PRICE: Phlebotomy to Prevent Blood Loss in Major Hepatic Resections

• Sponsor: Ottawa Hospital Research Institute (Other)
• Overall Status: Completed
• CT.gov ID: NCT02548910
• Collaborator: (none)
• Enrollment: 62
• Location: 1
• Arms: 2
• Duration (Months): 23
• Patients Per Site Per Month: 2.7

Study Details

Study Description

Brief Summary

Major liver resection is associated with substantial intraoperative blood loss. Blood loss 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.

Condition or Disease	Intervention/Treatment	Phase
Liver Neoplasms; Hepatectomy	Procedure: Phlebotomy; Device: Citrated whole blood collection bag	N/A

Detailed Description

Major liver resection is associated with significant intraoperative blood loss. Blood loss 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. 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 phlebotomy and controlled hypovolemia, it is possible to decrease blood loss and blood transfusions. To test this hypothesis the investigators plan to randomly allocate participants to phlebotomy plus standard of care or to standard of care. Participants will be those patients undergoing elective major liver resection at the Ottawa Hospital for any indication. The primary outcome will be intraoperative blood loss. Secondary outcomes will include transfusion requirements, perioperative morbidity and mortality, safety, physiologic parameters, and feasibility elements. A total of 62 patients will be randomized. The efficacy of phlebotomy in terms of blood loss prevention will be assessed.

Study Design

• Study Type: Interventional
• Actual Enrollment: 62 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: The PRICE Trial: Phlebotomy Resulting in Controlled Hypovolemia to Prevent Blood Loss in Major Hepatic Resections
• Study Start Date: Apr 1, 2016
• Actual Primary Completion Date: Mar 1, 2018
• Actual Study Completion Date: Mar 1, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Phlebotomy For patients randomized to phlebotomy, the intervention will consist of the standard of care (low CVP surgery), plus whole blood phlebotomy. Blood will be collected in citrated whole blood collection bag.	Procedure: Phlebotomy; A central venous catheter will be inserted for every patient to measure central venous pressure, as is the standard of care in elective liver surgery. Strict aseptic technique will be maintained. A total volume of whole blood of 7-10 mL per kg of body weight will be removed, as tolerated. The volume of removed blood will not be replaced by intravenous fluid administration. Collected blood will be transfused back at the end of the liver parenchymal transection, or within 8 hours of collection.; Device: Citrated whole blood collection bag; Transfusion Medicine will send the requested number of whole blood collection bags labelled with the patient's name and MRN. These whole blood collection bags are used in standard practice for collection of whole blood.
No Intervention: Control Standard of care (low CVP surgery). In this arm, standard anesthesia will be maintained.

Outcome Measures

Primary Outcome Measures

1. Total Intraoperative Blood Loss, by Measurement of Change in Hemoglobin Levels [1 week prior to surgery (hemoglobin level), and day two of post-op (hemoglobin again).]

   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.

2. Trial Feasibility [through study completion, an average of 2 years]

   Trial accrual

Secondary Outcome Measures

1. Blood Product Transfusion Rates [Will be measured in the operating room and in the first postoperative week]

2. Perioperative Morbidity (Dindo-Clavien Grade 3b of Higher) and Mortality [Postoperative setting up to 30 days following surgery]

3. Changes in Physiologic Parameters (CVP) [Will be measured in the operating room]

4. Change in Physiologic Parameters (Cardiac Index) [Will be measured in the operating room]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Any patient being considered for a major elective liver resection will be considered for trial enrollment. Patients who are undergoing a concurrent additional abdominal or thoracic procedure (eg. colonic resection) will also be included.

Exclusion Criteria:

• Age <18 years

• Pregnancy

• Refusal of blood products

• Active cardiac conditions: unstable coronary syndromes, decompensated heart failure (NYHA functional class IV; worsening or new-onset heart failure), significant arrhythmias, severe valvular disease

• History of significant cerebrovascular disease

• Renal dysfunction (patients with an estimated GFR <60 mL/min)

• Abnormal coagulation parameters (INR >1.5 not on warfarin and/or platelets count <100 X109/L )

• Evidence of hepatic metabolic disorder (bilirubin >35 umol/L)

• Presence of active infection

• Preoperative autologous blood donation

• Hemoglobin <100 g/L

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	The Ottawa Hospital - General Campus	Ottawa	Ontario	Canada	K1H 8L6

Sponsors and Collaborators

• Ottawa Hospital Research Institute

Investigators

• Principal Investigator: Guillaume Martel, MD, MSc, FRCSC, FACS, Ottawa Hospital Research Institute

