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.

Using Serum Cystatin C to Predict Acute Kidney Injury Following Infant Cardiac Surgery.

Acute kidney injury (AKI) following cardiopulmonary bypass (CPB) is associated with increased morbidity and mortality. Serum Cystatin C (CysC) is a novel biomarker synthesized by all nucleated cells that may act as an early indicator of AKI following infant CPB. Prospective observational study of infants (< 1 year) requiring CPB during cardiac surgery. CysC was measured at baseline and 12, 24, 48, and 72 h following CPB initiation. Each post-op percent difference in CysC (e.g. %CysC12h) from baseline was calculated. Clinical variables along with urine output (UOP) and serum creatinine (SCr) were followed. Subjects were divided into two groups: AKI and non-AKI based upon the Kidney Disease Improving Global Outcomes (KDIGO) classification. AKI occurred in 41.9% (18) of the 43 infants enrolled. Patient demographics and baseline CysC levels were similar between groups. CysC levels were 0.97 ± 0.28 mg/L over the study period, and directly correlated with SCr (R = 0.71, p < 0.0001). Although absolute CysC levels were not significant between groups, the %CysC12h was significantly greater in the AKI group (AKI: - 16% ± 22% vs. Non-AKI - 28% ± 9% mg/L; p = 0.003). However, multivariate analysis demonstrated that a lower UOP (Odds Ratio:0.298; 95% CI 0.073, 0.850; p = 0.02) but not %CysC12h was independently associated with AKI. Despite a significant difference in the %CysC12h, only UOP was independently associated with AKI. Larger studies of a more homogenous population are needed to understand these results and to explore the variability in this biomarker seen across institutions.

Pulmonary Venous Gradients in Healthy Controls and Following the Repair of Total Anomalous Pulmonary Venous Return.

The percent of children who can achieve a normal and physiologic pulmonary venous gradient and flow following the repair of Total Anomalous Pulmonary Venous Return (TAPVR) is not known. Pulmonary venous confluence gradients from infants with supra-, infra-, or mixed TAPVR, repaired using a direct anastomotic connection were measured. Data from age, weight, and gender-matched controls established the normal pulmonary venous gradient range (0.30-0.94 mmHg). TAPVR subjects were divided into three groups: (I) pulmonary venous gradient < 2 × normal with multiphasic flow (II) pulmonary venous gradient > 2 × normal with multiphasic flow, and (III) pulmonary venous gradient > 2 × normal with monophasic flow. From 63 children following TAPVR repair and 63 matched controls, pulmonary venous gradients were significantly lower [0.5 mmHg (IQR:0.4, 0.6) vs 1.6 mmHg (IQR:1.0, 2.4); p < 0.001], and multiphasic flow more frequent (100 vs. 84.1%; p = 0.001) within the control group. There were 38 children (60.3%) in group I, 15 (23.8%) in group II, and 10 (15.8%) in group III. Children in Group I were significantly older at the time of repair, had shorter cardiopulmonary bypass times, and did not utilize deep hypothermic circulatory arrest (DHCA). Multivariate analysis confirmed that avoiding DHCA [Odds Ratio 0.931 (0.913,0.994; p = 0.002)] and shorter cardiopulmonary bypass times [Odds Ratio 0.962 (0.861,0.968; p = 0.02)] during repair were associated with the lowest pulmonary venous gradients and multiphasic flow. Following TAPVR repair with a direct anastomosis, the majority of children can achieve a gradient two times normal or less with multiphasic pulmonary venous flow.

A modified approach in the repair of type I and II truncus arteriosus to promote branch pulmonary arterial growth and limit early reoperation.

