Thrombolysis of venous and arterial thrombosis by catheter-directed low-dose infusion of tissue plasminogen activator in children

Thrombolytic therapy is a well-defined treatment option for arterial and venous thrombosis in adults. In contrast, uniform recommendations regarding the indication, route of administration, and dosing of thrombolytic therapy in children are not available. The authors report the successful resolution of bilateral pulmonary embolism and popliteal artery thrombosis in an 11-year-old girl and 13-year-old girl, respectively, by catheter-directed thrombolysis with low-dose recombinant tissue plasminogen activator. Catheter-directed low-dose thrombolysis is an efficient treatment option for severe venous and arterial thrombosis in children.     

Catheter-Directed Thrombolysis with Recombinant Tissue Plasminogen Activator for Acute Pulmonary Embolism After Fontan Operation

We report the case of a 3-year-old girl who presented with near-lethal pulmonary thrombembolism 3 weeks after an uneventful Fontan operation. Complete occlusion of the left lower lobe pulmonary artery had occurred together with a cerebral infarction. Recombinant tissue plasminogen activator (rt-Pa) was used for thrombolysis because of its short half-life and its clot-selective properties. To further minimize the systemic effects of rt-PA, local catheter-directed lysis was performed. A prolonged course of low-dose rt-PA therapy achieved complete lysis without side effects.     

Low-dose tissue plasminogen activator thrombolysis in children

PURPOSE: To compare results of low-dose tissue plasminogen activator (TPA) in children with arterial and venous thrombi relative to standard published dosing. METHODS: Subjects consisted of all consecutive children with objectively confirmed thrombi for whom TPA thrombolysis was clinically ordered by the authors. Initial dosing used published standard dose (0.1-0.5 mg/kg per hour). With experience, a low-dose regimen (0.01-0.06 mg/kg per hour) was given in an attempt to derive a minimal effective dose. RESULTS: Thirty-five children were treated with TPA. Either standard or low-dose infusions of TPA resulted in complete thrombolysis of 28 of 29 (97%) acute thrombi, while all 6 chronic thrombi had a partial response. In contrast to the recommended adult-derived dosages of 0.1 to 0.5 mg/kg per hour, the authors found that initial doses of less than 0.01 mg/kg per hour were effective in 12 of 17 patients with acute thrombosis. Neonates required 0.06 mg/kg per hour. Route of administration (local or systemic) did not affect efficacy. Major bleeding occurred in only one extremely preterm infant. Minor bleeding, primarily oozing at intravenous sites, occurred in 27% of children during TPA infusions. Prophylactic unfractionated or low-molecular-weight heparin was infused concomitant with TPA in 42% of the children and did not increase the risk of bleeding. CONCLUSIONS: TPA in very low doses appears to be safe and effective for thrombolysis of acute thromboses in most children, given appropriate patient selection.     

Developing a pediatric endovascular thrombolysis program: a single-center experience

Deep venous thrombosis (DVT) is being increasingly recognized as a significant issue in children. Despite the low incidence of DVT, the risks of pulmonary embolism and death in children are significant. Post-thrombotic syndrome, a syndrome of chronic venous insufficiency, can have long-term adverse consequences in children and adolescents. Adult studies have shown that catheter-directed therapy can reduce the incidence of post-thrombotic syndrome. Safety of catheter-directed therapy in adolescents has also been demonstrated. These reasons compelled us to institute a pediatric endovascular thrombolysis program at our institute for management of pediatric DVT. We describe the process of developing a multi-disciplinary thrombolysis program involving interventional radiology (pediatric and adult), pediatric hematology, critical care, anesthesia and vascular surgery, and describe the role of each specialty in the development of the program. We also describe our experience with patient selection, endovascular therapy procedure, pre-, intra- and post-procedure monitoring, and follow-up management for endovascular therapy for DVT.     