Study Documents (Full-Text)

• Informed Consent Form - Feb 16, 2016
• Study Protocol and Statistical Analysis Plan - Oct 15, 2018

More Information

Publications

• 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.
• Andreou A, Aloia TA, Brouquet A, Dickson PV, Zimmitti G, Maru DM, Kopetz S, Loyer EM, Curley SA, Abdalla EK, Vauthey JN. Margin status remains an important determinant of survival after surgical resection of colorectal liver metastases in the era of modern chemotherapy. Ann Surg. 2013 Jun;257(6):1079-88. doi: 10.1097/SLA.0b013e318283a4d1.
• 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.
• Huntington JT, Royall NA, Schmidt CR. Minimizing blood loss during hepatectomy: a literature review. J Surg Oncol. 2014 Feb;109(2):81-8. doi: 10.1002/jso.23455. Epub 2013 Oct 4. Review.
• Jarnagin WR, Gonen M, Fong Y, DeMatteo RP, Ben-Porat L, Little S, Corvera C, Weber S, Blumgart LH. Improvement in perioperative outcome after hepatic resection: analysis of 1,803 consecutive cases over the past decade. Ann Surg. 2002 Oct;236(4):397-406; discussion 406-7.
• 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.
• McNally SJ, Revie EJ, Massie LJ, McKeown DW, Parks RW, Garden OJ, Wigmore SJ. Factors in perioperative care that determine blood loss in liver surgery. HPB (Oxford). 2012 Apr;14(4):236-41. doi: 10.1111/j.1477-2574.2011.00433.x. Epub 2012 Feb 28.
• Poon RT, Fan ST, Lo CM, Liu CL, Lam CM, Yuen WK, Yeung C, Wong J. Improving perioperative outcome expands the role of hepatectomy in management of benign and malignant hepatobiliary diseases: analysis of 1222 consecutive patients from a prospective database. Ann Surg. 2004 Oct;240(4):698-708; discussion 708-10.
• Sima CS, Jarnagin WR, Fong Y, Elkin E, Fischer M, Wuest D, D'Angelica M, DeMatteo RP, Blumgart LH, Gönen M. Predicting the risk of perioperative transfusion for patients undergoing elective hepatectomy. Ann Surg. 2009 Dec;250(6):914-21.
• Spolverato G, Ejaz A, Kim Y, Hall BL, Bilimoria K, Cohen M, Ko C, Pitt H, Pawlik TM. Patterns of care among patients undergoing hepatic resection: a query of the National Surgical Quality Improvement Program-targeted hepatectomy database. J Surg Res. 2015 Jun 15;196(2):221-8. doi: 10.1016/j.jss.2015.02.016. Epub 2015 Mar 19.

• Responsible Party: Ottawa Hospital Research Institute
• ClinicalTrials.gov Identifier: NCT02548910
• Other Study ID Numbers: 3588
• First Posted: Sep 14, 2015
• Last Update Posted: Mar 18, 2021
• Last Verified: Feb 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Additional relevant MeSH terms: Liver Neoplasms; Sodium Citrate; Citric Acid

Study Results

Participant Flow

Arm/Group Title	Phlebotomy	Control
Arm/Group Description	For patients randomized to phlebotomy, the intervention will consist of the standard of care (low CVP surgery), plus whole blood phlebotomy. Blood will be collected in citrated whole blood collection bag. Phlebotomy: A central venous catheter will be inserted for every patient to measure central venous pressure, as is the standard of care in elective liver surgery. Strict aseptic technique will be maintained. A total volume of whole blood of 7-10 mL per kg of body weight will be removed, as tolerated. The volume of removed blood will not be replaced by intravenous fluid administration. Collected blood will be transfused back at the end of the liver parenchymal transection, or within 8 hours of collection. Citrated whole blood collection bag: Transfusion Medicine will send the requested number of whole blood collection bags labelled with the patient's name and MRN. These whole blood collection bags are used in standard practice for collection of whole blood.	Standard of care (low CVP surgery). In this arm, standard anesthesia will be maintained.
Period Title: Overall Study
STARTED	31	31
COMPLETED	31	31
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Phlebotomy	Control	Total
Arm/Group Description	For patients randomized to phlebotomy, the intervention will consist of the standard of care (low CVP surgery), plus whole blood phlebotomy. Blood will be collected in citrated whole blood collection bag. Phlebotomy: A central venous catheter will be inserted for every patient to measure central venous pressure, as is the standard of care in elective liver surgery. Strict aseptic technique will be maintained. A total volume of whole blood of 7-10 mL per kg of body weight will be removed, as tolerated. The volume of removed blood will not be replaced by intravenous fluid administration. Collected blood will be transfused back at the end of the liver parenchymal transection, or within 8 hours of collection. Citrated whole blood collection bag: Transfusion Medicine will send the requested number of whole blood collection bags labelled with the patient's name and MRN. These whole blood collection bags are used in standard practice for collection of whole blood.	Standard of care (low CVP surgery). In this arm, standard anesthesia will be maintained.	Total of all reporting groups
Overall Participants	31	31	62
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	58 (14)	62 (11)	60 (12.6)
Sex: Female, Male (Count of Participants)
Female	16 51.6%	13 41.9%	29 46.8%
Male	15 48.4%	18 58.1%	33 53.2%
Race and Ethnicity Not Collected (Count of Participants)
Count of Participants [Participants]	0 0%
Region of Enrollment (participants) [Number]
Canada	31 100%	31 100%	62 100%

