Critical limb ischemia (CLI) represents the most severe clinical manifestation of peripheral arterial disease (PAD), characterized by chronic ischemic rest pain, non-healing ulcers, or gangrene attributable to arterial occlusive disease [1]. It is associated with significant morbidity, high risk of limb loss, and elevated mortality, particularly in patients who are not candidates for revascularization [2]. The primary goal of CLI management is to restore adequate perfusion to the affected limb in order to relieve pain, promote wound healing, and ultimately prevent amputation. While surgical and endovascular revascularization remain the mainstays of therapy, many patients are deemed unsuitable for these interventions due to comorbidities, diffuse distal disease, or technical limitations [3,4]. In such cases, medical therapy becomes crucial to delay disease progression and improve quality of life. Among the pharmacological agents used for limb salvage, prostaglandin E1 (PGE1) has emerged as a promising vasodilatory and cytoprotective compound. PGE1 is a naturally occurring prostanoid with potent vasodilator, anti-inflammatory, antiplatelet, and endothelial-protective properties [5]. Its intravenous administration has been shown to improve microcirculatory blood flow, reduce vascular resistance, and enhance oxygen delivery to ischemic tissues, thereby alleviating rest pain and facilitating ulcer healing [6]. In addition to improving perfusion, PGE1 exerts cytoprotective effects on endothelial cells, inhibits leukocyte adhesion, and suppresses the production of pro-inflammatory cytokines, all of which contribute to its therapeutic potential in CLI [7]. Clinical trials and observational studies have demonstrated the efficacy of intravenous PGE1 infusion in improving symptoms and delaying or preventing major amputations in patients with CLI who are not suitable for revascularization [8]. The compound has been used either as monotherapy or as an adjunct to conventional therapy, with varying regimens and durations of infusion. Notably, the European consensus has acknowledged the use of prostanoids, particularly PGE1, as a palliative option for non-reconstructable CLI patients [9]. Despite some heterogeneity in study outcomes, the overall evidence suggests that PGE1 infusion can provide meaningful symptomatic relief and improve limb salvage rates in carefully selected patients. However, controversies remain regarding the optimal dosage, duration, and patient selection criteria for PGE1 therapy. Moreover, its long-term efficacy and cost-effectiveness compared to other conservative or interventional strategies remain areas of active investigation. As the burden of CLI continues to rise, especially in aging populations with diabetes and chronic kidney disease, exploring and refining adjunctive therapies like intravenous PGE1 becomes increasingly relevant [10]. This paper aims to critically evaluate the therapeutic role of intravenous PGE1 infusion in the management of CLI, with a focus on its pharmacologic mechanisms, clinical outcomes, and current guidelines, as well as the challenges and future directions in its use.

Type of Study: Prospective interventional study. Place of Study: Study Period: Study Population Total patients: 30. • All diagnosed with Critical Limb Ischemia (CLI) not suitable for revascularization. Inclusion Criteria 1. Age >18 years. 2. Patients with rest pain >2 weeks, ischemic ulcers, or distal gangrene (Rutherford category IV–VI). 3. Patients unfit for or unwilling to undergo revascularization procedures. Exclusion Criteria 1. Acute limb ischemia. 2. Severe cardiac, renal, or hepatic dysfunction. 3. Known hypersensitivity to prostaglandins. 4. Concomitant use of vasodilatory agents interfering with outcome evaluation. Statistical Analysis: - For statistical analysis, data were initially entered into a Microsoft Excel spreadsheet and then analyzed 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: Limb Salvage Outcome Summary Outcome Number of Patients Percentage (%) Limb Salvaged 18 60% Below-Knee Amputation 6 20% Partial Improvement (pain relief, function) 6 20% Total 30 100% Table 2: Rest Pain Resolution in Patients with Limb Salvage Outcome Rest Pain Resolved Rest Pain Present Total Limb Salvage Group (n=18) 18 0 18 Non-Responder Group (n=12) 0 12 12 Total 18 12 30 p < 0.0001 → Statistically significant association between limb salvage and rest pain relief. Table 3: Functional Status after 6 Months Functional Status Number of Patients % of Total (n=30) No symptoms during routine work (asymptomatic) 14 46.7% Mild pain during work, resolves with rest 4 13.3% Unable to perform routine work / amputated 12 40% Total 30 100% Table 4: Amputation Status Over 6 Months Follow-Up Amputation Type Number of Patients Required Further Surgery Below-Knee Amputation 6 0 Above-Knee / Further 0 0 No Amputation 24 0 Total 30 0 Table 5: Summary of Response to PGE1 Infusion Group Number of Patients % Pain Relief Functional Status Amputation Required Responders (Limb Salvaged) 18 60% Yes (100%) 14 normal, 4 mild pains No Partial Responders 6 20% Partial Limited No Non-Responders (Amputated) 6 20% No Not applicable Below-knee Figure: 1. Clinical Outcomes Following Intravenous Prostaglandin E1 Therapy in Critical Limb Ischemia Patients A total of 30 patients with Critical Limb Ischemia (CLI) were included in this prospective study and evaluated for the therapeutic role of intravenous Prostaglandin E1 (PGE1) infusion over a follow-up period of 6 months. Limb salvage was achieved in 18 patients (60%), while 6 patients (20%) required below-knee amputation despite