Age-Dependent Heterogeneity in the Efficacy of Prophylaxis With Enoxaparin Against Catheter-Associated Thrombosis in Critically Ill Children: A Post Hoc Analysis of a Bayesian Phase 2b Randomized Clinical Trial.

OBJECTIVES: We explored the age-dependent heterogeneity in the efficacy of prophylaxis with enoxaparin against central venous catheter-associated deep venous thrombosis in critically ill children. DESIGN: Post hoc analysis of a Bayesian phase 2b randomized clinical trial. SETTING: Seven PICUs. PATIENTS: Children less than 18 years old with newly inserted central venous catheter. INTERVENTIONS: Enoxaparin started less than 24 hours after insertion of central venous catheter and adjusted to anti-Xa level of 0.2-0.5 international units/mL versus usual care. MEASUREMENTS AND MAIN RESULTS: Of 51 children randomized, 24 were infants less than 1 year old. Risk ratios of central venous catheter-associated deep venous thrombosis with prophylaxis with enoxaparin were 0.98 (95% credible interval, 0.37-2.44) in infants and 0.24 (95% credible interval, 0.04-0.82) in older children greater than or equal to 1 year old. Infants and older children achieved anti-Xa level greater than or equal to 0.2 international units/mL at comparable times. While central venous catheter was in situ, endogenous thrombin potential, a measure of thrombin generation, was 223.21 nM.min (95% CI, 8.78-437.64 nM.min) lower in infants. Factor VIII activity, a driver of thrombin generation, was also lower in infants by 45.1% (95% CI, 15.7-74.4%). Median minimum platelet count while central venous catheter was in situ was higher in infants by 39 × 103/mm3 (interquartile range, 17-61 × 103/mm3). Central venous catheter:vein ratio was not statistically different. Prophylaxis with enoxaparin was less efficacious against central venous catheter-associated deep venous thrombosis at lower factor VIII activity and at higher platelet count. CONCLUSIONS: The relatively lesser contribution of thrombin generation on central venous catheter-associated thrombus formation in critically ill infants potentially explains the age-dependent heterogeneity in the efficacy of prophylaxis with enoxaparin.

Efficacy of Early Prophylaxis Against Catheter-Associated Thrombosis in Critically Ill Children: A Bayesian Phase 2b Randomized Clinical Trial.

OBJECTIVES: We obtained preliminary evidence on the efficacy of early prophylaxis on the risk of central venous catheter-associated deep venous thrombosis and its effect on thrombin generation in critically ill children. DESIGN: Bayesian phase 2b randomized clinical trial. SETTING: Seven PICUs. PATIENTS: Children less than 18 years old with a newly inserted central venous catheter and at low risk of bleeding. INTERVENTION: Enoxaparin adjusted to anti-Xa level of 0.2-0.5 international units/mL started at less than 24 hours after insertion of central venous catheter (enoxaparin arm) versus usual care without placebo (usual care arm). MEASUREMENTS AND MAIN RESULTS: At the interim analysis, the proportion of central venous catheter-associated deep venous thrombosis on ultrasonography in the usual care arm, which was 54.2% of 24 children, was significantly higher than that previously reported. This resulted in misspecification of the preapproved Bayesian analysis, reversal of direction of treatment effect, and early termination of the randomized clinical trial. Nevertheless, with 30.4% of 23 children with central venous catheter-associated deep venous thrombosis on ultrasonography in the enoxaparin arm, risk ratio of central venous catheter-associated deep venous thrombosis was 0.55 (95% credible interval, 0.24-1.11). Including children without ultrasonography, clinically relevant central venous catheter-associated deep venous thrombosis developed in one of 27 children (3.7%) in the enoxaparin arm and seven of 24 (29.2%) in the usual care arm (p = 0.02). Clinically relevant bleeding developed in one child randomized to the enoxaparin arm. Response profile of endogenous thrombin potential, a measure of thrombin generation, was not statistically different between trial arms. CONCLUSIONS: These findings suggest the efficacy and safety of early prophylaxis that should be validated in a pivotal randomized clinical trial.

Protein biomarkers for incident deep venous thrombosis in critically ill adolescents: An exploratory study.

