Rowena C. Punzalan

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.

Low-molecular-weight heparin in thrombotic disease in children and adolescents.

PURPOSE The use of unfractionated heparin (UFH) in children is problematic. In adults, subcutaneous low-molecular-weight heparin (LMWH) is as effective as UFH in the treatment of thrombosis. Because pediatric data are limited, the authors studied the use of enoxaparin in children. PATIENTS AND METHODS Nineteen children (ages 18 days to 19 years; median age, 40 months) with indications for thrombosis treatment or prophylaxis were studied. Six patients (median age, 33 months), treated on a protocol that included pharmacokinetic studies, initially received enoxaparin 1 mg/kg subcutaneously every 12 hours; doses then were adjusted until target plasma levels of 0.5 to 1.2 anti-Xa U/mL were achieved. The records of 13 additional patients treated with enoxaparin off study were reviewed. RESULTS In the first six patients, enoxaparin pharmacokinetics was found to be similar to that in adults; once targeted levels were achieved, these remained stable. Among all 19 subjects, 14 had treatment of active thrombosis and 5 underwent thrombosis prophylaxis. For treatment of thrombosis, enoxaparin 1 mg/kg initially was administered subcutaneously every 12 hours. Target anti-Xa levels were achieved with 0.55 to 1.5 mg/kg every 12 hours (mean, 0.98 mg/kg; median, 1.0 mg/kg) in 1 to 7 days (median, 1 day). All patients in the treatment group had clinical improvement within 2 to 5 days, and 12 had follow-up radiological studies that confirmed this. For prophylaxis, enoxaparin was given at 1 mg/kg subcutaneously every 24 hours. No new thrombi were clinically evident in this group. There was no major bleeding with enoxaparin; one patient had transient mild mucosal oozing. CONCLUSION In this limited population, enoxaparin seems to be a safe, effective, and convenient alternative to UFH in children and adolescents. The adult therapeutic target range of 0.5 to 1.2 anti-Xa U/mL is readily achievable with a starting dose of 1 mg/kg every 12 hours in most children. Initial close monitoring with plasma anti-Xa activity should be done and doses adjusted to achieve target range, particularly in neonates. In the population of this study, enoxaparin seems as effective as UFH in the period immediately thrombotic episode. These results should be confirmed in the ongoing randomized trial comparing LMWH with UFH in children.

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.

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 childrens 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.

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.

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.

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.

Increased recombinant activated factor VII use and need for surgical reexploration following a switch from aprotinin to epsilon-aminocaproic acid in infant cardiac surgery

STUDY OBJECTIVE To evaluate whether conversion from aprotinin to epsilon-aminocaproic acid (EACA) during infant cardiac surgery was associated with increased perioperative bleeding. DESIGN Structured retrospective chart review. SETTING University-affiliated large congenital cardiac surgery program. MEASUREMENTS Records from 145 infants (age < 1 yr) receiving aprotinin as antifibrinolytic therapy for cardiac surgery between 6/1/2006 and 12/31/2006 were compared with a cohort of infants receiving EACA for cardiac surgery between 6/1/2008 and 12/31/2008. Sixty-eight infants received aprotinin and 77 infants received EACA. Measured indicators of perioperative bleeding included transfusion volumes, recombinant activated clotting factor VIIa (rFVIIa) administration, need for reexploration, and perioperative chest tube output. MAIN RESULTS EACA treated patients received significantly more rFVIIa for uncontrolled bleeding (19/77 [25%] vs 3/68 [4%]; P < 0.001) and required surgical reexploration more frequently (21/77 [27%] vs 7/68 [10%]; P = 0.01]. Median (25th-75th percentiles) intraoperative platelet transfusion requirements were also increased after the switch to EACA (28 mL [0-58 mL] vs 0 mL [0 mL - 34.5 mL]), but this difference did not reach statistical significance (P = 0.06). CONCLUSIONS Bleeding in infant cardiac surgery increased following the change in antifibrinolytic therapy from aprotinin to EACA. Given the potential for major harm, especially thrombotic complications, from rFVIIa use, prospective studies examining the safety of postcardiopulmonary bypass rFVIIa administration in infants are necessary before the routine off-label use may be recommended.

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.

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.