Low-dose warfarin for the prevention of central line-associated thromboses in children with malignancies--a randomized, controlled study

Background: Central venous lines (CVLs) are essential in the care of children with malignancies, but are associated with venous thromboembolism (VTE) and infections. Effective and safe prophylactic approaches are deficient. Aim: To perform a study of adjusted low-dose warfarin for the prevention of CVL-related VTE in children with malignancies. Methods: Children with newly diagnosed cancer, a CVL in a jugular vein and an expected treatment period of over 6 mo were eligible for the study. Participants were randomized to low-dose warfarin, with intended international normalized ratio (INR) 1.3-1.9, or to a control group. Primary outcome was VTE in a jugular vein diagnosed by ultrasonography at 1, 3 and 6 mo after inclusion. Secondary outcome was CVL-related infections, mainly measured as days on antibiotics or positive blood cultures. Results: The study enrolled 73 children, and 62 completed it fully. Asymptomatic CVL-related VTE was frequent (42%), but often transient. Regardless of severity, timing and duration, CVL-related VTE was equally frequent among children on warfarin as compared to controls (p=0.44). Low-dose warfarin (p=0.59) or jugular CVL-related VTE (p=0.91) did not have any impact on days on antibiotics, but we observed a tendency towards an association between CVL-related VTE and positive blood cultures (p=0.15).

Conclusion: Our randomized study of low-dose oral anticoagulation for the prevention of CVL-related asymptomatic VTE in children with cancer did not show any benefit of warfarin adjusted to maintain INR between 1.3 and 1.9.     

Post-thrombotic syndrome.

Post-thrombotic syndrome (PTS) is a potentially disabling complication occurring in up to 67% of adult patients following deep venous thrombosis (DVT). PTS has recently been recognised in children. We present three cases of symptomatic PTS in children, which occurred following the use of central venous lines (CVLs). In two cases, no symptoms of acute thrombosis were noted. The cases highlight the clinical presentation of this syndrome. A review of the literature revealed two reports describing PTS occurring in children following DVT with an estimated incidence of 7-12%. It is concluded that PTS is an important complication of DVT in children. The clinical findings of pain, swelling, and brawny induration are similar to adult patients. The effect on growing limbs is not known. Paediatricians should be aware of the potential of PTS in all children who are at risk of DVT, including patients with malignancy, congenital heart disease, and children who have had previous CVLs, even in the absence of documented acute DVT.     

Long term complications of inferior vena cava thrombosis.

AIM: To evaluate the long term outcome after paediatric inferior vena cava (IVC) thrombosis. METHODS: A combined retrospective and prospective study on infants and children with IVC thrombosis treated at Aachen and Maastricht University Hospitals between 1980 and 1999. RESULTS: Forty patients were enrolled, including four with preceding cardiac catheterisation, 18 with central venous saphenous lines, and an additional eight with umbilical venous catheters. Six patients died within three months of diagnosis; one patient was lost to follow up. Twelve of the remaining 33 patients had suffered from limited IVC thrombosis; during follow up (for up to nine years) none showed persisting caval obstruction (successful thrombolysis, n = 2; spontaneous recanalisation, n = 10). The remaining 21 patients presented with extensive IVC thrombosis. During follow up (for up to 18 years) complete restitution was found in only four cases (one thrombolysis, two surgery, one spontaneous recanalisation). Persisting iliac and/or caval venous obstruction occurred in 17 patients, including six with thrombolysis. Varicose veins were found in 12, and post-thrombotic syndrome in seven of these cases. According to Kaplan-Meier analysis, 30% of patients with persisting venous disease will develop post-thrombotic syndrome within 10 years of the thrombotic event. CONCLUSIONS: Infants and children with extensive IVC thrombosis are at high risk for persisting venous disease and serious long term complications. Prospective trials are urgently needed to establish effective treatment strategies and to improve long term prognosis. Central venous catheters, contributing to IVC thrombosis in the majority of cases reported here, should be inserted only if essential.     

