Efficacy of surveillance ultrasound for venous thromboembolism diagnosis in critically ill children after trauma.

INTRODUCTION: Venous thromboembolism (VTE) is increasingly prevalent in injured children admitted to the intensive care unit (ICU). Few data exist to support VTE pharmacologic prophylaxis or ultrasound (US) surveillance in children with high bleeding risk. After implementation of screening US guidelines, we sought to describe our experience, hypothesizing that screening US of children at highest risk for VTE results in earlier detection and management. STUDY DESIGN: A retrospective analysis was conducted on prospectively collected data of injured children admitted to an American College of Surgeons Verified level 1 Pediatric Trauma Center from 2010 to 2015. In patients at high risk for both VTE and bleeding (HRHR), guidelines recommended deferral of pharmacologic prophylaxis and a screening US at ≥7 ICU days if bleeding risk remained. Outcomes analyzed included VTE rates, guideline compliance, and US timing. The rate of deep vein thrombosis (DVT) detection (number of DVT captured/number of US obtained) was examined. RESULTS: Of 4061 trauma patients, 588 (14.5%) were critically injured including 112 patients who met HRHR criteria. The rate of VTE in the HRHR group ≥7 ICU days was 25% (14/56). Of 23 VTE diagnosed in the ICU, 17 were detected by 49 US performed (34.7%), with the remaining 6 diagnosed by computed tomography. DVT was detected earlier than the US guideline recommended 7 days, independent of symptoms. Guideline compliance was 86%. CONCLUSION: Critically injured children at risk for bleeding frequently develop VTE. Surveillance ultrasound in patients at high risk for both VTE and bleeding allows earlier detection and treatment. LEVEL OF EVIDENCE: Therapeutic study, level II.

Central Venous Catheter-associated Venous Thromboembolism in Children With Hematologic Malignancy.

In pediatric oncology, the diagnosis of a hematologic malignancy and presence of a central venous catheter (CVC) have been identified as significant risk factors for the development of a venous thromboembolism (VTE). There remain little data regarding CVC factors associated with CVC-related VTE. Using the VTE and oncology database in a quaternary care center, a retrospective cohort study was conducted in children below 18 years old with hematologic cancer from November 5, 2012 to April 4, 2016. Patient, CVC factors, and VTE occurrence were analyzed to identify significant patient and CVC factors associated with the development of clinically identified CVC-related VTE. Utilizing the χ, Mann-Whitney, and the Fisher exact tests, patient factors were compared across VTE yes/no groups. Of the 198 study patients, 22 VTE cases were identified. Eighteen VTE events were CVC-associated, occurring in 9% of study population. Peripherally inserted central catheter lines and older ages were associated with VTE. The use of tissue-plasminogen activator for CVC occlusion was associated with decreased VTE rates, suggesting a protective potential.

Evaluation of guidelines for injured children at high risk for venous thromboembolism: A prospective observational study.

BACKGROUND: Pharmacologic prophylaxis for venous thromboembolism (VTE) is a widely accepted practice in adult trauma patients to prevent associated morbidity and mortality. However, VTE prophylaxis has not been standardized in injured pediatric patients. Our institution identified factors potentially associated with a high risk of VTE in critically injured children that led to prospective implementation of VTE prophylaxis guidelines. We hypothesize that the guidelines are accurate in predicting children at risk for VTE. METHODS: Data were prospectively collected on injured children from August 2010 to August 2015. Pharmacologic prophylaxis was indicated for patients identified by the guidelines as high risk for VTE. Prophylaxis was deferred and a screening ultrasound was performed if the high-risk VTE patients were also at high risk for bleeding. To assess the accuracy of predicting confirmed cases of VTE, stepwise logistic regression analysis was used to measure the association of individual risk factors with VTE controlling for age (≥13 years). A receiver operating characteristic curve measured the accuracy of the final model to predict a VTE. RESULTS: Of 4,061 trauma patients, 588 were admitted to the ICU, with the guidelines identifying 199 as high risk for VTE. VTE occurred in 3.9% (23/588) of the ICU population and 10% (20/199) of the high risk group. The median age of VTE patients in the ICU was 9.7 years. Statistically significant predictors (p < 0.05) of VTE in the multivariate model included presence of a central venous catheter (OR = 5.2), inotropes (OR = 7.7), immobilization (OR = 5.5), and a Glasgow Coma Scale of <9 (OR = 1.3). The area under receiver operating characteristic curve of this model was 0.92, demonstrating its excellent predictive ability. CONCLUSION: Specific clinical factors in critically injured children are associated with a high risk for VTE. Incorporating these risk factors in VTE prophylaxis guidelines facilitates more accurate risk stratification and may allow for improved VTE prevention in pediatric trauma. LEVEL OF EVIDENCE: Prognostic study, level II.

