European Journal of Cardiovascular Medicine

A common clinical appearance of blunt force injury to the head is a post-traumatic scalp hematoma, which is frequently accompanied by localized inflammation, discomfort, and swelling of soft tissues.  Because of their analgesic and antipyretic properties, non-steroidal anti-inflammatory medicines (NSAIDs) like ibuprofen and analgesics and anti-inflammatory medications like paracetamol are commonly used for symptomatic relief [1].  However, especially when used for an extended period of time, NSAIDs can cause cardiovascular, renal, and gastrointestinal side effects [2]. A promising substitute for treating inflammation and edema is systemic enzyme therapy (SET), which combines the flavonoid rutoside with proteolytic enzymes such as trypsin and bromelain.  These substances may hasten recovery by modifying inflammatory mediators, improving microcirculation, and aiding hematoma resorption [3].  Trypsin helps break down proteins and reduce inflammation, whereas bromelain, a protease found in pineapple stems, has anti-inflammatory and fibrinolytic qualities. One semi-synthetic flavonoid that helps with capillary stability and vascular protection is rutoside [4].  Enzyme-flavonoid combinations may provide similar or better results than NSAIDs in soft tissue injuries, with less side effects, according to several studies [5]. The purpose of this randomized, active-controlled study was to compare the safety and effectiveness of trypsin-bromelain-rutoside systemic enzyme therapy with a combination of ibuprofen and paracetamol for the treatment of post-traumatic scalp hematoma.

Study Design: A prospective, randomized, open-label, active-controlled clinical trial study

Study Settings: The study was conducted at the outpatient and emergency departments of a tertiary care hospital. Patients with post-traumatic scalp hematoma were enrolled over a period of one year.

Place of Study: Barasat Government Medical College and hospital

Period of Study:  From 1st January 2024 to 31st December 2024

Sample Size: A total of 100 patients with post-traumatic scalp hematoma

Inclusion Criteria:

• Patients aged 18 to 60 years.
• Clinical diagnosis of post-traumatic scalp hematoma due to blunt head injury.
• Hematoma onset within 48 hours prior to enrollment.
• Willingness to participate and provide written informed consent.
• Hemodynamically stable with no signs of severe head injury.

Exclusion Criteria:

• Open or penetrating head injuries.
• Signs of intracranial hemorrhage or skull fracture on imaging.
• Known allergy or hypersensitivity to any study medications (trypsin, bromelain, rutoside, paracetamol, or ibuprofen).
• Patients on anticoagulant or antiplatelet therapy.
• Chronic liver or kidney disease.

Study Variables:

• Reduction in scalp hematoma size.
• Pain intensity (measured using Visual Analog Scale).
• Time to complete hematoma resolution.
• Incidence of adverse drug reactions.
• Patient-reported satisfaction with treatment.

Statistical Analysis:-

For statistical analysis, data were initially entered into a Microsoft Excel spreadsheet and then analysed using SPSS (version 27.0; SPSS Inc., Chicago, IL, USA) and GraphPad Prism (version 5). Numerical variables were summarized using means and standard deviations, while Data were entered into Excel and analysed using SPSS and GraphPad Prism. Numerical variables were summarized using means and standard deviations, while categorical variables were described with counts and percentages. Two-sample t-tests were used to compare independent groups, while paired t-tests accounted for correlations in paired data. Chi-square tests (including Fisher’s exact test for small sample sizes) were used for categorical data comparisons. P-values ≤ 0.05 were considered statistically significant.

Table 1: Baseline Demographics and Clinical Characteristics

Table 2: Change in Hematoma Volume over Time

Table 3: VAS Pain Score over Time

Table 4: Resolution Time of Hematoma (Days)

Table 5: Incidence of Adverse Events

Table 6: Tenderness Score (Graded 0–3)

