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Comparison of umbilical cord serum and amniotic membrane transplantation in acute ocular chemical burns
  1. Namrata Sharma1,
  2. Shiv Shankar Lathi1,
  3. Sri Vatsa Sehra1,
  4. Tushar Agarwal1,
  5. Rajesh Sinha1,
  6. Jeewan S Titiyal1,
  7. Thirumurthy Velpandian1,
  8. Radhika Tandon1,
  9. Rasik B Vajpayee2,3
  1. 1Dr Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India
  2. 2Centre for Eye Research Australia, University of Melbourne, Melbourne, Victoria, Australia
  3. 3Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia
  1. Correspondence to Dr Namrata Sharma Cornea and Refractive Surgery Services, Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, Ansari Nagar, New Delhi-110026, India; namrata.sharma{at}gmail.com

Abstract

Purpose To compare the efficacy of umbilical cord serum (UCS) with amniotic membrane transplantation (AMT) in cases of acute ocular chemical burns.

Methods In a retrospective, interventional, comparative case series, 55 eyes with grades III, IV and V chemical burns (Dua's classification) who presented within 3 weeks of injury were evaluated. Patients were treated with conventional medical (CM group, 20 eyes) management alone or combined with either UCS (UCS group, 17 eyes) or AMT (AMT group, 18 eyes). The parameters evaluated were time to epithelialisation, epithelial defect diameter, epithelial defect area, corneal clarity, tear break-up time (TBUT), Schirmer test and best-corrected vision.

Results UCS and AMT groups showed early epithelialisation as compared with the CM group (Kaplan–Meier analysis=0.01). Mean time for healing of epithelial defect was 57.7±29.3, 27.4±19.0, 41.1±28.9 days in the CM, UCS and AMT groups, respectively (p=0.02). Mean TBUT at the last follow-up was 8.6±0.7, 10.3±1.1, 9.4±1.2 s in the CM, UCS and AMT groups, respectively (p=0.02). The mean Schirmer value at the last follow-up was 13.7±1.0, 16.9±3.0 and 13.2±1.5 mm in the CM, UCS and AMT groups, respectively (p=0.01). The visual outcomes and the occurrence of corneal vascularisation, symblepheron, ectropion and entropion were comparable in between the groups.

Conclusions Our study suggests that the UCS therapy may be a better alternative to AMT in acute moderate to severe (grades III, IV and V) ocular chemical burns, as it avoids surgical manoeuvre in already inflamed eyes.

  • Cornea
  • Treatment Medical
  • Treatment Surgery

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Introduction

Chemical burns of the ocular surface are emergencies that require rapid assessment and initiation of treatment. The management of ocular chemical burns is both challenging and complex; the aims of therapy are to promote epithelialisation, control acute inflammatory reaction and prevent complications.1

Conventional medical (CM) therapy comprises of topical steroids, antibiotics, mydriatic cycloplegics, antiglaucoma therapy, citrate and ascorbate. Newer treatment modalities that have been tried include amniotic membrane transplantation (AMT) and umbilical cord serum (UCS) eye drops. These therapies reduce ocular surface inflammation and promote epithelial growth.2–7 Amniotic membrane contains growth factors like epidermal growth factor (EGF) and keratocyte growth factor and expresses anti-inflammatory cytokines, such as interleukin-10 and interleukin-1 receptor antagonist. This accelerates healing of the acute ocular chemical burns.8–11 UCS also has EGF, acidic and basic fibroblast growth factor (FGF), transforming growth factor (TGF)-β, nerve growth factor (NGF) and anti-inflammatory antiproteases like α2-macroglobulin.12–15

In our study, we compared the outcomes of AMT with UCS eye drops in the management of acute ocular chemical injury.

Methods

We conducted a retrospective comparative study and reviewed records of patients with acute ocular chemical injuries who had presented between May 2010 and December 2011. Previous approval from the institutional review board of Dr Rajendra Prasad Centre for Ophthalmic Sciences, and ethical clearance from the Ethics Committee of the All India Institute of Medical Sciences were taken. The study complied with the tenets of the Declaration of Helsinki.

Study population

The records of 55 eyes (of 53 consecutive patients) who had grade III, IV or V chemical burns (Dua's classification16) and presented to our centre within 3 weeks of injury were included. Patients having other grades of injury and impending corneal perforation were excluded. Appropriate first-aid therapy in the form of irrigation with normal saline to achieve a neutral pH and removal of any particulate matter from the ocular surface had been done. All patients received CM management. During the study period, 20 eyes had received CM therapy alone; 17 eyes received UCS eye drops (20%) 10 times per day additionally and 18 eyes underwent AMT. The treatment option was done as per the preference of the treating physician.

