A prospective comparative trial of collagenase and metronidazole in the topical management of diabetic foot ulcer

Collagenase and metronidazole in management of diabetic foot ulcer ISSN: 2394-0026 (P)Original Research Article ISSN: 2394-0034 (O) A prospective comparative trial ofcollagenase and metronidazole in the topical management of diabetic foot ulcerAnurag Ambroz Singh1, Abhishek Singh2*, Anil Kumar Goel3, SanjeetPanesar4, Virender K Chhoker5, Shelesh Goel6, Avinash Surana7, Nand Kishore Singh81Associate Professor, Department of General Medicine, SHKM Govt. Medical College, Haryana, India 2Assistant Professor, Department of Community Medicine, SHKM Govt. Medical College, Haryana, India 3Associate Professor, Department of Pediatrics, SHKM Govt. Medical College, Haryana, India4Senior Resident, Department of Community Medicine, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, India5Professor and Head, Department of Forensic Medicine, Santosh Medical College, Ghaziabad, Uttar Pradesh, India6Professor and Head, Department of Community Medicine, GFIMS&R, Ballabhghar, Haryana, India 7Deputy Assistant Director Health, 19 Inf. Div. 8Assistant Professor and Statistician, Department of Community Medicine, SHKM Govt. Medical College, Haryana, India *Corresponding author email: [email protected] to cite this article: Anurag Ambroz Singh, Abhishek Singh, Anil Kumar Goel, Sanjeet Panesar,Virender K Chhoker, Shelesh Goel, Avinash Surana, Nand Kishore Singh. A prospective comparativetrial of collagenase and metronidazole in the topical management of diabetic foot ulcer. IAIM, 2015;2(2): 27-33. Available online at www.iaimjournal.comReceived on: 03-01-2015 Accepted on: 15-01-2015AbstractObjective: To assess the efficacy of metronidazole and collagenase combination in the treatment ofdiabetic foot ulcers with regard to the reduction of slough formation, enhancement of granulationtissue and re-epithelization.Study design: Prospective, comparative study.Place and duration of study: Surgery department of a tertiary care teaching centre of rural Haryana,from January 2011 to February 2013.International Archives of Integrated Medicine, Vol. 2, Issue 2, February, 2015. Page 27Copy right © 2015, IAIM, All Rights Reserved.

Collagenase and metronidazole in management of diabetic foot ulcer ISSN: 2394-0026 (P) ISSN: 2394-0034 (O)Methodology: The patients who were admitted for diabetic foot ulcers at Surgery Department of atertiary care teaching centre during the study period were screened. 42 patients in the test groupwere treated with topical dressings of collagenase and metronidazole. The control group of 40patients was treated with conventional topical dressings and bed side debridement. Ulcer’s statuswas noted using visual score.Results: The number of patients with no necrotic tissue was significantly higher in test group at 3rd,4th, 5th, 6th and 7th weeks than control group. Granulation tissue was significantly higher in test groupat 3rd, 4th, 5th and 6th week. The test group patients had a faster wound bed preparation resulting infaster wound cover using secondary suturing, S.S.G., flap cover at the third week itself.Conclusion: Combination of collagenase and metronidazole topical application enhanced woundhealing of diabetic foot ulcer as compared to conventional treatment modalities.Key wordsDiabetic foot, Collagenase, Metronidazole.Introduction treatment of diabetic foot ulcer [7]. In this context no study has been conducted in our setOver the past few decades there has been an up. Hence present study was planned toalarming rise in prevalence of Diabetes [1, 2]. ascertain the efficacy of metronidazole andThe world health organization (WHO) report collagenase combination in the treatment ofsays diabetes in India will rise from 135 million diabetic foot ulcers with regard to the reductionin 1995 to 300 million by 2025 and India will of slough formation, enhancement ofbecome Diabetic capital of World [3]. The risk of granulation tissue and re-epithelization.ulcers or amputations is increased in peoplewho have had diabetes ≥10 years, are male, Material and methodshave poor glucose control, or havecardiovascular, retinal, or renal complications The present prospective, comparative trial was[4]. conducted in the patients who were admitted with diabetic foot ulcer in Surgery DepartmentFoot problems such as ulceration, infection, of a tertiary care teaching centre. All thegangrene are quiet common in Diabetic patients admitted for diabetic foot ulcersubjects. These accounts for the frequent and between Jan 2011 to February 2013 wereprolonged mortality and a rough estimate yields screened for a period of 2 weeks and those whothat 25% of all hospital admission of Diabetes fulfilled the inclusion criteria were included inare due to foot problems and nearly 5-10% study. Finally sample size was 82 out of which 42needs foot or leg amputations, 50% are related were in test group and 40 were in control group.to Diabetes [5, 6]. Inclusion criteriaHowever with proper foot care these problems • Patients aged more than 20 years withwould be prevented or minimised to a certain diabetic foot ulcer.extent. Collagenase and metronidazole are • Ulcers of Wagener’s Grade II – IV.being used as one of the topical modalities ofInternational Archives of Integrated Medicine, Vol. 2, Issue 2, February, 2015. Page 28Copy right © 2015, IAIM, All Rights Reserved.

