University of Groningen

Impact of hemostasis and blood loss on outcome after liver surgeryde Boer, Maria Theresia

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Citation for published version (APA):de Boer, M. T. (2015). Impact of hemostasis and blood loss on outcome after liver surgery. [Groningen]:University of Groningen.

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1General introduction and outline of this thesis

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Chapter 1

The liver and its role in hemostasis

The liver is a multifunctional, complex organ, playing a key role in metabolism of the human body.

The liver plays a central role in hemostasis, being the producer of the majority of coagulation factors.

In patients with liver disease the production of these coagulation factors can be reduced, which can

lead to disturbed clot formation. On the other hand, the liver produces also many anticoagulant

proteins such as antithrombin (AT), protein C and protein S, leading to a fragile, yet rebalanced

hemostatic system in patients with severe liver disease.1 Operating a patient with end-stage liver

disease is a challenge, because clotting disturbances and portal hypertension can lead to major

blood loss. (Figure 1)

Figure 1: Example of severe blood loss during liver transplantation.

Liver resection in patients with a normal liver function can be complicated by major blood loss

because the densely vascularized, soft structured parenchyma needs to be transected during

resection. Nowadays both liver resection and liver transplantation are generally accepted methods

to treat patients with liver tumors or patients with end-stage liver disease. Although Wendell2

described the first resection of the right side of the liver for a primary tumor in 1911, true anatomical

right hemihepatectomy was first described in 1952 by Lortat-Jacob and Robert.3 The first liver

transplantation was performed by Starzl in 1963.4 Unfortunately, this first patient died of hemorrhage,

illustrating that blood loss during liver transplantation was one of the hurdles to take in improving

outcome in liver transplantation in those early days. As in liver transplantation, hemorrhage was an

important risk factor for mortality in the early days of liver resection.5 Ongoing improvements in

surgical and anesthesiological techniques and postoperative patient management in liver resection

and transplantation have led to a significant improvement in short- and long-term outcome.6 Despite

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General introduction and outline of this thesis

1these improvements, even nowadays blood loss and blood transfusions remain independent risk

factors for morbidity and mortality after liver resection7-10 and liver transplantation.11-13

Use of hemostatic agents in liver surgery

Although topical hemostatic agents can never replace meticulous surgical hemostasis, they can

be helpful when bleeding problems persist. Hemostatic agents can roughly be divided in matrix

products, only providing a matrix to stimulate clot formation, and in active hemostatic agents.

Active hemostatic agents consist of human or bovine derived coagulation factors, when locally

applied they mimic clot formation or can help to stimulate clot formation.

Outline of this thesis

This thesis focuses on intraoperative blood loss and blood transfusion in liver surgery, and is

subdivided in two parts. Part 1 evaluates the impact of blood loss and blood transfusion on short-

and long-term outcome in liver resections. In this part the use and efficacy of hemostatic agents

in liver surgery is also evaluated. Part 2 focuses on blood loss and transfusion requirements in liver

transplantation and its impact on short- and long-term outcome after liver transplantation.

PART 1 Studies on liver resection

Since the first publication of a true anatomical right hemihepatectomy in 1952, the subsequent

early experience in hepatic resections has been discouraging. In major hepatectomy mortality was

reported to be over 20% in a retrospective series of 621 liver resections.5 Death was attributed to

hemorrhage in 20% of these cases. Over the years outcome has improved by evolution in surgical

and anesthesiological techniques and better understanding of segmental liver anatomy. Nowadays

major liver resections can be performed with a mortality rate below 5% in specialized centers, even

though the indications have been extended also to high-risk patients.6 Liver resection has now been

accepted as the standard treatment for most liver tumors. In 2004, Poon et al have described a

gradual reduction in the percentage of transfused patients from around 90% in 1989 to 5% in 2003

in a series of 1,222 consecutive liver resections.6 Despite these improvements blood loss remains

an important predictor of both perioperative morbidity and mortality after liver resection.9,10

Chapter 2 provides a review of the literature on the impact of blood loss and blood transfusion on

postoperative and oncological outcome in liver resections for hepatobiliary malignancies.