Sequelae and post-thrombotic syndrome after venous thromboembolism in acute lymphoblastic leukemia survivors treated on the NOPHO ALL2008 protocol

The treatment of acute lymphoblastic leukemia (ALL) is frequently complicated by toxicity, including venous thromboembolism (VTE) affecting roughly 8% of patients. VTE can lead to post-thrombotic syndrome (PTS), a group of signs and symptoms developed as a complication to deep venous thrombosis (DVT), imposing risk of permanent disability and reduced quality of life (QoL). PTS prevalence ranges from 0% to 70%, reflecting very heterogenous cohorts and assessment tools. We aimed to estimate sequelae, including PTS and QoL in children and adults (<45 years old) who had a DVT during ALL treatment. PTS and QoL scores were obtained through use of Villalta and Modified Villalta Scale, PedsQL, and Short Form-36 questionnaires. The cohort comprised 20 children (<18 years) and seven adults (median age: 12.9 years, range: 2–44 years) at the time of DVT diagnosis. In total, 25 ALL survivors underwent PTS examination. The examination took place when survivors were 7–48 years (median age: 20.3 years, median follow-up time 6.8 years). QoL was assessed correlating cases with three matching ALL survivors without VTE. Two adults (15.4%) showed mild or moderate PTS. Eight children (66.7%) were diagnosed with mild PTS, while three cases had collaterals as sole symptoms. Pain or symptoms affecting daily life were reported by 16%. No difference in QoL was found (p = .9). This study underscores the need for comprehensive population-based investigations with validation of PTS instruments in ALL survivors.     

Prevalence of thrombophilia and central venous catheter-associated neck vein thrombosis in 41 children with cancer--a prospective study

BACKGROUND: This study was designed to prospectively evaluate the prevalence of thrombophilia and central venous catheter-associated neck vein thrombosis in children with cancer. PROCEDURE: Children with cancer and central lines, treated at the National Hospital in Norway, were consecutively enrolled in the study. Biochemical analysis of thrombophilia and Doppler ultrasonography of neck veins were performed at inclusion, and ultrasonography was repeated 3-5 months later. We recorded systematically positive blood-cultures and days with intravenous antibiotics. In a subgroup of 13 patients with acute lymphoblastic leukaemia, the thrombophilia parameters were re-evaluated during asparaginase therapy. RESULTS: Forty-one children were included in the study and observed for a mean of 266 days (range 95-569 days). Eighteen patients (44%) developed venous thrombosis (VT), visualized by Doppler ultrasonography of the catheterized vein. Some clots were transient, but blood clots with diameters > 0.5 cm (n = 11) had a tendency to remain (P = 0.14). Twelve children (29%) were classified as thrombophilic at inclusion, with elevated serum levels of homocysteine and lipoprotein (a) as the most frequent alterations. Transient thrombophilia developed in all patients during asparaginase-therapy. Within the limitations of our study, we did not find any significant correlation between thrombophilia and development of VT, nor thrombosis and infectious disease. CONCLUSIONS: VT develops frequently in paediatric cancer patients with central lines, but the clinical implication of this observation remains to be clarified.     

Thromboprophylaxis of central venous lines in children with cancer: the first steps taken on the long road ahead

Approximately one third of children with malignancy and central venous lines develop catheter-related thrombosis, with the reported sequelae including death, pulmonary embolism, chylothoraces, superior vena cava syndrome and post-thrombotic syndrome. These complications prompt the design and completion of randomized, controlled trials to determine a safe and efficacious therapy to prevent these thromboses. The authors Ruud et al. have presented a well-designed, randomized, controlled trial which demonstrates the lack of utility of using low-dose warfarin to prevent catheter-related thrombosis in children with central lines and acute lymphoblastic leukaemia. The difficulties with warfarin in children are again demonstrated in this study.

Conclusion: Further studies are warranted using other thromboprophylactic agents with less or no monitoring and fewer drug interactions, including the newer anticoagulant agents such as direct thrombin inhibitors.     

