|Year : 2019 | Volume
| Issue : 3 | Page : 176-181
From compression to injections: Prostaglandins paving a new direction for venous leg ulcer treatment
Rajendra Prasad Basavanthappa, Ashwini Naveen Gangadharan, Sanjay C Desai, AR Chandrashekar
Department of Vascular and Endovascular Surgery, Ramaiah Medical College, Bengaluru, Karnataka, India
|Date of Web Publication||29-Aug-2019|
Dr. Rajendra Prasad Basavanthappa
Department of Vascular and Endovascular Surgery, Ramaiah Medical College, Bengaluru, Karnataka
Source of Support: None, Conflict of Interest: None
Objective: Venous ulcers play a major burden on the patient and health-care system in terms of morbidity and medical expenditure. The objective of the study was to evaluate the efficacy of prostaglandin E1 (PGE1) administered via intravenous infusion in the healing time of venous leg ulcer and to evaluate the safety of prostaglandin intravenous infusion. Materials and Methods: This was a prospective observational study at a single tertiary care center. Patients who had proven venous ulcers of the legs which are not healing for more than 3 months with conventional therapy were included. About 500 μg PGE1 was given in equally divided doses over 5 days as intravenous infusion along with regular compression therapy. Ulcers were followed up every 3 weeks for 18 weeks and measurement of ulcer area done. Results: A total of 47 patients with 50 ulcers were included in the study with a mean age of 55.9 years. About 50% of ulcers healed 9 weeks after PGE1 administration and 92% healed after 18 weeks of treatment. The estimated healing time of 25%, 50%, and 75% of the patients treated with PGE1 was 40, 63, and 86 days, respectively, which was statistically significant compared to the previous studies with compression therapy alone. The only factor to independently affect healing time was found to be the initial ulcer size. There were no major adversities with PGE1 administration, 2 patients developed minor symptoms, in the form of hypotension and tachycardia, which were managed with stoppage of infusion for short duration. Conclusion: The study shows the effectiveness of PGE1 in reducing the healing time of VLUs, thereby allowing patients for lesser hospitalization and quicker return to work and life producing improvement in the quality of life. The adverse effects were also very minor with PGE1 treatment, overall, acceptable and were well tolerated by the patients.
Keywords: Healing time, prostaglandin E1, prostaglandins, ulcer area, venous leg ulcer
|How to cite this article:|
Basavanthappa RP, Gangadharan AN, Desai SC, Chandrashekar A R. From compression to injections: Prostaglandins paving a new direction for venous leg ulcer treatment. Indian J Vasc Endovasc Surg 2019;6:176-81
|How to cite this URL:|
Basavanthappa RP, Gangadharan AN, Desai SC, Chandrashekar A R. From compression to injections: Prostaglandins paving a new direction for venous leg ulcer treatment. Indian J Vasc Endovasc Surg [serial online] 2019 [cited 2019 Dec 11];6:176-81. Available from: http://www.indjvascsurg.org/text.asp?2019/6/3/176/265771
| Introduction|| |
Venous ulcers play a major burden on the patient and health-care system in terms of morbidity and medical expenditure. With a prevalence of 0.25%–1.25% in the general population and poor healing tendency,, it causes significant social problems such as absence from work and invalidity.,
The mechanisms that lead to the formation of a venous ulcer are thought to be multifactorial. One of the most widely accepted one is that venous ulceration is initiated by venous hypertension and stasis which in turn develops due to an inadequate calf muscle pumping mechanism and valvular incompetence. This leads to alterations in the microcirculation and leakage of fibrinogen into the dermis which cause the formation of pericapillary fibrin cuffs and white cell trapping, thus impeding oxygen and nutrient delivery to the tissues. The chronic hypoxic damage thus caused led to fibrosis and ulceration.
No single procedure or available product is adequate for the treatment of all patients with venous ulcers. Treatment selection is determined by patient tolerance, patient's medical status, cost, availability, and physician's preference. Regardless of the existing adjunctive treatments used, compression is necessary for the treatment of venous ulcers. Compression dressings are the standard of care and are needed to assist venous return and to address the underlying pathophysiology of venous disease and venous ulceration., A Cochrane review in 2009 (evidence level A) concluded that healing of venous leg ulcers (VLU) was faster with compression therapy than with no compression and hence advised compression therapy for VLU treatment.
