the investigation of clotting abnormalities in

Coagulopathy in cytoreductive surgery patients

1

The investigation of clotting abnormalities in cytoreductive

surgery patients through thromboelastography

Dr Gary Sharp MBBS BSc (Hons)

A thesis submitted in fulfilment of the requirements for the degree of master of philosophy

Faculty of Medicine

University of Sydney

2021

Dedicated to my daughters, Poppy and Lola, who’s laughter and love give me such joy.


2

TABLE OF CONTENTS

Statement of originality 3

Acknowledgements 3

Assistants and nature of collaboration 4

Introduction 5

Chapter 1. Point of care viscoelastic assay devices (rotational thromboelastometry

and thromboelastography); a primer for surgeons.

13

Chapter 2. A systematic review of coagulopathy in cytoreductive surgery and

hyperthermic intraperitoneal chemotherapy patients.

31

Chapter 3. A pilot study to investigate the role of thromboelastography in

cytoreductive surgery and hyperthermic intraperitoneal chemotherapy patients.

59

Thesis discussion 87

Appendix 1. Project description. 95

Appendix 2. Patient information. 108

Appendix 3. Ethics approval. 110


3

STATEMENT OF ORIGINALITY

The work presented in this thesis is, to the best of my knowledge and belief, original except as

acknowledged in the text. I hereby declare that I have not submitted this material, either in full

or in part, for a degree at this or any other institution.

I understand that if my candidature is successful, my thesis will be lodged with the Director of

University Libraries and made available for immediate use.

Dr Gary Sharp

1/9/21

ACKNOWLEDGEMENTS

Thank you Professor Young for the continued support, not only during this MPhil but for the

years you have helped and motivated me. Thank you to the patients who so kindly agreed to

participate in these studies to further the knowledge of clinicians and ultimately help future.

Lastly, thank you to my family who have guided me and supported my dream for all these

years, I could not have achieved what I have without you. Paula, you are my rock.


4

ASSISTANTS AND NATURE OF COLLABORATION

Name Job title Nature of collaboration

A/Prof. Christopher

J. Young

Consultant colorectal

surgeon. Royal Prince

Alfred Hospital, Sydney,

Australia.

Supervisor. Reviewer in chief.

Dr Daniel Steffens Deputy director of

Surgical Outcomes

Research Centre, Royal

Prince Alfred Hospital,

Sydney, Australia.

Assistance with statistics during the following articles;

1. 1. Systematic review of the incidence and outcome of

coagulopathy in cytoreductive surgery and heated

intraperitoneal chemotherapy patients.

2. 2. A pilot study to investigate the role of thromboelastography

in cytoreductive surgery and hyperthermic intraperitoneal

chemotherapy patients.

Dr Rebecca

McNamara

Consultant anaesthetist.

Royal Prince Alfred

Hospital, Sydney,

Australia.

Data collection.

Collection of TEGs intraoperatively during “A pilot study to

investigate the role of thromboelastography in cytoreductive

surgery and hyperthermic intraperitoneal chemotherapy

patients”.

Dr Neil Pillinger Consultant anaesthetist.

Royal Prince Alfred

Hospital, Sydney,

Australia.

Data collection.

Collection of TEGs intraoperatively “A pilot study to

investigate the role of thromboelastography in cytoreductive

surgery and hyperthermic intraperitoneal chemotherapy

patients”.

Dr Nabila Ansari Consultant colorectal

surgeon. Royal Prince


Australia.

Assistance with forming a project description for “A pilot

study to investigate the role of thromboelastography in

cytoreductive surgery and hyperthermic intraperitoneal

chemotherapy patients”.

Dr Daniel Oh Senior resident medical

officer. Royal Prince


Australia.

Collected data from medical notes to assist with “A pilot

study to investigate the role of thromboelastography in

cytoreductive surgery and hyperthermic intraperitoneal

chemotherapy patients”.


5

Introduction

Abdominal cytoreductive surgery (CRS) is the macroscopic removal of intraperitoneal

malignancy (1, 2). CRS has been utilised in one form or another since the 1930’s during which

time tumour debulking procedures in ovarian malignancy were being undertaken to reduce

tumour burden (3). Further interest in CRS developed until eventually, positive survival

outcomes were consistently reported in the 1960’s (4). Following on from these positive

outcomes seen in gynaecological malignancy, surgeons began to investigate pseudomyxoma

peritonei (PMP), a mucus-producing tumour that arises from an appendiceal tumour or less

commonly an ovarian tumour (5,6). Surgeons set about reducing the PMP tumour burden

through evacuating the space-occupying mucin coupled with resection of affected viscera. The

rationale for this new cytoreductive practice was that if there was less tissue within the

peritoneal cavity the chemotherapy agents would have a greater impact of the residual tissue

volume, plus reducing the risk of later complications such as obstruction (6).

Coupled with the increased enthusiasm for CRS was a desire to identify the most potent but

least toxic route of chemotherapy. The use of intraperitoneal chemotherapy was initially

described by Weisberger et al. in 1955 who utilised intraperitoneal nitrogen mustard to manage

malignant ascites (7). Ensuing canine studies revealed that intraperitoneal chemotherapy,

versus intravenous, had much higher local anticancer effect without increased systemic

toxicity; (8) this remains true to today (9). The advent of a heated chemotherapy delivery

system to deliver intraperitoneal chemotherapy was realised by Spratt et al. (1980) and

although not termed HIPEC as yet it delivered heated chemotherapy safely (10). Spratt et al

went on to treat the first human with their design in 1979 for PMP; he survived.


6

CRS research continued to focus mostly on ovarian malignancy until Dr Paul H Sugarbaker of

the United States began to focus on CRS and HIPEC in gastrointestinal malignancies

presenting with peritoneal disease. Dr Sugarbaker’s plethora of research into this area began to

standardise intraabdominal CRS procedures (11). Sugarbaker also highlighted the use of a

“coliseum”, a plastic sheet secured to both the skin edges and a retraction device which elevates

skin edges, to administer the HIPEC solution a defect within the plastic sheet is made, thus

allowing an even distribution of chemotherapy solution throughout the abdomen whilst also

allowing manipulation of intraabdominal viscera by the surgeon to ensure all peritoneal

surfaces are in direct contact with the agent (12).

Next, researchers developed a standardised approach to classify peritoneal malignancy, the

Peritoneal Cancer Index (PCI). PCI was developed by a collaborative group in the 1990’s and

involves dividing the abdomen into 9 segments and the small bowel into a further 4 segments

(13). Each segment is then scored:

• 0 - no disease

• 1 - tumour deposits up to 0.5cm

• 2 - tumour >0.5-5.0cm

• 3 >5.0cm deposits

The score for all segments are calculated to provide a total out of 39 (13). PCI, used to this day,

allows surgeons to evaluate tumour burden and the possible effectiveness of CRS (14).

Subsequent to PCI, completeness of cytoreduction score (CC) was developed which aimed to

catagorise residual tumour following CRS prior to HIPEC (15):

• CC0 - no visible tumour seen post CRS

• CC1 - any single tumour deposit no larger than 2.5mm


7

• CC2 - tumour deposits of 2.5mm-2.5cm

• CC3 – tumour deposits >2.5cm (15).

Surgical curative intent is aimed at reaching a CC1 or less. The rationale for this size of tumour

deposit is directly related to the penetration depth of HIPEC, which at maximum is 5mm

(16,17). However, CC0 is the gold standard and produces the best outcome in terms of overall

survival (14). Many trials in the subsequent years have been carried out and the consensus now

is that CRS and HIPEC are beneficial in PMP (18) and selective peritoneal carcinomatosis

(9,14).

Despite evidence highlighting CRS and HIPEC’s survival advantages, it is also acknowledged

that it is a procedure not to be undertaken lightly. CRS procedures are long, some suggesting a

mean of 10.5 hours (16), they are financially demanding for the institution (14) and have

significant morbidity and mortality attached (16,19). Bleeding in the CRS/HIPEC population

is a well-known complication resulting in significant reoperation (16,19). These patients are

also known to be susceptible to coagulopathy (20), the cause of which is not entirely known

but is thought to be multifactorial (5,21). However, the outcome of this coagulopathy continues

to be inadequately understood (22).

Standard laboratory tests are commonly used to assess bleeding. These tests include an

international normalised ratio (INR), prothrombin time (PT) and activated partial prothrombin

time (aPTT). Unfortunately, their accuracy at assessing bleeding risk and managing blood

product replacement has been shown to be lacking (23). Instead, the use of viscoelastic (VE)

assays such as thromboelastography (TEG) have been suggested to be far more appropriate

in diagnosing and treating massive haemorrhage (24). The use of TEG in guiding blood


8

transfusion is gaining recognition in its ability to potentially reduce unnecessary blood product

transfusion which in turn reduces patient morbidity (25).

The use of TEG in general surgery is limited and as such, general surgeons and trainees know

little about VE assay mechanisms, interpretation and use. The first aim of this thesis is to

produce a narrative review of VE assay technology, result interpretation, current uses and

potential uses. Although research suggests the presence of CRS coagulopathy and the ensuing

complications there is limited data that actually quantifies this. Thus, the second aim of this

thesis is to highlight the incidence and outcome of coagulopathy in CRS and HIPEC patients

by way of a systematic review. The final chapter, and third aim, is a pilot study to investigate

the role of thromboelastography (TEG) in CRS and HIPEC patients.

REFERENCES

1. Ansari, N, Brown, K, McBride, K et al. (2019). Accelerating the learning curve in

cytoreductive surgery and hyperthermic intraperitoneal chemotherapy using an external mentor

model. ANZ J Surg 89, 1097–1101.

2. Hurdle, H, Bishop, G, Walker, A et al. (2017) Coagulation after cytoreductive surgery

and hyperthermic intraperitoneal chemotherapy: a retrospective cohort analysis, Can J Anesth,

64:1144–1152, DOI 10.1007/s12630-017-0952-7.

3. Meigs, JV (1934). Tumors of the female pelvic organs. New York: The Macmillan

Company.


9

4. Munnell, EW (1969). Surgical treatment of ovarian carcinoma. Clin Obstet

Gynecol;12:980-92.

5. Cooksley, T and Haji-Michael, P (2011). Post-operative critical care management of

patients, undergoing cytoreductive surgery and, heated intraperitoneal chemotherapy (HIPEC),

World Journal of Surgical Oncology, 9:169, http://www.wjso.com/content/9/1/169. Accessed

on 15/4/20.

6. Neuwirth, M, Alexander, R, Karakousis, G (2016). Then and now: cytoreductive

surgery with hyperthermic intraperitoneal chemotherapy (HIPEC), a historical perspective, J

Gastrointest Oncol, 7(1):18-28.

7. Weisberger AS, Levine B, Storaasli JP (1955). Use of nitrogen mustard in treatment of

serous effusions of neoplastic origin. JAMA, 159(18):1704–7.

8. Pretorius, RG, Petrilli, ES, Kean, CK, (1981). Comparison of the iv and ip routes of

administration of cisplatin in dogs. Cancer Treat Rep, 65:1055-62.

9. Jaaback K, Johnson N, Lawrie TA (2016). Intraperitoneal chemotherapy for the initial

management of primary epithelial ovarian cancer. Cochrane Database of Systematic Reviews,

Issue 1. Art. No.: CD005340. DOI:10.1002/14651858.CD005340.pub4.

10. Spratt, JS, Adcock, RA, Sherrill, W (1980). Hyperthermic peritoneal perfusion system

in canines. Cancer Res, 40: 253-5.

http://www.wjso.com/content/9/1/169


10

11. Sugarbaker, PH (1995). Peritonectomy procedures. Ann Surg, 221: 29-42.

12. Sugarbaker, PH, Yu W, Yonemura Y (2003). Gastrectomy, peritonectomy, and

perioperative intraperitoneal chemotherapy: The evolution of treatment strategies for advanced

gastric cancer. Semin Surg Oncol, 21:233-48.

13. Jacquet, P, Sugarbaker, PH (1996). Clinical research methodologies in diagnosis and

staging of patients with peritoneal carcinomatosis. Cancer Treat Res, 82:359-74.

14. Hallam, S, Tyler, R, Price, M et al. (2019). Meta-analysis of prognostic factors for

patients with colorectal peritoneal metastasis undergoing cytoreductive surgery and heated

intraperitoneal chemotherapy, BJS Open, DOI: 10.1002/bjs5.50179.

15. Glehen, O, Gilly, FN (2003). Quantitative prognostic indicators of peritoneal surface

malignancy: carcinomatosis, sarcomatosis, and peritoneal mesothelioma. Surg Oncol Clin N

Am, 12: 649-71.

16. Bell, J, Rylah, B, Chambers, R et al. (2012). Perioperative Management of Patients

Undergoing Cytoreductive Surgery Combined with Heated Intraperitoneal Chemotherapy for

Peritoneal Surface Malignancy: A Multi-Institutional Experience, Ann Surg Oncol, 19: 4244–

425 1 DOI 10.1245 /s10434-012-2496-y.

17. Gupta, N, Kumar, V, Garg, R et al. (2019). Anesthetic implications in hyperthermic

intraperitoneal chemotherapy, Journal of Anaesthesiology Clinical Pharmacology, 35; 3-11.


11

18. Moran B, Baratti D, Yan TD et al. (2008). Consensus statement on the loco-regional

treatment of appendiceal mucinous neoplasms with peritoneal dissemination (pseudomyxoma

peritonei). J Surg Oncol, 98:277– 82.

19. Saxena, A, Yan, T, Chua, C et al. (2009). Risk Factors for Massive Blood Transfusion

in Cytoreductive Surgery: A Multivariate Analysis of 243 Procedures. Ann Surg Oncol, 16:

2195–2203. DOI 10.1245/s10434-009-0484-7.

20. Raspé, C, Flöther, L, Schneider, R et al. (2016). Best practice for perioperative

management of patients with cytoreductive surgery and HIPEC, European Journal of Surgical

Oncology, 43: 1013-1027. DOI.org/10.1016/j.ejso.2016.09.008.

