- Email: [email protected]
Increased postoperative anterior chamber inflammation secondary to heat-resistant endotoxins
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ARTICLE
Increased postoperative anterior chamber inflammation secondary to heat-resistant endotoxins Javed Hussain Farooqui, MBBS, DNB, MNAMS, Arpan Gandhi, MBBS, MD, Umang Mathur, MBBS, MS, Gaurav Bharti, MBBS, DO, DNB, Suneeta Dubey, MBBS, MS
Purpose: To evaluate the cause of clusters of increased postoperative anterior chamber inflammation after uneventful cataract surgery, and to examine its relation to the presence of endotoxins in sterile consumables. Setting: Tertiary eye center in north India. Design: Single-center retrospective case series. Methods: All cataract surgeries performed at the tertiary eye center over 12 weeks (October 1, 2017 to December 31, 2017) were noted. Any patient with a “severe reaction” postoperatively was monitored closely and the postoperative drug regimen was altered accordingly. “Severe reaction” was defined as any patient with more than 4C cells and/or fibrin with or without hypopyon. The Hospital Infection Control committee was informed, and a root cause analysis was performed to determine the cause. All the consumables were recalled and replaced. The samples were sent for microbiological evaluations.
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ncreased postoperative anterior segment inflammation after cataract surgery is a cause of concern for all operating surgeons. The various possible causes are infectious, noninfectious (sterile), anaphylactic, or toxic anterior segment syndrome (TASS).1 Outbreaks of unexplained postoperative inflammation after cataract surgery are uncommon.1 Various degrees of anterior segment damage have been reported, ranging from inflammation to hypopyon caused by toxic substances.2 If the inflammation is restricted to the anterior segment, immediate appropriate therapy (with topical corticosteroids) can successfully treat the inflammation with no residual sightthreatening problems.3 Over a 3-month period, we experienced a sudden outbreak of increased postoperative anterior segment inflammation at a high volume surgical eye center based
Results: Of the 781 cataract surgeries performed, 81 patients had a severe reaction. Most patients were men (71%) and the mean age of the patients was 63 years. Twelve patients had fibrin, 3 of whom presented with hypopyon. Because all samples were negative of any growth, endotoxin tests were performed. All the samples were found to be negative, except for the ophthalmic viscosurgical device (OVD), which showed positive endotoxin levels. The OVD was changed and the anterior chamber reactions ceased to occur.
Conclusion: A careful, stepwise approach is necessary when investigating clusters of increased postoperative anterior chamber reactions after uneventful surgery. A high degree of suspicion is important to rule out all possible reasons and in the absence of any identifiable cause, sterile consumables should be checked for endotoxins. J Cataract Refract Surg 2018; -:-–- Q 2018 ASCRS and ESCRS
in northern India. To determine the cause of this outbreak, an extensive investigation and a root cause analysis was initiated. A multidepartmental approach, under the guidance of the Hospital Infection Control (HIC) committee, was sought to find out the cause of the sudden rise in the incidence of increased postoperative inflammation. Through this paper, we aim to share with the readers our experience of successfully investigating and managing the cases of increased postoperative anterior chamber reaction. Following the protocols, a thorough audit of the systems in place and prioritizing patient safety were the pillars of this study. PATIENTS AND METHODS Patients, Preoperative Assessment and Patient Preparation This is a single-center, retrospective study at a tertiary eye care center. Because this was a retrospective analysis with appropriate
Submitted: May 18, 2018 | Final revision submitted: August 24, 2018 | Accepted: September 4, 2018 From Dr. Shroff’s Charity Eye Hospital, Kedarnath Marg, Daryaganj, New Delhi, India. Corresponding author: Javed Hussain Farooqui, MBBS, DNB, MNAMS, Department of Cornea, Cataract and Refractive Surgery, Dr. Shroff’s Charity Eye Hospital, 5027 Kedarnath Marg, Daryaganj, New Delhi 110002, India. Email: [email protected]. Q 2018 ASCRS and ESCRS Published by Elsevier Inc.
0886-3350/$ - see frontmatter https://doi.org/10.1016/j.jcrs.2018.09.018
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INCREASED POSTOPERATIVE ANTERIOR CHAMBER REACTION AND ENDOTOXINS
corrective interventions, the Institutional Review Board was informed and exemption taken. However, all required consents were sought from the patients before clinical examinations and surgeries according to the hospital protocols, and all necessary steps were taken to safeguard patient identity and data. All cataract surgeries (phacoemulsification and small-incision cataract surgery [SICS], based on the surgeon’s judgment) performed at the center over a period of 12 weeks (October 1, 2017 to December 31, 2017) were noted. Data of the cataract surgeries performed a month before and a month after the aforementioned period were also retrieved. Three surgeons from the Department of Cataract and Intraocular Lens Services performed all the surgeries. Both rigid poly(methyl methacrylate) (PMMA) and foldable (hydrophilic and hydrophobic) intraocular lenses (IOLs) were used, depending on patient choice and affordability. The preoperative evaluation included a visual acuity check and a dilated ocular examination including type of cataract, anterior chamber reaction, and a fundus evaluation using a slitlamp (BM 900, Haag-Streit AG). The intraocular pressure (IOP) was measured using Goldmann applanation tonometry, and a physical examination was performed by an internist for systemic diseases. Topical ciprofloxacin 0.3%, 4 times a day, was started 1 day before surgery and instilled hourly on the day of surgery. Also, tropicamide 1% and proparacaine hydrochloride 0.5% was used on the day of surgery to achieve dilation. Peribulbar anesthesia was attained using 6 cc of 1:1 mixture of 2% lidocaine and 0.75% bupivacaine with 150 units of hyaluronidase per 20 cc, and it was administered with a 25-gauge needle. Before the surgery, a drop of 5% povidone iodine was instilled in the cul-de-sac and left for 2 minutes. In the operating room, the operative eye was prepared with 10% povidone iodine and sterilely draped. The cataract surgery was performed under aseptic conditions. Intraoperative details were mentioned in the patient’s chart at the end of each surgery, which included the steps of the surgery, any intraoperative events, and the time taken to finish the surgery. At the end of surgery, a subconjunctival injection of dexamethasone sodium phosphate (4 mg/mL) and gentamycin sulfate (20 mg/mL) was injected. A drop of moxifloxacin 0.5% was instilled in the cul-de-sac after the surgery, and the eye was bandaged. The bandage was kept on overnight and opened the next morning. Surgical Procedures The decision to perform phacoemulsification or manual SICS was determined by the operating surgeon. For the phacoemulsification, a superior clear corneal tunnel of 2.8 mm and a side port for the second instrument was made using a stainless steel keratome. A continuous circular capsulorhexis was made on the anterior capsule followed by hydrodissection and hydrodelineation. A phacoemulsification system (Laureate World Phaco System, Alcon Laboratories, Inc.) was used with a standardized microtip over a 30-gauge cannula to sculpt a deep central groove, and the nucleus was bisected. Using the Koch stop-andchop method,4 the nucleus was emulsified, and the remaining cortex was removed with the irrigation/aspiration (I/A) tip. The capsular bag was filled with ophthalmic viscosurgical device (OVD) of 2% hydroxypropyl methylcellulose ophthalmic solution (Viscolon, Contacare Ophthalmics and Diagnostics), and either a foldable hydrophilic acrylic IOL (Acryfold, AI Optics Ltd, or Ultima, Biovision Ltd.) or a hydrophobic acrylic IOL (Acrysof SA60AT or Acrysof.IQ SN60WF, Alcon Laboratories, Inc.) was implanted in the bag. The decision of which IOL to implant was dependent on patient choice and affordability. The anterior chamber was filled with irrigation fluid (Plasma Lyte A, Baxter India Private Ltd.) and the tunnel integrity was tested. For the manual SICS, a superior 6.5-mm frown-shaped sclerocorneal tunnel was constructed with a number 15 sterile blade on a