Objective: Maintaining adequate branch pulmonary arterial growth is critical in preventing early (<3 years) right ventricular outflow tract reoperation after the repair of truncus arteriosus. We hypothesized that a modified truncus arteriosus repair keeping the branch pulmonary arteries in situ would promote branch pulmonary arterial growth and limit early right ventricular outflow tract reoperation. Methods: For infants requiring repair for type I and II truncus arteriosus, the truncal root was septated through a hockey stick incision keeping the branch pulmonary arteries in situ, the ventricular septal defect was closed, and a short aortic homograft was used to reconstruct the right ventricular outflow tract. Echocardiograms measured preoperative and follow-up branch pulmonary artery diameter. Results: Between 1998 and 2020, 41 infants were repaired using the modified approach (type I, 28; type II, 13). With a median follow-up of 11.6 (interquartile range, 3.1-15.5) years, there was no significant change between preoperative left pulmonary artery and right pulmonary artery Z-scores and their corresponding follow-up measurement (left pulmonary artery: 0.97, interquartile range, 0.6-1.6 vs left pulmonary artery: 1.4, interquartile range, -0.3 to 1.9) (right pulmonary artery: 0.6, interquartile range, -0.4 to 1.7 vs right pulmonary artery: 0.3 interquartile range, 0.5-0.9). Only 7.3% (n = 2) of follow-up right pulmonary artery Z-scores were less than 2.5 Z-scores below preoperative measurements. Four children (9.8%) required early right ventricular outflow tract reoperation. On multivariable analysis, larger conduit Z-scores were associated with greater time to right ventricular outflow tract reoperation (hazard ratio, 0.55, confidence interval, 0.307-0.984; P = .043). Conclusions: Maintaining the branch pulmonary arteries in situ at initial truncus arteriosus repair allows for branch pulmonary arterial growth, limiting early right ventricular outflow tract reoperation.

Case report and review of the literature: Successful transition from acute continuous veno-venous hemodiafiltration therapy to chronic peritoneal dialysis in a chronically ventilated child with hypoplastic left heart syndrome following fontan.

Fontan palliation depends on low pulmonary vascular resistance in order to maintain pulmonary blood flow and adequate oxygenation. This physiology results in higher central venous pressures with limited renal perfusion pressure and cardiac output. Positive pressure ventilation with mechanical ventilation increases intrathoracic pressure and raises central venous pressure and can further limit pulmonary and renal perfusion. Fluid removal with intermittent hemodialysis can be challenging in Fontan patients and can cause intolerable hypotension, however the increased abdominal filling pressures during peritoneal dialysis dwells can exacerbate systemic venous hypertension seen in Fontan patients and threaten adequate pulmonary blood flow and cardiac output. Successful transition to peritoneal dialysis in a chronically ventilated patient with hypoplastic left heart syndrome, end-stage renal disease and Fontan physiology has not been described. We present details outlining the successful transition across multiple modalities of renal replacement therapy to assist other teams faced with similar challenges in chronically ventilated Fontan patients with end-stage renal disease.

Transfusion Strategies for Hemostatic Blood Products in Critically Ill Children: A Narrative Review and Update on Expert Consensus Guidelines.

Critically ill children commonly receive coagulant products (plasma and/or platelet transfusions) to prevent or treat hemorrhage or correct coagulopathy. Unique aspects of pediatric developmental physiology, and the complex pathophysiology of critical illness must be considered and balanced against known transfusion risks. Transfusion practices vary greatly within and across institutions, and high-quality evidence is needed to support transfusion decision-making. We present recent recommendations and expert consensus statements to direct clinicians in the decision to transfuse or not to transfuse hemostatic blood products, including plasma, platelets, cryoprecipitate, and recombinant products to critically ill children.

Plasma and Platelet Transfusions Strategies in Neonates and Children Undergoing Cardiac Surgery With Cardiopulmonary Bypass or Neonates and Children Supported by Extracorporeal Membrane Oxygenation: From the Transfusion and Anemia EXpertise Initiative-Control/Avoidance of Bleeding.

OBJECTIVES: To present the recommendations and consensus statements with supporting literature for plasma and platelet transfusions in critically ill neonates and children undergoing cardiac surgery with cardiopulmonary bypass or supported by extracorporeal membrane oxygenation from the Transfusion and Anemia EXpertise Initiative-Control/Avoidance of Bleeding. DESIGN: Systematic review and consensus conference of international, multidisciplinary experts in platelet and plasma transfusion management of critically ill children. SETTING: Not applicable. PATIENTS: Critically ill neonates and children following cardiopulmonary bypass or supported by extracorporeal membrane oxygenation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A panel of nine experts developed evidence-based and, when evidence was insufficient, expert-based statements for plasma and platelet transfusions in critically ill neonates and children following cardiopulmonary bypass or supported by extracorporeal membrane oxygenation. These statements were reviewed and ratified by the 29 Transfusion and Anemia EXpertise Initiative-Control/Avoidance of Bleeding experts. A systematic review was conducted using MEDLINE, EMBASE, and Cochrane Library databases, from inception to December 2020. Consensus was obtained using the Research and Development/University of California, Los Angeles Appropriateness Method. Results were summarized using the Grading of Recommendations Assessment, Development, and Evaluation method. We developed one good practice statement, two recommendations, and three expert consensus statements. CONCLUSIONS: Whereas viscoelastic testing and transfusion algorithms may be considered, in general, evidence informing indications for plasma and platelet transfusions in neonatal and pediatric patients undergoing cardiac surgery with cardiopulmonary bypass or those requiring extracorporeal membrane oxygenation support is lacking.

