1. Introduction
Visceral artery pseudoaneurysms (VAPs) are critical vascular abnormalities originating from the splanchnic circulation, often attributed to inflammatory, infectious, traumatic, iatrogenic, and neoplastic etiologies [
1,
2]. Distinguishing them from true aneurysms, pseudoaneurysms arise from the disruption of the intimal and medial layers of the arterial wall, lacking an epithelized wall structure [
3]. Pseudoaneurysms pose a significant risk to patient health and survival [
1,
2].
Accurate pre-procedural imaging is crucial to assess the anatomy of the pseudoaneurysm, its relationship with surrounding structures, and to plan the endovascular intervention [
4,
5]. It should be noted that there are no studies specifically designed to identify the best imaging work-up for VAP. However, some reviews suggest that CT-angiography (CTA) is preferred over other imaging methods, both in an emergency and in an election fashion, because of its high accuracy, low invasiveness, and ease of performance [
6,
7,
8,
9]. Ultrasonography frequently serves as the primary diagnostic modality, capable of incidentally identifying sizeable pseudoaneurysms that are superficially located or within solid organs such as the liver and spleen [
4,
10]. The utilization of MR-angiography (MRA) for VAP detection is infrequent due to limitations such as inapplicability in hemodynamically unstable patients, extended scan durations, elevated costs, and lower spatial resolution compared to CTA. Nonetheless, the absence of ionizing radiation and the availability of non-contrast techniques confer certain advantages to MRA [
4,
6,
11]. In exceptional cases, digital subtraction angiography (DSA) may be warranted in the identification of a VAP when there is a strong clinical suspicion and non-invasive imaging modalities such as CTA yield unremarkable findings [
12].
Treatment of VAPs is always indicated regardless of its diameters, as their risk of rupture is significantly higher than that of visceral artery aneurysms (VAAs) [
13,
14,
15]. VAPs ruptured at a substantially greater incidence than VAAs (76.3% vs. 3.1%), according to an investigation on 233 individuals by Pitton et al. [
16]. Visceral pseudoaneurysms with and without rupture did not differ significantly in size, and the rupture event is not reliably predicted by diameter [
16]. Compared to 30% of VAAs, 80% of VAPs were symptomatic upon presentation according to a series by Tulsyan et al. [
17]. Therefore, treatment of VAPs is recommended as soon as possible [
15].
Traditionally, surgical intervention has been the primary approach for addressing pseudoaneurysms [
13,
15]. Nevertheless, the invasiveness of surgery and its associated complications have led to a shift in favor of radiological interventions as the initial treatment of choice. Radiological interventions offer the advantages of minimally invasive procedures, demonstrating notable success rates and minimal complication rates [
10,
13,
15,
18,
19]. Endovascular treatment has become the preferred method for the management of VAPs in many cases, as it allows the pseudoaneurysm to be excluded from the arterial circulation, thus preventing its rupture and associated complications [
15].
However, there are still some unanswered questions and ongoing research in this field. Firstly, there is a lack of consensus regarding the optimal endovascular technique (e.g., coil embolization, liquid embolic agents, stent grafts) as it depends on various factors, including the size, location, and morphology of the pseudoaneurysm, as well as the patient's overall health condition [
12]. Further studies are needed to evaluate the efficacy of different techniques and identify patient-specific factors that influence treatment selection. Secondly, there is a need for further investigation into the potential complications associated with endovascular repair of VAPs, such as stent graft migration, infection, endoleaks, visceral ischemia, and long-term vascular complications [
15]. Understanding these risks and implementing strategies to minimize adverse events are essential for optimizing patient outcomes. Thirdly, a paucity of studies focused exclusively on reporting data regarding pseudoaneurysms, and the available studies exhibited limited sample sizes [
13,
20].
In this context, the purpose of the study was to retrospectively evaluate the efficacy and safety of endovascular treatment of visceral pseudoaneurysms using Ethylene-Vinyl Alcohol (EVOH) Copolymer-Based Non-Adhesive Liquid Embolic Agents (NALEAs). Data were collected exclusively on patients with VAPs, discarding cases of endovascular treatment of VAAs.