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Bard Parker handle. A side port was created to facilitate intraocular manipulations. A continuous circular capsulorhexis was made on the anterior capsule and the nucleus was prolapsed from the capsular bag by hydrodissection injection (hydro prolapse) or with a Sinskey hook. The OVD was injected around the nucleus and it was delivered in whole through the scleral tunnel using viscoexpression. The remaining cortex was removed with manual I/A (using a 23-gauge reusable stainless steel Simcoe cannula), and a 6.5 mm single-piece PMMA IOL (Eye-O-Care, Biovision, Ltd.) was implanted in the bag. The irrigating fluid (Plasma Lyte A, Baxter India Private Ltd.) was inserted through the side port to test the integrity of the tunnel. The surgery was sutureless with a self-sustaining tunnel. Postoperative Management As a routine practice postoperatively, patients were followed up on day 1, day 7 and day 30. A slitlamp evaluation was performed at every visit by the same observer, which included inspection for the presence or absence of conjunctival or circumciliary congestion, cornea clarity, anterior chamber reaction (described using the Standardization of Uveitis Nomenclature classification),5 IOL centration, and fundus examination. Any patient who had more than 4C cells and/or fibrin with or without hypopyon was documented and labeled as “severe reaction.” A dilated fundus examination was performed for cases with severe reaction. A B-Scan examination was performed for cases where the fundus was not visible, or the glow was compromised. All such patients were referred to the Retina Services for evaluation. An anterior chamber paracentesis in eyes with hypopyon was performed under all aseptic precautions, and the cultures were sent for microbiological evaluation. For the paracentesis, proparacaine 0.5% eyedrops were instilled 3 times over a 15-minute period, followed by instillation of betadine 5% antiseptic drops. The patient was positioned at the slitlamp, and the upper lid and eyelashes were held out of the way by an assistant. No lid speculum was required. The paracentesis was performed using a 27-gauge needle attached to an insulin syringe, which was inserted at the paralimbal clear cornea in a plane above and parallel to the iris with the bevel of the needle facing forward until the whole bevel penetrated the cornea. The unaided and pinhole visual acuities were noted at all visits. The final refraction was performed after 4 weeks for phacoemulsification and after 6 weeks for SICS. The routine postoperative care included a topical antibiotic (0.5% moxifloxacin) 4 times a day and a steroid (1% prednisolone acetate suspension) 6 times a day tapered over 4 weeks. For patients with a severe reaction, topical steroids were stepped up to every hour. Cycloplegic drops (homatropine 2%) were given 3 times a day, and the topical antibiotic was continued 4 times a day. These patients were kept under close observation and the follow-up visits were planned according to each patient’s response to treatment. A printout of postsurgical care instructions was given to all patients, and the same was explained orally by the nurse and/or the surgeon in the patients’ local language. The signs and symptoms of endophthalmitis were explained to the patients. Routine Sterilization Protocols The phacoemulsification microtip and the tip sleeve were changed after every surgery and sterilized by autoclaving. All the surgical blades, syringes, and needles used during the cataract procedure were disposed after single use, and new sterile blades were used for every patient. At the end of surgery, all 3 surgeons practiced the World Health Organization guidelines for scrubbing. Gloves and gowns were changed after every surgery. All unsterile instruments were rinsed with tap water and soap and then kept in an ultrasound bath for 5 minutes followed by cleaning with distilled water. They were then air dried and sent to autoclave. Chemical
INCREASED POSTOPERATIVE ANTERIOR CHAMBER REACTION AND ENDOTOXINS
disinfection was not practiced in the hospital. Sterilization was performed with moist heat by keeping the instruments in the autoclave for 20 minutes at a temperature of 134 C with a pressure of 30 mm Hg. During autoclaving, the required temperature and pressure was monitored by chemical and biological indicators. Chemical indicators were placed along with the instrument tray in every set whereas biological indicators were used bimonthly. The hospital followed strict quality checks and a recall policy in which all instruments from the same batch were recalled in cases of suspected breach in sterility. Wet mopping of the operating room walls, fixtures, and equipment was conducted once a week followed by fumigation of the operating room with 1.5% D-125 (Microgen Inc.). The operating room floor was mopped with diluted D-125 solution after every surgery. As a routine, weekly samples (culture swabs, HiMedia Labs Ltd.) are sent from multiple sites including the operating room microscope, operating room table, operating room walls, operating room air conditioner, operating room dehumidifier, scrub area tap nozzle, and autoclave machine. In case any of the microbiological tests are positive, the nurse in charge of the operating room informs the HIC. All surgeons were assessed for their surgical skills and competency monthly, based on their surgical outcomes, time taken for surgery, and events rate. Root Cause Analysis Following the sudden outbreak of increased postoperative anterior segment inflammation, the HIC was informed and the committee reviewed all the procedures at the hospital. All the patient charts with increased reactions were scrutinized to find the common cause. Because the increased reaction was not surgeon-specific, the surgeon factor was negated. The reaction occurred with both foldable and nonfoldable IOLs, thus the possibility of the IOL involvement was also much less likely. The autoclave records including the chemical and the biological indicators were normal for a complete sterilization cycle. On the basis of initial analysis, the probable causes were suspected to be either the consumables, including the Viscolon OVD (from now on referred to as OVD1), and the irrigating solution or a breach in the cleaning process of the instruments before autoclaving. The operating room was closed for 3 days for a thorough investigation and for terminal cleaning. All surgical surfaces and instruments were cleaned and cultured. Repeat samples with controls were sent to 2 different laboratories, one of which was an in-house laboratory. The overhead water tank was emptied, cleaned, and filled with fresh water. All the consumables, which were being used, were recalled and different batch for the same were sent as replacement. These included Ringer’s lactate (sodium lactate solution), IOLs, operating room water supply, and the ultrasound bath solution. The sterilization procedures at the eye center were reviewed. Between cataract surgeries, the instruments were washed in an ultrasound bath and flushed with distilled water before sending them for autoclaving. Phacoemulsification microtips were also flushed separately.
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Microbiological Investigation Bacterial Growth The specimens collected and cultured for bacterial growth from various sites showed no growth at both the laboratories where the samples were sent. The aqueous samples derived from the anterior chamber paracentesis were found to be sterile. Endotoxin Sampling Negative cultures and a literature search prompted a check for endotoxin levels in various samples including OVD1, Ringer’s lactate, fluids from various places in the operating room, and controls. It was assumed that the anterior chamber inflammation was attributable to an immunogenic reaction to these heat stable toxins in the anterior chamber that incited a polymorphonuclear reaction in some patients. The endotoxin test was performed with the litmus lysate assay at 2 independent laboratories. A fresh set of dilutions from the stock endotoxin solution were prepared on the day of the test run. The OVD1 sample was very viscous and had to be diluted to 1:5. Dilutions were made in test tubes and the test volume transferred to the reaction tubes amounting to 0.1 mL in each tube. The test was performed using a gel clot method, and it was considered positive if there was gel formation (O0.05 IU/mL) that did not collapse when the tube was inverted.
