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.     

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.     

Thrombolysis with low dose tissue plasminogen activator.

Two cases of vena caval thrombosis in infants were successfully treated with low dose (0.01-0.05 mg/kg/hour) local infusions of tissue plasminogen activator after conventional anticoagulant treatment had been unsuccessful. This approach is useful for clots associated with indwelling intravascular catheters, and a low dose infusion of tissue plasminogen activator as a regional application is recommended to achieve clot lysis with minimal systemic effects.     

Safety and outcomes of thrombolysis with tissue plasminogen activator for treatment of intravascular thrombosis in children.

OBJECTIVES: In this study, we tried to determine the safety and outcomes of thrombolysis with tissue plasminogen activator of intravascular thrombus. STUDY DESIGN: Eighty consecutive children were treated between 1985 and 1999 in a tertiary care setting in a retrospective case series. There were 65 arterial thrombi (56 after cardiac catheterization) and 15 venous thrombi treated with tPA at an average dose of tPA of 0.5 mg/kg/hour for a median duration of 6 hours. RESULTS: Clot resolution was complete in 65% of children, partial in 20%, and there was no effect in 15%. There were major complications in 40%, minor complications in 30%, and no complications in 30%. Two patients had cerebral ischemia secondary to hypotension because of profound bleeding, with intracranial hemorrhage in 2 additional patients. Clot resolution was not related to patient age or weight, dose, and duration of tPA therapy and fibrinogen levels. However, complications were more likely in patients who weighed less, had a longer duration of therapy, a greater decrease in fibrinogen levels, and who failed to have resolution of their clot. CONCLUSIONS: tPA therapy can be effective in the thrombolysis of intravascular thrombus in children, but is associated with a low margin of safety and an unknown risk-benefit ratio.     

Early intracardiac thrombosis in preterm infants and thrombolysis with recombinant tissue type plasminogen activator.

OBJECTIVES: To determine the incidence of catheter related thrombosis and to test the efficacy of recombinant tissue type plasminogen activator (rt-PA) in preterm infants. STUDY DESIGN: From January 1995 to December 1998, echocardiography was performed in the first few days of life in 76 very low birthweight (< or = 1500 g) infants out of a total of 147 having an umbilical catheter placed. When intracardiac thrombosis was diagnosed, rt-PA infusion was performed. RESULTS: Four infants (5%) developed an intracardiac thrombosis during the first few days of life. In three of them, rt-PA at a dose of 0.4-0.5 mg/kg in a 20-30 minute bolus led to dissolution of the clot. One patient received a three hour infusion after the bolus, at a dose of 0.1 mg/kg/h, with resolution of the thrombus. No systemic effects were observed after rt-PA infusion. CONCLUSIONS: Early thrombosis may occur as a complication of umbilical catheterisation in preterm infants; early echocardiographic detection of this disorder allows complete, safe, and rapid lysis with rt-PA.     

Management of a large organized intraatrial catheter-tip thrombus in a child with acquired immunodeficiency syndrome using escalating tissue plasminogen activator infusions.

OBJECTIVES: To describe the dissolution of a large organized intraatrial catheter-tip thrombus using a novel aggressive dose escalation of tissue plasminogen activator infusion. DESIGN: Case report. SETTING: A six-bed pediatric intensive care unit (ICU) at a university hospital. PATIENT: An 8-yr-old with acquired immunodeficiency syndrome with a large organized intraatrial thrombus at the tip of an indwelling central venous catheter placed for total parenteral nutrition 2 months before presentation. INTERVENTION: Escalating dose of tissue plasminogen activator infusion. MEASUREMENTS: A large intraatrial catheter-tip thrombus (2.5 x 3 cm) was an incidental finding on an echocardiogram done to assess cardiac function. The thrombus occupied almost half the right atrial cavity and hit the tricuspid valve with each heartbeat without obstruction of tricuspid inflow. The catheter had no blood return from either lumen for >1 month. Protein C, protein S, and antithrombin III were normal, and factor V Leiden and prothrombin gene mutations were absent. Blood cultures were negative. Pediatric and cardiovascular surgeons recommended open-heart surgery as the safest option for catheter removal to avoid the risk of superior vena cava occlusion, vascular rupture, or embolization. A second opinion concurred. A trial of thrombolytic therapy with tissue plasminogen activator infusions was started at 0.1 mg/kg/hr for 6 hrs daily. No change in thrombus size was seen on a followup echocardiogram after 4 days. An aggressive dose escalation (0.15, 0.2, 0.25 mg/kg/hr for 6 hrs) was done over the next 5 days in an attempt to avoid open-heart surgery. Risks regarding disseminated intravascular coagulation and bleeding were presented to the parents. MAIN RESULTS: Followup echocardiogram on day 10 showed complete resolution of the thrombus. No changes in respiratory/hemodynamic status or oxygen saturation were observed. Studies for disseminated intravascular coagulation remained stable, and no clinical bleeding was seen. The catheter was safely removed surgically; pathology examination showed no residual thrombus. CONCLUSIONS: Prolonged infusion of tissue plasminogen activator in escalating doses was safe and effective in the management of a large intracardiac catheter-tip thrombus and helped avoid open-heart surgery. In view of the potential hazards of tissue plasminogen activator, close pediatric ICU monitoring is indicated with the use of high-dose tissue plasminogen activator infusions.     

