- Email: [email protected]
Generic trypan blue as possible cause of a cluster of toxic anterior segment syndrome cases after uneventful cataract surgery
848
CASE REPORT
Generic trypan blue as possible cause of a cluster of toxic anterior segment syndrome cases after uneventful cataract surgery Artemis Matsou, MD, MRCP, Argyrios Tzamalis, MD, PhD, Nikolaos Chalvatzis, MD, PhD, Asimina Mataftsi, MD, PhD, Ioannis Tsinopoulos, MD, PhD, Periklis Brazitikos, MD, PhD
Five of 16 patients having uneventful cataract surgery over 2 consecutive days presented on the first postoperative day with painless, unexpected blurry vision; marked limbus-to-limbus corneal edema; and severe anterior chamber inflammation with hypopyon and fibrin formation. Review of the records showed the 5 patients had received an intracameral injection of generic trypan blue solution 0.06% to facilitate the capsulorhexis. Patients who had not received the trypan blue injection had an uneventful firstday check and subsequent course. Management comprised
T
oxic anterior segment syndrome (TASS) is an acute and intense sterile inflammatory reaction of unknown incidence that can occur after any anterior segment surgery.1 It typically presents within 12 to 48 hours of intraocular surgery. The timing of the onset of symptoms is the hallmark of the syndrome, in contrast to acute infectious endophthalmitis in which symptoms commonly develop 2 to 7 days postoperatively.1,2 Toxic anterior segment syndrome is presumed to be induced by noninfectious toxic substances that are introduced intracamerally. Patients complain of blurry vision, minimal or no pain, and redness of the eye. Clinically, the inflammation is restricted to the anterior segment and is characterized by pronounced limbus-to-limbus corneal edema caused by a toxic insult to the endothelial cell layer, marked cellular and fibrinous anterior chamber reaction with hypopyon formation due to breakdown of the blood– aqueous barrier, as well as a potential increase in intraocular pressure (IOP) due to iris and trabecular meshwork damage. Several causes of TASS have been reported and can be roughly categorized into 2 types: extraocular agents that inadvertently enter the eye, such as talc from surgical gloves, topical antiseptics, and ophthalmic ointments
intense topical steroids and close follow-up, which led to gradual improvement in all cases. The batch of trypan blue vials was withdrawn, and there were no additional cases of toxic anterior segment syndrome (TASS). This TASS cluster highlights a rarely reported cause of the syndrome, underscoring the need for thorough documentation of solutions and/or medications used intraoperatively and surgeon awareness of possible adverse events. J Cataract Refract Surg 2017; 43:848–852 Q 2017 ASCRS and ESCRS
and substances commonly used intraocularly as part of the surgical procedure and irritants on the surface of surgical instruments, such as impurities or contamination of irrigating solutions, instruments, intraocular lenses, preservatives, mitomycin-C, medications, and ophthalmic viscosurgical devices (OVDs).3,4 New potential risk factors for TASS need to be reported and become common knowledge to the ophthalmic community to prevent further episodes. We present an outbreak of TASS in which the investigation process identified the use of a generic trypan blue solution as the possible etiology. CASE REPORTS Uneventful cataract surgery by phacoemulsification was performed over 2 consecutive days by 2 separate senior surgeons (N.C., I.T.). The same phacoemulsification device (Centurion Vision System, Alcon Surgical, Inc.) and technique (phacochop) were used, and no intraoperative complications were recorded in any case. Five of the 16 patients reported unexpected blurry vision with no pain on the first postoperative day and were requested to proceed for a postoperative follow-up. The ophthalmic examination revealed marked limbus-tolimbus corneal edema (5 eyes), severe anterior chamber inflammation (5 eyes), hypopyon (2 eyes), fibrin reaction (2 eyes), and mild vitritis (1 eye). The corrected distance visual acuity (CDVA) varied
Submitted: February 14, 2017 | Final revision submitted: April 23, 2017 | Accepted: May 14, 2017 From the 2nd Department of Ophthalmology, Papageorgiou General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece. Corresponding author: Argyrios Tzamalis, MD, PhD, 2nd Department of Ophthalmology, Papageorgiou General Hospital, Aristotle University of Thessaloniki, Faculty of Medicine, GR - 56 403, Thessaloniki, Greece. E-mail: [email protected]. Q 2017 ASCRS and ESCRS Published by Elsevier Inc.
