NEOnatal Central-venous Line Observational study on Thrombosis (NEOCLOT): evaluation of a national guideline on management of neonatal catheter-related venous thrombosis.

BACKGROUND: In critically ill (preterm) neonates, catheter-related venous thromboembolism (CVTE) can be a life-threatening complication. Evidence on optimal management in the literature is lacking. In the Netherlands, a consensus-based national management guideline was developed to create uniform CVTE management. OBJECTIVES: To evaluate the efficacy and safety of the national guideline. METHODS: This prospective, multicenter, observational study included all infants aged ≤6 months with CVTE in the Netherlands between 2014 and 2019. CVTE was divided into thrombosis in veins and that in the right atrium, with their own treatment algorithms. The primary outcomes were recurrent venous thrombotic events (VTEs) and/or death due to CVTE as well as major bleeding. RESULTS: Overall, 115 neonates were included (62% male; 79% preterm). The estimated incidence of CVTE was 4.0 per 1000 neonatal intensive care unit admissions. Recurrent thrombosis occurred in 2 (1.7%) infants and death due to CVTE in 1 (0.9%) infant. Major bleeding developed in 9 (7.8%) infants: 2 of 7 (29%) on recombinant tissue plasminogen activator, which was given for high-risk right-atrium thrombosis, and 7 of 63 (11%) on low-molecular-weight heparin (LMWH). Five of the 7 bleedings because of LMWH were complications of subcutaneous catheter use for LMWH administration. CONCLUSION: The management of neonatal CVTE according to the Dutch CVTE management guideline led to a low incidence of recurrent VTEs and death due to VTEs. Major bleeding occurred in 7.8% of the infants. Specific guideline adjustments may improve efficacy and, especially, safety of CVTE management in neonates.

Effectiveness and Safety of Nadroparin Therapy in Preterm and Term Neonates with Venous Thromboembolism.

INTRODUCTION: Optimal neonatal nadroparin dosages to treat venous thromboembolism (VTE) are unknown. OBJECTIVE: To evaluate therapeutic nadroparin dosages to reach therapeutic target ranges (TTR: 0.5-1.0 International Unit (IU)/mL) and the effectiveness and safety of nadroparin in neonatal VTE. METHODS: Retrospective study including neonates with VTE on nadroparin in a tertiary center between 2007 and 2018. Two groups were distinguished: neonates before (group 1) and after (group 2) switch to higher starting dosages in 2014. RESULTS: Sixty-one neonates (44 preterm, 17 term) with 64 VTEs were included. TTR was reached in 32/64 (50%) VTEs (group 1: 35.7%; group 2: 61.1%). Median nadroparin dosage to reach TTR was 197 (97.9-330.3) IU/kg/12 h. No therapy-related deaths occurred. Recurrent VTE developed in 6 (9.8%) neonates. Complete clot resolution was observed in 31/41 (75.6%) VTEs. TTR was reached in 58.1% VTEs with complete clot resolution. No major bleeding occurred. Non-major clinically relevant bleedings occurred in 3/64 (4.7%) VTEs, consisting of large hematomas due to the use of subcutaneous catheters. CONCLUSIONS: High nadroparin dosages are needed to reach TTR in neonates, which seem to be safe. Clot resolution may occur without reaching TTR. Subcutaneous catheters may cause important bleeding complications.

Are low-molecular-weight heparins safe and effective in children? A systematic review.

The incidence of venous thromboembolism (VTE) in children is rising. Hence, there is an increasing off-label use of low-molecular-weight heparin (LMWH). There is little data about therapeutic and prophylactic LWMH dosages, and their safety and efficacy. This systematic review provided an oversight of the therapeutic and prophylactic dosages of LMWH required to reach therapeutic and prophylactic target ranges. Furthermore, the safety and efficacy of LMWH, in terms of bleeding complications, achieving therapeutic and prophylactic anti-factor Xa levels, development of (recurrent) VTE and cloth resolution were reviewed. A total of 49 studies were included, encompassing 3101 patients. Initial weight-adjusted dosages to reach therapeutic or prophylactic target ranges decreased with age. In children with therapeutic use of LMWH, major bleeding complications occurred in 1.8% (95% CI: 1.1-2.5%) of the patients, a mean of 79.9% (95% CI: 77.5-82.3%) of the children achieved the target range with or without dosage adjustments, recurrent VTE occurred in 3.2% (95% CI: 2.1-4.3%) and thrombus resolution in 63.5% (96% CI: 60.2-66.8%) of the patients. In children with prophylactic LMWH, major bleedings occurred in 0.6% (95% CI: 0.2-1.0%) of the patients, a mean of 90.4% (95% CI: 84.6-96.2%) of the children achieved the target range, and 2.2% (95% CI: 1.3-3.1%) experienced a new VTE. In conclusion, a higher initial therapeutic dosage of LMWH was needed in comparison to advised dosages, to achieve target range, especially in neonates and children <5 years. LMWH appeared to be safe and effective for therapeutic and prophylactic treatment of VTE in children.

