Transfusion Reduction in High-Bleeding-Risk Cardiac Surgery With Desmopressin

• INTRODUCTION AND RATIONALE

3.1 The current role of prophylactic use of desmopressin in low-risk cardiac surgery patients.

The efficacy of "routine prophylactic administration" of desmopressin 0.3 ug/kg after anesthesia induction or protamine administration to reduce bleeding and transfusion has been revisited in a Cochrane review of 39 randomized controlled trials (RCTs) focusing on cardiac surgery [5] which demonstrated that compared with placebo, desmopressin used resulted in a slight decreased total volume of red blood cells (RBCs) transfused (mean difference (MD) -0.52 units, 95%CI -0.96 to -0.08 units; 14 trials, 957 participants) and total blood loss (MD -135.24 mL, 95% CI -210.80 mL to -59.68 mL; 22 trials, 1,358 participants) in adult cardiac surgery. These RCTs had low methodological quality.

Desmopressin may reduce postoperative bleeding in cardiac surgery patients who have received preoperative aspirin within 7 days of surgery, longer cardiopulmonary bypass (CPB) bypass than 140 minutes, and those with platelet dysfunction [6].

A recent European Association for Cardio-Thoracic Surgery (EACTS) and the European Association of Cardiothoracic Anaesthesiology and Intensive Care (EACTAIC) guidelines on patient blood management (PBM) in adult cardiac surgery, in collaboration with the European Board of Cardiovascular Perfusion (EBCP), [7] concluded a task force of professionals specializing in patient blood management recommend that the prophylactic use of desmopressin is not recommended to reduce bleeding complications in cardiac surgery patients (a class III of recommendation and level A of evidence). However, it suggests considering desmopressin for bleeding patients with platelet dysfunction to reduce bleeding complications. (a class IIa of recommendation and level C of evidence).

3.2 Efficacy of Desmopressin in Reducing Postoperative Bleeding and Allogenic Blood Transfusion Needs

Although desmopressin showed a slight decrease in transfusion requirement in patients with post-CPB bleeding due to its positive effects on the coagulation system responsible for such bleeding, there is a continued debate on the "efficacy" and "safety" of prophylactic use of desmopressin for cardiac surgery [8-9].

A previous small study demonstrated the efficacy of desmopressin in reducing homologous blood requirement in cardiac surgical patients treated with aspirin within 5 days before surgery [10].

3.3. Does the timing of the Desmopressin Administration Make A Difference?

The timing of the administration of desmopressin might explain such controversial results. Infusing desmopressin following protamine administration failed to show significant differences in transfusion requirements in small studies, including few patients [11-13]. Similar results were reported when desmopressin was administered after chest closure [14]. Delaying desmopressin administration until the termination of CPB or chest closure, with its impact on the coagulation system and platelet functions, might explain these reported low or no efficacy in reducing bleeding compared with placebo. Additionally, this is contradictory to the highly recommended routine use of antifibrinolytics (class 1, Level of evidence A) and using protamine to heparin ratio of less than one (class 1, Level of evidence B) by the current EACTS/EACTAIC/EBCP Guidelines on PBM [6], that was not considered in these studies [10-14].

3.4. Can Repeating Desmopressin Administration Increase the Efficacy?

Repeating the administration of desmopressin after CPB and then 12 hours after surgery did not result in a significant difference despite the blood loss being less than that of the placebo in the former in a small, unpowered study [15-16].

3.5. Safety of Desmopressin Administration

Rapid infusing desmopressin over ten or 15 minutes, particularly shortly after administering protamine with its unique vasodilatation and histamine release effect, might explain the notable reduced systemic vascular resistance (SVR) and blood pressure and increased pulmonary vascular resistance (PVR) in some studies [10-14, 16], which was unlikely due to the associated histamine release [17].

Desmopressin use did not result in significant changes in urine output [12] or increased myocardial infarction incidence [15]; these studies included few patients to examine these secondary outcomes.

3.6. Can Slower Desmopressin Administration Increase Its Safety

A slower infusion of desmopressin over 30 rather than 10 minutes was only associated with less increased PVR in this small cohort [18]. That raises the need to examine the "safety" of a more extended infusion of desmopressin.

3.7. Can Point-of-Care Coagulation Testing Improve Efficacy of Desmopressin Administration

Point-of-care (POC) thromboelastography (TEG) guided hemostasis and transfusion reduced RBCs, plasma, and platelet transfusion, operating room (OR) length of stay (LOS), intensive care unit (ICU) LOS, and bleeding rate (P = 0.002) were reduced with compared with controls in a metanalysis include 9 RCTs, two of them on cardiac surgery patients [19]. However, that was not translated into associated reduced mortality rates [19].

Interestingly, a single-Canadian-center, retrospective, observational propensity-matched study demonstrated increased desmopressin administration after the introduction of point-of-care (POC) rotational thromboelastometry (ROTEM) testing with and associated statistically higher platelets transfusion [20].

3.8. Feasibility

Extended infusion of desmopressin from induction of anesthesia to the end of CPB has never been compared in terms of "efficacy," "safety," and "cost-effectiveness" in high-risk cardiac surgery patients for bleeding. Cardiac surgery in patients with a high risk for bleeding is more complex to perform, and it might take longer durations to be accomplished, increasing the overall healthcare costs, which could be unacceptable for the stakeholders. Using desmopressin infusion over a more extended period might be an "effective," "safe," and "affordable" choice.

3.6. Why this randomized clinical trial?

Infusing the same desmopressin dose of 0.3 ug/kg over a more extended duration from anesthesia induction until before administering protamine might have its potential benefits and disadvantages in patients with higher risks for bleeding. The proposed randomized clinical trial here will compare extended intraoperative infusion of 'desmopressin' with 'placebo' procedures concerning effects on cumulative blood loss, need for allogenic blood transfusion, and hemostatic drugs and their overall costs, safety, and feasibility. If 'desmopressin' is more effective and less safe and is cost-effective than the "placebo,' it should be used in this group of patients. If 'desmopressin' is comparable and less safe than the "placebo,' it should not be used in this group of patients.

Inclusion criteria

• Adult 18 years or older.
• Scheduled for any type of elective cardiac surgery.
• Using CPB.
• General anesthesia is provided in an endotracheally intubated patient.
• A high risk of postoperative bleeding is defined as any of the following [21-23];

• Redo or repeated surgery.
• Treatment with platelet P2Y12 receptor--inhibiting drugs was discontinued for 7 days (ticlopidine, clopidogrel, and prasugrel) or 5 days (ticagrelor).
• Any known coagulation disorders.
• Hypofibrinogenemia less than 150 mg/dl.
• Platelet count <100.000 cells/μL.
• Chronic renal failure, whether dialysis-dependent or not.
• Liver cell failure Child-Pugh class B or C or the Model for End-Stage Liver Disease (MELD) >=29
• Infective endocarditis.
• Acute type-A aortic dissection.
• Expected surgery with CPB time longer than 150 minutes.
• Preoperative estimated Papworth Bleeding Risk Score of 8% or greater [23].

Exclusion criteria

• Planned for cardiac surgery without CPB;
• Planned for a combined coronary revascularization surgery and a valve or intra-cardiac surgery;
• Pregnancy;
• Consent for another interventional study during anesthesia;
• No written informed consent;
• Preoperative need for mechanical circulatory support;