Research Priorities for Plasma and Platelet Transfusion Strategies in Critically Ill Children: From the Transfusion and Anemia EXpertise Initiative-Control/Avoidance of Bleeding.

OBJECTIVES: To present a list of high-priority research initiatives for the study of plasma and platelet transfusions in critically ill children from the Transfusion and Anemia EXpertise Initiative-Control/Avoidance of Bleeding. DESIGN: Systematic review and consensus conference of international, multidisciplinary experts in platelet and plasma transfusion management of critically ill children. SETTING: Not applicable. PATIENTS: Critically ill pediatric patients at risk of bleeding and receiving plasma and/or platelet transfusions. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A panel of 13 experts developed research priorities for the study of plasma and platelet transfusions in critically ill children which were reviewed and ratified by the 29 Transfusion and Anemia EXpertise Initiative-Control/Avoidance of Bleeding experts. The specific priorities focused on the following subpopulations: severe trauma, traumatic brain injury, intracranial hemorrhage, cardiopulmonary bypass surgery, extracorporeal membrane oxygenation, oncologic diagnosis or stem cell transplantation, acute liver failure and/or liver transplantation, noncardiac surgery, invasive procedures outside of the operating room, and sepsis and/or disseminated intravascular coagulation. In addition, tests to guide plasma and platelet transfusion, as well as component selection and processing, were addressed. We developed four general overarching themes and 14 specific research priorities using modified Research and Development/University of California, Los Angeles methodology. CONCLUSIONS: Studies are needed to focus on the efficacy/harm, dosing, timing, and outcomes of critically ill children who receive plasma and/or platelet transfusions. The completion of these studies will facilitate the development of evidence-based recommendations.

Executive Summary of Recommendations and Expert Consensus for Plasma and Platelet Transfusion Practice in Critically Ill Children: From the Transfusion and Anemia EXpertise Initiative-Control/Avoidance of Bleeding (TAXI-CAB).

OBJECTIVES: Critically ill children frequently receive plasma and platelet transfusions. We sought to determine evidence-based recommendations, and when evidence was insufficient, we developed expert-based consensus statements about decision-making for plasma and platelet transfusions in critically ill pediatric patients. DESIGN: Systematic review and consensus conference series involving multidisciplinary international experts in hemostasis, and plasma/platelet transfusion in critically ill infants and children (Transfusion and Anemia EXpertise Initiative-Control/Avoidance of Bleeding [TAXI-CAB]). SETTING: Not applicable. PATIENTS: Children admitted to a PICU at risk of bleeding and receipt of plasma and/or platelet transfusions. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A panel of 29 experts in methodology, transfusion, and implementation science from five countries and nine pediatric subspecialties completed a systematic review and participated in a virtual consensus conference series to develop recommendations. The search included MEDLINE, EMBASE, and Cochrane Library databases, from inception to December 2020, using a combination of subject heading terms and text words for concepts of plasma and platelet transfusion in critically ill children. Four graded recommendations and 49 consensus expert statements were developed using modified Research and Development/UCLA and Grading of Recommendations, Assessment, Development, and Evaluation methodology. We focused on eight subpopulations of critical illness (1, severe trauma, intracranial hemorrhage, or traumatic brain injury; 2, cardiopulmonary bypass surgery; 3, extracorporeal membrane oxygenation; 4, oncologic diagnosis or hematopoietic stem cell transplantation; 5, acute liver failure or liver transplantation; 6, noncardiac surgery; 7, invasive procedures outside the operating room; 8, sepsis and/or disseminated intravascular coagulation) as well as laboratory assays and selection/processing of plasma and platelet components. In total, we came to consensus on four recommendations, five good practice statements, and 44 consensus-based statements. These results were further developed into consensus-based clinical decision trees for plasma and platelet transfusion in critically ill pediatric patients. CONCLUSIONS: The TAXI-CAB program provides expert-based consensus for pediatric intensivists for the administration of plasma and/or platelet transfusions in critically ill pediatric patients. There is a pressing need for primary research to provide more evidence to guide practitioners.

