Evaluation of Efficacy of Heparin in Patients with Cellulitis

Introduction

Cellulitis is an acute inflammatory condition of skin that is characterized by local pain, erythema, swelling, and local elevation of temperature.¹ In developed countries the incidence of cellulitis is estimated to be approximately 16.4 to 24.6/1,000 person-years.² Cellulitis is caused by indigenous flora colonizing the skin and appendages and associated endogenous causes.¹

Most common organisms causing cellulitis are Staphylococcus aureus (51%), group A β-hemolytic Streptococcus (21%), Streptococcus pyogenes, Haemophilus influenza, and Pseudomonas aeruginosa.¹ In the preantibiotics era the estimated mortality due to cellulitis was approximately 11%. Due to advent of antibiotics, this incidence was significantly reduced and only those with severe disease requiring admission suffer from mortality and overall mortality in this group of patients remains approximately 5 to 7.2%.³ Most cases of cellulitis are managed empirically. Blood culture, needle aspirate, and skin biopsies are various methods of evaluation to determine the causative organism but seldom yield significant results and are not commonly employed in majority of cases. Traditionally, cellulitis has been managed empirically with antibiotics chosen to cover staphylococci and streptococci.³ Until the antimicrobial susceptibility result is awaited, empirical treatment with aminoglycosides, third-generation cephalosporins, and semisynthetic penicillin (ticarcillin, mezlocillin, or piperacillin) is commenced until culture and sensitivity reports are available.^3,4

For over 60 years heparin is being used routinely in clinical practice as an anticoagulant and antithrombotic agent. Studies have shown that the anti-inflammatory role of heparin is mainly because of the blockade of P-selectin and L-selectin.^5,6 In a randomized study by Katakkar to explore the use of heparin as a topical anti-inflammatory and antithrombotic agent, the author showed that heparin application decreased the incidence of pain, redness, and swelling. They concluded that use of heparin is safe, effective, and well tolerated.⁷

With the background of the abovementioned studies, our study aimed at evaluating the role of heparin in the treatment of cellulitis in addition to antibiotics.

Materials and Methods

Results

All patients presenting with clinical diagnosis of cellulitis and willing to participate in the study were included till the sample size was reached and recruitment was stopped at completion of sample size. A total of 104 patients were screened and 8 of them refused to consent for study and 96 patients were included in the final analysis. Of the 96, 71 (74%) patients were male and 25 (26%) patients were female.

Ninety-six patients were divided into two groups of 48 each; there were no significant differences between the two groups regarding outcome-related factors at admission (day 1) as indicated in ►Table 1. Group A patients with cellulitis were treated with antibiotics and heparin, while group B patients with cellulitis were treated with antibiotics alone.

In group A treated with both antibiotics and subcutaneous injection of unfractionated heparin, there was improvement in area of cellulitis as measured on day 5 with mean area of 174.563 cm² (32.36% decrease of area of cellulitis) as compared with 234.5 cm² (10.99% decrease in area) in controls treated with antibiotics alone (►Table 1; ►Fig. 1).

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Fig. 1

Comparison of area of involvement of cellulitis (cm²) between the two groups.

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On comparing the two groups based on reduction in limb swelling, that is, edema on day 5, there was reduction of 7.6 cm (26.3%) in the experimental group as compared with 3.7 cm (12.9%) in the control group, which was found to be statistically significant (►Table 1; ►Fig. 2).

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Fig. 2

Comparison of limb girth (cm) between the two groups.

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The mean pain score based on visual analog scale was found to be significantly lower at 4.3 points (45.36% reduction from admission) on day 5 in the experimental group as compared with 5.2 points (38.02% reduction since admission) in controls (►Table 1; ►Fig. 3).

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Fig. 3

Comparison of pain (visual analog scale [VAS]) between the two groups.

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The drop is mean total leucocyte count on day 5 was 3,540 cells/cu.mm (29.18% drop) in the experimental group as compared with 3,353 (25.87% drop) in the control group, which was found to be statistically significant (►Table 1; ►Fig. 4).