21. Owusu-Agyemang, P, Soliz, J, Hayes-Jordan, A et al. (2014). Safety of Epidural

Analgesia in the Perioperative Care of Patients Undergoing Cytoreductive Surgery with

Hyperthermic Intraperitoneal Chemotherapy, Ann Surg Oncol, 21:1487–1493. DOI

10.1245/s10434-013-3221-1.

22. Korakianitis, O, Daskalou, T, Alevizos, L et al. (2015). Lack of significant

intraoperative coagulopathy in patients undergoing cytoreductive surgery and hyperthermic

intraperitoneal chemotherapy (HIPEC) indicates that epidural anaesthesia is a safe option. Int

J Hyperthermia, 31(8): 857–862.

23. Gonzalez, E, Moore, E, Moore, H (2017). Management of Trauma-Induced

Coagulopathy with Thrombelastography. Crit Care Clin, 33: 119-34.


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24. Thomas, D, Wee, M, Clyburn, P et al. (2010). GUIDELINES. Blood transfusion and

the anaesthetist: management of massive haemorrhage. Association of Anaesthetists of Great

Britain and Ireland. Anaesthesia, 65: 1153-61.

25. Wikkelsø, A, Wetterslev, J, Møller, A et al. (2016). Thromboelastography (TEG) or

thromboelastometry (ROTEM) to monitor haemostatic treatment versus usual care in adults or

children with bleeding. Cochrane Database of Systematic Reviews, Issue 8. Art. No.:

CD007871. DOI: 10.1002/14651858.CD007871.pub3.


13

CHAPTER 1

Point of care viscoelastic assay devices (rotational thromboelastometry and

thromboelastography); a primer for surgeons.

Authors:

Gary Sharpa MBBS, BSc (Hons)

A/Prof. Christopher J. Younga,b MBBS, MS, FRACS, FACS, FASCRS

Institutions:

a Department of Colorectal Surgery, Royal Prince Alfred Hospital, Sydney, Australia.

b The University of Sydney, Discipline of Surgery, Sydney, New South Wales, Australia.

Citation

Sharp, G, Young, C (2018). Point‐of‐care viscoelastic assay devices (rotational

thromboelastometry and thromboelastography): a primer for surgeons, ANZ Journal of

Surgery, 89: 291-295.

https://onlinelibrary.wiley.com/journal/14452197

https://onlinelibrary.wiley.com/journal/14452197


14

Abstract

Introduction

Bleeding is a common occurrence in surgery. Point of care testing with viscoelastic assays such

as TEG and ROTEM has become more common place. TEG and ROTEM have the

potential to guide management of coagulopathy. Many health care professionals still rely upon

standard laboratory tests to manage a bleeding patient. We aimed to investigate the literature

surrounding management of the surgically bleeding patient via viscoelastic assays.

Methods

Literature review of Embase, Medline, Pubmed and the Cochrane library using “TEG,

ROTEM, surgery” search terms.

Results

Via the literature search and reference lists reviewed by both authors, a total of 62 articles have

been evaluated, 35 of these have been included in this review.

Discussion

Viscoelastic assays are used most commonly during orthotopic liver transplantation, trauma,

post-partum haemorrhage and cardiac surgery. Although the evidence is not overwhelming, we

have identified recurrent themes where viscoelastic assays seem to be beneficial. Viscoelastic

assay use, especially when incorporated into an algorithm, appears to reduce blood product

administration which in turn reduces costs and potential adverse events. They are quicker than

standard laboratory tests and they can detect hyperfibrinolysis, the hallmark of coagulopathy,

via in vivo clot analyses which standard laboratory tests are unable to do. Ultimately more

randomised controlled trials are required.


15

Point of care viscoelastic assay devices (rotational thromboelastometry and

thromboelastography): a primer for surgeons

Introduction

Haemorrhagic shock accounts for 80% of intraoperative deaths(1). Greater knowledge of

coagulopathy and the potential gains from point of care (POC) testing using viscoelastic (VE)

assays such as rotational thromboelastometry (ROTEM) and thromboelastography (TEG)

may benefit our patients. These two VE assays are very similar and have been evaluated as a

single entity in many reviews(2). Perioperative analysis of coagulation and haemoglobin is

paramount in managing pathological states arising from haemorrhage. Patient assessment starts

long before entering the operating room (OR) via preoperative assessment to identify bleeding

risk(3). Intraoperative monitoring includes diligently recording blood loss, organ perfusion,

haemoglobin concentration, unwanted effects of blood product transfusion and

coagulopathy(3).

Standard laboratory tests (SLT’s) such as INR/PT and aPTT were originally used to diagnose

bleeding disorders and subsequently used to evaluate anticoagulants(1). The end-point of these

tests is the first detectable fibrin level(4) which equates to approximately the first 20-60

seconds of clot formation(5). APTT measures the intrinsic pathway, PT measures the extrinsic

pathway, while INR is a ratio of PT and a “normal” mean PT, it also measures the extrinsic

pathway(2, 6). SLT’s are used routinely within general surgery despite being shown to poorly

correlate with bleeding risk(1, 4, 6). They are poor prognosticators for haemorrhage in the

critically unwell(5). Furthermore, they remain unsatisfactory in the evaluation of orthotopic

liver transplantation (OLT), post-partum haemorrhage (PPH) and trauma-induced


16

coagulopathy (TIC)(7). These time-consuming tests(7-9) lack real-time evaluation(7) with

values derived from plasma, not whole blood(8, 10). They also lack information concerning

platelet function, fibrin formation, fibrinolysis(8) and importantly hyperfibrinolysis(11).

Hyperfibrinolysis is the abnormal accelerated breakdown of clot which leads to further

haemorrhage and is seen in many coagulopathies(12). Many studies suggest SLT’s are

inadequate when used alone to guide haemorrhagic resuscitation(5) and management of

coagulopathy, which is present in many critically ill patients upon emergency department (ED)

presentation(6, 7). Recent evidence proposes the use of more robust VE assays such as TEG

and ROTEM(1, 3, 8, 11). VE assays are regarded as POC assays performed on whole blood

which assess clot formation and breakdown(7). They are also regularly utilised worldwide(13)

to guide allogenic blood product resuscitation(4) which is associated with significant costs,

morbidity and mortality(14). The ability of VE assays to rationalise blood product transfusion

subsequently lowers transfusion complications(8) and costs(14) especially in trauma, cardiac

and OLT surgery(15). Lastly, VE assays are quicker to perform than SLT’s and can guide

individual treatment of specific causes of coagulopathy(16).

Techniques of Viscoeleastic assessment of Coagulation

TEG, originally known as “Harterts Instrument”, was produced in 1948 by Hartert at

Heidelberg University School of Medicine(7). Used throughout Europe in the 1950’s to

identify anticoagulant effects, thrombocytopaenia and fibrinolysis, it was later utilised by Swan

et al in 1958 during cardiac surgery(4, 10). It’s use in research then commenced around

1990(10) and began in earnest with trauma patients and the evaluation of TIC(4). TEG is a

POC device that analyses clot production, growth and breakdown(17). It’s performed on whole

blood at the bedside allowing quicker evaluation of coagulation status(8). Once the TEG is

complete clinicians are supplied with a graphical representation and assay data regarding


17

coagulation(11) allowing rationalised blood product replacement(8, 11, 17). A rapid-TEG

assay will give results within 5-15 minutes(2) due to addition of tissue factor (TF) which

accelerates the clotting process(10). TEG works by placing whole blood into a plastic

cartridge which contains a cup and extending into the whole blood from above is a thin torsion

wire. The plastic cup then rotates at a set rate and degrees of motion(10). The viscoelastic

changes in clot property are registered via the torsion wire and an electromagnetic transducer

which in turn produces a physical trace(10) (Figure 4 and Table 1). As clot lysis occurs the

torsion wire is moved less allowing near real-time clot evaluation(21). Apart from rapid-TEG

all other TEG samples have the anticoagulant citrate within them(10) to ensure whole blood

is tested and not partially clotted/clotted blood(4).

ROTEM is a modified version of Harterts original thromboelastography(22). Whole citrated

blood is inserted into a cuvette and a sensor pin is partially submerged within the sample which

moves back and forth through an angle of 4.75°(22). Reagents are then added to assess specific

clotting pathways(2). Resistance is transmitted to an optical detector system and subsequently

recorded(2). The viscoelastic clot properties are then displayed providing information on

coagulation initiation, growth, strength and breakdown(22). Preliminary results are ready

within 5-10 minutes and the full report within 20 minutes(2). Six assays are routinely utilised:

INTEM, EXTEM, HEPTEM, FIBTEM, APTEM, Na-TEM(2) which isolate the origin of

numerous causes of haemorrhage(22). INTEM assesses clot formation and fibrinolysis via the

intrinsic pathway(23). EXTEM assesses the extrinsic pathway(23). FIBTEM measures the

function, not concentration, of fibrinogen(23).

Trauma


18

Worldwide, trauma accounts for approximately six million deaths per annum, with

uncontrolled haemorrhage comprising almost half(18). It is the leading cause of mortality and

morbidity in adults <36 years worldwide(2) and the second most common cause of death in

developed countries(5). Two-thirds of these deaths and 80% of blood product administration

will occur within six hours post-injury(24) from uncontrollable haemorrhage(25).

Haemorrhage, massive transfusion protocol (MTP) and coagulopathy are noted as the most

significant factors regarding outcome(22). Debate continues regarding the best transfusion

ratio, however a 1:1:1 ratio of RBC/FFP/Platelets has been suggested as most appropriate with

significant reductions in mortality due to rapid restoration of haemostasis(8, 11). Activation of

an MTP and subsequent administration of potentially large volumes of blood products is not

without complication (Table 2) and significant financial costs(18). MTP’s are of proven benefit

in haemorrhagic shock treatment(3, 5), but we must consider not only the blood products

required but other adjuncts to ensure maximal effect(11). Several factors are known to

contribute to TIC (Table 3) however, the exact pathophysiology remains unclear(18). TIC is

present in up to 35% of severely injured patients on ED arrival(19). As Injury Severity Score

(ISS) rises, so does the incidence of coagulopathy, mortality(26) and morbidity(2). VE assay-

based MTP versus a generic MTP has been shown to; reduce mortality(19, 20): rationalise

blood product use(2, 10, 25); reduce ICU stay and ventilator days(25). Hyperfibrinolysis,

identified on VE, is an important component of TIC(4, 7) and correlates with trauma

severity(5), poorer outcome(4, 21) and TIC mortality(2, 10, 22). Fulminant hyperfibrinolysis

(complete clot fibrinolysis within <30 minutes) has a mortality of >85%(7).

Cardiac surgery

Perioperative haemorrhage regularly complicates cardiac surgery culminating in increased ICU

stay, morbidity and mortality(2, 16). The aetiology of cardiac surgery coagulopathy is


19

multifactorial but includes; heparin use during bypass, coagulation factor

consumption/dilution, platelet dysfunction, hypothermia and hyperfibrinolysis(1, 2, 9, 16). VE

assays are able to discriminate between a large majority of these and guide an individual

approach to haemorrhage management(16). The cause of coagulopathy aside, up to 8% of

cardiac surgical patients require a further procedure for haemorrhage(2) culminating in

cardiothoracic surgery using 5% of all donated blood in the UK(2) and 15-20% worldwide(16).

This consumption comes at vast financial expense and correlates with increased morbidity and

mortality(2, 16). Several studies have highlighted significant reductions in blood product

consumption when following a VE assay-related algorithm compared with SLT’s(2, 3, 9, 16).

As such VE was noted to be cost-saving when compared to SLT’s(2). These beneficial

outcomes have culminated in the National Institute for Health and Care Excellence (NICE)

recommending TEG use during cardiac surgery(13).

Post-partum haemorrhage

Pregnancy induces pronounced vicissitudes in haemostasis(27, 28) preparing the mother for

childbirth(12). PPH remains the greatest cause of obstetric morbidity and mortality

worldwide(27) with a rising incidence(23). In 2012 78,000 maternal deaths were directly

attributed to PPH worldwide(29) with an incidence of ~3.7/1000 births in the UK(2). It is a

common cause for MTP activation(11) with severe PPH leading to emergency hysterectomies,

a mortality rate of 0.6%, and prolonged ICU admissions(12, 23). The most common cause is

uterine atony but multiple aetiologies exist(30) such as dilutional coagulopathy, local and

disseminated coagulation factor consumption and/or hyperfibrinolysis(1, 12). Many PPH cases

remain idiopathic(12). PPH manifests abruptly and requires constant re-evaluation(29). SLT’s

are of poor prognostic value in PPH and may remain normal even in the face of severe blood

loss(12). Management requires identification of the underlying aetiology without delay(27)


20

which in turn positively influences maternal outcome(30). VE assays have been hypothesised

to assist in differentiating the cause of PPH and managing it(27). Fibrinogen decline manifests

rapidly and is prognostic of progression to severe PPH(12, 23, 30) thus, prompt correction is

imperative(23). Fibrinogen function can be measured via ROTEM FIBTEM assay(15, 23,

30). A VE assay-based algorithm incorporating FIBTEM testing and fibrinogen concentrate

supplementation was associated with less blood product use, less volume transfused and fewer

adverse outcomes(23).

Orthotopic liver transplant surgery

End-stage liver disease is now commonly treated with OLT(31). This intricate procedure

associated with considerable risk(32) and substantial haemorrhage(33) may require major

blood product replacement(31, 32). A great range of allogenic transfusion rates exists across

transplantation centres worldwide(33), regardless, blood product transfusion within this

population is linked with adverse postoperative outcomes(31, 32) and mortality(33). The

pathogenesis of coagulopathy and subsequent haemorrhage in OLT remains multifactorial(33).

It does however, include hyperfibrinolysis during the anhepatic phase and the patient’s inability

to clear tissue plasminogen activators(33). Several authors noted significant benefits of a VE

assay-based algorithm in OLT such as; reduced transfusion requirements(19, 21, 31, 32),

especially FFP(31), less MTP activation(32), fewer complications(19, 32), re-do surgeries(21,

32), shorter ICU stays, reduced treatment costs(19) and mortality(21). Of note MTP activation

and administration is associated with shorter survival and more renal dysfunction(32) which in

itself is an independent factor known to increase mortality in OLT pts(32).