Long term complications of inferior vena cava thrombosis

AIM—To evaluate the long term outcome after paediatric inferior vena cava (IVC) thrombosis.
METHODS—A combined retrospective and prospective study on infants and children with IVC thrombosis treated at Aachen and Maastricht University Hospitals between 1980 and 1999.
RESULTS—Forty patients were enrolled, including four with preceding cardiac catheterisation, 18 with central venous saphenous lines, and an additional eight with umbilical venous catheters. Six patients died within three months of diagnosis; one patient was lost to follow up. Twelve of the remaining 33 patients had suffered from limited IVC thrombosis; during follow up (for up to nine years) none showed persisting caval obstruction (successful thrombolysis, n = 2; spontaneous recanalisation, n = 10). The remaining 21 patients presented with extensive IVC thrombosis. During follow up (for up to 18 years) complete restitution was found in only four cases (one thrombolysis, two surgery, one spontaneous recanalisation). Persisting iliac and/or caval venous obstruction occurred in 17patients, including six with thrombolysis. Varicose veins were found in 12, and post-thrombotic syndrome in seven of these cases. According to Kaplan-Meier analysis, 30% of patients with persisting venous disease will develop post-thrombotic syndrome within 10years of the thrombotic event.
CONCLUSIONS—Infants and children with extensive IVC thrombosis are at high risk for persisting venous disease and serious long term complications. Prospective trials are urgently needed to establish effective treatment strategies and to improve long term prognosis. Central venous catheters, contributing to IVC thrombosis in the majority of cases reported here, should be inserted only if essential.

     

Post-thrombotic syndrome in children: a single center experience

BACKGROUND: Development of post-thrombotic syndrome (PTS) is increasingly being recognized as a complication of deep venous thrombosis (DVT) in children. OBJECTIVE: To determine the prevalence, clinical characteristics, and predictors of moderate to severe PTS in children. METHODS: A retrospective chart review was performed on those children who were followed in the coagulation clinic for objectively confirmed DVTs from December 2004 to December 2006. The scoring system used by Kuhle et al was used to grade the severity of PTS as: mild, moderate, and severe. RESULTS: PTS developed in 20% (11/55; 95% confidence interval 9.4-30.1) of children, in which 8/11 were moderate and 3/11 were severe. Median interval between diagnosis of PTS and DVT was 90 days (range, 46 d to 3 y). The majority (72.7%) of patients in the non-PTS group received treatment intervention within 48 hours of diagnosis of DVT. Delay in treatment initiation (>48 h) and recurrence of DVT were associated with the development of PTS (P<0.05). Variables including occlusive thrombus, location and number of vessels involved with DVT, age at diagnosis, underlying thrombophilia, intensity of anticoagulation, and body mass index were not associated with the development of PTS. Other debilitating consequences of DVT requiring intervention included portal hypertension (n=2), chylothorax (n=1), and reflux sympathetic dystrophy (n=1). The small sample size and limited follow up restricted the statistical analysis. CONCLUSIONS: PTS is a significant problem in children with symptomatic DVTs. Early treatment intervention within the first 48 hours of diagnosis of DVT and prevention of thrombosis recurrence may prevent development of PTS. Although PTS refers to consequences of intravenous hypertension owing to extremity DVTs, sequlae of nonextremity DVTs require special consideration in pediatric PTS classification.     

Catheter-related thrombosis in children with cancer

OBJECTIVE: The prevalence of asymptomatic catheter-related thrombosis of the upper venous system in children with cancer has not been determined. We evaluated patients with cancer and implantable central venous catheters (ports) for this complication. STUDY DESIGN: Children with cancer undergoing port removal were eligible for this study. Vessel patency was evaluated by contrast venography. We examined each child for physical stigmata of thrombosis and retrospectively assessed catheter-related mechanical difficulties and infections. RESULTS: Thirty-one ports had been placed in 24 children (aged 20 months to 18 years; median age, 9 years) with diagnoses of leukemia/lymphoma (n = 10), solid tumor (n = 12), and histiocytosis (n = 2). Venography showed abnormalities in 12 of the 24 patients. Physical examination revealed dilated superficial veins on the chest in 3 patients. Venograms showed abnormalities in all 3 children with prominent superficial thoracic veins. Nine of the 21 other patients had clinically occult central venous occlusion. CONCLUSION: Fifty percent (95% CI, 30% to 70%) of children who had implantable ports removed during or after treatment of cancer exhibited deep venous thrombosis at the site of catheter placement. Future studies should determine the contribution of inherited and other acquired risk factors for thrombosis and assess measures to prevent and/or treat catheter-related thrombosis in this population.     