Transfusion-Associated Delirium in Children: No Difference Between Short Storage Versus Standard Issue RBCs.

OBJECTIVES: Primary objective is to determine if transfusion of short storage RBCs compared with standard issue RBCs reduced risk of delirium/coma in critically ill children. Secondary objective is to assess if RBC transfusion was independently associated with delirium/coma. DESIGN: This study was performed in two stages. First, we compared patients receiving either short storage or standard RBCs in a multi-institutional prospective randomized controlled trial. Then, we compared all transfused patients in the randomized controlled trial with a single-center cohort of nontransfused patients matched for confounders of delirium/coma. SETTING: Twenty academic PICUs who participated in the Age of Transfused Blood in Critically Ill Children trial. PATIENTS: Children 3 days to 16 years old who were transfused RBCs within the first 7 days of admission. INTERVENTIONS: Subjects were randomized to either short storage RBC study arm (defined as RBCs stored for up to seven days) or standard issue RBC study arm. In addition, subjects were screened for delirium prior to transfusion and every 12 hours after transfusion for up to 3 days. MEASUREMENTS AND MAIN RESULTS: Primary outcome measure was development of delirium/coma within 3 days of initial transfusion. Additional outcome measures were dose-response relationship between volume of RBCs transfused and delirium/coma, and comparison of delirium/coma rates between transfused patients and individually matched nontransfused patients. We included 146 subjects in the stage I analysis; 69 were randomized to short storage RBCs and 77 to standard issue. There was no significant difference in delirium/coma development between study arms (79.5% vs 70.1%; p = 0.184). In the stage II analysis, adjusted odds for delirium in the transfused cohort was more than eight-fold higher than in the nontransfused matched cohort, even after controlling for hemoglobin (adjusted odds ratio, 8.9; CI, 2.8-28.4; p < 0.001). CONCLUSIONS: RBC transfusions (and not anemia) are independently associated with increased odds of subsequent delirium/coma. However, storage age of RBCs does not affect delirium risk.

Hematologic Dysfunction Criteria in Critically Ill Children: The PODIUM Consensus Conference.

CONTEXT: Studies of organ dysfunction in children are limited by a lack of consensus around organ dysfunction criteria. OBJECTIVES: To derive evidence-informed, consensus-based criteria for hematologic dysfunction in critically ill children. DATA SOURCES: Data sources included PubMed and Embase from January 1992 to January 2020. STUDY SELECTION: Studies were included if they evaluated assessment/scoring tools to screen for hematologic dysfunction and assessed outcomes of mortality, functional status, organ-specific outcomes, or other patient-centered outcomes. Studies of adults or premature infants, animal studies, reviews/commentaries, small case series, and non-English language studies with inability to determine eligibility were excluded. DATA EXTRACTION: Data were abstracted from each eligible study into a standard data extraction form along with risk of bias assessment. RESULTS: Twenty-nine studies were included. The systematic review supports the following criteria for hematologic dysfunction: thrombocytopenia (platelet count <100000 cells/µL in patients without hematologic or oncologic diagnosis, platelet count <30000 cells/µL in patients with hematologic or oncologic diagnoses, or platelet count decreased ≥50% from baseline; or leukocyte count <3000 cells/µL; or hemoglobin concentration between 5 and 7 g/dL (nonsevere) or <5 g/dL (severe). LIMITATIONS: Most studies evaluated pre-specified thresholds of cytopenias. No studies addressed associations between the etiology or progression of cytopenias overtime with outcomes, and no studies evaluated cellular function. CONCLUSIONS: Hematologic dysfunction, as defined by cytopenia, is a risk factor for poor outcome in critically ill children, although specific threshold values associated with increased mortality are poorly defined by the current literature.

Factors Associated With an Abnormal Blood Pressure Response During Exercise After Coarctation Repair.

