Coagulation Considerations for Children undergoing Cardiac Surgery By Marwa A. Khairy, MD

The coagulation criteria of pediatrics and cardiac surgery. Use of antifibrinolytic agents. Heparin dosing and monitoring during CPB. Evaluation and treatment of coagulopathies post-CPB

Case A 3 kg, one-week-old male infant with a history of d-TGA presents for an arterial switch procedure. He underwent a successful balloon atrial septostomy on his first day of life and has been on the floor and stable. The FH is -ve for bleeding disorders.

Question What makes Alterations of coagulation in pediatric cardiac patients? What makes Alterations of coagulation in pediatric cardiac patients? Patient age Pathophysiology Exposure to CPB

Patient Age Coagulation system is immature at birth K-dependent factors (II, VII, IX, and X) Hepatic immaturity & BMR

Patient Age birth until 6 months Procoagulant factor 40–50% Procoagulant factor 40–50% Inhibitors of coagulation low. Inhibitors of coagulation low. PT and thrombin clotting time within normal aPTT is prolonged till 3 months of age. Thrombotic complications are more common in neonates By TEG

Pathophysiology Coagulation abnormalities in: Coagulation abnormalities in: 58% non-cyanotic defects 71% cyanotic defects ( correlates with the severity of polycythemia) Causes: Causes: hepatic dysfunction from hypoperfusion or from perfusion with hypoxemic, hyperviscous blood

Exposure to CPB

Case During your setup in the operating room, the perfusionist notifies you that there is both a whole blood unit and a packed red blood cell unit for this patient. She asks, which one should be used to prime the pump? B

Questions Is there any evidence that the type of blood prime relates to subsequent bleeding post- CPB? How old of a unit will you accept for the prime (e.g. 48 hour old blood, 5 day old blood, > 7day old blood)?

Questions Is there any evidence that the type of blood prime relates to subsequent bleeding post- CPB? Is there any evidence that the type of blood prime relates to subsequent bleeding post- CPB? There is little evidence “safe” hemodilution level during CPB cannot be defined (??24%).

Fresh whole blood no advantage Increased length of stay in the ICU increased perioperative fluid overload. Mou et al.N Engl J Med 2004;351:

Reconstituted fresh whole blood used for the prime, throughout cardiopulmonary bypass, and for all transfusion requirements within the first 24 hours postoperatively results in reduced chest tube volume loss Improved clinical outcomes in neonatal patients undergoing cardiac surgery. Gruenwald et al, 2008

Questions How old of a unit will you accept for the prime (e.g. 48 hour old blood, 5 day old blood, > 7day old blood)? Ideal less than 48 hrs (availability??)

Questions Are there any other steps by you or the perfusionist that may be beneficial to limit bleeding complications post CPB (e.g. heparin coatings of the circuit, taking off patient blood prior to CPB, pre bypass filtration (PBUF)? Are there any other steps by you or the perfusionist that may be beneficial to limit bleeding complications post CPB (e.g. heparin coatings of the circuit, taking off patient blood prior to CPB, pre bypass filtration (PBUF)?

“Biocompatible” circuits Types: Heparin bonding of the circuit (Carmeda, Duraflo) ( fibrinolytic syst) polymer bonding (X-Coating) ( plt activation) Studies?: adult populations pts only. Heparin coated adv.: less heparin so less protamine Less effects on platelets

Autologous Blood Removal Adv.: Beneficial in that platelets remain relatively functional Disadv.: Lower hematocrit. By taking off 15 mL/kg of blood before CPB and reinfusing post CPB. They showed a significant reduction in blood loss post surgery.

CPB pump filtration Hemofiltration of the circuit prime prior to the start of CPB has been suggested as a method to normalize electrolyte balance (particularly potassium and pH) and reduce inflammatory mediator concentrations.

Case The patient is induced and invasive lines are placed without problems. After sternotomy, the surgeon asks, “You are going to use aprotinin, right?”

Questions What are the risks and benefits for using antifibrinolytic agents in this case? What are the risks and benefits for using antifibrinolytic agents in this case?

EACATAEACATA AprotoninAprotonin

Antifibrinolytic EACA intravenously as loading dose followed by a continuous infusion loading dose of 75 mg/kg followed by an infusion of 15 mg/kg/h loading dose of 150 mg/kg followed by and infusion of 30 mg/kg/h

Antifibrinolytic Tranxemic Acid as loading dose followed by a continuous infusion because of rapid renal elimination of. A dosing protocol using: a loading dose of 100 mg/kg after induction followed by another 100 mg/kg dose in the pump prime an infusion of 10 mg/kg/h

Aprotonin Multiple RCTs: aprotonin ↓ blood loss 2006 observational study [Mangano]: Aprotinin AEs: renal, cardiac + neuro outcome. Labeling changed by manufacturer + ongoing studies stopped abruptly

Case The surgeon asks for the heparin to be given.

