Safety aspect of intraoperative,local urokinase lysis in patients with acute lower limb ischemia

1. Introduction

Acute lower limb ischemia (ALI) is a limb- and life-threatening condition caused by thrombotic and/or embolic occlusion of peripheral vessels. Urgent treatment is needed to avoid prolonged hospitalization, major limb amputation and/or death of patients, who are often critically ill. Limb loss occurs in about 10–70% of all ALI cases in one year, depending on Rutherford class [1]. Mortality following ALI reaches up to 15% [1].Treatment options include intra-arterial catheter-directed thrombolysis (CDT), percutaneous mechanical thrombectomy (PMT), surgical thrombectomy or a combination of mechanical techniques and lysis, depending on clinical presentation and resources of the vascular centre.

High technical success can be achieved by CDT (79.3% in a review including 10 articles with 1249 patients) [2]. 88.5% of treated patients survived without amputation within 30 days [2]. The drawback is the risk of severe systemic or intracranial bleeding. Major life-threatening complications occur in up to 22.9% of the cases, and death within 30 days in up to 4.2% [2]. Nevertheless, overall mortality after endovascular revascularization is lower compared to surgically treated patients (5.4% versus 13.2% at 30 days) [3]. Urokinase or recombinant tissue plasminogen activator (rtPA, alteplase) are common thrombolytic agents for the treatment of occluded vessels. The approved indications for urokinase are peripheral artery thrombosis, deep vein thrombosis, pulmonary embolism, thrombosed arteriovenous fistula, and thrombosed central venous catheter. In contrast, alteplase is approved for myocardial infarction, pulmonary embolism, and stroke. Literature describes a similar major amputation rate for both agents, but a lower incidence of complications (major and intracerebral haemorrhage and mortality) for urokinase compared to rtPA [4, 5]. Patients with Rutherford class IIb or III at high risk of amputation are excluded from most CDT protocols or the use of low dose thrombolytic agents because they need urgent revascularization [6]. Possible treatment options for these patients are accelerated CDT [6], PMT [1, 7] or surgical thrombectomy.

The surgical procedure is highly effective (90.7%), especially in patients presenting with failed bypass grafts (95.0%) [3]. Amputation rates are comparable to endovascular revascularization (19.6% versus 13.0% at 1 year) [3]. Patients with occluded outflow tract after the surgical thrombectomy –and, therefore, at a remaining risk of major amputation –continue to be a challenge. Therapeutic option for these patients is the intraoperative, local application of thrombolytics directly into the best outflow vessel.

The purpose of the present single-centre registry analysis was to assess the safety and efficacy of intraoperative, local urokinase lysis for patients with ALI and occluded outflow tract after the initial surgical thrombectomy. The incidence of minor and major bleeding, intracranial and fatal bleeding, as well as the effect of local lysis, major limb amputation rate, and amputation-free survival were investigated.

2. Patients and methods

2.3 Operative procedures

All patients had direct and/or indirect (Fogarty technique) surgical thrombectomy of the occluded native artery or bypass graft. The affected vessels were native arteries in 69 out of 115 legs (60%), vein grafts in 25/115 legs (22%), and prosthetic bypass grafts in 21/115 legs (18%). Additional patch angioplasty was performed in 38/115 procedures (33%), graft replacement in 23/115 (20%), balloon/stent angioplasty in 23/115 (20%), and local endarterectomy in 14/115 procedures (12%). Surgical treatment of acute compartment syndrome was necessary in 22/115 legs (19%).

In this study, all patients had a persistent distal occlusion of all crural and/or pedal arteries and ab-sent pedal collateralization after the surgical procedure documented by intraoperative angiography (Fig. 1A). Intraoperative urokinase (medac GmbH, Wedel, Germany) was fractionally administered directly into the best outflow vessels for at least 30 minutes. These were the anterior tibial artery in 45/115 cases, the peroneal artery in 44/115 cases, the posterior tibial artery in 40/115 cases, and the tra-ctus tibiofibularis in 20/115 cases.