Other attempted VE assay uses


21

• A ROTEM guided algorithm used to treat burns patients was found to reduce blood

product consumption(3).

• TEG guided enoxaparin dosing for thromboprophylaxis in trauma and surgical

patients showed no improvement in venous-thromboembolism rates(34).

• The European Society of Anaesthesiology recommended the use of VE for major

orthopaedic, neurosurgical and paediatric surgery(15).

• The diagnosis of coagulopathy in patients unable to respond verbally and potentially

taking platelet antagonists(17).

• TEG guided haemostatic normalisation in catastrophically injured patients resulted

in fifteen organs being donated from two donors(17).

• Lastly, a study has highlighted the advantageous use of VE assays in venomous snake

bite management(35).

VE assay limitations

A lack of cost-effectiveness when used less than 326 times per year/per device(2). VE assay

devices require quality control(9), regular calibration(13), are costly and not always

available(9). Clinicians must be trained in the correct use and interpretation(2, 12) making them

operator dependent, open to error(4, 13, 17) and inter-sampling inconsistencies(4, 12).

Ultimately there appears to be a lack of current evidence(13) especially regarding improvement

in morbidity or mortality(13) and a significant lack of RCT’s(12).

Conclusion

This literature review describes numerous benefits and limitations regarding VE assays.

Benefits tend to fall into one of the following categories: reduced blood product use(4, 13)


22

culminating in reduced costs(2, 13) and diminished exposure to allogenic products and their

associated morbidity and mortality(2). Over 30 million units of blood are transfused in the

United States annually and the rate is rising(6). Any reduction has the potential to reduce

morbidity and costs; in fact this has been noted in cardiac surgery, trauma, postpartum

haemorrhage and liver transplantation(13). Overall VE assays are quicker than SLT’s(2, 11).

VE assays detect hyperfibrinolysis(11), the hallmark of coagulopathy in many catastrophic

situations. VE assays have the ability to detect all facets of clot formation and breakdown(11);

SLT’s do not.

VE assays are also cost-effective when compared to SLT’s in the trauma population(2).

However, VE assays did not show any improvement to clinical outcome in trauma, cardiac

surgery or PPH(2) and several limitations are outlined. Ultimately more robust research is

necessary to identify VE assays’ true potential.

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11. Pham, H, Shaz, B (2013). Update on massive transfusion. British Journal of

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ROTEM® or TEG® validated. Scandinavian Journal of Clinical and Laboratory Investigation.

76(6): 503-7.

14. Gorlinger, K, Fries, D, Dirkmann, D et al. (2012). Reduction of Fresh Frozen Plasma

Requirements by Perioperative Point-of-Care Coagulation Management with Early Calculated

Goal-Directed Therapy. Transfus Med Hemother. 39: 104-13.

15. Sibylle, A, Kozek-Langenecker, A (2013). Management of severe perioperative

bleeding. Guidelines from the European Society of Anaesthesiology. Eur J Anaesthesiol. 30:

270-382.

16. Gorlinger, K, Dirkmann, D, Hanke, A (2013). Potential value of transfusion protocols

in cardiac surgery. Curr Opin Anesthesiol. 26(2): 230-43.

17. Walsh, M, Thomas, S, Howard, J et al. (2011). Blood Component Therapy in Trauma

Guided with the Utilization of the Perfusionist and Thromboelastography. The Journal of Extra

Corporeal Technology. 43: 162-7.


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18. Chin, T, Moore, E, Moore, H et al. (2014). A prinicpal component analysis of

postinjury viscoelastic assays: clotting factor depletion versus fibrinolysis. Surgery. 156(3):

570-7.

19. Spahn, D. (2014). TEG®- or ROTEM®-based individualized goal-directed coagulation

algorithms: don’t wait - act now! Critical Care. 18(637).

20. Einerson, P, Moore, E, Chapman, M et al. (2016). Rapid Thrombelastography

thresholds for goal-directed resuscitation of patients at risk of massive transfusion. J Trauma

Acute Care Surg. 82(1): 114-9.

21. Johansson, P, Sorensen, A, Larsen, C et al. (2013). Low hemorrhage-related mortality

in trauma patients in a level 1 trauma center employing transfusion packages and early

thromboelastography-directed hemostatic resuscitation with plasma and platelets. Transfusion.

53: 3088-99.

22. Schochl, H, Frietsch, T, Pavelka, M et al. (2009). Hyperfibrinolysis After Major

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The Journal of Trauma, Injury, Infection, and Critical Care. 67(1): 125-31.

23. Mallaiah, S, Barclay, P, Harrod, I et al. (2015). Introduction of an algorithm for

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24. Chapman, M, Moore, E, Ramos, C et al. (2013). Fibrinolysis greater than 3% is the

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26. Brohi, K, Singh, J, Heron, M et al. (2003). Acute Traumatic Coagulopathy. The Journal

of TRAUMA Injury, Infection, and Critical Care. 54: 1127-30.

27. de Lange, N, Rheenen-Flach, L, Lance, M et al. (2014). Peri-partum reference ranges

for ROTEM thromboelastometry. British Journal of Anaesthesia. 112(5): 852-9.

28. Armstrong, A, Fernando, R, Ashpole, K et al. (2011). Assessment of coagulation in the

obstetric population using ROTEM thromboelastometry. International Journal of Obstetric

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29. Collins, P, Thachil, J, (2016). For the Subcommittees on Women’s Health Issues in

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30. Huissoud, C, Carrabin, N, Audibert, F et al. (2009). Bedside assessment of fibrinogen

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31. Wang, C, Shieh, J, Chang, K et al. (2010). Thrombolastography-guided transfusion

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32. Leon-Justel, A, Noval-Padillo, J, Alvarez-Rios, A et al. (2015). Point-of-care

haemostasis monitoring during liver transplantation reduces transfusion requirements and

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33. Dalmau, A, Sabate, A, Aparicio, I (2009). Hemostasis and coagulation monitoring and

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34. Connelly, C, Van, P, Hart, K et al. (2016). Thrombelastography-Based Dosing fo

Enoxaparin for Thromboprophylaxis in Trauma and Surgical Patients. A Randomised Clinical

Trial. JAMA Surgery. 151(10) doi: 10.1001/jamasurg.2016.2069.

35. Nag, I, Datta, S, De, D et al. (2017). Role of thromboelastography in the management

of snake bite: A case report from India. Transfus Apher Sci. 56(2): 127-9.


28

Table 1: TEG variables, meaning and treatment of abnormalities

Variable Acronym ROTEM

comparison

Measures Correlates to Value Abnormality

treated with

Clinically

validated

Reaction time †R-time From beginning to clot and fibrin

formation. Reflects coagulation cascade

enzymatic activity(10,17)

Analagous to INR/PT &

APTT(4)

Minutes FFP(17)

Yes(10)

Activated clot time

(Rapid-TEG only)

†ACT CT (clotting

time)

Time taken for tissue factor to activate

clot formation(10, 18, 19)

Coagulation factor

activity and thrombin

generation(18)

Seconds FFP(20) Yes(10)

Angle Rate of clot strength increase and

formation(18, 19, 20)

Fibrinogen concentration

and function(18, 20)

Degrees Cryo(17) or

fibrinogen

concentrate(4)

Yes(10)

Maximum amplitude MA MCF

(maximal

clot

firmness)

Greatest clot strength(18, 19) the widest

width of the TEG(4). Due to function

and number of platelet-fibrin bonding(17)

Platelet count and

function and platelet-

fibrinogen interaction(18,

20)

mm

Platelets(17, 20)

Yes(10)

Lysis at 30 minutes LY 30 CL 30 Percentage of clot lysis at 30mins after

MA(10, 17, 18, 19, 20)

Fibrinolysis (18, 20)

30 minutes TXA(17, 20) Yes(10)

Coagulation Time k-time Occurs at the same time as angle. Angle

has superseded K-time(4)

† R-time and ACT measure the same haemostatic period (factor activation and thrombin)(4)


29

Table 2: Complications associated with MTP

Complication Reason

Generic complications Transfusion reactions(15)

Immunological reactions(15)

Infection(15)

Air embolism(15)

Transfusion associated circulatory overload(8, 15)

Bacterial contamination(3)

ABO incompatibility reactions(3, 8)

Transfusion related acute lung injury (TRALI)(3, 13)

Hyperkalaemia, (non-crush

trauma)

PRBC’s potassium (K+) concentration increases with storage duration(13) due to lysis and/or irradiation(15).

Hypokalaemia Multifactorial; ATPase pump dysfunction, citrate within the PRBCs, aldosterone/ADH/Catecholamine release(13), K+ uptake

into transfused RBC’s(13, 15)

Hypocalcaemia Due to citrate binding to calcium and magnesium(3, 7, 15). The rate of infusion is proportional to the hypocalcaemic effect(7).

Hypomagnesemia Magnesium deplete fluids and citrate binding to magnesium(13, 15).

Acid-base disturbance Acidosis

Frequent post MTP(14). Due to hypoperfusion, liver dysfunction, citrate overload(7, 13, 15) and 0.9% saline infusion(13). pH <7.2

impairs coagulation(7).

Alkalosis

Metabolic alkalosis due to citrate overload(15).

TRALI Leading cause of transfusion related fatalities(3)

Two theories;

1. Passive transfer of antileukocyte antibodies from the donor(3, 8, 13).

2. Biological response modifiers that accumulate during storage(13).

FFP is the most common blood product to cause TRALI(7, 8).

Dilution of clotting factors Dilution of clotting factors by IV fluid administration (15).

Hypothermia

Frequent(14), due to cold fluids/blood products/open body cavities/decreased heat production/impaired thermal control(15).


30

Table 3: Factors contributing to TIC

Factor

Hypothermia(24)

Acidosis(13)

Tissue injury(13)

Hypoperfusion(13, 24)

Dilution(2, 13, 24)

Clotting factor consumption(2, 13)

Platelet consumption(13)

Tissue damage(15)

Anaemia(15)

Hyperfibrinolysis(24)

Hormonal or cytokine induced changes(2)

Table 4: Table of abbreviations

POC Point of care

VE Viscoelastic

ROTEM Rotational thromboelastometry

TEG Thromboelastography

OR Operating room

SLT Standard laboratory tests

INR International normalised ratio

PT Prothrombin time

APTT Activated partial thromboplastin time

OLT Orthotopic liver transplantation

PPH Post-partum haemorrhage

TIC Trauma induced coagulopathy

ED Emergency department

MTP Massive transfusion protocol

ISS Injury Severity Score

FFP Fresh frozen plasma

TXA Tranexamic acid

Cryo Cryoprecipitate


31

CHAPTER 2

Title: Systematic review of coagulopathy in cytoreductive surgery and hyperthermic

intraperitoneal chemotherapy patients.

Short title: Coagulopathy in cytoreductive surgery patients

Authors: Dr Gary Sharp1 BSc (Hons), MBBS (Hons)

Dr Daniel Steffens1,2 BPhty (Hons), PhD

A/Prof Christopher Young1,3,4 MBBS (Hons), MS, FRACS

Affiliations:

1. Surgical Outcomes Research Centre (SOuRCe), Royal Prince Alfred Hospital, Sydney,

Australia.

2. Faculty of Medicine and Health, The University of Sydney, Sydney, Australia.

3. Department of Colorectal Surgery, Royal Prince Alfred Hospital, Sydney, Australia.

4. RPA Institute of Academic Surgery, Royal Prince Alfred Hospital, Sydney, Australia.

Corresponding Author: Gary Sharp

Address: Surgical Outcomes Research Centre (SOuRCe), PO Box M157, Missenden Rd.

Camperdown. NSW. Australia.

Tel: + 61 2 9515 3200

Fax: + 61 2 9515 3200

No funding has been applied for or used during this research project.


32

Original systemic review article.

This is not based upon any previous communications.

Abstract

Introduction

Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC)

procedures are prone to several perioperative complications. Coagulopathy has been

recognised within this population for many years. The exact cause of CRS/HIPEC associated

coagulopathy is unknown as is the incidence and perioperative outcomes.

Methods

Systematic review of literature from database inception to April 2020 (Medline, PubMed,

Cochrane, Embase). Search terms used: Coag*, cytoreductive surgery OR cytoreductive

surgery, HIPEC OR Hyperthermic intraperitoneal chemotherapy OR Heated intraperitoneal

chemotherapy. Eligible studies included the investigation of: incidence/prevalence/reported

occurrence and outcome of coagulopathy in CRS and HIPEC patients. Descriptive analysis

was performed to provide summative figures of the included studies.

Results

Database search located 120 articles, 14 met inclusion criteria. No randomised controlled trials

or systematic reviews were identified. All research was published between 2008-2019 with a

total of 1493 patients. Thirteen articles reported the presence of deranged clotting through

varying tests and definitions; of these, three authors reported a return to the operating theatre

due to bleeding. No direct mortalities associated with abnormal bleeding were documented.

The cause of coagulation was classified as multifactorial.


33

Discussion

Coagulopathy incidence ranged from 4-80% but was inadequately documented within the

literature. No consensus exists within the reviewed literature on the definition of coagulopathy

in CRS/HIPEC patients. The use of a standardised coagulopathy definition should be utilised.

From the 1493 patients reviewed 8 required reoperation for bleeding (0.5%). Eight studies

utilised epidural analgesia (N=786). Two studies reported delay in epidural removal due to

abnormal clotting and platelet tests, all were subsequently removed without issue. No other

epidural complications were documented.

Conclusion

A large proportion of CRS/HIPEC patients have deranged clotting tests perioperatively,

however, this review has failed to find a significant level of morbidity attached.


34

Introduction

Cytoreductive surgery (CRS) is the surgical resection of macroscopic malignancy and can

involve several intrabdominal procedures (1). CRS has been shown to benefit those presenting

with pseudomyxoma peritonei (2) and selected peritoneal carcinomatosis (1,3).

Heated/hyperthermic intraperitoneal chemotherapy (HIPEC) is the continued turbulent

perfusion of a heated cytotoxic agent into the abdominal cavity, at a temperature of 41-43

degrees celsius (4-7). Hyperthermia results in greater drug uptake by malignant cells, protein

synthesis and mitosis arrest in malignant cells, induction of lysosomal enzymes and accelerates

malignant cell death (5). Contact of cytotoxic agents with the visceral surface ensures a high

concentration with low systemic absorption and elimination of microscopic disease (3,8).