Collagenase and metronidazole in management of diabetic foot ulcer ISSN: 2394-0026 (P) ISSN: 2394-0034 (O)Exclusion criteria Results• Clinical signs of infection, cellulitis.• Ulcers of Wagener’s Grade V and VI. Data of 82 subjects were analysed. Most of the• X-ray showing osteomyelitis. patients fell in the age group between 40 to 70• Doppler showing gross atherosclerotic years. The Mean ± SD for test group was (57.33arterial changes and venous ±14.67) and control was (55.35 ±14.40). Maleabnormalities like varicosities. and female ratio of the test group was 61.9: 39.1• Malnutrition, uncontrolled diabetes. and the control group was 67.5: 32.5. It was• Other clinically significant medical observed in our study most of the patientsconditions that would impair wound presented with diabetes mellitus of durationhealing including renal, hepatic, with Mean ± SD of test group10.1 ± 6.72 andhematological, neurological, and control 10.2 ± 5.62, most of the patients hadimmunological diseases. Grade III and IV ulcers in both test and control• Patients receiving corticosteroids, groups. The grade of ulcer was statisticallyimmunosuppressive agents, radiation, similar between the two groups.or chemotherapy within one monthprior to entry into the study were also Number of patients with no necrotic tissue wereexcluded. significantly higher in test group at 3rd week follow up (P = 0.001), at 4th week (P < 0.001), atAfter the initial screening period the eligible 5th Week (P < 0.001), at 6th week (P < 0.001) andpatients who required bed side debridement at the 7th week (P = 0.002) when compared towere divided randomly in to test group and control group as per the Chi-Square /Fishercontrol groups. Test group received collagenase Exact test.ointment with bed side surgical debridementwhen ever required for wounds / ulcers which The number of patients with no necrotic tissuehad slough in the floor and till granulation tissue was significantly higher in test group at 3rd, 4th,appeared. Metronidazole ointment was applied 5th, 6th and 7th weeks with significant p value <along with it to promote the growth of healthy 0.002, than control group. Granulation tissuegranulation tissue. Control group received bed was significantly higher in test group at 3rd, 4th,side surgical debridement with conventional 5th and 6th week with p value < 0.001. The testlocal antiseptics. Both the test and control group patients had a faster wound bedgroups were matched regarding their age, preparation resulting in faster wound coverdiabetic status, nutritional status, and grade of using secondary suturing, S.S.G, flap cover at theulcer. Wounds were treated once daily until third week itself as per Table – 1.complete debridement or up to seven weeks.The amount of nonviable tissue, degree of The number of patients with 75-100% woundwound granulation, and overall wound response filled by granulation tissue was significantlywas evaluated weekly using a visual score [8]. higher in test group at 3rd week follow up (P =The final parameters and wound characteristics 0.001), at 4th week (P < 0.001), at 5th Week (P <of the two randomized groups were analysed 0.001), at 6th week (P < 0.001) and at the 7thand compared. week (P = 0.024) when compared to control group as per Table – 2.International Archives of Integrated Medicine, Vol. 2, Issue 2, February, 2015. Page 29Copy right © 2015, IAIM, All Rights Reserved.