Screening Guidelines for Venous Thromboembolism Risk in Hospitalized Children Have Low Sensitivity for Central Venous Catheter-Associated Thrombosis.

OBJECTIVES: Local pediatric screening guidelines for venous thromboembolism (VTE) are developed from incomplete pediatric data and extrapolated from adult data in which immobility is a major risk factor. We hypothesized that screening guidelines centered on immobility are inadequate for identifying children at risk of central venous catheter (CVC)-associated VTE. METHODS: This retrospective case-control (4:1) study at an academic, quaternary-level, free-standing children's hospital applied screening guidelines for VTE risk to all cases of VTE from July 2012 to April 2014. Cases and controls were classified as "at risk" or "not at risk" of VTE by guideline criteria. These guidelines assessed VTE risk factors, including CVC, as reported in the pediatric literature. RESULTS: VTE prevalence was 0.5 per 100 admissions. Sixty-nine of 114 patients with radiographically confirmed VTE were classified as being "at risk" by the guidelines, with a sensitivity of 61%, specificity of 90.8%, a positive predictive value of 2.4%, and negative predictive value of 99.8%. There was no difference in screening guidelines sensitivity for identifying CVC-associated VTE versus non-CVC-associated VTE. Half of the 45 patients with VTE who were not captured as being "at risk" did not have decreased mobility, the entry point to the algorithm, and 80% of these patients had a CVC. CONCLUSIONS: Screening guidelines have low sensitivity for identifying hospitalized children at increased risk of both CVC-associated and other VTE events. Decreased mobility is not a requirement for CVC-associated VTE. Risk factors extrapolated from adult data are insufficient for identifying children at risk of VTE.

Use and Future Investigations of Recombinant and Plasma-Derived Coagulation and Anticoagulant Products in the Neonate.

Although congenital bleeding disorders can manifest in the newborn period, the most common causes of bleeding and thrombosis in neonates are acquired conditions. Factor concentrates are used for specific diagnoses (hemophilia with inhibitors, specific factor deficiency, von Willebrand disease) and approved indications, and increasingly for off-label indications (bleeding in surgery cardiopulmonary bypass, extracorporeal membrane oxygenation). We will review the approved indications for factor products in the neonate and discuss the evidence and rationale for off-label use of factor products in management of bleeding and thrombosis in the neonate.

A Pilot Study of Antithrombin Replacement Prior to Cardiopulmonary Bypass in Neonates.

Neonates have low levels of antithrombin. Inadequate anticoagulation during cardiopulmonary bypass (CPB) due to low antithrombin activity may result in a poor preservation of the coagulation system during bypass. We hypothesize that antithrombin replacement to neonates prior to CPB will preserve the hemostatic system and result in less postoperative bleeding. A randomized, double-blinded, placebo-controlled pilot study of antithrombin replacement to neonates prior to CPB was conducted. Preoperative antithrombin levels determined the dose of recombinant antithrombin or placebo to be given. Antithrombin levels were measured following the dosing of the antithrombin/placebo, after initiation of bypass, near the completion of bypass, and upon intensive care unit admission. Eight subjects were enrolled. No subject had safety concerns. Mediastinal exploration occurred in two antithrombin subjects and one placebo subject. Antithrombin activity levels were significantly higher in the treated group following drug administration; levels continued to be higher than preoperatively but not different from the placebo group at all other time points. Total heparin administration was less in the antithrombin group; measurements of blood loss were similar in both groups. A single dose of recombinant antithrombin did not maintain 100% activity levels throughout the entire operation. Although no safety concerns were identified in this pilot study, a larger trial is necessary to determine clinical efficacy.

