edema, the most frequent treatment approach was 3 initial monthly injections, followed by PRN treatment. Table 1 outlines the frequency of each protocol used.
DISCUSSION Several suggested practices guidelines for IVIs have been discussed in recent years.4–10 Similar to other recent surveys of IVI technique, we report a wide range of practice patterns in terms of aseptic technique, anaesthetics, antibiotics, postinjection monitoring, and treatment protocol by Canadian retina specialists.11,12 Frequency and setting
In our study, 57% of surgeons routinely performed simultaneous bilateral IVIs when necessary. A 2011 survey of retina specialists in the United States reported that 46% performed simultaneous bilateral IVIs at that time.12 This may indicate a regional variation, or more ophthalmologists have become comfortable with simultaneous bilateral injections as their experience with IVIs has grown. Two recent studies have reported that performing simultaneous bilateral IVIs does not increase the rate of adverse events compared with unilateral injections.13,14 Patients in both of these studies preferred bilateral injections over alternating ones presumably for convenience reasons. Our survey indicated that most surgeons performed IVIs in an office setting (72%). Anijeet and associates11 reported that, in the United Kingdom, 76% of retina specialists primarily performed IVIs in an operating room (OR) setting. There is evidence that filtered air in the OR may decrease surgical infection rates; however, to our knowledge, this phenomenon has not been reported with respect to IVI in the ophthalmic literature.5 Many of the recent studies on incidence of endophthalmitis were based on IVIs done in an
office setting, quoting rates varying between 0.029% and 0.09%.15,16 We are not aware of any reports of endophthalmitis rates with IVIs done exclusively in the OR. Aseptic technique
Thirty-nine percent of retina specialists used gloves while performing IVI. Among those who wore gloves, 72% used sterile ones. The overall use of gloves was similar to the 42% of U.S. surgeons in 2011, although only 58% of these surgeons wore sterile gloves.12 In the U. K. survey, 86% of surgeons donned gloves, likely related to increased percentage of IVIs done in the OR.11 In our study, the majority of specialists (71%) did not wear a mask during the IVI procedure. Recent studies of microbes implicated in endophthalmitis have found common oral flora.10,17 It is uncertain whether these were introduced by the surgeon or the patient, and whether prevention of contamination would lead to fewer cases of endophthalmitis. Nevertheless, measures to prevent airborne contamination with either masks or a “no speak” policy has been suggested as reasonable practice.4,18 Povidone-iodine was used by all surgeons on the conjunctiva and by 48% on the periocular skin as well. Nearly all of U.K. and U.S. surgeons also used povidine-iodine.11,12 The application of povidone-iodine has been shown to reduce bacterial load.19 Excessive eyelid scrubbing, however, has been reported to actually increase the conjunctival bacterial load and, therefore, should be avoided.4,20 For those who apply periocular povidone-iodine before IVI, a balance should be struck between eyelid antisepsis and inadvertently increasing bacterial dispersion. An eyelid speculum was used by almost all surgeons (91%). Again, this is similar to the 92% usage rate by U.S. surgeons.12 The use of a sterile lid speculum was strongly recommended on the basis that it would help prevent needle contamination by the lashes during IVI.4,9 Anaesthetics
The anaesthetic most frequently used was topical drops (90%), followed by topical gel (25%), pledget (23%), and subconjunctival injection (23%). It appears that the surveyed surgeons favoured methods that were least invasive and most convenient. Previous studies have showed no significant difference in pain score between pledget and subconjunctival injection,21 and between subconjunctival injection, topical drops, and pledget.22 Topical gel was demonstrated to be superior in pain scores to topical drops
Table 1—Intravitreal injection treatment protocols used by surgeons (N ¼ 75) for each indication Treatment Protocol
Indication AMD DME RVO
Monthly IVIs
3 Initial IVIs, Then PRN with Regular Follow-up
PRN, with Follow-up
3 Monthly IVIs (initial and retreatment) with Regular Follow-up
Treat and Extend
Other
4 (5%) 4 (5%) 10 (13%)
19 (25%) 38 (51%) 25 (33%)
0 (0%) 8 (11%) 10 (13%)
14 (19%) 12 (16%) 18 (24%)
38 (51%) 12 (16%) 11 (15)
0 (0%) 1 (1%) 1 (1%)
IVI, intravitreal injection; PRN, pro re nata (as needed); AMD, age-related macular degeneration; DME, diabetic macular edema; RVO, retinal vein occlusion–related edema.
