Effectiveness Of Trypsin - Chymotrypsin as an Anti Inflammatory in Maxillofacial Trauma - A Double Blinded Randomised Clinical Trial

Keywords

Maxillofacial Trauma; Pain; Swelling; Fractures; Proteolytic Enzyme; Trypsin Chymotrypsin.

Introduction

Maxillofacial region involves soft and hard tissues forming the face extending from frontale superiorly to the mandible inferiorly [1]. The face being the foremost exposed to a part of the body is especially susceptible to trauma. Trauma to the facial region causes injuries to skeletal components, dentition also as soft tissues of the face [2]. Injuries to the maxillofacial region are increasing in frequency and severity due to the heavy reliance on road transportation and therefore the increasing socio-economic activities of the population.During wound healing, the formation and remodelling of the extracellular matrix involves a series of events that occur during a sequential fashion [3]. The clot formed during the method of healing consists mainly of fibronectin and fibrin. Afterward plasmin, breaks down the fibrin barrier to revive circulation. As a response to trauma the liver releases acute phase proteins like alpha 1 antitrypsin and alpha 2 macroglobulin which bind to plasmin and hence fibrinolysis is packed up [4].

Trypsin: chymotrypsin combination minimizes fibrinolytic pack up and therefore the severity of the inflammatory phase might be reduced. Various other areas where use the enzyme can be made used of are: • Resolves oedema post operatively and modulates inflammation associated with various conditions including accidental and surgical trauma. • Inflammation of a vein associated with thrombus, Thrombophlebitis. • Gynaecological surgery such as vasectomies and caesarean post operatively. • In dentistry specially for tooth extraction, periapical abscess and maxillofacial surgery. Implement in bronchitis for the reduction in viscosity of mucus and sputum. • Fractures and dislocation, sprains and strains. • In ocular trauma such as macular oedema, black eye, hyphema, uveal tract inflammation, subconjunctival haemorrhage, extraocular trauma. • In ENT such as nasal fractures, para pharyngeal abscess. • Conjunction with conventional therapy in treatment of patients with cancer of breast, lungs, head etc. Previously our team has a rich experience in working on various research projects across multiple disciplines [5-48] Now the growing trend in this area motivated us to pursue this project. The aim of this study is to evaluate the effectiveness of Trypsin -Chymotrypsin as an anti-inflammatory agent in maxillofacial trauma.

Materials and Methods

A total of 30 electively posted surgical patients were selected. The patients were grouped into two categories: group I (n = 15) were given placebo in place of trypsin: chymotrypsin preparation, categorized as the control group/placebo group; group II (n = 15) patients were treated with oral preparation of trypsin:chymotrypsin in the ratio of 6:1 with an enzymatic activity of 200,000 A.U./ tablet (tab. chymoral forte). These patients received 1 tablet of chymoral forte 3 times a day × for 7 days postoperatively.Patients diagnosed with fracture of parasymphysis of mandible were included in the study. The study being Double-blinded, the operating surgeon was not aware of the drug dispensed by the controller to the patient’s postoperatively neither did the patients nor the investigators aware of the drug given. The codes of the drugs were disclosed to the investigator by the controller after the pain assessment.

Only clean and electively posted surgical cases were selected and patients with significant comorbidities like uncontrolled diabetes mellitus, hypertension etc. were eliminated from our study. The mean average age group of individuals taken in both the groups ranged from 20- 40years. Routine blood investigations like complete blood picture, urine routine and microscopy, renal functional tests, liver function tests, ECG, chest X ray was done to all the patients from both the groups prior to surgery. Patients with all the investigations within normal limits and a baseline hemoglobin of greater than or equal to 10 were included in the present study. Intra operatively a single shot of third generation cephalosporins antibiotic, cefotaxime 1gm intravenously has been administered to all the patients from both the groups at the time of induction during anaesthesia. Post operatively a uniform antibiotic coverage of cefotaxime 200mg in tablet form (oral preparation) over a period 5 days was given to individuals of both placebo group and chymoral forte treated group. Facial swelling was quantified by 2 linear distances(Tragus-pogonion).Pain was recorded by means of VAS scale. All the outcomes were measured on day 1, 3, and 7 postoperatively.The statistical analysis was done using Statistical Package for Social Sciences (SPSS) Version 15.0 Statistical Analysis Software. The values were represented in mean ± SD.