Medical treatment

All patients received CM that included topical moxifloxacin hydrochloride (0.3%; Alcon, Texas, USA) every 8 h; sodium ascorbate (10%), sodium citrate (10%), preservative-free lubricants and topical prednisolone acetate (1%; Allergan, Bangalore, India) every 2 h; homatropine sulfate (2%) three times per day and oral vitamin C (500 mg) four times a day for 2–4 weeks. Antiglaucoma therapy in the form of timolol maleate (0.5%) two times per day and oral acetazolamide were given, if required.

UCS preparation and storage

The umbilical cord blood had been collected from seronegative donors (hepatitis B, hepatitis C, HIV and syphilis) with uncomplicated caesarean deliveries after obtaining informed consent. Earlier screening for parenterally transmitted diseases had been done at the time of antenatal care registration and repeated at the time of cord blood collection and preparation of the serum sample. Cord blood was collected according to the standard technique which has been described previously.7 Serum bottles were stored at −20°C before opening and 4°C once they were opened. Patients were instructed to use the serum vials within 7 days. The UCS eye drops (20%) were given in the frequency of 10 times per day until complete epitelialisation occurred.

Amniotic membrane preparation and surgical technique

Amniotic membrane was obtained from voluntary seronegative donors (HIV, hepatitis B surface antigen, hepatitis C virus, syphilis) after caesarian section. The amniotic membrane preparation was done using the standard technique which has been described before.3

AMT was done using the onlay or patch technique. After the amniotic membranes were thawed and rinsed with normal saline, surgery was performed under peribulbar anaesthesia in adults and general anaesthesia in children. The amniotic membrane was transferred onto the operative field, the nitrocellulose paper was peeled off and the membrane was arranged to cover the entire ocular surface with the stromal side touching the eye. Interrupted 8-0 Vicryl sutures (Ethicon, Johnson & Johnson, Ahmedabad, India) were applied to anchor the underlying conjunctiva and episclera to the membrane around the limbus.3 A symblepharon ring was inserted to spread the membrane and to flatten it against the surface of the eye, especially in the fornices and along the palpebral conjunctiva. Interrupted Vicryl sutures were applied to anchor the membrane along the lid margins. The symblepharon ring was subsequently removed and sutures were applied to fix the membrane to the underlying tissues in the bulbar area and to anchor it deep in the fornices. The eyes were then bandaged after the operation and topical medications were continued postoperatively.

Examinations

The case records and the clinical photographs of the patients were reviewed by masked observers.

Baseline: The history of the patients with special regard to the nature of injury and earlier treatment was reviewed. Uncorrected vision and best-corrected vision (BCVA) that had been recorded using the logarithm of the minimum angle of resolution (logMAR) chart was noted. Slit-lamp (Haag-Streit AG, Koeniz, Switzerland) examination records were reviewed to assess the following parameters: grade of chemical injury according to Dua's classification, corneal clarity (table 1), epithelial defect diameter (EDD) and the extent of limbal involvement. Additionally, epithelial defect area (EDA) was calculated as the product of the largest diameter and the diameter perpendicular to it as is a part of routine protocol at our centre.17 Tear film status, which had been assessed using the Schirmer test and tear break-up time (TBUT), intraocular pressure and any other anterior chamber or fundus abnormalities were noted.

Table 1

Corneal clarity grading

Follow-up: The follow-up protocol for cases of ocular chemical injuries at our casualty services is as follows: patients are followed up at day 1, day 3, day 7, weekly thereafter until 1 month, biweekly for a minimum of 3 months. The parameters recorded at each follow-up visit in our predesigned Performa are as follows: time to complete epithelialisation, corneal clarity, epithelial defect status, corneal vascularisation, symblepharon formation or any complication.

Statistical analysis

Keeping the power of study as 0.8 and the level of significance at 0.05, with the primary outcome measure being the mean time for complete epithelialisation, a minimum sample size of 15 eyes in each group was required. Analysis was done using SPSS statistical software for Windows. Rates of corneal epithelialisation were analysed using Kaplan–Meier analysis. χ2 test was used for categorical variables; for parametric quantitative data, one-way analysis of variance (ANOVA) was used to compare intergroup means and Bonferroni correction was used to analyse post-test results; Kruskal–Wallis and Mann–Whitney tests were used for non-parametric quantitative data. Repeated-measures ANOVA and the Wilcoxon signed rank test were used for longitudinal analysis in a group. For descriptive purposes, qualitative data has been expressed as a percentage and quantitative data has been expressed as mean±SD.