0886-3350/$ - see frontmatter http://dx.doi.org/10.1016/j.jcrs.2017.06.002
849
CASE REPORT: GENERIC TRYPAN BLUE AS CAUSE OF TASS
Table 1. Demographic and clinical characteristics of the TASS cases on the first postoperative day. Case
Sex/Age (Y)
CDE
Conjunctival Injection
Hypopyon
Fibrin
Corneal Edema*
Vitritis
IOP (mm Hg)
CDVA
1
F/78
17.09
None
Yes
–
†††
None
21
CF
2
F/77
9.34
None
No
†
††
None
17
CF
3
F/74
6.72
Mild
No
†
†††
Mild
16
1/20
4
F/81
28.90
Mild
Yes
–
†††
None
18
HM
5
M/69
11.76
None
No
–
†††
None
14
1/20
CDE Z cumulative dissipated energy (indicated by phacoemulsification device); CDVA Z corrected distance visual acuity; CF Z counting fingers; HM Z hand motion; IOP Z intraocular pressure *Graded by the Oxford Cataract Treatment and Evaluation Team
between hand motion and 20/400. The clinical and demographic details of each case are shown in Table 1, and Figure 1 shows representative photographs of each case. The medical records of the patients were thoroughly reviewed after the TASS diagnosis was established to investigate the possible cause of the cluster. The operation protocols showed that the 5 patients had received an injection of generic trypan blue 0.06% intraoperatively for better visualization of the capsule due to mature cataracts. None of the other 11 patients who were operated on during the 2 days and had an uneventful postoperative course had received the trypan blue injection. All cluster cases were managed with intense topical steroid treatment (dexamethasone 0.1% wt/vol eyedrops hourly with gradual tapering) in addition to routine topical antibiotic cover (ofloxacin 0.3% eyedrops 4 times a day) and close follow-up, except 1 patient (Case 3). This patient was treated based on a doubtful diagnosis of acute infectious endophthalmitis due to coexisting vitritis and received a pars plana intravitreal injection of 1 mg/0.1 mL vancomycin and 2.25 mg/0.1 mL ceftazidime on the second postoperative day. At the 7-day follow-up, corneal edema and inflammatory reaction were significantly decreased and the mean Snellen CDVA had improved to 0.43 G 0.16 (SD); the IOP measurement did not show any spikes that had to be managed, remaining within normal levels. At 1 month, there were no signs of inflammation or permanent ocular damage in any case and the corneal edema resolved completely, increasing CDVA to 0.82 G 0.18.
The suspected causative agent, the generic trypan blue solution, was examined in the Laboratory of Analytical Chemistry of the Aristotle University of Thessaloniki, Greece. Chemical analysis did not reveal impurities in the solution. However, a direct comparison of the generic and brand solutions of trypan blue for capsule staining using chromatography showed a significantly higher concentration of trypan blue in the generic drug (Figure 2). All vials of the generic trypan blue were immediately withdrawn and replaced with the previously used trypan blue solution. No TASS cases were recorded following these actions.
DISCUSSION Toxic anterior segment inflammation was described by Monson et al. in 1992.1 Previously, the condition had been known as sterile endophthalmitis or postoperative uveitis of unknown origin; it was later renamed toxic anterior segment syndrome. It is an acute postoperative inflammatory reaction of the anterior segment without vitreal involvement, caused when a noninfectious substance inadvertently enters the eye during surgery. Cellular toxicity of the corneal endothelium or the trabecular meshwork is the underlying pathophysiological mechanism. The actual incidence of TASS has been unknown, however, with increasing awareness and reporting of the
Figure 1. Representative images of TASS cases. Case 2 (A): Marked corneal edema with Descemet folds and fibrin formation. Case 4 (B): Limbus-to-limbus corneal edema with mild conjunctival injection. Case 3 (C): Ultrasound B-scan showing mild vitritis. Case 5 (D): Anterior segment OCT (0 to 180 degrees) showing significant corneal edema (central corneal thickness Z 940 mm).
Volume 43 Issue 6 June 2017
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CASE REPORT: GENERIC TRYPAN BLUE AS CAUSE OF TASS
Figure 2. Chromatography analysis comparing the trypan blue concentration in the generic (left image) and the brand (right image) solutions shows a higher trypan blue concentration in the generic product (mAbs Z milli absorbance units).