OPEN IN VIEWER

Fig. 1

Angiographic examples of occluded crural vessel after surgical thrombectomy (A) and improved crural collateralization after intraoperative urokinase lysis (B). ATA: Anterior tibial artery, PA: Peroneal artery, PTA: Posterior tibial artery.

Overall urokinase dose was defined by the attending surgeon based on the individual bleeding risk and ischemic manifestation. Altogether, 10,000–50,000 IE urokinase were applied in 32/115 legs (28%), 60 000 –100 000 IE urokinase in 69/115 legs (60%), and 110,000–250,000 IE urokinase in 14/115 legs (12%). Most frequent dose was 100,000 IE in 51/115 legs (44%). Mean administered urokinase dose was 85,000±45,000 IE. The efficacy of intraoperative urokinase lysis was documented by angiography. Complete restoration of peripheral blood supply was defined as “at least one open crural artery to the foot and visible pedal collaterals”, improved blood supply as “visible crural collateralization and visible pedal collaterals” (Fig. 1B), and failing lysis effect as “no improvement of peripheral blood supply and no visible pedal collaterals”.

3. Results

3.1 Efficacy of treatment

The efficacy of intraoperative urokinase lysis was documented by angiography. The complete restoration of at least one run-off vessel to the foot was reached in 74/115 legs (64%), and improved collateralization in 39/115 legs (34%, Fig. 1B). Lysis completely failed in 2/115 legs (2%).

The 30-day rate for major amputations above ankle was 12% (14/115), and overall major amputation rate was 27% (31/115). The amputation rate within 30 days did not significantly differ between male and female, diabetics and non-diabetics, and patients with different degrees of chronic kidney disease (Table 2). Rutherford class of ALI at presentation affected the amputation rate during follow-up. Within the first 30 days, major amputation was performed in 2/35 legs (6%) of class IIa, 5/30 legs (17%) of class IIb, 4/27 legs (15%) of class III, and 3/23 legs (13%) of patients with acute-on-chronic ischemia. Overall, major amputations were carried out in 4/35 legs (11%) of patients with initial Rutherford class IIa, in 6/30 legs (20%) of patients with initial class IIb, and in 10/27 legs (37%) of patients with initial Rutherford class III. Patients with acute-on-chronic ischemia suffered from major amputation in 11/23 legs (48%) altogether. Patients with Rutherford IIa had a statistically better limb salvage compared to all other groups (p < 0.05).

OPEN IN VIEWER

Table 2

Major amputation rate of treated patient cases (n = 115)

	Number (%)	Number (%)	p
	Male (n = 75)	Female (n = 40)
Overall	25 (33.3)	6 (15.0)	<0.05
-Within 30 days	10 (13.3)	4 (10.0)	ns
	Diabetics (n = 44)	Non-diabetics (n = 71)
Overall	12 (27.3)	19 (26.8)	ns
-Within 30 days	8 (18.2)	6 (8.5)	ns
	CKD 3–5 (n = 30)	CKD 1-2/no CKD (n = 85)
Overall	9 (30.0)	22 (25.9)	ns
-Within 30 days	5 (16.7)	9 (10.6)	ns

CKD, chronic kidney disease; ns, not significant.

Amputation-free survival was 82% after 30 days, 58% after one year, and 41% after five years (Fig. 2A). The 30-day mortality in the treatment group turned out to be 14%. There was a statistically significant difference of overall survival between patients requiring major amputation and patients with limb salvage (Fig. 2B). Survival rate of patients with major amputation was 65% after 30 days and 51% after one year. Patients with limb salvage survived in 91% after 30 days and 79% after one year (p < 0.05, Fig. 2B).

OPEN IN VIEWER

Fig. 2

Kaplan-Meier analysis of amputation-free survival (A) and overall survival (B) of patients with limb salvage (group 1) and with major amputation (group 2). Difference between group 1 and group 2 is statistically significant (p < 0.05). ds:days, y: year, ys: years.

