Femoral artery thrombosis is one of the complications of left cardiac catheterization and has been reported to be associated with claudication, ischemia, tissue necrosis.1 The introduction of percutaneous arterial catheterization and the use of smaller catheters have reduced the incidence of femoral arterial thrombosis, however, it is the most common complication of catheterization in infants and young children. Pulse loss after cardiac catheterization has been reported to occur in 8% to 39% of infants weighing <14 kg despite prophylactic use of heparin.2,3 Systemic heparinization has been shown to reduce the occurrence of arterial thrombosis in both children and adults.4 In older children with persistently poor capillary refill and absent pulses, surgical thrombectomy has been undertaken with good but not uniform success.3 However, infants have been identified as the highest risk group for arterial thrombosis, and the risk of extending vascular damage in this population may limit the number of candidates for successful thrombectomy or restrict them from surgical intervention altogether. A successful alternative therapy to thrombectomy in adults with arterial thrombosis has been introduced with the development of fibrinolytic agents, such as streptokinase (SK), urokinase, and tissue-type plasminogen activator (t-PA)3,5 The usefulness of these agents in small children with arterial thrombosis has not been established. Given the adverse reactions of SK and the expensive price of t-PA, urokinase has shown more advantages. The present study investigated the safety and efficacy of urokinase therapy in selected children with clinical evidence of femoral artery thrombosis after cardiac catheterization.
From February 2006 to June 2008, 2500 pediatric patients accepted cardiac catheterization in our department, of which 8 cases presented femoral artery thrombosis after the procedures. Those patients were reviewed retrospectively in this study (Table). The gathered information included age, body weight and height, size of the largest catheter or sheath used for arterial access, type of catheterization procedure, time of administration and doses of urokinase, outcome, and complications of urokinase therapy. The study was approved by the institutional review board. Before and after catheterization, bilateral femoral artery pulses, pedal pulses, the skin temperature and the skin color of the lower extremities were assessed. In this study, the criteria used to determine the left femoral artery spasm with/without thrombosis after cardiac catheterization included 5 aspects: (1) nonpalpable or markedly diminished pedal pulses; (2) lower skin temperature and pale skin; (3) lower systolic blood pressure; (4) thrombosis detected by Doppler technique; (5) filling defect or obliteration detected by selective arteriography.
Arterial access was obtained percutaneously using the Seldinger technique. The 5F Terumo lower limb sheaths (Terumo Corp., USA) were used in 5 patients and the 5F arterial sheathes (Cordis Corp., Miami Lakes, FL, USA) were used in other 3 cases. For infants and young children, especially those with cyanotic congenital heart disease, a single bolus injection of heparin sulfate (50 U/kg) was given before pulling the sheath off. The children accepting the ventricular septal defect closure procedure required 100 U/kg of heparin immediately after placing the arterial catheter. However, heparin was not used in the procedure of diagnostic angiography. All patients signed informed consent by their parents as guardians before operation.
After catheterization, pulses in the extremity were assessed by palpation and by measurement of systolic blood flow using Doppler technique. If the extremity was cool with nonpalpable or markedly diminished pedal pulses 4 hours later, an intravenous heparin bolus of 100 U/kg was given. Another four hours later, if the pulse in the affected extremity was absent, a constant infusion of urokinase was given at a rate of 10 000-50 000 U/h associated with a loading dose of 30 000-100 000 U. Blood pressure in the ankle and vital signs in the leg were measured and recorded hourly. To determine the presence and degree of systemic fibrinolysis and to avoid inducing a consumption coagulopathy, prothrombin time, partial thromboplastin time, and fibrinogen level were measured before and at 4-hour intervals after therapy started. If the treatment kept invalid in 24 hours, transcatheter thrombo-lysis through the opposite femoral artery was performed as soon as possible. Transcatheter thrombolysis was carried out under general anesthesia with oxygen inhalation. Manipulation steps were as follows: (1) The 5F sheath was inserted through the contralateral femoral artery. (2) The 5F end-to-side hole catheter (or 5F Cobra catheter) was delivered in. Then the iliac artery angiography was done in affected femoral artery. (3) Put the catheter tip close to the upper part of the thrombus, and urokinase was given at a rate of 10 000-50 000 U/h after a loading dose of 5000-10 000 U/kg. (4) The pedal pulses, skin temperature and skin color of the affected lower limb were estimated every hour and the iliac artery angiography was repeated every 4 to 5 hours. (5) If the affected femoral artery showed residual stenosis after thrombolysis, 200 μg of nitroglycerin was given for identification of possible arterial spasm. (6) When the thrombolysis ended, the sheath was removed and the puncture site was oppressed to stop bleeding. From then on, 500-1000 U of heparin was given every two hours and the indicators of blood coagulation were analyzed every 4 hours. The low-molecular-weight heparin was used 24 hours after the sheath was removed. At the next day, one week and two weeks after transcatheter thrombolysis, the bilateral pedal artery pulses and the vascular ultrasound were reviewed. Clinically, return of a normal pedal pulse in the affected foot was considered a complete success of thrombolytic therapy, and return of a palpable but diminished pedal pulse compared with the pulse in the unaffected foot was considered a partial success.
Continuous variables were expressed as mean±standard deviation. Statistical significance was assessed by paired t test. Values were considered significantly different when P < 0.05. All statistical analyses were conducted with SAS 9.1 (SAS Institute Inc., USA).
