Highlights from CREF 2018: New Clinical Practice Guidelines

Associations Jointly Present First Guidelines for Anticoagulation in Cardiopulmonary Bypass

Healthcare practitioners have been lacking concise, evidence-based guidelines for cardiopulmonary bypass (CPB). The Society of Thoracic Surgeons (STS), Society of Cardiovascular Anesthesiologists (SCA), and American Society of Extracorporeal Technology (AmSECT) convened a work group of multidisciplinary professionals to review, appraise, and report on high-quality evidence about CPG in order to reduce practice variability and improve outcomes.

The work group—made up of cardiovascular surgeons, anesthesiologists, perfusionists, scientists, and epidemiologists—has already published reports on inflammation and temperature management in CPB. The group’s most recent recommendations fill the evidence gap and establish best practices in anticoagulation, a critically important aspect of CPB. Specifically, the guidelines cover heparin dosing for initiation and maintenance of CPB, heparin’s contraindications and alternatives, and reversal of anticoagulation during cardiac operations.

The guidelines were recently published in the Annals of Thoracic Surgery, Anesthesia & Analgesia, and the Journal of Extracorporeal Technology. In addition, coauthor David C. Fitzgerald, MPH, CCP, LP, of the Cardiovascular Perfusion Program at the Medical University of South Carolina, presented the guidelines at CREF 2018, the 38th Annual Cardiothoracic Surgery Symposium.

This article provides an overview of the key recommendations. For details on the methodological framework, the guideline development process, and evidence supporting the recommendations, please see the article in the Journal of ExtraCorporeal Technology (Shore-Lesserson et al., 2018).

Heparin Dosing for Initiation and Maintenance of CPB

The workgroup issued a class I recommendation stating that “a functional whole blood test of anticoagulation, in the form of a clotting time, should be measured and should demonstrate adequate anticoagulation before initiation of and at regular intervals during cardiopulmonary bypass.”

Class IIa recommendations conclude that it is reasonable to use bolus administration of unfractionated heparin based upon weight. However, they stressed that individual responses to heparin are heterogeneous; therefore, therapeutic functional tests of clot inhibition are required before initiation of CPB. Also in the class IIa category, the authors wrote, “It is reasonable to use activated clotting time (ACT) tests that produce ‘maximally activated’ clotting times since these tests mitigate ACT variability, are less susceptible to hypothermia, and correlate more closely with Factor Xa activity compared to tests that employ a single activator.” In another class IIa recommendation, the authors said it is reasonable to maintain activated clotting time above 480 seconds during CPB, although that is an approximate minimum threshold value and may vary.

According to the authors, “Use of a heparin dose-response formula may identify reduced sensitivity to heparin but has not been shown to be more useful than weight-based heparin dosing in determining the heparin dose required to achieve an adequate ACT for initiation of CPB,” a class IIb recommendation. The class IIb guidelines in this category also indicate that clinicians may consider heparin concentration monitoring in addition to ACT. According to the evidence, that strategy has reduced thrombin generation, fibrinolysis, and neutrophil activation. Finally, clinicians may consider routine administration of unfractionated heparin at fixed intervals, along with ACT monitoring.

Heparin’s Contraindications and Alternatives

In the class IIa recommendations in this category, the guidelines state that “clinical scoring estimates that use a fall in platelet count greater than 50% and/or a thrombotic event between 5 and 14 days following a heparin exposure may be used to determine whether a heparin-platelet antibody test should be performed to diagnose heparin-induced thrombocytopenia (HIT).” Serum tests that include functional testing with serotonin release assay (SRA) or heparin-induced platelet activation (HIPA) also may identify patients with HIT. Clinicians may decide to delay elective cardiac operations requiring CPB in patients who are seropositive for heparin-platelet antibodies or have a recent history of HIT, at least until functional testing and/or antigenic assays are negative. The final class IIa recommendation is that anticoagulation with bivalirudin may be considered in patients with HIT who need an urgent operation requiring CPB.

The guidelines also address patients with significant renal dysfunction who are seropositive for HIT but require urgent operation requiring CPB. It is reasonable, per a class IIb recommendation, to use plasmapheresis, argatroban, or heparin with antiplatelet agents, the authors wrote; however, clinicians must be aware of the increased risks of bleeding with those interventions.

Reversal of Anticoagulation

On the topic of protamine for heparin reversal, the guidelines suggest calculating the dose based on titration to existing heparin in the blood, which has been associated with reduced bleeding and blood transfusions (a class IIa recommendation). Regarding protamine overdose, the guidelines recommend limiting the ratio of protamine to heparin to less than 2.6 mg to 100 units (also a class IIa recommendation). Total doses higher than that ratio may inhibit platelet function, prolong ACT, and increase the risk of bleeding, according to the evidence.

Patients who require high doses of heparin and have prolonged CPB times may be at risk for heparin rebound; in such cases, the guidelines offer a class IIb recommendation for low-dose protamine infusion at 25 mg/hour for up to six hours after CPB, as part of a blood-conservation program.

Some patients may experience complications associated with protamine reversal. In those who have

anaphylactic reactions (pulmonary hypertension and circulatory collapse shortly after protamine administration), the guidelines offer a class I recommendation to discontinue protamine and apply resuscitative measures, such as restarting CPB with adequate anticoagulation.

Finally, the authors stressed that there is no ideal CPB anticoagulation strategy for patients who cannot take heparin, as heparin and protamine are the gold standard. However, some patients may require bivalirudin. In patients who have received bivalirudin for anticoagulation and are bleeding excessively after CPB, the guidelines call for a combination of modified ultrafiltration, hemodialysis, and recombinant factor VIIa with blood product replacement to improve hemostasis (a class IIb recommendation).

Conclusion

The authors said they hope the guidelines, the only available comprehensive recommendations of their kind, will encourage researchers to build on the evidence available, as well as help clinicians reduce practice variability and improve outcomes.

References

Fitzgerald, D. The STS/SCA/AmSECT Anticoagulation Clinical Practice Guidelines. Presented at: CREF 2018; September 7, 2018; San Diego, CA.

Shore-Lesserson L, Baker RA, Ferraris V, et al. STS/SCA/AmSECT Clinical Practice Guidelines: Anticoagulation during cardiopulmonary bypass. J Extra Corpor Technol. 2018;50(1):5-18.