HIPEC should be carried out immediately after CRS but prior to anastomoses formation (9)

and has visceral surface penetration up to 5mm (5). The heat and chemotherapy agents act

synergistically to eliminate malignancy (5). The chemotherapy agent and the time period for

HIPEC perfusion depend on tumour histology (10).

Although CRS and HIPEC has been proven beneficial in the population outlined above it has

also been associated with numerous perioperative physiological disturbances (4,11) and

complications (12). Perioperative coagulopathy is one such disturbance documented in many

studies (3,4,13-17). Coagulopathy has gained recognition as a cause of surgical mortality in

recent times. The impact of coagulopathy is most apparent in trauma (18). Coagulopathy must

be identified and treated in order to control intraoperative haemorrhage (15) and the potential

complications due to blood and blood product resuscitation such as transfusion reactions,

immunological reactions, circulatory overload(19,20) and transfusion-related acute lung injury

(TRALI)(21, 22) to name but a few. Haemorrhagic shock accounts for 80% of intraoperative


35

deaths(23). Perioperative analysis of coagulation and haemoglobin is paramount in managing

pathological states arising from haemorrhage. A high proportion of those few CRS and HIPEC

patients who return to the operating theatre (OT) do so due to haemostatic problems (3,14,24).

The cause of the coagulopathy in CRS and HIPEC is multifactorial (17). Suggested operative

causes include long operating times (6,8,13,25,26), large surface area of raw tissue exposed

post-resection (6,8,27), blood loss (5,6,8,15,24,25,26), protein loss (3,6,9), high fluid

exchanges and temperature fluctuations (3,5,6,8,13,15-17,27). Chemotherapy also affects

coagulation through side effects such as acidosis (17) and myelosuppression (9). Lastly,

malignancy malnutrition, with its associated protein loss, also contributes to coagulopathy (17).

All CRS patients are evaluated preoperatively for their suitability and robustness to undertake

such a procedure including a focussed evaluation of their bleeding risk(21). Intraoperative

monitoring includes diligently recording blood loss, organ perfusion, haemoglobin

concentration and coagulopathy(21).

The aim of this systematic review is twofold. Firstly, to investigate the incidence of

coagulopathy in patients undergoing abdominal CRS and HIPEC. Secondly, to investigate the

perioperative outcome of coagulopathy on this patient population.

Methods

Protocol

The protocol of this systematic review followed the Preferred Reporting Items for Systematic

Reviews and Meta-Analyses Protocols (PRISMA-P) guidelines (28). This manuscript also


36

followed the PRISMA Statement (29). No institutional review board approval or consent was

required.

Search strategy

A sensitive literature search was conducted on MEDLINE, PubMed, Cochrane and Embase

databases from inception to April 2020. The search was limited to English language and

humans. The search terms used were Coag* (1), cytoreductive surgery OR cytoreductive

surgery (2), HIPEC OR Hyperthermic intraperitoneal chemotherapy OR Heated intraperitoneal

chemotherapy (3). These searches were then combined #1 AND #2 AND #3. References of

included articles and review articles were hand-searched to ensure the search was

comprehensive.

Study selection

Peer-reviewed articles investigating CRS, HIPEC and any reference to coagulation were

selected. Eligible studies should include the investigation on at least one of the following;

incidence/prevalence/reported occurrence and outcome of coagulopathy in CRS and HIPEC

patients. We excluded commentaries, editorials, abstracts, case reports, professional practice

reviews and articles that focussed on a device or system.

Data extraction and critical appraisal

A data extraction sheet was used by two independent reviewers (GS, CY) to extract data from

studies. This data included: demographic details, country, methodology, neoplasm, peritoneal

carcinomatosis index (PCI), surgical time, HIPEC regime used, thoracic epidural insertion,

fluid regime, body temperature, venous thromboembolism (VTE) protocol, length of stay,

mortality, definition of transfusion triggers, transfused volumes intraoperatively, coagulation


37

tests used, incidence of coagulopathy and the outcome of coagulopathy. Disagreements within

the data extraction was resolved between the review authors.

Statistical analysis

Descriptive analysis was performed to provide summative figures of the included studies. For

continuous data, range, median and mean have been reported.

Results

Study selection

Search of databases yielded: Embase 58, Medline 22, Pubmed 27, Cochrane 13. A total of 120

articles were found. Of these, 14 met the inclusion and exclusion criteria and were included in

the review (Figure 1).

Study characteristics

There were no randomised controlled trials or systematic reviews identified. Of the 14 articles

included, 5 were prospective cohort studies and 8 were retrospective cohort studies and one

had mixed retrospective and prospective groups. The majority of the studies were undertaken

in European institutions (n=6), with the remaining undertaken in USA (n=3), England (n=2),

Australia (n=1), Canada (n=1) and Singapore (n=1). All the included research was published

between 2008-2019 (Table 1).

Patient Characteristics

A total of 1493 patients from the 14 studies were included in the review. Gender was reported

in 12 (86%) studies and female patients accounted for 62% (n=865). Age ranged from 14 to 81

years with an overall mean of 54.3 years (Table 1).


38

Malignancy type, PCI and operating time

Eleven studies (79%) reported malignancy type treated in 1213 patients. In descending order

these were; appendiceal 397 (33%), colorectal 246 (20%), pseudomyxoma peritonei 219

(18%), mesothelioma 118 (10%), ovarian 115 (9%), other/unknown 62 (5%), upper

gastrointestinal (UGI) 19 (2%), desmoplastic 17 (1%), “primary peritoneal” 8 (0.7%),

pancreatic 6 (0.5%), sarcoma 4 (0.3%), uterine 2 (0.2%). PCI was recorded in 10 studies (71%)

with the mean ranging from 8-25. Operating time was recorded in 12 studies (86%), the mean

operating time in these was 485.3 minutes (Table 1).

HIPEC, Thoracic epidural use and body temperature

Eleven studies (79%) reported HIPEC agent administered. Mitomycin was the most commonly

employed. Four studies (29%) focussed solely on the use of epidural catheters in CRS/HIPEC

patients (12,15,16, 27). However, epidural analgesia was used in 8 studies (57%), although two

reported only a percentage of their sample receiving such pain management 72% and 61%

respectively (8,27). Body temperature, a core component of coagulation, was poorly

documented with only 3 studies (21%) supplying data (Table 2).

VTE prophylaxis

Two studies (14%) used heparin for venous-thromboembolism (VTE) prophylaxis (3,26), 3

(21%) used low molecular weight heparin (LMWH) (4,7,11), 1 (14%) utilised both LMWH

and heparin (13), 1 used Dextran (24) and 1 prescribed Dalteparin (27). The remainder (43%)

did not document their VTE guidelines.

30-day Mortality and length of stay


39

From the total of 1493 patients 8 (0.6%) 30-day mortalities were recorded in 3 studies and

ranged from 0.5%-2.3% (7,16,26). Length of stay ranged from 7-188 days (Table 2).

Blood product transfusion triggers

Six authors (43%) reported packed red blood cell (PRBC) transfusion triggers. There was a

mix of clinical signs and biochemical measurements employed to guide transfusion, with

haemoglobin (Hb) of <80g/dL most commonly utilised (3,7,11,12,26). Korakianitis (2015)(15)

transfused with a Hb <90g/dL. Signs of anaemia that triggered PRBC transfusion were; sinus

tachycardia, SBP <100 mmHg, urine output (UO) <30 ml/h (26). Indication for fresh frozen

plasma (FFP) was documented in two studies (14%) both of whom used INR, not a viscoelastic

assay to define the need for transfusion (11,12). The FFP administration triggers were INR

>1.2 (11) and INR >1.5 (12). Two authors reported the trigger for platelet (PLT) administration

which was platelets <50 x109 L-1 (12,25) (Table 3).

Blood product replacement

Eleven studies (79%) reported intraoperative blood product replacement, the net sample of

these studies was 996. The number of patients who received intraoperative replacements were;

PRBC 489 (49%), PLT 37 (4%), FFP 103 (10%), cryoprecipitate 5 (0.5%), transexamic acid

(TXA) 134 (13%). Postoperative blood product replacements were reported in 4 studies (28%)

with a net sample of 308 (3,4,1,13). The number of patients who received blood product

replacement was as follows; PRBC 93 (30%), PLT 7 (2%), FFP 24 (8%), cryoprecipitate 3

(1%), no documented TXA administration. Only 1 study (8) used an irradiated cell saver.

Lastly, 1 study reported the intraoperative use of fibrinogen and specific factor products (30)

(Table 3).


40

Coagulopathy

One study focused on VTE (24) and so was removed from this sub-analysis. The remaining 13

articles reported the presence of deranged clotting within the CRS/HIPEC population. The

diagnostic test used to define coagulopathy differed between studies. Clotting studies: defined

here as international normalised ratio (INR), activated partial thromboplastin time (aPTT) and

prothrombin time (PT), were used in 8 studies (67%) (4,7,8,12,13,15,16,25,26). Rotational

thromboelastometry (ROTEM) was used in 3 studies (25%) (3,11,30) and

thromboelastography (TEG) utilised in 1 study (8%) (27). Whilst nearly all the studies

reported deranged clotting only 4 (29%) reported the incidence of coagulopathy (7,13,26,27).

Hurdle et al. (2017) (13) used clotting studies to define coagulopathy, results showed that 65

patients (38%) suffered “coagulopathy” whilst “severe coagulopathy” was encountered in 8

(4.7%). Saxena et al. (2009) (26) used clotting studies to show that 28 (12%) had impaired

coagulation. Thong et al (2017) (7) too utilised clotting studies to define coagulopathy, their

results showed that N=80 (80%) of their sample had abnormal clotting studies. Teoh et al

(2019) (27) utilised TEG to define coagulopathy in 4 (14%) between the second and fifth

postoperative days. The aforementioned 4 authors reported the following coagulation related

complications: Hurdle et al (2017) (13) recorded 3 patients required return to the operating

theatre for “bleeding complications”, no specifics given; Saxena et al. (2009) (26) reported no

complications: Thong et al (2017) (7) reported 4 postoperative bleeds requiring reoperation

between postoperative day (POD) 1 and 39, Teoh et al. (2019) reported no coagulation

associated complications. Only 1 of the remaining 9 studies reported the need for reoperation

due to bleeding (11), whilst another quoted delayed removal of 2 epidurals due to deranged

clotting (16). Nine studies (69%) reported no coagulation associated complications

(3,4,8,12,15,25-27,30). Those studies which reported the cause of coagulopathy suggested it

was multifactorial (3,4,7,8,11,13,15,16,25,26,27).


41

Discussion

The first aim of this systematic review was to investigate the incidence of coagulopathy in

patients undergoing abdominal CRS and HIPEC. As outlined above, coagulopathy incidence

ranged from 4-80% (7,13,26,27). However, the incidence of coagulopathy is poorly

documented within the literature. Most studies instead give mean values for the sample as a

whole which makes it impossible to extrapolate information regarding specific affected

individuals. The literature also has no consensus on the definition of coagulopathy. In the four

studies (7,13,26,27) that reported coagulopathy incidence each used differing definitions or

indeed did not define the definition of coagulopathy at all (7). Hurdle et al. (2017) (13) defined

coagulopathy as an abnormality of platelet count <100 x109/L, INR 1.5, or PTT 45 sec and

“severe coagulopathy” as a platelet count <50 x109/L, INR>2.0, or PTT>60 sec. Saxena et al.

(2009) (26) defined coagulopathy as an INR 1.2. Teoh et al. (2019) (27) used both clotting

studies and TEG to define coagulopathy; abnormal coagulation was defined by any one of:

platelet count <100 x109/L, INR 1.5, PTT 45. Manufacturer reference values were used as

control values for TEG parameters. Thong et al (2017) (7) gave no normal parameters, but

stated that “80% of patients had elevated PT or/and aPTT”. It is our suggestion that a

standardised coagulopathy definition be used and to categorise results; these two simple

strategies would allow the reader to evaluate the true coagulopathy incidence.

The second aim was to highlight the outcome of coagulopathy on this patient population.

Hurdle et al’s. (2017) (13) research had a cumulative number of 73 patients defined as

coagulopathic or severely coagulopathic. Three returned to the OT for “bleeding

complications”. Unfortunately, there was no further information regarding what day the

patients returned to the OT, the procedure they required or their coagulation profile prior to


42

theatre return. It would therefore be unwise if we presumed they were coagulopathic at this

point and the return to OT was due to coagulopathy. Despite such a high rate of clotting

derangement the authors interestingly reported no significant changes to PTT values.

Saxena et al. (2009) (26), explain that there were complications in 108 (44%) and 40 (16%)

returned to OT, coupled with 5 (2%) deaths within 30 days. However, no further breakdown

of this information was given so it is not possible to ascertain if these are due to postoperative

coagulopathy or another issue.

Thong et al. (2017) (7) reported 3 patients requiring a return to OT for bleeding complications.

These included postoperative day (POD) 1 diaphragmatic and pancreatic bleed requiring

laparotomy. POD 2 bleeding from a non-defined source necessitating laparotomy. POD 26

“massive” per rectal bleed requiring medical intervention and a POD 39 jejunal bleed requiring

surgical resection. Unfortunately, once again there are no individual clotting assays for these

patients and as such we are unaware of their coagulation profile at the point of bleeding and

return to OT. Regardless, evidence suggests that the coagulopathy recognised post CRS/HIPEC

peaks between 24 and 72 hours post procedure (4,13) and then returns to normal at around

POD 3 (12). If this evidence is correct then perhaps the bleeding events at POD 1 and 2 could

be attributed to postoperative coagulopathy but the POD 26 and 39 episodes of bleeding cannot.

These bleeding events and others might be iatrogenic due to VTE prophylaxis or potentially a

separate second pathological cause. Lastly, Van Poucke et al. (2018) (11) reported that 2

patients required reoperation to treat bleeding complications within the study period; no further

information was given.