RESULTS Demographic Data
From October 1, 2017 to December 31, 2017, 781 cataract surgeries were performed at a tertiary eye center in north India. Of the 781 cases, 81 eyes of 81 patients (10.3%) who had undergone uneventful cataract surgery (45 had phacoemulsification and 36 had manual SICS), showed varied levels of increased postoperative inflammation on the first postoperative day and fulfilled the criteria for “severe reaction.” The majority were men (57 [70.4%]), and the mean age of patients was 63 years (range 39 to 99 years). The presenting preoperative corrected distance visual acuity (CDVA) of 20/200 or worse was seen in 60 patients (74.1%). Nineteen patients (23.5%) had hydrophobic IOLs (12 Acrysof SA60AT and 7 Acrysof IQ SN60WF) implanted and 26 patients (32.1%) had hydrophilic IOLs (15 Acryfold and 11 Ultima) implanted. All patients who had manual SICS received single-piece PMMA IOLs (Eye-OCare). Of the 81 patients who had a severe reaction, 12 patients (9 men, 3 women) had varying levels of fibrin at the pupillary margin and 3 male patients had streak hypopyon (!1.0 mm measured on the slitlamp) (Figure 1, A and B). However, in all the patients, the corneas were clear with minimal Descemet membrane folds, and their IOPs
Figure 1. A: Postoperative day 1 slitlamp photograph of a patient with increased postoperative reaction and fibrin in the pupillary area. B: Another patient with streak hypopyon and a severe reaction 1 day postoperatively.
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were lower than 20 mm Hg (by Goldmann applanation tonometry). For all the patients with fibrin and hypopyon, the patients were referred to the Retina Services and ultrasound B-scan was performed to rule out posterior segment involvement. The B-scans were normal with anechoic vitreous cavity in all the 12 patients. In addition, an anterior chamber paracentesis was performed in the 3 patients presenting with an increased reaction and hypopyon. Samples were sent for microbiological growth and culture, which were found to be sterile. All 81 patients who had a severe reaction were kept on close watch with frequent follow-ups, and the postoperative schedule was modified based on findings during scheduled visits. The fundal glow with a good retinal view was present in all patients and there was no pain, no lid edema, and no conjunctival chemosis. None of the patients had a history of uveitis or any significant systemic illness. Over the next 4 weeks, 70 patients (86.4%) recovered to a CDVA of 20/ 60 or better and all the patients had a CDVA of 20/160 or better. The 11 patients in the low vision group (20/70 to 20/160) had low vision attributable to factors other than cataract surgery. Table 1 shows the demographic features of the patients who presented with increased postoperative inflammation after cataract surgery, and Figure 2 shows the “severe reaction” epidemic curve. The data of cataract surgeries performed in September were unremarkable. Out of the 235 cataract surgeries, performed in the months preceding October, none of the patients had a severe reaction and/or fibrin with or without hypopyon. There was no change in the operating surgeons, the techniques of surgery, or the disinfection protocols. Figure 3 shows the probable factors that could have been responsible for the increased reaction. Endotoxin Text Results
Endotoxin tests that were performed for 2 different batches of the OVD1 that was being used for the surgeries showed positive results at 1:5 dilution and all the other samples (Ringer’s lactate, fluids, and controls) were negative (Figures 4 to 6). The 2% hydroxypropyl methylcellulose ophthalmic solution (OVD1) was changed to an OVD from a different company, OVD2 (2% Appavisc, Appaswamy Associates) and checked for endotoxin levels before being used. Once OVD2 was found negative for endotoxins, it was used as a replacement for OVD1. All the rest of the supplies and consumables remained unchanged. After this intervention of replacing OVD1 with OVD2, the postoperative inflammations ceased in subsequent surgeries. All the surgeries that took place in January 2018 were reviewed as well. After the last documented “severe reaction,” which occurred in the last week of December, none of the 247 surgeries, which occurred in January, showed any severe reaction. DISCUSSION At the outset, no direct cause of this problem was identified. Even though the operating room was closed for 3 days for terminal cleaning, we were in a dilemma Volume - Issue - - 2018
Table 1. Demographic characteristics of the patients who presented with increased postoperative inflammation after cataract surgery. Number of Patients
Characteristic Age group !40 y 40 to 60 y 60 to 80 y O80 y Sex Male Female Cataract type Nuclear sclerosis grade 1 Nuclear sclerosis grade 2 Nuclear sclerosis grade 3 Nuclear sclerosis grade 4 Mature senile cataract Hyper mature senile cataract Preop CDVA 20/200 or worse 20/70 to 20/160 (low vision) 20/60 or better Surgery performed Phacoemulsification SICS IOL implanted PMMA Hydrophilic Hydrophobic Patients w/3C or more cells in AC Patients w/fibrin in AC Patients w/hypopyon in AC Postop CDVA (at final follow-up) 20/200 or worse 20/70 to 20/160 (low vision) 20/60 or better Cause of low vision Corneal opacity Macular dystrophy Other
October 2017
November 2017
December 2017
0 10 12 5
3 17 21 2
0 5 6 0
20 7
30 13
8 3
1 6 8 9 2 1
2 12 11 13 3 2
1 2 4 3 1 0
16 6
35 5
9 2
5
3
0
17 10
21 22
7 4
10 12 5 27
22 10 11 43
4 4 3 11
5 0
5 3
2 0
0 4
0 5
0 2
23
38
9
2 0 2
1 2 2
1 0 1
AC Z anterior chamber; CDVA Z corrected distance visual acuity; IOL Z intraocular lens; PMMA Z poly(methyl methacrylate); SICS Z small-incision cataract surgery
about whether to continue operating or discontinue the surgeries. The fact that all our patients responded well to treatment and had improved CDVAs better than 20/60 gave us confidence. We based our hypothesis of this incident as being a result of an immunological reaction on the fact that all the cultures were negative and it has been proven previously that heat-stable endotoxins can cause an exaggerated inflammatory
INCREASED POSTOPERATIVE ANTERIOR CHAMBER REACTION AND ENDOTOXINS
Figure 2. Severe postoperative reaction epidemic curve.
response.6 Endotoxins are bacterial lipopolysaccharides present in the outer cell walls of gram-negative bacteria.7,8 These can survive short-cycle sterilization, unlike the bacteria. Although rare, an immune reaction after heat-stable contamination of surgical instruments and consumable products is not unknown. Mondino et al.9 in 1977 and later Schultz et al.10,11 described the effects of endotoxin injections in rabbit corneas. They showed that endotoxin-related keratitis was most severe 4 to 5 hours after exposure, and that the severity of inflammation was related to higher doses and previous exposure. In a literature review, we found that in 1986, Richburg et al.12 and in 1992, Kreisler et al.1 observed an outbreak of sterile hypopyon that was attributed to heat stable endotoxins. Other ophthalmic surgeries have also been affected by endotoxins. In 1999, Holland et al.6 and in 2000, Yuhan et al.13 reported diffuse lamellar keratitis after laser in situ keratomileusis (LASIK) procedures because of endotoxins in biofilms occurring in a sterilized water storage reservoir. In India, Patnaik et al.14 reported sterile endophthalmitis
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after vitreoretinal surgery caused by an endotoxin. The positive trend in all the various series was the fact that no active major surgical intervention was required for management, all patients recovered with only medication, and good final visual outcomes were achieved. One might argue and label the “severe reaction” in this study as TASS, at least for the 3 patients with sterile hypopyon. We acknowledge that the fact that the severe reaction was within 24 hours of cataract surgery and it mimics TASS; however, there was no corneal edema, decreased vision, pain, dilated pupil, or increase in IOP, all of which are described as clinical features of TASS.2,15,16 Previously, TASS and an increased reaction caused by an endotoxin has been used interchangeably, with the reactions caused by an endotoxin being described as a subset or a less severe form of TASS.15 There is the possibility that TASS can progress unfavorably; however, all previous reports of patients with a severe reaction attributable to an endotoxin, including our study, have had full recoveries.1,6,12,13,17 In summary, we believe that 2 important observations came out of this investigation. First, increased postoperative inflammation after cataract surgery is worthy of consideration and proactive steps should be taken to find out its cause. Clinicians should not shy away from reporting such sudden, sporadic outbreaks of sterile postoperative inflammation, and a thorough investigation should be undertaken. We feel that this condition is rather under reported and protocols should be formulated by hospitals to tackle this problem. In a country such as India, where approximately 3 million cataract surgeries are performed each year and the cataract surgical rate is steadily increasing, it is very important that good quality eyecare standards are maintained throughout the country.18,19 To our knowledge, ours is the first case series of postcataract surgery increased inflammation for which an endotoxin test was performed in India. This is an interesting observation and, in a way, it reiterates our concerns that probably this condition is being under reported or
Figure 3. Fish bone diagram of probable factors for increased reaction (HEPA Z high-efficiency particulate air; OVD Z ophthalmic viscosurgical device; Phaco Z phacoemulsification).