4. Discussion
Visceral pseudoaneurysms form a heterogeneous category due to their occurrence in diverse arterial locations and their association with a range of etiologies [
15,
22]. The etiology of VAP recognizes a few main causes, including trauma, iatrogenic procedures (e.g., biopsies, percutaneous nephrolithotomy, surgery, radiation therapy, etc.), and medical conditions (e.g., acute pancreatitis, tumors, abscesses, etc.) [
13,
14]. The majority of the studies available in the literature include a mixed population comprising both VAAs and VAPs, thus introducing an additional source of data heterogeneity given their distinct pathological conditions [
13]. Besides, the assessment of outcomes in endovascular treatment is further complicated by the presence of studies in which various endovascular techniques were employed, but the outcomes were not differentiated based on the specific technique used [
22,
39,
40]. It would be desirable to have outcome data specific to each technique in order to conduct comparative evaluations among homogeneous patient groups according to the site and etiology of the VAP.
Endovascular treatment aims to effectively exclude the VAP from the systemic circulation [
6]. Nagaraja et al. conducted one of the few comparative assessments between surgery and angioembolization for the treatment of hepatic artery pseudoaneurysms, concluding that both techniques are effective. However, they found that endovascular treatment offers faster hemostasis, reduced transfusion requirements, and shorter hospital stays [
41]. The choice of endovascular technique and embolic agent relies on several factors, including the size of the pseudoaneurysm sac and neck, the expendability of the parent artery, the presence of terminal or collateral circulation, the feasibility of superselective catheterization of the pseudoaneurysm considering vessel tortuosity and hostile anatomy, the availability of adequate landing zones for a covered stent, the patient's coagulation status, and the operator's preferences [
12,
42,
43].
Deliberate parent artery sacrifice is generally considered in cases of end-arteries (e.g., intraparenchymal renal pseudoaneurysm) or when the presence of collateral circulations minimizes the risk of end-organ ischemia. Fascinatingly, the study conducted by Nagaraja et al. provided evidence that the occlusion of the common hepatic artery is generally well-tolerated when treating VAP in patients with preserved liver function. This favorable tolerance is attributed to the phenomenon of flow reversal in the gastroduodenal artery and the hypertrophy of branches originating from the inferior phrenic artery [
41,
44]. In the presence of collateral circulation (e.g., splenic, hepatic and gastroduodenal VAPs), the sandwich embolization of afferent and efferent vessels is essential to achieve effective embolization, thus preventing backdoor bleeding [
6]. Conversely, in the case of end-arteries (e.g., renal circulation), proximal embolization of the afferent artery alone proved to be effective [
45,
46]. Liquid embolics may allow to avoid direct negotiation of the pseudoaneurysm sac; however, they are associated with a risk of non-target embolization. In such situations, in addition to adjusting the density of the liquid embolic, it is possible to employ the sandwich technique by pre-embolizing the outflow with coils to minimize the risk of unintentional leakage of the liquid embolic [
6,
19,
47,
48].
When intentional parent artery sacrifice is not indicated, it is necessary to exclude the VAP from the circulation while preserving the patency of the parent artery [
6,
12]. The task can be accomplished through selective embolization of the pseudoaneurysm sac using coils, vascular plugs, or liquid embolics such as NALEA or n-butyl cyanoacrylate (NBCA) [
49]. Unlike coils, liquid embolics can avoid exerting radial force on the sac, but they carry a higher risk of reflux and non-target embolization [
19,
47]. In some cases of wide neck, stent-assisted or balloon-remodelling techniques can be employed to provide a scaffold for safer delivery of the embolic agent [
4,
6]. Finally, in the presence of adequate landing zones, the pseudoaneurysm can be excluded while preserving patency of the parent artery through the deployment of a covered stent [
50,
51]. The successful placement of stent grafts is often impeded by the small size or tortuous nature of numerous visceral arteries, leading to a restricted range of stent graft options available [
52]. Recently, the use of multi-layered flow-diverting stents has emerged in the treatment of true visceral aneurysms due to their ability to induce flow stagnation and subsequent thrombosis within the sac while preserving the patency of the parent artery and any collateral branches originating from the segment covered by the stent [
53]. However, evidence regarding their use in visceral pseudoaneurysms is limited, as thrombosis requires time to occur, whereas the risk of imminent rupture remains substantial [
12,
54,
55].