Safe use of alteplase in a 10 months old infant with cardio-embolic stroke

The knowledge about safety and efficacy of thrombolysis in paediatric stroke is limited, especially for very young children. We present an infant with cardioembolic stroke treated with alteplase. He had hypoplastic left heart syndrome since birth. He underwent Norwood operation, followed by bidirectional cavopulmonary anastomosis at 3 months. On aspirin therapy he was well until heart failure developed at the age of 9 months with 2 thrombi in the right ventricle. During the course of enoxaparin therapy sudden acute left-sided haemiplegia occurred. The emergency brain CT scan was normal. Informed consent was obtained from parents after explaining the alteplase treatment protocol and possible complications. Alteplase was administered i.v. according to standard adult stroke regimen. A control CT scan obtained 24 h later was negative for intracranial haemorrhage but the hypodense area in insula, internal capsule and subcortical area of the right parietal region were indicative of ischaemic stroke. Anticoagulation therapy was continued. He recovered hand functions after 5 days and full repertoire of movements on his left side 3 weeks later. A neurological examination performed 2 months after indicated mild residual haemiparesis and a modified Rankin scale score of 1. Three months later, the patient died of progressive heart failure. An international multicentre prospective trial is ongoing to investigate the safety and appropriate dose of alteplase for paediatric ages 2–17 years. The aim of this paper is to report safe use of alteplase even in a very young child.     

Successful partial lysis of a 4-level-thrombosis by rt-PA - case report

Thromboembolism of the vena cava, the venae iliaca communis, externa, femoralis, poplitea, and the fibular vein group of the left lower limb was diagnosed in a 13 year old girl. Several thrombogenic risk factors (APC-resistence, homocystinuria, contraception, smoking) were identified. Due to painful symptoms and for prevention of postthrombotic syndrome continuous systemic thrombolysis with rt-PA (0,5 mg/kg/d), in addition to heparine, was performed for 6 days. Diagnostic imaging at the end of therapy demonstrated complete and partial recanalization of the vena cava inferior, venae iliaca communis and externa. The distal veins of the leg remained occluded. After catheterization of the internal jugular vein and placement of a cava filter only mild pulmonary embolism occurred during systemic thrombolysis. No further complications were observed. All in all, therapy was tolerated well. Systemic thrombolysis with rt-PA in children and adolescents, although not established for regular treatment, is an effective therapeutic option in severe venous thrombosis.     

Bivalirudin during thrombolysis with catheter‐directed tPA in a heparin‐refractory patient: A case report

Venous thromboembolism has increasing significance in hospitalized pediatric patients. Patients who have life‐threatening or limb‐threatening thrombotic events require thrombolysis in addition to anticoagulation. In patients who show signs of heparin resistance or heparin‐induced thrombocytopenia, it is imperative to identify alternative therapeutic options. We present a child in whom bivalirudin was used for systemic anticoagulation during catheter‐directed thrombolysis along with tissue plasminogen activator (Alteplase^®) for the treatment of a near‐occlusive organ‐threatening thrombus. We also review the currently available literature on the use of combination therapy of an intravenous direct thrombin inhibitor with alteplase.     

Thrombolysis with rt-PA in children with arterial and venous thromboses--a new therapy concept

Thrombolytic therapy usually used for thrombosis in the adult has been administered as a therapeutic regiment in pediatric patients (parental consent was sought prior to the treatment with rt-PA). We report our experience with rt-PA in 17 children and adolescents suffering from arterial (n = 4) or venous thrombosis (n = 13) due to local rhabdomyosarcoma, acute lymphoblastic leukemia, chronic myeloblastosis, sickle cell anaemia, parenteral nutrition, haemolytic uremic syndrome, central arterial and venous catheters and septicemia Thrombotic diseases have been diagnosed by Doppler ultrasound, computed tomography, angiography and phlebography. Rt-PA therapy was started immediately after diagnostic procedures had been performed. Rt-PA dose varied from 0.2 mg as a single dose to 0.8 mg/kg bw/d over a three day period in children local thrombolysis was performed. In patients requiring systemic thrombolytic therapy rt-PA was administered from 0.8 mg/kg bw/d in three days to 2.0 mg/kg bw/d over a whole period of three weeks in both groups during thrombolysis low dose heparin was added. When rt-PA infusion was terminated heparin (70 IU - 400 IU/kg bw/d) was administered for 7 to 14 days in order to prevent reocclusion. Later prophylaxis with coumarin derivatives in venous thrombosis and antiplatelet agents in arterial occlusive diseases was performed. In no patient did we see a decrease of fibrinogen and plasminogen during rt-PA therapy.(ABSTRACT TRUNCATED AT 250 WORDS)     

Daily versus as-needed inhaled corticosteroid for mild persistent asthma (The Helsinki early intervention childhood asthma study).