Outcome Measures

1. Primary Outcome

Title	Total Intraoperative Blood Loss, by Measurement of Change in Hemoglobin Levels
Description	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.
Time Frame	1 week prior to surgery (hemoglobin level), and day two of post-op (hemoglobin again).

Outcome Measure Data

Analysis Population Description

incomplete data

Arm/Group Title	Phlebotomy	Control
Arm/Group Description	For patients randomized to phlebotomy, the intervention will consist of the standard of care (low CVP surgery), plus whole blood phlebotomy. Blood will be collected in citrated whole blood collection bag. Phlebotomy: A central venous catheter will be inserted for every patient to measure central venous pressure, as is the standard of care in elective liver surgery. Strict aseptic technique will be maintained. A total volume of whole blood of 7-10 mL per kg of body weight will be removed, as tolerated. The volume of removed blood will not be replaced by intravenous fluid administration. Collected blood will be transfused back at the end of the liver parenchymal transection, or within 8 hours of collection. Citrated whole blood collection bag: Transfusion Medicine will send the requested number of whole blood collection bags labelled with the patient's name and MRN. These whole blood collection bags are used in standard practice for collection of whole blood.	Standard of care (low CVP surgery). In this arm, standard anesthesia will be maintained.
Measure Participants	31	31
Anaesthetist Estimate	862	872
Surgeon Estimate	761	872
Calculated EBL	1116	1249

2. Primary Outcome

Title	Trial Feasibility
Description	Trial accrual
Time Frame	through study completion, an average of 2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Participant Accrual
Arm/Group Description	Enrolment of participants in either group (Phlebotomy or Control)
Measure Participants	62
Count of Participants [Participants]	62 200%

3. Secondary Outcome

Title	Blood Product Transfusion Rates
Time Frame	Will be measured in the operating room and in the first postoperative week

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phlebotomy	Control
Arm/Group Description	For patients randomized to phlebotomy, the intervention will consist of the standard of care (low CVP surgery), plus whole blood phlebotomy. Blood will be collected in citrated whole blood collection bag. Phlebotomy: A central venous catheter will be inserted for every patient to measure central venous pressure, as is the standard of care in elective liver surgery. Strict aseptic technique will be maintained. A total volume of whole blood of 7-10 mL per kg of body weight will be removed, as tolerated. The volume of removed blood will not be replaced by intravenous fluid administration. Collected blood will be transfused back at the end of the liver parenchymal transection, or within 8 hours of collection. Citrated whole blood collection bag: Transfusion Medicine will send the requested number of whole blood collection bags labelled with the patient's name and MRN. These whole blood collection bags are used in standard practice for collection of whole blood.	Standard of care (low CVP surgery). In this arm, standard anesthesia will be maintained.
Measure Participants	31	31
Intraoperative	1 3.2%	1 3.2%
Postoperative	5 16.1%	3 9.7%
Total	5 16.1%	4 12.9%

4. Secondary Outcome

Title	Perioperative Morbidity (Dindo-Clavien Grade 3b of Higher) and Mortality
Time Frame	Postoperative setting up to 30 days following surgery

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phlebotomy	Control
Arm/Group Description	For patients randomized to phlebotomy, the intervention will consist of the standard of care (low CVP surgery), plus whole blood phlebotomy. Blood will be collected in citrated whole blood collection bag. Phlebotomy: A central venous catheter will be inserted for every patient to measure central venous pressure, as is the standard of care in elective liver surgery. Strict aseptic technique will be maintained. A total volume of whole blood of 7-10 mL per kg of body weight will be removed, as tolerated. The volume of removed blood will not be replaced by intravenous fluid administration. Collected blood will be transfused back at the end of the liver parenchymal transection, or within 8 hours of collection. Citrated whole blood collection bag: Transfusion Medicine will send the requested number of whole blood collection bags labelled with the patient's name and MRN. These whole blood collection bags are used in standard practice for collection of whole blood.	Standard of care (low CVP surgery). In this arm, standard anesthesia will be maintained.
Measure Participants	31	31
postoperative complications	10 32.3%	15 48.4%
Major complication	2 6.5%	3 9.7%

