|Year : 2020 | Volume
| Issue : 2 | Page : 102-108
Wound-healing potential of Nimbadi Kalka in diabetic foot ulcer: a clinical study
Rabinarayan Tripathy1, Saranya V Nair1, Vivek Lakshman2, Shaithya Raj1, Susmita Priyadarshinee Otta3
1 Department of Shalya Tantra (Surgery), Amrita School of Ayurveda, Amritapuri, Amrita Vishwa Vidyapeetham, India
2 Department of Endocrinology and Podiatry, Amrita Institute of Medical Science, Kochi, Kerala, India
3 Central Research Institute for Hepatobiliary Disorder, CCRAS, Bhubaneswar, Odisha, India
|Date of Submission||11-Jun-2020|
|Date of Decision||24-Jul-2020|
|Date of Acceptance||29-Jul-2020|
|Date of Web Publication||07-Sep-2020|
Dr. Rabinarayan Tripathy
Department of Shalya Tantra (Surgery), Amrita School of Ayurveda, Amritapuri, Amrita Vishwa Vidyapeetham, Clappana, Kerala.
Source of Support: None, Conflict of Interest: None
Background: One of the most dangerous complications of diabetes mellitus is the loss of lower limb by amputation as a consequence to diabetic foot ulcer (DFU). The estimated global prevalence of DFU is around 6.3%. The DFU is a type of nonhealing ulcer. Ayurveda explains it as Dusta Vrana (chronic nonhealing ulcer). Depending on its etiological factor, it can also be termed as Pramehajanya Dusta Vrana (nonhealing ulcer due to diabetes). The general line of management of Pramehajanya Vrana (diabetic wound/ulcer) mentioned by Acharya Sushuta says that one should adopt the principle and protocol of Dusta Vrana management. While describing the Sasti Upakrama (60 modalities of ulcer management), Nimbadi Kalka (a paste where neem leaves are the main ingredient) is mentioned, having both Vrana Sodhana (cleansing) and Vrana Ropana (healing) properties and beneficial for nonhealing ulcer. Keeping in view the above factor, 15 patients of DFUs were taken with a baseline HbA1c (6–7). Aims: The aim of this study was to evaluate the wound-healing property of Nimbadi Kalka in DFU. Settings and Design: The study was an open-label single-arm prospective design to find the pre- and post-effect of Nimbadi Kalka application on DFU. Materials and Methods: The study was conducted on 15 patients of DFU excluding dropouts. Nimbadi Kalka was applied on daily basis over the wound site for 45 days. Assessment was done on parameters such as wound surface area, granulation tissue, and exudates. Results and Conclusion: Nimbadi Kalka shows a marked reduction in wound size and exudates. In the case of granulation tissue, on the 15th day of treatment there was a peak increase indicating the formation of granulation tissue. Hence, Nimbadi Kalka promotes wound healing by reducing the size of ulcer in DFU.
Keywords: Anti-inflammatory, anti-microbial, anti-oxidant, Nimbadi Kalka, Pramehajanya Vraṇa
|How to cite this article:|
Tripathy R, Nair SV, Lakshman V, Raj S, Otta SP. Wound-healing potential of Nimbadi Kalka in diabetic foot ulcer: a clinical study. J Indian Sys Medicine 2020;8:102-8
|How to cite this URL:|
Tripathy R, Nair SV, Lakshman V, Raj S, Otta SP. Wound-healing potential of Nimbadi Kalka in diabetic foot ulcer: a clinical study. J Indian Sys Medicine [serial online] 2020 [cited 2020 Sep 24];8:102-8. Available from: http://www.joinsysmed.com/text.asp?2020/8/2/102/294439
| Introduction|| |
According to the World Health Organization (WHO) India ranks fourth in the world for diabetes. The prevalence rate of diabetes mellitus (DM) in India has increased from 61.9 million in 2012 to 69.2 million in 2015. Such an increase is the result of rapid industrialization and urbanization, due to which the lifestyle has become more sedentary with no compensatory recreational physical activities. Consumption pattern has also changed from coarse grains to refined wheat flour and white rice, junk foods, and sweet beverages. It is also the highest regional contributor in terms of diabetes mortality. Morbidity and mortality occur due to its microvascular and macrovascular complications such as Retinopathy, Nephropathy, Neuropathy, Coronary artery disease (CAD), Peripheral vascular disease (PVD), and diabetic foot ulcer (DFU). Epidemiological data show that approximately 90% of the Indians with diabetes have diabetic foot infections.
