Intra-Arterial Contrast-Enhanced Ultrasound for Transcatheter Thrombolysis in Post-Transplant Hepatic Artery Thrombosis: A Preliminary Study

Introduction

Liver transplantation is commonly performed in malignant hepatic tumors and end-stage liver diseases [1–3]. Vascular complications after liver transplantations are often of significant concern, as they can jeopardize the blood supply to the newly transplanted liver [4]. Among them, hepatic artery thrombosis is the most common and severe vascular complication, with an incidence ranging from 2% to 9% [5,6]. Failure to promptly and effectively manage hepatic artery thrombosis could result in biliary complications, hepatic infarction, liver abscess, and, in severe cases, graft loss and recipient death [7].

Early diagnosis and appropriate treatment measures could significantly improve the prognosis of the recipients [7]. Historically, revisional surgery, including thrombectomy and reanastomosis, served as the main treatment strategy. Re-transplantation becomes an alternative when revision fails. However, this approach was often limited by donor shortage and the overall physical states of the patient [8–10]. Over the past decades, endovascular interventional therapies became an alternative for those patients. The effectiveness and safety of catheter-based endovascular intervention therapy have been verified, and the therapy has even replaced surgical procedures for the first choice in selected cases [9,11,12]. Transcatheter arterial thrombolysis involves the placement of a catheter into the corresponding hepatic artery under the guidance of digital subtraction angiography (DSA) for continuous thrombolysis. It has advantages such as high selectivity, low drug dosage, high local drug concentration, and minimal impact on systemic coagulation function [9,11]. The technical success rate of thrombolysis could reach up to 80% [13,14], making it a viable alternative for graft salvage.

The thrombolysis process requires continuous monitoring with DSA, which can present with several limitations: repeated exposure to radiation, infeasibility of bedside execution, and the inability to assess overall liver perfusion. Compared with DSA and computed tomography (CT) angiography, contrast-enhanced ultrasound (CEUS) is radiation-free and repeatable, can be performed bedside, and can be used for assessing liver perfusion. In addition, the ultrasound contrast agent, sulfur hexafluoride microbubbles, are excreted by breathing in a few minutes, which is especially suitable for patients with hepatic or renal insufficiency. Some studies have reported that CEUS allows for the diagnosis of hepatic artery thrombosis [15,16] and reduces the use of invasive imaging methods [17]. To date, there have been no studies on the use of intra-arterial contrast-enhanced ultrasound (IA-CEUS) for evaluating the efficacy of hepatic artery thrombolysis. In this study, we aim to describe the value of IA-CEUS on monitoring transcatheter hepatic artery thrombolysis by presenting a series of cases.

Material and Methods

This study was approved by the institutional review board of our hospital, and all enrolled patients signed written informed consent forms.

A total of 468 cases of orthotopic liver transplantation were performed from November 2016 to May 2023. Color Doppler ultrasound was used for follow-up of the liver transplant recipients in the postoperative period. Once the hepatic artery blood flow was not detected, a DSA or CT angiography examination was conducted immediately to verify whether hepatic artery thrombosis developed. A total of 22 patients developed hepatic artery thrombosis after the surgery. Of these patients, 8 patients (7 men and 1 women, aged from 28 to 69 years, with average age of 44 years) underwent continuous transcatheter-based thrombolysis through the hepatic artery and were monitored using IA-CEUS. Six patients developed early postoperative hepatic artery thrombosis (within 1 month after the surgery), and 2 developed late postoperative hepatic artery thrombosis (more than 1 month after the surgery). All liver grafts were obtained from brain-dead donors.

The Mindray Resona7 ultrasound diagnostic system was used, along with the SC5-1U convex array transducer, with frequency of 3.5 to 5.0 MHz. IA-CEUS was performed with a mechanical index set between 0.04 and 0.12. The contrast agent used was a sulfur hexafluoride microbubble (SonoVue, Bracco, Italy), which was diluted with 5 mL of 0.9% sodium solution and thoroughly shaken to form a suspension.