BACKGROUND: There are no tests to identify critically ill children at high risk of deep venous thrombosis (DVT). In this exploratory study, we aimed to identify proteins that are associated with incident DVT in critically ill adolescents. PROCEDURE: Plasma samples were obtained from critically ill adolescents within 24 hours after initiation of cardiopulmonary support. The adolescents were followed with ultrasound to detect the development of DVT of the lower extremity and clinically for bleeding. Thrombin-antithrombin complex and prothrombin fragment 1+2 were measured using immunosorbent assays, whereas procoagulation and anticoagulation factors were measured using multiplex assays. Plasma samples were also analyzed using SOMAscan, an aptamer-based capture assay. The associations between DVT and the log-transformed level of the proteins were assessed using logistic regression adjusting for the presence of femoral venous catheter and severity of illness. Associations were expressed as odds ratio (OR) for every log-fold increase in level of the protein with 95% confidence interval (CI). RESULTS: Plasma from 59 critically ill adolescents, of whom 9 developed incident DVT, was analyzed. The median age of the adolescents was 15.1 years (interquartile range, 14.0-16.7 years). Higher levels of thrombin-antithrombin complex (OR: 31.54; 95% CI: 2.09-475.92) and lower levels of factor XIII (OR: 0.03; 95% CI: 0.002-0.44) were associated with DVT. CD36, MIC-1, and EpoR were marginally associated with DVT. Only factor XIII was associated with clinically relevant bleeding (OR: 0.27; 95% CI: 0.08-0.97). CONCLUSIONS: We identified candidate protein biomarkers for incident DVT. We plan to validate our findings in adequately powered studies.

Epidemiology of Clinically Relevant Bleeding in Critically Ill Adolescents.

OBJECTIVES: The epidemiology of clinically relevant bleeding in critically ill adolescents, particularly those who are at high risk of venous thromboembolism, is unclear. In preparation for a randomized clinical trial of pharmacologic prophylaxis against venous thromboembolism, we characterized the epidemiology of clinically relevant bleeding in critically ill adolescents. DESIGN: Post hoc analysis of data from a pediatric multicenter observational study of venous thromboembolism. SETTING: Six PICUs. PATIENTS: Adolescents 13-17 years old who received cardiac or pulmonary support for at least 48 hours were eligible. Those admitted with venous thromboembolism or receiving therapeutic anticoagulation were excluded. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Adolescents (n = 88) were followed daily for the development of any bleeding event. The severity of the event was categorized based on the definitions by the International Society on Thrombosis and Haemostasis. The frequency of clinically relevant bleeding was 29.5% (95% CI, 20.3-40.2%) or 3.7 events (95% CI, 2.5-5.4 events) per 100 patient-days. Adolescents with venous thromboembolism were more likely to develop clinically relevant bleeding (hazard ratio, 2.06; 95% CI, 1.08-3.94). Age was negatively associated with clinically relevant bleeding (hazard ratio for every 1-year increase in age: 0.68; 95% CI, 0.58-0.79). In contrast, predicted risk of mortality (hazard ratio for every 0.10 increase in risk: 1.35; 95% CI, 1.05-1.74) and admission for trauma or surgery (hazard ratio: 2.04; 95% CI, 1.21-3.44) were positively associated with clinically relevant bleeding. The association of clinically relevant bleeding with medications, interventions, or laboratory tests, including mechanical ventilation and pharmacologic prophylaxis with anticoagulation, did not reach statistical significance. Adolescents with clinically relevant bleeding stayed in the hospital longer than those without clinically relevant bleeding. CONCLUSIONS: Clinically relevant bleeding is common in critically ill adolescents who are at high risk of venous thromboembolism. Admission for trauma or surgery can be used to stratify the risk of clinically relevant bleeding in these adolescents.

Epidemiology of Lower Extremity Deep Venous Thrombosis in Critically Ill Adolescents.