In the present study, 8 patients (aged (3.1±2.3) years (8 months to 7 years), body weight (13.1±4.2) kg (7 to 20 kg)) presented lower limbs ischemia after left cardiac catheterizations was performed, of which 7 required thrombolytic therapy with urokinase. Cardiac catheterization was diagnostic in 2 patients and interventional in 6 patients. In the 8 cases, there were 7 cases with the nonpalpable pedal pulses of the affected side and 1 case with markedly diminished pedal pulses.
Pedal pulse was restored in all patients. In 5 patients, peripheral intravenous thrombolysis was considered completely successful with restoration of a normal pulse. In the other 3 cases, peripheral intravenous thrombolysis failed, followed by successful transcatheter thrombolysis. The average duration of therapy was (7.25±5.31) hours (1-17 hours). The average dose of heparin and urokinase were (1600±723) U (800-3000 U) and (268 571±177 240) U (50 000-500 000 U) respectively. Patency of the target vessel was evaluated in all the patients for 2 weeks. They underwent ultrasonographic studies that showed the previously occluded femoral artery to be patent in 7 patients. Only one case showed residual stenosis of external iliac artery (Figure).
There was no episode of systemic bleeding. Only one case had bleeding at the puncture site. We did not find any serious hemodynamic abnormality, hematoma formation, and allergic reactions. There were no statistically significant differences in partial thromboplastin time before and during urokinase therapy ((40.6±22.3) to (49.9±39.2) seconds). However, the prothrombin time was longer ((12.7±2.58) to (48.1±18.6) seconds, P <0.05).
Femoral arterial thrombosis is a known complication of cardiac catheterization in infants and children. The issue of arterial thrombosis following cardiac catheterization in infants and children is gaining importance as some of these cases with complex congenital heart disease may need multiple catheterizations or arterial interventions following cardiac surgery.6
Several mechanisms of arterial thrombosis have been described, although the mechanism of thrombus formation after left-sided heart catheterization and angiography is not clarified. Some studies suggested that intimal trauma plays a central role during catheterization.5,6 The large size and irregular surface of the sheath may contribute to increased intimal trauma, cause spasm, and result in thrombosis. In the present study, similar associations were found.6,7 Many factors such as patient age, hemodynamic states, technique, and total time of arterial cannulation interplay in risk of thrombosis.3 Previous studies confirmed that the younger the children, the higher the incidence of femoral artery thrombosis.2,3 The femoral arteries of children are relatively slim and vulnerable to spasm. Repeated puncture often results in arterial spasm and intimal trauma.4,8 Lin and the colleagues7 indicated that arterial complications were more common when there was intervention with balloon angioplasty or valvotomy. In the study of Victor and his colleagues,4 increased arterial thrombosis was noticed with increased duration of catheterization. Groin compression was usually necessary to stop bleeding of puncture site after catheterization. But excessive compression may be another factor resulting in femoral artery thrombosis in the present study. Additionally, we should pay attention to systemic heparinization during catheterization procedures. Insufficient heparinization may lead to increased incidence of femoral arterial thrombosis. Systemic heparinization has been shown to significantly reduce the occurrence of arterial thrombosis in both children and adults.9,10 However, some studies have indicated that the action of heparin is only prophylactic and not thrombolytic.10,11
The use of thrombolytic agents has become common in treating patients under a variety of clinical circumstances. Two plasminogen activators, SK and urokinase, have been used.12 Urokinase is isolated from human urine and directly activates plasminogen without formation of an activator complex.13 SK and urokinase are equally effective in acute arterial occlusion.14 Although SK is considerably less expensive than urokinase, its antigenecity may limit its use. t-PA has been reported with more advantages, but it is 5 times more expensive than SK and urokinase.3,13
Thrombolytic agents have been applied successfully in adults in the treatment of a wide variety of thromboembolic phenomena including arterial thrombi, usually in adults with peripheral vascular disease.14 Experience with infants and children is limited and has yielded variable results.4 In our study, 4 patients were successfully treated with a systemic infusion of urokinase and 3 accepted intraarterial thrombolytic therapy. Several investigators have demonstrated that low-dose intraarterial infusion may yield equally excellent therapeutic effects without the risk of inducing a state of systemic hemorrhage.15,16
It should be emphasized that the majority of bleeding episodes occur at the site of the arterial puncture as the occluding thrombosis is dissolved. No serious bleeding was recognized in our study. Only one patient need prolonged groin compression at the puncture site. Hematologic monitoring is an important aspect of thrombolytic therapy to determine the presence and degree of systemic fibrinolysis.17,18 Additionally, the measurement of plasminogen and fibrinogen levels may be used as a guide to the presence of a lytic state and may be useful in adjusting the dose. Monitoring of prothrombin and partial thromboplastin times is useful to avoid inducing a generalized hemorrhagic state.4
In brief, our investigation indicated that fewer attempts at arterial puncture, use of a smaller sheath, maintaining a minimum procedure time can achieve minimal incidence of femoral thrombosis of post-catheterization. Systemic heparinization was still effective in the prevention of arterial thrombosis. However, once femoral arterial thrombosis happened, systemic thrombolysis should be considered at first. When systemic thrombolysis failed, transcatheter thrombolysis should be executed as soon as possible. At the same time, hematologic monitoring is also mandatory during thrombolysis.
Thrombolytic therapy with urokinase is a safe and useful modality in children with femoral artery thrombosis after left cardiac catheterization.
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