Post-thrombotic syndrome is uncommon in childhood cancer survivors

Deep vein thrombosis occurs in up to 50% of children with tunneled central venous catheters (CVCs). CVC-related deep vein thrombosis involving the upper extremity is usually asymptomatic but can result in post-thrombotic syndrome (swelling, pain, skin changes, and functional impairment). In a cohort of childhood cancer survivors evaluated clinically a mean of 7.5 +/- 2.8 years after completion of therapy who previously had CVCs in place for a median 15.5 months, none of 50 patients (95% CI = 0% to 6%) had these features diagnostic of post-thrombotic syndrome. Five patients had arm circumference 3% to 5% greater ipsilateral to the prior CVC.     

Evaluation of pediatric oncology patients with previous multiple central catheters for vascular access: Is doppler ultrasound needed?

BACKGROUND/PURPOSE: Pediatric oncology patients who have undergone placement of multiple central venous catheters may have thrombosis or stenosis in the upper venous system. The purpose of this study was to identify factors that predict venous thrombosis or stenosis and to evaluate the role of Doppler ultrasonography in assessing the upper venous system of pediatric patients requiring multiple central vascular catheters. METHODS: The medical records of eligible patients were reviewed with regard to demographics, primary disease, type of catheter, duration of previous central venous access, association with infection, operative notes, and Doppler ultrasonographic findings. RESULTS: Our evaluation criteria were met in 50 cases (47 patients). In 10 cases, Doppler ultrasonography revealed abnormality in the upper venous system. Patient demographics, primary disease, type of catheter, duration of previous central venous access, or association with infection were not found to significantly predict the abnormality in the upper venous system. Placement of central venous access device was performed without difficulty when the site of placement was chosen on the basis of ultrasonographic findings. CONCLUSION: Doppler ultrasonography is useful in diagnosing thrombosis or stenosis in asymptomatic pediatric patients requiring placement of multiple central venous catheters.     

Bacterial aetiology of acute osteoarticular infections in children

Aim: To study the bacterial aetiology of acute osteoarticular infections in children and to analyse the efficiency of culture methods. Methods: Bacteriological data of 407 cases of clinically suspected osteoarticular infections affecting 406 children hospitalized in an orthopaedic surgery department between 1999 and 2002 were retrospectively reviewed. Results: Bacterial cultures from clinical specimens were positive in 74 cases (18%): 38 cases of septic arthritis and 36 cases of bone infections (osteitis, osteomyelitis or osteoarthritis). The use of liquid medium bottles to grow bacteria from articular fluids increased the rate of positive cultures compared to the use of standard solid media (p=0.0001). The most commonly recovered pathogen was Staphylococcus aureus (44%) followed by Kingella kingae (14%), Streptococcus pyogenes (10%) and Streptococcus pneumoniae (10%). K. kingae was most frequently isolated among children under 36 mo of age (p=0.0003), whereas S. aureus was most frequently isolated among children over 36 mo (p=0.0015).

Conclusion: By improving our culture method, we observed a recrudescence of isolation of K. kingae, but S. aureus remains the main pathogen isolated from osteoarticular infections in children. This finding is useful for the adaptation of a probabilistic antibiotic treatment of these infections.     

Inferior vena cava thrombosis as a complication of femoral vein catheterisation.

Indwelling femoral venous catheters were prospectively studied by ultrasonography to define the frequency and evolution of inferior vena cava (IVC) thrombosis. IVC thrombosis was identified in six of 56 catheters (54 children). Only one patient with a positive ultrasound scan had clinical signs of thrombosis. All children with IVC thrombosis had had catheters in place for over six days. It is recommended that either the femoral central venous catheters are routinely changed at six days or ultrasound studies are routinely performed twice a week in all patients with catheters in situ for six or more days and that the catheter is removed immediately if evidence of thrombosis appears.     