condition, TASS is now estimated to occur in approximately 0.1% to 0.22% of anterior segment procedures annually.2,5,6 It tends to present in outbreaks, which pose the greatest interest and concern and warrant further investigation, whereas sporadic cases may be overlooked or attributed to causes such as retained cortex, iris manipulation, or individual susceptibility to inflammation.7 When investigating the underlying etiology of a TASS cluster, it is important to identify, when possible, the offending agent or faulty sterilizing equipment and prevent further cases. Various causes of and associations with TASS have been reported, with intracamerally used substances among the most common risk factors for the development of the condition. The intracameral substances usually include nonsteroidal antiinflammatory medication, anesthetics, epinephrine, antibiotics, and OVDs. We present 5 cases of TASS that occurred in our department and were attributed to the use of a generic trypan blue solution. To our knowledge, this is the second reported association of TASS with generic trypan blue.8 Trypan blue dyes have been used in ophthalmic surgery since 1970, when they were mainly useful in preoperative staining of the corneal endothelium.9 In 1999, Melles et al.10 described the first intraoperative use of trypan blue to visualize the anterior lens capsule in mature cataracts, thereby facilitating the capsulorhexis. It has since been the preferred and safest choice for anterior segment surgeons in challenging cataract cases to enhance visualization of the capsule when the red reflex is compromised. The concentration of trypan blue required to adequately stain the anterior capsule has been a matter of investigation. Chang et al.11 and Yetik et al.12 have reported concentrations as low as 0.1% and 0.0125%, respectively, to sufficiently achieve capsule staining; various other concentrations, 0.06%,13 0.4%,14 and 0.6%,15 have occasionally been described. The available studies suggest applying trypan blue for 60 seconds.16 Following a 2005 U.S. Food and Drug Administration (FDA) report that certain batches of 0.06% trypan blue Volume 43 Issue 6 June 2017
were possibly contaminated with Pseudomonas aeruginosa, causing blindness in 2 cases, more caution about the type of trypan blue used was advised.A In our case series, the cause of the TASS outbreak was thought to be the use of the generic trypan blue solution in the affected patients. We reached this conclusion after careful consideration of the other possibilities. First, we suspected a disparity in the sterilization process because inadequate sterilization, ultrasonic bath contamination, and steam impurities are among the most common causes of the syndrome.7,17 Following careful review of our sterilization protocols, we concluded that we adhered to international recommendations as proposed by the American Society of Cataract and Refractive Surgery and the European Society of Cataract and Refractive Surgeons in 200717 and that the autoclave steam generator used in our operating room was adequately maintained. Furthermore, the same cleaning protocol is followed after each cataract case for all surgical instruments and all syringes and cannulas used are disposable, which means that improper cleaning technique or faulty sterilizing equipment would have resulted in complications in all patients who were operated on in the 2 days. Having ruled out sterilization and cleaning as possible causes of the outbreak, we considered other commonly reported etiologies, such as balanced salt solution contamination18; however, no recent alteration in balanced salt solution vials had occurred so this was thought an unlikely cause. Intraocular antibiotic (cefuroxime, 1.0 mg in 0.1 mL solution) is routinely given to all our patients in the same dose and mixture, automatically ruling out a dose- or mixing-related error as a cause of TASS. Inadvertent entrance of topical ointments intraocularly could not be the case because we do not apply them postoperatively. Intracameral preservative toxicity was also dismissed because all medications used in the 16 cases were preservative free. Denatured residual OVD on surgical instruments or inside the lumen of cannulas or tubing or OVD preserved with
CASE REPORT: GENERIC TRYPAN BLUE AS CAUSE OF TASS
benzalkonium chloride have also been reported as possible etiologies of TASS,6 but there was no change in the OVD brand and, as mentioned, no discrepancy in sterilization and cleaning of the surgical instruments was discovered. After eliminating the other possibilities and carefully reviewing patients’ records, we concluded that the outbreak was most likely associated with the use of a generic trypan blue solution that had been recently introduced in our department and was required intraoperatively in the 5 cases that developed TASS due to mature cataracts with poor red reflex. This was the first batch of vials used in our department. Prior to that, we had been using the original trypan blue solution, but in an effort to reduce costs, we switched to the generic product. No TASS cases had been recorded with the former product. Following the TASS outbreak, we reverted to the previously used solution. None of the other patients who were operated on during the 2 days and did not develop TASS had received an injection of the solution, even though many of the patients also had mature cataracts for which the operating surgeon did not deem the use of trypan blue necessary. At this point, we should emphasize that although no direct link between mature cataracts and the development of TASS has been reported, a mature or difficult cataract may lead to TASS as it potentially compromises the red reflex, necessitating the use of possibly toxic substances such as trypan blue to facilitate the capsulorhexis. The next step we took was to immediately withdraw all trypan blue vials and request a chemical analysis of the concentration and preservatives of the solution. The laboratory issued a report based on analytical chromatography that confirmed a higher concentration of trypan blue in the generic product than in the original solution, reinforcing our suspicion that the TASS outbreak could be attributed to the generic trypan blue. All vials of the generic solution were immediately withdrawn and