BACKGROUND: Although resting blood pressures following aortic arch repair or the extended end-to-end anastomosis (EEA) repair for coarctation can be physiologic, factors associated with an abnormal blood pressure response after exercise are unknown. We measured blood pressure gradients following exercise in children who had undergone previous repair in accordance with a surgical selection algorithm and sought to identify factors associated with an abnormal blood pressure response. METHODS: In accordance with our practice's surgical algorithm for repair of coarctation, infants were stratified to aortic arch repair when the distal transverse arch-to-left carotid artery ratio (DTA:LCA) ≤ 1.0, or when a brachiocephalic trunk or intra-cardiac lesion requiring repair was present. A thoracotomy and EEA were otherwise used. A follow-up exercise stress test (EST) measured the arm:leg blood pressure gradient after exercise, and a gradient ≥ 20 mm Hg was defined as an abnormal blood pressure response. RESULTS: Thirty-seven infants who had previously undergone coarctation repair (aortic arch repair-19, EEA-18) completed an EST at 12.3 ± 2.2 years of age. Thirteen (35%) children (aortic arch repair-5, EEA-8; p = .3) exhibited an abnormal blood pressure response. Factors associated with an abnormal blood pressure response included: smaller DTA:LCA ratios prior to repair (1.0 ± .2 vs. 1.2 ± .3; p = .04) and greater body weight at the time of EST (57.5 ± 19.1 vs. 40.9 ± 15.6 kg; p = .03). CONCLUSION: An abnormal blood pressure response following exercise is associated with smaller DTA:LCA ratios at the time of repair and increased weight during follow-up suggesting that patients with these factors warrant close observation.

Enoxaparin Reduces Catheter-associated Venous Thrombosis After Infant Cardiac Surgery.

BACKGROUND: Central venous catheter (CVC) related venous thrombosis (VT) after pediatric cardiac surgery increases morbidity and mortality. Although VT prevention using low-dose anticoagulation therapy has proven ineffective, anticoagulation therapy using high-dose enoxaparin to achieve a therapeutic anti-Xa level has not been studied. We hypothesized that high-dose enoxaparin would reduce VT after pediatric cardiac surgery. METHODS: Enoxaparin was administered to infants aged less than 150 days when postoperative CVC duration was anticipated to extend beyond 5 days. The primary outcome was the rate of VT, reexploration for bleeding, and postoperative red blood cell transfusions per 1000 CVC days. RESULTS: From 2012 to 2019, 157 infants were treated with enoxaparin. Infants were divided into two groups: (1) subtherapeutic (n = 51), in which therapeutic anti-Xa level (0.5 to 1.0 IU/mL) was not achieved; and (2) therapeutic (n = 106), in which therapeutic anti-Xa level was achieved. Baseline demographics demonstrated a lower age at operation in the therapeutic group. The subtherapeutic group had a higher VT rate per 1000 CVC days (8.2) compared with the therapeutic group (2.6; P = .005). Reexploration for bleeding was similar between groups. The number of postoperative red blood cell transfusions per 1000 CVC days was significantly greater in the subtherapeutic group (109.4 vs 81.6; P = .008). Multivariate analysis demonstrated that higher median anti-Xa levels reduced the risk of VT (odds ratio 0.02; 95% confidence interval, 0.001 to 0.63; P = .02). CONCLUSIONS: These data suggest that enoxaparin treatment resulting in a therapeutic anti-Xa level reduces postoperative CVC-associated VT without increasing bleeding complications.

Cell Saver Blood Reinfusion Up to 24 Hours Post Collection in Pediatric Cardiac Surgical Patients Does Not Increase Incidence of Hospital-Acquired Infections or Mortality.