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Survey of intravitreal injection techniques—Xing et al. in 1 study, but there was debate on whether the gel may affect the efficacy of the antisepsis if not applied correctly.10 Antibiotics
In our study, 57% of surgeons did not prescribe periinjection antibiotics at all, and the remaining 43% did so using a variety of regimens. In comparison, 81% of U.S. surgeons used prophylactic antibiotics postinjection in 2010.12 Antibiotic use before or after IVI has been a controversial topic, as reflected in the varying practice patterns of the surveyed retina specialists. Because postinjection endophthalmitis has a low incidence, definitive evidence of the efficacy of peri-injection antibiotics in reducing the rate of infection would be very difficult to obtain.23,24 Recent studies suggests that it is safe to perform IVIs without topical antibiotic prophylaxis, and that even short-term use of prophylactic peri-injection antibiotics can induce significant antibiotic resistance in treatment-naïve patients.24–28 It is our experience that the proportion of ophthalmologists using peri-injection antibiotics has been decreasing in recent years, which may account for our lower rate of peri-injection antibiotics usage than in the previous studies from the United Kingdom and United States in 2004 and 2010, respectively. Preinjection considerations
The majority of specialists (83%) routinely dilated the pupil with each IVI. Previous guidelines have recommended routine dilation with IVI for adequate visualization postinjection; however, no data exist on whether dilation affects complication rates.4,9
the 41% of Canadian surgeons who reported using direct pressure as their method of preventing reflux, which was not addressed in the U.S. study, our rate would be 19%. This is likely the reason for such discrepancy in our data compared with Green-Simms et al.12 (Table 2). AC paracentesis was sometimes performed by 51% of respondents, and only 10% did so in all patients.9 This is comparable with the 45% of U.K. surgeons.11 Short-term IOP elevation after IVI has been well described, typically resolving in less than 30 to 120 minutes.32–36 Decreased vision immediately postinjection may be secondary to decreased retinal perfusion if IOP is elevated beyond diastolic arterial pressure at the optic nerve. In patients whose vision is decreased immediately postinjection, we recommend funduscopy to assess retinal perfusion, as well as to rule out retinal detachment or vitreous hemorrhage. Postinjection considerations
Only 32% of respondents formally assessed retinal and optic nerve perfusion. This is lower than the 83% who dilate before injection. In comparison, a much higher number of U.S. surgeons (72%) formally assessed retinal and optic nerve perfusion postinjection.12 Because of the potential for ischemic damage and several reports of shortterm increases in IOP,32–36 it is recommended that patients with decreased vision immediately after IVI are assessed expediently.9 This may be done through direct visualization of the optic nerve, IOP testing, or gross visual acuity as reported by the patient. Injection protocol
Injection technique
Forty-five percent of specialists determined the site of injection by visual estimation. Similar data were reported by Green-Simms et al.12 in 2011. It has been recommended that IVIs should be made 3.5 to 4 mm from the limbus in the inferotemporal quadrant, although no clear consensus has been reached.4,29,30 The inferotemporal quadrant was the most commonly injected area, followed by the superotemporal quadrant. A potential advantage of an inferotemporal injection is avoiding drug deposition in the visual axis. Also, in the event that an IVI resulted in a retinal break near the injection site, an inferotemporal break may be less likely to rapidly lead to fovea-involving retinal detachment. The preference for injecting in the superotemporal quadrant may be related to the fact that a retinal break there is likely more amenable to pneumatic retinopexy. A majority (60%) of the respondents reported using at least 1 method of preventing vitreous reflux. The “vitreous wick syndrome” has been described and is thought to create an entry for bacteria into the globe, although there are no large studies demonstrating the relationship between vitreous leak and rates of endophthalmitis.31 Green-Simms et al.12 reported 20% of U.S. surgeons use methods to prevent vitreous reflux, specifically mentioning scleral tunnel and conjunctival displacement. If we exclude
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For patients with neovascular AMD, the most common treatment protocol was treat and extend (51%), in which patients were treated on a monthly basis until dry, after which the treatment interval would be extended on subsequent visits. Of the 44% that used 3 initial monthly treatments followed by PRN treatment, 58% used regular Table 2—Comparison of intravitreal injection practice pattern between this study and previous studies by Green-Simms et al.12 (United States) and Anijeet et al.11 (United Kingdom)
Survey response rate (%) IVI practice pattern (%) Office setting Bilateral IVI Gloves Sterile draping Mask Lid speculum Povidone-iodine Pupil dilatation Measured injection site Postinjection antibiotics Vitreous reflux prevention AC paracentesis (pre or post) Optic nerve perfusion
Canada: 2012
United States: 2010
United Kingdom: 2004
64
44
63
72 57 39 9 29 91 100 83 55 20 60
— 46 58 12 — 92 100 — 56 81 21
19 — 86 63 — — 94 78 — 58 —
51
—
64
48
72
—
IVI, intravitreal injection; AC, anterior chamber.
Survey of intravitreal injection techniques—Xing et al. follow-up when dry with a single injection each month if neovascular activity was noted clinically, angiographically, or on OCT, as in the PrONTO trial.37 The remaining 42% also followed patients regularly when dry, but would re-treat with 3 monthly injections if neovascular activity was noted, as in the IVAN trial.38 Five percent of respondents continued to prefer and use monthly treatment as in the MARINA/ANCHOR trials.39,40 For patients with diabetic clinically significant macular edema involving the fovea, 67% of respondents used 3 initial monthly injections followed by PRN treatment, with 76% of those treating with 1 injection for recurrences of edema (as in the RESOLVE and RESTORE studies), and 24% treating with 3 injections for each recurrence of edema.41,42 Less commonly used were a treat and extend protocol, PRN treatment (as per READ-2 study), and monthly injections (as per RISE/RIDE studies).43,44 For patients with macular edema secondary to retinal vein occlusion, 48% of respondents used 3 initial monthly injections followed by PRN treatment, with 69% of those treating with 1 injection for recurrences of edema, and 31% treating with 3 injections for each recurrence of edema. Less commonly used were a treat and extend protocol, monthly injections, and PRN only treatment. These protocols are largely similar, but not identical, to the BRAVO/CRUISE protocol of 6 initial injections followed by PRN treatment.45,46
CONCLUSION Our study had an overall response rate of 64%. This compares favourably with recent national surveys of Canadian ophthalmologists regarding DME treatment protocols and cataract surgery practices, as well as the recent U.S. IVI techniques survey.12,47,48 A possible limitation, as in any survey, is selection bias in the surgeons who chose to respond. We demonstrated there are various IVI practice patterns by retina specialists in Canada. Overall, Canadian surgeons’ practice patterns were similar to ones in the United States and United Kingdom, with some differences in aseptic technique, optic nerve perfusion assessment, and antibiotic use (Table 2). Further studies are needed to examine the evidence behind these practice patterns. It is our hope that our results will serve as a baseline for future studies to monitor changes over time and to allow comparison with techniques done elsewhere in the world.
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