Acute aortic dissection (AAD) involving the ascending aorta (Stanford classification type A) remains a life-threatening disease. Excessive perioperative bleeding requiring massive transfusion of allogeneic blood products, and surgical reexploration remain major challenges in these patients. Previous research has indicated that patients with AAD show pronounced haemostatic alterations prior to surgery which are aggravated during major aortic surgery with cardiopulmonary bypass and hypothermia full heparinization. Intensified anticoagulation management guided by heparin dose response (HDR) calculation, and repeated measurement of heparin concentration may be more effective than standard empiric weight-based heparin and protamine management monitored by activated clotting time (ACT) measurements to suppress thrombin generation during surgery for AAD. This randomized controlled clinical trial compares the impact of two recommended anticoagulation management strategies during surgery for AAD including deep hypothermia on activation of coagulation: Heparin/protamine-management based on HDR-titration by means of HMS Plus® versus current institutional standard (HDR- versus ACT-approach). Primary endpoint is thrombin generation as measured by early postoperative prothrombin fragment 1+2 (F1+2). Secondary endpoints are other markers of coagulation and fibrinolysis as well as clinical outcome.
Hypotheses: Primary: HDR-approach is superior to ACT-approach in terms of suppressing thrombin generation after emergent surgery for acute aortic dissection (Stanford type A). Secondary: HDR-approach is superior with regard to * early postoperative haemostatic capacity * requirement of blood product transfusion and haemostatic agents * postoperative bleeding Design: Investigator-initiated, single-site, parallel-group (1:1), prospective, randomized, partially double-blinded trial in patients undergoing emergent surgery for acute aortic dissection comparing two heparin management strategies with superiority design. Prior to randomization, patients are stratified according to preoperative organ dysfunction and anticoagulation therapy. Acute research study design as patients with acute aortic dissection are considered incompetent according to the Danish Research Ethics Committees definition. Deferred consent by the competent patient or her/his proxy (next of kin) and an independent physician) is used. 26 consecutive patients undergoing emergent surgery for acute aortic dissection (Stanford type A) are randomized 1:1 into the following heparin management strategies with an ACT target of 480 seconds: * Individualised HDR-approach * Conventional ACT-approach No interim analysis. A sub-study to compare cost-benefit of both strategies is planned.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
TRIPLE
Enrollment
26
Heparin concentration necessary to achieve target ACT \> 480 sec. calculated based on individual HDR-curve. If HDR slope ˂80 s/IU/mL (reduced sensitivity to heparin), 1000 IU of AT concentrate (Antitrombin III "Baxalta"®, Takeda Pharma, Vallensbæk Strand, DK). Whole blood concentration of circulating heparin assessed by heparin assays. Additional heparin given as required. After weaning, protamine necessary to reverse circulating heparin calculated according to heparin-protamine titration measurement. After protamine, heparin reversal evaluated with low-range heparin-protamine titration cartridge and additional protamine given as required.
Initial Heparin 400 IU/kg (500 IU/kg if treated with heparin prior to surgery). ACT Assessment with Hemochron® Signature Elite (ITC, International Technidyne Corp., Edison, NJ, USA). Additional heparin until ACT \> 480 sec. If ACT \< 480 sec. after despite repeated heparin supplement with 1000 IU of AT III concentrate. Target ACT \> 480 sec. during normothermic CPB, and target ACT \> 700 seconds during hypothermia After weaning, protamine 10mg/mL (0.7 mg of protamine/ 100 IU total heparin administered). Heparin reversal is evaluated with an activated partial thromboplastin (APTT). If APTT \> 40 seconds, additional protamine (25-50 mg i.v.).
Aarhus University Hospital Skejby
Aarhus, Denmark
F1+2
Prothrombin fragment 1+2 (pmol/L)
Time frame: up to 2 days after surgery
TAT
Thrombin-Antithrombin Complex (ug/L)
Time frame: up to 2 days after surgery
ETP
Endogenous Thrombin Potential (nmol/L x min)
Time frame: up to 2 days after surgery
Thrombin time
High-dose thrombin time (sec)
Time frame: up to 2 days after surgery
Antithrombin
(kIU/L)
Time frame: up to 2 days after surgery
D-dimer
D-dimer (mg/L)
Time frame: up to 2 days after surgery
Clot lysis
Clot lysis
Time frame: up to 2 days after surgery
Heparin sensitivity
Heparin sensitivity (slope)
Time frame: prior to surgery
Heparin (total)
Total amount of heparin
Time frame: immediately after surgery
Protamin (total)
Total amount of protamin
Time frame: immediately after surgery
Ratio
Protamin/heparin ratio
Time frame: immediately after surgery
Resistance
Heparin resistance
Time frame: immediately after surgery
Blood cell-saver
Volume of blood processed in cell-saver (mL)
Time frame: immediately after surgery
Blood loss sponges
Gravimetric estimation of intraoperative blood loss (calculation based on the change between dry and blood-soaked sponges, accounting for irrigation) in mL
Time frame: immediately after surgery
Drain output
Total mediastinal drain output (ml)
Time frame: 48 hours after surgery
Blood tranfusion
Tranfusion of blood products (units): Red blood cells, fresh frozen plasma, platelet concentrates
Time frame: 48 hours after surgery
Fibrinogen
Administration of fibrinogen concentrate (mg)
Time frame: 24 hours after surgery
PCC
Administration of prothrombin complex concentrate (Octaplex) (IU)
Time frame: 24 hours after surgery
AT concentrate
Administration of Antithrombin concentrate (IU)
Time frame: 24 hours after surgery
Cryoprecipitate Plasma
Administration of cryoprecipitate plasma
Time frame: 24 hours after surgery
Recombinant FVIIa
Administration of Recombinant FVIIa
Time frame: 24 hours after surgery
2. Closure
Secondary closure
Time frame: 30 days after surgery
Reoperation for bleeding
Reexploration for bleeding (yes/no)
Time frame: 30 days after surgery
Protocol violation
Protocol violation (yes/no)
Time frame: immediately after surgery
Mortality
All-cause mortality
Time frame: up to 90 days after surgery
Stroke
Stroke (yes/no)
Time frame: 30 days after surgery
Myocardial infarction
Perioperative myocardial infarction (yes/no)
Time frame: 30 days after surgery
Renal
Requirement of continuous renal replacement therapy (yes/no)
Time frame: 30 days after surgery
Low cardiac output syndrome
Low cardiac output syndrome requiring inotropics or mechanical support (yes/no)
Time frame: 30 days after surgery
Vascular malperfusion
Visceral og peripheral vascular malperfusion requiring surgical or percutaneous intervention
Time frame: 30 days after surgery
Intraop. coagulation
Clinical signs of coagulation during CPB (yes/no)
Time frame: Immediately after surgery
Length of surgery
minutes
Time frame: 30 days after surgery
Length of stay ICU
days
Time frame: 30 days after surgery
Length of hospitalization
Hospitalization (days)
Time frame: 30 days after surgery
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