43

From the entire sample included in this systematic review (n=1493) we were able to find 8

patients who required reoperation for bleeding, this equates to 0.5%. This low figure of

reoperation seems to be contrary to other authors who have suggested that return to OT

secondary to bleeding is common in this population (3,14,24).

There is great interest in the use and potential complications of epidurals in CRS patients. There

is a high level of concern expressed within the literature regarding epidural complications,

especially epidural haematomas, due to CRS/HIPEC coagulopathy. Within this review, we

included 8 studies (57%) that employed thoracic epidural analgesia (4,8,12,13,15,16,27,30).

The total sample of individuals within the literature having an epidural was 786. Complications

regarding epidurals were noted in 2 studies. Owusu-Agyemang et al. (2014) (16) reported 2

patients had a delay in epidural removal requiring platelets due to thrombocytopaenia. The

epidurals were subsequently removed without issue. Hurdle et al. (2017) (13) also noted a

delay in epidural removal due to abnormal clotting and required blood products. All epidurals

were eventually removed successfully without complication. No epidural haematomas were

documented in any study. As such the epidural complication rate in the study sample was 0.4%.

Interestingly, in one study 5 epidurals were accidentally traumatically removed in patients all

of whom had an INR >1.5 (12). No complications arose in any of these patients.

A large percentage (79%) of the studies reviewed transfused blood and blood products, whilst

TXA use is becoming more common use. However, only 4 studies used a viscoelastic assay,

either ROTEM (3) (3,11,30) and TEG (1) (27) to aid in their transfusion validation. With

such a large proportion of the studies administering blood products one could argue that the

use of viscoelastic assays may have assisted to manage appropriate administration.


44

Conclusion

Numerous articles exist regarding the potential complications perioperatively due to

coagulopathy in the CRS/HIPEC population. In this systematic review we have found no

evidence to suggest that there is a significantly high rate of bleeding complications. Thoracic

epidural use was also not associated with an increase in complications. The use of non-

standardised definitions of “coagulopathy” needs to be addressed. The use of more specific

viscoelastic assays may assist in defining coagulopathy.

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50

Figure 1. Flow diagram of study selection

Records identified through database searching

(n = 123)

Additional records identified through other sources

(n = 0)

Records after duplicates removed (n = 86)

Records screened (n = 86)

Records excluded and reasons; abstracts n = 30

Non CRS focussed n = 12 Non-English n = 9 case studies n = 4

letters n = 1 thoracic procedures n =1 chemotherapy trial n = 1

Full-text articles assessed for eligibility

(n = 29)

Full-text articles excluded, with reasons;

Professional practice reviews n = 7 Focussed on a device/system n=2

Animal study n = 1 Case report n = 1

Review of transexamic acid n= 1 Review of hemophagocytic

syndrome n = 1 Focused on colorectal metastatic

disease n = 1 Perioperative fluid review n = 1

Studies included in qualitative synthesis

(n = 14)


51

Table 1. Study characteristics

Author, year Country Study design Sample Female

sex (%)

Mean age

(range),

years

Neoplasm N %

Mean PCI

(range)

Arana, 2015 Spain Prospective

cohort

41

41

(100%)

54.5 (34-

76)

Colorectal 7 17

Ovarian 31 76

Pseudomyxoma

peritonei

3 7

12.9 (SD=9)

Cooksley, 2011 UK Retrospective

cohort

69

45

(65%)

53 (30-73)

Appendix 52 75

Colorectal 11 16

Mesothelioma 1 1

Other/unknown 3 4

Ovarian 2 3

10.5 (NR)

Fichmann, 2019 Switzerlan

d

Two armed

study;

1. Retrospectiv

e review

2. Prospective

study

106

(112

procedur

es)

63

(67%)

51 (42-59) Appendix 62 69

Colorectal 31 35

Mesothelioma 8 9

Other 11 12

8 (3-19) (retro

cohort)

10 (6-28) (pro

cohort)

Foster, 2017 USA Retrospective

cohort

81

patients

43

(35%)

58 (30-81)

Appendix 5 7

Colorectal 11 16

Mesothelioma 4 6

Other 15 22

Ovarian 12 17

Pseudomyxoma

peritonei

22 32

25 (NR)

Hurdle, 2017 Canada Retrospective

cohort

171

96

(56%)

54 (47-64)

Appendix 99 58

Colon 57 33

Mesothelioma 4 2

Ovarian 2 1

UGI 9 5

20.5 (6-34)


52

Korakianitis,

2015

Greece Prospective

cohort

51

32

(63%)

53 (23-77) Colorectal 13 26

Ovarian cancer 19 37

Pancreatic 6 12

Primary peritoneal 1 2

Sarcoma 4 8

UGI 7 14

Uterine 1 2

NR (NR)

Owusu-

Agyemang, 2014

USA Retrospective

cohort

215 121

(56%)

48 (18-75) Appendiceal 15

6

73

Colon 15 7

Desmoplastic 17 8

Mesothelioma 16 7

Other 11 5

NR (NR)

Piccioni, 2015 Italy Retrospective

cohort

101 55

(54%)

56 (23-81) Colon cancer 5 5

Mesothelioma 42 42

Ovarian 2 2

Primary peritoneal 4 4

Pseudomyxoma

peritonei

47 47

Uterine 1 1

18.8 (3-38)

Sargant, 2016 UK Prospective

cohort

201 131

(65%)

55 (NR) NR NR (NR)

Saxena, 2009 Aus Retrospective

cohort

213

(243

procedur

es)

128

(60%)

53 (SD

=12)

Colorectal 55

Mesothelioma 30

Other 22

Pseudomyxoma

peritonei

13

6

17 (SD=9)

Schmidt, 2008 Germany Retrospective

cohort

78 41

(53%)

52 (20-80) NR NR (NR)

Teoh, 2019 USA Prospective

cohort

28 17

(61%)

58 (46-70) Appendiceal 11 40

Colorectal 6 21

Mesothelioma 5 18

9.0 (0-20)


53

Ovarian 4 14

UGI 2 9

Thong, 2017 Singapore Retrospective

cohort

111 95

(84%)

52 (14-74) Appendiceal 12 11

Colorectal 35 31

Mesothelioma 8 7

Ovarian 43 38

Primary peritoneal

carcinoma

3 3

Pseudomyxoma

peritonei

11 10

UGI 1 1

14.3 (SD=8.9)

Van Poucke,

2018

Belgium Prospective

cohort

27 NR 63 (36-76) NR 15 (3-29)

PCI – peritoneal carcinomatosis index, SD – standard deviation, NR – not reported.


54

Table 2. Perioperative parameters

Author, year Mean

surgical time

(range),

minutes

HIPEC

regime

Epidural Fluid regime Mean body

temperature

degrees Celsius

(range)

VTE

protocol

30 day

mortality

(%)

Mean LOS, days (range)

Arana, 2015 309.4 (180-

550)

Cisplatinum

Mitomycin

NR Ringers lactate at

15ml/kg/h.

NR Heparin 0 (0%) 6.8 (SD=2.7)

Cooksley, 2011 525 (NR) Cisplatinum

Doxorubicin

Mitomycin

Y

(100%)

1.5% dextrose NR LMWH 0 (0%) 13 (8-36)

Fichmann, 2019 Early 510

(450-720)

Late 625 (480-

735)

Cisplatinum

Doxorubicin

Mitomycin

Y

(100%)

Crystolloids,

colloids and in the

late group 20%

albumin

NR (35-38) NR NR Early group 17 (14-25)

Late group 15 (11-20)

Foster, 2017 NR (NR) Carboplatin

Mitomycin

NR NR NR Dextran 0 (0%)

12 (NR)

Hurdle, 2017 414.2 (350-

477)

Adriamycin

Cisplatin

Mitomycin

Oxaliplatin

Y

(100%)

Crystalloid and/or

colloid

NR LMWH,

heparin

NR NR

Korakianitis,

2015

344.4 (245-

510)

Cisplatin

Doxorubicin

Gemcitabine

Mitomycin

Y

(100%)

Crystalloid NR NR NR NR

Owusu-

Agyemang, 2014

663.5 (294-

1254)

Cisplatin

Mitomycin

Oxaliplatin

Y

(100%)

Crystalloid and/or

colloid

NR NR 1 (0.5%) 38.4 (7-113)

Piccioni, 2015 568.3 (563-

574)

Cisplatinum

Doxorubicin

Mitomycin

Y

(100%)

NR NR NR NR 39.4 (7-98)

Sargant, 2016 NR NR NR NR NR NR 0 (0%) NR (NR)


55

Saxena, 2009 540 (SD=210) Cisplatin

Doxorubicin

Mitomycin

NR NR NR Heparin 5 (2.3%) NR (NR)

Schmidt, 2008 406.8 (240-

700)

NR 56 (72%) Crystalloid and/or

colloid

NR NR NR NR (NR)

Teoh, 2019 360 (304-416) NR 17 (61%) Crystalloid and

colloid

35.9 (SD=0.7) Dalteparin NR NR (NR)

Thong, 2017 550 (SD=176) Cisplatin

Mitomycin

NR Crystalloid and

colloid

Lowest mean

35.0 (SD=0.7)

Highest mean

37.4 (SD=0.8)

LMWH 2 (1.8%) 14 (7-188)

Van Poucke, 2018 493 (293-800) Cisplatin

Doxorubicin

Oxaliplatin

NR Crystalloid and

colloid

NR LMWH NR 23 (5-87)

VTE – venous thromboembolism; LOS – length of stay; NR – not reported; SD – standard deviation; LMWH – low molecular weight heparin;


56

Table 3 – Transfusion triggers and product usage

Intraoperative transfusion Postoperative transfusion

Author,

year

Clotting

assay

used

Transfusion

triggers

Product N

(patients)

Median

(units/packs)

Range Product N

(patients)

Median

(units/packs)

Range

Arana, 2015 ROTEM Hb <8g/dl 0 - - - RBC 9 2 1-3

Cooksley,

2011

Clotting

studies

- 0 - - - RBC 15 - -

Fichmann,

2019

ROTEM - RBC*

PLT*

FFP*

TXA

Fibrinogen

Factor XIII

Factors

(IX, II,

VII, X)

RBC+

PLT+

FFP+

TXA

Fibrinogen

Factor XIII

Factors

(IX, II,

VII, X)

15

4

3

0

21

6

9

9

2

5

14

30

27

6

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

Foster, 2017 - - - -6 - - - - - -

Hurdle,

2017

Clotting

studies

- RBC

PLT

FFP

76

17

27

3

1

4

2-5

1-2

2-8

RBC

PLT

FFP

63

5

23

2

1

4

2-4

1-1

2-6


57

Cryo

TXA

4

103

10

-

10-10

-

Cryo

3 10 10-10

Korakianitis,

2015

Clotting

studies

Hb <9 RBC

FFP

5

6

2

3

1-6

2-8

- - - -

Owusu-

Agyemang,

2014

Clotting

studies

- - - - - - - - -

Piccioni,

2015

Clotting

studies

Hb <8-8.5

g/dl

FFP - INR

>1.5

PLT <50 x109

L-1

RBC

PLT

FFP

78

6

-

3

1

-

0-20

1-2

-

- - - -

Sargant,

2016

Clotting

studies

Cryo -

fibrinogen <2

g L-1

PLT <50-75

x109 L-1

- - - - - - - -

Saxena,

2009

Clotting

studies

Hb <80 g/l

and signs of

anaemia

(sinus

tachycardia,

SBP <100

mmHg, UO

<30 ml/h due

to ongoing

blood loss)

RBC

PLT

FFP

Cryo

186

-

-

-

4

0

4

0

0-43

0-20

0-40

0-50

- - - -

Schmidt,

2008

Clotting

studies

- RBC litres

(L)

FFP (L)

21

35

6

0.6L

1.2L

0.4L

0.3-1.5L

0.6-3.2L

0.2-1.0L

- - - -


58

Irradiated

cell saver

blood (L)

Teoh, 2019 TEG - RBC

PLT

FFP

TXA

8

1

3

17

-

-

-

-

713 ±

374mls

244MLS

1003 ±

1065

mls

-

- - - -

Thong, 2017 Clotting

studies

Hb 8-

10mg/dL and

“… clinical

estimation of

blood loss…”

RBC

PLT

FFP

Cryo

87

7

21

1

1089 mls

(mean)

476 mls

(mean)

604 mls

(mean)

150 mls

250-

3129mls

200-

1000mls

241-

1000mls

-

- - - -

Van Poucke,

2018

ROTEM Hb <8±10

mg/dL and

“… clinical

estimation of

blood loss …”

FFP - INR

>1.2

RBC

PLT

FFP

4

0

3

-

-

-

-

-

-

RBC

PLT

FFP

6

2

1

-

-

-

-

-

-

- = not reported; Hb – haemoglobin; g/dL – grams per decilitre; *this study had an early* and late group+ – the early group comprised of patients

treated prior to the enrolment of an anaesthetic care pathway, those who received this anaesthetic care pathway are termed the late group, PRBC

– packed red blood cells, CCU – coronary care unit; FFP – fresh frozen plasma; PLT – platelets; Cryo – cryoprecipitate; TXA – transexamic

acid;


59

CHAPTER 3

Title: A pilot study to investigate the role of thromboelastography in cytoreductive surgery and

hyperthermic intraperitoneal chemotherapy patients

Short title: Thromboelastography in cytoreductive surgery patients

Authors: Dr Gary Sharp1 BSc (Hons), MBBS (Hons)

Dr Rebecca McNamara2 MBBS, FANZCA

Dr Neil Pillinger2 MB BCh MSc, FANZCA

Dr Daniel Steffens1,3 BPhty (Hons), PhD

Dr Nabila Ansari1,4,5 MBBS (Hons), FRACS

Dr Daniel Oh3 MBBS (Hons)

A/Prof Christopher Young1,4,5 MBBS (Hons), MS, FRACS

Affiliations:

1. Surgical Outcomes Research Centre (SOuRCe), Royal Prince Alfred Hospital, Sydney,

Australia.