NEOnatal Central-venous Line Observational study on Thrombosis (NEOCLOT): evaluation of a national guideline on management of neonatal catheter-related thrombosis.

BACKGROUND: In critically ill (preterm) neonates, central venous catheters (CVCs) are increasingly used for administration of medication or parenteral nutrition. A serious complication, however, is the development of catheter-related thrombosis (CVC-thrombosis), which may resolve by itself or cause severe complications. Due to lack of evidence, management of neonatal CVC-thrombosis varies among neonatal intensive care units (NICUs). In the Netherlands an expert-based national management guideline has been developed which is implemented in all 10 NICUs in 2014. METHODS: The NEOCLOT study is a multicentre prospective observational cohort study, including 150 preterm and term infants (0-6 months) admitted to one of the 10 NICUs, developing CVC-thrombosis. Patient characteristics, thrombosis characteristics, risk factors, treatment strategies and outcome measures will be collected in a web-based database. Management of CVC-thrombosis will be performed as recommended in the protocol. Violations of the protocol will be noted. Primary outcome measures are a composite efficacy outcome consisting of death due to CVC-thrombosis and recurrent thrombosis, and a safety outcome consisting of the incidence of major bleedings during therapy. Secondary outcomes include individual components of primary efficacy outcome, clinically relevant non-major and minor bleedings and the frequency of risk factors, protocol variations, residual thrombosis and post thrombotic syndrome. DISCUSSION: The NEOCLOT study will evaluate the efficacy and safety of the new, national, neonatal CVC-thrombosis guideline. Furthermore, risk factors as well as long-term consequences of CVC-thrombosis will be analysed. TRIAL REGISTRATION: Trial registration: Nederlands Trial Register NTR4336 . Registered 24 December 2013.

Developmental Hemostasis and Management of Central Venous Catheter Thrombosis in Neonates.

Neonatal hemostasis differs qualitatively, but in particular quantitatively, from hemostasis in older children and adults. Nevertheless, hemostasis in healthy neonates is functionally stable with no tendency to bleeding or thrombotic complications. In sick neonates, however, risk factors may disrupt this equilibrium and lead to thrombosis. The most important risk factor is the central venous catheter. Management of neonatal central venous catheter thrombosis is challenging, as no controlled trials have been performed. Therapeutic options include (1) observation and supportive treatment; (2) anticoagulant agents, including low-molecular-weight heparin and unfractionated heparin; (3) thrombolytic agents; and (4) thrombectomy. Prevention of thrombosis with anticoagulation is not advised yet. Careful consideration of the necessity of the catheter and optimal hygienic care are important preventative measures.

Chronic Complications After Femoral Central Venous Catheter-related Thrombosis in Critically Ill Children.

Prescription of thromboprophylaxis is not a common practice in pediatric intensive care units. Most thrombi are catheter-related and asymptomatic, without causing acute complications. However, chronic complications of these (a)symptomatic catheter-related thrombi, that is, postthrombotic syndrome (PTS) and residual thrombosis have not been studied. To investigate these complications, critically ill children of 1 tertiary center with percutaneous inserted femoral central venous catheters (FCVCs) were prospectively followed. Symptomatic FCVC-thrombosis occurred in 10 of the 134 children (7.5%; 95% confidence interval [CI], 2.4-9.5). Only FCVC-infection appeared to be independently associated (P=0.001) with FCVC-thrombosis. At follow-up 2 of the 5 survivors diagnosed with symptomatic thrombosis developed mild PTS; one of them had an occluded vein on ultrasonography. A survivor without PTS had a partial occluded vein at follow-up. Asymptomatic FCVC-thrombosis occurred in 3 of the 42 children (7.1%; 95% CI, 0.0-16.7) screened by ultrasonography within 72 hours after catheter removal. At follow-up, mild PTS was present in 6 of the 33 (18.2%; 95% CI, 6.1-30.3) screened children. Partial and total vein occlusion was present in 1 (3%) and 4 (12%) children, respectively. In conclusion, children on pediatric intensive care units are at risk for (a)symptomatic FCVC-thrombosis, especially children with FCVC-infection. Chronic complications of FCVC-thrombosis are common. Therefore, thromboprophylaxis guidelines are warranted in pediatric intensive care units to minimize morbidity as a result of FCVC-thrombosis.

Serial cranial US for detection of cerebral sinovenous thrombosis in preterm infants.