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Figure 4. Report of the endotoxin test performed for tap water. The results are circled in red.
Figure 5. Report of the endotoxin test performed for the irrigating fluid used during the surgeries. The results are circled in red.
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INCREASED POSTOPERATIVE ANTERIOR CHAMBER REACTION AND ENDOTOXINS
Figure 6. Report of the endotoxin test performed for the ophthalmic viscosurgical device of 2% hydroxypropyl methylcellulose ophthalmic solution (Viscolon, Contacare Ophthalmics and Diagnostics). The results are circled in red.
surgeons are not aware of the fact that such tests can be used in clinical practice in cases of increased anterior chamber reaction where it is difficult to pinpoint a causative factor. To implement endotoxin tests as a routine in hospital disinfection policy is debatable, especially in an Indian scenario, where hospitals run on a tight budget. However, in situations of cluster-increased postoperative reactions, for which no other cause can be attributed, endotoxin tests should be performed. Second, we believe that the contamination must have been a result of faulty manufacturing. This is a worrisome situation because clinicians rely solely on the drug companies’ word as far as sterility of consumables is concerned. Although the endotoxin levels are checked by all drug manufacturing companies and the report is available from them, whether we can rely on that report is controversial. We recommend that the government and drug controllers consider formulating stricter laws to maintain standards of medicines used in clinical practice and surgery. To conclude, the challenge of increased postoperative reactions should be dealt with a heightened sense of awareness amongst surgeons, timely reporting, and a careful stepwise approach while investigating the cause. All possible causes, including the possibility of endotoxins, should be ruled out. The cause is usually in front of us, it is just about realizing it by joining the dots and solving the mystery.
WHAT WAS KNOWN Increased postoperative inflammation confined to the anterior segment can be managed effectively with topical steroids and close follow-up. A thorough root cause analysis should be performed to determine the reason for increased inflammation after any intraocular procedure.
WHAT THIS PAPER ADDS It should be borne in mind that bacterial and endotoxin contamination of drugs and consumables can take place during the manufacturing process, and clinicians should be cautious of this possibility. The reliability of sterility and endotoxin tests from the manufacturer might not be enough, and the tests should be repeated in cases of doubt.
REFERENCES 1. Kreisler KR, Martin SS, Young CW, Anderson CW, Mamalis N. Postoperative inflammation following cataract extraction caused by bacterial contamination of the cleaning bath detergent. J Cataract Refract Surg 1992; 18:106–110 2. Choi JS, Shyn KH. Development of toxic anterior segment syndrome immediately after uneventful phaco surgery. Korean J Ophthalmol 2008; 22:220– 227 3. Holzer MP, Sandoval HP, Vargas LG, Kasper TJ, Vroman DT, Apple DJ, Solomon KD. Evaluation of preoperative and postoperative prophylactic regimens for prevention and treatment of diffuse lamellar keratitis. J Cataract Refract Surg 2004; 30:195–199
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4. Koch PS, Katzen LE. Stop and chop phacoemulsification. J Cataract Refract Surg 1994; 20:566–570 5. Jabs DA, Nussenblatt RB, Rosenbaum JT. Standardization of uveitis nomenclature for reporting clinical data: Results of the First International Workshop; Standardization of Uveitis Nomenclature (SUN) Working Group. Am J Ophthalmol 2005; 140:509–516 6. Holland SP, Mathias RG, Morck DW, Chiu J, Slade SG. Diffuse lamellar keratitis related to endotoxins released from sterilizer reservoir biofilms. Ophthalmology 2000; 107:1227–1234 7. Costerton JW, Lewandowski Z, Caldwell DE, Korber DR, Lappin-Scott HM. Microbial biofilms. Annu Rev Microbiol 1995; 49:711–745 8. Rietschel ET, Brade H. Bacterial endotoxins. Sci Am 1992; 267:54–61 9. Mondino BJ, Rabin BS, Kessler E, Gallo J, Brown SI. Corneal rings with gram-negative bacteria. Arch Ophthalmol 1977; 95:2222–2225 10. Schultz CL, Buret AG, Olson ME, Ceri H, Read RR, Morck DW. Lipopolysaccharide entry in the damaged cornea and specific uptake by polymorphonuclear neutrophils. Infect Immun 2000; 68:1731–1734 11. Schultz CL, Morck DW, McKay SG, Olson ME, Buret A. Lipopolysaccharide induced acute red eye and corneal ulcers. Exp Eye Res 1997; 64:3–9 12. Richburg FA, Reidy JJ, Apple DJ, Olson RJ. Sterile hypopyon secondary to ultrasonic cleaning solution. J Cataract Refract Surg 1986; 12:248–251 13. Yuhan KR, Nguyen L, Wachler BSB. Role of instrument cleaning and maintenance in the development of diffuse lamellar keratitis. Ophthalmology 2002; 109:400–404 14. Patnaik B, Biswas C, Patnaik RK. Sterile endophthalmitis in vitrectomised eyes due to suspected heat resistant endotoxins in the infusion fluid. Indian J Ophthalmol 2004; 52:127–131
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15. Mamalis N, Edelhauser HF, Dawson DG, Chew J, LeBoyer RM, Werner L. Toxic anterior segment syndrome. J Cataract Refract Surg 2006; 32:324– 333 16. Monson MC, Mamalis N, Olson RJ. Toxic anterior segment inflammation following cataract surgery. J Cataract Refract Surg 1992; 18:184–189 17. Worst JGF. A retrospective view on the sterilization of intraocular lenses and incidents of sterile hypopyon. J Am Intraocular Implant Soc 1980; 6:10–12 18. Foster A, ed, Vision 2020: the cataract challenge. Community Eye Health 2000; 13:17–19 19. Murthy GVS, Jain B, Shamanna B, Subramanyam D. Improving cataract services in the Indian context. Community Eye Health 2014; 27:4–5
Disclosures: None of the authors has a financial or proprietary interest in any material or method mentioned.
