Anti-inflammatory Effect of Low-Molecular-Weight Heparin in Pediatric Cataract Surgery: A Randomized Clinical Trial




Purpose


To determine if intraocular infusion of low-molecular-weight heparin (enoxaparin) reduces postoperative inflammation in pediatric eyes undergoing cataract surgery with IOL implantation.


Design


Prospective masked randomized controlled trial.


Methods


setting: Private, institutional practice. study population: Twenty children (40 eyes) undergoing bilateral cataract surgery with IOL implantation were randomized to receive enoxaparin in the intraocular infusion fluid (BSS) (Group I) or not to receive enoxaparin (Group II). The first eye was randomly assigned to 1 of the 2 groups and the second eye received alternate treatment. observation procedure: Patients were followed up in the first week and 1 and 3 months after surgery. main outcome measures: Anterior chamber flare and cells (Hogan’s criteria), cell deposits on IOL, posterior synechiae.


Results


One week postoperatively, no eyes had >grade 2 flare/cells. Proportion of eyes with grade 2 cells was higher in eyes that did not receive enoxaparin (Group II: 80% vs Group I: 40%, P = .009). In the first week >10 small cell deposits were noted in the eyes that received enoxaparin (Group I: 20%, Group II: none, P = .005). Large cell deposits first appeared at 1 month in 40% of eyes in Group I and 55% of eyes in Group II ( P = .34) and increased at 3 months (60% in both groups, P > .999). Posterior synechiae were seen in 10% of eyes in Group I at 1 month, which persisted at 3 months; no eyes in Group II showed posterior synechiae ( P = .14).


Conclusion


The results of our study suggest that there does not seem to be a benefit of using enoxaparin in the infusion fluid with respect to early postoperative inflammation.


High risk of postoperative complications after pediatric cataract surgery is related to the greater inflammatory response in children compared to adults after surgery. Although cataract surgical techniques have seen a plethora of improvements, postoperative inflammation continues to be a significant factor compromising the outcome of pediatric cataract surgery. Therefore, techniques that might prevent or at least lower the inflammatory response may be beneficial.


A study of existing literature has shown that when heparin is added to the irrigating solution during cataract surgery, it results in a lower level of disturbance of the blood-aqueous barrier. The use of heparin in pediatric cataract surgery has been mentioned in the literature. Enoxaparin, a low-molecular-weight heparin (molecular weight 4500 Da), was developed to decrease the risks of active bleeding during major surgeries such as blood vessel surgery. Enoxaparin has anti-inflammatory mechanisms similar to heparin but poses a lower risk of incurring complications such as major bleeding. As a consequence, it might be expected that the risk of ocular bleeding may be a little less with enoxaparin.


In a nonrandomized unmasked series the authors showed that intraoperative irrigation of enoxaparin was effective in reducing postoperative inflammation following pediatric cataract surgery. There is little information available on a prospective randomized masked clinical trial of an intraocular infusion of enoxaparin in children undergoing cataract surgery with intraocular lens (IOL) implantation. This prospective randomized controlled masked clinical trial was designed to evaluate whether an intraocular infusion of enoxaparin helps in reducing the inflammatory response following bilateral congenital cataract surgery and IOL implantation.


Materials and Methods


This is a prospective randomized controlled double-masked trial in children undergoing bilateral cataract surgery carried out between February 1, 2008 and February 1, 2009 at the Iladevi Cataract & IOL Research Centre, Ahmedabad, India. A CONSORT flow diagram and an outline of components of the CONSORT statement as they pertain to this trial are included as a Supplemental Figure and Supplemental Table (available at AJO.com ). The study population comprised children from birth to 15 years with bilateral cataract undergoing cataract surgery with IOL implantation. Exclusion criteria were eyes with coexisting uveitis, microphthalmos, persistent fetal vasculature, glaucoma, aniridia, or chorioretinal coloboma, or those with a history of ocular trauma or previous ocular surgery; and children with history of blood dyscrasias or coagulopathies.


Clinical Evaluation and Procedures


A comprehensive preoperative evaluation was performed (under anesthesia when necessary) on the slit lamp or the slit lamp attachment of an operating microscope. Type of cataract was documented as lamellar, cortical, total, and preexisting posterior capsule defect. Axial length was measured with immersion ultrasound (Ocuscan; Alcon, Fort Worth, Texas, USA). Intraocular pressure (IOP) was measured with a Perkins handheld applanation tonometer. Blood investigations were performed for every child (prothrombin time and activated prothrombin time) to rule out any bleeding tendency.