Questions What dose are you going to use? How will you determine whether anticoagulation is adequate (ACT, heparin concentration, other)?

Heparin Dose Low Antithrombin III (ATIII) levels (adult values until 3–6 months). 400 IU/kg Initial heparin dose of 400 IU/kg and higher. Other thrombin inhibitors are depressed compared with healthy infants. 200–400 IU/kg 50–100 IU/kg 200–400 IU/kg in the circuit, and 50–100 IU/kg ongoing administration every 30–120 minutes. If >500 IU/kg failed ; Heparin resistance should be considered.

Limitation of ACT ACT values may prolongsd by following factors Hypothermia Haemodilutation Aprotonin ACT values and heparin levels do not correlate in neonates and children during the course of CPB

Heparin concentration The ACT is prolonged even in conjunction with unchanged or decreasing heparin levels. For this reason, the functional measure of heparin anticoagulation may be supplemented with the quantitative measure of the whole blood heparin concentration. Protamine titration test: Protamine titration test: 1ml of blood is added to several glass tubes at 37ºC containing a known conc. Of protamine. First tube to clot determine the concentration of heparine. Hepcon is an automated protamine titration test.

Case After 60 minutes on CPB, the perfusionist states that the ACT is still greater than 800 sec

Questions Is there any need for more heparin? Is there any need for more heparin? Heparin levels have significantly fallen within 1 hour of CPB despite the maintenance of adequate ACT values Consider the administration of additional heparin if CPB is expected to continue for a substantial period of time.

Case During CPB, the surgeon mentions that he has a suspicion that this patient is going to “bleed a lot” given the difficult dissection and long suture lines. He asks if you have platelets available.

Questions How do you determine what blood products should be ordered for this patient post CPB? How do you determine what blood products should be ordered for this patient post CPB?

Post Bypass Transfusion fresh whole blood with functional platelets (rare) component therapy such as PRBCs + plts + cryo. (small volumes + dilutional anemia) Plts usually suspended in FFP FFP after plt transfusion may be hazardous (dilutional thrombpcytopenia) Cryo more beneficial after plt than FFP (fibrinogen, factor VIII/vWF, and factor XIII )

Transfusions Guided Algorithm

TEG-guided component replacement Increased R time →FFP Decreased maximum amplitude (MA) →Platelet Decreased α angle →Cryoprecipitate

Case Once the repair has been finished, inotropes have been started and the heart function looks great. The surgeon requests separation from CPB that initially goes without problems. However, it becomes quickly apparent that there is significant bleeding, and that you have to go back on CPB just to keep up with the bleeding. The surgeon looks at all of his suture lines and after placing a few additional stitches says that at this point the bleeding seems to be non-surgical.

Case On further questioning, he states that there may be “a tiny amount” of oozing on the back of one of the vessels. He argues that the more stitches he puts in will only lead to more bleeding at that site. Further, to adequately “get at that tiny site”, he’d have to take down the pulmonary artery anastamosis. He states that the extra time on CPB to do that would be worse than just giving the patient platelets.

Case You successfully separate from CPB and you are initially able to keep up with the bleeding by starting to transfuse blood components. The bleeding is still significant and the surgeon says, “what about recombinant factor VIIa for this bleeding? We’ve used it just last week in a teenager having a 3 time redo valve and it was magical how the bleeding stopped?” He goes on to say, “This would be a great case for it, so that you don’t have to give all those blood products to the patient leading to fluid overload.”

Questions How do you respond to that? If you decided to use it, what dose would you use? What are the risks and benefits of factor VIIa in this case?

Recombinant FVII Doses 30 to 500 mcg/kg to children with 90 mcg/kg reported. t ½ rFVIIa is only 2.5 hours but may be shorter in children because of an increased clearance rate (repeat doses)

Recombinant FVII Adv. : small volume (1 to 5 ml) (decrease fluid overload) The reduction in “blood donor exposures”. recombinant no infectious risk.Dis.: very expensive systemic hemostasis is occurring TF is also carried around in the blood via activated inflammatory cells. few literature included older children and not neonates.

Case Lets say you give a dose of factor VIIa and within about 15 minutes you notice significant ST elevation. What is the differential?

Answer Important small anastamosis, the potential risk of occluding a coronary artery with clot is too great. There isn’t enough data, activated factor VII should be used with caution.

Any Questions?