First author: Javed Hussain Farooqui, MBBS, DNB, MNAMS Dr. Shroff’s Charity Eye Hospital, Kedarnath Marg, Daryaganj, New Delhi, India
ARTICLE
Increased postoperative anterior chamber inflammation secondary to heat-resistant endotoxins Javed Hussain Farooqui, MBBS, DNB, MNAMS, Arpan Gandhi, MBBS, MD, Umang Mathur, MBBS, MS, Gaurav Bharti, MBBS, DO, DNB, Suneeta Dubey, MBBS, MS
Purpose: To evaluate the cause of clusters of increased postoperative anterior chamber inflammation after uneventful cataract surgery, and to examine its relation to the presence of endotoxins in sterile consumables. Setting: Tertiary eye center in north India. Design: Single-center retrospective case series. Methods: All cataract surgeries performed at the tertiary eye center over 12 weeks (October 1, 2017 to December 31, 2017) were noted. Any patient with a “severe reaction” postoperatively was monitored closely and the postoperative drug regimen was altered accordingly. “Severe reaction” was defined as any patient with more than 4C cells and/or fibrin with or without hypopyon. The Hospital Infection Control committee was informed, and a root cause analysis was performed to determine the cause. All the consumables were recalled and replaced. The samples were sent for microbiological evaluations.
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ncreased postoperative anterior segment inflammation after cataract surgery is a cause of concern for all operating surgeons. The various possible causes are infectious, noninfectious (sterile), anaphylactic, or toxic anterior segment syndrome (TASS).1 Outbreaks of unexplained postoperative inflammation after cataract surgery are uncommon.1 Various degrees of anterior segment damage have been reported, ranging from inflammation to hypopyon caused by toxic substances.2 If the inflammation is restricted to the anterior segment, immediate appropriate therapy (with topical corticosteroids) can successfully treat the inflammation with no residual sightthreatening problems.3 Over a 3-month period, we experienced a sudden outbreak of increased postoperative anterior segment inflammation at a high volume surgical eye center based
Results: Of the 781 cataract surgeries performed, 81 patients had a severe reaction. Most patients were men (71%) and the mean age of the patients was 63 years. Twelve patients had fibrin, 3 of whom presented with hypopyon. Because all samples were negative of any growth, endotoxin tests were performed. All the samples were found to be negative, except for the ophthalmic viscosurgical device (OVD), which showed positive endotoxin levels. The OVD was changed and the anterior chamber reactions ceased to occur.
Conclusion: A careful, stepwise approach is necessary when investigating clusters of increased postoperative anterior chamber reactions after uneventful surgery. A high degree of suspicion is important to rule out all possible reasons and in the absence of any identifiable cause, sterile consumables should be checked for endotoxins. J Cataract Refract Surg 2018; -:-–- Q 2018 ASCRS and ESCRS
in northern India. To determine the cause of this outbreak, an extensive investigation and a root cause analysis was initiated. A multidepartmental approach, under the guidance of the Hospital Infection Control (HIC) committee, was sought to find out the cause of the sudden rise in the incidence of increased postoperative inflammation. Through this paper, we aim to share with the readers our experience of successfully investigating and managing the cases of increased postoperative anterior chamber reaction. Following the protocols, a thorough audit of the systems in place and prioritizing patient safety were the pillars of this study. PATIENTS AND METHODS Patients, Preoperative Assessment and Patient Preparation This is a single-center, retrospective study at a tertiary eye care center. Because this was a retrospective analysis with appropriate
Submitted: May 18, 2018 | Final revision submitted: August 24, 2018 | Accepted: September 4, 2018 From Dr. Shroff’s Charity Eye Hospital, Kedarnath Marg, Daryaganj, New Delhi, India. Corresponding author: Javed Hussain Farooqui, MBBS, DNB, MNAMS, Department of Cornea, Cataract and Refractive Surgery, Dr. Shroff’s Charity Eye Hospital, 5027 Kedarnath Marg, Daryaganj, New Delhi 110002, India. Email: [email protected]. Q 2018 ASCRS and ESCRS Published by Elsevier Inc.
0886-3350/$ - see frontmatter https://doi.org/10.1016/j.jcrs.2018.09.018
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INCREASED POSTOPERATIVE ANTERIOR CHAMBER REACTION AND ENDOTOXINS
corrective interventions, the Institutional Review Board was informed and exemption taken. However, all required consents were sought from the patients before clinical examinations and surgeries according to the hospital protocols, and all necessary steps were taken to safeguard patient identity and data. All cataract surgeries (phacoemulsification and small-incision cataract surgery [SICS], based on the surgeon’s judgment) performed at the center over a period of 12 weeks (October 1, 2017 to December 31, 2017) were noted. Data of the cataract surgeries performed a month before and a month after the aforementioned period were also retrieved. Three surgeons from the Department of Cataract and Intraocular Lens Services performed all the surgeries. Both rigid poly(methyl methacrylate) (PMMA) and foldable (hydrophilic and hydrophobic) intraocular lenses (IOLs) were used, depending on patient choice and affordability. The preoperative evaluation included a visual acuity check and a dilated ocular examination including type of cataract, anterior chamber reaction, and a fundus evaluation using a slitlamp (BM 900, Haag-Streit AG). The intraocular pressure (IOP) was measured using Goldmann applanation tonometry, and a physical examination was performed by an internist for systemic diseases. Topical ciprofloxacin 0.3%, 4 times a day, was started 1 day before surgery and instilled hourly on the day of surgery. Also, tropicamide 1% and proparacaine hydrochloride 0.5% was used on the day of surgery to achieve dilation. Peribulbar anesthesia was attained using 6 cc of 1:1 mixture of 2% lidocaine and 0.75% bupivacaine with 150 units of hyaluronidase per 20 cc, and it was administered with a 25-gauge needle. Before the surgery, a drop of 5% povidone iodine was instilled in the cul-de-sac and left for 2 minutes. In the operating room, the operative eye was prepared with 10% povidone iodine and sterilely draped. The cataract surgery was performed under aseptic conditions. Intraoperative details were mentioned in the patient’s chart at the end of each surgery, which included the steps of the surgery, any intraoperative events, and the time taken to finish the surgery. At the end of surgery, a subconjunctival injection of dexamethasone sodium phosphate (4 mg/mL) and gentamycin sulfate (20 mg/mL) was injected. A drop of moxifloxacin 0.5% was instilled in the cul-de-sac after the surgery, and the eye was bandaged. The bandage was kept on overnight and opened the next morning. Surgical Procedures The decision to perform phacoemulsification or manual SICS was determined by the operating surgeon. For the phacoemulsification, a superior clear corneal tunnel of 2.8 mm and a side port for the second instrument was made using a stainless steel keratome. A continuous circular capsulorhexis was made on the anterior capsule followed by hydrodissection and hydrodelineation. A phacoemulsification system (Laureate World Phaco System, Alcon Laboratories, Inc.) was used with a standardized microtip over a 30-gauge cannula to sculpt a deep central groove, and the nucleus was bisected. Using the Koch stop-andchop method,4 the nucleus was emulsified, and the remaining cortex was removed with the irrigation/aspiration (I/A) tip. The capsular bag was filled with ophthalmic viscosurgical device (OVD) of 2% hydroxypropyl methylcellulose ophthalmic solution (Viscolon, Contacare Ophthalmics and Diagnostics), and either a foldable hydrophilic acrylic IOL (Acryfold, AI Optics Ltd, or Ultima, Biovision Ltd.) or a hydrophobic acrylic IOL (Acrysof SA60AT or Acrysof.IQ SN60WF, Alcon Laboratories, Inc.) was implanted in the bag. The decision of which IOL to implant was dependent on patient choice and affordability. The anterior chamber was filled with irrigation fluid (Plasma Lyte A, Baxter India Private Ltd.) and the tunnel integrity was tested. For the manual SICS, a superior 6.5-mm frown-shaped sclerocorneal tunnel was constructed with a number 15 sterile blade on a