OBJECTIVE: To compare the effect of inhaled budesonide given daily or as-needed on mild persistent childhood asthma. Patients, design and INTERVENTIONS: 176 children aged 5-10 years with newly detected asthma were randomly assigned to three treatment groups: (1) continuous budesonide (400 microg twice daily for 1 month, 200 microg twice daily for months 2-6, 100 microg twice daily for months 7-18); (2) budesonide, identical treatment to group 1 during months 1-6, then budesonide for exacerbations as needed for months 7-18; and (3) disodium cromoglycate (DSCG) 10 mg three times daily for months 1-18. Exacerbations were treated with budesonide 400 microg twice daily for 2 weeks. MAIN OUTCOME MEASURES: Lung function, the number of exacerbations and growth. RESULTS: Compared with DSCG the initial regular budesonide treatment resulted in a significantly improved lung function, fewer exacerbations and a small but significant decline in growth velocity. After 18 months, however, the lung function improvements did not differ between the groups. During months 7-18, patients receiving continuous budesonide treatment had significantly fewer exacerbations (mean 0.97), compared with 1.69 in group 2 and 1.58 in group 3. The number of asthma-free days did not differ between regular and intermittent budesonide treatment. Growth velocity was normalised during continuous low-dose budesonide and budesonide therapy given as needed. The latter was associated with catch-up growth. CONCLUSIONS: Regular use of budesonide afforded better asthma control but had a more systemic effect than did use of budesonide as needed. The dose of ICS could be reduced as soon as asthma is controlled. Some children do not seem to need continuous ICS treatment.     

Local low-dose urokinase treatment of acquired intracardiac thrombi in preterm infants

We report three cases of intracardiac thrombi in preterm infants of very low birth weight, in whom local low-dose urokinase treatment achieved complete thrombolysis without any signs of systemic fibrinolytic activity or side-effects. Conclusion This new treatment strategy seems to be safe, requires minimal monitoring of fibrinolytic activity, and may be a new option for thrombolysis in high-risk patients such as premature infants, patients recently operated on, and patients presenting with other contra-indications for systemic fibrinolytic therapy. Received: 4 November 1998 / Accepted in revised form: 5 February 1999     

Symptomatic Upper-Extremity Deep Venous Thrombosis After Pacemaker Placement in a Pediatric Patient: How to Treat?

Symptomatic upper-extremity deep venous thrombosis (UEDVT) after pacemaker placement in adults has been reported, but the occurrence of UEDVT in pediatric patients is poorly defined, and no treatment guidelines exist. This report describes a 14-year old girl with a history of complete atrioventricular block who experienced a symptomatic UEDVT 8 months after placement of a transvenous pacemaker. The girl was treated initially with anticoagulation including subcutaneous enoxaparin and a heparin drip, which did not resolve the venous obstruction. In the interventional laboratory, a venogram demonstrated complete obstruction of the left subclavian vein, which was treated successfully with catheter-directed alteplase, direct thrombus removal by manual suctioning, and balloon angioplasty. Warfarin therapy was continued for an additional 6 months, with follow-up venous ultrasounds demonstrating left subclavian vein patency. Soon after completing warfarin therapy, the girl presented with minimal edema of her left distal extremity and was thought to have post-thrombotic syndrome, which resolved quickly. She continued to receive aspirin therapy, with no recurrence of symptoms. In conclusion, symptomatic UEDVT after pacemaker placement in a pediatric patient can be treated successfully with both anticoagulation and interventional therapies. Further studies are needed to evaluate the incidence of thrombus formation among children with transvenous pacemaker placement together with the development of guidelines based on the safety and effectiveness of differing treatments.     

Low-dose insulin infusion in the treatment of diabetic ketoacidosis: bolus versus no bolus

The effects of an initial iv bolus of insulin upon plasma glucose, blood gases, and electrolytes were assessed in 19 children with 20 episodes of diabetic ketoacidosis treated by a continuous low-dose insulin infusion of 0.1 unit/kg/hour. An iv bolus of insulin administered prior to low-dose insulin infusion accelerated the decline of plasma glucose concentration during the first hour of treatment, but differences in decline of mean plasma glucose concentration were not apparent thereafter. The mean time required for attaining "normoglycemia" (250 mg/dl) was similar, whether or not the initial bolus of insulin was given, with a smooth and predictable correction of initial hyperglycemia in the majority of children. However, an accelerated response was more frequent in those patients with compensated metabolic acidosis, who received an initial iv bolus of insulin; those with more severe metabolic acidosis took longer to recover. The data suggest that an initial iv bolus of insulin may not be required nor desirable in the majority of children with diabetic ketoacidosis treated by a standard low-dose insulin infusion regimen.     