Collagenase and metronidazole in management of diabetic foot ulcer ISSN: 2394-0026 (P) ISSN: 2394-0034 (O)The duration of hospital stay was less in test Conclusiongroup compared to control group.Discussion Our study concluded that collagenase with metronidazole is an effective topical applicant inOur study presented use of metronidazole and faster reduction of slough, regeneration ofcollagenase combination in the treatment of granulation tissue and re-epithelization indiabetic foot ulcers with regard to the reduction diabetic foot ulcer. This helps in faster woundof slough formation, enhancement of bed preparation for healing, suturing, skin graftgranulation tissue and re-epithelization. The and flap.patients treated with collagenase andmetronidazole gel had faster reduction of Referencesslough/ necrotic tissue and increasedgranulation tissue, compared to study by Alvarez 1. World Health Organization. The WorldOM, Fernandez-Obregon A, Rogers RS, et al. The Health Report 1997. Conquering,study showed that the papain urea debridement suffering, enriching humanity. Geneva;ointment was more effective then the WHO, 1997.collagenase in the 3rd and 4th week recording thereduction of slough, increasing the growth of 2. King H, Alberti RE, Herman WH. Globalgranulation tissue. In our study patients showed burden of diabetes, 1995-2025,similar improvement in 3rd and 4th week [8]. prevalence. Diabetes Care, 1998; 21: 1414-1431.Another study observed that the collagenase is awell known and established enzyme preparation 3. Rama Lakshmi G, Bandyopadhyay SS,for wound debridement and helps in healing of Bhaskar LVKS, Sharma M, Raothe ulcers [9]. Similar results were obtained in Raghavendra V. Appraisal of risk factorsour study. for diabetes mellitus type 2 in central Indian population: A case control study.Collagenase ointment is a sterile enzymatic Antrocom Online Journal ofdebriding ointment containing collagenase in Anthropology, 2011; 7(1): 103-110.petrolatum. Its labelled Indications includedebriding dermal ulcers and severely burned 4. Mayfield JA, Reiber GE, Sanders LJ,areas. Dermal ulcers include pressure ulcers, Janisse D, Pogach LM. Preventive footarterial ulcers, venous ulcers and Diabetic ulcers. care in people with diabetes (TechnicalThere are no recent clinical trials that compare Review). Diabetes Care, 1998; 21: 2161–collagenase ointment with placebo in burns or 2177.decubitus ulcers. Published studies are poorlycontrolled and unblinded. Although not well 5. Boyko EJ, Ahroni JH, Smith DG, Davignondone these studies suggest that collagenase D. Increased mortality associated withointment is an effective enzymatic debriding diabetic foot ulcer. Diabetic Medicine,agent [10]. 1996; 13(11): 967-72. 6. Apelqvist J, Larsson J, Agardh CD. Long term prognosis for diabetic patients with foot ulcers. Journal Internal Medicine, 1993; 233(6): 485-91. 7. Burgos A, Gimenez J, Moreno E, et al. Collagenase ointment application at 24- versus 48-hour intervals in theInternational Archives of Integrated Medicine, Vol. 2, Issue 2, February, 2015. Page 30Copy right © 2015, IAIM, All Rights Reserved.