OBJECTIVE: To determine the epidemiology of lower extremity deep venous thrombosis (DVT) in critically ill adolescents, which currently is unclear. STUDY DESIGN: We performed a multicenter, prospective, cohort study. Adolescents aged 13-17 years who were admitted to 6 pediatric intensive care units and were anticipated to receive cardiopulmonary support for at least 48 hours were eligible, unless they were admitted with DVT or pulmonary embolism or were receiving or anticipated to receive therapeutic anticoagulation. While patients were in the unit, serial sonograms of the lower extremities were performed, then centrally adjudicated. Bayesian statistics were used to leverage the similarities between adults and adolescents. RESULTS: A total of 88 adolescents were enrolled, from whom 184 lower extremity sonograms were performed. Of these, 9 adolescents developed DVT, with 1 having bilateral DVT. The frequency of DVT was 12.4% (95% credible interval: 6.1%, 20.1%), which ranged from 6.3% to 19.8% with a variability of 41.0% across units. All cases of DVT occurred in adolescents who received invasive mechanical ventilation (frequency: 16.5%; 95% credible interval 8.1%, 26.6%). DVT was associated with femoral central venous catheterization (OR 15.44; 95% credible interval 1.62, 69.05) and severe illness (OR for every 0.1 increase in risk of mortality 3.11; 95% credible interval 1.19, 6.85). DVT appears to be associated with prolonged days on support. CONCLUSIONS: Our findings highlight the similarities and differences in the epidemiology of DVT between adults and adolescents. They support the conduct and inform the design of a trial of pharmacologic prophylaxis in critically ill adolescents.

A regional cohort study of the treatment of critically ill children with bronchiolitis.

OBJECTIVE: To describe the treatment practices in critically ill children with RSV bronchiolitis across four regional PICUs in the northeastern United States, and to determine the factors associated with increased ICU length of stay in this population. METHODS: We conducted a retrospective cohort study of children who were admitted with RSV bronchiolitis between July 2009 and July 2011 to the PICUs of Connecticut Children's Medical Center, Yale-New Haven Children's Hospital, Maria Fareri Children's Hospital, and Baystate Children's Hospital. Data were collected regarding clinical characteristics and intensive care course among these hospitals. RESULTS: During the study period, 323 children were admitted to one of the four ICUs with RSV bronchiolitis. Despite similar mortality risk scores among ICUs, there was considerable variation in the use of therapies, particularly intubation and mechanical ventilation, in which there was greater than a 3.5-fold increased risk of intubation between sites with the highest and lowest frequency of intubation (odds ratio: 3.8; 95% confidence interval: 2.2-6.4). Albuterol was the most commonly used respiratory treatment, followed by chest physiotherapy, high-flow nasal cannula, and hypertonic saline. Longer stays in the ICU were associated with more frequent use of therapies, specifically invasive mechanical ventilation, inhaled corticosteroids, intrapulmonary percussive ventilation, and chest physiotherapy. CONCLUSIONS: Even within a close geographic region, there is significant variation in the treatment provided to critically ill children with RSV bronchiolitis. None of these treatments were associated with shorter durations of hospitalization in this population and some, such as mechanical ventilation, were associated with longer ICU lengths of stay.

Diagnostic accuracy of point-of-care ultrasound for catheter-related thrombosis in children.

BACKGROUND: Compared with consultative US performed by the radiology department, point-of-care US performed by non-radiology physicians can accurately diagnose deep venous thrombosis in adults. OBJECTIVE: In preparation for a multicenter randomized controlled trial, we determined the accuracy of point-of-care US in diagnosing central venous catheter-related thrombosis in critically ill children. MATERIALS AND METHODS: Children <18 years old with a central venous catheter who were admitted to the intensive care unit were enrolled. Consultative and point-of-care compression ultrasounds with Doppler were done on the vein where the catheter was inserted within 24 h after insertion. Repeat US was obtained within 24 h of removal of the catheter. All images were centrally, blindly and independently adjudicated for thrombosis by a team of pediatric radiologists. Chance-corrected agreement between readings was calculated. RESULTS: From 84 children, 152 pairs of consultative and point-of-care ultrasounds were analyzed. A total of 38 (25.0%) consultative and 17 (11.2%) point-of-care ultrasounds were positive for thrombosis. The chance-corrected agreement between consultative and point-of-care ultrasounds was 0.17 (standard error: 0.07; P = 0.008). With consultative US as a reference, the sensitivity of point-of-care US was 28.1% (95% confidence interval: 13.7%-46.7%) with a specificity of 91.8% (95% confidence interval: 84.4%-96.4%). A catheter in the subclavian vein was associated with discordant readings (adjusted odds ratio: 4.00; 95% confidence interval: 1.45-13.94). CONCLUSION: Point-of-care US, when performed by non-radiology physicians and centrally adjudicated by pediatric radiologists in the setting of a multicenter randomized controlled trial, may not accurately diagnose catheter-related thrombosis in critically ill children.

Factor VIII May Predict Catheter-Related Thrombosis in Critically Ill Children: A Preliminary Study.