replaced with the formerly used trypan blue solution. No TASS cases were recorded following these actions. On further follow-up, the 5 patients showed a favorable response to topical therapy with corticosteroid eyedrops, with good recovery of visual acuity and resolution of corneal edema and intraocular inflammation. The inflammation seen in TASS is, by definition, considered to be restricted to the anterior chamber; however, mild anterior vitritis by virtue of cell spillover has been described.7 The vitritis encountered in 1 patient was managed as potential endophthalmitis for safety reasons. Of note, the surgeon who performed that case reported a blue reflex on lens removal, suggesting vitreous staining through permeable zonular fibers. Our investigation unveiled generic trypan blue as the most plausible source of the TASS cluster documented in our department. One comparable report by Buzard et al.8 describes 2 cases of TASS resulting from impurities of the generic trypan blue applied. In that series, both
851
patients had a more detrimental outcome, with severe corneal endothelial cell loss and decompensation, eventually requiring penetrating keratoplasty. Cell culture analysis comparing the trypan blue used in those patients to a proprietary trypan blue solution disclosed a twofold increase in endothelial toxicity of the former, identifying it as the most reasonable explanation of the situation. To conclude, intraocularly used agents can be hazardous and potentially carry deleterious risks, highlighting the importance of documenting the type and lot numbers of all products used to enable prompt identification of the causative agent when adverse events such as TASS occur. Generic products are considered to behave the same as the brand equivalents; however, several issues emerge occasionally, such as the physical properties of the active product, including particle size, chemical, and biochemical properties of the preparation, differences in pharmacokinetic or pharmacodynamic properties, and variations between different batch preparations of the drug.B In addition, the FDA-approval process for generic products can sometimes be less meticulous than for brand products. In our case series, the generic trypan blue agent was found to have a higher concentration of the active ingredient, which would indicate a faulty batch of vials. Ophthalmic surgeons should be apprehensive when using generic products intraocularly and promptly report any adverse events with products used. REFERENCES 1. Monson MC, Mamalis N, Olson RJ. Toxic anterior segment inflammation following cataract surgery. J Cataract Refract Surg 1992; 18:184–189 2. Sengupta S, Chang DF, Gandhi R, Kenia H, Venkatesh R. Incidence and long-term outcomes of toxic anterior segment syndrome at Aravind Eye Hospital. J Cataract Refract Surg 2011; 37:1673–1678 3. Cutler Peck CM, Brubaker J, Clouser S, Danford C, Edelhauser HE, Mamalis N. Toxic anterior segment syndrome: common causes. J Cataract Refract Surg 2010; 36:1073–1080 4. Bodnar Z, Clouser S, Mamalis N. Toxic anterior segment syndrome: update on the most common causes. J Cataract Refract Surg 2012; 38:1902–1910 5. Eydelman MB, Tarver ME, Calogero D, Buchen SY, Alexander KY. The Food and Drug Administration’s Proactive Toxic Anterior Segment Syndrome Program. Ophthalmology 2012; 119:1297–1302 6. Althomali TA. Viscoelastic substance in prefilled syringe as an etiology of toxic anterior segment syndrome. Cutan Ocul Toxicol 2016; 35:237–241 7. Holland SP, Morck DW, Lee TL. Update on toxic anterior segment syndrome. Curr Opin Ophthalmol 2007; 18:4–8 8. Buzard K, Zhang J-R, Thumann G, Stripecke R, Sunalp M. Two cases of toxic anterior segment syndrome from generic trypan blue. J Cataract Refract Surg 2010; 36:2195–2199 9. Norn MS. Per operative trypan blue vital staining of corneal endothelium; eight years’ follow up. Acta Ophthalmol (Copenh) 1980; 58:550–555 10. Melles GRJ, de Waard PWT, Pameyer JH, Beekhuis WH. Trypan blue capsule staining to visualize the capsulorhexis in cataract surgery. J Cataract Refract Surg 1999; 25:7–9 11. Chang Y-S, Tseng S-Y, Tseng S-H. Comparison of dyes for cataract surgery. Part 2: efficacy of capsule staining in a rabbit model. J Cataract Refract Surg 2005; 31:799–804 12. Yetik H, Devranoglu K, Ozkan S. Determining the lowest trypan blue concentration that satisfactorily stains the anterior capsule. J Cataract Refract Surg 2002; 28:988–991 13. de Waard PWT, Budo CJ, Melles GRJ. Trypan blue capsular staining to “find” the leading edge of a “lost” capsulorhexis. Am J Ophthalmol 2002; 134:271–272 € Erakgu lu O, €n T, Gu €ler C. Trypan blue mixed with sodium hyalur14. Kayikic¸iog onate for capsulorhexis. J Cataract Refract Surg 2001; 27:970
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15. Jacob S, Agarwal A, Agarwal A, Agarwal S, Chowdhary S, Chowdhary R, Bagmar AA. Trypan blue as an adjunct for safe phacoemulsification in eyes with white cataract. J Cataract Refract Surg 2002; 28:1819–1825 16. Fritz WL. Digital image analysis of trypan blue and fluorescein staining of anterior lens capsules and intraocular lenses. J Cataract Refract Surg 2002; 28:1034–1038 17. American Society of Cataract and Refractive Surgery and the American Society of Ophthalmic Registered Nurses. Recommended practices for cleaning and sterilizing intraocular surgical instruments. J Cataract Refract Surg 2007; 33:1095–1100. Available at: http://www.ascrs.org/sites/default/ files/resources/TASS_guidelines-CBC.pdf. Accessed May 15, 2017 18. Kutty PK, Forster TS, Wood-Koob C, Thayer N, Nelson RB, Berke SJ, Pontacolone L, Beardsley TL, Edelhauser HF, Arduino MJ, Mamalis N, Srinivasan A. Multistate outbreak of toxic anterior segment syndrome, 2005. J Cataract Refract Surg 2008; 34:585–590 OTHER CITED MATERIAL A. Ford FD, Afshari NA. Trypan blue dye: capsular staining for cataract surgery and more. American Academy of Ophthalmology Clinical News, April 1,
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2006. Available at: https://www.aao.org/current-insight/trypan-blue-dyecapsular-staining-cataract-surgery. Accessed May 15, 2017 B. Cantor LB. Generic ophthalmic medications: as good as a Xerox? Medscape Ophthalmology, 2008
Disclosure: None of the authors has a financial or proprietary interest in any material or method mentioned.