The eye to be operated upon first was selected by a computer-generated table of random numbers by one of the authors (V.V.). The second eye underwent cataract surgery after a gap of at least 2 weeks following surgery in the first eye. Pupillary dilation was achieved using cyclopentolate 1% (Sunways, Mumbai, Maharashtra, India) eye drops instilled twice, 12 and 2 hours before surgery. In addition, phenylephrine 10% (Sunways) eye drops were administered 15 minutes apart, twice, 30 minutes before surgery. Patients were randomized to either receive enoxaparin in the intraocular infusion fluid (Group I) or not receive enoxaparin (Group II). The randomization code was allocated inside the operating room just before the surgery on the first eye. The second eye received alternate treatment. If an eye received a randomization code to use low-molecular-weight heparin, enoxaparin (Clexane; Aventis Pharmaceuticals, Mumbai, Maharashtra, India) was added to the irrigating solution (balanced salt solution) in a concentration of 40 mg/500 mL.


Surgical standardization and consistency was maintained throughout the study by ensuring that a single surgeon (A.R.V.) carried out all the surgical procedures using the principles of the closed chamber technique. The surgeon was masked to the intervention received. The surgical procedure used in both groups is as follows: corneal tunnel, multiquadrant hydrodissection, bimanual irrigation/aspiration, posterior continuous curvilinear capsulorrhexis (PCCC) in children below 6 years of age, and anterior vitrectomy in children below 2 years of age. A single-piece hydrophobic acrylic aspheric IOL (AcrySof IQ, SN60WF; Alcon Laboratories, Fort Worth, Texas, USA) was implanted in the capsular bag in all eyes. If in-the-bag IOL implantation could not be achieved, the eye was planned to be excluded from the study. No patient was administered subconjunctival steroids. The postoperative treatment regime was also standardized for both groups. This included prednisolone acetate (1%) eye drops (Allergan Pharma, Bangalore, Karnataka, India), 6 times a day tapered every 2 weeks; moxifloxacin (Vigamox, Alcon Laboratories) eye drops, thrice a day for 4 weeks; cyclopentolate eye drops (Sunways), twice a day for 2 weeks; and timolol maleate 0.5% eye drops (Alcon), twice a day for 2 weeks. Postoperatively, administration of eye drops commenced 2 hours after surgery. Data collection was carried out using a standardized form. The parameters of data collection were age, sex, surgical details including intraoperative trauma (if any), and postoperative examination.


The follow-up visits were in the first week (allowed anywhere from day 2 to day 7) and subsequently at 1 month (allowed between 20 and 40 days postoperatively) and 3 months (allowed between 80 and 100 days postoperatively) . The follow-up duration was deliberately maintained as a range rather than as a fixed time period, keeping in mind logistical reasons (eg, the patient’s inability to come on a specific day). All the examinations were performed by a single skilled observer (S.S.) who was masked to the intervention, under anesthesia when required. The operating surgeon and the examiner were masked to the type of irrigating fluid used during surgery. Postoperative assessment was performed by slit-lamp microscopy in the clinic or in the operating room, using the slit lamp attachment of the operating microscope. As described below, anterior chamber cells and flare were analyzed using Hogan’s criteria while cell deposits were analyzed using the method published previously.


Hogan’s criteria grades anterior chamber cells as: 0 = no cells; 1 = 5 to 10 cells; 2 = 11 to 20 cells; 3 = 21 to 50 cells; and 4 = >50 cells per high-power field. Hogan’s criteria grades anterior chamber flare as: 0 = no flare; 1 = faint and just detectable flare; 2 = moderate flare with iris details clear; 3 = marked flare with iris details hazy; and 4 = intense flare with severe fibrinous exudates per high-power field. Number of small cell deposits on IOL was graded as: grade 0 = no cells; grade 1 = up to 2 cells; grade 2 = 2 to 5 cells; grade 3 = 6 to 10 cells; grade 4 = more than 10 cells. Number of large cell deposits on IOL was graded as: grade 0 = none; grade 1 = less than 5; grade 2 = 6 to 10; grade 3 = up to 20; grade 4 = more than 20.


In addition, the presence and extent (in clock hours) of posterior synechiae were recorded.


Sample Size Calculation


Anterior chamber cells and flare are the earliest indicators of early postoperative inflammation. Early postoperative inflammation may be correlated to long-term inflammatory sequelae. In the absence of available literature, we used data from a pilot study of 11 patients (11 eyes in each group) to arrive at the sample size. The main outcome measure was the presence of grade 2 anterior chamber cells in the first postoperative week. In the first week, cells with grade 2 were seen in 18% of the eyes in Group I (enoxaparin group) and 55% of the eyes in Group II (no enoxaparin group). To detect the difference of 33% between the 2 groups, using the test of proportions at 5% level of significance, a sample size of 24 in each group was necessary to achieve 80% power.