Blood loss in liver resection is mainly related to the technical difficulty to transect the liver

parenchyma, which makes blood transfusion sometimes inevitable. Several techniques can be

applied to reduce blood loss: reduction of the central venous pressure (CVP), vascular occlusion

techniques, and the choice of the device to transect the parenchyma. Besides these techniques

several topical agents have been developed to improve hemostasis on the resection surface. The

purpose of Chapter 3 is to describe the use of topical hemostatic agents during liver resections in

the Netherlands and to describe when and for which purpose these agents are used.

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Chapter 1

Topical hemostatic agents are not only used to achieve hemostasis but are also used with the aim

to reduce postoperative resection surface-related complications, such as bile leakage. In Chapter

4 a study is described in which the evidence for hemostatic and biliostatic capacities of different

fibrin sealants in liver surgery is assessed through a review of the literature. In Chapter 5 the effect

of prophylactic use of fibrin sealants on the liver resection surface is described in a prospective

randomized controlled study including 310 patients.

PART 2 Studies on liver transplantation

After reporting the first successful liver transplantations with prolonged survival in 1968 by Starzl et

al,14 liver transplantation was considered a possible, but hazardous treatment for end stage chronic

liver failure. Many hurdles towards successful liver transplantation have been overcome over the

last decades. The introduction of cyclosporine in the early 1980s and development of the University

of Wisconsin preservation solution in the late 1980s were important steps in improving outcome

after liver transplantation.15,16 However, high morbidity and mortality rates kept being reported,

frequently related to high intraoperative blood loss and transfusion requirements.17,18 In Chapter 6

techniques and developments are described which have contributed to an impressive reduction in

blood loss and transfusion requirements in liver transplantation over the years.

It is well known that blood transfusions have an immunosuppressive effect,19 which may play a role in

the negative correlation between the amount of intraoperative blood transfusion and postoperative

outcome in liver transplantation. In Chapter 7 the impact of transfusion of different blood products

on graft and patient survival after liver transplantation was assessed retrospectively. Chapter 8

focuses on the influence of platelet transfusion on short term outcome after liver transplantation.

Nowadays several centers describe liver transplantation without the need for blood transfusion in

26 up to 80% of cases.13,20,21 Given the immunosuppressive effects of blood transfusion, this raises

the question whether patients who did not require any blood transfusion have an increased risk of

developing acute rejection. In Chapter 9 the relation between blood transfusion and the incidence

of acute rejection after liver transplantation is evaluated.

In an era of organ shortage expanding the donor pool by accepting extended criteria donor

(ECD) grafts is a way to reduce waiting list mortality.22,23 Aim of Chapter 10 is to determine the

impact of implantation of ECD grafts on intraoperative blood transfusion requirements during liver

transplantation.

Chapter 11 consists of 3 appendixes. Appendix 1 is the dutch questionnaire used for the analysis in

Chapter 3; Appendix 2 are letters to the editor and reply, related to Chapter 5; Appendix 3 is a letter

to the editor and reply, related to Chapter 7.

In Chapter 12 the previous chapters are summarized and discussed in a broader perspective. Finally,

this chapter provides directions for future research.

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General introduction and outline of this thesis

1The aims of this thesis were to study:

1. The impact of blood loss and blood transfusion on postoperative and oncological outcome

in liver resections for hepatobiliary malignancies.

2. The use of topical hemostatic agents during liver resections in the Netherlands and

describe when and for which purpose these agents are used.

3. The evidence for hemostatic and biliostatic capacities of different fibrin sealants in liver

surgery.

4. The effect of prophylactic use of fibrin sealants on the liver resection surface in a

multicenter prospective randomized controlled study.

5. Techniques and developments which have contributed to an impressive reduction in

blood loss and transfusion requirements in liver transplantation over the years.

6. The impact of transfusion of different blood products on graft and patient survival after

liver transplantation.

7. The influence of platelet transfusion on short term outcome after liver transplantation.

8. The relation between blood transfusion and the incidence of acute rejection after liver

transplantation.

9. The impact of implantation of ECD liver grafts on intraoperative blood transfusion

requirements during liver transplantation.

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Chapter 1

REFERENCES

1. Lisman T, Porte RJ. Rebalanced hemostasis in patients with liver disease: evidence and clinical consequences. Blood 2010;116:878-885.

2. Wendell W. Beitrag zur Chirurgie de Leber. Arch Klin Chir 1911;95:887.

3. Lortat-Jacob JL, Robert HG. Well defined technic for right hepatectomy. Presse Med 1952;60:549-551.

4. Starzl TE, Marchioro TL, Vonkaulla KN, Hermann G, Brittain RS, Waddell WR. Homotransplantation of the Liver in Humans. Surg Gynecol Obstet 1963;117:659-676.