First author: Artemis Matsou, MD, MRCP 2nd Department of Ophthalmology, Papageorgiou General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
CASE REPORT
Generic trypan blue as possible cause of a cluster of toxic anterior segment syndrome cases after uneventful cataract surgery Artemis Matsou, MD, MRCP, Argyrios Tzamalis, MD, PhD, Nikolaos Chalvatzis, MD, PhD, Asimina Mataftsi, MD, PhD, Ioannis Tsinopoulos, MD, PhD, Periklis Brazitikos, MD, PhD
Five of 16 patients having uneventful cataract surgery over 2 consecutive days presented on the first postoperative day with painless, unexpected blurry vision; marked limbus-to-limbus corneal edema; and severe anterior chamber inflammation with hypopyon and fibrin formation. Review of the records showed the 5 patients had received an intracameral injection of generic trypan blue solution 0.06% to facilitate the capsulorhexis. Patients who had not received the trypan blue injection had an uneventful firstday check and subsequent course. Management comprised
T
oxic anterior segment syndrome (TASS) is an acute and intense sterile inflammatory reaction of unknown incidence that can occur after any anterior segment surgery.1 It typically presents within 12 to 48 hours of intraocular surgery. The timing of the onset of symptoms is the hallmark of the syndrome, in contrast to acute infectious endophthalmitis in which symptoms commonly develop 2 to 7 days postoperatively.1,2 Toxic anterior segment syndrome is presumed to be induced by noninfectious toxic substances that are introduced intracamerally. Patients complain of blurry vision, minimal or no pain, and redness of the eye. Clinically, the inflammation is restricted to the anterior segment and is characterized by pronounced limbus-to-limbus corneal edema caused by a toxic insult to the endothelial cell layer, marked cellular and fibrinous anterior chamber reaction with hypopyon formation due to breakdown of the blood– aqueous barrier, as well as a potential increase in intraocular pressure (IOP) due to iris and trabecular meshwork damage. Several causes of TASS have been reported and can be roughly categorized into 2 types: extraocular agents that inadvertently enter the eye, such as talc from surgical gloves, topical antiseptics, and ophthalmic ointments
intense topical steroids and close follow-up, which led to gradual improvement in all cases. The batch of trypan blue vials was withdrawn, and there were no additional cases of toxic anterior segment syndrome (TASS). This TASS cluster highlights a rarely reported cause of the syndrome, underscoring the need for thorough documentation of solutions and/or medications used intraoperatively and surgeon awareness of possible adverse events. J Cataract Refract Surg 2017; 43:848–852 Q 2017 ASCRS and ESCRS
and substances commonly used intraocularly as part of the surgical procedure and irritants on the surface of surgical instruments, such as impurities or contamination of irrigating solutions, instruments, intraocular lenses, preservatives, mitomycin-C, medications, and ophthalmic viscosurgical devices (OVDs).3,4 New potential risk factors for TASS need to be reported and become common knowledge to the ophthalmic community to prevent further episodes. We present an outbreak of TASS in which the investigation process identified the use of a generic trypan blue solution as the possible etiology. CASE REPORTS Uneventful cataract surgery by phacoemulsification was performed over 2 consecutive days by 2 separate senior surgeons (N.C., I.T.). The same phacoemulsification device (Centurion Vision System, Alcon Surgical, Inc.) and technique (phacochop) were used, and no intraoperative complications were recorded in any case. Five of the 16 patients reported unexpected blurry vision with no pain on the first postoperative day and were requested to proceed for a postoperative follow-up. The ophthalmic examination revealed marked limbus-tolimbus corneal edema (5 eyes), severe anterior chamber inflammation (5 eyes), hypopyon (2 eyes), fibrin reaction (2 eyes), and mild vitritis (1 eye). The corrected distance visual acuity (CDVA) varied
Submitted: February 14, 2017 | Final revision submitted: April 23, 2017 | Accepted: May 14, 2017 From the 2nd Department of Ophthalmology, Papageorgiou General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece. Corresponding author: Argyrios Tzamalis, MD, PhD, 2nd Department of Ophthalmology, Papageorgiou General Hospital, Aristotle University of Thessaloniki, Faculty of Medicine, GR - 56 403, Thessaloniki, Greece. E-mail: [email protected]. Q 2017 ASCRS and ESCRS Published by Elsevier Inc.