However, along with the standard-of-care compression therapy, additional effective VLU treatments which will result in more rapid healing are clearly required. Faster healing would result in fewer hospital admissions, lower infection rates, decreased need for antibiotics, improved mobility, decreased morbidity, and fewer surgical procedures with better quality of life for patients with VLUs.
Many studies in the past have demonstrated augmentation of healing of venous ulcers by various drugs.,,,,, But none of them were really able to replicate the results in a larger perspective with added advantages. Prostaglandin E1 (PGE1), a metabolite of the polyunsaturated dihomogamma-linoleic acid, falls in one of this category of drugs and shows anti-ischemic effects along with VLU healing augmentation. It is a constituent of membrane phospholipids and acts on membrane receptors, producing a consequent increase in cyclic adenosine monophosphate, thus exerting multiple actions. Some of the pharmacologic effects of PGE1 reported are reduction of platelet adhesion and aggregation, reduction of blood viscosity, inhibition of the chemotaxis and white cell activation, and stimulation of formation and growth of collateral circulation.,,,,,
From the results of the previous studies and the probable pharmacologic actions, we conducted a study to determine if PGE1 administration, in addition to regular compression and local therapy, has a favorable effect on the healing of venous ulcers.
| Materials and Methods|| |
This was a prospective observational study at a single tertiary care center, where we evaluated the effect of PGE1 intravenous infusion in the healing time of venous ulcers of the lower limbs without complications in 47 patients.
Patients – patients who had proven venous ulcers of the legs both, clinically and sonologically, which are not healing for more than 3 months with conventional therapy either surgical or endovenous along with compression therapy were included in the study. Patients were between 27 and 78 years old.
Other indications for inclusion being,
- Ulcers that extend through the epidermis but not through the muscle, tendon, or bone
- Ulcer between 0.5 and 60 cm2 postdebridement
- An Ankle-Brachial Index (ABI) not <0.75 for both limbs and
- No contraindications for the use of PGE1.
- Noncompliant to compression therapy
- Ulcer with clinical signs of severe infection, significant necrotic tissue, osteomyelitis, bone, tendon, or capsule exposure
- Surgical intervention for varicose veins or sclerotherapy or endovenous laser/radiofrequency therapy within the last 6 months.
In patients with bilateral limb ulcers, each limb was considered separately and included. In Patients having multiple ulcers, only the largest ulcer which was separated from other ulcers by at least 2 cm was considered to be the target ulcer. The total study duration was 18 weeks among which ulcers were assessed for the efficacy of the treatment by measuring the ulcer area once in every 3 weeks till 18 weeks.
All patients were initially evaluated with color Doppler of the leg to determine venous etiology of the ulcer and were admitted with proper consent after basic laboratory investigations and baseline 2D Echo. Baseline ulcer measurements were recorded. PGE1, 500 μg in 1 ml, was diluted with 4 ml of normal saline and divided equally into five 100 ml normal saline bottles. Infusion of the prostaglandin was titrated at 10 ml/h over 10 h per day. During the infusion therapy, patients were closely monitored with hourly recording of blood pressures and pulse rate.
Education regarding leg elevation, wound care, and venous disease was provided for each patient. Standard care of ulcers was done with four-layer compression bandages and if necessary, wound debridement and antibiotics according to culture sensitivity. The four-layer dressings were applied for a maximum of 1 week. Dressings were changed more frequently in cases with excessive ulcer drainage. Once the ulcer healed, patients were given knee-high class II graded compression stockings.
The protocol was approved by the ethics committee, and all patients gave informed consent.
Measurement and outcomes
Ulcer measurements were done with the help of contour sheets [Figure 1], planimetry performed to obtain ulcer area at intervals of 0, 21, 42, 63, 84, 105, and 126 days (3, 6, 9, 12, 15, and 18 weeks). During each visit, assessment of ulcer was done with measurement of size and evaluated for any evidence of infection.
The outcome was the percentage of the ulcers healed at the end of the 126-day observation period and the referred time of healing. The reduction in the extension of the ulcers from the baseline measurement to the last observation was also evaluated.