Table 7: Global Patient Satisfaction on Day 14

Figure 1: Global Patient Satisfaction on Day 14

In our study, there were no statistically significant differences between Group A and Group B across key baseline parameters. The mean age was comparable between the groups (32.4 ± 9.1 vs. 33.1 ± 8.7 years; p = 0.62), and the gender distribution was similar, with males comprising 62% of Group A and 58% of Group B (p = 0.68). Mean hematoma size (12.8 ± 2.1 vs. 13.1 ± 2.4 cm³; p = 0.47), VAS pain scores (6.5 ± 1.1 vs. 6.3 ± 1.2; p = 0.41), and time since trauma (5.6 ± 2.2 vs. 5.4 ± 1.9 hours; p = 0.71). In our study, both groups showed a progressive reduction in hematoma volume over time; however, Group A demonstrated a significantly faster resolution compared to Group B. At baseline, hematoma sizes were comparable (12.8 ± 2.1 vs. 13.1 ± 2.4 cm³; p = 0.47). By Day 3, Group A showed a significantly smaller mean hematoma volume than Group B (9.1 ± 2.0 vs. 10.6 ± 2.2 cm³; p = 0.002). This difference became more pronounced on Day 7 (5.2 ± 1.6 vs. 7.4 ± 1.9 cm³; p < 0.001) and Day 14 (1.1 ± 0.8 vs. 3.8 ± 1.3 cm³; p < 0.001). In our study, both groups showed a decline in pain scores over time; however, Group A experienced significantly faster and greater pain relief. At baseline, VAS scores were comparable between the groups (6.5 ± 1.1 vs. 6.3 ± 1.2; p = 0.41). By Day 3, Group A reported lower pain scores than Group B (4.2 ± 1.0 vs. 5.3 ± 1.2; p < 0.001). This trend continued on Day 7 (2.1 ± 0.9 vs. 3.8 ± 1.1; p < 0.001) and Day 14 (0.4 ± 0.6 vs. 1.9 ± 0.8; p < 0.001). In our study, Group A showed significantly better outcomes in terms of hematoma resolution. Complete resolution was achieved in 96% of patients in Group A compared to 74% in Group B (p = 0.002). Additionally, the mean resolution time was significantly shorter in Group A (10.2 ± 1.8 days) than in Group B (13.1 ± 2.5 days; p < 0.001). In our study, adverse events were significantly fewer in Group A compared to Group B. Gastric irritation occurred in only 2% of Group A versus 14% of Group B (p = 0.03), while nausea and allergic reactions were not significantly different between the groups (p = 0.24 and p = 0.31, respectively). Overall, total adverse events were significantly lower in Group A (6%) compared to Group B (26%) (p = 0.007). In our study, both groups showed a reduction in scalp swelling scores over time, but Group A exhibited a significantly faster decline. Baseline scores were comparable (2.8 ± 0.4 vs. 2.7 ± 0.5; p = 0.38). By Day 3, Group A showed significantly lower swelling (1.9 ± 0.5 vs. 2.3 ± 0.6; p = 0.001), with the difference widening on Day 7 (0.9 ± 0.6 vs. 1.7 ± 0.5; p < 0.001) and Day 14 (0.2 ± 0.4 vs. 0.8 ± 0.5; p < 0.001). In our study, overall patient satisfaction was significantly higher in Group A than in Group B. A greater proportion of participants in Group A reported being "very satisfied" (76%) compared to Group B (42%) (p< 0.0001). Additionally, 20% of Group A were "satisfied" versus 38% in Group B, while "neutral" responses were less frequent in Group A (4%) than in Group B (16%). Notably, none in Group A were "dissatisfied," whereas 4% of Group B reported dissatisfaction.

We found that the baseline characteristics between Group A and Group B were comparable, with no statistically significant differences observed. The mean age was similar in both groups (32.4 ± 9.1 vs. 33.1 ± 8.7 years, p = 0.62), and the male distribution was nearly equal (62% vs. 58%, p = 0.68). The mean hematoma size (12.8 ± 2.1 cm³ vs. 13.1 ± 2.4 cm³, p = 0.47), VAS pain score (6.5 ± 1.1 vs. 6.3 ± 1.2, p = 0.41), and time since trauma (5.6 ± 2.2 hrs vs. 5.4 ± 1.9 hrs, p = 0.71) also showed no significant differences. Similar findings regarding comparable baseline parameters between treatment groups were observed by Bansal et al. (2013) [6], Khan et al. (2016) [7], supporting the robustness of group matching in randomized trials involving post-traumatic or post-operative interventions.

We found that both groups showed a progressive reduction in hematoma size over time; however, Group A demonstrated significantly greater reduction at each follow-up point. While baseline hematoma volumes were comparable between Group A and Group B (12.8 ± 2.1 cm³ vs. 13.1 ± 2.4 cm³, p = 0.47), Group A showed a significantly lower mean volume on Day 3 (9.1 ± 2.0 vs. 10.6 ± 2.2 cm³, p = 0.002), Day 7 (5.2 ± 1.6 vs. 7.4 ± 1.9 cm³, p < 0.001), and Day 14 (1.1 ± 0.8 vs. 3.8 ± 1.3 cm³, p < 0.001). Similar patterns of enhanced hematoma or edema resolution with enzyme-based or anti-inflammatory therapies have been reported by Rathore et al. (2019) [8], , who also demonstrated superior outcomes in intervention groups over standard therapy in terms of swelling or hematoma regression.

