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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Phlebotomy | Experimental | 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. |
|
| Control | No Intervention | Standard of care (low CVP surgery). In this arm, standard anesthesia will be maintained. |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Phlebotomy | Procedure | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| Total Intraoperative Blood Loss, by Measurement of Change in Hemoglobin Levels | 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. | 1 week prior to surgery (hemoglobin level), and day two of post-op (hemoglobin again). |
| Trial Feasibility | Trial accrual | through study completion, an average of 2 years |
| Measure | Description | Time Frame |
|---|---|---|
| Blood Product Transfusion Rates | Will be measured in the operating room and in the first postoperative week | |
| Perioperative Morbidity (Dindo-Clavien Grade 3b of Higher) and Mortality | Postoperative setting up to 30 days following surgery |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Guillaume Martel, MD, MSc, FRCSC, FACS | Ottawa Hospital Research Institute | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| The Ottawa Hospital - General Campus | Ottawa | Ontario | K1H 8L6 | Canada |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 17457160 | Background | 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. | |
| 19150318 | Background | 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. |
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| ID | Title | Description |
|---|---|---|
| FG000 | 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. 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. |
| FG001 | Control | Standard of care (low CVP surgery). In this arm, standard anesthesia will be maintained. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. 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. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Total Intraoperative Blood Loss, by Measurement of Change in Hemoglobin Levels | 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. | incomplete data | Posted | Median | Inter-Quartile Range | mL | 1 week prior to surgery (hemoglobin level), and day two of post-op (hemoglobin again). |
|
adverse event data were collected for each participant for up to 30 days post surgery (intervention)
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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. 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. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Dialysis | Renal and urinary disorders | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Postoperative compliations (Dindo-clavien grade I-II) | General disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Guillaume Martel | Ottawa Hospital Research Institute | 6137378899 | 71053 | gumartel@toh.ca |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| ICF | No | No | Yes | Informed Consent Form | Feb 16, 2016 | Feb 23, 2021 | ICF_000.pdf |
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Oct 15, 2018 | Feb 23, 2021 | Prot_SAP_001.pdf |
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| ID | Term |
|---|---|
| D008113 | Liver Neoplasms |
| ID | Term |
|---|---|
| D004067 | Digestive System Neoplasms |
| D009371 | Neoplasms by Site |
| D009369 | Neoplasms |
| D004066 | Digestive System Diseases |
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| ID | Term |
|---|---|
| D018962 | Phlebotomy |
| ID | Term |
|---|---|
| D001800 | Blood Specimen Collection |
| D013048 | Specimen Handling |
| D019411 | Clinical Laboratory Techniques |
| D019937 | Diagnostic Techniques and Procedures |
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|
| Citrated whole blood collection bag | Device | 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. |
|
| Changes in Physiologic Parameters (CVP) | Will be measured in the operating room |
| Change in Physiologic Parameters (Cardiac Index) | Will be measured in the operating room |
| 24449171 | Background | 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. |
| 22404261 | Background | 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. |
| 12368667 | Background | 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. doi: 10.1097/01.SLA.0000029003.66466.B3. |
| 15383797 | Background | 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. doi: 10.1097/01.sla.0000141195.66155.0c. |
| 23426338 | Background | 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. |
| 19953711 | Background | 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. |
| 25881789 | Background | 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. |
| 20216483 | Background | 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. |
| 31965573 | Derived | Martel G, Baker L, Wherrett C, Fergusson DA, Saidenberg E, Workneh A, Saeed S, Gadbois K, Jee R, McVicar J, Rao P, Thompson C, Wong P, Abou Khalil J, Bertens KA, Balaa FK. Phlebotomy resulting in controlled hypovolaemia to prevent blood loss in major hepatic resections (PRICE-1): a pilot randomized clinical trial for feasibility. Br J Surg. 2020 Jun;107(7):812-823. doi: 10.1002/bjs.11463. Epub 2020 Jan 22. |
| 27712877 | Derived | 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. |
| BG001 | Control | Standard of care (low CVP surgery). In this arm, standard anesthesia will be maintained. |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants | No |
|
| Race and Ethnicity Not Collected | Race and Ethnicity were not collected from any participant. | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| OG000 | 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. 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. |
| OG001 | Control | Standard of care (low CVP surgery). In this arm, standard anesthesia will be maintained. |
|
|
| Primary | Trial Feasibility | Trial accrual | Posted | Count of Participants | Participants | through study completion, an average of 2 years |
|
|
|
| Secondary | Blood Product Transfusion Rates | Posted | Count of Participants | Participants | No | Will be measured in the operating room and in the first postoperative week |
|
|
|
| Secondary | Perioperative Morbidity (Dindo-Clavien Grade 3b of Higher) and Mortality | Posted | Count of Participants | Participants | Postoperative setting up to 30 days following surgery |
|
|
|
| Secondary | Changes in Physiologic Parameters (CVP) | the number analyzed in one or more rows differs from overall number analyzed due to incomplete data | Posted | Median | Inter-Quartile Range | cmH2O | Will be measured in the operating room |
|
|
|
| Secondary | Change in Physiologic Parameters (Cardiac Index) | the number analyzed in one or more rows differs from overall number analyzed due to incomplete data | Posted | Median | Inter-Quartile Range | I per min per m2 | Will be measured in the operating room |
|
|
|
| 2 |
| 31 |
| 0 |
| 31 |
| 8 |
| 31 |
| EG001 | Control | Standard of care (low CVP surgery). In this arm, standard anesthesia will be maintained. | 1 | 31 | 1 | 31 | 12 | 31 |
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| D008107 |
| Liver Diseases |
| D003933 | Diagnosis |
| D011677 | Punctures |
| D013812 | Therapeutics |
| D013514 | Surgical Procedures, Operative |
| D008919 | Investigative Techniques |
| Total |
|
| transection |
|
|
| transection |
|
|