5. Foster JH, Berman MM. Solid liver tumors. Major Probl Clin Surg 1977;22:1-342.

6. Poon RT, Fan ST, Lo CM, Liu CL, Lam CM, Yuen WK, et al. 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;240:698-708.

7. Cescon M, Vetrone G, Grazi GL, Ramacciato G, Ercolani G, Ravaioli M, et al. Trends in perioperative outcome after hepatic resection: analysis of 1500 consecutive unselected cases over 20 years. Ann Surg 2009;249:995-1002.

8. Huang ZQ, Xu LN, Yang T, Zhang WZ, Huang XQ, Cai SW, et al. Hepatic resection: an analysis of the impact of operative and perioperative factors on morbidity and mortality rates in 2008 consecutive hepatectomy cases. Chin Med J (Engl) 2009;122:2268-2277.

9. Jarnagin WR, Gonen M, Fong Y, DeMatteo RP, Ben-Porat L, Little S, et al. Improvement in perioperative outcome after hepatic resection: analysis of 1,803 consecutive cases over the past decade. Ann Surg 2002;236:397-406.

10. Kooby DA, Stockman J, Ben-Porat L, Gonen M, Jarnagin WR, Dematteo RP, et al. Influence of transfusions on perioperative and long-term outcome in patients following hepatic resection for colorectal metastases. Ann Surg 2003;237:860-869.

11. Boin IF, Leonardi MI, Luzo AC, Cardoso AR, Caruy CA, Leonardi LS. Intraoperative massive transfusion decreases survival after liver transplantation. Transplant Proc 2008;40:789-791.

12. Dunn LK, Thiele RH, Ma JZ, Sawyer RG, Nemergut EC. Duration of red blood cell storage and outcomes following orthotopic liver transplantation. Liver Transpl 2012;18:475-481.

13. Ramos E, Dalmau A, Sabate A, Lama C, Llado L, Figueras J, et al. Intraoperative red blood cell transfusion in liver transplantation: influence on patient outcome, prediction of requirements, and measures to reduce them. Liver Transpl 2003;9:1320-1327.

14. Starzl TE, Groth CG, Brettschneider L, Penn I, Fulginiti VA, Moon JB, et al. Orthotopic homotransplantation of the human liver. Ann Surg 1968;168:392-415.

15. Calne RY, Rolles K, White DJ, Thiru S, Evans DB, McMaster P, et al. Cyclosporin A initially as the only immunosuppressant in 34 recipients of cadaveric organs: 32 kidneys, 2 pancreases, and 2 livers. Lancet 1979;2:1033-1036.

16. Belzer FO, Southard JH. Principles of solid-organ preservation by cold storage. Transplantation 1988;45:673-676.

17. Lewis JH, Bontempo FA, Cornell F, Kiss JE, Larson P, Ragni MV, et al. Blood use in liver transplantation. Transfusion 1987;27:222-225.

18. Bismuth H, Castaing D, Ericzon BG, Otte JB, Rolles K, Ringe B, et al. Hepatic transplantation in Europe. First Report of the European Liver Transplant Registry. Lancet 1987;2:674-676.

19. Brand A. Immunological aspects of blood transfusions. Transpl Immunol 2002;10:183-190.

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General introduction and outline of this thesis

120. Cacciarelli TV, Keeffe EB, Moore DH, Burns W, Chuljian P, Busque S, et al. Primary liver transplantation

without transfusion of red blood cells. Surgery 1996;120:698-704.

21. Massicotte L, Beaulieu D, Thibeault L, Roy JD, Marleau D, Lapointe R, et al. Coagulation defects do not predict blood product requirements during liver transplantation. Transplantation 2008;85:956-962.

22. Barshes NR, Horwitz IB, Franzini L, Vierling JM, Goss JA. Waitlist mortality decreases with increased use of extended criteria donor liver grafts at adult liver transplant centers. Am J Transplant 2007;7:1265-1270.

23. Tector AJ, Mangus RS, Chestovich P, Vianna R, Fridell JA, Milgrom ML, et al. Use of extended criteria livers decreases wait time for liver transplantation without adversely impacting posttransplant survival. Ann Surg 2006;244:439-450.

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Part I. Studies in liver resection

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