We found that both groups experienced a gradual decrease in pain intensity over time; however, Group A showed a significantly greater reduction at all post-treatment timepoints. At baseline, the VAS pain scores were comparable between Group A and Group B (6.5 ± 1.1 vs. 6.3 ± 1.2, p = 0.41). By Day 3, pain scores in Group A had decreased more markedly (4.2 ± 1.0 vs. 5.3 ± 1.2, p < 0.001), and this trend continued on Day 7 (2.1 ± 0.9 vs. 3.8 ± 1.1, p < 0.001) and Day 14 (0.4 ± 0.6 vs. 1.9 ± 0.8, p < 0.001). These findings align with previous studies by Sharma et al. (2021) [9], who also reported significantly faster and more substantial reductions in VAS pain scores in groups receiving enzyme-based or anti-inflammatory interventions compared to controls.

We found that Group A had significantly better clinical outcomes in terms of hematoma resolution. A higher percentage of patients in Group A achieved complete resolution compared to Group B (96% vs. 74%, p = 0.002). Additionally, the mean resolution time was significantly shorter in Group A (10.2 ± 1.8 days) than in Group B (13.1 ± 2.5 days, p < 0.001). Similar outcomes have been reported in studies by Mehta et al. (2024) [10], where intervention groups receiving enzyme-based or anti-inflammatory therapies showed significantly faster resolution and higher rates of complete recovery compared to conventional treatments.

We found that adverse events were significantly less frequent in Group A compared to Group B. Gastric irritation occurred in only 2% of Group A versus 14% in Group B (p = 0.03), indicating a statistically significant difference. Although nausea and allergic reactions were more common in Group B (10% and 2%, respectively) compared to Group A (4% and 0%), these differences were not statistically significant (p = 0.24 and p = 0.31, respectively). Overall, the total incidence of adverse events was significantly lower in Group A (6%) than in Group B (26%, p = 0.007). These findings align with other studies reporting fewer gastrointestinal side effects and better tolerability with enzyme‑based therapies. Bhagat et al. (2013) [11] conducted a systematic review noting that serratiopeptidase is generally well tolerated with rare reports of nausea or mild gastric discomfort.

We found that both groups showed improvement in swelling scores over time, but the reduction was significantly greater in Group A at each follow-up. At baseline, the mean swelling scores were comparable between Group A (2.8 ± 0.4) and Group B (2.7 ± 0.5, p = 0.38). By Day 3, Group A showed a greater reduction in swelling (1.9 ± 0.5), while Group B had a mean score of 2.3 ± 0.6 (p = 0.001). This trend continued on Day 7, with mean scores of 0.9 ± 0.6 in Group A and 1.7 ± 0.5 in Group B (p < 0.001), and by Day 14, scores decreased to 0.2 ± 0.4 in Group A and 0.8 ± 0.5 in Group B (p < 0.001). These findings are consistent with earlier clinical evidence showing accelerated edema resolution using enzyme-based therapies. In a randomized, intra-individual crossover study, Al‑Khateeb and Nusair (2008) [12] observed significantly reduced cheek swelling with serratiopeptidase versus placebo on postoperative Days 2–7 following third molar extraction.

We found that patient satisfaction levels differed significantly between the groups. In Group A, 38 of 50 patients (76%) reported being very satisfied, 10 (20%) were satisfied, 2 (4%) were neutral, and none were dissatisfied. In Group B, 21 of 50 patients (42%) were very satisfied, 19 (38%) were satisfied, 8 (16%) were neutral, and 2 (4%) were dissatisfied (p < 0.001). Similar high satisfaction rates linked with better outcomes have been documented in several independent studies. For instance, a German randomized trial using Phlogenzym after limb fracture surgery reported superior patient comfort and satisfaction with enzyme-based therapy versus standard antiedematous drugs Wermker et al. (2014) [13] found higher subjective satisfaction in the enzyme therapy group based on reduced edema and faster recovery.

We concluded that this randomized active-controlled study shows that trypsin-bromelain-rutoside systemic enzyme therapy is superior to paracetamol-ibuprofen for treating post-traumatic scalp hematoma.  At every follow-up point, Group A patients showed improved edema scores, increased pain reduction, and noticeably quicker hematoma clearance.  In addition, the enzyme group experienced fewer side effects and much less stomach discomfort than the NSAID group.  The clinical benefit of enzyme therapy is further supported by Group A's higher rates of full resolution and patient satisfaction.  These results are consistent with earlier research indicating that flavonoids and proteolytic enzymes maximize fibrinolytic and anti-inflammatory activity while reducing side effects.  Consequently, in the conservative treatment of post-traumatic soft tissue injuries, systemic enzyme therapy offers a safer and more effective substitute.

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