2. Department of Anaesthesia, Royal Prince Alfred Hospital, Sydney, Australia.

3. Faculty of Medicine and Health, The University of Sydney, Sydney, Australia.

4. Department of Colorectal Surgery, Royal Prince Alfred Hospital, Sydney, Australia.

5. RPA Institute of Academic Surgery, Royal Prince Alfred Hospital, Sydney, Australia.

Corresponding Author: Gary Sharp

Address: Surgical Outcomes Research Centre (SOuRCe), PO Box M157, Missenden Rd.

Camperdown. NSW. Australia.


60

Tel: + 61 2 9515 3200

Fax: + 61 2 9515 3200

No funding has been applied for or used during this research project.

Original research article.

This is not based upon any previous communications.

Key words

Thromboelastography, TEG, cytoreductive surgery, HIPEC

ABSTRACT

Introduction

Cytoreductive surgery (CRS) is the surgical excision of macroscopic malignancy whilst

hyperthermic intraperitoneal chemotherapy (HIPEC) is the perfusion of a heated chemotherapy

agent directly into the peritoneal cavity to remove microscopic malignancy. CRS/HIPEC is

associated with abnormal coagulation, as noted through standard laboratory tests. TEG is a

viscoelastic (VE) assay that analyses whole blood coagulation. This pilot study will evaluate

TEG parameters in CRS/HIPEC patients in order to identify a clearer cause/ pattern of

coagulopathy.

Methods

Prospective observational single centre pilot study. Fifteen patients, >18 years old and have no

known deranged liver function tests or coagulation disorders undergoing a general anaesthesia

for CRS/HIPEC. Three TEG samples were taken, the first at point of incision (baseline),

second pre-HIPEC and the third post-HIPEC. Differences were calculated using Wilcoxon


61

Signed Rank Test. Differences in baseline, pre HIPEC and post HIPEC TEG scores according

to TXA, PCI and surgical time were calculated using Mann-Whitney U Test.

Results

No bleeding complications were observed. A significant difference was seen in CK R values

between baseline, pre and post HIPEC (P 0.004). CKH R time was also significant (P 0.002).

All other results were not significant. All median results were within normal range. Univariant

analyses of TXA, PCI and surgical time showed no statistical significance. No epidural

complications were observed.

Discussion

The results revealed that there was a significant difference between CK R values throughout

the three tests. Although, clinically they were irrelevant. Only minor abnormal inter quartile

ranges were found, all other results were normal. No detrimental clinical outcome was

encountered in anyone with abnormal TEG results. Despite reservations expressed in studies

concerning thoracic epidural use due to potential bleeding complications we had no epidural

complications within our sample.

Conclusion

This pilot study has shown no detrimental coagulopathy. TEG results showed clinically

insignificant disturbance to coagulation pathways during our studied time period.


62

Introduction

Cytoreductive surgery (CRS) is a term encompassing numerous intra-abdominal surgical

procedures/resections to remove macroscopic malignancy (1). Evidence suggests that CRS is

beneficial in peritoneal mesothelioma (2), metastatic peritoneal malignancies (3),

pseudomyxoma peritonei (4) and some ovarian malignancies (5). Heated/hyperthermic

intraperitoneal chemotherapy (HIPEC) is the continuous perfusion of a heated chemotherapy

agent directly into the peritoneal cavity via a circuit (6). The role of HIPEC is the elimination

of microscopic malignant cells after the macroscopic removal of malignant tissues through

CRS (7). The chemotherapy agent is heated due to its synergistic action in eliminating

malignant cells (6).

Prior to CRS, the multidisciplinary team will attempt to calculate the peritoneal cancer index

(PCI) through imaging (8). PCI can also, if achievable, be evaluated preoperatively via

diagnostic laparoscopy (9) and then again at laparotomy. The intraabdominal disease is

assessed and given a numerical score via the PCI as first described by Sugarbaker (1996) (10).

To calculate the PCI one first divides the abdominopelvic cavity into nine regions and the small

bowel into four. Each region is then given a score (0-3) dependent upon the size of malignant

deposits found in that region (10). The total score of all of regions are calculated to give a total

out of 39 (10). The higher the PCI the worse the macroscopic disease. The hope of these

complex procedures is a complete cytoreduction.

Researchers have noted that standard laboratory tests (SLT’s): prothrombin time

(PT)/international normalised ratio (INR) and activated prothrombin time (aPTT), can become

significantly deranged in CRS/HIPEC patients perioperatively. The cause of the coagulopathy

is multifactorial (11) but potentially includes the following: loss of protein due to drainage of


63

ascites during laparotomy and extensive debulking of tissue (5-7,11-15). Several blood

disorders have been noted such as a reduction in antithrombin III levels (12), platelet count

(11,14) and generalised blood loss (5-7,11,14-18). The operative exposure required for

CRS/HIPEC is extensive, leading to heat loss but also hyperthermia during the HIPEC phase,

both temperature extremes can negatively affect coagulation (7,19). The complex procedures

involved in CRS result in lengthy operative time which in turn worsen coagulopathy

(7,13,15,17,18). Lastly, the HIPEC agents themselves have been postulated as a cause of

worsening bleeding (5,11). These potential causes are additional to the already nutritionally

deplete cancer patient (11).

The measurement of coagulation during CRS in the vast majority of institutions is with SLT’s

e.g. PT/INR and aPTT. These tests have been used in general surgery and other specialties for

decades and continue to be used despite recent evidence suggesting their poor correlation with

risk of haemorrhage (20-22). SLT’s report information about the early initiation of clotting

only (21) and have been found to be unsatisfactory in multiple surgical populations when

attempting to evaluate the bleeding patient (23). Values of these tests are calculated from

plasma, not whole blood (24,25) and as such do not evaluate numerous factors/pathways

involved in coagulation and clot formation (24). Importantly, SLT’s do not evaluate or

measure hyperfibrinolysis (26) which is abnormal amplified clot lysis, resulting in worsening

haemorrhage and culminating in coagulopathy (27).

TEG is a viscoelastic (VE) assay that analyses whole blood in order to evaluate clot formation

and breakdown (28). TEG utilises cartridges containing a patients blood to supply a graphical

representation and numerical data regarding coagulation based against normal parameters (26)

allowing rationalised blood product replacement (24,26,28). A rapid-TEG assay will give


64

results quicker, within 5-15 minutes (29), due to the addition of tissue factor which accelerates

the clotting process (25). TEG uses a torsion wire suspended in the blood to calculate the

viscoelastic clot properties, allowing near real time clot analysis (25). This has the potential for

clinicians to diagnose specific clotting deficits requiring replacement (30), guiding blood

product transfusion, maintaining coagulation equilibrium (21), reducing costs, morbidity and

mortality (30). Viscoelastic (VE) assays, which include TEG, have been beneficially utilised

in multiple surgical specialities including liver transplantation, cardiac surgery and trauma (31).

The rationale for this pilot study was to evaluate TEG parameters in CRS patients in order to

identify a clearer cause/ pattern of coagulopathy. Our aim was to highlight the TEG profile

of CRS and HIPEC patients intraoperatively which may in turn identify possible coagulation

kinetic patterns and better treatment options.

Methodology

Ethical consent was granted by the local health district research ethics and clinical governance

department (X17-0400, HREC/17/RPAH/598) for this prospective observational single-centre

pilot study. The sample size was chosen as 15, no sample size calculations were employed.

Participants had to be >18 years old and have no known deranged liver function tests or

coagulation disorders. No patients were anticoagulated preoperatively. Primary disease

pathology was not an inclusion criteria, as such, if the MDT approved the patient as an

operative candidate they were offered participation. Informed consent was gained by one of

two consultant anaesthetists (NP, RM) during the preoperative anaesthetic assessment of 15

consecutive patients. No patients refused participation.


65

The anaesthetists on the day of CRS/HIPEC were those who had gained informed consent

previously, thus ensuring continuity of care and allowing patients to ask clarifying questions.

All patients had a thoracic epidural inserted prior to their general anaesthetic with midazolam

for anxiolysis. Induction of general anaesthesia was achieved with a combination of propofol,

opioid and muscle relaxant. All patients were intubated and mechanically ventilated throughout

the procedure. Anaesthesia was maintained with either a target-controlled infusion of propofol

or inhaled sevoflurane. Once anaesthetised invasive haemodynamic monitoring was achieved

via placement of a central venous catheter and a peripheral arterial line. All patients had

received bowel preparation, were catheterised and placed in the lithotomy position with

appropriate pressure support care. Heparin (5000 IU) was administered in all patients at the

beginning of the surgical procedure one hour post thoracic epidural placement. Antibiotic cover

was given prior to skin incision. Temperature was monitored via an oesophageal temperature

probe. Normothermia was maintained via forced air warming blankets and heated fluids until

the commencement of HIPEC. Hyperthermia was minimised during the HIPEC period using

cooled fluids and forced air warmers placed on a “ambient” setting.

Once the patient was prepped and the midline laparotomy incision made, the first TEG was

taken (baseline). All blood samples were drawn from arterial lines under aseptic conditions and

analysed within 5 minutes via a Rapid TEG 6s analyser (Haemonetics Corporation, USA),

the same machine was used for all samples throughout the study. The Rapid TEG 6s was

maintained and calibrated, only TEG 6s cartridges from verified stockists were used. The

second sample (pre-HIPEC) was taken just prior to the administration of HIPEC and the last

sample (post-HIPEC) taken after completion of HIPEC but before abdominal closure.


66

The Rapid TEG 6s uses a citrated 4-chanelled cartridge to which the subjects blood is added

via the instrument itself. Each one of these channels contains several reagents and activators to

execute four tests. These are;

1. CK – citrated kaolin.

2. CRT – citrated rapid TEG, uses both tissue factor and kaolin activators. This test

also supplies the TEG-ACT (activated clotting time) result.

3. CKH – citrated kaolin with heparinase neutralises any potential effect heparin may

have on the test sample.

4. CFF – citrated functional fibrinogen test which uses a platelet inhibiting factor to

evaluate the role of fibrinogen on clot structure and strength (32).

Each sample was evaluated for CK (R, K, angle, MA, LY30, TEG-ACT), CRT (R, K, angle,

MA, LY30), CKH (R, K, angle, MA), CFF (MA). There were no missing TEG data. Baseline

demographics and surgical outcomes were summarised as median (interquartile range) or

frequency (percentage), for continuous and dichotomous outcomes, respectively. Differences

in CK, CRT, CKH, and CFF between baseline and pre HIPEC, baseline and post HIPEC and

pre HIPEC and post HIPEC were calculated using Wilcoxon Signed Rank Test. Differences in

baseline, pre HIPEC and post HIPEC CK scores accordingly to TXA (yes versus no), PCI (≤13

versus >13) and surgical time (≤9.6 hours versus >9.6 hours) were calculated using Mann-

Whitney U Test. All statistical analyses were calculated using SPSS IBM statistical Package

version 25. Statistical significance was set at p<0.05.

HIPEC agent administration depended on tumour type, previous chemotherapy exposure and

allergies. Prior to chemotherapy being added to the circuit, the crystalloid solution (2-4Litres)

was run through the system continuously until a temperature of 41 degrees Celsius was reached.


67

Chemotherapy was then added to the circuit. The apparatus delivering the HIPEC was a rollator

pump driven perfusion circuit (HT2000, ThermoChem; ThermaSolutions Inc, MN, USA).

HIPEC consisted of Mitomycin C (15 mg/m2), Oxaliplatin (350 mg/m2) or Mitomycin and

Cisplatin. These agents were perfused for 60 or 30 minutes respectively.

Results

Median age was 56 years, with the majority being female (60%). BMI was within healthy range

for all patients. The majority were ASA grade III (70%), the remainder were grade II. Primary

tumour was classified as colonic 53%, mesothelioma 20%, pseudomyxoma peritonei 20% and

appendiceal 7%. Core body temperature (measured in degrees Celsius) during the CRS stage

of the procedure had a median low of 34.9 (34.5-35.2) and a median high of 36.9 (36.3-37.2).

Temperature during HIPEC increased to a median low of 36.9 (36.2-37.2) and a median high

of 37.6 (37.3-38.0). All patients had an open colosseum during HIPEC. The majority received

Mitomycin C (60%), the remainder received Oxaliplatin (20%) or Mitomycin C and Cisplatin

(20%).

Intraoperative intravenous fluid administration comprised of mostly plasmalyte 4.8 litres (L)

median, followed by compound sodium lactate 1.2L median and finally a single patient

received 1 litre of normal saline. Four percent albumin was used in 67% with a range of 0.2-

3.0L (median 1.2L). Blood product replacement was as follows; 50% received PRBC’s with a

median of 2 units, 2 (13%) received cryoprecipitate with a median volume of 270mls, 3 subjects

received FFP with a median volume of 900mls each. TXA was administered in 67% of the

population with 13% (N-2) of those receiving a 1g dose coupled with an infusion of

125mls/hour for either 4 hours or 2.5 hours. The median TXA volume per subject was 1.73g.


68

The PCI median was 13.0 (5-27) and 90% had a CC0 score, one patient had a CC1 score.

Surgical operative time ranged between 8.3-10.1 hours with a median of 9.6 hours. The

majority were extubated in the operating theatre (OT) (70%), the remained were extubated in

the intensive care unit (ICU). All patients went to ICU and spent a median of 5 days there. All

patients were extubated by the latest day 2 (median 0.5 days). Thoracic epidural analgesia was

utilised in 100% of the sample, there were no epidural haematomas and no other complications.

Epidural removal was not hampered by coagulopathy either. The median hospital stay was 17

days. There were no 30 day mortalities. A single return to the OT was encountered for fascial

wound breakdown which required wound wash out only. There were no bleeding complications

observed.

A P value <0.05 was considered significant when analysing the TEG data (tables 2-5). There

was a significant difference seen in CK R values between baseline, pre and post HIPEC

(P=0.004) (table 2). CKH R time was also significant (P 0.002) (table 2). All other results were

not significant. All median results were within normal range. When evaluating IQR data,

several abnormalities were identified on the baseline TEG: CRT angle elevation by 1.4

degrees: CRT MA was elevated by 1.3mm; CKH R time was elevated by 1.4 minutes and the

CFF MA was elevated by 2.1 mm. All pre-HIPEC IQR data were within normal range. Post

HIPEC IQR data highlighted only one abnormality in CKH angle which was elevated by

0.8mm. Univariant analyses of TXA (received V did not receive); PCI ≤13 or >13) and surgical

time (≤9.6h or >9.6h) showed no statistically significant between any CK variables (tables 3-

5).