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Bard Parker handle. A side port was created to facilitate intraocular manipulations. A continuous circular capsulorhexis was made on the anterior capsule and the nucleus was prolapsed from the capsular bag by hydrodissection injection (hydro prolapse) or with a Sinskey hook. The OVD was injected around the nucleus and it was delivered in whole through the scleral tunnel using viscoexpression. The remaining cortex was removed with manual I/A (using a 23-gauge reusable stainless steel Simcoe cannula), and a 6.5 mm single-piece PMMA IOL (Eye-O-Care, Biovision, Ltd.) was implanted in the bag. The irrigating fluid (Plasma Lyte A, Baxter India Private Ltd.) was inserted through the side port to test the integrity of the tunnel. The surgery was sutureless with a self-sustaining tunnel. Postoperative Management As a routine practice postoperatively, patients were followed up on day 1, day 7 and day 30. A slitlamp evaluation was performed at every visit by the same observer, which included inspection for the presence or absence of conjunctival or circumciliary congestion, cornea clarity, anterior chamber reaction (described using the Standardization of Uveitis Nomenclature classification),5 IOL centration, and fundus examination. Any patient who had more than 4C cells and/or fibrin with or without hypopyon was documented and labeled as “severe reaction.” A dilated fundus examination was performed for cases with severe reaction. A B-Scan examination was performed for cases where the fundus was not visible, or the glow was compromised. All such patients were referred to the Retina Services for evaluation. An anterior chamber paracentesis in eyes with hypopyon was performed under all aseptic precautions, and the cultures were sent for microbiological evaluation. For the paracentesis, proparacaine 0.5% eyedrops were instilled 3 times over a 15-minute period, followed by instillation of betadine 5% antiseptic drops. The patient was positioned at the slitlamp, and the upper lid and eyelashes were held out of the way by an assistant. No lid speculum was required. The paracentesis was performed using a 27-gauge needle attached to an insulin syringe, which was inserted at the paralimbal clear cornea in a plane above and parallel to the iris with the bevel of the needle facing forward until the whole bevel penetrated the cornea. The unaided and pinhole visual acuities were noted at all visits. The final refraction was performed after 4 weeks for phacoemulsification and after 6 weeks for SICS. The routine postoperative care included a topical antibiotic (0.5% moxifloxacin) 4 times a day and a steroid (1% prednisolone acetate suspension) 6 times a day tapered over 4 weeks. For patients with a severe reaction, topical steroids were stepped up to every hour. Cycloplegic drops (homatropine 2%) were given 3 times a day, and the topical antibiotic was continued 4 times a day. These patients were kept under close observation and the follow-up visits were planned according to each patient’s response to treatment. A printout of postsurgical care instructions was given to all patients, and the same was explained orally by the nurse and/or the surgeon in the patients’ local language. The signs and symptoms of endophthalmitis were explained to the patients. Routine Sterilization Protocols The phacoemulsification microtip and the tip sleeve were changed after every surgery and sterilized by autoclaving. All the surgical blades, syringes, and needles used during the cataract procedure were disposed after single use, and new sterile blades were used for every patient. At the end of surgery, all 3 surgeons practiced the World Health Organization guidelines for scrubbing. Gloves and gowns were changed after every surgery. All unsterile instruments were rinsed with tap water and soap and then kept in an ultrasound bath for 5 minutes followed by cleaning with distilled water. They were then air dried and sent to autoclave. Chemical
INCREASED POSTOPERATIVE ANTERIOR CHAMBER REACTION AND ENDOTOXINS
disinfection was not practiced in the hospital. Sterilization was performed with moist heat by keeping the instruments in the autoclave for 20 minutes at a temperature of 134 C with a pressure of 30 mm Hg. During autoclaving, the required temperature and pressure was monitored by chemical and biological indicators. Chemical indicators were placed along with the instrument tray in every set whereas biological indicators were used bimonthly. The hospital followed strict quality checks and a recall policy in which all instruments from the same batch were recalled in cases of suspected breach in sterility. Wet mopping of the operating room walls, fixtures, and equipment was conducted once a week followed by fumigation of the operating room with 1.5% D-125 (Microgen Inc.). The operating room floor was mopped with diluted D-125 solution after every surgery. As a routine, weekly samples (culture swabs, HiMedia Labs Ltd.) are sent from multiple sites including the operating room microscope, operating room table, operating room walls, operating room air conditioner, operating room dehumidifier, scrub area tap nozzle, and autoclave machine. In case any of the microbiological tests are positive, the nurse in charge of the operating room informs the HIC. All surgeons were assessed for their surgical skills and competency monthly, based on their surgical outcomes, time taken for surgery, and events rate. Root Cause Analysis Following the sudden outbreak of increased postoperative anterior segment inflammation, the HIC was informed and the committee reviewed all the procedures at the hospital. All the patient charts with increased reactions were scrutinized to find the common cause. Because the increased reaction was not surgeon-specific, the surgeon factor was negated. The reaction occurred with both foldable and nonfoldable IOLs, thus the possibility of the IOL involvement was also much less likely. The autoclave records including the chemical and the biological indicators were normal for a complete sterilization cycle. On the basis of initial analysis, the probable causes were suspected to be either the consumables, including the Viscolon OVD (from now on referred to as OVD1), and the irrigating solution or a breach in the cleaning process of the instruments before autoclaving. The operating room was closed for 3 days for a thorough investigation and for terminal cleaning. All surgical surfaces and instruments were cleaned and cultured. Repeat samples with controls were sent to 2 different laboratories, one of which was an in-house laboratory. The overhead water tank was emptied, cleaned, and filled with fresh water. All the consumables, which were being used, were recalled and different batch for the same were sent as replacement. These included Ringer’s lactate (sodium lactate solution), IOLs, operating room water supply, and the ultrasound bath solution. The sterilization procedures at the eye center were reviewed. Between cataract surgeries, the instruments were washed in an ultrasound bath and flushed with distilled water before sending them for autoclaving. Phacoemulsification microtips were also flushed separately.
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Microbiological Investigation Bacterial Growth The specimens collected and cultured for bacterial growth from various sites showed no growth at both the laboratories where the samples were sent. The aqueous samples derived from the anterior chamber paracentesis were found to be sterile. Endotoxin Sampling Negative cultures and a literature search prompted a check for endotoxin levels in various samples including OVD1, Ringer’s lactate, fluids from various places in the operating room, and controls. It was assumed that the anterior chamber inflammation was attributable to an immunogenic reaction to these heat stable toxins in the anterior chamber that incited a polymorphonuclear reaction in some patients. The endotoxin test was performed with the litmus lysate assay at 2 independent laboratories. A fresh set of dilutions from the stock endotoxin solution were prepared on the day of the test run. The OVD1 sample was very viscous and had to be diluted to 1:5. Dilutions were made in test tubes and the test volume transferred to the reaction tubes amounting to 0.1 mL in each tube. The test was performed using a gel clot method, and it was considered positive if there was gel formation (O0.05 IU/mL) that did not collapse when the tube was inverted.