Acute limb ischemia has a high risk of major amputation and death. Surgical revascularization for ALI has several advantages. It can be promptly performed, allows immediate therapeutic heparinization, and, if successful, completely restores blood supply to the ischemic limb [9]. Intraoperative imaging after surgical thrombectomy is necessary to detect vascular lesions that can cause arterial re-occlusion [10]. Patients with an occluded outflow tract after surgical thrombectomy have a pending risk of major amputation. Intra-arterial application of thrombolytic agents directly into the best outflow vessel can improve collateralization and reopen crural or pedal arteries. However, it is not a standard procedure [11]. Large studies addressing the safety and efficacy of intraoperative, local lysis are lacking.

Alternative treatment as the intra-arterial CDT is well-accepted for acute lower limb ischemia due to the occlusion of native arteries, stents or bypass grafts [12, 13] with a good short- and long-term clinical outcome [13]. Overall mortality compared to surgically treated patients is low with 5.4% versus 13.2% at 30 days [3]. In a large review, amputation-free survival was reported to be 88.5% within 30 days [2]. For an Asian population, amputation-free survival turned out to be 81% within 30 days and 63% within 1 year [14].

However, the benefit of catheter-directed thrombolysis is limited by severe haemorrhagic complications [2] such as systemic or intracranial bleeding. In 2018, a review of 10 articles included 1249 patients and 1361 lower extremities treated for ALI [2]. The overall technical success rate was 79.3%. Complications occurred in 28.7%. Only 20.1% of the reported complications were classified as minor, with 79.9% constituting major, life-threatening complications [2]. For an Asian population, the occurrence of bleeding after CDT was described in 12% of patients. 6% of these events were classified as major. In-hospital mortality was 6% [14]. A retrospective analysis of prospective databases from two vascular centres using rtPA reported 749 CDT procedures. The reported complications were: bleeding in 30.3%, blood transfusion in 13.9%, intracranial fatal bleeding in 0.4%, and death within 30 days in 4.4% [15]. Preoperative severe ischemia with motor deficit was the only independent risk factor for major bleeding [15]. Plasma fibrinogen level has been suggested as a predictor of haemorrhagic complications, but the predictive value has not been proven so far [16].

Three different prospective randomized controlled studies in 1994 and 1996 compared thrombolysis with surgical treatment [1]: the Rochester study [17], the STILE trial [18, 19], and the TOPAS trial [20, 21], favouring CDT as first-line line therapy for ALI unless there are absolute CDT contraindications [1]. In 2018, these results were confirmed by the database of the Swedish Vascular Registry (Swedvasc) demonstrating lower mortality and better amputation-free survival after endovascular treatment compared to primary surgical revascularization at 30 days and at one year [22]. A large Cochrane meta-analysis from the same year found no evidence in favour of either initial thrombolysis or primary surgery as the preferred option in terms of limb salvage, amputation, or death [23]. With low-quality evidence, thrombolysis might be associated with a higher risk of haemorrhagic complications and distal embolization [23]. Therefore, individual decision is necessary in each case [23].

Urokinase and rtPA are two common thrombolytic agents. Also, urokinase seems to have an additional effect on rheological blood properties as viscosity and red cell aggregability [24]. A large literature review of 2004 focused on the risk of complications after urokinase versus rtPA thrombolytic treatment of peripheral arterial occlusions. Overall, 48 studies (22 with urokinase, 22 with rtPA, and 4 with both agents) were identified in the English literature between 1985 and 2002, encompassing 2226 urokinase- and 1927 rtPA-treated patients [4]. The major amputation rate was similar for both treatment groups, constituting 7.9% for the use of urokinase and 7.2% for the rtPA use [4]. Interestingly, the incidence of major haemorrhage varied widely, but overall rate was significantly lower among urokinase- compared to rtPA-treated patients (6.2% and 8.4% respectively). The overall incidence of intracranial haemorrhage was 0.4% after urokinase treatment and 1.1% after rtPA treatment. Transfusions were needed by 11.1% of patients in the urokinase group, and 16.1% in the rtPA-group. Mortality rate after the application of urokinase was 3.0% compared to 5.6% after rtPA. All these variations were statistically significant. Thus, urokinase appears associated with a lower bleeding incidence than rtPA [4].