May-Thurner syndrome (iliac vein compression) and thrombosis in adolescents

May-Thurner syndrome refers to anatomic compression of the left iliofemoral vein by the overriding right iliac artery. We report three adolescents who presented to our pediatric hospital with iliac vein thrombosis and were diagnosed with May-Thurner syndrome. Each received catheter-directed thrombolysis followed by balloon angioplasty to restore flow. Two patients had endovascular stents placed. The procedures were well tolerated, without major complications. Additional thrombophilic risk factors were identified in each patient. Though uncommon, pediatric hematologists should consider May-Thurner syndrome in adolescents who present with a left lower extremity thrombosis. Aggressive therapy may be warranted due to the risk of post-thrombotic syndrome.     

Comparison of high-dose and low-dose aspirin plus intravenous immunoglobulin in the treatment of Kawasaki syndrome

The efficacy of intravenous immunoglobulin (IVIG) in the treatment of Kawasaki syndrome (KS) has been unequivocally established, but questions remain concerning the proper dose of adjunctive aspirin therapy in the treatment of KS. The medical records of 72 children with KS were reviewed. All patients were treated with IVIG; 21 received 400 mg/kg/dose on 4 consecutive days and 51 received 2 g/kg as a single infusion. Seventy patients also received aspirin. Twenty-four of the 70 patients were started on high-dose aspirin (80-100 mg/kg/day) at the time of diagnosis. High-dose aspirin was given for a mean (+/- SE) duration of 6.1+/-0.9 days, then switched to low-dose aspirin (3-5 mg/kg/day). Forty-six of the 70 patients were started on low-dose aspirin at the time of diagnosis and remained on low-dose aspirin for the duration of treatment. Coronary artery abnormalities were present at the time of diagnosis in 12 of 72 patients (17%), including 6 of 6 of patients (100%) with atypical KS and 6 of 66 patients (9%) with typical KS. None of the remaining 60 patients developed coronary artery abnormalities after treatment with IVIG and aspirin. The mean duration of fever after initiation of therapy was 44+/-6 hours in patients treated with IVIG 400 mg/kg/dose on 4 consecutive days and 35+/-5 hours in patients treated with 2 g/kg as a single infusion (p=0.3). The mean duration of fever after the initiation of therapy was 47+/-8 hours in patients treated with high-dose aspirin compared to 34+/-5 hours in patients treated with low-dose aspirin (p=0.13). These preliminary results indicate there is no benefit to high-dose aspirin compared to low-dose aspirin in the treatment of children with KS.     

糖皮质激素在急性呼吸窘迫综合征中的应用

持久的全身和肺部炎症反应是急性呼吸窘迫综合征（acute respiratory distress syn-drome,ARDS）使用糖皮质激素（简称激素）治疗的基本依据,但目前ARDS患者使用激素的剂量、时间、疗程和效果仍然存在争议.大剂量、短疗程激素疗效欠佳,甚至增加病死率.现阶段认为相对中长疗程（2周～1个月）、小剂量或替代剂量（如甲泼尼龙1 ～2 mg/kg）激素,可降低ARDS病死率,缩短住ICU时间和呼吸机使用时间,并减轻肺纤维化.儿童ARDS的激素治疗仍缺少多中心、随机对照研究.     

Synchronization of plasmapheresis and pulse therapy in the complex treatment of children with highly active glomerulonephritis]

To suppress the activity of glomerulonephritis, lupus and primary chronic mixed one, 13 children received plasmapheresis synchronously with pulse therapy with cyclophosphamide or prednisolone. Plasmapheresis was carried out daily for 3 days. Six hours after the last session and on days 4 and 5 of the treatment pulse therapy was provided, followed by conventional intake of prednisolone per os in combination with azathioprine or cyclophosphamide. Beneficial therapeutic results were obtained in 10 patients within 3 to 6 weeks. The effect turned out insufficient in a patient with associated systemic lupus erythematosus, and rapid-progressing nephritis and in a child with primary chronic glomerulonephritis of the mesangiocapillary type with fibroplastic transformation and persistent nephrotic syndrome. No therapeutic effect was attained in a patient with focal segmental glomerulosclerosis running its course with long persistent nephrotic syndrome.     