OBJECTIVE: If we can identify critically ill children at high risk for central venous catheter-related thrombosis, then we could target them for pharmacologic thromboprophylaxis. We determined whether factor VIII activity or G value was associated with catheter-related thrombosis in critically ill children. DESIGN: Prospective cohort study. SETTING: Two tertiary academic centers. PATIENTS: We enrolled children younger than 18 years who were admitted to the PICU within 24 hours after insertion of a central venous catheter. We excluded children with a recently diagnosed thrombotic event or those anticipated to receive anticoagulation. Children with thrombosis diagnosed with surveillance ultrasonography on the day of enrollment were classified as having prevalent thrombosis. Those who developed catheter-related thrombosis thereafter were classified as having incident thrombosis. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We enrolled 85 children in the study. Once enrolled, we measured factor VIII activity with one-stage clotting assay and determined G value with thromboelastography. Of those enrolled, 25 had incident and 12 had prevalent thromboses. The odds ratio for incident thrombosis per SD increase in factor VIII activity was 1.98 (95% CI, 1.10-3.55). The area under the receiver operating characteristic curve was 0.66 (95% CI, 0.52-0.79). At factor VIII activity more than 100 IU/dL, which was the optimal threshold identified using Youden index, sensitivity and specificity were 92.0% and 41.3%, respectively. The association between factor VIII activity and incident thrombosis remained significant after adjusting for important clinical predictors of thrombosis (odds ratio, 1.93; 95% CI, 1.10-3.39). G value was associated with prevalent but not with incident thrombosis. CONCLUSION: Factor VIII activity may be used to stratify critically ill children based on their risk for catheter-related thrombosis.

Antithrombin activity and central venous catheter-associated thrombosis in critically ill children at high risk of bleeding.

BACKGROUND: Normalization of antithrombin activity may prevent catheter-associated thrombosis in critically ill children at high risk of bleeding. OBJECTIVES: To characterize the temporal pattern of antithrombin activity, assess its association with catheter-associated thrombosis and clinically relevant bleeding, and evaluate its relationship with thrombin generation in these children. METHODS: In this prospective cohort study, critically ill children <18 years old at high risk of bleeding with central venous catheter were eligible. Antithrombin activity and thrombin generation were measured from platelet-poor plasma and after in vitro antithrombin supplementation. Systematic surveillance ultrasound was performed to diagnose thrombosis. Children were followed for bleeding. RESULTS: We enrolled 8 infants (median age: 0.2 years, IQR: 0.2, 0.3 years) and 72 older children (median age: 14.3 years, IQR: 9.1, 16.1 years). Mean antithrombin on the day of catheter insertion was 64 IU/dL (SD: 32 IU/dL) in infants and 83 IU/dL (SD: 35 IU/dL) in older children. Antithrombin normalized by the day of catheter removal. Thrombosis developed in 27 children, while 31 children bled. Thrombosis (regression coefficient: 0.008, 95% CI: -0.01, 0.03) and bleeding (regression coefficient: -0.0007, 95% CI: -0.02, 0.02) were not associated with antithrombin. Antithrombin was not correlated with in vivo change in endogenous thrombin potential (correlation coefficient: -0.07, 95% CI: -0.21, 0.08). In vitro supplementation reduced endogenous thrombin potential (correlation coefficient: -0.78; 95% CI: -0.95, -0.23). CONCLUSION: These findings may not support normalization of antithrombin activity to prevent catheter-associated thrombosis in critically ill children at high risk of bleeding.

Incidence and acute complications of asymptomatic central venous catheter-related deep venous thrombosis in critically ill children.

OBJECTIVE: To determined the current incidence and acute complications of asymptomatic central venous catheter (CVC)-related deep venous thrombosis (DVT) in critically ill children. STUDY DESIGN: We performed a prospective cohort study in 3 pediatric intensive care units. A total of 101 children with newly inserted untunneled CVC were included. CVC-related DVT was diagnosed using compression ultrasonography with color Doppler. RESULTS: Asymptomatic CVC-related DVT was diagnosed in 16 (15.8%) children, which equated to 24.7 cases per 1000 CVC-days. Age was independently associated with DVT. Compared with children aged <1 year, children aged >13 years had significantly higher odds of DVT (aOR, 14.1, 95% CI, 1.9-105.8; P = .01). Other patient demographics, interventions (including anticoagulant use), and CVC characteristics did not differ between children with and without DVT. Mortality-adjusted duration of mechanical ventilation, a surrogate for pulmonary embolism, was statistically similar in the 2 groups (22 ± 9 days in children with DVT vs 23 ± 7 days in children without DVT; P = .34). Mortality-adjusted intensive care unit and hospital lengths of stay also were similar in the 2 groups. CONCLUSION: Asymptomatic CVC-related DVT is common in critically ill children. However, the acute complications do not seem to differ between children with and without DVT. Larger studies are needed to confirm these results. Future studies should also investigate the chronic complications of asymptomatic CVC-related DVT.