Higher doses of low-molecular-weight heparin (enoxaparin) are needed to achieve target anti-Xa concentrations in critically ill children*.

OBJECTIVES: To demonstrate that low-molecular-weight heparin (enoxaparin) can be used in critically ill pediatric patients to achieve target anti-factor Xa concentrations and determine appropriate dosing corrected for age and illness severity. DESIGN: Retrospective cohort study. SETTING: Single tertiary level PICU. PATIENTS: One hundred ninety-two children age 1 day through 18 years admitted to PICU undergoing every 12-hour enoxaparin therapy with at least one anti-factor Xa concentration obtained. Patients receiving renal replacement therapy or infants with corrected gestational age less than 37 weeks were excluded. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We collected patient characteristics including age, weight, height/length, gender, corrected gestational age, illness severity markers, diagnosis, creatinine, enoxaparin dose and times of administration, anti-factor Xa concentrations, and collection times. Only 42% of critically ill children (80 of 192) and only 29% of children (9 of 31) on inotropes achieved recommended target range of anti-factor Xa concentrations on initial recommended enoxaparin dosing (1.5 mg/kg/dose < 2 mo; 1 mg/kg/dose > 2 mo), but 81% were ultimately within target range with dose titration. Increased enoxaparin dose was required to reach target concentrations in younger patients and those with worse illness severity as evidenced by concurrent use of inotropes, previous ICU admission, mechanical ventilation, cardiac surgery, and increased risk of mortality defined by severity-of-illness scores. CONCLUSIONS: Enoxaparin can be used to reach recommended target range of anti-factor Xa concentrations in the PICU patient. However, younger patients and patients with higher illness severity are less likely to achieve target concentrations using currently recommended dosing and may require higher doses of enoxaparin to reach target anti-factor Xa concentrations. Starting enoxaparin dose at least 1.3 mg/kg dosed every 12 hours for treatment of thromboembolic disease in critically ill patients aged 61 days to 1 year or those requiring inotropic support should be confirmed in prospective study.

The use of novel Therakos™ Cellex® for extracorporeal photopheresis in treatment of graft-versus-host disease in paediatric patients.

Extracorporeal photopheresis (ECP) is an established second line treatment option for graft-versus-host disease (GVHD) post-haematopoietic progenitor cell transplant. At our centre, the Therakos™ Cellex(®) has replaced the Therakos™ UVAR-XTS™ machine for ECP since 2009. We reviewed the records of 385 procedures using the Therakos™ Cellex(®) for safety and tolerability. Nine patients underwent ECP for GVHD. The median age was 13·5 years (range 3·7-24) and weight was 49·2 kg (range 18·5-86·3). The mean duration per procedure was 106 min (range 60-205). Fifteen (3·9%) procedures were cancelled and 10 (2·6%) were delayed, with central venous line (CVL) issues being the most frequent problem. With the use of prophylactic tissue plasminogen activator, fewer CVL-related occlusions were observed (4·7% vs. 2·3%). There was one episode of a CVL-associated thrombosis and one episode of delayed bleeding. There were four episodes of viral reactivation, four CVL-associated infections (1142 catheter days) and one episode of systemic inflammatory response syndrome. No patient experienced symptomatic hypotension. This is the first report outlining the safety and tolerability of the Therakos™ Cellex(®) device for ECP in children and young adults.

Severe thrombocytopenia in a child secondary to passive platelet antibody transfer from a plasma transfusion.