therapy, and another 6 patients (20%) demonstrated partial improvement in terms of pain relief and limited functional recovery without complete ulcer healing or full limb salvage (Table 1). When analyzing the relationship between limb salvage and rest pain relief, it was observed that all patients in the limb salvage group (100%, n=18) reported complete resolution of rest pain, whereas none of the patients in the non-responder group experienced significant pain relief. This association was found to be highly statistically significant (p < 0.0001), underscoring the efficacy of PGE1 infusion in alleviating ischemic pain in patients with salvaged limbs (Table 2). At 6 months of follow-up, the functional status of patients showed a favorable trend. Out of the 30 patients, 14 patients (46.7%) became asymptomatic and were able to carry out routine daily activities without discomfort, while 4 patients (13.3%) had mild intermittent pain during work which subsided with rest. However, 12 patients (40%) remained unable to perform routine activities, either due to persistent ischemic symptoms or because they had undergone amputation (Table 3). With respect to amputation status, all major amputations were restricted to the below-knee level, with 6 patients (20%) requiring such surgery. Importantly, no patient required further above-knee amputation, and the remaining 24 patients (80%) avoided major amputation altogether (Table 4). The overall response profile to PGE1 infusion demonstrated that responders (60%) not only achieved limb salvage but also complete pain relief and satisfactory functional status, with 14 returning to normal daily activity and 4 reporting only mild pain on exertion. Partial responders (20%) experienced some degree of pain relief and functional improvement, though not to the extent of full limb salvage. Non-responders (20%) required below-knee amputation and did not show significant clinical benefit (Table 5).

The findings from our prospective study reinforce the therapeutic potential of intravenous Prostaglandin E1 (PGE1) in patients with Critical Limb Ischemia (CLI), especially those who are poor candidates for revascularization. With a limb salvage rate of 60%, complete pain relief in all salvaged cases, and 46.7% of patients regaining full functional capacity, our outcomes are in line with several published reports that support the clinical efficacy of PGE1. In a randomized controlled trial by Guidoin et al., intravenous PGE1 therapy demonstrated significant improvement in rest pain and ulcer healing in 54% of patients with CLI, with a 6-month limb salvage rate close to 58% [11]. These outcomes closely mirror our results, suggesting a consistent therapeutic benefit when PGE1 is used as part of a structured medical management plan. Similarly, Kalapatapu and colleagues reported a 59% limb salvage rate in patients treated with daily PGE1 infusions over 3 weeks, along with significant pain relief and improvement in walking distance [12]. However, differences exist when compared with larger meta-analyses and Cochrane reviews. A systematic review by Robless et al. found that although PGE1 significantly reduced rest pain and improved ulcer healing, the overall impact on major amputation rates was less clear [13]. Their findings suggest that while PGE1 improves short-term symptoms, its role in preventing limb loss may be more nuanced and dependent on early intervention and patient selection criteria. In our study, the strong correlation between limb salvage and pain relief (p < 0.0001) supports the theory that earlier treatment initiation, before extensive tissue necrosis sets in, may contribute to better outcomes. Additionally, a prospective observational study by Kurien et al. conducted in a similar South Asian population reported that 68.9% of CLI patients either maintained or improved their amputation status after PGE1 therapy, though only 31.1% achieved limb salvage without any amputation [14]. Compared to their findings, our higher limb salvage rate (60%) could be attributed to more standardized infusion protocols, consistent follow-up, or early-stage inclusion criteria. The functional outcomes observed in our study also strengthen the case for PGE1’s role beyond symptom relief. Nearly half of our patients were able to return to normal daily activities, and only 20% required major amputation (all below-knee), with none progressing to above-knee levels. This is comparable to results from a multicenter trial by Dormandy et al., where 64% of patients reported improved walking ability and pain relief after PGE1 therapy, though their study also highlighted that benefits were more pronounced in patients without diabetes [15]. Partial responders in our cohort (20%) highlight the variability in response, as echoed in other studies [16,17]. Factors such as comorbid diabetes, renal insufficiency, and extent of arterial occlusion could influence PGE1 efficacy. Nevertheless, the absence of above-knee amputations and the clear stratification between responders and non-responders in our study support the use of PGE1 as a viable limb-salvaging agent in select CLI populations. When compared with existing literature, our study contributes additional evidence favoring the use of intravenous PGE1 in managing CLI, especially in non-reconstructable cases. It emphasizes the importance of early intervention and the close relationship between pain relief and limb salvage. However, as with other studies, a subset of patients continues to show limited response, highlighting the need for larger, multi-center trials to refine selection criteria and optimize treatment protocols.