Corticosteroid therapy in critically ill pediatric asthmatic patients.

OBJECTIVES: IV corticosteroids are routinely prescribed to treat critically ill children with asthma. However, no specific dosing recommendations have been made for children admitted to the PICU. We aim to determine current asthma corticosteroid dosing preferences in PICUs within North America. DESIGN: Cross-sectional, self-administered survey. SETTING: North American PICUs. SUBJECTS: Pediatric intensivists working in the United States and Canada. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 104 intensivists completed the survey. Of these, 70% worked in the United States, 67% attended in PICUs with at most 20 beds, and 79% had more than 10 years of PICU experience. The majority of asthmatics were admitted to PICUs based on clinical asthma examination/score or because the patient was receiving continuous albuterol. IV methylprednisolone is prescribed by a large majority of intensivists (96%). Of those who prescribe methylprednisolone, 66% use a starting dose of 4 mg/kg/d, whereas 31% use a starting dose of 2 mg/kg/d, and only 3% use 1 mg/kg/d. The large majority of respondents (85%) use "clinical experience" as their rationale for their preferred dosage. In multivariate logistic regression analysis, only knowledge of the National Heart, Lung, and Blood Institute guidelines was an independent predictor of prescribing an initial corticosteroid dose of 4 mg/kg/d (odds ratio, 3.69 [95% CI, 1.26-10.80]; p = 0.017). Country of practice, years of experience, and PICU size were not associated with corticosteroid dosing preference. CONCLUSIONS: Most intensivists administer methylprednisolone to critically ill asthmatics at doses 2 to 4 times higher than recommended by the National Heart, Lung, and Blood Institute guidelines for hospitalized asthmatic children. The rationale for these decisions is likely multifactorial, but in the absence of evidence-based data, most of them cite clinical experience as their deciding factor. Future research is needed to determine the most appropriate corticosteroid dosage in this critically ill patient population.

Accuracy of physical examination in detecting central venous catheter-associated thrombosis in critically ill children.

INTRODUCTION: Lack of standardized definition impedes our ability to understand the clinical significance of asymptomatic central venous catheter (CVC) associated deep venous thrombosis (CADVT). Using standardized definitions, we aimed to determine the accuracy of physical examination in detecting CADVT in critically ill children and to identify characteristics associated with this accuracy. MATERIALS AND METHODS: In a post hoc study, we analyzed 236 children <18 years old admitted to the pediatric intensive care unit, had an untunneled CVC and surveilled for CADVT using ultrasound with paired physical examination. RESULTS: Of 236 paired examinations, 79 (33.5 %) had CADVT on ultrasound, while 56 (23.7 %) had signs of inflammation or venous obstruction on physical examination or CVC dysfunction. Sensitivity was 29.2 % (95 % confidence interval, CI: 19.9 %, 38.5 %), specificity was 80.2 % (95 % CI: 73.9 %, 86.4 %) and area under the receiver operating characteristic curve (AUROC) was 0.55 (95 % CI: 0.49, 0.60). When CVC dysfunction was excluded, sensitivity was lower (11.1 %; 95 % CI: 4.6 %, 17.6 %; p = 0.002), but specificity was higher (88.7 %; 95 % CI: 83.6 %, 93.7 %, p = 0.04). AUROC was 0.50 (95 % CI: 0.46, 0.54; p = 0.17). Use of point-of-care ultrasound and CVC inserted in the internal jugular vein (vs femoral vein) had lower sensitivity. Sepsis or infection and vasoactive support had lower specificity. Center of enrollment was associated with variable sensitivity. CONCLUSIONS: Physical examination has poor accuracy in detecting CADVT in critically ill children. Despite poor accuracy, physical examination that includes assessment of CVC dysfunction, in combination with imaging, is key to understanding the clinical significance of asymptomatic CADVT.