Antifibrinolytic Drugs for the Prevention of Bleeding in Pediatric Cardiac Surgery on Cardiopulmonary Bypass: A Systematic Review and Meta-analysis.

BACKGROUND: Bleeding is one of the commonest complications affecting children undergoing cardiac surgery on cardiopulmonary bypass. Antifibrinolytic drugs are part of a multifaceted approach aimed at reducing bleeding, though sufficiently sized pediatric studies are sparse, and dosing algorithms are heterogeneous. Our objective was to evaluate the efficacy and safety of antifibrinolytic agents as well as the effectiveness of different dosing regimens in pediatric cardiac surgery using cardiopulmonary bypass. METHODS: We performed a systematic review and meta-analysis evaluating randomized controlled trials published between 1980 and 2019, identified by searching the databases MEDLINE, EMBASE, PubMed, and CENTRAL. All studies investigating patients <18 years of age without underlying hematological disorders were included. The primary outcome was postoperative bleeding; secondary end points included blood product transfusion, mortality, and safety (thromboses, anaphylaxis, renal or neurological dysfunction, and seizures). Different dosing regimens were compared. Studies were dual appraised, outcomes were reported descriptively and, if appropriate, quantitatively using the Review Manager 5 (REVMAN 5) software (The Cochrane Collaboration). RESULTS: Thirty of 209 articles were included, evaluating the following drugs versus control: aprotinin n = 14, tranexamic acid (TXA) n = 12, and epsilon-aminocaproic acid (EACA) n = 4. The number of participants per intervention group ranged from 11 to 100 (median, 25; interquartile range [IQR], 20.5) with a wide age span (mean, 13 days to 5.8 years) and weight range (mean, 3.1-26.3 kg). Methodological quality was low to moderate.All agents reduced mean 24-hour blood loss compared to control: aprotinin by 6.0 mL/kg (95% confidence interval [CI], -9.1 to -3.0; P = .0001), TXA by 9.0 mL/kg (95% CI, -11.3 to -6.8; P < .00001), and EACA by 10.5 mL/kg (95% CI, -21.1 to 0.0; P = .05). Heterogeneity was low for TXA (I2 = 29%; P = .19), moderate for aprotinin (I2 = 41%; P = .11), and high for EACA (I2 = 95%; P < .00001). All agents also reduced 24-hour blood product transfusion. There was no clear dose-response effect for TXA nor aprotinin. Studies were underpowered to detect significant differences in mortality, thromboses, anaphylaxis, and renal or neurological dysfunction. CONCLUSIONS: The available data demonstrate efficacy for all 3 antifibrinolytic drugs. Therefore, the agent with the most favorable safety profile should be used. As sufficient data are lacking, large comparative trials are warranted to assess the relative safety and appropriate dosing regimens in pediatrics.

Strategies for Prevention and Management of Bleeding Following Pediatric Cardiac Surgery on Cardiopulmonary Bypass: A Scoping Review.

OBJECTIVE: We aimed to systematically describe, via a scoping review, the literature reporting strategies for prevention and management of mediastinal bleeding post pediatric cardiopulmonary bypass surgery. DATA SOURCES: MEDLINE, EMBASE, PubMed, and Cochrane CENTRAL Register. STUDY SELECTION: Two authors independently screened publications from 1980 to 2016 reporting the effect of therapeutic interventions on bleeding-related postoperative outcomes, including mediastinal drain loss, transfusion, chest re-exploration rate, and coagulation variables. Inclusions: less than 18 years, cardiac surgery on cardiopulmonary bypass. DATA EXTRACTION: Data from eligible studies were extracted using a standard data collection sheet. DATA SYNTHESIS: Overall, 299 of 7,434 screened articles were included, with observational studies being almost twice as common (n = 187, 63%) than controlled trials (n = 112, 38%). The most frequently evaluated interventions were antifibrinolytic drugs (75 studies, 25%), blood products (59 studies, 20%), point-of-care testing (47 studies, 16%), and cardiopulmonary bypass circuit modifications (46 studies, 15%). The publication rate for controlled trials remained constant over time (4-6/yr); however, trials were small (median participants, 51; interquartile range, 57) and overwhelmingly single center (98%). Controlled trials originated from 22 countries, with the United States, India, and Germany accounting for 50%. The commonest outcomes were mediastinal blood loss and transfusion requirements; however, these were defined inconsistently (blood loss being reported over nine different time periods). The majority of trials were aimed at bleeding prevention (98%) rather than treatment (10%), nine studies assessed both. CONCLUSIONS: Overall, this review demonstrates small trial sizes, low level of evidence, and marked heterogeneity of reported endpoints in the included studies. The need for more, higher quality studies reporting clinically relevant, comparable outcomes is highlighted. Emerging fields such as the use of coagulation factor concentrates, goal-directed guidelines, and anti-inflammatory therapies appear to be of particular interest. This scoping review can potentially guide future trial design and form the basis for therapy-specific systematic reviews.