This study aims to mitigate the data heterogeneity prevalent in the literature by presenting the outcomes of endovascular treatment specifically for VAPs managed by embolization with EVOH-copolymer based NALEAs. The efficacy endpoints in the present series are comparable to those in other research, although the frequent case mix in previous reports (i.e., VAAs/VAPs, endovascular/surgical treatments, parent artery sacrifice/preservation, various embolic agents) makes comparative evaluation difficult. Evidence on endovascular treatment of VAPs using EVOH Copolymer-Based NALEAs is poor and often limited to mixed reports involving visceral true aneurysms and pseudoaneurysms [
56]. Ghoneim et al. reported the outcomes of the endovascular management of 15 renal arterial pseudoaneurysms following partial nephrectomy. They achieved an 80% clinical success rate with coils embolization technique [
20]. In their mixed cohort of 33 VAAs/VAPs, Regus et al. treated with coils embolization technique 2 splenic artery VAPs, 2 hepatic artery VAPs and 2 pancreaticoduodenal artery VAPs, achieving a 100% technical success rate. Interestingly, the average diameter of ruptured VAPs was found to be 2 cm, whereas non-ruptured VAPs measured 3.5 cm on average [
14]. In a recent investigation by Zabicki et al. on 15 pancreatitis-related pseudoaneurysms, coil embolization was conducted in five patients, while one patient received treatment with a stent graft. Liquid embolic agents were utilized in seven cases, with thrombin injection being employed in five patients and Squid in two patients. A combination of techniques was employed in two patients. A technical success rate of 93.3% and a reintervention rate of 6.7% were noted [
39]. Balderi et al. examined the short- and medium-term outcomes of endovascular repair of 31 VAAs/VAPs using coils (84%), multilayer stents (9.5%), and a combination of coils with either vascular plug or covered stent (6.5%). Successful immediate exclusion of VAAs/VAPs was achieved in all instances, indicating a 100% technical success rate. However, one patient with a coeliac axis pseudoaneurysm succumbed to renewed hemorrhage and passed away 10 days following the procedure, resulting in a 3% 30-day bleeding-related mortality rate [
40]. Fankhauser presented the results of percutaneous endovascular treatment in a large cohort of patients with visceral artery aneurysms (66 cases, 36%) and pseudoaneurysms (119 cases, 64%). In the majority of cases, specifically 144 instances (78%), the exclusive interventional approach involved the utilization of endovascular coiling. Furthermore, in 10 cases (5%), the sole technique employed was the placement of a covered stent to exclude the vascular lesion from circulation. A 98% technical success rate, a 97% clinical success rate, and a 3.4% 30-day bleeding-related mortality rate were noticed [
22]. In their investigation on endovascular treatment of 22 VAAs and 7 VAPs, Laganà et al. reported a 100% technical success rate and a 10.3% reintervention rate [
57]. Recently, Gong et al. reported a 40% mortality rate for pseudoaneurysms; all patients who died had ruptured VAPs. This finding differs from other evidence probably because of the extremely small sample size (i.e., only 5 VAPs included in the study) [
52]. Roberts et al. treated 48 patients with hemorrhaging coeliac or mesenteric artery aneurysms (6%) and pseudoaneurysms (94%); they highlighted a 91.7% technical success rate and a 6.25% 30-day bleeding-related mortality, thus demonstrating the efficacy of endovascular treatment even in cases of bleeding ruptured VAPs [
58]. Therefore, endovascular treatment of both ruptured and non-ruptured visceral pseudoaneurysms using EVOH-copolymer-based non-adhesive liquid embolic agents (NALEAs) has comparable efficacy to other embolic agents, as demonstrated by literature review, and can be a valuable tool, especially in certain clinical scenarios where the unique characteristics of NALEAs offer particular advantages.