The patients were placed in a supine position on the DSA examination table. With routine electrocardiographic monitoring, the femoral artery was punctured using the Seldinger technique. After successful puncture, a guidewire and vascular sheath were inserted. Guided by the guidewire, a 5F Yashiro or hepatic artery catheter was introduced into the celiac trunk or the vessel opening of the hepatic artery-anastomosis. Contrast agent was injected to perform angiography and accurately locate the hepatic artery thrombus. Then, urokinase was administered through the catheter for thrombolysis, with a pump rate of 100 000 units/10 min, and a maximum dose of up to 300 000 units during the procedure. Continuous infusion was given to maintain thrombolysis, with a total urokinase dose not exceeding 1 200 000 units within 24 h. The duration of thrombolysis did not exceed 7 days.

All IA-CEUS examinations were conducted at the bedside by an ultrasound physician (NingBo Zhao), who has more than 5 years of experience in liver IA-CEUS and interpretation of the results. Prior to IA-CEUS, a 2-dimensional ultrasound and color Doppler ultrasound examination was performed to assess liver parenchyma, portal and hepatic arterial blood flow, and spectra. A mixture of contrast agent suspension and 0.9% saline solution in a ratio of 1: 49 was prepared. Then, 3 mL of the mixture was injected by continuous injection through the catheter. The dynamic contrast-enhanced images videos were stored for 5 min. The observations included hepatic artery and liver parenchymal perfusion, as well as the position of the catheter tip. DSA was used as the reference standard. All patients were monitored using IA-CEUS during continuous intra-arterial thrombolysis, The initial IA-CEUS examination was performed 6 h after thrombolysis, followed by subsequent examinations every 6 h until the catheter was removed. DSA examinations were performed 24 h before catheter removal to verify the result of IA-CEUS.

Results

Among the 8 patients with hepatic artery thrombosis confirmed by DSA, 6 patients were asymptomatic and received a diagnosis during routine follow-up; 1 patient required hepatic artery balloon dilation, due to low hepatic arterial blood flow, and subsequently developed hepatic artery thrombosis; and 1 patient developed hepatic artery thrombosis after the splenic artery embolization procedure, due to splenic artery steal syndrome.

Thrombosis in 6 patients occurred near the anastomosis of the hepatic artery, and 2 occurred in the right hepatic artery away from the anastomosis. The duration of thrombolysis ranged from 1 to 7 days. After continuous thrombolysis treatment (3 patients also received arterial stent placement, due to poor thrombolysis effect), thrombolysis was successful in 6 patients and showed hepatic artery perfusion within 1 to 2 s after contrast agent injection (Figure 1). Thrombolysis was ineffective in 2 patients and showed no hepatic artery perfusion over time; therefore, the vascular reconstruction surgery was conducted. In all cases, IA-CEUS showed a decrease in enhancement of the hepatic parenchyma in the hepatic artery supply region. In the 2 patients with thrombolysis failure, most hepatic segments showed no enhancement during the arterial phase, with small enhanced areas by the liver collateral artery blood supplies. Three patients formed biloma with non-enhancement, of which 2 were confirmed by surgery, and 1 by puncture drainage fluid (Figure 2).

Two patients experienced catheter-related complications. In 1 patient, IA-CEUS showed peeling intima in the dilated hepatic artery and the true and false lumen. DSA confirmed the development of a dissecting aneurysm. In the other patient, IA-CEUS showed a pseudo-aneurysm adjacent to the hepatic artery, with the catheter displacement in the pseudo-aneurysm (Figure 3). One patient experienced thrombolysis-related spontaneous bleeding, resulting in a retroperitoneal hematoma. No serious bleeding complications, such as intracranial hemorrhage were observed in the patients. Also, there were no ultrasound contrast agent-related complications (Tables 1, 2).

Discussion

In this study, we described the efficacy and safety of a new method of IA-CEUS for the dynamic monitoring of intra-arterial thrombolysis in patients with hepatic artery thrombosis after liver transplantation.