0886-3350/$ - see frontmatter http://dx.doi.org/10.1016/j.jcrs.2017.06.002
849
CASE REPORT: GENERIC TRYPAN BLUE AS CAUSE OF TASS
Table 1. Demographic and clinical characteristics of the TASS cases on the first postoperative day. Case
Sex/Age (Y)
CDE
Conjunctival Injection
Hypopyon
Fibrin
Corneal Edema*
Vitritis
IOP (mm Hg)
CDVA
1
F/78
17.09
None
Yes
–
†††
None
21
CF
2
F/77
9.34
None
No
†
††
None
17
CF
3
F/74
6.72
Mild
No
†
†††
Mild
16
1/20
4
F/81
28.90
Mild
Yes
–
†††
None
18
HM
5
M/69
11.76
None
No
–
†††
None
14
1/20
CDE Z cumulative dissipated energy (indicated by phacoemulsification device); CDVA Z corrected distance visual acuity; CF Z counting fingers; HM Z hand motion; IOP Z intraocular pressure *Graded by the Oxford Cataract Treatment and Evaluation Team
between hand motion and 20/400. The clinical and demographic details of each case are shown in Table 1, and Figure 1 shows representative photographs of each case. The medical records of the patients were thoroughly reviewed after the TASS diagnosis was established to investigate the possible cause of the cluster. The operation protocols showed that the 5 patients had received an injection of generic trypan blue 0.06% intraoperatively for better visualization of the capsule due to mature cataracts. None of the other 11 patients who were operated on during the 2 days and had an uneventful postoperative course had received the trypan blue injection. All cluster cases were managed with intense topical steroid treatment (dexamethasone 0.1% wt/vol eyedrops hourly with gradual tapering) in addition to routine topical antibiotic cover (ofloxacin 0.3% eyedrops 4 times a day) and close follow-up, except 1 patient (Case 3). This patient was treated based on a doubtful diagnosis of acute infectious endophthalmitis due to coexisting vitritis and received a pars plana intravitreal injection of 1 mg/0.1 mL vancomycin and 2.25 mg/0.1 mL ceftazidime on the second postoperative day. At the 7-day follow-up, corneal edema and inflammatory reaction were significantly decreased and the mean Snellen CDVA had improved to 0.43 G 0.16 (SD); the IOP measurement did not show any spikes that had to be managed, remaining within normal levels. At 1 month, there were no signs of inflammation or permanent ocular damage in any case and the corneal edema resolved completely, increasing CDVA to 0.82 G 0.18.
The suspected causative agent, the generic trypan blue solution, was examined in the Laboratory of Analytical Chemistry of the Aristotle University of Thessaloniki, Greece. Chemical analysis did not reveal impurities in the solution. However, a direct comparison of the generic and brand solutions of trypan blue for capsule staining using chromatography showed a significantly higher concentration of trypan blue in the generic drug (Figure 2). All vials of the generic trypan blue were immediately withdrawn and replaced with the previously used trypan blue solution. No TASS cases were recorded following these actions.
DISCUSSION Toxic anterior segment inflammation was described by Monson et al. in 1992.1 Previously, the condition had been known as sterile endophthalmitis or postoperative uveitis of unknown origin; it was later renamed toxic anterior segment syndrome. It is an acute postoperative inflammatory reaction of the anterior segment without vitreal involvement, caused when a noninfectious substance inadvertently enters the eye during surgery. Cellular toxicity of the corneal endothelium or the trabecular meshwork is the underlying pathophysiological mechanism. The actual incidence of TASS has been unknown, however, with increasing awareness and reporting of the
Figure 1. Representative images of TASS cases. Case 2 (A): Marked corneal edema with Descemet folds and fibrin formation. Case 4 (B): Limbus-to-limbus corneal edema with mild conjunctival injection. Case 3 (C): Ultrasound B-scan showing mild vitritis. Case 5 (D): Anterior segment OCT (0 to 180 degrees) showing significant corneal edema (central corneal thickness Z 940 mm).
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CASE REPORT: GENERIC TRYPAN BLUE AS CAUSE OF TASS
Figure 2. Chromatography analysis comparing the trypan blue concentration in the generic (left image) and the brand (right image) solutions shows a higher trypan blue concentration in the generic product (mAbs Z milli absorbance units).
condition, TASS is now estimated to occur in approximately 0.1% to 0.22% of anterior segment procedures annually.2,5,6 It tends to present in outbreaks, which pose the greatest interest and concern and warrant further investigation, whereas sporadic cases may be overlooked or attributed to causes such as retained cortex, iris manipulation, or individual susceptibility to inflammation.7 When investigating the underlying etiology of a TASS cluster, it is important to identify, when possible, the offending agent or faulty sterilizing equipment and prevent further cases. Various causes of and associations with TASS have been reported, with intracamerally used substances among the most common risk factors for the development of the condition. The intracameral substances usually include nonsteroidal antiinflammatory medication, anesthetics, epinephrine, antibiotics, and OVDs. We present 5 cases of TASS that occurred in our department and were attributed to the use of a generic trypan blue solution. To our knowledge, this is the second reported association of TASS with generic trypan blue.8 Trypan blue dyes have been used in ophthalmic surgery since 1970, when they were mainly useful in preoperative staining of the corneal endothelium.9 In 1999, Melles et al.10 described the first intraoperative use of trypan blue to visualize the anterior lens capsule in mature cataracts, thereby facilitating the capsulorhexis. It has since been the preferred and safest choice for anterior segment surgeons in challenging cataract cases to enhance visualization of the capsule when the red reflex is compromised. The concentration of trypan blue required to adequately stain the anterior capsule has been a matter of investigation. Chang et al.11 and Yetik et al.12 have reported concentrations as low as 0.1% and 0.0125%, respectively, to sufficiently achieve capsule staining; various other concentrations, 0.06%,13 0.4%,14 and 0.6%,15 have occasionally been described. The available studies suggest applying trypan blue for 60 seconds.16 Following a 2005 U.S. Food and Drug Administration (FDA) report that certain batches of 0.06% trypan blue Volume 43 Issue 6 June 2017