Sonographic evaluation of suspected pediatric vascular diseases

Sonographic studies on 52 children with suspected peripheral vascular disease examined between January 1988 and December 1989 were retrospectively reviewed. A technique for examining the jugular, subclavian veins, and superior vena cava (SVC) was developed and is described. The technique for examining the extremities in the child is similar to the adult except higher frequency transducers are used. Twenty-six patients had normal examinations. Twenty-six examinations were abnormal with arterial or venous thrombosis in patients with central lines [10 patients], deep venous thrombosis in patients with painful swollen extremities [9], arterial pseudoaneurysm as a complication of vascular punctures [1], arteriovenous fistula in a renal dialysis patient [1], dilated vessel presenting as a mass [1], compression of a vessel by a mass resulting in extremity swelling [2]. Two patients had other etiologies causing their symptoms and diagnosed on sonography including an infected hematoma and a hip effusion. The advantages of sonography include no contrast material necessary, nonionizing radiation, qualitative and quantitative characterization of vascular flow is possible with Doppler, and the examination can be performed portably. Color Doppler aided in localizing the vessel, visualizing the thrombus, as well as decreasing exam time. Doppler sonography usually answered the clinical question and made further invasive procedures such as venograms and arteriograms unnecessary.     

Prolonged bacteremia with catheter-related central venous thrombosis

Infection of a central venous thrombus is a serious but rarely recognized complication of the use of central venous catheters in children. We report the cases of seven children with persistent bacteremia or fungemia in which central venous thrombosis was demonstrated by ultrasonography after removal of the catheter. All patients had signs and symptoms of infection, but only one had clinical evidence of central venous stasis. Bacteremia persisted from 6 to 35 days. Infection did not resolve in any patient prior to catheter removal, and five patients had positive blood cultures for 5 or more days after removal of the catheter. Six patients, including all who survived, were treated parenterally with antibiotics for more than 28 days. Two patients died; neither death was directly attributable to infection. Central venous thrombosis should be suspected in patients with persistent catheter-related bacteremia. Optimal treatment of this problem is not yet known.     

Percutaneous endoscopic gastrostomy in children with cancer

We reviewed the clinical course of 32 children with cancer who received nutrition through a feeding tube placed percutaneously during gastroscopy (PEG). Their median age was 5.1 y (75%, range: 1.8-13.7 y, min: 3.5 mo) when the PEG was done 0.7-23 mo after diagnosis (median: 1.8 mo, 75%; range: 0.9-8 mo). Five of the children underwent bone marrow transplantation with the gastrostomy in place. There was a significant (p     

Central venous catheter insertion by femoral vein: safety and effectiveness for the pediatric patient

Prospective observations made during surveillance of routine central venous catheterizations for hemodynamic monitoring were evaluated to determine the safety and effectiveness of femoral insertion of central venous catheters and to demonstrate the feasibility of teaching pediatric residents to perform this procedure. During a 19-month period of observation, 29 pediatric patients requiring a central venous catheter underwent attempted percutaneous femoral vein catheterization. Femoral catheterization was successful in 86% of patients attempted, and insertions by pediatric residents were successful in 68% of patients attempted. Arterial puncture was the only significant complication of insertion, occurring in 14%, and was not associated with adverse sequelae. During 33 months of observations, complications of indwelling femoral central venous catheters did not significantly exceed the frequency for internal and external jugular, subclavian, and antecubital central venous catheters. During more than 4 years of observation, the significant complications associated with indwelling femoral central venous catheters were swelling of the leg or documented thrombosis in 11% of 74 critically ill patients. These observations indicate safety and effectiveness of femoral central venous catheters which compares favorably to central venous catheter insertion by other routes. In contrast to previous reports of central venous catheter insertion via subclavian and internal jugular veins, we observed no cardiorespiratory compromise as a result of femoral central venous catheter complications. Skill in this technique is a feasible educational goal for pediatric residents.     