Successful use of tissue plasminogen activator (t-PA) in catheter-related intracardiac thrombi of two premature infants

We describe the cases of two premature infants carrying a central venous line who developed on the fourth day of life a catheter related intracardiac thrombus. Although they were clinically asymptomatic we opted for thrombolytic treatment considering the potential risks of this situation. Treatment with recombinant tissue plasminogen activator (rt-PA) was performed for one day in the first case and for three days in the second one, in association with fresh frozen plasma. Thrombus dissolution occurred in both patients and no adverse effects were noted. In our experience tissue plasminogen activator was a therapy acceptably safe and effective inducing clot lysis in very low birthweight neonates into critical situations.     

Hemothorax under thrombolytic therapy with recombinant tissue: plasminogen activator (rt-PA) in a 16-year-old girl

We present the case of a 16-year-old girl with an extended thrombosis of the femoral and iliac vein and the inferior vena cava during pleuropneumonia; predisposing risk factors for thrombophilia were: use of contraceptives, nicotine abuse and congenital deficiency of antithrombin III (not previously diagnosed). Thrombolytic therapy with recombinant tissue plasminogen activator (rt-PA; initial dose: 0.08 mg/kg/h) was started. 2 days later--after diagnosis of an extended hemothorax: 1500 ml blood were obtained after thoracocentesis, transfusion of packed red blood cells was necessary--rt-PA was stopped, with only heparin (400 U/kg/d) being administered. 36 h later--the thrombosis had not yet changed--the thrombolytic therapy with rt-PA was continued in a markedly reduced dose (0.015 mg/kg/d) with no further bleeding complications. 8 days later--after successful thrombolysis--t-PA was stopped, heparin was given for another 10 days, then cumarin was administered orally.     

Hemothorax under thrombolytic therapy with recombinant tissue

We present the case of a 16-year-old girl with an extended thrombosis of the femoral and iliac vein and the inferior vena cava during pleuropneumonia; predisposing risk factors for thrombophilia were: use of contraceptives, nicotine abuse and congenital deficiency of antithrombin III (not previously diagnosed). Thrombolytic therapy with recombinant tissue plasminogen activator (rt-PA; initial dose: 0.08 mg/kg/h) was started. 2 days later - after diagnosis of an extended hemothorax: 1500 ml blood were obtained after thoracocentesis, transfusion of packed red blood cells was necessary - rt-PA was stopped, with only heparin (400 U/kg/d) being administered. 36 h later - the thrombosis had not yet changed - the thrombolytic therapy with rt-PA was continued in a markedly reduced dose (0.015 mg/kg/d) with no further bleeding complications. 8 days later - after successful thrombolysis - rt-PA was stopped, heparin was given for another 10 days, then cumarin was administered orally.     

Clopidogrel use in children

OBJECTIVES: To review a pediatric experience with the antiplatelet agent clopidogrel and suggest a dosage regimen. STUDY DESIGN: A retrospective chart review of all infants and children treated with clopidogrel at The Hospital for Sick Children, Toronto between January 2001 and April 2004. Clopidogrel dosages, duration of therapy, complications, and adverse effects in a pediatric population were explored. RESULTS: Fifteen infants and children with congenital and acquired heart disease were treated with clopidogrel (median age, 3.5 years; range, 6 weeks to 16 years). Dosages ranged from 1 to 6 mg/kg/day for periods between 1 month and 6 months. Although no thrombotic events were reported, 1 child had a bleeding complication (gastrointestinal) while on triple antithrombotic therapy. Other complications reported in adults, including rash and clinical thrombocytopenia, were not noted in this pediatric series. CONCLUSIONS: Clopidogrel was well tolerated. We suggest a starting dose of 1 mg/kg/day for children.     