were possibly contaminated with Pseudomonas aeruginosa, causing blindness in 2 cases, more caution about the type of trypan blue used was advised.A In our case series, the cause of the TASS outbreak was thought to be the use of the generic trypan blue solution in the affected patients. We reached this conclusion after careful consideration of the other possibilities. First, we suspected a disparity in the sterilization process because inadequate sterilization, ultrasonic bath contamination, and steam impurities are among the most common causes of the syndrome.7,17 Following careful review of our sterilization protocols, we concluded that we adhered to international recommendations as proposed by the American Society of Cataract and Refractive Surgery and the European Society of Cataract and Refractive Surgeons in 200717 and that the autoclave steam generator used in our operating room was adequately maintained. Furthermore, the same cleaning protocol is followed after each cataract case for all surgical instruments and all syringes and cannulas used are disposable, which means that improper cleaning technique or faulty sterilizing equipment would have resulted in complications in all patients who were operated on in the 2 days. Having ruled out sterilization and cleaning as possible causes of the outbreak, we considered other commonly reported etiologies, such as balanced salt solution contamination18; however, no recent alteration in balanced salt solution vials had occurred so this was thought an unlikely cause. Intraocular antibiotic (cefuroxime, 1.0 mg in 0.1 mL solution) is routinely given to all our patients in the same dose and mixture, automatically ruling out a dose- or mixing-related error as a cause of TASS. Inadvertent entrance of topical ointments intraocularly could not be the case because we do not apply them postoperatively. Intracameral preservative toxicity was also dismissed because all medications used in the 16 cases were preservative free. Denatured residual OVD on surgical instruments or inside the lumen of cannulas or tubing or OVD preserved with
CASE REPORT: GENERIC TRYPAN BLUE AS CAUSE OF TASS
benzalkonium chloride have also been reported as possible etiologies of TASS,6 but there was no change in the OVD brand and, as mentioned, no discrepancy in sterilization and cleaning of the surgical instruments was discovered. After eliminating the other possibilities and carefully reviewing patients’ records, we concluded that the outbreak was most likely associated with the use of a generic trypan blue solution that had been recently introduced in our department and was required intraoperatively in the 5 cases that developed TASS due to mature cataracts with poor red reflex. This was the first batch of vials used in our department. Prior to that, we had been using the original trypan blue solution, but in an effort to reduce costs, we switched to the generic product. No TASS cases had been recorded with the former product. Following the TASS outbreak, we reverted to the previously used solution. None of the other patients who were operated on during the 2 days and did not develop TASS had received an injection of the solution, even though many of the patients also had mature cataracts for which the operating surgeon did not deem the use of trypan blue necessary. At this point, we should emphasize that although no direct link between mature cataracts and the development of TASS has been reported, a mature or difficult cataract may lead to TASS as it potentially compromises the red reflex, necessitating the use of possibly toxic substances such as trypan blue to facilitate the capsulorhexis. The next step we took was to immediately withdraw all trypan blue vials and request a chemical analysis of the concentration and preservatives of the solution. The laboratory issued a report based on analytical chromatography that confirmed a higher concentration of trypan blue in the generic product than in the original solution, reinforcing our suspicion that the TASS outbreak could be attributed to the generic trypan blue. All vials of the generic solution were immediately withdrawn and replaced with the formerly used trypan blue solution. No TASS cases were recorded following these actions. On further follow-up, the 5 patients showed a favorable response to topical therapy with corticosteroid eyedrops, with good recovery of visual acuity and resolution of corneal edema and intraocular inflammation. The inflammation seen in TASS is, by definition, considered to be restricted to the anterior chamber; however, mild anterior vitritis by virtue of cell spillover has been described.7 The vitritis encountered in 1 patient was managed as potential endophthalmitis for safety reasons. Of note, the surgeon who performed that case reported a blue reflex on lens removal, suggesting vitreous staining through permeable zonular fibers. Our investigation unveiled generic trypan blue as the most plausible source of the TASS cluster documented in our department. One comparable report by Buzard et al.8 describes 2 cases of TASS resulting from impurities of the generic trypan blue applied. In that series, both