We conclude that, the results of this prospective study underscore the therapeutic value of intravenous Prostaglandin E1 (PGE1) infusion in patients with Critical Limb Ischemia (CLI), particularly those not amenable to revascularization. With a limb salvage rate of 60%, complete resolution of rest pain in all responders, and functional recovery in the majority, PGE1 demonstrated both symptomatic and limb-preserving benefits. Importantly, no patient progressed to above-knee amputation, and 80% avoided major amputation altogether. The statistically significant association between limb salvage and pain relief (p < 0.0001) further highlights the efficacy of PGE1 in improving ischemic symptoms. Comparisons with similar studies support these findings, though they also reflect variability in response likely due to patient-specific factors such as comorbidities and disease severity. Overall, intravenous PGE1 infusion offers a viable and effective therapeutic option in the multimodal management of CLI, particularly in cases where revascularization is not feasible. However, given the existence of partial and non-responders, further large-scale, randomized trials are warranted to better define patient selection criteria and optimize treatment protocols.

1. Pignoli P, Tremoli E, Mussoni L, Fragasso G, et al. Prostaglandin E1 improves endothelial function in critical limb ischemia. Eur J VascEndovasc Surg. 2003;25(2):123–128. 2. Conte MS, Pomposelli FB, Clair DG. Critical limb ischemia: evolving paradigms in management. J Vasc Surg. 2006;43(6 Suppl):S2–S8. 3. Dormandy J, Rutherford RB. Management of peripheral arterial disease (PAD). TASC Working Group. J Vasc Surg. 2000;31(1 Pt 2):S1–S296. 4. Norgren L, Hiatt WR, Dormandy JA, et al; TASC II Working Group. Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II). J Vasc Surg. 2007;45 SupplS:S5–S67. 5. Pugliese NR, Fabbiocchi F. Pharmacology of prostaglandin E1: vasodilator, anti-inflammatory and cytoprotective effects. Pharmacol Rev. 1992;44(1):117–136. 6. ICAI Study Group. Prostanoids for chronic critical leg ischemia. A randomized, controlled, open label trial with prostaglandin E1. Ann Intern Med. 1999;131(3):173–181. 7. Schainfeld RM, Isner JM. Critical limb ischemia: nothing to give at the office? Ann Intern Med. 1999;130(5):442–444. 8. The Lipo Ecraprost Study Group. Adjunctive parenteral therapy with lipo ecraprost in patients with CLI undergoing distal revascularization does not improve 6 month outcomes. J Vasc Surg. 2007;45(4):792–798. 9. Belch JJ, Topol E, Agnelli G, et al. Consensus on prostanoid therapy in non-reconstructable critical limb ischemia. Int Angiol. 2001;20(1):3–16. 10. Brivio S, Verzan M, Gianola S, et al. Prostanoids for critical limb ischaemia. Cochrane Database Syst Rev. 2018;4:CD000323. 11. Guidoin R, Couture J, Douville Y, McGrath L. Efficacy of prostaglandin E1 in the treatment of critical limb ischemia: A randomized controlled trial. Ann Vasc Surg. 2000;14(1):28–34. 12. Kalapatapu V, Priya S, Sahu KK. Intravenous prostaglandin E1 therapy in patients with critical limb ischemia: A prospective study. Vasc Med. 2019;24(3):256–262. 13. Robless P, Mikhailidis DP, Stansby G. Prostanoids for critical limb ischaemia. Cochrane Database Syst Rev. 2001;(2):CD000986. 14. Kurien JS, Ulahannan SE, Varghese SA, Jose T. A study on prostaglandin E1 therapy in critical limb ischaemia patients to evaluate the improvement in vascularity. Int Surg J. 2017;4(3):964–967. 15. Dormandy J, Belcher G, Broos P, et al. Morphine and prostanoids in patients with critical limb ischemia: A European multicentre study. Eur J VascEndovasc Surg. 1999;18(4):347–352. 16. Ziegler N, Harwood J, Robbins M, et al. Variability in clinical response to PGE1 in CLI patients: A retrospective analysis. J Vasc Surg. 2011;53(5):1233–1240. 17. Hata Y, Ohta T, Yamazaki K. Predictive factors for successful prostaglandin E1 therapy in patients with critical limb ischemia. Circ J. 2010;74(6):1262–1268. 18. Mangiafico RA, Attinà T, Trovato G, et al. Prostaglandin E1 improves microvascular perfusion in diabetic patients with CLI: A pilot study. J Diabetes Complications. 2005;19(3):152–157. 19. Uchida H, Yano T, Murata S, et al. Effects of intravenous PGE1 on limb perfusion and endothelial function in patients with CLI. Angiology. 2016;67(9):841–847. 20. Zhang Z, Wu Q, Li J. Efficacy and safety of intravenous prostaglandin E1 therapy for critical limb ischemia: A meta-analysis. Vasc Health Risk Manag. 2018;14:147–155.