Hypovolemic Phlebotomy to Reduce Blood Transfusions in Major Hepatic Resections

Liver Neoplasms Clinical Trial

— PRICE2  

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03651154
• Other study ID #: 502
• Status: Active, not recruiting
• Phase: N/A
• Start date: September 28, 2018
• Est. completion date: March 2024

Study information

• Verified date: March 2023
• Source: Ottawa Hospital Research Institute
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 440
• Est. completion date: March 2024
• Est. primary completion date: July 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Blood Loss, Surgical
• Blood Transfusion
• Hemorrhage
• Hepatectomy
• Liver Neoplasms

Intervention

Procedure:
• Hypovolemic Phlebotomy
Removal of 7-10ml/kg of blood from participant, as tolerated after patient is under anesthesia, before liver resection start time

Locations

Country	Name	City	State
Canada	Centre Hospitalier de l"Université de Sherbrooke	Montréal	Quebec
Canada	Centre Hospitalier de l'Université de Montréal	Montréal	Quebec
Canada	The Ottawa Hospital	Ottawa	Ontario
Canada	Vancouver General Hospital	Vancouver	British Columbia

Sponsors (1)

Lead Sponsor	Collaborator
Ottawa Hospital Research Institute

Country where clinical trial is conducted

Canada, 

References & Publications (8)

Alkozai EM, Lisman T, Porte RJ. Bleeding in liver surgery: prevention and treatment. Clin Liver Dis. 2009 Feb;13(1):145-154. doi: 10.1016/j.cld.2008.09.012. — View Citation

Bennett S, Baker LK, Martel G, Shorr R, Pawlik TM, Tinmouth A, McIsaac DI, Hebert PC, Karanicolas PJ, McIntyre L, Turgeon AF, Barkun J, Fergusson D. The impact of perioperative red blood cell transfusions in patients undergoing liver resection: a systematic review. HPB (Oxford). 2017 Apr;19(4):321-330. doi: 10.1016/j.hpb.2016.12.008. Epub 2017 Feb 1. — View Citation

Hallet J, Tsang M, Cheng ES, Habashi R, Kulyk I, Hanna SS, Coburn NG, Lin Y, Law CH, Karanicolas PJ. The Impact of Perioperative Red Blood Cell Transfusions on Long-Term Outcomes after Hepatectomy for Colorectal Liver Metastases. Ann Surg Oncol. 2015 Nov;22(12):4038-45. doi: 10.1245/s10434-015-4477-4. Epub 2015 Mar 10. — View Citation

Hashimoto T, Kokudo N, Orii R, Seyama Y, Sano K, Imamura H, Sugawara Y, Hasegawa K, Makuuchi M. Intraoperative blood salvage during liver resection: a randomized controlled trial. Ann Surg. 2007 May;245(5):686-91. doi: 10.1097/01.sla.0000255562.60215.3b. — View Citation

Massicotte L, Perrault MA, Denault AY, Klinck JR, Beaulieu D, Roy JD, Thibeault L, Roy A, McCormack M, Karakiewicz P. Effects of phlebotomy and phenylephrine infusion on portal venous pressure and systemic hemodynamics during liver transplantation. Transplantation. 2010 Apr 27;89(8):920-7. doi: 10.1097/TP.0b013e3181d7c40c. — View Citation

Rekman J, Wherrett C, Bennett S, Gostimir M, Saeed S, Lemon K, Mimeault R, Balaa FK, Martel G. Safety and feasibility of phlebotomy with controlled hypovolemia to minimize blood loss in liver resections. Surgery. 2017 Mar;161(3):650-657. doi: 10.1016/j.surg.2016.08.026. Epub 2016 Oct 4. — View Citation

Ryckx A, Christiaens C, Clarysse M, Vansteenkiste F, Steelant PJ, Sergeant G, Parmentier I, Pottel H, D'Hondt M. Central Venous Pressure Drop After Hypovolemic Phlebotomy is a Strong Independent Predictor of Intraoperative Blood Loss During Liver Resection. Ann Surg Oncol. 2017 May;24(5):1367-1375. doi: 10.1245/s10434-016-5737-7. Epub 2017 Jan 4. — View Citation

Sima CS, Jarnagin WR, Fong Y, Elkin E, Fischer M, Wuest D, D'Angelica M, DeMatteo RP, Blumgart LH, Gonen M. Predicting the risk of perioperative transfusion for patients undergoing elective hepatectomy. Ann Surg. 2009 Dec;250(6):914-21. doi: 10.1097/sla.0b013e3181b7fad3. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Packed Red Blood Cell Transfusion Rates	Units of packed red blood cells transfused to participants	30 days post-operation
Secondary	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
Secondary	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
Secondary	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
Secondary	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)
Secondary	Changes in physiologic parameters (Pulse Pressure Variation)	Pulse Pressure variation (in %) is a predictor of fluid responsiveness	measured during surgery (intraoperatively)