Foot ulcers are defined as lesions involving a skin break with loss of epithelium that can extend into the dermis and deeper layers sometimes involving bone and muscle. According to WHO, diabetic foot is “ulceration or infection or destruction of deeper tissues which are associated with neurological abnormalities, peripheral vascular disease and metabolic complications.”, Even with new and improved methods such as hyperbaric oxygen therapy, sterile maggot therapy, and tissue-engineered substitute, the prognosis is not satisfactory. The reason for this is that either these treatments are costly, which are not affordable by low-income group of people, or require continuous medical observations, to prevent adverse effects or need more clinical research.
For the treatment of diabetic ulcer, Acharya Sushruta has advised to follow the treatment protocol of chronic wounds (Dustavrana Cikitsa Vidhi). In the chapter Dvivraṇayacikitsa (treatment of two different types of ulcer––name of the chapter), Sushruta has mentioned 60 treatment measures (Sasthi Upakrama) for the management of wounds (Vraṇa), in which Kalka (paste) is mentioned for Sodhana (cleaning) and Ropana (healing). The blend of Tila Kalka (seasame seed paste) mixed with honey and Nimba Patra (neem leaves) helps for Vrana Sodhana (cleansing) and when, mixed with ghee promotes healing. So, the combination of Tila, Nimba, Madhu and Sarpi was proposed here to assess its healing property on DFU.
| Materials and Methods|| |
The study was an open-label single-arm pre- and post-study to evaluate the effect of Nimbadi Kalka in DFUs, conducted on a group of 15 patients after initial screening, proper examination, and investigation as mentioned in the inclusion criteria excluding dropouts.
After approval from the institutional ethics committee (IEC-AIMS-2017-AYUR-259), the study was registered in CTRI with registration number CTRI/2018/02/012255. Written informed consent was taken from each patient. Demographic data, medical history, personal history, chief complaints, and concomitant medication were recorded in the CRF form. The patient was advised to sit in a comfortable position to expose the wound site which was cleaned with normal saline followed by application of Nimbadi Kalka. The Kalka was applied with a thickness of 3 mm approximately (1/4th Angula as Doshaghna Lepa). It was secured with bandage and the patient was advised to keep the area clean and tidy till next dressing. Kalka was kept for 24h and removed on the next day for new dressing. The same procedure was continued for 45 days and assessment was done on every 15 days, that is, 0th day, 15th day, 30th day, and 45th day on parameters such as wound surface area, exudates, and granulation tissue.
The inclusion criteria of the study were (a) the patients aged between 40 and 70 years, irrespective of sex, (b) HbA1c between 6% and 7% (well controlled), (c) Texas classification of DFU till B2 (i.e., wound penetrating to tendon with infection), and (d) wound sites at plantar surface of foot (metatarsal heads and mid foot), toes (dorsal interphalangeal joints or distal tip), dorsum of foot, and ankle were included in the study.
The exclusion criteria of the study were (a) the patients aged below 40 and above 70 years, (b) HbA1c above 7, (c) DFU more than B2 Texas classification, (d) wound elsewhere except the foot and ankle region, (e) patient having other systemic pathology (TB, HIV/AIDS, HBs Ag, VDRL, pregnancy, malignancy, any arterial disease), and (f) patient on other medications such as steroids were excluded.
Preparation of Kalka
The drugs needed for the preparation of Nimbadi Kalka were procured from the local market, except nimba leaves. The neem leaves were collected from herbal Garden attached to the teaching Ayurveda college. The ingredients were identified as genuine by taxonomist. The Kalka (Paste) was prepared on daily basis, as per the textual reference [Table 1].
To assess the baseline and outcome following criteria were used.
Wound measurement in cm2:
Greatest length and width method: the greatest length and the greatest width of the wound were measured across the diameter of the wound, length and width can be multiplied to yield the square area of the wound. This single digit can be compared over time and should decrease if the wound is healing. Measurement of wound size helps in determining if the wound is healing or deteriorating.
It was graded as follows: present (1) and absent (0) [Table 2].
Exudations or discharge was assessed based on the grading of WUWHS (World Union of Wound Healing Society), 2007 [Table 3].
| Observation and Results|| |
The mean age for this study was 56.67 years with majority of patients in the age group of 60–70 years. Delayed wound healing in aged was due to decreased inflammatory response, delayed macrophage and lymphocyte infiltration, delayed re-epithelialization, delayed collagen deposition, and angiogenesis.
The male-to-female ratio was 2:1. It may be because males were having more outside activities that lead to more foot exposure to different risks. Recent studies have shown that sex hormones play an important role in age-related wound healing. Female hormone estrogen, and male hormone progesterone, influences the wound-healing process. Estrogen improves the healing process, whereas progesterone affects the healing negatively.