Increased enoxaparin dosing is required for obese children

Weight-based dosing for enoxaparin is recommended in the 2008 American College of Chest Physicians (ACCP) guidelines for venous thromboembolism (VTE) prophylaxis. Enoxaparin 0.5 mg/kg per dose administered subcutaneously every 12 hours is recommended for this indication in children. There is no established upper dosing limit of enoxaparin for prophylaxis in children, and the US Food and Drug Administration-approved enoxaparin dose for adults for VTE prophylaxis is 30 mg subcutaneously every 12 hours or 40 mg subcutaneously daily. Therefore, we assumed that the upper limit for children is 40 mg subcutaneously daily. We reviewed 3 cases of obese adolescent boys who required large doses of enoxaparin to achieve the ACCP-recommended anti-factor Xa range of 0.1 to 0.3 IU/mL for the prevention of VTE. All 3 patients required doses of enoxaparin that are higher than that recommended for adults for VTE prophylaxis: patient A (BMI: 105.9) required >0.28 mg/kg per dose, patient B (BMI: 95.7) required 0.15 mg/kg per dose, and patient C (BMI: 29.9) required 0.49 mg/kg per dose. The desired anti-factor Xa range was achieved when enoxaparin was administered every 12 hours in each patient with no reported episodes of VTE. One patient had minor bruising, but no other adverse events were noted. Because of the variability in dose requirements and unpredictability in patient responses demonstrated in our 3 adolescents, prospective studies are needed to provide definitive recommendations on dosing of enoxaparin for VTE prophylaxis in this subset of obese pediatric patients.     

Successful treatment of infective endocarditis with recombinant tissue plasminogen activator

OBJECTIVES: In a prospective study, we examined the effect of treatment with recombinant tissue plasminogen activator (r-TPA) on survival and morbidity in a series of high-risk children with infectious endocarditis (IE) after prolonged treatment with indwelling catheters. We hypothesized that r-TPA is an adjunctive therapy for dissolution of infected thrombi in drug-resistant IE. STUDY DESIGN: In the prospective 3-year study (1998-2001), we identified high-risk children with chronic illness and prolonged treatment with indwelling catheters who developed IE and overwhelming sepsis. Patients were allocated to receive r-TPA after persistent and enlarging intracardiac vegetations and failure to respond to conventional medical management. Complications associated with treatment, survival, and cardiac morbidity were observed. RESULTS: Seven infants were treated prospectively with r-TPA. All infants responded promptly to treatment, with resolution of the intracardiac vegetations within 3 to 4 days of commencement and without any adverse complications. All patients survived without long-term cardiac morbidity. CONCLUSION: Recombinant tissue plasminogen activator may offer a safe alternative to surgical intervention in the high-risk infant with IE.     

Combined thrombolytic and anticoagulant therapy for venous thrombosis in children

OBJECTIVES: To evaluate safety, efficacy, and outcome after combination thrombolytic and anticoagulant therapy.Study design: An open nonrandomized clinical protocol with prospective standardized monitoring and data collection. Children with a documented first episode of deep vein thrombosis were treated with urokinase 4400 U/kg load and per hour with unfractionated heparin at 10 U/kg/h. At 48 hours heparin infusions were increased to achieve a therapeutic level for 5 days. Children were given therapeutic warfarin for at least 3 months. Outcome was assessed at 48 hours and > or =1 year with history, physical examination, high-resolution imaging, and Doppler ultrasonography +/- impedance and photo plethysmography. RESULTS: Thirty-two children were treated. There was 1 thrombotic death, 1 nonfatal thrombus progression, and 1 pulmonary embolism. At 48 hours half of the children showed substantial clot lysis, and on follow-up these children had complete resolution and had no symptoms. Three children with poor early clot lysis had recurrent thromboemboli, pulmonary embolism, or both, 2 had limb pain and swelling, and 2 had asymptomatic swelling. Two children had minor bleeding, whereas systemic reactions were common. CONCLUSIONS: Combination therapy in children (urokinase and unfractionated heparin) was safe and efficacious. A prospective, randomized, controlled study in children is needed.     

Combined thrombolytic therapy for atrial thrombus in a preterm infant

Intracardiac thrombosis is a rare event in newborn (5.1 per 100000 live births). It is associated with an high morbidity and mortality. Most of intracardiac thrombi are related to intravascular catheterism. The use of thrombolytic therapy in neonates has rapidly improved in the last few years, particularly with the introduction of more clot-selective second-generation agents like urokinase and tissue plasminogen activator. In literature there is no therapeutic trial concerning the pharmacological approach of atrial thrombosis in newborns; different approaches are described in the case reports present in literature. In all of them, tissue plasminogen activator or urokinase are alternatively administered. In no case report urokinase and tissue plasminogen activator are administered in a combined thrombolytic therapy. Combined thrombolytic therapy with urokinase and tissue plasminogen activator, in association with low-dose heparin, allows the use of lower drug doses, less therapy's duration and a rapid resolution of thrombus. Thormbolytic therapy is sometimes complicated with hemorrhagic complications. This article describes the case of a preterm infant (25 weeks of gestational age) with peduncolate thrombus in the right atrium, treated with combined thrombolytic therapy. The authors noticed a rapid decrease in thrombus dimension, no thrombus replacement and no organ bleeding.     