Data were statistically described in terms of mean, frequencies (number of cases), and percentages when appropriate. Nonparametric data were evaluated using median as measure of the center of the distribution. The Chi-square square test and Fisher's exact test were used to compare differences between proportions as and when required. P < 0.05 was considered statistically significant. Time to recovery was evaluated with the life table analysis for cumulative ulcer healing over time. All statistical calculations and graphical representations were done using computer programs SPSS (Statistical Package for the Social Science; SPSS Inc., Chicago, IL, USA) version 20 and Microsoft Excel for Office 365 (Microsoft Corporation, NY, USA).
| Results|| |
During the study period, from January 2016 to December 2017, a total of 49 patients were included in the study. Four patients had bilateral ulcers, hence a total of 53 limbs were included. Among these, one patient was lost to follow-up, while another was not compliant. Thus, the effective number of patients was 47 with 50 limb ulcers.
The minimum age among the patients was 27, maximum being 78, while the mean age was 55.95 years. 17% (8) of the patients were female. Hypertension was seen in 53% (25) of patients and diabetes was seen in 45% (21) of patients. Other comorbidities such as ischemic heart disease, hypothyroidism, and cerebrovascular attack history were seen in 17% (8) of patients. 25.5% (12) patients had no comorbidities. Baseline characteristics have been summarized in [Table 1].
Ulcer as the lone primary complaint was seen in 10 (21%) patients. Along with nonhealing ulcer as the chief complaint, 79% (37) of patients presented with pain and 26% (12) with itching. 25% of patients had undergone some form of varicose vein intervention in the past either open surgery or laser/radiofrequency ablation. 60% of patients had not undergone any surgery in the past. One patient had previous femoropopliteal bypass surgery with presently normal ABI.
Initial Doppler studies showed deep venous reflux in 12% of limbs, 62% limbs had superficial reflux, and 66% had perforator incompetence. Details of Doppler results are given in [Table 2].
The largest ulcer area included in the study was 56 cm2, while the smallest ulcer was 6 cm2. At the end of the study, area of the largest ulcer remaining was 11.9 cm2. The smallest ulcer healed at 21 days. The initial average ulcer area was 24.38 cm2 (ranging from 6 to 56 cm2). At the initial examination, 22 ulcers (44%) measured ≤20 cm2 and 28 ulcers (56%) were >20 cm2 in size [Table 3]. The mean ulcer area at different time frames has been summarized in [Chart 1]. Some clinical pictures of different ulcers at various stages of healing have been provided [Figure 2], [Figure 3], [Figure 4].
A total of 50 limbs were followed up with four-layer compression bandages after administration of PGE1 and regular measurements of the ulcer area done at each follow-up. A progressive reduction in extension of ulcerated wounds was observed; 50% of ulcers healed 9 weeks after PGE1 administration and 92% healed after 18 weeks of treatment. The only factor to independently affect healing time on multivariate analysis was found to be initial ulcer size. Of the 22 ulcers with size ≤20 cm2 at initial presentation, 95% healed at the end of 12 weeks, whereas only 57% of ulcers with size >20 cm2 healed at the same duration [Chart 2]. Ulcers that were ≤20 cm2 at initial presentation healed significantly faster (100% at 15 weeks) than ulcers larger than 20 cm2 (68% at 15 weeks) [Chart 2]. The life table analysis shows that estimated healing time of 25%, 50%, and 75% for the patients treated with PGE1 was 40, 63, and 86 days, respectively [Chart 3]. This compared to the previous studies with compression therapy alone was statistically significant (Fisher exact test statistic value is 0.0006 with P < 0.05).,
The incidence of adverse events was 4.25% (2/47). There were no major adversities with PGE1 administration. Two patients developed minor symptoms, in the form of hypotension and tachycardia, which were managed with stoppage of infusion for short duration. Thereafter, restarting the infusion with close monitoring of vitals.
| Discussion|| |
PGE1 (alprostadil) is a naturally-occurring prostaglandin which is shown to result in improved blood flow. Its uses inthe medical field are in the treatment of erectile dysfunction, maintaining the patency of the ductus arteriosus in babies with congenital heart defects till cardiac surgery can be performed and in critical limb ischemia with nonreconstructable disease. PGE1 was isolated in 1957 and approved for medical use in the United States in 1981.
The method of action of prostaglandin is not well defined in the published trials. Probable actions are thought to be due to small vessel dilatation and augmented blood flow in the capillaries, increased fibrinolytic activity, reduction of white cell activation, effects on reducing platelet aggregation, and adherence to endothelium.
