This prospective observational study was conducted according to the standards set forth by the Declaration of Helsinki and Good Clinical Practice guidelines. Following the local ethics committee’s approval (Ethics Committee of Hanover Medical School, Germany, Chairperson Prof. Dr. H. D. Troeger, No. 7349 dated February 2, 2017), 50 children ranging from 0 to 6 years of age scheduled for cardiac surgery with CPB and one or more risk factors for bleeding were included (Fig. 1). The risk factors were predefined as an age of less than 1 year, hypothermia on CPB < 32 °C, expected CPB duration > 90 min, re-sternotomy or extensive aortic suture lines. Children with pre-existing coagulation disorders or on anticoagulant or antiplatelet therapy were excluded. The study was conducted from April 2017 to November 2018 at the Clinic for Anesthesiology and Intensive Care Medicine, Hanover Medical School, Germany, and all operations were performed by the same team of surgeons.
Anesthesia was induced by injection of 0.5 mg kg− 1 etomidate, 0.5 μg kg− 1 sufentanil and 0.5 mg kg− 1 atracurium and maintained by sufentanil 1 μg kg− 1 h− 1 and sevoflurane (on CPB administered via oxygenator).
CPB was performed with the heart-lung machine LivaNova S5 (LivaNova PLC, London, UK) and the oxygenator system TerumoFX05 (Terumo Corporation, Tokyo, Japan). The system was prepared in a standardized fashion: The circuit was primed with a bicarbonate-buffered hemofiltration solution (BB-HS; Duosol, B. Braun, Melsungen, Germany), 2 mL kg− 1 mannitol, 150 IU kg− 1 of heparin and 20 mL kg− 1 gelatin. In infants with a body weight below 5 kg, 10 mL kg− 1 albumin 20% was used instead of gelatin. Packed red blood cells were added if necessary to achieve hemoglobin levels of 8–10 g dL− 1. According to patient’s weight, the total priming volume fluctuated between 180 and 450 ml. To achieve a physiological composition, priming volume was hemofiltered before CPB using a polysulfone hemofilter (ME HF0S 0020, Medos AG, Stolberg, Germany) by ten minutes circulation until approximately 1000 mL of ultrafiltrate were restored by BB-HS . During the last 30 min of CPB, 20–30 mL kg− 1 fresh frozen plasma was added, and a higher amount of fluid was removed by hemofiltration. Target pump flow was 2.7 L min− 1 m− 2 for children and 3.0 L min− 1 m− 2 for infants below one year of age. Target mean arterial pressure was guided by near-infrared spectroscopy (NIRS) and continuously measured central venous oxygen saturation in the venous line of the bypass. Before CPB, a heparin bolus of 400 IU kg− 1 was given to achieve anticoagulation. During CPB, activated clotting time (ACT) was maintained longer than 400 s by adding additional heparin if necessary. Tranexamic acid was administered at 10 mg kg− 1 h− 1. At the end of CPB, the administered heparin was reversed by protamine starting at a ratio of 0.8 until the ACT had returned to < 130 s.
After CPB weaning, heparin reversal and clinical bleeding evaluation, the hemostatic therapy was started with 50 mg kg− 1 human fibrinogen (Haemocomplettan®, CSL Behring GmbH, Marburg, Germany), 50 IU kg− 1 human prothrombin complex (Beriplex®, CSL Behring GmbH, Marburg, Germany) and 20 mL kg− 1 platelets. Repeat doses were guided by clinical bleeding evaluation and TEG as follows: In case of MA-fib < 15 mm, fibrinogen was added; in case of R > 9.5 min, prothrombin complex was added; and in case of MA < 52 mm and normal MA-fib (> 15 mm), platelets were added until the bleeding situation improved clinically significant and closure of the thorax was possible.
Results of blood gas analysis, hematologic (hemoglobin, hematocrit, platelets), coagulation standard (Quick value of prothrombin time (Quick), activated partial thromboplastin time (aPTT), activated clotting time (ACT), fibrinogen (Clauss method), antithrombin III, factor II, factor V and TEG parameters (reaction time (R), kinetic time (K), angle, maximum amplitude (MA), functional fibrinogen, maximum amplitude of functional fibrinogen (MA-fib), fibrinolysis at 30 min after maximum amplitude (LY30)) were collected at the following points in time: at baseline before skin incision (T1); after CPB and reversal of heparin by protamine before administration of coagulation factors or blood products (T2); at sternal closure (T3); and after 12 h in the ICU (T4). For the TEG analysis, the TEG 6 s analyzer (Haemonetics, Braintree, Massachusetts, USA) was used. At T2 and T3, the operating surgeon was asked to evaluate the bleeding on a numeric rating scale from 0 to 10 (NRS; 0 = absolutely dry, no signs of any bleeding at all; 10 = massive bleeding with no signs of coagulation). The administered coagulation factors and blood products were documented. Intraoperative data included CPB time, cross-clamp time, duration of deep hypothermic circulatory arrest (if used) and the lowest temperature during CPB. Postoperative data included chest drainage output within the first six postoperative hours, rate of re-intervention and postoperative transfusion, the occurrence of thrombosis, length of mechanical ventilation, ICU stay and mortality. Significant postoperative bleeding was defined as a blood loss of more than 10% of the child’s estimated blood volume within the first six postoperative hours.
Data were recorded in an Excel database, analyzed using MS Excel (Excel 2010; Microsoft, Seattle, USA) and GraphPad Prism (Prism 7; Graph Pad Software Inc., San Diego, USA) software tools, and presented as mean values plus standard deviation (range) or as median (range). Spearman correlation, regression analysis and independent-samples Mann-Whitney-U tests were performed with a pre-defined significance level of α = 0.05.