Failure of thrombolytic therapy in four children with extensive thromboses.

In three children with central vein thromboses and a fourth with a pulmonary artery thrombosis, thrombolytic therapy failed to produce ultrasonographic evidence of clot lysis. Low-dose streptokinase (50 to 250 U/kg per hour) was infused directly into the clot in three children, followed by streptokinase and urokinase in systemic doses (streptokinase, 1000 to 1750 U/kg per hour; urokinase, 4400 to 5000 U/kg per hour). A fourth child treated sequentially with systemic doses of streptokinase, urokinase, and recombinant tissue-type plasminogen activator developed a significant retroperitoneal and intrapleural hemorrhage after 19 hours of recombinant tissue-type plasminogen activator infusion at a dose of 0.7 mg/kg per hour. All of the children survived. The most likely reason for treatment failure was that the clots (estimated to be between 2 and 3 weeks of age) were organized and thus resistant to lysis. Early diagnosis and prompt thrombolysis of significant lesions may contribute to the successful management of pediatric thrombosis. However, controlled studies are clearly needed to establish guidelines for the optimal use of thrombolytic agents in children.     

Pharmacokinetics of 2-chlorodeoxyadenosine in a child undergoing hemofiltration and hemodialysis for acute renal failure

The clearance of 2-chlorodeoxyadenosine (2-CdA) in patients with renal insufficiency has not been characterized previously. The authors describe the clinical course and the pharmacokinetics of 2-CdA in a child with acute monoblastic leukemia who experienced acute renal failure during treatment with cytarabine and 2-CdA. 2-CdA (9 mg/m per day) was infused over 30 minutes daily for 5 days. Plasma and dialysate concentrations of 2-CdA were measured by high-performance liquid chromatography. The rate of this patient's 2-CdA clearance was lower than the rates reported for children with normal renal function. The average clearance rate, reflecting systemic clearance and clearance by continuous venovenous hemofiltration and hemodialysis, was 12.4 L/hour per m for the first 3 days of 2-CdA therapy. He did not experience untoward hematologic toxicity. Because high 2-CdA plasma concentrations were observed in this patient, clinicians are advised to exercise caution when using this drug in patients with renal dysfunction. More experience in the administration of 2-CdA to patients with renal insufficiency will be necessary to determine the need for dosage adjustment.     

Course of treated juvenile dermatomyositis

Sixty-six patients with possible juvenile dermatomyositis (JDMS) were observed at the Children's Hospital of Los Angeles from 1960 to 1982. In patients initially given high doses of corticosteroids followed by low-dose therapy, three different clinical courses had previously been observed: monocyclic, polycyclic, and chronic continuous. We reviewed the records of 32 patients who met study criteria. The course of JDMS was monocyclic in eight children, chronic polycyclic in 10, and chronic continuous in 14. Of these children, 25 are well and not receiving medication; one has mild JDMS, without corticosteroid therapy; four have active JDMS despite corticosteroid therapy (one is severely handicapped); and two have died. Our results support the improved prognosis of JDMS after corticosteroid therapy, but also the great clinical variability of the disease. Understanding of this variability, as reflected in the three disease courses, facilitates physician choice of the optimal treatment with the least drug toxicity for the individual patient, continuing efforts to clarify the disease pathogenesis, and research efforts to improve current treatment programs for the patient with severe JDMS.     

Low-dose continuous intravenous insulin infusion in childhood diabetic ketoacidosis.

We studied 58 children with diabetic ketoacidosis using a random, prospective protocol, with insulin administered either as a low-dose continuous infusion or as high-dose intermittent subcutaneous injections. There were no statistically significant differences between admission pH and glucose determinations or the time to metabolic correction. The incidence of hypoglycemia and hypokalemia was higher in patients receiving subcutaneous insulin. Insulin levels in the low-dose patients were 85--160 microU/ml. The insulin required to achieve metabolic recovery was 1.6 U/kg in the low-dose group and 4.5 U/kg in the high-dose group (p less than 0.01). Glucose administered at a rate of 3 to 4 g er unit of insulin infused in the low-dose group maintained a serum glucose of 150 to 250 mg/dl. Our studies suggest that low-dose intravenous insulin therapy is safe, as effective as high-dose intermittent subcutaneous injections and avoids the risks of hypoglycemia and hypokalemia. Meticulous attention to individual patient care, however, must remain the most important single variable.