RESULTS Demographic Data
From October 1, 2017 to December 31, 2017, 781 cataract surgeries were performed at a tertiary eye center in north India. Of the 781 cases, 81 eyes of 81 patients (10.3%) who had undergone uneventful cataract surgery (45 had phacoemulsification and 36 had manual SICS), showed varied levels of increased postoperative inflammation on the first postoperative day and fulfilled the criteria for “severe reaction.” The majority were men (57 [70.4%]), and the mean age of patients was 63 years (range 39 to 99 years). The presenting preoperative corrected distance visual acuity (CDVA) of 20/200 or worse was seen in 60 patients (74.1%). Nineteen patients (23.5%) had hydrophobic IOLs (12 Acrysof SA60AT and 7 Acrysof IQ SN60WF) implanted and 26 patients (32.1%) had hydrophilic IOLs (15 Acryfold and 11 Ultima) implanted. All patients who had manual SICS received single-piece PMMA IOLs (Eye-OCare). Of the 81 patients who had a severe reaction, 12 patients (9 men, 3 women) had varying levels of fibrin at the pupillary margin and 3 male patients had streak hypopyon (!1.0 mm measured on the slitlamp) (Figure 1, A and B). However, in all the patients, the corneas were clear with minimal Descemet membrane folds, and their IOPs
Figure 1. A: Postoperative day 1 slitlamp photograph of a patient with increased postoperative reaction and fibrin in the pupillary area. B: Another patient with streak hypopyon and a severe reaction 1 day postoperatively.
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were lower than 20 mm Hg (by Goldmann applanation tonometry). For all the patients with fibrin and hypopyon, the patients were referred to the Retina Services and ultrasound B-scan was performed to rule out posterior segment involvement. The B-scans were normal with anechoic vitreous cavity in all the 12 patients. In addition, an anterior chamber paracentesis was performed in the 3 patients presenting with an increased reaction and hypopyon. Samples were sent for microbiological growth and culture, which were found to be sterile. All 81 patients who had a severe reaction were kept on close watch with frequent follow-ups, and the postoperative schedule was modified based on findings during scheduled visits. The fundal glow with a good retinal view was present in all patients and there was no pain, no lid edema, and no conjunctival chemosis. None of the patients had a history of uveitis or any significant systemic illness. Over the next 4 weeks, 70 patients (86.4%) recovered to a CDVA of 20/ 60 or better and all the patients had a CDVA of 20/160 or better. The 11 patients in the low vision group (20/70 to 20/160) had low vision attributable to factors other than cataract surgery. Table 1 shows the demographic features of the patients who presented with increased postoperative inflammation after cataract surgery, and Figure 2 shows the “severe reaction” epidemic curve. The data of cataract surgeries performed in September were unremarkable. Out of the 235 cataract surgeries, performed in the months preceding October, none of the patients had a severe reaction and/or fibrin with or without hypopyon. There was no change in the operating surgeons, the techniques of surgery, or the disinfection protocols. Figure 3 shows the probable factors that could have been responsible for the increased reaction. Endotoxin Text Results
Endotoxin tests that were performed for 2 different batches of the OVD1 that was being used for the surgeries showed positive results at 1:5 dilution and all the other samples (Ringer’s lactate, fluids, and controls) were negative (Figures 4 to 6). The 2% hydroxypropyl methylcellulose ophthalmic solution (OVD1) was changed to an OVD from a different company, OVD2 (2% Appavisc, Appaswamy Associates) and checked for endotoxin levels before being used. Once OVD2 was found negative for endotoxins, it was used as a replacement for OVD1. All the rest of the supplies and consumables remained unchanged. After this intervention of replacing OVD1 with OVD2, the postoperative inflammations ceased in subsequent surgeries. All the surgeries that took place in January 2018 were reviewed as well. After the last documented “severe reaction,” which occurred in the last week of December, none of the 247 surgeries, which occurred in January, showed any severe reaction. DISCUSSION At the outset, no direct cause of this problem was identified. Even though the operating room was closed for 3 days for terminal cleaning, we were in a dilemma Volume - Issue - - 2018
Table 1. Demographic characteristics of the patients who presented with increased postoperative inflammation after cataract surgery. Number of Patients
Characteristic Age group !40 y 40 to 60 y 60 to 80 y O80 y Sex Male Female Cataract type Nuclear sclerosis grade 1 Nuclear sclerosis grade 2 Nuclear sclerosis grade 3 Nuclear sclerosis grade 4 Mature senile cataract Hyper mature senile cataract Preop CDVA 20/200 or worse 20/70 to 20/160 (low vision) 20/60 or better Surgery performed Phacoemulsification SICS IOL implanted PMMA Hydrophilic Hydrophobic Patients w/3C or more cells in AC Patients w/fibrin in AC Patients w/hypopyon in AC Postop CDVA (at final follow-up) 20/200 or worse 20/70 to 20/160 (low vision) 20/60 or better Cause of low vision Corneal opacity Macular dystrophy Other
October 2017
November 2017
December 2017
0 10 12 5
3 17 21 2
0 5 6 0
20 7
30 13
8 3
1 6 8 9 2 1
2 12 11 13 3 2
1 2 4 3 1 0
16 6
35 5
9 2
5
3
0
17 10
21 22
7 4
10 12 5 27
22 10 11 43
4 4 3 11
5 0
5 3
2 0
0 4
0 5
0 2
23
38
9
2 0 2
1 2 2
1 0 1
AC Z anterior chamber; CDVA Z corrected distance visual acuity; IOL Z intraocular lens; PMMA Z poly(methyl methacrylate); SICS Z small-incision cataract surgery
about whether to continue operating or discontinue the surgeries. The fact that all our patients responded well to treatment and had improved CDVAs better than 20/60 gave us confidence. We based our hypothesis of this incident as being a result of an immunological reaction on the fact that all the cultures were negative and it has been proven previously that heat-stable endotoxins can cause an exaggerated inflammatory
INCREASED POSTOPERATIVE ANTERIOR CHAMBER REACTION AND ENDOTOXINS
Figure 2. Severe postoperative reaction epidemic curve.
response.6 Endotoxins are bacterial lipopolysaccharides present in the outer cell walls of gram-negative bacteria.7,8 These can survive short-cycle sterilization, unlike the bacteria. Although rare, an immune reaction after heat-stable contamination of surgical instruments and consumable products is not unknown. Mondino et al.9 in 1977 and later Schultz et al.10,11 described the effects of endotoxin injections in rabbit corneas. They showed that endotoxin-related keratitis was most severe 4 to 5 hours after exposure, and that the severity of inflammation was related to higher doses and previous exposure. In a literature review, we found that in 1986, Richburg et al.12 and in 1992, Kreisler et al.1 observed an outbreak of sterile hypopyon that was attributed to heat stable endotoxins. Other ophthalmic surgeries have also been affected by endotoxins. In 1999, Holland et al.6 and in 2000, Yuhan et al.13 reported diffuse lamellar keratitis after laser in situ keratomileusis (LASIK) procedures because of endotoxins in biofilms occurring in a sterilized water storage reservoir. In India, Patnaik et al.14 reported sterile endophthalmitis
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after vitreoretinal surgery caused by an endotoxin. The positive trend in all the various series was the fact that no active major surgical intervention was required for management, all patients recovered with only medication, and good final visual outcomes were achieved. One might argue and label the “severe reaction” in this study as TASS, at least for the 3 patients with sterile hypopyon. We acknowledge that the fact that the severe reaction was within 24 hours of cataract surgery and it mimics TASS; however, there was no corneal edema, decreased vision, pain, dilated pupil, or increase in IOP, all of which are described as clinical features of TASS.2,15,16 Previously, TASS and an increased reaction caused by an endotoxin has been used interchangeably, with the reactions caused by an endotoxin being described as a subset or a less severe form of TASS.15 There is the possibility that TASS can progress unfavorably; however, all previous reports of patients with a severe reaction attributable to an endotoxin, including our study, have had full recoveries.1,6,12,13,17 In summary, we believe that 2 important observations came out of this investigation. First, increased postoperative inflammation after cataract surgery is worthy of consideration and proactive steps should be taken to find out its cause. Clinicians should not shy away from reporting such sudden, sporadic outbreaks of sterile postoperative inflammation, and a thorough investigation should be undertaken. We feel that this condition is rather under reported and protocols should be formulated by hospitals to tackle this problem. In a country such as India, where approximately 3 million cataract surgeries are performed each year and the cataract surgical rate is steadily increasing, it is very important that good quality eyecare standards are maintained throughout the country.18,19 To our knowledge, ours is the first case series of postcataract surgery increased inflammation for which an endotoxin test was performed in India. This is an interesting observation and, in a way, it reiterates our concerns that probably this condition is being under reported or
Figure 3. Fish bone diagram of probable factors for increased reaction (HEPA Z high-efficiency particulate air; OVD Z ophthalmic viscosurgical device; Phaco Z phacoemulsification).