PGE1 also decreases the peripheral arterial resistance without causing significant changes in myocardial contractility or mean systemic arterial pressure. It has been shown to cause bronchodilation, inhibit platelet aggregation, and mediate in the inflammatory process. PGE1 increases blood flows markedly and decreases peripheral resistances in the brachial, femoral, carotid, and renal arteries without any significant change in mean systemic arterial pressure and myocardial contractile force. PGE1 has potent direct vasodilator action on all peripheral vascular beds which induces the multiple effects mentioned and indirectly through reflex sympathetic stimulation. These can cause profound physiological effects at very dilute concentrations as the molecules are extremely potent. Some of the adverse effects which have been observed are apnea, bleeding, bradycardia, cardiac arrest, congestive heart failure, disseminated intravascular coagulation, fever, flushing, hypotension, prolonged erection, seizures, supraventricular tachycardia, tachycardia, and ventricular fibrillation.
In a randomized, placebo-controlled, single-blind study on the efficacy of PGE1 in purely venous ulcers conducted by Milio et al., 75% of VLUs treated with PGE1 healed by 72 days, whereas it took 108 days with only compression which was statistically significant. 100% of the PGE1 treated ulcers healed in <100 days and concluded that PGE1 is effective in reducing the healing time of venous ulcers.
Rudofsky, demonstrated in a double-blind controlled study, a complete healing of 40% of “resisting” ulcers in patients treated with PGE1 versus 9% in patients on placebo.
De Caridi et al. showed that the reduction in the size of the mixed ulcers was faster in the patients treated with PGE1, 100% of the ulcers healed in <100 days, whereas in the placebo group, only 84.2% did so by the end of the 120-day observation period (P < 0.05).
In a study conducted by Marston et al. regarding healing rates of venous ulcers with compression therapy, it was shown that the average healing time for 75% of ulcers were 112 days and also showed that it took 21 weeks for healing 50% for ulcers larger than 20 cm2 area.
In our study, patients with venous ulcers were treated with PGE1 administration along with regular compression therapy. Doppler study was used to ensure that only patients with pure venous ulcers were included. The 4-month observation time was sufficiently long enough to assess the long-term effects., Our study demonstrates that treatment with PGE1 is effective in hastening the healing of VLUs. This treatment caused a quicker healing, which took place for 92% of ulcers in <126 days. [Table 4] gives the percentage of ulcers healed at different times compared with compression alone therapy in other studies. Estimated healing time for 75% of ulcers was 86 days in PGE1-treated group in our study compared to 112 days for regular compression therapy in the study by Marston et al. which was statistically significant (P < 0.05). This data are in accordance with those reported by Rudofsky and Milio et al. By augmentation of healing of VLUs by administration of PGE1, the mental and financial burdens of patient along with the prolonged ritual of four-layer dressing were significantly reduced.
Many theories explain the mode of action of PGE1 but how they hasten the healing of venous ulcers is yet to be proven. PGE1 has a very brief half-life of about 30s; its clinical efficacy persists well beyond its period of administration. Studies have postulated that the prolonged efficacy is related to one of its metabolites, PGE-0, that provides a longer half-life., On the other hand, the explanation could be found in the numerous actions of PGE1 explained earlier. Furthermore, such effect could also be related to local improvement in microcirculation as suggested by Rudofsky.
Even if treatment with PGE1 involves a cost, the faster healing of ulcers reduces the duration of hospitalization, and it improves the quality of life of patients who are mostly young individuals. The reduction in healing times should produce positive socioeconomic benefits, but more studies performing a cost–benefit analysis are required for verification.
The main drawback of the study was that we could not directly compare the ulcer healing with a control group of the same population. More patients could not be enrolled mostly because of financial issues.
| Conclusion|| |
The use of PGE1 in critical limb ischemia with nonreconstructable diseases is well recognized but is yet to be proven in venous ulcers. The data from our study show the effectiveness of PGE1 in reducing the healing time of VLUs, thereby allowing patients for lesser hospitalization and quicker return to work and life producing improvement in the quality of life. The adverse effects were also very minor with PGE1 treatment, overall, acceptable and were well tolerated by the patients, but the safety of drug has to be confirmed with larger studies and analysis. In conclusion, in patients affected by venous ulcers of the lower limbs, the intravenous infusion of PGE1 improves healing and microcirculation, and it should be proposed for difficult-to-heal ulcers of the lower limbs.
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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]