Although rare, passive transfer of platelet antibodies through blood products can result in thrombocytopenia, acute transfusion reactions, and death. We report a case of severe alloimmune thrombocytopenia from a plasma transfusion. A postliver transplant patient with a normal platelet count received fresh frozen plasma before liver biopsy. Postbiopsy, she developed cardiorespiratory distress, petechiae, and severe thrombocytopenia (platelet count 2000/µL). Her platelet count recovered to normal after 1 week. This diagnosis should be considered whenever an unexpected drop in the platelet count occurs after a plasma-rich transfusion. Conservative transfusion practices and more targeted donor screening may prevent similar events.

Use of purified fibrinogen concentrate for dysfibrinogenemia and importance of laboratory fibrinogen activity measurement.

We report a patient with dysfibrinogenemia treated with purified fibrinogen concentrate who had discrepant post-treatment laboratory values. The patient had mild bleeding symptoms and was diagnosed with dysfibrinogenemia based on fibrinogen activity of 51 mg/dl and antigen of 240 mg/dl. He was treated for an adenoidectomy with purified fibrinogen concentrate (RiaSTAP®) at a dose of 70 mg/kg. A discrepancy in post-treatment fibrinogen activity was observed between the hospital and reference laboratories. Investigation revealed differences in laboratory assay and calibration methods. Fibrinogen concentrate may be a treatment option for patients with dysfibrinogenemia, but accurate laboratory technique is critical for fibrinogen measurement.

Effectiveness of clinical guidelines for deep vein thrombosis prophylaxis in reducing the incidence of venous thromboembolism in critically ill children after trauma.

BACKGROUND: Historically, 6% of critically ill children developed clinically apparent venous thromboembolism (VTE) after trauma at our Level I pediatric trauma center. We hypothesized that implementation of clinical guidelines for thrombosis prophylaxis incorporating both VTE risk and bleeding risk would reduce VTE incidence without increased bleeding. METHODS: VTE, both clinically apparent and those only detected by guideline-directed screening, were prospectively identified for all children admitted to the intensive care unit after trauma during three time periods: preimplementation of guidelines for VTE thromboprophylaxis (PRE; April 1, 2006-June 30, 2007), the intervening period (ROLL OUT; July 1, 2007-November 4, 2008), and postguideline implementation (POST; November 5, 2008-June 1, 2010). For patients classified as high risk for VTE, anticoagulation was recommended. For those patients at high risk of VTE with high risk of bleeding, anticoagulation was deferred and screening ultrasound performed. RESULTS: Fourteen of 546 subjects developed VTE. There was a decrease in total VTE (p = 0.041) and clinical VTE (p = 0.001) after guideline implementation. The nine VTE PRE (5.2%) were clinically symptomatic, while the three VTE POST (1.8%) were detected by guideline-directed screening ultrasound. Implementation of guidelines did not increase overall thromboprophylaxis, with decreased anticoagulation in patients at low risk of VTE. No bleeding complications occurred. No patients classified by the guidelines as low risk for VTE developed VTE. CONCLUSION: The incidence of clinical VTE and total VTE decreased after implementation of clinical guidelines for thromboprophylaxis in critically ill children after trauma. This decrease in VTE was not associated with increased prophylactic anticoagulation nor increased bleeding. The guidelines were predictive in identifying patients at low risk for VTE. LEVEL OF EVIDENCE: II, therapeutic study.

Incidence and risk factors for venous thromboembolism in critically ill children with cardiac disease.

Cardiac disease is a risk factor for venous thromboembolism (VTE) in children. In this study, we investigated the incidence and risk factors of VTE in critically ill children with cardiac disease, who were prospectively followed-up for VTE after admission to a tertiary care pediatric intensive care unit (PICU). Risk factors were compared between VTE cases and (1) patients in the cohort who did not develop VTE and (2) the next three cardiac patients sequentially admitted to the PICU (case control). Forty-one cases of VTE were identified from 1070 admissions (3.8%). Thirty-seven percent of VTE cases were central venous catheter (CVC)-associated, and 56% of cases were intracardiac. Sixty-six percent of patients were receiving anticoagulation at the time of VTE diagnosis. Increased VTE incidence was associated with unscheduled PICU admission, age <6 months, extracorporeal membrane oxygenation, increased number of CVCs, increased number of CVC days, higher risk of mortality score, and longer PICU stay. Using logistic regression, VTE was associated with single-ventricle physiology (odds ratio [OR] 11.2, 95% CI 3.0-41.9), widened arterial-to-somatic oxygen saturation gradient (SpO(2)-rSO(2) >30) (OR 4.3, 95% CI 1.1-16), and more CVC days (OR 1.1, 95% CI 1.04-1.13). Risk factors for VTE in critically ill children with cardiac disease include younger age, single-ventricle cardiac lesions, increased illness severity, unscheduled PICU admission, and complicated hospital course.