Most intra-arterial CDT protocols recommend treatment with low dose thrombolytic agents excluding patients in need of urgent revascularisation [6]. Accelerated thrombolysis with rtPA is an interventional alternative. Protocol describes application of 10 mg rtPA for 30 minutes followed by a 3-hour course of continuous intra-arterial 10 mg/hour rtPA infusion and unfractionated heparin [6]. In this study, satisfactory lysis was achieved in 90.2% with a major amputation rate of 10.3% within 1 months [6]. Complications developed in 22%, mostly puncture site hematoma (9.8%) [6]. Percutaneous mechanical thrombectomy –e.g. using the Rotarex^® device –can restore blood flow faster and at one session without potentially life-threatening bleeding complications or the need for observation in an intensive care unit [1, 7]. However, due to the catheter size, crural arteries lie outside the scope of application [7]. Further techniques for ALI treatment are manual aspiration thrombectomy, rheolytic thrombectomy (AngioJet^®), or aspiration thrombectomy (Aspirex^®, ThromCat XT^®, Indigo^®, MegaVac^®) [9]. Tenecteplase and Reteplase as third-generation plasminogen activators might have superior efficacy and safety profiles. Conclusive data for ALI are not yet available [9].

This registry analysis includes a cohort of 107 critically ill patients with 115 ischemic legs treated by surgical thrombectomy and intraoperative, local urokinase lysis. Half of all patients in this analysis presented with an advanced ALI of Rutherford class IIb (26%) and III (24%). With the combined ther-apy of surgical thrombectomy, revascularisation and intraoperative urokinase-lysis, amputation-free survival was possible in 82% at 30 days, 58% at one, and 41% at five years. A large randomized, multi-centre trial of 1998 with 544 patients comparing vascular surgery with catheter-directed urokinase-thrombolysis reported an amputation-free survival of 83.5–88.6 at discharge, 71.8–74.8% at six months and 65.0–69.9% at one year. Of all patients, 47–53% had a sensory deficit and 23–28% a motor deficit before treatment [21]. A matched cohort analysis of the Swedish Vascular Registry of 2018 with 6730 patients with ALI < 14 days who underwent open surgery or endovascular treatment included about 43% of patients with Rutherford IIb and 0.2% with Rutherford III. Amputation-free survival in this cohort was 82.1–84.8% at 30 days and 61.6–65.7% at one year [22].

Major bleeding was low, occurring only in 4/115 treated patient cases (3.5%). One of these patients died as a consequence of intraabdominal and pulmonary haemorrhage. Intracranial bleeding was not found in our study group.

The key limitation of the study is the fact that the registry analysis used non-randomized data of a single-centre patient cohort with only one treatment modality. Its greatest strength is the large number of patients treated for ALI with surgical thrombectomy and intraoperative urokinase lysis for occluded outflow tract over a long period. All procedures were performed by four experienced vascular surgeons.

5. Conclusion

Patients with acute limb ischemia are at high risk for major amputation and death. The efficacy of catheter-directed thrombolysis is well-proven, but the treatment with low dose thrombolytic agents excludes patients in need of urgent revascularisation and is associated with complications (mainly haemorrhages) and potential distal embolization. Surgical thrombectomy can be promptly performed in an urgent setting and enables the direct application of thrombolytic agents if distal vessel occlusions and thus the risk of major amputation persist. In our experience, intraoperative urokinase lysis is safe, causing low major and intracranial bleeding. It can be offered to all patients undergoing emergency surgery for severe ischaemia when surgical restoration of the outflow tract fails.