Results

A total of 55 eyes with acute ocular chemical burns were studied. The median follow-up period was 3 months. The baseline characteristics such as age, time of presentation and nature of causative chemical injury were comparable between the groups (table 2). Alkali burns were the most common, occurring in 25 eyes, acid burns occurred in 23 eyes, four eyes were exposed to gunpowder and three to colouring agents; the groups were comparable with regard to the nature of chemical exposure (p 0.94). According to Dua's classification, 24 eyes had grade III injury, 20 eyes had grade IV injury and 11 eyes had grade V injury.16 The distribution was comparable across the groups (p=0.60; table 2). In the AMT group, surgery was done within 1 day of presentation, and the amniotic membrane remained intact for a mean duration of 10.46±2.72 days.

Table 2

Baseline pretreatment characteristics in conventional, umbilical cord serum therapy and amniotic membrane transplantation groups

The pretreatment corneal clarity was comparable between the three groups (p=0.89; table 3). After 3 months follow-up, there was no significant difference in corneal clarity between the groups (p=0.12). However, intergroup analysis revealed that UCS was superior to CM therapy in terms of corneal clarity, even though it was comparable with AMT (p=0.04 and p=0.22, respectively).

Table 3

Corneal clarity at day 0 and 3 months. At day 0, p=0.89; at 3 months, p=0.12

The mean EDD at presentation was 7.19±1.57, 6.91±2.33, 7.74±1.48 mm in the CM, UCS and AMT groups, respectively; the difference was not significant (p=0.73). Statistically significant decrease in EDD was seen earlier in the UCS group compared with the other groups. At 1-week follow-up, the mean EDD in the UCS group (2.47±1.50 mm) was significantly less than the EDD in the AMT (5.13±2.05 mm) and the CM groups (5.03±1.70 mm) (p=0.01; table 4). The mean EDA at presentation was 53.88±22.59, 52.70±25.47, 76.13±26.68 mm2 in the CM, UCS and AMT groups, respectively; the difference was not significant (p=0.05). Significant decrease in mean EDA was seen earlier in the UCS group; at 1 week follow-up, mean EDA in the UCS group (24.60±15.98 mm2) was significantly less than the AMT (30.24±22.97 mm2) and CM (27.95±16.73 mm2) groups (P=0.00; table 4), respectively.

Table 4

Epithelial defect diameter (mm) and epithelial defect area in the groups at various follow-up times

Kaplan–Meier analysis revealed that the differences in survival of corneal epithelialisation between the three groups were statistically significant (figure 1, p=0.01, log-rank test). The epithelial defect had healed in all eyes in the UCS and AMT groups at 3 months follow-up (figures 2 and 3). In the CM group, the epithelial defect healed in 17 eyes (85%) at 3 months; the defect healed after 4 months in two eyes (10%) and after 5 months in one eye (5%). The mean time for epithelialisation was 27.4±19.02, 41.13±28.90, 57.75±29.36 days in UCS, AMT and CM groups, respectively; the time was significantly less in the UCS group (p=0.02).

Figure 1

Percentage of eyes which had epithelialisation during the study period in the three groups. CM, conventional medical therapy; UCS, umbilical cord serum; AMT, amniotic membrane transplantation.

Figure 2

A case from cord serum therapy group.

Figure 3

A case from amniotic membrane transplantation group.

The mean TBUTs at the last follow-up were 8.6±0.7, 10.3±1.1, 9.4±1.2 s in the CM, UCS and AMT groups, respectively. The UCS group had a significantly longer TBUT than the AMT or the CM group (p=0.02 and p=0.00, respectively). The mean Schirmer values at the last follow-up were 13.73±1.08, 16.93±3.02, 13.26±1.57 mm in the CM, UCS and AMT groups, respectively. The UCS group had significantly better values than the AMT and CM groups (p=0.01 and p=0.00, respectively).

The mean BCVA at presentation was 1.57±0.87, 1.54±0.88, 1.61±0.84 logMAR units in the CM, UCS and AMT groups, respectively; the groups were comparable (p=0.90). After 3 months, the mean BCVA was 0.61±0.71, 0.25±0.49, 0.34±0.29 logMAR units in the CM, UCS and AMT groups, respectively; there was no significant difference between the groups (p=0.64).