Trimethoprim-induced immune hemolytic anemia in a pediatric oncology patient presenting as an acute hemolytic transfusion reaction.

A 10-year-old male with acute leukemia presented with post-chemotherapy anemia. During red cell transfusion, he developed hemoglobinuria. Transfusion reaction workup was negative. Drug-induced immune hemolytic anemia was suspected because of positive direct antiglobulin test, negative eluate, and microspherocytes on smear pre- and post-transfusion. Drug studies using the indirect antiglobulin test were strongly positive with trimethoprim and trimethoprim-sulfamethoxazole but negative with sulfamethoxazole. The patient recovered after discontinuing the drug, with no recurrence in 2 years. Other causes of anemia should be considered in patients with worse-than-expected anemia after chemotherapy. Furthermore, hemolysis during transfusion is not always a transfusion reaction.

Incidence and risk factors for venous thromboembolism in critically ill children after trauma.

BACKGROUND: Venous thromboembolism (VTE) causes major morbidity in adults after trauma, occurring in up to 50% of patients without prophylaxis. The incidence of VTE after trauma is lower in children. No study has measured the incidence of and risk factors for VTE in critically ill children after trauma. METHODS: Nested case-control study of children, younger than 18 years, admitted to the pediatric intensive care unit at a level I trauma center. Three controls were selected for each identified VTE case. RESULTS: Nine of 144 children admitted to the pediatric intensive care unit after trauma developed VTE (incidence 6.2%, 95% confidence interval [CI] 2.3-10.2), with a median age of 8.6 years (range, 2.3-17.9). VTE was diagnosed at a median of 9 days after admission, with 67% of VTE located at the site of previous or existing central venous line (CVL). Significant risk factors for thrombosis included parenteral nutrition (odds ratio [OR] 20, 95% CI 1.9-227), CVL (OR 19, 95% CI 2-178), deep sedation (OR 13, 95% CI 1.6-48), neuromuscular blockade (OR 10, 95% CI 1.4-70), inotropic support (OR 10, 95% CI 1.7-59), and recombinant factor VIIa administration (p = 0.012, OR not calculable). Logistic analysis found a 7.9-fold increase in the odds of developing VTE for each additional CVL (p = 0.005), a threefold increase with each additional risk factor present (p = 0.009), and a 1.3-fold increase for an increase in injury severity (p = 0.03). VTE was not associated with sepsis, spinal cord injury, fracture, or elevated D-dimer level. CONCLUSIONS: VTE is not a rare event in critically ill children after trauma. Most patients developing thrombosis have multiple risk factors, including poor perfusion, immobility, and presence of a CVL.

Activated recombinant factor VII for refractory bleeding during extracorporeal membrane oxygenation.