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INCREASED POSTOPERATIVE ANTERIOR CHAMBER REACTION AND ENDOTOXINS
Figure 4. Report of the endotoxin test performed for tap water. The results are circled in red.
Figure 5. Report of the endotoxin test performed for the irrigating fluid used during the surgeries. The results are circled in red.
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INCREASED POSTOPERATIVE ANTERIOR CHAMBER REACTION AND ENDOTOXINS
Figure 6. Report of the endotoxin test performed for the ophthalmic viscosurgical device of 2% hydroxypropyl methylcellulose ophthalmic solution (Viscolon, Contacare Ophthalmics and Diagnostics). The results are circled in red.
surgeons are not aware of the fact that such tests can be used in clinical practice in cases of increased anterior chamber reaction where it is difficult to pinpoint a causative factor. To implement endotoxin tests as a routine in hospital disinfection policy is debatable, especially in an Indian scenario, where hospitals run on a tight budget. However, in situations of cluster-increased postoperative reactions, for which no other cause can be attributed, endotoxin tests should be performed. Second, we believe that the contamination must have been a result of faulty manufacturing. This is a worrisome situation because clinicians rely solely on the drug companies’ word as far as sterility of consumables is concerned. Although the endotoxin levels are checked by all drug manufacturing companies and the report is available from them, whether we can rely on that report is controversial. We recommend that the government and drug controllers consider formulating stricter laws to maintain standards of medicines used in clinical practice and surgery. To conclude, the challenge of increased postoperative reactions should be dealt with a heightened sense of awareness amongst surgeons, timely reporting, and a careful stepwise approach while investigating the cause. All possible causes, including the possibility of endotoxins, should be ruled out. The cause is usually in front of us, it is just about realizing it by joining the dots and solving the mystery.
WHAT WAS KNOWN Increased postoperative inflammation confined to the anterior segment can be managed effectively with topical steroids and close follow-up. A thorough root cause analysis should be performed to determine the reason for increased inflammation after any intraocular procedure.
WHAT THIS PAPER ADDS It should be borne in mind that bacterial and endotoxin contamination of drugs and consumables can take place during the manufacturing process, and clinicians should be cautious of this possibility. The reliability of sterility and endotoxin tests from the manufacturer might not be enough, and the tests should be repeated in cases of doubt.
REFERENCES 1. Kreisler KR, Martin SS, Young CW, Anderson CW, Mamalis N. Postoperative inflammation following cataract extraction caused by bacterial contamination of the cleaning bath detergent. J Cataract Refract Surg 1992; 18:106–110 2. Choi JS, Shyn KH. Development of toxic anterior segment syndrome immediately after uneventful phaco surgery. Korean J Ophthalmol 2008; 22:220– 227 3. Holzer MP, Sandoval HP, Vargas LG, Kasper TJ, Vroman DT, Apple DJ, Solomon KD. Evaluation of preoperative and postoperative prophylactic regimens for prevention and treatment of diffuse lamellar keratitis. J Cataract Refract Surg 2004; 30:195–199
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4. Koch PS, Katzen LE. Stop and chop phacoemulsification. J Cataract Refract Surg 1994; 20:566–570 5. Jabs DA, Nussenblatt RB, Rosenbaum JT. Standardization of uveitis nomenclature for reporting clinical data: Results of the First International Workshop; Standardization of Uveitis Nomenclature (SUN) Working Group. Am J Ophthalmol 2005; 140:509–516 6. Holland SP, Mathias RG, Morck DW, Chiu J, Slade SG. Diffuse lamellar keratitis related to endotoxins released from sterilizer reservoir biofilms. Ophthalmology 2000; 107:1227–1234 7. Costerton JW, Lewandowski Z, Caldwell DE, Korber DR, Lappin-Scott HM. Microbial biofilms. Annu Rev Microbiol 1995; 49:711–745 8. Rietschel ET, Brade H. Bacterial endotoxins. Sci Am 1992; 267:54–61 9. Mondino BJ, Rabin BS, Kessler E, Gallo J, Brown SI. Corneal rings with gram-negative bacteria. Arch Ophthalmol 1977; 95:2222–2225 10. Schultz CL, Buret AG, Olson ME, Ceri H, Read RR, Morck DW. Lipopolysaccharide entry in the damaged cornea and specific uptake by polymorphonuclear neutrophils. Infect Immun 2000; 68:1731–1734 11. Schultz CL, Morck DW, McKay SG, Olson ME, Buret A. Lipopolysaccharide induced acute red eye and corneal ulcers. Exp Eye Res 1997; 64:3–9 12. Richburg FA, Reidy JJ, Apple DJ, Olson RJ. Sterile hypopyon secondary to ultrasonic cleaning solution. J Cataract Refract Surg 1986; 12:248–251 13. Yuhan KR, Nguyen L, Wachler BSB. Role of instrument cleaning and maintenance in the development of diffuse lamellar keratitis. Ophthalmology 2002; 109:400–404 14. Patnaik B, Biswas C, Patnaik RK. Sterile endophthalmitis in vitrectomised eyes due to suspected heat resistant endotoxins in the infusion fluid. Indian J Ophthalmol 2004; 52:127–131
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15. Mamalis N, Edelhauser HF, Dawson DG, Chew J, LeBoyer RM, Werner L. Toxic anterior segment syndrome. J Cataract Refract Surg 2006; 32:324– 333 16. Monson MC, Mamalis N, Olson RJ. Toxic anterior segment inflammation following cataract surgery. J Cataract Refract Surg 1992; 18:184–189 17. Worst JGF. A retrospective view on the sterilization of intraocular lenses and incidents of sterile hypopyon. J Am Intraocular Implant Soc 1980; 6:10–12 18. Foster A, ed, Vision 2020: the cataract challenge. Community Eye Health 2000; 13:17–19 19. Murthy GVS, Jain B, Shamanna B, Subramanyam D. Improving cataract services in the Indian context. Community Eye Health 2014; 27:4–5
Disclosures: None of the authors has a financial or proprietary interest in any material or method mentioned.
First author: Javed Hussain Farooqui, MBBS, DNB, MNAMS Dr. Shroff’s Charity Eye Hospital, Kedarnath Marg, Daryaganj, New Delhi, India