Two eyes (10%) in the CM group and one eye each in the UCS (5.8%) and AMT (5.5%) groups had evidence of corneal vascularisation at presentation; the groups were comparable (p=0.82). After 3 months, vascularisation was evident in 13 eyes (65%) in the CM group, 8 eyes (47%) in the UCS group and 9 eyes (50%) in the AMT groups; the difference was not significant (p=0.49). The presence of symblepheron, ectropion and entropion were seen in comparable frequencies in all the groups at the last follow-up (table 5).

Table 5

Outcomes in cases of acute chemical injuries at 3 months follow-up 

Discussion

The management of chemical burns is challenging and CM treatment often gives suboptimal results.1 Given the limitations of conventional treatment, many authors have described the successful use of experimental therapies like autologous and UCS eye drops, AMT and limbal stem cell transplantation.2–7 ,18–20 Sorsby and Symons first described the use of amniotic membrane in the treatment of acute ocular chemical burns in 1946.21 Recently, there has been a renewed interest in this treatment modality with a number of studies documenting faster epithelial growth rates in cases of moderate to severe burns. UCS has been used for the management of dry eye syndrome, recurrent corneal erosions, neurotrophic keratitis and persistent corneal epithelial defects with favourable outcomes.12–15

In 2005, we, in a randomised controlled trial, demonstrated that epithelialisation was faster with AMT compared with the conventional therapy in mild to moderate acute chemical burns (Grades II–IV, Roper–Hall classification).18 In another randomised trial in 2011, it was shown that UCS is superior to both autologous serum and conventional therapy for the same ailment.7 The aim of our current study was to compare the efficacy of UCS with AMT in the treatment of ocular chemical burns; to the best of our knowledge this is the first study to compare these treatment modalities.

We found that there is no significant difference between UCS eye drops and AMT in the healing of the epithelial defect; both of them are superior to conventional management. Our results corroborate the findings of previous studies that both UCS and AMT are efficacious adjuncts to CM management in ocular chemical burns. Both UCS and amniotic membranes are rich in growth factors like EGF, NGF, FGF, TGF-β, vitamin A, fibronectin and serum antiproteases like α2-macroglobulin.8–15 These stimulate proliferation of corneal epithelium and increase the tensile strength of wounds.22 ,23 Furthermore, we found that UCS is superior to AMT in terms of a healthier ocular surface given that patients treated with cord serum have longer TBUTs and higher Schirmer values (p=0.02 and p=0.01, respectively). This finding is significant, as maintaining a wet ocular surface is essential for future reconstructive surgeries. One reason for this could be that UCS eye drops can be administered for prolonged periods, whereas, amniotic membrane is retained on the ocular surface for only a limited time period (mean 10.46±2.72 days in our study). This may limit the total exposure and availability of the aforementioned growth factors to the ocular surface.

UCS has another significant advantage over AMT in that the surgery is avoided in the inflamed and painful eyes. A large number of chemical injuries occur in children in whom we can also avoid unnecessary general anaesthesia. UCS drops can also be used in patients with poor general health and those unfit for surgery.

Even though both UCS and AMT are beneficial for management of ocular chemical burns, they require expensive processing and preservation facilities which are scarce in a developing country like ours. Furthermore, both of them pose a risk for the transmission of parenteral diseases. Serological testing should be done at least twice to account for the window period of infections and minimise this risk.

In conclusion, UCS therapy may be a better adjuvant to conventional management than AMT in cases of moderate to severe (grades III, IV and V) ocular chemical burns. The treatment option in our study was done as per the preference of the treating physician; however, this is the limitation of our study, and a more appropriate study design would have been a prospective randomised controlled trial. The potential drawback of use of UCS therapy routinely is the resource-limited settings, as the facility for the procurement of cord serum may not be available at all centres since it is not commercially available.

References

Footnotes

  • Correction notice This article has been corrected since it was published Online First. Tushar Agarwal has been added into the author list as he was accidentally missed off the first version.

  • Contributors NS: conception of the study, analysis and manuscript writing. SSL: collection of data and manuscript writing. SVS: statistical analysis and writing of manuscript. RS: collection of data. JST: critical analysis of manuscript. TV: logistics for study material such as cord serum and AMT. RT: critical analysis. RBV: design of study and manuscript evaluation.

  • Competing interests None.

  • Ethics approval Ethics Committee, All India Institute of Medical sciences.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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