69

Discussion

The aim of this study was to highlight the TEG profile of CRS and HIPEC patients

intraoperatively. Our hypothesis was that if we could identify disturbances in TEG variables

subsequent blood product replacement and intraoperative management could be more specific.

The results revealed a significant difference between CK R values throughout the 3 tests

(P=0.005) coupled with CKH R time also being significant throughout the 3 tests (P=0.002).

Although these parameters were significant, clinically they are irrelevant as the baseline test

was normal and became more normal in subsequent tests.

When analysing the interquartile ranges (IQR) there were 4 minor abnormal results found

within the IQR for baseline TEGs and 1 minor abnormality in the IQR for post-HIPEC TEG

all other results were normal. The aforementioned deranged results did not have a detrimental

clinical outcome, neither did they cause a deviation in perioperative management. All median

TEG ranges were normal for all variables. Nonetheless, there were a number of other

interesting findings.

It is well known that CRS can result in vast blood loss (7,17,33), what is not currently known

is the true cause of this population’s coagulopathy (7,15). Saxena et al. (2009) investigated

preoperative and intraoperative risk factors for massive RBC transfusion within the CRS

population. (18) Their results found several significant risk factors for intraoperative bleeding,

these included operation length >9h, and PCI 16 (18). We found no significant link between

either length of surgical procedure and TEG variables or PCI and TEG variables within our

study. However, Saxena et al. (2009) did report a higher mean transfusion rate of 5.9 units per

procedure and 77% received blood (18) when compared to our results which showed only 50%

received PRBCs, similar to other research (33,34), with a median of 2 units. Therefore it could


70

be argued that their population was more morbid than ours and at higher risk of bleeding.

Regardless, the administration of PRBCs is associated with an increased morbidity and

mortality in some surgical oncology groups with the accepted principle that transfusion should

only occur when completely necessary (19,35,36).

Upon reviewing other blood product use, 20% of our sample received FFP and only 13%

received cryoprecipitate. These figures are encouraging, especially when coupled with the

normal TEG results. Some authors have suggested the pre-emptive administration of blood

products, such as FFP and/or cryoprecipitate in the hopes to treat any potential bleeding issues

before they arise (34). Piccioni et al. (2015) admitted to administering “extreme” amounts of

FFP in order to maintain an INR<1.5 in the non-bleeding CRS patient (37). Others see this pre-

emptive strategy as unwarranted and argue product replacement should only be administered

when there is a clinical need (7,19). Furthermore, the administration of blood products without

a clear issue potentially puts the patient at more harm than benefit due to well-known infusion

complicatons. Our results suggest pre-emptive product replacement is not necessary.

TXA was administered in 67% of our sample. Results found no CK TEG differences between

those who received versus those who did not receive TXA. Its use appears to becoming more

common place in CRS with research focusing on its potential to reduce transfusion

requirements (17). Sargant et al. (2016) used a protocol with the proactive administration of

TXA and cryoprecipitate to investigate the effect on product transfusion (17). They

administered TXA at the start of surgery and 4 hours into the procedure, coupled with 2 pools

of cryoprecipitate once surgical haemorrhage started but before 2L of blood loss. Their

prospective study consisting of 95 patients found that pre-emptive treatment with TXA and

cryoprecipitate resulted in significantly less intraoperative PRBC, FFP and platelet transfusion


71

(17). Raspe et al. (2016) agree and state that routine TXA every 8 hours perioperatively should

be considered in the CRS/HIPEC population (19). Teoh et al. (2019) also utilised TXA in 57%

of their sample and found no TEG abnormalities in either those receiving TXA or those who

didn’t (38). Interestingly, in a recent Cochrane review focussing on the effectiveness of TXA

in reducing blood loss in CRS/HIPEC for advanced ovarian cancer they found only 1 study

that met inclusion criteria (39). Ultimately, the recommendation from this review was that there

was insufficient evidence to routinely use TXA in this population (39). It is clear these findings

cannot be extrapolated to non-ovarian malignancies being treated with CRS/HIPEC, however,

the use of TXA in further CRS/HIPEC populations is a potential area of future research.

One hundred percent of our sample underwent uncomplicated insertion and removal of a

thoracic epidural. CRS/HIPEC is a painful procedure (11) and thoracic epidural analgesia has

been referred to as the ideal analgesic choice (11). Epidural analgesia use is not solely

beneficial for analgesia in patients undergoing major abdominal surgery, it is also effective in

reducing opioid use and quicker return of normal bowel function. It has also been suggested

that epidural analgesia is a factor assisting in early extubation within the OT (33) reducing

ventilator-associated complications (40). Conversely, some suggest thoracic epidural use may

result in a higher risk of spinal haematoma in CRS/HIPEC patients due to coagulopathy (15).

The literature regarding coagulopathy and epidural analgesia highlights the potential

catastrophic complications, such as spinal haematoma and epidural abscess (5,6), however, in

this small pilot study no such issues were found, this is mirrored by the results of several other

studies (5,14,33,34). Research within the CRS/HIPEC community actually appears to highlight

the fact that thoracic epidurals are well tolerated (37). In the only other TEG study within the

CRS population Teoh et al. (2019) also found no TEG abnormalities and reported no epidural

complications (38). However, Teoh et al. (2019) unfortunately reported that >50% of their


72

sample complained of poor analgesia despite having a functional epidural in situ (38). There

are of course situations were an epidural is not appropriate such as profound coagulopathy (5)

and the removal of epidurals must be treated with as much respect as the insertion with at the

least normal SLT’s available before removal (14).

Thermal regulation is paramount in any surgical patient. Despite our best efforts temperatures

during CRS were at times hypothermic. Perioperative hypothermia, defined as a core body

temperature <36 degrees Celsius, is a common occurrence (41) especially in the CRS

population (15) but must be controlled to ensure normal coagulation (6). Hypothermia has the

ability to negatively affect coagulation and worsen blood loss (41). CRS is known to cause

hypothermia, due to multiple factors, and despite the use of heated fluids, heated air blankets

and appropriately warmed OT’s we were still unable to consistently keep the core temperature

above 36 degrees Celsius. Interestingly, it did not affect coagulation as per the TEG results.

HIPEC can lead to hyperthermia (7,11) which too must be prevented to ensure normal

coagulation (6) and inhibit unwanted systemic effects such as vasodilatation resulting in

reduced systemic vascular resistance and mean arterial pressure (11). The level of hyperthermia

was minimal in our study population with the median highest temperature during HIPEC being

37.6 with a range of 37.3-38.0 degrees Celsius.

Despite several authors suggesting the use of TEG and other VE assays to assist in CRS and

HIPEC periopeartive management (6,7,11,19,34) we have not found this to be the case. Due to

the nature of this pilot study the sample size is small and findings cannot be extrapolated to the

wider community. TEGs can be time consuming to carry out, they are an added cost (42) to

an already expensive procedure and they are not warranted for all CRS patients (42). Perhaps


73

carrying out TEG studies post operatively may highlight further coagulopathy especially in

light of most authors stating their clotting derangement peaked between 24 (19,40) and 48

hours (13,43). Although this study has not highlighted any coagulopathy in our sample the

CRS/HIPEC team must remain vigilant to possible coagulopathy.

Conclusion

This pilot study has shown no detrimental coagulopathy. TEG results showed clinically

insignificant disturbance to coagulation pathways. Regardless, coagulopathy in CRS/HIPEC

patients can cause greater morbidity and mortality and must be recognised and acted upon,

TEG or a similar viscoelastic assay may be beneficially in such patients.

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Table 1. Baseline characteristics

Age 56.0 (44.0 to 71.0)

Sex

Female 9 (60%)

Male 6 (40%)

BMI 29.3 (25.9 to 30.8)

ASA score

II 4 (30%)

III 11 (70%)

Temperature during CRS

Lowest 34.9 (34.5 to 35.2)

Highest 36.9 (36.2 to 37.2)

Temperature during HIPEC

Lowest 36.9 (36.2 to 37.1)

Highest 37.6 (37.3 to 38.0)

Intravenous fluid administration

(litres)

Compound Sodium Lactate 1.2 (0-5)

Plasmalyte 4.8 (0-8)

Saline 1 (0-1)

4% albumin 1.2 (0.2-3.0)

RBC received

Yes 8 (50%)

No 7 (50%)

RBC (units) 2.0 (1.0 to 3.0)

Cryoprecipitate received 13%

Cryoprecipitate (mls) 270 (240-300)

FFP received 20%

FFP (mls) 900 (540-1350)

TXA received

TXA infusions

TXA no infusion

67%

13%

54%

TXA (g) 1.73 (1.0 to 2.0)

Primary tumour

Colonic 8 (53%)

Mesothelioma 3 (20%)

Pseudomyxoma Peritonei 3 (20%)

Appendiceal 1 (7%)

PCI 13.0 (5.0 to 27.0)

HIPEC agent

Mitomycin 9 (60%)

Oxaliplatin 3 (20%)

Mitomycin and Cisplatin 3 (20%)

Surgical time, hours 9.6 (8.3 to 10.1)

CC score

CC0 14 (90%)

CC1 1 (10%)


82

Place of extubation

ICU 5 (30%)

OT 10 (70%)

Days intubated 0.5 (0-2)

ICU stay, days 5.0 (3.0 to 7.0)

Hospital stay, days 17.0 (13.0 to 22.0)

Data presented as median (interquartile range) or frequency

(percentage).


83

Table 2. TEG results

Variables Normal

range

Baseline Pre HIPEC Post HIPEC P value

CK

R (min) 4.6-9.1 (min) 7.4 (6.8 to

9.8)

6.5 (5.7 to

7.3)

5.7 (4.5 to

7.4)

0.004

K (min) 0.8-2.1 (min) 1.4 (0.9 to

1.8)

1.2 (0.9 to

1.8)

1.1 (0.8 to

1.4)

0.508

Angle (deg) 63-78 (deg) 71.1 (68.3 to

76.7)

74.2 (68.0 to

77.9)

74.8 (72.2 to

78.0)

0.622

MA (mm) 52-69 (mm) 63.3 (58.8 to

67.7)

63.5 (59.4 to

68.6)

61.5 (57.6 to

68.5)

0.883

LY30 (%) 0.0-2.6 (%) 0.1 (0.0 to

0.5)

0.0 (0.0 to

0.0)

0.0 (0.0 to

0.1)

0.018

TEG-ACT

(sec)

82-152 (sec) 116.0 (116.0

to 134.0)

125.3 (116.0

to 134.7)

125.3 (116.0

to 153.4)

0.477

CRT

R (min) 0.3-1.1 (min) 0.7 (0.7 to

0.9)

0.8 (0.7 to

0.9)

0.8 (0.7 to

1.1)

0.477

K (min) 0.8-2.7 (min) 1.1 (0.8 to

1.4)

1.3 (0.9 to

1.5)

1.3 (1.1 to

1.8)

0.053

Angle (deg) 60-78 (deg) 76.0 (74.1 to

79.4)

72.9 (70.1 to

77.4)

72.9 (67.7 to

75.7)

0.026

MA (mm) 52-70 (mm) 64.2 (62.0 to

71.3)

62.2 (59.7 to

69.7)

61.7 (56.3 to

67.6)

0.192

LY30 (%) 0.0-2.2 (%) 0.2 (0.0 to

0.4)

0.0 (0.0 to

0.0)

0.0 (0.0 to

0.2)

0.007

CKH

R (min) 4.3-8.3 (min) 7.9 (6.7 to

9.7)

6.5 (5.3 to

7.5)

6.0 (4.7 to

6.7)

0.002

K (min) 0.8-1.9 (min) 1.5 (1.0 to

1.8)

1.2 (1.0 to

1.5)

1.2 (0.9 to

1.7)

0.431

Angle (deg) 64-77 (deg) 71.0 (68.6 to

75.5)

73.2 (71.7 to

76.6)

74.5 (69.5 to

77.8)

0.614

MA (mm) 52-69 (mm) 60.3 (56.0 to

67.2)

63.9 (58.7 to

68.0)

63.3 (57.8 to

67.9)

0.436

CFF

MA (mm) 15-32 (mm) 23.4 (19.6 to

34.1)

19.3 (17.8 to

30.5)

19.8 (15.9 to

26.6)

0.111

Data presented as median (interquartile range).


84

Table 3. Table showing P values for table 2

Variables Baseline x Pre

HIPEC

Baseline x Post

HIPEC

Pre HIPEC x Post

HIPEC

CK

R (min) 0.010 0.003 0.340

K (min) 0.739 0.226 0.503

Angle (deg) 0.787 0.254 0.724

MA (mm) 0.836 0.520 0.455

LY30 (%) 0.005 0.041 0.309

TEG-ACT (sec) 0.274 0.316 0.966

CRT

R (min) 0.274 0.316 0.966

K (min) 0.089 0.024 0.370

Angle (deg) 0.044 0.011 0.547

MA (mm) 0.330 0.051 0.206

LY30 (%) 0.004 0.013 0.654

CKH

R (min) 0.012 0.001 0.271

K (min) 0.175 0.440 0.754

Angle (deg) 0.281 0.663 0.724

MA (mm) 0.221 0.458 0.527

CFF

MA (mm) 0.115 0.064 0.407

A10

CRT (mm) 0.190 0.055 0.280

CFF (mm) 0.169 0.036 0.232


85

Table 3. Table showing univariant analysis of TXA and TEG

Variables Baseline Pre HIPEC Post HIPEC

CK Yes - TXA (N=10) NO TXA (N=5) Yes - TXA (N=10) NO TXA (N=5) Yes - TXA (N=10) NO TXA (N=5)

R (min) 7.4 (7.0 to 9.9) 7.4 (6.7 to 9.7) 6.3 (5.4 to 6.9) 7.1 (5.3 to 8.7) 5.6 (4.7 to 7.4) 6.2 (4.1to 7.5)

K (min) 1.5 (0.8 to 1.9) 1.3 (1.0 to 1.8) 1.1 (0.8 to 1.4) 1.6 (1.2 to 2.1) 1.0 (0.8 to 1.4) 1.3 (1.0 to 1.6)

Angle (deg) 69.9 (67.5 to 78.2) 71.9 (68.3 to 75.8) 74.8 (72.1 to 78.5) 68.2 (65.3 to 74.5) 75.6 (72.4 to 78.3) 73.2 (69.1 to 75.3)

MA (mm) 65.4 (58.8 to 68.6) 61.5 (57.4 to 65.5) 66.6 (59.8 to 70.3) 60.2 (58.2 to 64.0) 62.5 (57.4 to 68.8) 60.0 (56.1 to 63.2)

LY30 (%) 0.0 (0.0 to 0.5) 0.4 (0.0 to 0.6) 0.0(0.0 to 0.0) 0.0 (0.0 to 0.1) -- --

TEG-ACT

(sec)

116.0 (113.6 to

125.3) 134.7 (111.3 to 134.7) 125.3 (116.0 to 137.0) 125.3 (116.0 to 139.3)

125.3 (116.0 to

155.7)

116.0 (111.3 to

144.0)

Data presented as median (interquartile range). No statistical difference between groups observed.