PURPOSE: To report the incidence of cerebral sinovenous thrombosis (CSVT) in a prospective cohort of preterm infants with a gestational age of less than 29 weeks. MATERIALS AND METHODS: The local medical ethics review board approved this study, and written parental consent was obtained. Preterm infants with a gestational age of less than 29 weeks who were admitted to the neonatal intensive care unit were prospectively studied with cranial ultrasonography (US). The scanning protocol included visualization with color Doppler imaging of the superior sagittal sinus and transverse sinuses through the anterior (8.5-MHz probe) and mastoid (13-MHz probe) fontanelles. When feasible, magnetic resonance imaging was performed to confirm cranial US-diagnosed CSVT. The differences between preterm infants with and those without CSVT were analyzed by using Mann-Whitney tests for continuous variables and Fisher exact tests for categorical data. RESULTS: Cranial US was used to document CSVT in 11 of 249 preterm infants with a gestational age of less than 29 weeks. Transverse sinuses were most frequently affected (in all 11 patients with CSVT). All infants with CSVT were asymptomatic. Postnatal age at diagnosis ranged from 5 to 34 days. The mean gestational age was significantly lower in infants with CSVT (25.9 weeks vs 26.8 weeks, P = .038). Of the risk factors studied, only duration of mechanical ventilation was associated with CSVT; it was significantly longer in the CSVT group. CONCLUSION: Systematic serial cranial US of infants with a gestational age of less than 29 weeks showed a remarkably high incidence of CSVT of 4.4%. Cranial US including color Doppler imaging with scans obtained through the mastoid fontanelle can depict CSVT at an early stage. Treatment of this possibly important condition needs attention.

An explorative study on quality of life and psychological and cognitive function in pediatric survivors of septic shock.

OBJECTIVE: To evaluate self-reported health-related quality of life, anxiety, depression, and cognitive function in pediatric septic shock survivors. DESIGN: A retrospective cohort study. SETTING: A 14-bed tertiary pediatric intensive care unit. PATIENTS: Children aged >or=8 yrs at the time of the follow-up who were admitted between 1995 and 2004 for septic shock. Inotropic and or vasoconstrictive agents were administered to these patients for >or=24 hrs. INTERVENTION: Health-related quality of life was assessed with the KIDSCREEN-52, anxiety with the State Trait Anxiety Inventory for Children, depression with the Children's Depression Inventory, and cognitive function with the cognitive scale of the TNO-AZL Children's Quality of Life Questionnaire Child Form. MEASUREMENTS AND MAIN RESULTS: Fifty of 82 eligible pediatric septic shock survivors were evaluated. The median age of the children at pediatric intensive care unit admission was 4.2 yrs (range, 0.0-17.0 yrs); the median age at follow-up was 10.7 yrs (range, 8.0-20.4 yrs). Health-related quality of life and anxiety scores were comparable to the age-related Dutch norm population. Depression scores were significantly better than the norm population, whereas cognitive function was significantly lower than the norm population. We found that 44% of the children had cognitive scores <25% of the norm population. Young age at the time of pediatric intensive care unit admission was predictive of cognitive problems, and cognitive problems were associated with lower emotional function. CONCLUSIONS: In this group of septic shock survivors, health-related quality of life, anxiety, and depression are equal to or slightly better than the age-related Dutch norm population. Cognitive function is decreased, especially in children admitted at younger ages. Follow-up studies with adequate neuropsychological testing are warranted to evaluate the association between septic shock, cognitive function, and risk factors for cognitive problems.

Cardiac function in pediatric septic shock survivors.

OBJECTIVE: To evaluate the long-term effects of septic shock on cardiac function in children treated with inotropic and/or vasoconstrictive agents for 24 hours or longer. DESIGN: Cohort study. SETTING: Tertiary pediatric intensive care unit and outpatient follow-up clinic. PARTICIPANTS: One hundred eight of 144 eligible children who were admitted to our tertiary pediatric intensive care unit with septic shock from 1995 through 2005 and were alive in 2006 were invited to participate and visit our outpatient follow-up clinic. Fifty-two healthy controls were included. MAIN EXPOSURE: Septic shock survival. OUTCOME MEASURES: History, physical examination, electrocardiogram during rest and exercise, 24-hour electrocardiography registration, and left and right ventricular function. RESULTS: No children had abnormalities when histories were taken or during physical examination that were attributable to cardiac dysfunction. Six children (6%) had cardiac abnormalities: polymorphic premature ventricular contractions during exercise and 24-hour electrocardiography registration (2 patients), decreased left ventricular function (2 patients), decreased left ventricular function and polymorphic premature ventricular contractions (1 patient), and decreased right ventricular function (1 patient). CONCLUSIONS: In this small and diverse group of pediatric septic shock survivors, we found an excellent recovery of cardiac performance in most patients. In a limited number of patients, we found rhythm disturbances and decreased ventricular function. We believe that, against the background of aging, long-term cardiac follow-up of these patients is important.