Acute limb ischemia (ALI) is one of the most hazardous medical conditions from the vascular surgeons’ point of view, which necessitates immediate action  The symptoms are due to rapid decrease of blood supply to muscles, nerves, and skin without any chance for neovascularization. Urgent diagnosis and treatment with revascularization are necessary to maintain limb viability. Despite the progress in the treatment, there is no special test for the diagnosis, which is mainly clinical, and if it was mistaken or delayed, the consequences would be amputation with increased rate of mortality . Thrombosis or embolism in the arteries supplying the limb are suggested to be the most common two causes of ALI.
The literature revealed presence of many ways for treatment of ALI. These ways include open thrombectomy, catheter-directed thrombolysis, catheter-directed thrombus aspiration, and pharmacomechanical thrombolysis . The degree of ischemia is the main determinant of the procedure to be used for the treatment. In severe ALI, both urgent surgical thrombectomy and pharmacomechanical thrombolysis could be used in combination, whereas catheter-directed thrombolysis could be used in mild to moderate ALI or in patients with other comorbidities and relatively contraindicated for general anesthesia .
Rutherford et al.  had provided guidelines for classification of ALI in general. They classified it into three categories: stage I, in which the limb is still viable with audible limb’s arteries and veins; stage II, in which the limb is threatened; and stage III, in which irreversible limb ischemia occurs. Furthermore, stage II was subdivided in two stages: stage IIa associated with mild symptom included sensory symptoms, and in stage IIb, the symptoms included pain and sensory and motor symptoms with the necessity of urgent interference .
Thrombolysis was revealed to be beneficial in viable limbs or even marginally threatened limbs (stages I and IIa) and if the stent or graft was occluded by thrombus within 2 weeks. Thrombolysis as a treatment for ALI was developed more than 20 years ago with Surgery vs. Thrombolysis for Ischemia of the Lower Extremity (STILE)  and Thrombolysis or Peripheral Arterial Surgery (TOPAS)  trials. Since then, there was a challenge among vascular surgeons regarding choosing appropriate treatment for each type and stage of peripheral limb ischemia and develop new modalities for the treatment. Owing to the presence of comorbidities, the all-endovascular procedure could be helpful in patients with ALI . Owing to the emergency presentation of the patients, thrombolysis could be an effective treatment option with technical success of about 80% as shown in the literature . However, there was similar results with surgical thrombectomy. Therefore, we aimed to investigate the outcomes of thrombolysis in the treatment of ALI and the factors that cause failure of this treatment.
Patients and methods
This was a retrospective observational study in which the archived files of eligible patients who came to our hospital and underwent thrombolysis from 2008 till 2019 were reviewed for data analysis.
The study was approved by the Institutional Review Board of Faculty of Medicine, Al-Azhar University, and an informed written consent was obtained from all participants. The study was conducted in accordance with Helsinki standards as revised in 2013.
Adult patients aged 18–60 years old with ALI and who underwent thrombolysis were included in the study. On the contrary, patients with known hypercoagulable states, patients who underwent thrombolysis for a limb with aortic endograft, patients with a history of thrombolysis in the same limb or contralateral one, or patients with contraindications of thrombolytic therapy were excluded from the study.
Rather than the demographic variables, preoperative extracted variables were the risk factors and comorbidities, symptoms, and signs, in addition to the procedure performed. Rutherford classification was applied for all patients. Thrombolysis was considered as the index procedure until the removal of the catheter. Thrombolysis was performed using a multi-side-hole AngioJet catheter with continuous infusion of tissue plasminogen activator (rt-PA, Actilysew; Boehringer-Ingelheim GmbH, Ingelheim, Germany) with dosage of 25 mg as a bolus dosage followed by subsequent continuous infusion with a rate equal to 0.5 mg/h. This continuous infusion was stopped after complete lysis of the thrombus, occurrence of major complications, or after 2 days of infusion. During the infusion, angiogram was performed every 12 h for each patient, and the catheter was repositioned if needed.