Collagenase and metronidazole in management of diabetic foot ulcer ISSN: 2394-0026 (P) ISSN: 2394-0034 (O)treatment of pressure ulcers. A trophic ulcerations in the diabeticrandomised multicentre study. Clin Drug patients. J Am Pod Assoc, 1978; 68: 11-Invest, 2000; 19: 399-407. 5.8. Alvarez OM, Obregon A, Rogers RS. A 10. Alan Knudsen MS, Joseph W Shands.prospective, randomized comparative Drugs and Therapy Bulletin. Drugstudy of collagenase and papain-urea for information and pharmacy Resourcepressure ulcer debridement. Wounds, Center, 1999; 13(1): 32-35.2002; 14(8): 293-301.9. Altman MI, Goldstein L, Horowitz S.Collagenase: An adjunct to the healingSource of support: Nil Conflict of interest: None declared.International Archives of Integrated Medicine, Vol. 2, Issue 2, February, 2015. Page 31Copy right © 2015, IAIM, All Rights Reserved.

Collagenase and metronidazole in management of diabetic foot ulcer ISSN: 2394-0026 (P) ISSN: 2394-0034 (O)Table - 1: Distribution of subjects according to presence of necrotic tissue or slough.Study Test group (n = 42), Number (%) Control group (n = 40), Number (%)Period Visual score of slough covering the ulcer Visual score of slough Study covering the ulcerBaseline 123456 123456 23 12 6 1 - - 23 10 7 - - - (54.8) (28.6) (14.3) (2.4) (57.5) (25.0) (17.5)1st 10 11 8 7 5 1 20 9 5 3 3 -Week (23.8) (26.2) (19.0) (16.7) (11.9) (2.4) (50.0) (22.5) (12.5) (7.5) (7.5)2nd 1 9 8 4 11 9 6 17 6 4 2 5Week (2.4) (21.4) (19.0) (9.5) (26.2) (21.4) (15.0) (42.5) (15.0) (10.0) (5.0) (12.5)3rd - 2 5 10 1 24 2 12 9 4 5 8Week - (4.8) (11.9) (23.8) (2.4) (57.1) (5.0) (30.0) (22.5) (10.0) (12.5) (20.0)4th - 2 4 4 32 - 1 14 8 4 13Week (4.8) (9.5) (9.5) (76.2) (2.5) (35.0) (20.0) (10.0) (32.5)5th - - - 2 3 37 - - 4 11 9 16Week - - (4.8) (11.9) (88.1) (10.0) (27.5) (22.5) (40.0)6thWeek - - - 1 41 - - - 6 11 237th (2.4) (97.6) (15.0) (27.5) (57.5)Week - - - - 42 - - - - 8 32 (100.0) (20.0) (80.0%)International Archives of Integrated Medicine, Vol. 2, Issue 2, February, 2015. Page 32Copy right © 2015, IAIM, All Rights Reserved.

Collagenase and metronidazole in management of diabetic foot ulcer ISSN: 2394-0026 (P) ISSN: 2394-0034 (O)Table - 2: Distribution of subjects according to presence of granulation tissue.Study Test group (n = 42), Number (%) Control group (n = 40), Number (%)period Visual score of presence of granulation tissue Visual score of presence of granulationBaseline 1 2 34 23 (54.8) 15 (35.7) 4 tissue (9.5) 1 234 23 13 4 - (57.5) (32.5) (10.0)1st Week 11 12 (28.6) 18 1 23 9 8 - (26.2) (42.9) (2.4) (57.5) (22.5) (20.0)2nd Week 1 12 19 10 9 17 9 (22.5) 5 (2.4) (28.6) (45.2) (23.8) (22.5) (42.5) (12.5)3rd - 3 17 22 1 22 9 8Week (7.1) (40.5) (52.4) (2.5) (55.0) (22.5) (20.0)4th - 1 10 31 - 12 16 12Week - (2.4) (23.8) (73.8) (30.0) (40.0) (30.0)5th - - 4 38 - - 24 16Week - (60.0) (40.0)6th (9.5) (90.5) - 21 19Week - 2 40 - (52.5) (47.5)7th Week - 5 35 (4.8) (95.2) (12.5) (87.5) - - 42 - (100.0)International Archives of Integrated Medicine, Vol. 2, Issue 2, February, 2015. Page 33Copy right © 2015, IAIM, All Rights Reserved.