Complications of central venous catheterization in critically ill children

BACKGROUND: Placement of central venous catheter is essential in the management of critically ill children. The purpose of the present paper was to evaluate the success rate, mechanical and thrombotic complications and risk factors associated with these complications from different central venous access sites in critically ill children. METHODS: A prospective study was undertaken from February 2000 to March 2005 of 369 central venous catheterizations in children in a pediatric intensive care unit. RESULTS: The veins most frequently used were femoral vein (45%), subclavian vein (32.2%), and internal jugular vein (22.8%). Mean +/- SD duration of catheterization was 9.5 +/- 6.5 days. The procedure was performed under emergency conditions in 18% of patients with an overall success rate of 92.4%. The success rate was significantly lower in younger patients with subclavian catheterization. Insertion-related complications were noted, including 33 arterial punctures (8.9%), 27 cases of malposition (7.3%), 19 hematomas (5.2%), 12 cases of minor bleeding (3.3%), and three cases of pneumothorax (0.8%), and they were more common in the subclavian vein than in the internal jugular and femoral vein. Multiple attempts and failed attempts significantly correlated with higher incidence of complications. Maintenance-related complications included obstruction (n = 26; 7%), accidental removal (n = 14; 3.8%), central venous thrombosis (n = 8; 2.2%), subcutaneous extravasation (n = 14; 3.8%), dislodgment (n = 1; 0.25%), and extravascular infusion (n = 1; 0.25%). The frequency of catheter maintenance-related complications was significantly higher in femoral catheterizations and increased significantly with an increase in the duration of catheterization. A total of five serious complications were seen (pneumothorax in three, dislodgment in one and extravascular infusion in one) in the present series. CONCLUSIONS: Central venous catheterization in critically ill children is a relatively safe procedure, with a 1.3% rate of serious complications and no mortality. It seems safer to choose initially the femoral or internal jugular vein instead of the subclavian vein because of high success rate without serious insertion-related complications.     

Sonographic detection of internal jugular vein thrombosis after central venous catheterization in the newborn period

We sonographically investigated the internal jugular veins of 40 children who had undergone catheterization of the vein (group A: silastic catheter,n-24; group B: polyurethane catheter,n=16) in the neonatal period. The average age at catheter implantation was 43±73 days, the average birthweight 2414±1145 g, and the average gestational age 34.8±5.0 weeks. We performed follow-up longitudinal and transverse high resolution sonographic scans including routine examination of the contralateral jugular vein at a mean age of 3.7±1.5 years. In group A thrombotic alterations were detected in 8 aut of 24 patients. In three of these patients we found mild clinical symptoms. In group B thrombotic alterations were detected in 1 aut of 16 patients without clinical symptoms. Mean birthweight (1815 versus 3313 g) and mean gestational age (32.3 versus 38 weeks) were significantly lower and indwelling time of the catheters (18 versus 11 days) was significantly longer in group A. Our results indicate that jugular vein thrombosis is a frequent long-term complication in neonates after jugular vein catheterization. High resolution ultrasonography is an adequate method for detecting jugular vein thrombosis and should therefore routinely be performed for long-term follow-up.     

Prophylaxis with urokinase in pediatric oncology patients with central venous catheters

This study evaluated the effects of urokinase in the prevention of central venous catheter (CVC)-related complications in children with malignancy. Fifteen patients with 16 CVCs (study group A) received an intraluminal application of urokinase (10,000 IU in each catheter lumen for 4 h) once a week. They were monitored prospectively with quantitative blood cultures and ultrasonography (color Doppler ultrasound of the great veins and echocardiography). The rate of complications was compared with that of 15 children with 19 CVCs without thromboprophylaxis, treated the previous year (control group B). The authors found a significantly lower incidence of CVC dysfunction (3/16 versus 13/19), no major thrombosis, fewer CVC-related bacteremias (2/16 versus 8/19), and a higher salvage of CVCs (1/16 versus 5/19 CVC removals due to persistent bacteremia) in the thromboprophylaxis group. Asymptomatic thrombosis rate was also lower (7/16 cases in group A versus 9/11 in group B when sonography was performed). No hemorrhagic complications were noted. Thromboprophylaxis with urokinase seems a safe and effective measure for reducing the rate of CVC-related complications.