Ketamine and midazolam for invasive procedures in children with malignancy: a comparison of routes of intravenous, oral, and rectal administration

We investigated the efficacy of a combination of ketamine and midazolam, comparing intravenous, oral, and rectal administrations for invasive procedures in children with malignancy. Seventy-three children under 5 years of age, who were scheduled for invasive procedure, were assigned to one of three groups: IV group (n = 25), ketamine 1 mg/kg and midazolam 0.05-0.1 mg/kg were given intravenously; PO group (n = 24), ketamine 3 mg/kg and midazolam 0.5 mg/kg were given orally; and PR group (n = 24), ketamine 3 mg/kg and midazolam 0.5 mg/kg given rectally. Vital signs including blood pressure, pulse rate, respiratory rate, and oxygen saturation were monitored, and patients were observed for side-effects. Optimal sedation (drowsy and asleep) was provided in 78 per cent of all patients and no statistical difference was observed among the three groups. No severe complications were observed in all groups. Recovery time from sedation was significantly longer in the intravenous group (>120 min in two patients). Hallucination was noted in three (12 per cent) patients given intravenous medication, but not in those given oral or rectal medications. It is concluded that intravenous, oral, and rectal midazolam/ketamine are equally effective for invasive procedures in children with malignancy. The use of intravenous ketamine/midazolam may produce prolonged sedation and psychedelic effects in children. These adverse effects may alter the child's comfort and parental satisfaction.     

Effect of metoclopramide on prolonged intraesophageal pH testing in infants with gastroesophageal reflux

The effect of metoclopramide (MCP) on prolonged intraesophageal pH testing was evaluated in 42 infants with gastroesophageal reflux (GER). Following a baseline period of intraesophageal pH monitoring, MCP was administered by injection at 0.1 mg/kg/dose (10 patients), 0.2 mg/kg/dose (11 patients), or 0.3 mg/kg/dose (21 patients). The percentage of time of intraesophageal pH less than 4, reflux frequency, and acid clearance time were calculated for each subject before and after MCP for both 5% dextrose and formula feedings. These parameters were further separated into 2-hour or shorter and more than 2-hour postprandial periods. No significant differences with either type of feeding were noted at either 0.1 or 0.2 mg/kg/dose. Significant decreases in the percentage of time the intraesophageal pH was less than 4 (30.0 +/- 2.9 versus 15.6 +/- 3.1, p = 0.001), the reflux frequency (episodes/hour; 6.5 +/- 0.9 versus 4.0 +/- 0.6, p = 0.004), and the acid clearance time (minutes/episode; 3.8 +/- 0.7 versus 2.2 +/- 0.3, p = 0.047) were noted in the 2-hour or shorter period following 5% dextrose feedings but not following the formula feedings in the subjects receiving 0.3 mg/kg/dose. Three of the 42 study patients developed increased irritability, and one developed dystonia following MCP. These data suggest that if a clinical trial of MCP in infants with GER is performed, a larger dose of the medication than previously appreciated might be required.     

Safety, dose, and timing of reteplase in treating occluded central venous catheters in children with cancer

OBJECTIVES: Recombinant tissue plasminogen activator, alteplase, began to be commonly used to restore the patency of occluded central venous catheters (CVCs) as urokinase production was halted in the late 1990s. However, alteplase often requires an extended dwell time to restore patency to occluded CVCs. In adults, reteplase, a newer thrombolytic agent, has been reported to restore patency to CVCs in 30 minutes. The authors prospectively evaluated the safety and efficacy of reteplase in restoring patency to occluded CVCs in children with cancer. METHODS: This was a dose escalation trial. The dose of reteplase was initiated at 0.1 units and increased by increments of 0.1 units to a maximum dose of 0.4 units. Each dose was tested on at least three participants. Time to patency after reteplase administration was recorded by nurses caring for the patients. Attempts to access the line occurred every 15 minutes for 1 hour. CVCs that remained occluded after 1 hour were treated with alteplase. RESULTS: Reteplase was administered to 15 clotted CVCs. Twelve of the 15 were cleared with an average dwell time of 38 minutes. The time to patency did not appear to correlate with the dose. No adverse events were reported. CONCLUSIONS: Reteplase can restore patency to occluded CVCs in a pediatric population. Reteplase appears to have comparable efficacy with alteplase, but reteplase may require shorter dwell times. A prospective, randomized, clinical trial is warranted to determine whether reteplase is as effective as alteplase in restoring patency to occluded CVCs.     