Firstly, the unique flow characteristics resembling molten magma facilitate the transportation of the embolic agent through narrow arteries, enabling successful embolization of targets located at considerable distances from the microcatheter tip [
59,
60]. In contrast, the efficacy of coil embolization is diminished when dealing with small-caliber vessels that are challenging to catheterize, and it is less effective in controlling backdoor bleeding stemmed from collateral circulation if the efferent vessels is not embolized [
61,
62]. Secondly, EVOH-based NALEAs ensure a secure, swift, and efficient embolization process through polymerization, thereby accomplishing mechanical embolization without necessitating coagulation activation. This property is particularly advantageous in patients with coagulation disorders, as supported by previous studies [
59,
60,
63]. Intriguingly, coil embolization exhibits reduced efficacy in individuals with coagulopathy, while liquid embolics do not appear to encounter this limitation [
27,
64,
65,
66,
67,
68,
69]. Thirdly, in the study conducted by Khalil et al., it was recommended that EVOH be prioritized for embolization procedures involving compromised blood vessels. This preference stems from the fact that EVOH is capable of deployment without exerting radial pressure on the vessel walls, in contrast to coils and vascular plugs that have the potential to cause rupture in fragile vessels [
23].
Repeated endovascular treatment, surgery, percutaneous or endoscopic embolization are the main options if the first-line endovascular therapy fails [
58]. If the endovascular management is the first-line therapy, surgery will be needed in less than 5% of cases [
58]. Roberts et al. reported a 17% reintervention rate [
58]. The underlying causes for the endovascular treatment failure were diverse, yet they predominantly fell into two discernible categories: either the radiological access to the VAP was unsuccessful or the initial attempts at hemorrhage control failed. In instances where radiological access proved unsuccessful, alternative methods such as percutaneous embolization or surgical repair were employed to attain effective control. Conversely, in cases where initial attempts at hemorrhage control failed, it was deemed reasonable to make repeated efforts utilizing the endovascular management, as this approach yielded satisfactory results in half of such instances. A major cause of bleeding control failure is ineffective hemostasis with coils [
58]. In our study we observed a very low reintervention rate, may be due to the effectiveness of NALEAs in patients with coagulopathy.
In this study, endovascular embolization using EVOH-copolymer-based NALEAs has been proven to be a safe treatment for both ruptured and unruptured pseudoaneurysms. Other reports on endovascular management of VAPs have shown comparable data. Ghoneim et al. reported a 13.3% procedure-related complication rate in their series on endovascular management with coils embolization of 15 renal arterial pseudoaneurysms following partial nephrectomy [
20]. In their cohort of 7 VAPs treated with coils embolization technique (5 patients) or surgery (2 patients), Regus et al. recorded a 14.3% procedure-related complication rate due to a case of bleeding [
14]. In a recent investigation by Zabicki et al. on 15 pancreatitis-related pseudoaneurysms treated various techniques including coils embolization, stent graft, and liquid embolic agents, a 13.3% procedure-related complication rate was noted (two cases of splenic ischemia requiring splenectomy) [
39]. End-organ ischemia is one of the most feared complications. Balderi et al. observed splenic ischemia in 50% of patients treated for splenic VAAs/VAPs and renal infarction in 75% of patients with renal artery VAPs. However, the evidence agrees that the practical consequences of end-organ ischemia are often minimal; in the series by Balderi et al. only 1 case (3.2%) required surgical treatment (splenectomy) [
40]. Similarly, Fankhauser et al. showed 25 cases (13.5%) of splenic or hepatic infarction, but only one case required hepaticojejunostomy for bile duct ischemia; furthermore, a 7.3% VASC rate was noticed [
22]. In their investigation on endovascular treatment of 22 VAAs and 7 VAPs, Laganà et al. reported a 27.6% procedure-related complication rate with 7 cases of splenic infarction out of 8 cases of complications [
57]. Roberts et al. demonstrated the safety of endovascular treatment even in cases of bleeding ruptured VAPs, highlighting a 6.1% procedure-related complication rate [
58]. Furthermore, the safety results of our report, including vascular access site complications, align with previous studies conducted on endovascular treatments and transcatheter arterial embolization [
70,
71,
72,
73,
74,
75,
76,
77,
78,
79,
80,
81,
82]. Finally, this retrospective multicenter study provides further evidence supporting the safety and efficacy of endovascular embolization using EVOH-copolymer-based non-adhesive liquid embolic agents (NALEAs) for the management of visceral pseudoaneurysms. These findings also extend to patients with ruptured visceral pseudoaneurysms, highlighting the suitability of this treatment approach in such cases.