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patients had a more detrimental outcome, with severe corneal endothelial cell loss and decompensation, eventually requiring penetrating keratoplasty. Cell culture analysis comparing the trypan blue used in those patients to a proprietary trypan blue solution disclosed a twofold increase in endothelial toxicity of the former, identifying it as the most reasonable explanation of the situation. To conclude, intraocularly used agents can be hazardous and potentially carry deleterious risks, highlighting the importance of documenting the type and lot numbers of all products used to enable prompt identification of the causative agent when adverse events such as TASS occur. Generic products are considered to behave the same as the brand equivalents; however, several issues emerge occasionally, such as the physical properties of the active product, including particle size, chemical, and biochemical properties of the preparation, differences in pharmacokinetic or pharmacodynamic properties, and variations between different batch preparations of the drug.B In addition, the FDA-approval process for generic products can sometimes be less meticulous than for brand products. In our case series, the generic trypan blue agent was found to have a higher concentration of the active ingredient, which would indicate a faulty batch of vials. Ophthalmic surgeons should be apprehensive when using generic products intraocularly and promptly report any adverse events with products used. REFERENCES 1. Monson MC, Mamalis N, Olson RJ. Toxic anterior segment inflammation following cataract surgery. J Cataract Refract Surg 1992; 18:184–189 2. Sengupta S, Chang DF, Gandhi R, Kenia H, Venkatesh R. Incidence and long-term outcomes of toxic anterior segment syndrome at Aravind Eye Hospital. J Cataract Refract Surg 2011; 37:1673–1678 3. Cutler Peck CM, Brubaker J, Clouser S, Danford C, Edelhauser HE, Mamalis N. Toxic anterior segment syndrome: common causes. J Cataract Refract Surg 2010; 36:1073–1080 4. Bodnar Z, Clouser S, Mamalis N. Toxic anterior segment syndrome: update on the most common causes. J Cataract Refract Surg 2012; 38:1902–1910 5. Eydelman MB, Tarver ME, Calogero D, Buchen SY, Alexander KY. The Food and Drug Administration’s Proactive Toxic Anterior Segment Syndrome Program. Ophthalmology 2012; 119:1297–1302 6. Althomali TA. Viscoelastic substance in prefilled syringe as an etiology of toxic anterior segment syndrome. Cutan Ocul Toxicol 2016; 35:237–241 7. Holland SP, Morck DW, Lee TL. Update on toxic anterior segment syndrome. Curr Opin Ophthalmol 2007; 18:4–8 8. Buzard K, Zhang J-R, Thumann G, Stripecke R, Sunalp M. Two cases of toxic anterior segment syndrome from generic trypan blue. J Cataract Refract Surg 2010; 36:2195–2199 9. Norn MS. Per operative trypan blue vital staining of corneal endothelium; eight years’ follow up. Acta Ophthalmol (Copenh) 1980; 58:550–555 10. Melles GRJ, de Waard PWT, Pameyer JH, Beekhuis WH. Trypan blue capsule staining to visualize the capsulorhexis in cataract surgery. J Cataract Refract Surg 1999; 25:7–9 11. Chang Y-S, Tseng S-Y, Tseng S-H. Comparison of dyes for cataract surgery. Part 2: efficacy of capsule staining in a rabbit model. J Cataract Refract Surg 2005; 31:799–804 12. Yetik H, Devranoglu K, Ozkan S. Determining the lowest trypan blue concentration that satisfactorily stains the anterior capsule. J Cataract Refract Surg 2002; 28:988–991 13. de Waard PWT, Budo CJ, Melles GRJ. Trypan blue capsular staining to “find” the leading edge of a “lost” capsulorhexis. Am J Ophthalmol 2002; 134:271–272 € Erakgu lu O, €n T, Gu €ler C. Trypan blue mixed with sodium hyalur14. Kayikic¸iog onate for capsulorhexis. J Cataract Refract Surg 2001; 27:970
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15. Jacob S, Agarwal A, Agarwal A, Agarwal S, Chowdhary S, Chowdhary R, Bagmar AA. Trypan blue as an adjunct for safe phacoemulsification in eyes with white cataract. J Cataract Refract Surg 2002; 28:1819–1825 16. Fritz WL. Digital image analysis of trypan blue and fluorescein staining of anterior lens capsules and intraocular lenses. J Cataract Refract Surg 2002; 28:1034–1038 17. American Society of Cataract and Refractive Surgery and the American Society of Ophthalmic Registered Nurses. Recommended practices for cleaning and sterilizing intraocular surgical instruments. J Cataract Refract Surg 2007; 33:1095–1100. Available at: http://www.ascrs.org/sites/default/ files/resources/TASS_guidelines-CBC.pdf. Accessed May 15, 2017 18. Kutty PK, Forster TS, Wood-Koob C, Thayer N, Nelson RB, Berke SJ, Pontacolone L, Beardsley TL, Edelhauser HF, Arduino MJ, Mamalis N, Srinivasan A. Multistate outbreak of toxic anterior segment syndrome, 2005. J Cataract Refract Surg 2008; 34:585–590 OTHER CITED MATERIAL A. Ford FD, Afshari NA. Trypan blue dye: capsular staining for cataract surgery and more. American Academy of Ophthalmology Clinical News, April 1,
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2006. Available at: https://www.aao.org/current-insight/trypan-blue-dyecapsular-staining-cataract-surgery. Accessed May 15, 2017 B. Cantor LB. Generic ophthalmic medications: as good as a Xerox? Medscape Ophthalmology, 2008
Disclosure: None of the authors has a financial or proprietary interest in any material or method mentioned.
First author: Artemis Matsou, MD, MRCP 2nd Department of Ophthalmology, Papageorgiou General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece