Abstract

OBJECTIVES To present consensus statements and supporting literature for plasma and platelet product variables and related laboratory testing for transfusions in general 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 10 experts developed evidence-based and, when evidence was insufficient, expert-based statements for laboratory testing and blood product attributes for platelet and plasma transfusions. 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 five expert consensus statements and two recommendations in answer to two questions: what laboratory tests and physiologic triggers should guide the decision to administer a platelet or plasma transfusion in critically ill children; and what product attributes are optimal to guide specific product selection? CONCLUSIONS The Transfusion and Anemia EXpertise Initiative-Control/Avoidance of Bleeding program provides some guidance and expert consensus for the laboratory and blood product attributes used for decision-making for plasma and platelet transfusions in critically ill pediatric patients.

Abstract

INTRODUCTION Premature neonates have a high risk of intraventricular hemorrhage (IVH) at birth, the blood products of which activate inflammatory cascades that can cause hydrocephalus and long-term neurological morbidities and sequelae. However, there is no consensus for one treatment strategy. While the mainstay of treatment involves CSF diversion to reduce intracranial pressure, a number of interventions focus on blood product removal at various stages including extraventricular drains (EVD), intra-ventricular thrombolytics, drainage-irrigation-fibrinolytic therapy (DRIFT), and neuroendoscopic lavage (NEL). METHODS We performed a systematic review and meta-analysis to compare the risks and benefits commonly associated with active blood product removal treatment strategies. We searched MEDLINE, Embase, Scopus, Cochrane Library, and CINAHL databases through Dec 2020 for articles reporting on outcomes of EVDs, thrombolytics, DRIFT, and NEL. Outcomes of interest were rate of conversion to ventriculoperitoneal shunt (VPS), infection, mortality, secondary hemorrhage, and cognitive disability. RESULTS Of the 10,398 articles identified in the search, 23 full-text articles representing 22 cohorts and 530 patients were included for meta-analysis. These articles included retrospective, prospective, and randomized controlled studies on the use of EVDs (n = 7), thrombolytics (n = 8), DRIFT therapy (n = 3), and NEL (n = 5). Pooled rates of reported outcomes for EVD, thrombolytics, DRIFT, and NEL for ventriculoperitoneal shunt (VPS) placement were 51.1%, 43.3%, 34.3%, and 54.8%; for infection, 15.4%, 12.5%, 4.7%, and 11.0%; for mortality, 20.0%, 11.6%, 6.0%, and 4.9%; for secondary hemorrhage, 5.8%, 7.8%, 20.0%, and 6.9%; for cognitive impairment, 52.6%, 50.0%, 53.7%, and 50.9%. Meta-regression using type of treatment as a categorical covariate showed no effect of treatment modality on rate of VPS conversion or cognitive disability. CONCLUSION There was a significant effect of treatment modality on secondary hemorrhage and mortality; however, mortality was no longer significant after adjusting for year of publication. Re-hemorrhage rate was significantly higher for DRIFT (p < 0.001) but did not differ among the other modalities. NEL also had lower mortality relative to EVD (p < 0.001) and thrombolytics (p = 0.013), which was no longer significant after adjusting for year of publication. Thus, NEL appears to be safer than DRIFT in terms of risk of hemorrhage, and not different than other blood-product removal strategies in terms of mortality. Outcomes-in terms of shunting and cognitive impairment-did not differ. Later year of publication was predictive of lower rates of mortality, but not the other outcome variables. Further prospective and randomized studies will be necessary to directly compare NEL with other temporizing procedures.

Abstract

IMPORTANCE Tranexamic acid is widely available and used off-label in patients with bleeding traumatic injury, although the literature does not consistently agree on its efficacy and safety. OBJECTIVE To examine the association of tranexamic acid administration with mortality and thromboembolic events compared with no treatment or with placebo in patients with traumatic injury in the literature. DATA SOURCES On March 23, 2021, PubMed, Embase, and the Cochrane Library were searched for eligible studies published between 1986 and 2021. STUDY SELECTION Randomized clinical trials and observational studies investigating tranexamic acid administration compared with no treatment or placebo among patients with traumatic injury and traumatic brain injury who were 15 years or older were included. Included studies were published in English or German. The electronic search yielded 1546 records, of which 71 were considered for full-text screening. The selection process was performed independently by 2 reviewers. DATA EXTRACTION AND SYNTHESIS The study followed the Cochrane Handbook for Systematic Reviews of Interventions and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Data were extracted by 2 independent reviewers and pooled using the inverse-variance random-effects model. MAIN OUTCOMES AND MEASURES Outcomes were formulated before data collection and included mortality at 24 hours and 28 and 30 days (1 month) as well as the incidence of thromboembolic events and the amount of blood products administered. Owing to missing data, overall mortality was added and the amount of blood products administered was discarded. RESULTS Thirty-one studies with a total of 43 473 patients were included in the systematic review. The meta-analysis demonstrated that administration of tranexamic acid was associated with a significant decrease in 1-month mortality compared with the control cohort (risk ratio, 0.83 [95% CI, 0.71-0.97]; I2 = 35%). The results of meta-analyses for 24-hour and overall mortality and thromboembolic events were heterogeneous and could not be pooled. Further investigations on clinical heterogeneity showed that populations with trauma and trial conditions differed markedly. CONCLUSIONS AND RELEVANCE These findings suggest that tranexamic acid may be beneficial in various patient populations with trauma. However, reasonable concerns about potential thromboembolic events with tranexamic acid remain.

