Hypovolemic Phlebotomy to Reduce Blood Transfusions in Major Hepatic Resections

Study Overview
=================
Brief Summary
-----------------
Major liver resection is associated with substantial intraoperative blood loss and subsequently blood transfusions. Blood transfusion in elective liver surgery is a significant factor of perioperative morbidity and mortality, as well as possibly long-term oncologic outcome. The purpose of this study is to use whole blood phlebotomy to decrease the central venous pressure, resulting in a state of relative hypovolemia. It is hypothesized that this intervention will lead to a decrease in blood loss at the time of liver resection and thus reduced blood transfusion in major liver surgeries.

Detailed Description
-----------------
Major liver resection is associated with significant intraoperative blood loss and blood transfusions. Blood transfusion in elective liver surgery is a key determinant of perioperative morbidity and mortality, as well as possibly long-term oncologic outcome. Whole blood phlebotomy is a simple intervention, whose aim is to decrease the central venous pressure yielding a state of relative hypovolemia and thus lead to decreased blood loss and subsequently blood transfusion. Small studies, mostly from the liver transplant literature, would suggest that phlebotomy with controlled hypovolemia can result in decreased blood loss and blood transfusion. Since blood loss is an important issue in liver surgery, and the benefits of phlebotomy and controlled hypovolemia are unknown in liver resection patients, a rigorously conducted trial in a representative population of patients undergoing liver resection is warranted, and feasible. In this proposal, it is hypothesized that by the use of hypovolemic phlebotomy, it is possible to decrease blood loss and blood transfusions. To test this hypothesis the investigators plan to randomly allocate participants to hypovolemic phlebotomy plus standard of care or to standard of care. Participants will be those patients undergoing elective major liver resection at The Ottawa Hospital, le Centre Hospitalier de l'Université de Montréal, and le Centre Hospitalier de l'Université de Sherbrooke for any indication. The primary outcome will be red blood cells transfusion up to 30 days following surgery. Secondary outcomes will include intraoperative blood loss, other blood product transfusion requirements, perioperative morbidity and mortality, safety, physiologic parameters, and feasibility elements. A total of 440 patients will be randomized across the 3 sites in Ontario and Quebec. The efficacy of phlebotomy in terms of blood loss and transfusion prevention will be assessed.

Official Title
-----------------
PRICE 2: A Phase 3 Randomized Controlled Trial of Phlebotomy Resulting in Controlled Hypovolemia to Prevent Blood Loss in Major Hepatic Resections

Conditions
-----------------
Blood Transfusion, Liver Neoplasms, Hepatectomy, Blood Loss, Surgical

Intervention / Treatment
-----------------
* Procedure: Hypovolemic Phlebotomy


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Adult patients (≥18 years) projected to undergo a major liver resection (≥3 segments resected or partially resected), a right posterior sectionectomy (segments 6/7), or central resection (4b/5) for any indication, or the resection of 1 or more segments in a known cirrhotic patient. Exclusion Criteria: Age <18 years Preoperative hemoglobin <100g/L GFR clearance <60mL/min Abnormal coagulation parameters (not on warfarin and/or platelets count <100 X10^9/L) Evidence of hepatic metabolic disorder Active cardiac conditions: Unstable coronary syndromes; Severe valvular disease; and Myocardial infarction within 6 months prior to surgery History of significant cerebrovascular disease: Patients with clinically-significant stroke/CVA within the past 6 months or severe carotid stenosis (defined as >70%) History of significant peripheral vascular disease: Non-revascularized with regular/ongoing claudication Pregnancy Refusal of blood products Presence of active infection Preoperative autologous blood donation Planned intraoperative use of cell saver

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Hypovolemic Phlebotomy<br>Hypovolemic Phlebotomy will consist of the withdrawal of 7-10 mL/kg of whole blood from the patient, as tolerated (e.g. for a 70kg patient, 490 to 700 mL of whole blood will be removed) The volume of removed blood will not be replaced by the administration of intravenous fluids. Removed blood will be transfused back to participant at the end of surgery. The phlebotomized whole blood will be transfused back after liver transection regardless of blood loss. | Procedure: Hypovolemic Phlebotomy<br>* Removal of 7-10ml/kg of blood from participant, as tolerated after patient is under anesthesia, before liver resection start time<br>|
| No Intervention: Control (Standard of Care)<br>Standard of care (low CVP surgery). In this arm, standard anesthesia will be maintained. | |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Packed Red Blood Cell Transfusion Rates | Units of packed red blood cells transfused to participants | 30 days post-operation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Blood product transfusion rates | Types and amount of other blood product transfusion rates in the 30 day period following surgery. | Postoperative setting up to 30 days following surgery | 
| Intraoperative blood loss | Intraoperative blood loss is notoriously difficult to measure. It is suggested that calculation of blood loss using preoperative and postoperative hemoglobin levels in most consistently accurate. In order to minimize the risk of bias associated with any one method of intraoperative measurement of blood loss, three methods will be used independently. In the operating room, all blood and fluid aspirated from the abdomen will be measured accurately using graduated suction containers. As well, the amount of irrigation fluid will be carefully monitored and recorded. Finally, the weight of all surgical sponges will be measured. This information will be used by the surgeon and anesthesiologist to independently visually estimate blood loss, as is commonly done in clinical practice. In parallel, intraoperative blood loss will also be calculated based on an equation. | up to 90 days before surgery; and on post-operative day 2 | 
| Perioperative morbidity and mortality | Perioperative morbidity is assessed using the Dindo-Clavien scale and is defined as any deviation from the normal post-operative course. The scale (1-5) indicates the severity of an adverse event; where 1 is low (i.e. any deviation from normal postoperative course without the need for intervention) and 5 means death of the patient (i.e. mortality). | Postoperative setting up to 30 days following surgery | 
| Changes in physiologic parameters (Central Venous Pressure) | Central venous pressure (CVP) is a physiologic parameter that measures the blood pressure in the thoracic vena cava (in cm H20) | measured during surgery (intraoperatively) | 
| Changes in physiologic parameters (Pulse Pressure Variation) | Pulse Pressure variation (in %) is a predictor of fluid responsiveness | measured during surgery (intraoperatively) |