Color Doppler ultrasound is the most commonly used method for vascular monitoring after liver transplantation. Hepatic artery thrombosis appears as a loss of hepatic arterial flow on Doppler ultrasound. However, this could be influenced by operator experience, equipment quality, and patient conditions, resulting in unreliable results [18]. CEUS uses the nonlinear effects and backscatter properties of microbubbles in the sonic field to enhance the contrast between tissues and blood flow, thereby enabling clearer visualization of blood perfusion. Compared with Doppler ultrasound, CEUS is more sensitive and accurate in blood vessel visualizing and vascular-related lesion detection [15]. The contrast agent used in this study, SonoVue, is a pure blood-pool contrast agent that does not extravasate into the extravascular space and is primarily composed of sulfur hexafluoride microbubbles, which provide a duration of approximately 8 min of continuous enhancement in the liver. IA-CEUS is a non-radiating procedure that could be performed bedside and allows for repeated injections, making it particularly suitable for the dynamic monitoring of the therapeutic effect of hepatic artery thrombolysis. Moschouris et al [19] and Lekht et al [20] reported that IA-CEUS can effectively display the blood supply arteries of hepatocellular carcinoma, improving the accuracy of selective arterial embolization. It could also predict the prognosis by assessing changes in microvascular perfusion before and after transarterial chemoembolization of hepatocellular carcinoma [21,22].

In our study, IA-CEUS successfully evaluated vascular patency in 8 patients after hepatic artery thrombolysis. Additionally, IA-CEUS demonstrated positive diagnostic performance in monitoring vascular complications. Bleeding is the most common complication of thrombolysis, with an incidence of approximately 20% [23]. In cases with bleeding complications, IA-CEUS can assist clinical doctors in adjusting the dosage by dynamically monitoring the hematomas. In the present study, 1 patient developed a retroperitoneal hematoma, which was considered to be spontaneous bleeding caused by coagulation dysfunction rather than hepatic artery hemorrhage. Studies have shown that iatrogenic pseudoaneurysms are associated with vascular wall damage of invasive procedures [24–26], with an incidence of rupture ranging from 21% to 80% in iatrogenic cases [27]. One patient developed a pseudoaneurysm with catheter displacement, which was directly related to the vascular wall damage of the catheter. Dynamic monitoring with IA-CEUS could detect pseudoaneurysms promptly, enabling quick intervention. One patient developed hepatic artery dissection, likely caused by intravascular intimal dissection during the intervention, which could increase the risk of postoperative hepatic artery stenosis and thrombosis, potentially leading to graft failure. Early detection by IA-CEUS dynamic monitoring and proactive intervention can help prevent the occurrence of serious complications.

IA-CEUS can also show hepatic parenchymal perfusion [28], in addition to hepatic artery thrombosis-related liver complications. In this study, IA-CEUS detected ischemic areas in the liver for all patients, which were manifested as hypoenhancement of the liver supplied by the hepatic artery [18]. Three of the patients developed biloma, one of the most severe complications related to bile ducts. Biloma could be a result of ischemia and necrosis of intrahepatic bile ducts, which is attributed to the accumulation and encapsulation of bile within the liver. In the case of concurrent infection, liver abscesses can form and require drainage treatment [18,28].

The preliminary results showed the feasibility and safety of using IA-CEUS for the dynamic assessment of the efficacy and complications of intra-arterial hepatic artery thrombolysis. However, there were also some limitations of IA-CEUS, which is highly operator-dependent. Also, IA-CEUS could not provide comprehensive image information, like that of CT and magnetic resonance imaging. Therefore, in some cases, IA-CEUS might not provide sufficient diagnostic information. To date, no previous reports have described the application of IA-CEUS specifically for the dynamic evaluation of intra-arterial hepatic artery thrombolysis. IA-CEUS using the catheter approach enables highly selective CEUS imaging, avoiding repeated exposures to radiation for patients during thrombolysis and additional invasive procedures, such as intravenous injections.

The present study had several limitations. First, this was a small-sample, descriptive, and single-center study, without comparison with other imaging modalities in validating the efficacy of IA-CEUS. Additional prospective, multicenter studies are needed to confirm the results and compare them with other imaging methods. Second, IA-CEUS describes hepatic artery thrombolysis efficacy based on vessel patency or occlusion, without assessing the partial reperfusion of the hepatic artery, which requires further investigated. Finally, this technique relies on the placement of a catheter in the hepatic artery, which is inherently invasive, making it potentially more suitable for the dynamic monitoring of arterial interventional therapy rather than screening for hepatic artery diseases in routine clinical practice.

Conclusions

IA-CEUS is a novel and effective method for the assessment of continuous transcatheter arterial thrombolysis for post-liver transplant hepatic artery thrombosis.