Having the target segment eligible for treatment, patients were classified into patients with native artery, patients with stent, patients with vein bypass, and patients with prosthetic bypass. Technical failure was defined as conversion from thrombolysis to surgical thrombectomy, revision, bypass segment, or amputations.
The primarily assessed outcomes were primary and secondary potency, overall survival, and amputation-free survival (AFS). The secondary outcomes were conversion to surgery, reintervention within the first month, and amputation within the first month. Any endovascular procedure that was conducted on the ipsilateral limb was considered as reintervention. The patency of the occluded segment was assessed, and its data were extracted from the patients’ file regardless of the reintervention.
Statistical analysis was conducted using SPSS platform for Windows version 23 (SPSS Inc., Chicago, Illinois, USA). The sample size was calculated using MedCalc software version 15.2.2 (MedCalc Software, Mariakerke, Belgium) using the mean duration of the primary patency of the artery published in previous studies  and putting the power as 80% and alpha value as 5%. Continuous data were presented as mean and SD or median and range according to the normality, whereas categorical data were presented as median and range. Preoperative data and intraoperative data were analyzed using analysis of variance with either Mann–Whitney or Wilcoxon test after descriptive statistics as described. Primary and secondary outcomes were analyzed using Kaplan–Meier curve and Cox regression model. The level of significance was considered when the P value was less than 0.05.
The revision of achieved files revealed that 49 patients fulfilled the eligibility criteria. Among these patients, 34 were males, with a mean of age of 54.9±3.61 years. Having the risk factors, 41 patients were hypertensive, 27 patients were hyperlipidemic, 23 were diabetic, 25 with coronary artery disease, 36 were smokers, and six had chronic renal insufficiency. Table 1 reveals the demographic characteristics of the included patients.
Having the Rutherford classification, 25 patients were class I, 20 were class IIa, two were class IIb, and two patients were class III. The mean gap between start of symptoms and the thrombolysis was 3.1±12.9 days. Having the affected limb, 33 patients had lower limb ischemia (seven cases were bilateral) and 16 cases had upper limb ischemia. Regarding the treated segment, 40.8% of the patients were treated for affected native artery, 20.4% were treated for affected stent, 32.6% were treated for prosthetic bypass, and 6.1% were treated for vein bypass. In ∼8.1% of the patients, the thrombolysis was performed for vein bypass. Having the culprit lesion, it was present in aortoiliac segment in 4.08% of the patients, present in femoropopliteal segment in 18.36% of the patients, tibial segment in 44.89% of the patients, axillary segment in 8.16% of the patients, brachial segment in 6.12% of the patients, and ulnar segment in 12.24% of the patients (Table 2).
The mean time of thrombolysis was 1.79±0.79 days, with a mean rate of infusion of 0.63±0.21 mg/h. Only thrombolysis was conducted for 24 patients, whereas 25 patients received additional procedures including angioplasty, aspiration thrombectomy, stenting, or pulse-spray thrombectomy (Table 2).
A total of 15 patients with thrombolysis were subjected to conversion to surgery (Table 3). Bypass, embolectomy, and endarterectomy were included in the surgery options that were performed. Conversion was defined as failure of thrombolysis and preparation of surgery within 1 month after thrombolysis. Within 1 month after technically successful thrombolysis, reintervention occurred for three patients and major amputation occurred for other three patients. In addition, major complications that occurred preoperatively for three patients were myocardial infarction, hemorrhage, and stroke, and death occurred in two patients.
The mean follow-up period was 32.4±29.1 months. The primary patency in the first year of follow-up was 38%, whereas in the second year, it was 26%, and in the third year, it was 22%. The primary patency was conserved in the native artery for 20.3±32.7 months, whereas the secondary patency was conserved for the same segment for 24.4±33.1 months. Regarding the stent segment, the primary patency was preserved for 17.6±21.1 months, whereas the secondary patency was preserved for 21.3±20.9 months. Regarding the bypass graft, the primary patency was preserved for 9.91±23.1 months, whereas the secondary patency was preserved for 21.3±20.9 months. The primary patency was associated with adding further treatment [HR=0.571; 95% confidence interval (CI): 0.375–0.973; P=0.043] (Fig. 1). Similarly, the improved secondary patency was associated with thrombolysis of native artery and additional treatment (HR=0.635, 95% CI: 0.340–1.07, P=0.087 and HR=0.513, 95% CI: 0.296–0.889, P=0.017, respectively). However, negative secondary patency was associated with thrombolysis of bypass graft (HR=0.590, 95% CI: 0.327–0.985, P=0.047).