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Fig. 4

Comparison of total leucocyte count (cells/cu.mm) between the two groups.

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Mean duration of hospital stay in group A was significantly less at 7.15 (±1.2) days while group B was 9.23 (±1.5) days (p < 0.001).

There were no significant adverse events, allergic reactions, anaphylaxis, local, or bleeding-related complications due to heparin injections in the experimental group in our study. There were no antibiotic-related complications in both the groups. There was no mortality in both the groups.

Discussion

Cellulitis is a commonly encountered clinical problem and due to lack of specific therapies leads to prolonged duration of symptoms and suffering. Various guidelines for management exist and our study aimed at outcomes with use of heparin in addition to antibiotics for faster recovery and all endpoints were directed toward this. Patients in both groups were compared in terms of decrease in erythema, edema (limb girth) pain, fever, total leucocyte count on day 1, day 5, and day 7, and duration of hospital stay.

Katakkar has previously validated the use of heparin as a topical anti-inflammatory and antithrombotic agent. This randomized study showed that heparin application decreased the incidence of pain, redness, and swelling and concluded that use of heparin is safe, effective, and well tolerated.⁷ In our study, there was faster resolution of area of erythema, tissue edema, and pain at day 5 of treatment with heparin as compared with the control group.

Chen et al investigated the effect of heparin in second degree burn wounds in 100 patients selected randomly and concluded that the addition of heparin results in shorter healing time with less duration of stay and reduction in pain.⁹ In our study, patients with burns were not included but only those with cellulitis were included. However, the mechanism of inflammation in both cases is similar and anti-inflammatory effect of heparin should make it safe for use even in burn cases if there is no evidence of coagulopathy.

Jordan and Piotrowski reported usage of light density heparin in treatment of orbital phlegmonous cellulitis and thrombophlebitis of cavernous sinus and hypothesized it was responsible for stopping the process of thrombophlebitis of orbital veins and cavernous sinus thrombosis owing to its anticoagulant as well as anti-inflammatory properties.¹⁰ Heparin containing irrigation fluid has also been shown to reduce postoperative inflammation among patients undergoing cataract surgery.¹¹

Potent anti-inflammatory property of heparin results primarily from blockade of P-selectin and L-selectin.^12,13 Ability of heparin to maintain blood flow by preventing sludging and clots, anti-inflammatory effect, neoangiogenic effects that revascularizes tissues, and reduced translocation bacteria are responsible for improvement in clinical parameters.^14–16 The anti-inflammatory effect of nebulized heparin has also been used to treat acute respiratory distress syndrome and reduce alveolar damage. The proposed mechanisms have been reduction in fibrin deposition and reduction in microvascular thrombosis.^17,18

With the analysis of the available literature, our present study comparing the clinical outcomes suggests that there was significant decrease in area of cellulitis (erythema), edema (limb girth), pain, and total leucocyte count on day 5 in the experimental group treated with subcutaneous injection of heparin and conventional intravenous antibiotics when compared with the control group treated with conventional intravenous antibiotics alone without heparin. Duration of hospital stay was less in group A compared with group B. As the duration of stay is significantly decreased, it is found to be cost effective, and we suggest its use in regular practice.

Limitations of this study include the relatively smaller number of cases for comparison and cost of heparin has been not compared. As the duration of stay is less in cases compared with controls, it may be cost effective but overall treatment cost is not calculated to comment on the same. Patients with severe cellulitis with systemic symptoms like renal failure, hypotension, sepsis, and multiorgan dysfunction syndrome were not included so the role of addition of heparin in such cases cannot be commented. Future studies can be focused on such cases to have a broader clinical spectrum for use of heparin.

Conclusion

The authors conclude that the addition of subcutaneous injection of unfractionated heparin to conventional antibiotics in cellulitis is more beneficial when compared with the conventional antibiotics alone and lead to rapid resolution of clinical symptoms and expedited recovery with shorter duration of hospital stay. So, it may be used as a fundamental tool in the treatment of cellulitis.