Based on habitat, 80% belonged to rural regions indicating that people may be prone to rodent bites and barefoot walking can also be a cause for developing ulcer compared with 20% belonging to urban area, where there is more access to specialized hospitals for early assessment and management. 86.66% of the patients had a mixed diet, whereas 13.33% were vegetarians. In the mixed diet category, there is more consumption of seafood on daily basis due to easy availability, as the area is coastal. And intake of Matsya (fish) and Anupa Mamsa (seafood) is said to be the cause for Kapha Prakopaka Ahara (food that aggravates Kapha) ultimately leading to diabetes.
Effect on exudates
On the 15th day of treatment, based on Wilcoxon sign rank test, it was evident that 10 patients had reduction in the level of exudates, whereas five patients had no change. During the 30th day of treatment, 12 patients had reduced exudation, whereas in three patients there was no change compared with before treatment. A similar result was noted on the 45th day of the treatment as well. As such there were no patients in the positive ranks, indicating that there was no increase in the level of exudation after treatment on the 15th day and also on subsequent assessment. No patients had positive ranks, indicating that there were no recurrences or increase in severity during the treatment procedure. At the end of the treatment, there was 95% relief in exudation [Table 4].
Effect on Granulation tissue
For granulation tissue, the mean value increased from 0 to 0.2. This indicates that before treatment there was no granulation tissue and after treatment there was an increase in the granulation tissue formation. Based on Wilcoxon sign rank test, on the 15th day all patients had granulation tissue, which was evident from the positive ranks. On the 30th day of treatment, 10 patients had granulation tissue, whereas five patients had no change compared with before treatment. At the end of treatment, the wound was completely healed and there was no granulation tissue noted, which was evident on the 45th day of assessment, that is, 12 patients had no granulation indicating the wound has healed, whereas 3 patients had granulation tissue indicating the wound was not healed completely [Table 5].
Effect on wound size
The mean value before treatment was 4.8, which reduced to 0.6 on the 45th day of the treatment, which shows that there was reduction in wound size after treatment. On the 15th day, there was a 37% reduction in wound size. On the 30th and 45th day, there was a 56% and 88% reduction, respectively. Based on the p-value of 15th, 30th, and 45th day i.e. 0.007, 0.001, and 0.001, it can be inferred that the treatment was statistically significant [Table 6].
| Discussion|| |
In the trial drug overall combination of the ingredients, the Rasa (~taste) involved are Madhura (Sweet), Kashaya (astringent), and Tikta (Pungent). Madhura Rasa is Dhatu Vardhaka (proliferates tissue), Sandhana Kara (Helps in approximation of tissue) and Sonita Prasadana (increases blood perfusion). Kashaya Rasa is Ropaṇa (helps in healing), Sodhana (Cleansing), Lekhana (debriding), Kleda Upashoshana (reduces exudation). Tikta Rasa is Chedhana (removing dead tissue), Sodhana (cleansing), Kleda-Meda-Vasa-Puya Upashoshana (that reduces pus and other exudation). However, when Madhura-Kashaya-Tikta drugs applied all around the sugar-laden cells the astringent action, drags the glucose concentration from the cells and may alter the cytoplasmic concentration of sugar. At the same time, more perfusion all around the cell and the presence of Madhura Dravya may initiate the tissue proliferation.
Based on “T.I.ME.” strategy, it can also be explained as follows:
T––Removal of non-viable tissue––Properties such as Lekhana and Chedhana helps in scrapping out the unwanted tissues (slough) from the wound.
I––Infection and inflammation control––Features of infected wound includes local rise of temperature, slough, excess discharge from the wound and pain. Properties such as Kleda-Puya Upashoshanam and Sodhana help in localized cleaning of the wound thereby decreasing the infection and inflammation.
M––Moisture balance––Rasa Prasadana helps in maintaining the moisture balance.
E––Epithelialization––Ropana, Sandhana, and Dhatu Vardhaka help in angiogenesis, and epithelialization, thereby granulation tissue formation thus healing of the wound.
Tila is Snigdha (unctuousness) which helps in keeping the wound environment moist and is considered as wholesome for applying over the wound. Twachya (nourishing to skin) property of Tila implies that it is beneficial for skin which in other sense can be taken as that which helps in re-epithelialization. Previous studies reveal that sesame helps in faster re-epithelialization and wound contraction by its potent anti-oxidant, Sesamol, which facilitating proliferation of epithelial cells from wound edges. Due to its anti-oxidant properties, it promotes healing by preventing oxidative damages.