In patients with thrombolysis in native artery, the AFS was significantly increased (HR=0.524, 95% CI: 0.289–0.891, P=0.019). After 3 years of follow-up, OS was 91%, whereas AFS was 87% (Fig. 2).
The literature is crowded with studies that encourage the use of thrombolysis for ALI classes I and IIa within the first 2 weeks with a technical success rate of more than 80% [7,8,9]. In contrary to our study, those previous studies considered the addition of open surgery as success of the endovascular procedure. This may explain the relatively low success rate revealed by our results, as we considered the need for open surgery as failure. In peripheral diseases, open surgeries are considered as the last line of treatment when endovascular techniques fail to achieve technical success. This was approved by a literature review which revealed that many patients were listed for open surgery in spite of being considered as technical success. For instance, Kuoppola et al.  worked on 220 patients and considered the 29% who underwent additional surgeries as technical success. Furthermore, a study performed in Cleveland Clinic revealed that ∼46% of the patients with technical success were listed for surgery. Another study of thrombolysis on the vein bypass showed 67% needed open surgeries .
The partial clot breaking could reduce the chance of the need for surgeries and therefore reduce the rate of morbidity. All of these studies considered open surgeries as the main procedure and the thrombolysis as the additional treatment. Open surgery was proposed to be effective from the start without the need for thrombolysis. Therefore, a comparison between open surgery and thrombolysis is needed to illustrate the effect of both of them and which one could be more effective. Thrombolysis is associated with long stay in the intensive care unit and the high cost of the device. Even the complication of thrombolysis may prolong the stay in the intensive care. Major bleeding, intracranial hemorrhage, and myocardial infarction were the complications of thrombolysis in our study. They can be the cause of mortality in 5% of population preoperatively.
Most studies on thrombolysis considered AFS as the main outcome and did not mention the potency rate; however, the potency rate in our study was not high. Despite including patients with additional open surgeries, the primary potency in the study performed by Kashyap and colleagues was 50% in the first year and 37% in the second year. A significant difference was found when the patients were subclassified according to the segment to be lysed into native arteries, stents, and bypasses. Most of our cases had occlusion in the naïve artery, and thrombosis in the bypass or stent is not common. The best potency rate was found in the naive artery, whereas the worst potency rate was found in the bypass. A previous thrombolysis study revealed poor potency regarding the vein and prosthetic bypass . Most studies agreed that the worst outcome was associated with vein graft as thrombolysis could cause damage of the vein wall and subsequent failure .
Most of studies revealed that salvage rate ranged from 70% to 80% in the first year [10,12,13]. Delaying limb salvage in patients with affected naïve artery to more than 3 years was trendy and would be significant. Despite literature revealing the many risk factors that are association with technical failure, our study did not reveal that association. These risk factors are diabetes, old age (more than 70), degree of ischemia, and renal insufficiency [13,14,15]. These factors were not frequently found in our sample of population. Adding further treatment to thrombolysis was revealed to be associated with better primary and secondary potency than thrombolysis without additional treatment.
In conclusion, thrombolysis was effective in treating ALI. However, adding further treatment was associated with better outcome and less complications. When adding to open surgery, thrombolysis could help in minimizing the length of the bypass segment or limit the surgery to thrombectomy. Thrombolysis is the ideal option for treatment in patients with high risk of anesthesia, high risk of open surgery, risk of low bleeding, or cannot be operated. The thrombolysis of vein bypass and prosthetic grafts did not show technical success as that is seen with native artery.
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Conflicts of interest
There are no conflicts of interest.
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