Immediate metabolic response to a low dose of insulin in children presenting with diabetes

Seventeen new cases of diabetes in childhood were given an initial mean dose of insulin of 0-29 unit/kg body weight by intramuscular injection (mean age of patient 7-4 years). This resulted in a fall in blood glucose over the first 2 hours at a mean rate of 88 mg/100 ml per hour. Over the same time the mean total blood ketones fell from 3-23 to 2-3 mmol; and plasma insulin levels rose from a mean of 6 muU/ml to a mean of 65 muU/ml. Thus, with this small initial dose of insulin the 2-hour plasma insulin values were within the range which in adults has been associated with a maximum fall in blood glucose concentration. Three children with established diabetes presenting with ketoacidosis were also treated with a small initial dose of intramuscular insulin, 0-1 unit/kg in 2 of the patients and 0-5 unit/kg in the third. In 2 during a period of rehydration before insulin was given, blood glucose fell at a rate of 100 mg/100 ml per hour. Over the 2 hours after the initial dose of insulin the mean rate of fall of blood glucose for all 3 patients was 73 mg/100 ml per hour. None of these children developed hypoglycaemia nor hypokalaemia during treatment. We conclude that an initial intramuscular injection of soluble insulin in the dose range of 0-1-0-5 units/kg body weight may be more appropriate and possibly safer for the treatment of diabetic ketoacidosis in children than the currently recommended larger doses divided between intravenous and intramuscular routes. Adequate rehydration must, however, remain the first priority in the management of such cases.     

咪哒唑仑与地西泮治疗小儿急性惊厥的对照研究

目的：比较咪哒唑仑（MDL）与地西泮（DZP）治疗小儿急性惊厥的疗效,探讨小儿急性惊厥安全、高效的治疗方法。方法：将120例急性惊厥患儿随机分为MDL组(60例)和DZP组(60例),分别予MDL（0.3~0.5 mg/kg）和DZP(0.5~1 mg/kg)治疗,对出现惊厥反复或呈惊厥持续状态患儿,前组给予MDL维持（每小时1~8 mg/kg）,后组给予DZP维持（每小时0.5~1 mg/kg）或联合苯巴比妥钠治疗,比较两种方法疗效。结果：全部患儿于10 min内惊厥得到基本控制,MDL组与DZP组平均控制时间差异无统计学意义。MDL组与DZP组分别有5例及13例患儿10 min后出现惊厥反复或呈惊厥持续状态。维持治疗后平均控制时间分别为40±32 min和69±24 min,差异有统计学意义 (P<0．05)。两组中无一例出现与MDL及DZP相关的副反应。结论：MDL用于治疗小儿急性惊厥安全、高效,对于惊厥反复或呈惊厥持续状态患儿,疗效优于DZP。［中国当代儿科杂志,2010,12（7）：530-532］     

Immediate metabolic response to a low dose of insulin in children presenting with diabetes.

Seventeen new cases of diabetes in childhood were given an initial mean dose of insulin of 0-29 unit/kg body weight by intramuscular injection (mean age of patient 7-4 years). This resulted in a fall in blood glucose over the first 2 hours at a mean rate of 88 mg/100 ml per hour. Over the same time the mean total blood ketones fell from 3-23 to 2-3 mmol; and plasma insulin levels rose from a mean of 6 muU/ml to a mean of 65 muU/ml. Thus, with this small initial dose of insulin the 2-hour plasma insulin values were within the range which in adults has been associated with a maximum fall in blood glucose concentration. Three children with established diabetes presenting with ketoacidosis were also treated with a small initial dose of intramuscular insulin, 0-1 unit/kg in 2 of the patients and 0-5 unit/kg in the third. In 2 during a period of rehydration before insulin was given, blood glucose fell at a rate of 100 mg/100 ml per hour. Over the 2 hours after the initial dose of insulin the mean rate of fall of blood glucose for all 3 patients was 73 mg/100 ml per hour. None of these children developed hypoglycaemia nor hypokalaemia during treatment. We conclude that an initial intramuscular injection of soluble insulin in the dose range of 0-1-0-5 units/kg body weight may be more appropriate and possibly safer for the treatment of diabetic ketoacidosis in children than the currently recommended larger doses divided between intravenous and intramuscular routes. Adequate rehydration must, however, remain the first priority in the management of such cases.