Data Analysis


The differences in anterior segment inflammation, cell deposits on the IOL, and posterior synechiae between the 2 groups were analyzed using the test of proportions. Data were stratified to evaluate any difference between first eyes and second eyes (irrespective of the use of enoxaparin), as inflammation, compliance with medications, and familiarity with evaluation techniques may influence results. We also analyzed eyes that underwent anterior vitrectomy vs eyes that did not undergo vitrectomy.


All statistical analysis was performed using the SPSS software (version 12.0; IBM, Morrisville, North Carolina, USA). A P value of less than .05 was considered statistically significant.




Results


Twenty-four children were recruited for the study. In the first eye of 2 patients, a peripheral extension of PCCC was noted and in-the-bag IOL implantation could not be achieved. Consequently, these patients were excluded from the study after the first eye surgery itself. Two patients missed the follow-up visits. Statistical analysis was carried out on the remaining 20 patients (40 eyes). The mean age at the time of cataract surgery in Group I was 40.89 ± 26.17 months and in Group II was 40.80 ± 24.80 months. The mean duration of follow-up was 3.00 ± 0.02 months in Group I and 3.0 ± 0.08 months in Group II. There were 13 male and 7 female patients in the study. All patients were of Indian origin. Both groups were comparable in preoperative parameters such as type of cataract, preoperative axial length, and IOP ( Table 1 ).



TABLE 1

Comparison of Preoperative Characteristics in Pediatric Eyes Receiving Enoxaparin or No Enoxaparin During Cataract Surgery With Intraocular Lens Implantation

















































Enoxaparin Group (N = 20) No Enoxaparin Group (N = 20) P Value
Axial length (mm) 20.32 ± 0.08 20.00 ± 0.16 .60
Type of cataract
Lamellar 6 4
Cortical 4 4
Total 5 3
Lamellar + cortical 4 7
Preexisting posterior capsule defect 1 2
Intraocular pressure (mm Hg) 14.8 ± 2.9 14.2 ± 1.64 .40


PCCC was performed in 32 of 40 eyes (80%), of which 19 of 40 eyes (47.5%) also received anterior vitrectomy. None of the eyes in either group developed intraoperative or postoperative hyphema, subconjunctival hemorrhage, or intraocular hemorrhage. Tables 2 and 3 display the anterior chamber cells and flare at each postoperative follow-up in both groups. Anterior chamber cells and flare of more than grade 2 were not detected in any eye at any follow-up. In the first postoperative week, a significantly higher proportion of eyes in Group II (N = 20) had grade 2 cells as compared to Group I (N = 20; 80% vs 40%, P = .009). There were no detectable cells and flare in any of the eyes at 3 months. Fibrinous exudates were not detected in any of the eyes and inflammatory membrane formation was also not observed. The occurrence of small and large cell deposits on the IOL is reported in Tables 4 and 5 respectively. Small cell deposits were detected as early as within the first week after surgery. The maximum number of small cell deposits was noted at 1 month and they persisted even at 3 months. In the first week, a higher proportion of eyes in Group I (20%) had >10 small cells on the IOL surface when compared with none in Group II ( P = .005). In the ensuing follow-up visits, no detectable difference was noted between the 2 groups. Large cell deposits appeared at 1 month, increasing slightly at 3 months. The number of large cell deposits on the IOL surface was comparable between the 2 groups at all the follow-up visits. At 1 month postoperatively, posterior synechiae were seen in 2 eyes (10%) in Group I, which persisted at 3 months. Posterior synechiae were not detected in any of the eyes in Group II ( P = .14).



TABLE 2

Comparison of Anterior Chamber Cells Postoperatively, Following Use of Enoxaparin (Low-Molecular-Weight Heparin) and Without Enoxaparin in Pediatric Cataract Surgery With Intraocular Lens Implantation













































Enoxaparin Group (N = 20) No Enoxaparin Group (N = 20)
Postoperative Period None n (%) Grade 1 n (%) Grade 2 n (%) None n (%) Grade 1 n (%) Grade 2 n (%) P Value
1 week 0 12 (60) 8 (40) 0 4 (20) 16 (80) .009
1 month 20 (100) 0 (0) 0 (0) 20 (100) 0 (0) 0 (0) >.999
3 months 20 (100) 0 (0) 0 (0) 20 (100) 0 (0) 0 (0) >.999