Madhu (Honey) helps in absorbing the wound discharge or exudates by its Rukṣana (drying or dehydrating) property, also helps in clearing the wound debris, necrotic or devitalized tissue and bacteria by virtue of its Lekhana, Sleṣma-Meda-Krimi Prasamana (that reduces thick exudates and other infective organisms) properties. Due to Sodhana, Ropaṇa, and Sandhana properties, it helps in cleaning the wound surface, promotes neo-vascularization, granulation tissue formation, and re-epithelialization. Various studies explain its effectiveness on DFU that honey being a biologic wound dressing that enhances the healing process with multiple bioactivities. Its acidity, releases oxygen from hemoglobin and makes the wound environment less favorable for destructive proteases, stimulate epithelialization and minimizes scar formation. Acidic nature of honey releases oxygen needed by the cells and stimulates the white blood cells. Honey keeps the wound moist and clean, promotes formation of healthy granulation tissue and accelerates epithelialization of wound without producing any adverse effects because of its osmolarity. The high osmolarity of honey pulls up fluid out of the wound bed to create a flow of lymph like the negative pressure wound therapy. Honey is a broad-spectrum antibacterium due to hydrogen peroxide and methylglyoxal. Honey is used as base in wound-care products as it can withstand dilution with substantial amounts of wound exudates, still inhibit the growth of bacteria. Adequate evidences are there that bioactivities of honey stimulate the immune response, thus promoting the growth of tissues, wound repair, suppress inflammation, and initiates rapid autolytic debridement., It also acts as an antibacterial agent due to the lowering of prostaglandins and elevating nitric oxide content. Further, it contains a wide range of amino acids, vitamins, and trace elements, hence exerts direct nutrient effect on regeneration of tissue.
Neem helps in reducing the inflammation, bacterial invasion, slough, and wound size. Sarpi (Ghee) maintains the wound moisture by its Snehana (lubricating) property and reduces wound pain with its Sūla Prasamana (pacifying pain or tranquillizing) property. A study evaluated on the wound-healing activity of the extracts of leaves of A. indica using excision and incision wound models in Sprague Dawley rats revealed that extract significantly promoted the wound-healing activity in both excision and incision wound models through increased inflammatory response and neo-vascularization.Nimba has shown significant anti-microbial and anti-inflammatory activity. Anti-inflammatory activity occurs via nimbindin which suppresses the neutrophil and macrophage functions thereby reducing inflammation. This will promote neo-vascularization, thereby improves circulation by providing more oxygen to the wound side, thus helping in wound healing.
Ghee and honey have been advocated gratifying results to reduce the foul odor and discharge, significantly improving the quality of life in malignant lesions and DFU. Fatty acids in ghee exert antimicrobial properties (anti-fungal) and also it maintains the wound moisture. Hence when it is mixed with other ingredients, it helps in maintaining the viscosity at body temperature thereby it will have longer contact duration with the wound.
In chronic ulcer, there is prolongation of inflammatory phase which leads to delaying the proliferation and remodeling phase. The main aim of inflammatory stage is the removal of bacteria, debris, and damaged tissue by neutrophils and macrophages. They protect against microbial invasion and removes devitalized tissue by production of proteolytic enzymes and reactive oxygen species (ROS). However, increased accumulations of neutrophils during the inflammatory phase prolong the inflammatory symptoms leading to tissue damage and thereby prevent wound healing. Drugs with anti-inflammatory property decrease the neutrophil accumulation and inhibit polymorphonuclear (PMN) functions and thereby limit excessive PMN secretory damage. Excessive accumulation of neutrophils results in high concentrations of ROS, which cause severe tissue damage and decrease the healing process by damaging the DNA, proteins, cellular membranes, and lipids. These adverse effects are reduced by antioxidants and counter the excess ROS. Also, these effects protect protease inhibitors from oxidative damage. Thus, compounds with high antioxidant content facilitate wound-healing. Moist environment helps in accelerating the inflammatory phase. For the wound to heal, a drug should possess properties such as antioxidant, anti-inflammatory, antimicrobial, and to maintain moisture balance. Overall, Nimbadi Kalka possesses all these characteristics, hence effective in reducing the wound size, stimulate granulation tissue, and decrease wound exudates in DFU [Figure 1][Figure 2][Figure 3][Figure 4].
| Conclusion|| |
Nimbadi Kalka possesses properties such as antioxidant, anti-inflammatory, antimicrobial, and it also maintains the moisture balance of the wound environment. These help in reducing the inflammatory phase of the chronic wound and thereby promotes the proliferation and remodeling phase. No adverse drug reaction (ADR) and side effects were reported during the course of treatment. Also, the drug is cost-effective and easy to prepare due to its better availability.
The authors declare that all appropriate patient consent were taken. In the consent form the patients have given their consent that their images and other clinical information to be reported in the journal. The patients understand that their identity will not be published, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]