Cell saver blood reinfusion, a blood conservation technique recently available for pediatric use, is typically limited to 6 hours post processing to guard against bacterial contamination. We hypothesize that reinfusion of cell saver blood up to 24 hours post collection in children after cardiac surgery will not increase the incidence of hospital-acquired infections (HAI). The primary aim is to compare incidence of HAI between children receiving cell saver blood ≤6 hours vs. >6 to ≤24 hours from its collection. The secondary aim is to compare mortality and clinical outcomes. Retrospective chart review of children ≤18 years undergoing cardiac surgery with cardiopulmonary bypass (CPB) from 2013 to 2018 when cell saver collection and bedside temperature controlled storage became standard of care. Patients on extracorporeal membrane oxygenation (ECMO) within 48 hours postoperatively and those who did not receive cell saver were excluded. The primary outcome was HAI incidence postoperative days 0-6. Demographic data included diagnosis, surgical severity score, and clinical outcomes. 466 patients, 45% female. No significant between-group differences identified. There was no significant difference in HAI (control 8.5% vs. treatment 8.0%, p = .80) and death (control 7.9% vs. treatment 4.9%, p = .20). Noninferiority testing indicated the treatment group was not statistically inferior to the control group (p = .0028). Kaplan-Meier curve depicted similar status between-group rates of no infection or death; 92% treatment vs. 91% control. Total volume allogeneic red blood cell transfusion (allogeneic blood transfusion [ABT]) up to 24 hours postoperatively was significantly less in the treatment group, p < .0001. Incidence of HAI or mortality was not increased in patients receiving cell saver blood reinfusion >6 to ≤24 hours post collection. Treatment subjects received significantly less volume of ABT. Considering the risks of ABT, these findings support cell saver blood reinfusion up to 24 hours post collection.

In Vitro and In Vivo Comparison of Hemoglobin and Electrolytes Following the Collection of Cell Saver Blood Washed with Either Normal Saline or Plasma-Lyte A.

Cell saver blood is typically washed with normal saline (NS); however, recent studies have reported decreased red blood cell hemolysis and increased platelet function when a more physiologic washing solution, such as Plasma-Lyte A (PL-A) is used. We evaluated the in vitro and in vivo effects of NS compared to PL-A as washing solutions for cell saver blood in pediatric cardiac surgery. Cell saver blood was re-infused for up to 24 hours post-collection. Laboratory and clinical data were collected from infants receiving cell saver washed with either NS (n = 20) or PL-A (n = 21). Compositions of the cell saver blood were compared between groups at 5 in vitro time points and in vivo patient blood at 24 hours post-bypass. Although there were differences in in vitro laboratory values between groups; 24 hours post-bypass, in vivo results were similar. Our data supports 24-hour reinfusion of cell saver washed with either NS versus PL-A in pediatric cardiac surgery patients, and provides data on the differences in cell saver composition to guide future studies.

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.

Intraoperative Cortical Asynchrony Predicts Abnormal Postoperative Electroencephalogram.

BACKGROUND: Postoperative electroencephalograms (EEGs) can identify seizure activity and neurologic dysfunction in high-risk neonates requiring cardiac surgical procedures. Although intraoperative EEG monitoring is uncommon, variations in cerebral blood flow and temperature during antegrade cerebral perfusion (ACP) can manifest as cortical asynchrony during EEG monitoring. We hypothesized that intraoperative EEG cortical asynchrony would identify neonates at risk for abnormal postoperative EEG tracings. METHODS: Neonates requiring ACP for cardiac repair or palliation had continuous baseline, intraoperative, and postoperative hemodynamic and EEG monitoring. Synchronous and asynchronous cortical bursts were quantified during (1) cooling before ACP, (2) ACP, and (3) rewarming. Asynchronous bursts were defined as interhemispheric variations in electrical voltage or frequency. Neonates were divided into 2 groups, those with and without an abnormal postoperative EEG, which was defined as either persistent asynchrony for more than 2 hours or seizure activity on EEG. RESULTS: Among 40 neonates, 296 asynchronous bursts were noted, most commonly during rewarming. Eight (20%) neonates had an abnormal postoperative EEG (seizure activity, n = 3; persistent asynchrony, n = 5). Baseline demographics and intraoperative hemodynamics were similar between the groups. However, the total number of intraoperative asynchronous bursts was greater in neonates with an abnormal postoperative EEG (17 [11, IQR:24] vs 3 [IQR:1, 7]; P < .001). Multivariate analysis confirmed that the number of asynchronous bursts was independently associated with an abnormal postoperative EEG (odds ratio,1.35; confidence interval,:1.10, 1.65; P = .004). CONCLUSIONS: Neonates with a greater number of intraoperative asynchronous cortical bursts had an abnormal postoperative EEG.

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.

Effect of Fresh vs Standard-issue Red Blood Cell Transfusions on Multiple Organ Dysfunction Syndrome in Critically Ill Pediatric Patients: A Randomized Clinical Trial.

Importance: The clinical consequences of red blood cell storage age for critically ill pediatric patients have not been examined in a large, randomized clinical trial. Objective: To determine if the transfusion of fresh red blood cells (stored ≤7 days) reduced new or progressive multiple organ dysfunction syndrome compared with the use of standard-issue red blood cells in critically ill children. Design, Setting, and Participants: The Age of Transfused Blood in Critically-Ill Children trial was an international, multicenter, blinded, randomized clinical trial, performed between February 2014 and November 2018 in 50 tertiary care centers. Pediatric patients between the ages of 3 days and 16 years were eligible if the first red blood cell transfusion was administered within 7 days of intensive care unit admission. A total of 15 568 patients were screened, and 13 308 were excluded. Interventions: Patients were randomized to receive either fresh or standard-issue red blood cells. A total of 1538 patients were randomized with 768 patients in the fresh red blood cell group and 770 in the standard-issue group. Main Outcomes and Measures: The primary outcome measure was new or progressive multiple organ dysfunction syndrome, measured for 28 days or to discharge or death. Results: Among 1538 patients who were randomized, 1461 patients (95%) were included in the primary analysis (median age, 1.8 years; 47.3% girls), in which there were 728 patients randomized to the fresh red blood cell group and 733 to the standard-issue group. The median storage duration was 5 days (interquartile range [IQR], 4-6 days) in the fresh group vs 18 days (IQR, 12-25 days) in the standard-issue group (P < .001). There were no significant differences in new or progressive multiple organ dysfunction syndrome between fresh (147 of 728 [20.2%]) and standard-issue red blood cell groups (133 of 732 [18.2%]), with an unadjusted absolute risk difference of 2.0% (95% CI, -2.0% to 6.1%; P = .33). The prevalence of sepsis was 25.8% (160 of 619) in the fresh group and 25.3% (154 of 608) in the standard-issue group. The prevalence of acute respiratory distress syndrome was 6.6% (41 of 619) in the fresh group and 4.8% (29 of 608) in the standard-issue group. Intensive care unit mortality was 4.5% (33 of 728) in the fresh group vs 3.5 % (26 of 732) in the standard-issue group (P = .34). Conclusions and Relevance: Among critically ill pediatric patients, the use of fresh red blood cells did not reduce the incidence of new or progressive multiple organ dysfunction syndrome (including mortality) compared with standard-issue red blood cells. Trial Registration: ClinicalTrials.gov Identifier: NCT01977547.

Bleeding Assessment Scale in Critically Ill Children (BASIC): Physician-Driven Diagnostic Criteria for Bleeding Severity.

OBJECTIVE: Although bleeding frequently occurs in critical illness, no published definition to date describes the severity of bleeding accurately in critically ill children. We sought to develop diagnostic criteria for bleeding severity in critically ill children. DESIGN: Delphi consensus process of multidisciplinary experts in bleeding/hemostasis in critically ill children, followed by prospective cohort study to test internal validity. SETTING: PICU. PATIENTS: Children at risk of bleeding in PICUs. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Twenty-four physicians worldwide (10 on a steering committee and 14 on an expert committee) from disciplines related to bleeding participated in development of a definition for clinically relevant bleeding. A provisional definition was created from 35 descriptors of bleeding. Using a modified online Delphi process and conference calls, the final definition resulted after seven rounds of voting. The Bleeding Assessment Scale in Critically Ill Children definition categorizes bleeding into severe, moderate, and minimal, using organ dysfunction, proportional changes in vital signs, anemia, and quantifiable bleeding. The criteria do not include treatments such as red cell transfusion or surgical interventions performed in response to the bleed. The definition was prospectively applied to 40 critically ill children with 46 distinct bleeding episodes. The kappa statistic between the two observers was 0.74 (95% CI, 0.57-0.91) representing substantial inter-rater reliability. CONCLUSIONS: The Bleeding Assessment Scale in Critically Ill Children definition of clinically relevant bleeding severity is the first physician-driven definition applicable for bleeding in critically ill children derived via international expert consensus. The Bleeding Assessment Scale in Critically Ill Children definition includes clear criteria for bleeding severity in critically ill children. We anticipate that it will facilitate clinical communication among pediatric intensivists pertaining to bleeding and serve in the design of future epidemiologic studies if it is validated with patient outcomes.