Results

Of all the 30 patients studied divided into 2 groups, we found that in Group 1 (PLACEBO), 15 patients with a mean age of 28.4 years, included 5 Females (33%) and 10 Males (67%) who received conventional therapy post-surgery. In Group 2 (TRYPSIN-CHYMOTRYPSIN)) 15 patients with a mean age of 31.6 years, included 9 Males (60%) and 6 Females(40%) as shown in Fig who received oral preparation of trypsin:chymotrypsin in the ratio of 6:1 with an enzymatic activity of 200,000 A.U./tablet (tab. chymoral forte).The mean value of swelling for Group 1 pre operatively was found to be 15.33cm (SD: 0.94),on day one mean distance was 16.53 cm (SD:0.96), on day 3 mean distance was 16.13 cm (SD: 1.03), and on day 7 mean distance was 15.57 cm (SD:0.93).The mean value of swelling for Group 2 pre operatively was found to be 14.57cm (SD:0.94),on day 1 mean distance was 15.36 cm (SD: 0.89), on day 3 mean distance was 15.13 cm (SD: 0.99), and on day 7 mean distance was 14.64 cm (SD: 0.95).Swelling was more in Placebo group receiving conventional therapy when compared to Study group receiving oral preparation of trypsin:chymotrypsin in the ratio of 6:1 with an enzymatic activity of 200,000 A.U./tablet (tab. chymoral forte) ,as shown in Table 1.Mean value of pain was more in group 2(Trypsin-chymotrypsin) compared to group 1(Placebo), as shown in Table 2.

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Figure 1:

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Figure 1. Gender distribution in the study.

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Table 1:

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Table 1. Swelling measurements on 1st, 3rd and 7th day post operatively.

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Table 2:

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Table 2. VAS score on 1st, 3rd and 7th day post operatively.

Discussion

Following an acute injury, there is a pointy rise within the levels of the protease inhibitors a1-antitrypsin and a2 macroglobulin [48]. These acute phase reactants inhibit several proteolytic enzymes, which if uncontrolled can lead to unregulated inflammation and impair healing. The order of affinity of a1antitrypsin with proteolytic enzymes is as follows: elastase>chymotrypsin>cathepsin G>trypsin>plasmin.9,10 Similarly, a2macroglobulin shows greatest affinity with cathepsin G. At now , it must be reiterated that plasmin causes fibrinolysis, and its inhibition prevents fibrinolysis. Therefore, a steep rise in a1 antitrypsin and a2 macroglobulin following acute injury results in a period of fibrinolytic shutdown, with consequent maintenance of inflammatory response and edema and delay in repair [50].

Oral combination of trypsin: chymotrypsin targets this early stage of inflammation. Since a1-antitrypsin shows greater affinity for trypsin and chymotrypsin compared to plasmin, oral supplementation of the enzyme complex ensures that plasmin remains available for fibrinolysis and therefore the period of fibrinolytic shutdown is shortened [51]. As a result, local microcirculation is restored, inflammatory edema is cleared, and tissue repair is facilitated. The activity of proteolytic enzymes and their degradative effects are countered, resulting in reduction in inflammatory milieu, ROS and oxidative stress, and faster healing.

Ravi kumar et al studied the efficacy of trypsin:chymotrypsin (Chymoral) in accidental soft tissue injuries. The study included 156 patients presenting in the casualty department with bruises, lacerations, hematomas, and sprains.The conclusion drawn was that trypsin:chymotrypsin treatment in patients with accidental soft tissue injuries hastens the healing process and significantly reduces the recovery time [52]. This above mentioned study results are in accordance with the results of the present study.

Brakenbury and Kotowski also demonstrated that trypsin: chymotrypsin treatment improved the recovery rate in patients with ankle sprains. A double-blind randomized controlled trial involving 252 patients with sprains of the medial/lateral ligaments of the ankle that were immobilized using either below-the-knee plaster cast or an elastic bandage applied from the toes to below the knee. The results suggest that trypsin: chymotrypsin treatment hastens the recovery of accidental soft tissue injuries [53]. The above-mentioned study also is also in accordance with the results of the present study.

A multicentric study investigated the efficacy and safety of trypsin: chymotrypsin (Chymoral Forte) in patients with traumatic injuries from accidents, surgeries, burns, and others. It concluded that trypsin: chymotrypsin treatment in patients with surgical injuries, accidental injuries, and burns effectively resolves inflammation and improves healing [54]. The efficacy and safety of trypsin: chymotrypsin in accidental injuries, surgical and orthopaedic injuries, burns, and sciatica has been corroborated by a substantial and largely consistent body of evidence from clinical trials. Our institution is passionate about high quality evidence-based research and has excelled in various fields [55-65].

Conclusion

Trypsin: chymotrypsin combination hastens repair in surgical patients, shows high bioavailability without losing its biological activities as an anti-inflammatory agent. These properties help in resolving signs and symptoms of inflammation, tissue injury and facilitate the repair process. It also demonstrates analgesic effects and reduces the pain related to healing. It's thus concluded that trypsin: chymotrypsin treatment in patients hastens the healing process and reduces the recovery time. Overall, the use of trypsin:chymotrypsin in patients with acute injury reduces inflammation which in turn facilitates rapid healing.