TABLE 3

Comparison of Anterior Chamber Flare Postoperatively, Following Use of Enoxaparin (Low-Molecular-Weight Heparin) and Without Enoxaparin in Pediatric Cataract Surgery With Intraocular Lens Implantation





































Enoxaparin Group (N = 20) No Enoxaparin Group (N = 20)
Postoperative Period None n (%) Grade 1 n (%) None n (%) Grade 1 n (%) P Value
1 week 16 (80) 4 (20) 16 (80) 4 (20) >.999
1 month 20 (100) 0 (0) 20 (100) 0 (0) >.999
3 months 20 (100) 0 (0) 20 (100) 0 (0) >.999


TABLE 4

Comparison of Small Cell Deposits on Intraocular Lens Surface Postoperatively, Following Use of Enoxaparin (Low-Molecular-Weight Heparin) and Without Enoxaparin in Pediatric Cataract Surgery With Intraocular Lens Implantation













































Enoxaparin Group (N = 20) No Enoxaparin Group (N = 20)
Postoperative Period None, n (%) <10, n (%) >10, n (%) None, n (%) <10, n (%) >10, n (%) P Value
1 week 8 (40) 8 (40) 4 (20) 16 (80) 4 (20) 0 (0) .005
1 month 0 (0) 4 (20) 16 (80) 0 (0) 4 (20) 16 (80) >.999
3 months 0 (0) 8 (40) 12 (60) 0 (0) 8 (40) 12 (60) >.999


TABLE 5

Distribution of Large Cell Deposits on Intraocular Lens Surface Postoperatively, Following Use of Enoxaparin (Low-Molecular-Weight Heparin) and Without Enoxaparin in Pediatric Cataract Surgery With Intraocular Lens Implantation





































Enoxaparin Group (N = 20) No Enoxaparin Group (N = 20)
Postoperative Period None n (%) <10 n (%) None n (%) <10 n (%) P Value
1 week 20 (100) 0 (0) 20 (100) 0 (0) >.999
1 month 12 (60) 8 (40) 9 (45) 11 (55) .34
3 months 8 (40) 12 (60) 8 (40) 12 (60) >.999


There was no significant difference in the inflammatory response whether the eye was operated first or second, irrespective of the use of enoxaparin or not ( Table 6 ). Table 7 illustrates the impact of anterior vitrectomy on postoperative inflammatory response. There was no significant impact of performing vitrectomy on the postoperative inflammatory response.



TABLE 6

Postoperative Inflammatory Response in Eyes Operated First vs Eyes Operated Second, Irrespective of Low-Molecular-Weight Heparin Infusion, Following Cataract Surgery With Intraocular Lens Implantation

















































Anterior Chamber Cells
First Eye (N = 20) Second Eye (N = 20)
Postoperative Period None n (%) Grade 1 n (%) Grade 2 n (%) None n (%) Grade 1 n (%) Grade 2 n (%) P Value
1 week 0 10 (50) 10 (50) 0 14 (70) 6 (30) .33
1 month 20 (100) 0 (0) 0 (0) 20 (100) 0 (0) 0 (0) >.999
3 months 20 (100) 0 (0) 0 (0) 20 (100) 0 (0) 0 (0) >.999



































Anterior Chamber Flare
None n (%) Grade 1 n (%) None n (%) Grade 1 n (%)
1 week 17 (85) 3 (15) 16 (80) 4 (20) .77
1 month 20 (100) 0 (0) 20 (100) 0 (0) >.999
3 months 20 (100) 0 (0) 20 (100) 0 (0) >.999



































Small Cell Deposits on IOL
<10 n (%) >10 n (%) <10 n (%) >10 n (%)
1 week 14 (80%) 8 (20%) 17 (85%) 3 (15%) .77
1 month 8 (20%) 14 (80%) 6 (30%) 14 (70%) .67
3 months 8 (40%) 12 (60%) 9 (75%) 11 (25%) .36



































Large Cell Deposits on IOL
None n (%) <10 n (%) None n (%) <10 n (%)
1 week 20 (100%) 0 20 (100%) 0 >.999
1 month 7 (35%) 13 (65%) 12 (60%) 8 (40%) .06
3 months 9 (45%) 11 (55%) 14 (70%) 6 (30%) .10

IOL = intraocular lens.

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Jan 12, 2017 | Posted by in OPHTHALMOLOGY | Comments Off on Anti-inflammatory Effect of Low-Molecular-Weight Heparin in Pediatric Cataract Surgery: A Randomized Clinical Trial
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