Abstract

Pediatric upper gastrointestinal bleeding refers to an acute massive hemorrhage of the upper digestive tract and biliary tract, which is a common clinical emergency in pediatrics. This study aimed to evaluate the clinical effect of octreotide combined with omeprazole in pediatric upper gastrointestinal bleeding. Totally 84 cases of pediatric upper gastrointestinal bleeding admitted to Ningbo Women and Children's Hospital from November 2019 to April 2021 were divided into groups according to the admission order. The control group received omeprazole treatment and the observation group received octreotide plus. The total clinical effective rate of children in the observation group was higher than that of the control group. The observation group was superior to the control group with respect to the average hemostasis time, hemostasis rate, rebleeding rate and length of stay after treatment. The observation group witnessed a significantly better quality of life than the control group. For children with acute upper gastrointestinal bleeding, the combination of omeprazole and octreotide yields a promising effect in the adjustment of blood creatinine and serum urea nitrogen levels and hemostasis, which is worthy of clinical application.

Abstract

INTRODUCTION Low titer group O whole blood (LTOWB) resuscitation is increasingly common in both military and civilian settings. Data regarding the safety and efficacy of prehospital LTOWB remains limited. METHODS We performed a single center, prospective, cluster randomized, prehospital thru in-hospital whole blood pilot trial for injured air medical patients. We compared standard prehospital air medical care including red cell transfusion and crystalloids followed by in-hospital component transfusion to prehospital and in-hospital LTOWB resuscitation. Prehospital vital signs were used as inclusion criteria (SBP ≤ 90 mmHg and HR ≥ 108 bpm) or (SBP ≤ 70 mmHg) for patients at risk of hemorrhage. Primary outcome was feasibility. Secondary outcomes included 28-day and 24 hour mortality, multiple organ failure, nosocomial infection, 24 hr transfusion requirements and arrival coagulation parameters. RESULTS Between November 2018 thru October 2020, 86 injured patients were cluster randomized by helicopter base. The trial has halted early at 77% enrollment. Overall, 28-day mortality for the cohort was 26%. Injured patients randomized to prehospital LTOWB (n = 40) relative to standard care (n = 46) were similar in demographics and injury characteristics. Intent to treat Kaplan-Meier survival analysis demonstrated no statistical mortality benefit at 28 days (25.0% vs. 26.1%, p = 0.85). Patients randomized to prehospital LTOWB relative to standard care had lower red cell transfusion requirements at 24 hours (p < 0.01) and a lower incidence of abnormal thromboelastographic measurements. No transfusion reactions during the prehospital or in-hospital phase of care were documented. CONCLUSION Prehospital through in-hospital LTOWB resuscitation is safe and may be associated with hemostatic benefits. A large-scale clinical trial is feasible with protocol adjustment and would allow the effects of prehospital LTOWB on survival and other pertinent clinical outcomes to be appropriately characterized. LEVEL OF EVIDENCE II, Cluster randomized pilot trial.

Abstract

BACKGROUND The objective of this study was to evaluate factors associated with intraventricular hemorrhage (IVH) expansion and its association with long-term outcomes. METHODS We performed a post hoc analysis of the international, multi-center CLEAR III trial (Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage) which enrolled IVH patients between September 1, 2009, and January 31, 2015. The exposure was IVH expansion, defined as >1 mL increase in volume between baseline and stability computed tomography scans, before treatment randomization. We assessed factors associated with IVH expansion and secondarily assessed the relationship of IVH expansion with clinical outcomes: composite of death or major disability (modified Rankin Scale score, >3), and mortality alone at 6 months. The relationship of IVH expansion on ventriculoperitoneal shunt placement was additionally explored. Multivariable logistic regression was used for all analyses. RESULTS Of 500 IVH patients analyzed, the mean age was 59 (±11) years old, 44% were female and 135 (27%) had IVH expansion. In multivariable regression models, factors associated with IVH expansion were baseline parenchymal intracerebral hemorrhage (ICH) volume (adjusted odds ratio [OR], 1.04 per 1 mL increase [95% CI, 1.01-1.08]), presence of parenchymal hematoma expansion: >33% (adjusted OR, 6.63 [95% CI, 3.92-11.24]), time to stability head CT (adjusted OR, 0.71 per 1 hour increase [95% CI, 0.54-0.94]), and thalamic hematoma location (adjusted OR, 1.68 [95% CI, 1.01-2.79]) while additionally adjusting for age, sex, and race. In secondary analyses, IVH expansion was associated with higher odds of poor 6-month outcomes (adjusted OR, 1.84 [95% CI, 1.12-3.02]) but not mortality (OR, 1.40 [95% CI, 0.78-2.50]) after adjusting for baseline ICH volume, thalamic ICH location, age, anticoagulant use, Glasgow Coma Scale score, any withdrawal of care order, and treatment randomization arm. However, there were no relationships of IVH expansion on subsequent ventriculoperitoneal shunt placement (adjusted OR, 1.02 [95% CI, 0.58-1.80]) after adjusting for similar covariates. CONCLUSIONS In a clinical trial cohort of patients with large IVH, acute hematoma characteristics, specifically larger parenchymal volume, hematoma expansion, and thalamic ICH location were associated with IVH expansion. Given that IVH expansion resulted in poor functional outcomes, exploration of treatment approaches to optimize hemostasis and prevent IVH expansion, particularly in patients with thalamic ICH, require further study. REGISTRATION URL: https://www.clinicaltrials.gov; Unique identifier: NCT00784134.

Abstract

BACKGROUND The antifibrinolytic drug tranexamic acid (TXA) improves survival in adults with traumatic hemorrhage; however, the drug has not been evaluated in a trial in injured children. We evaluated the feasibility of a large-scale trial evaluating the effects of TXA in children with severe hemorrhagic injuries. METHODS Severely injured children (0 up to 18(th) birthday) were randomized into a double-blind randomized trial of 1) TXA 15 mg/kg bolus dose, followed by 2 mg/kg/hr infusion over 8 hours, 2) TXA 30 mg/kg bolus dose, followed by 4 mg/kg/hr infusion over 8 hours, or 3) normal saline placebo bolus and infusion. The trial was conducted at 4 pediatric Level I trauma centers in the United States between June 2018 and March 2020. We enrolled patients under federal exception from informed consent (EFIC) procedures when parents were unable to provide informed consent. Feasibility outcomes included the rate of enrollment, adherence to intervention arms, and ability to measure the primary clinical outcome. Clinical outcomes included global functioning (primary), working memory, total amount of blood products transfused, intracranial hemorrhage progression, and adverse events. The target enrollment rate was at least 1.25 patients per site per month. RESULTS A total of 31 patients were randomized with a mean age of 10.7 years (standard deviation [SD] 5.0 years) and 22 (71%) patients were male. The mean time from injury to randomization was 2.4 hours (SD 0.6 hours). Sixteen (52%) patients had isolated brain injuries and 15 (48%) patients had isolated torso injuries. The enrollment rate using EFIC was 1.34 patients per site per month. All eligible enrolled patients received study intervention (9 patients TXA 15 mg/kg bolus dose, 10 patients TXA 30 mg/kg bolus dose, and 12 patients placebo) and had the primary outcome measured. No statistically significant differences in any of the clinical outcomes were identified. CONCLUSION Based on enrollment rate, protocol adherence, and measurement of the primary outcome in this pilot trial, we confirmed the feasibility of conducting a large-scale, randomized trial evaluating the efficacy of TXA in severely injured children with hemorrhagic brain and/or torso injuries using EFIC.

Abstract

BACKGROUND Patients requiring emergent warfarin reversal (EWR) have been prescribed three-factor prothrombin complex concentrate (PCC3) and four-factor prothrombin complex concentrate (PCC4) to reverse the anticoagulant effects of warfarin. There is no existing systematic review and meta-analysis of studies directly comparing PCC3 and PCC4. METHODS The primary objective of this systematic review and meta-analysis was to determine the effectiveness of achieving study defined target INR goal after PCC3 or PCC4 administration. Secondary objectives were to determine the difference in safety endpoints, thromboembolic events (TE), and survival during the patients' hospital stay. Random-effects meta-analysis models were used to estimate the odds ratios (OR), and heterogeneity associated with the outcomes. The Newcastle-Ottawa Scale was used to assess study quality, and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. RESULTS Ten full-text manuscripts and five abstracts provided data for the primary and secondary outcomes. Patients requiring EWR had more than three times the odds of reversal to goal INR when they were given PCC4 compared to PCC3 (OR = 3.61, 95% CI: 1.97-6.60, p < 0.001). There was no meaningful clinical association or statistically significant result between PCC4 and PCC3 groups in TE (OR = 1.56, 95% CI: 0.83-2.91, p = 0.17), or survival during hospital stay (OR = 1.34, 95% CI: 0.81-2.23, p = 0.25). CONCLUSION PCC4 is more effective than PCC3 in meeting specific predefined INR goals and has similar safety profiles in patients requiring emergent reversal of the anticoagulant effects of warfarin.

Abstract

BACKGROUND The TRACT trial established the timing of transfusion in children with uncomplicated anaemia (haemoglobin 4-6 g/dL) and the optimal volume (20 vs 30 mL/kg whole blood or 10 vs 15 mL/kg red cell concentrates) for transfusion in children admitted to hospital with severe anaemia (haemoglobin <6 g/dL) on day 28 mortality (primary endpoint). Because data on the safety of blood components are scarce, we conducted a secondary analysis to examine the safety and efficacy of different pack types (whole blood vs red cell concentrates) on clinical outcomes. METHODS This study is a secondary analysis of the TRACT trial data restricted to those who received an immediate transfusion (using whole blood or red cell concentrates). TRACT was an open-label, multicentre, factorial, randomised trial conducted in three hospitals in Uganda (Soroti, Mbale, and Mulago) and one hospital in Malawi (Blantyre). The trial enrolled children aged between 2 months and 12 years admitted to hospital with severe anaemia (haemoglobin <6 g/dL). The pack type used (supplied by blood banks) was based only on availability at the time. The outcomes were haemoglobin recovery at 8 h and 180 days, requirement for retransfusion, length of hospital stay, changes in heart and respiratory rates until day 180, and the main clinical endpoints (mortality until day 28 and day 180, and readmission until day 180), measured using multivariate regression models. FINDINGS Between Sept 17, 2014, and May 15, 2017, 3199 children with severe anaemia were enrolled into the TRACT trial. 3188 children were considered in our secondary analysis. The median age was 37 months (IQR 18-64). Whole blood was the first pack provided for 1632 (41%) of 3992 transfusions. Haemoglobin recovery at 8 h was significantly lower in those who received packed cells or settled cells than those who received whole blood, with a mean of 1·4 g/dL (95% CI -1·6 to -1·1) in children who received 30 mL/kg and -1·3 g/dL (-1·5 to -1·0) in those who received 20 mL/kg packed cells versus whole blood, and -1·5 g/dL (-1·7 to -1·3) in those who received 30 mL/kg and -1·0 g/dL (-1·2 to -0·9) in those who received 20 mL/kg settled cells versus whole blood (overall p<0·0001). Compared to whole blood, children who received blood as packed or settled cells in their first transfusion had higher odds of receiving a second transfusion (odds ratio 2·32 [95% CI 1·30 to 4·12] for packed cells and 2·97 [2·18 to 4·05] for settled cells; p<0·001) and longer hospital stays (hazard ratio 0·94 [95% CI 0·81 to 1·10] for packed cells and 0·86 [0·79 to 0·94] for settled cells; p=0·0024). There was no association between the type of blood supplied for the first transfusion and mortality at 28 days or 180 days, or readmission to hospital for any cause. 823 (26%) of 3188 children presented with severe tachycardia and 2077 (65%) with tachypnoea, but these complications resolved over time. No child developed features of confirmed cardiopulmonary overload. INTERPRETATION Our study suggests that the use of packed or settled cells rather than whole blood leads to additional transfusions, increasing the use of a scarce resource in most of sub-Saharan Africa. These findings have substantial cost implications for blood transfusion and health services. Nevertheless, a clinical trial comparing whole blood transfusion with red cell concentrates might be needed to inform policy makers. FUNDING UK Medical Research Council (MRC) and the Department for International Development. TRANSLATION For the French translation of the abstract see Supplementary Materials section.

Abstract

OBJECTIVES To present the consensus statements with supporting literature for plasma and platelet transfusions in critically ill neonates and children with malignancy, acute liver disease and/or following liver transplantation, and sepsis and/or disseminated intravascular coagulation 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 with malignancy, acute liver disease and/or following liver transplantation, and sepsis and/or disseminated intravascular coagulation. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS A panel of 13 experts developed evidence-based and, when evidence was insufficient, expert-based statements for plasma and platelet transfusions in critically ill neonates and children with malignancy, acute liver disease and/or following liver transplantation, and sepsis and/or disseminated intravascular coagulation. 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 12 expert consensus statements. CONCLUSIONS In the Transfusion and Anemia EXpertise Initiative-Control/Avoidance of Bleeding program, the current absence of evidence for use of plasma and/or platelet transfusion in critically ill children with malignancy, acute liver disease and/or following liver transplantation, and sepsis means that only expert consensus statements are possible for these areas of practice.