5. Secondary Outcome

Title	Changes in Physiologic Parameters (CVP)
Time Frame	Will be measured in the operating room

Outcome Measure Data

Analysis Population Description

the number analyzed in one or more rows differs from overall number analyzed due to incomplete data

Arm/Group Title	Phlebotomy	Control
Arm/Group Description	For patients randomized to phlebotomy, the intervention will consist of the standard of care (low CVP surgery), plus whole blood phlebotomy. Blood will be collected in citrated whole blood collection bag. Phlebotomy: A central venous catheter will be inserted for every patient to measure central venous pressure, as is the standard of care in elective liver surgery. Strict aseptic technique will be maintained. A total volume of whole blood of 7-10 mL per kg of body weight will be removed, as tolerated. The volume of removed blood will not be replaced by intravenous fluid administration. Collected blood will be transfused back at the end of the liver parenchymal transection, or within 8 hours of collection. Citrated whole blood collection bag: Transfusion Medicine will send the requested number of whole blood collection bags labelled with the patient's name and MRN. These whole blood collection bags are used in standard practice for collection of whole blood.	Standard of care (low CVP surgery). In this arm, standard anesthesia will be maintained.
Measure Participants	31	31
before transection	8	7
transection	8	7.5

6. Secondary Outcome

Title	Change in Physiologic Parameters (Cardiac Index)
Time Frame	Will be measured in the operating room

Outcome Measure Data

Analysis Population Description

the number analyzed in one or more rows differs from overall number analyzed due to incomplete data

Arm/Group Title	Phlebotomy	Control
Arm/Group Description	For patients randomized to phlebotomy, the intervention will consist of the standard of care (low CVP surgery), plus whole blood phlebotomy. Blood will be collected in citrated whole blood collection bag. Phlebotomy: A central venous catheter will be inserted for every patient to measure central venous pressure, as is the standard of care in elective liver surgery. Strict aseptic technique will be maintained. A total volume of whole blood of 7-10 mL per kg of body weight will be removed, as tolerated. The volume of removed blood will not be replaced by intravenous fluid administration. Collected blood will be transfused back at the end of the liver parenchymal transection, or within 8 hours of collection. Citrated whole blood collection bag: Transfusion Medicine will send the requested number of whole blood collection bags labelled with the patient's name and MRN. These whole blood collection bags are used in standard practice for collection of whole blood.	Standard of care (low CVP surgery). In this arm, standard anesthesia will be maintained.
Measure Participants	31	31
Before transection	3.5	4.2
transection	3.5	3.9

Adverse Events

Time Frame	adverse event data were collected for each participant for up to 30 days post surgery (intervention)
Arm/Group Title	Phlebotomy		Control
Arm/Group Description	For patients randomized to phlebotomy, the intervention will consist of the standard of care (low CVP surgery), plus whole blood phlebotomy. Blood will be collected in citrated whole blood collection bag. Phlebotomy: A central venous catheter will be inserted for every patient to measure central venous pressure, as is the standard of care in elective liver surgery. Strict aseptic technique will be maintained. A total volume of whole blood of 7-10 mL per kg of body weight will be removed, as tolerated. The volume of removed blood will not be replaced by intravenous fluid administration. Collected blood will be transfused back at the end of the liver parenchymal transection, or within 8 hours of collection. Citrated whole blood collection bag: Transfusion Medicine will send the requested number of whole blood collection bags labelled with the patient's name and MRN. These whole blood collection bags are used in standard practice for collection of whole blood.		Standard of care (low CVP surgery). In this arm, standard anesthesia will be maintained.
All Cause Mortality
	Phlebotomy		Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/31 (6.5%)		1/31 (3.2%)
Serious Adverse Events
	Phlebotomy		Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/31 (0%)		1/31 (3.2%)
Renal and urinary disorders
Dialysis	0/31 (0%)	0	1/31 (3.2%)	1
Other (Not Including Serious) Adverse Events
	Phlebotomy		Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/31 (25.8%)		12/31 (38.7%)
General disorders
Postoperative compliations (Dindo-clavien grade I-II)	8/31 (25.8%)		12/31 (38.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.