However, it is important to acknowledge several limitations associated with EVOH-based non-adhesive liquid embolic agents (NALEAs). Firstly, it is necessary to shake the mixture containing EVOH and tantalum powder vigorously for a duration of 20 minutes to make the embolic agent for use. Consequently, this may limit its application in time-sensitive scenarios [
72,
83,
84]. At our institute, we have successfully tackled this concern by instructing staff to initiate shaking of the vials with a Vortex shaking mixer upon activating the catheterization lab for an angioembolization. Secondly, dimethyl sulfoxide (DMSO) requires the use of a DMSO-compatible microcatheter and exhibits toxicity towards blood vessels, resulting in vasospasm, pain, and the occurrence of atypical reflexes like the trigeminocardiac reflex [
48,
85,
86,
87,
88]. Thirdly, the addition of tantalum powder to EVOH-based NALEAs enhances radiopacity, facilitating visibility during the embolization procedure; however, it can introduce beam hardening artifacts in subsequent CT examinations. To address this issue, both Onyx and Squid offer reduced tantalum formulations known as Onyx L and Squid LD, respectively, which minimize the occurrence of beam hardening artifacts [
89,
90].
Some limitations of the study should be noted. The extensive length of the follow-up period instills confidence that our investigation has captured the majority of recurrences or treatment-related complications. However, it is important to acknowledge that the possibility of unreported complications, recurrences, or even fatalities cannot be completely ruled out. Notably, Guillon et al. observed no cases of long-term recurrence in their own study [
91]. The implementation of a multicenter registry would allow to collect data prospectively and to be able to carry out comparative evaluations for homogeneous groups taking into account etiology, comorbidities, endovascular technique and embolic agent used. The retrospective nature of the analysis weakens the study also because some cases may have been missed, although we believe this hypothesis unlikely given the research carried out using the radiological electronic database present in all participating centers.
Author Contributions
Conceptualization, R.M. and D.L.; methodology, G.G. and A.S.; software, M.V.; validation, R.M., D.L., F.F., M.V., F.P., A.C., G.G., M.S., A.S., D.C., N.I., Raffaele Serra, Rita Santoro, P.G., L.B. and MGJRT; formal analysis, A.C. and F.P.; investigation, Raffaele Serra, D.C. and N.I.; resources, P.G.; data curation, D.L.; writing—original draft preparation, R.M., D.L., F.F., M.V., F.P., A.C., G.G., M.S., A.S., D.C., N.I., Raffaele Serra, Rita Santoro, P.G., L.B. and MGJRT; writing—review and editing, L.B. and MGJRT; visualization, R.M., D.L., F.F., M.V., F.P., A.C., G.G., M.S., A.S., D.C., N.I., Raffaele Serra, Rita Santoro, P.G., L.B. and MGJRT; supervision, D.L. All authors have read and agreed to the published version of the manuscript.