OBJECTIVE: To determine the frequency of adverse events with the use of activated recombinant factor VII during extracorporeal membrane oxygenation support and to quantify the effect on bleeding parameters. DESIGN: Retrospective case series from January 1999 to August 2006. SETTING: Pediatric intensive care unit at a tertiary academic children's hospital. PATIENTS: Seventeen patients received a total of 26 doses of activated recombinant factor VII while supported on extracorporeal membrane oxygenation or within 3 hrs of initiation of extracorporeal membrane oxygenation support from February 2003 to August 2006, and 23 historical controls from January 1999 to December 2002 with bleeding complications reported to the Extracorporeal Life Support Organization database while supported on extracorporeal membrane oxygenation before the use of activated recombinant factor VII. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: No significant difference in the rate of thromboembolic complications, extracorporeal membrane oxygenation circuit failures, or mortality was found between the patients and historical controls. No trend toward increased survival was found, and a significant number of circuit complications was seen in both groups. In patients treated with activated recombinant factor VII, a significant reduction in chest tube output and blood product transfusion rates was seen within 5 hrs of activated recombinant factor VII administration. CONCLUSION: Activated recombinant factor VII administration during extracorporeal membrane oxygenation support was associated with a decrease in bleeding severity (indicated by chest tube output and blood product transfusion rates) and was not associated with an increased rate of thromboembolic complications.

Prevalence of heparin-dependent platelet antibodies in children after cardiopulmonary bypass.

OBJECTIVE: To determine the prevalence of heparin-dependent platelet antibodies (HDPA) in children requiring heparin for >5 days after cardiopulmonary bypass surgery. DESIGN: Prospective, observational study. SETTING: Tertiary care pediatric intensive care unit. PATIENTS: Thirty children were enrolled: 15 patients <30 days old and 15 patients between 30 days and 12 yrs of age. INTERVENTIONS: Detection of HDPA by heparin-platelet factor 4 enzyme-linked immunosorbent assay after 5-10 days of postoperative heparin exposure. Positive or equivocal results were confirmed with serotonin release assay. MEASUREMENTS AND MAIN RESULTS: There were no confirmed cases of HDPA in this study (95% confidence interval 0-11.6%). Despite the lack of HDPA, the study population was at high risk of thrombosis with symptomatic clot developing in six patients (20%). Clinical models developed in adults to determine the pretest risk of heparin-induced thrombocytopenia were not valid in this study population. CONCLUSIONS: The prevalence of HDPA in children after cardiopulmonary bypass surgery is low. After bypass surgery, critically ill children are at risk of developing thrombosis from multiple etiologies, and suspicion of heparin-induced thrombocytopenia needs to be confirmed with laboratory testing including a functional assay.

Erythrocyte adhesion is modified by alterations in cellular tonicity and volume.

We tested the hypothesis that dehydration-induced alterations in red blood cell (RBC) membrane organisation or composition contribute to sickle cell adhesion in sickle cell disease (SCD). To examine the role of RBC hydration in adhesion to the subendothelial matrix protein thrombospondin-1 (TSP), normal and sickle RBCs were incubated in buffers of varying tonicity and tested for adhesion to immobilised TSP under flow conditions. Sickle RBCs exhibited a decrease in TSP binding with increasing cell hydration (P<0.005), suggesting that cellular dehydration may contribute to TSP adhesion. Consistent with this hypothesis, normal RBCs showed an increase in TSP adhesion with increasing dehydration (P<0.01). Furthermore, increased TSP adhesion of normal RBCs could also be induced by isotonic dehydration using nystatin-sucrose buffers. Finally, TSP adhesion of both sickle RBCs and dehydrated normal RBCs was inhibited by the anionic polysaccharides, chondroitin sulphate A and high molecular weight dextran sulphate, but not by competitors of CD47-, band 3-, or RBC phosphatidylserine-mediated adhesion. More importantly, we found increased adhesion of nystatin-sucrose dehydrated normal mouse RBCs to kidney capillaries following re-infusion in vivo. In summary, these findings demonstrate that changes in hydration can significantly impact adhesion, causing normal erythrocytes to display adhesive properties similar to those of sickle cells and vice versa.

Concurrent poststreptococcal glomerulonephritis and autoimmune hemolytic anemia.

We describe three cases of poststreptococcal glomerulonephritis (PSGN) associated with autoimmune hemolytic anemia. Along with the classic findings of PSGN, the patients had a positive direct antiglobulin test. Two patients had a cold-reacting anti-I autoantibody. This is the first description of this association. Autoimmune hemolytic anemia should be considered in children with PSGN and significant anemia or signs of hemolysis.