Ed an increase in endogenous thrombin potential [14], whereas in another study PCC did not reverse the effect of dabigatran as measured by activated partial thromboplastin time (aPTT) [15]. A specific antibody fragment to dabigatran (aDabi-Fab) is in development, and in a rat model of anticoagulation it rapidly reversed the anticoagulant activity of dabigatran [16]. However, this antidote is not yet licensed for clinical use. This porcine study was performed to evaluate the potential use of commonly available haemostatic agents (PCC, aPCC and rFVIIa), as well as the specific antidote aDabi-Fab, to reverse dabigatran-induced coagulopathy in an anticoagulation/trauma model. In addition, the study investigated the
3,3-Dimethyl-7-nitro-2,3-dihydrobenzo[b][1,4]oxazepin-4(5h)-one sensitivity of different coagulation tests, including thromboelastometry variables, for diagnosis and reversal of dabigatran/trauma-induced coagulopathy.Prior to surgery, DE (Pradaxa, Boehringer Ingelheim, Biberach, Germany) was administered orally twice daily for 3 days (30 mg/kg bid). On the day of surgery, animals received an intramuscular injection of 4 mg/kg azaperone (Stresnil, Janssen, Neuss, Germany) and 0.1 mg/kg atropine (atropine sulphate, B Braun, Melsungen, Germany) as premedication. Anaesthesia was induced by intravenous injection of 3 mg/kg propofol (Disoprivan, Astra Zeneca, Wedel, Germany) followed by orotracheal intubation. The animals were ventilated with a
tidal volume of 8 mL/kg and 16 to 22 breaths/minute (Cato, Draeger, Luebeck, Germany) to maintain end-tidal carbon dioxide between 36 and 42 mmHg. Anaesthesia was maintained with isoflurane (Forane, Abbott Laboratories Inc., Abbott Park, IL, USA) at an end-tidal concentration of 1 and a continuous infusion of fentanyl (Janssen, Neuss, Germany) at 3 to
4 g/kg/h. Ringer's solution (Sterofundin, Braun, Germany) was infused at 4 mL/kg/h initially, increasing to 10 mL/kg/h after laparotomy until infliction of trauma. Throughout the experiment, body temperature was maintained at 36.5 to 37.0 with a warming blanket. Monitoring included electrocardiography (ECG), tail pulse oximetry, temperature, and arterial and central venous pressure measured by femoral catheters connected to a standard anaesthesia monitor
2-Bromo-1,3-difluoro-4-nitrobenzene (AS/3, Datex Ohmeda, Helsinki, Finland).Surgical preparation and dabigatran infusionMaterials and methodsEthics and anaesthesiaAll experiments were performed in accordance with German legislation governing animal studies following the Principles of Laboratory Animal Care. Ethical approval
PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/20460822 for these studies was obtained from the regional governmental animal care and use
PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/18218841 office (No. 84?2.04.2012.A197). Before surgery, pigs were housed in ventilated rooms and allowed to acclimatise to their surroundings for a minimum of seven days. Animals were fasted overnight before surgical procedures, with unrestricted access to water.Two 8.5-Fr catheters were surgically implanted in the right and left jugular veins for volume substitution and insertion of a pulmonary artery
catheter. The right femoral artery was cannulated with an 18-G catheter to collect blood samples and to measure continuous arterial pressure. After line placement, a midline laparotomy with cystostomy was performed. Subsequently, dabigatran (active substance; Boehringer Ingelheim, Biberach, Germany) was infused at a rate of 0.77 mg/kg/h for 30 minutes and 0.52 mg/kg/h for 60 minutes to achieve consistent, supratherapeutic plasma concentrations of dabigatran. A reproducible blunt liver injury was induced.