Clinical trial NCT03651154: Hypovolemic Phlebotomy to Reduce Blood Transfusions in Major Hepatic Resections
Official title: PRICE 2: A Phase 3 Randomized Controlled Trial of Phlebotomy Resulting in Controlled Hypovolemia to Prevent Blood Loss in Major Hepatic Resections
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Liver Neoplasms
Hepatectomy
Blood Transfusion
Blood Loss, Surgical
Lead sponsor: Ottawa Hospital Research Institute
Sponsor class: OTHER
First posted: 2018-08-29
Enrollment: 440
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.

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

Primary outcomes:
measure: Packed Red Blood Cell Transfusion Rates
timeFrame: 30 days post-operation
Secondary outcomes:
measure: Blood product transfusion rates
timeFrame: Postoperative setting up to 30 days following surgery
measure: Intraoperative blood loss
timeFrame: up to 90 days before surgery; and on post-operative day 2
measure: Perioperative morbidity and mortality
timeFrame: Postoperative setting up to 30 days following surgery
measure: Changes in physiologic parameters (Central Venous Pressure)
timeFrame: measured during surgery (intraoperatively)
measure: Changes in physiologic parameters (Pulse Pressure Variation)
timeFrame: measured during surgery (intraoperatively)
Other outcomes:
Locations:
city: Vancouver
country: Canada
facility: Vancouver General Hospital
state: British Columbia
city: Ottawa
country: Canada
facility: The Ottawa Hospital
state: Ontario
city: Montréal
country: Canada
facility: Centre Hospitalier de l"Université de Sherbrooke
state: Quebec
city: Montréal
country: Canada
facility: Centre Hospitalier de l'Université de Montréal
state: Quebec
Study officials:
affiliation: Ottawa Hospital Research Institute
name: Guillaume Martel, MD, MSc, FRCSC, FACS
role: PRINCIPAL_INVESTIGATOR
References:
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.
citation: 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.
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.
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.
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.
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.
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.
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.