Table 4. Table showing univariant analysis of PCI and TEG


CK PCI ≤13 (N=8) PCI >13 (N=7) PCI ≤13 (N=8) PCI >13 (N=7) PCI ≤13 (N=8) PCI >13 (N=7)

R (min) 7.4 (6.7 to 9.7) 7.4 (6.8 to 10.3) 5.8 (4.5 to 6.6) 7.1 (6.2 to 7.6) 5.2 (4.4 to 5.2) 6.2 (5.6 to 7.6)

K (min) 1.6 (0.92 to 1.9) 1.1 (0.9 to 1.8) 1.2 (0.9 to 1.3) 1.6 (0.9 to 1.8) 1.1 (0.8 to 1.7) 1.3 (0.8 to 1.4)

Angle (deg) 69.4 (67.1 to 76.9) 75.0 (68.3 to 76.7) 74.5 (736 to 77.9) 68.7 (66.6 to 77.9) 74. (67.8 to 77.4) 73.2 (72.2 to 78.3)


LY30 (%) 0.0 (0.0 to 0.8) 0.1 (0.0 to 0.5) 0.0 (0.0 to 0.0) 0.0 (0.0 to 0.0) -- --

TEG-ACT

(sec)

125.3 (116.0 to

134.7) 116.0 (106.6 to 125.3) 125.3 (116.0 to 125.3) 125.3 (116.0 to 144.0)

120.6 (116.0 to

125.3)

144.0 (116.0 to

162.7)



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Table 5. Table showing univariant analysis of surgical time and TEG


CK Surgical time ≤9.6h

(N=7)

Surgical time >9.6h

(N=8)

Surgical time ≤9.6h

(N=7)

Surgical time >9.6h

(N=8)

Surgical time ≤9.6h

(N=7)

Surgical time >9.6h

(N=8)

R (min) 7.5 (6.5 to 9.8) 7.3 (7.2 to 9.7) 6.5 (5.9 to 6.7) 6.6 (4.8 to 7.6) 4.8 (4.2 to 7.4) 6.0 (5.6 to 7.4)

K (min) 1.4 (1.1 to 1.6) 1.3 (0.9 to 2.1) 1.2 (0.8 to 1.8) 1.2 (.9 to 1.7) 1.1 (0.8 to 1.5) 1.2 (0.8 to 1.4)

Angle (deg) 71.1 (68.8 to 75.0) 71.8 (65.7 to 77.7) 74.4 (68.0 to 78.5) 74.0 (67.1 to 77.2) 75.1 (70.8 to 78.0) 74.0 (72.4 to 77.8)


LY30 (%) 0.1 (0.0 to 0.4) 0.2 (0.0 to 0.9) 0.0 (0.0 to 0.0) 0.0 (0.0 to 0.0) -- --

TEG-ACT

(sec)

116.0 (116.0 to

134.0) 116.0 (108.9 to 132.3) 125.3 (116.0 to 153.4) 120.6 (116.0 to 125.3)

125.3 (116.0 to

144.0)

120.6 (116.0 to

162.7)



87

THESIS DISCUSSION

Prior to the first cytoreductive procedures in the 1930’s, peritoneal malignant disease was

deemed inoperable with a 100% mortality. The pioneers of CRS have since slowly reduced

that mortality. Dr Paul H Sugarbaker revolutionised CRS surgery, producing complete

operative manuals for peritoneal and visceral resections which are utilised to this day. The

standardised approach to classifying peritoneal malignancy, via PCI, has culminated in

treatment being offered to those who will benefit most. PCI also allows surgeons to anticipate

those with the potential to achieve a CC0 resection.

CRS is one of the largest general surgical procedures performed today. As such the morbidity

and mortality attached are not to be taken lightly. There are a plethora of potential

complications. This thesis concentrated upon viscoelastic assay technology and CRS/HIPEC

induced coagulopathy. CRS/HIPEC coagulopathy is thought to be multifactorial (1,2), but in

reality is still poorly understood and can culminate in reoperation (3,4).

SLTs are no longer as reliable as once thought when evaluating bleeding risk and identification,

in fact they can be rather misleading especially when used in a resuscitative capacity. Focus

has instead been directed towards the use of viscoelastic (VE) assays. In chapter 1 attention

was on current evidence-based use of VE assays in the surgical population. VE’s assays, which

include TEG, are assays that use whole blood and the constituents therein to formulate a

clotting profile. This clotting profile is then represented in graphical and numerical form. Data

can subsequently be analysed to guide blood product or factor replacement. Evidence suggests

that VE assays are superior in assessing bleeding (5) and potentially reducing morbidity (6).

However, the use of VE assays is limited to a few specialist procedures currently, namely

orthotopic liver transplantation, trauma, post-partum haemorrhage and cardiac surgery, due to


88

cost and lacking evidence of their benefits elsewhere. Benefits within the subset outlined above

showed potential benefits in the rationalisation and utilisation of blood product use, which in

turn reduced allogenic exposure and reduces cost. VE assays have the unique ability to detect

hyperfibrinolysis, the marker of trauma induced coagulopathy and other coagulopathies. As

such they are able to detect abnormalities undetected by SLT’s. However, it is acknowledged

that further research into their use outside of the specialist subset of patients is required.

Following on from the findings in chapter 1, we investigated the association between

CRS/HIPEC and the related bleeding risk and coagulation derangements. No clear cause of

CRS/HIPEC coagulopathy exists currently. Most literature explains the concomitant

coagulopathy as multifactorial. In Chapter 2 a systematic literature review was carried out to

highlight the incidence, cause and impact of CRS-induced coagulopathy, the results of which

highlighted that the current incidence was difficult to calculate. There are several reasons for

this: firstly coagulopathy reporting is modest at best, the definition of coagulopathy is not

standardised within any studies.

The aetiology of CRS coagulopathy was unanimously deemed “multifactorial”. The systematic

review did not shed further light on a potential single pathophysiological cause. CRS and

HIPEC have many potential risk factors for induction of coagulopathy and one may argue that

multifactorial pathogenesis is in fact the most accurate aetiological definition. However, when

defining CRS coagulopathy there is no standardised definition, thus each author employs their

own criteria to define coagulopathy. Interestingly, most authors still use SLT results to define

their criteria for CRS coagulopathy; only 4 studies used VE assays (7-10).


89

The impact of CRS coagulopathy was also poorly reported. Due to the aforementioned and

retrospective reporting there is a paucity of information regarding the actual cause of bleeding

and return to OT. Return to OT due to “bleeding” was found in 0.5% of the sample.

Unfortunately no SLT or VE assays defined quantitatively the clotting deviation associated

with the return to OT. Thus, the return to OT may not be due to coagulopathy but in fact due

to inadequate surgical haemostasis. These results question previous suggestions that bleeding

and reoperating is common place in CRS patients (8,11,12). Ultimately the incidence of

coagulopathy was not calculated, the cause not really explained and the impact seemed

insignificant.

In light of the above, a pilot study was launched to investigate the role of thromboelastography

in cytoreductive surgery and hyperthermic intraperitoneal chemotherapy patients. Through this

prospective study, the CRS/HIPEC patients TEG results would follow their operative journey

and highlight the specific clotting deficiencies. The aspiration was to find a specific coagulation

deformity of this patient population that could be targeted by either individual clotting facets

or products to reduce the morbidity and cost associated with generalised blood product

transfusion.

Our results concluded that there was a significant difference between CK R values throughout

the three tests (P=0.005) coupled with CKH R time also being significant throughout the three

tests (P=0.002). However, clinically theses statistical findings were irrelevant as the baseline

test was normal and became more normal in subsequent tests. All median TEG ranges were

normal for all variables. Nonetheless, there were a number of other interesting findings.


90

We found no link between operative length or PCI and level of coagulopathy, unlike other

authors (4). Our blood product use was far less than others have documented. We did not

transfuse “pre-emptively” and were not led to transfuse simply by an INR unlike previous

researchers (3,13) and we did not have worse outcomes for it.

There is debate within the literature regarding the use of thoracic epidurals in CRS patients and

the potential risk of epidural haematomas due to coagulopathy. Epidural haematomas and their

sequelae can lead to spinal cord compression and ultimately paralysis. With this catastrophic

complication in mind, some anaesthetists avoid their use. Nonetheless, the debate regarding

epidural use and associated risks appears to be a theoretical one. In our review we found no

evidence of any catastrophic thoracic epidural-associated complications. In fact the most

sinister complications were delays in epidural removal reported due to deranged SLTs (14,15).

All epidurals were subsequently removed uneventfully. The overall thoracic epidural

complication rate was 0.4%, all of which were minor. All of our patients received an

uncomplicated insertion and removal of a thoracic epidural. As such the use of this powerful

analgesic adjunct should be made available to CRS/HIPEC patients.

The use of TXA has increased in recent years and was ultilised in 67% of our sample. We

found no TEG variation between those who did and those who did not receive TXA, results

mirrored by others (9). A recent Cochrane review focussing on the effectiveness of TXA in

reducing blood loss in CRS for advanced ovarian cancer concluded that insufficient evidence

exists to routinely use TXA (16). As such we would recommend not using TXA.

Temperature control of CRS/HIPEC patients is vital to inhibit coagulopathy (17). The team

struggled to maintain normothermia and indeed there were several times during the procedures


91

that hypothermia was encountered. Despite the hypothermia being clinically irrelevant without

TEG disturbance, this is an area that needs to be improved upon. To conclude, our study did

not find a significant level of TEG disturbance nor a significant bleeding risk. We concede

that our sample is small and that we focussed solely on intraoperative coagulation. It may in

fact be the case that most coagulopathy develops further in the postoperative period. The hope

is to further reduce the morbidity and mortality and as such postoperative coagulation profiling

is an area of future interest.

REFERENCE LIST


patients undergoing cytoreductive surgery and heated intraperitoneal chemotherapy (HIPEC).

World Journal of Surgical Oncology, 9:169, http://www.wjso.com/content/9/1/169.




10.1245/s10434-013-3221-1.



Peritoneal Surface Malignancy: A Multi-Institutional Experience, Ann Surg Oncol, 19:4244–

425 1 DOI 10.1245 /s10434-012-2496-y.

4. Saxena, A, Yan, T, Chua, T et al. (2009). Risk Factors for Massive Blood Transfusion

in Cytoreductive Surgery: A Multivariate Analysis of 243 Procedures, Ann Surg Oncol,

16:2195–2203. DOI 10.1245/s10434-009-0484-7.



92




6. Wikkelso, A, Wetterslev, J, Moller, AM et al. (2016). Thromboelastography (TEG) or

thromboelastometry (ROTEM) to monitor haemostatic treatment versus usual care in adults

or children with bleeding, Cochrane database of systematic reviews, Issue 8, DOI:

10.1002/14651858.CD007871.pub3.

7. Van Poucke, S, Huskens, D, Van der Speeten, K et al. (2018). Thrombin generation

and platelet activation in cytoreductive surgery combined with hyperthermic intraperitoneal

chemotherapy – A prospective cohort study. PLoS ONE 13(6): e0193657.

https://doi.org/10.1371/journal.




9. Teoh, D, Hutton, M, Else, S et al. (2019). Epidural analgesia? A prospective analysis

of perioperative coagulation in cytoreductive surgery and hyperthermic intraperitoneal


https://doi.org/10.1016/j.amjsurg.2019.01.034.



https://doi.org/10.1371/journal


93


26:3652–3662, https://doi.org/10.1245/s10434-019-07644-w.

11. Sugarbaker, P, Alderman, R, Edwards, G et al. (2006), “Prospective morbidity and

mortality assessment of cytoreductive surgery plus perioperative intraperitoneal chemotherapy

to treat peritoneal dissemination of appendiceal mucinous malignancy. Ann Surg Oncol, 13,

535-44.



intraperitoneal chemotherapy, The American Surgeon, 83,134-140.

13. Piccioni, F, Casiraghi, C, Fumagalli, L et al. (2015). Epidural analgesia for

cytoreductive surgery with peritonectomy and heated intraperitoneal

chemotherapyInternational Journal of Surgery 16 (2015) 99e106,

http://dx.doi.org/10.1016/j.ijsu.2015.02.025.



64:1144–1152. DOI 10.1007/s12630-017-0952-7.




10.1245/s10434-013-3221-1.

https://doi.org/10.1245/s10434-019-07644-w

http://dx.doi.org/10.1016/j.ijsu.2015.02.025


94

16. Kietpeerakool, C, Supoken, A, Laopaiboon, M et al. (2016). Effectiveness of

tranexamic acid in reducing blood loss during cytoreductive surgery for advanced ovarian

cancer. Cochrane Database of Systematic Reviews, Issue 1. CD011732.

DOI:10.1002/14651858.CD011732.pub2.

17. Ruetzle, K and Kurz, A (2018).Consequences of perioperative hypothermia, Handbook

of Clinical Neurology. 157:687-697, 2018.


95

APPENDICES

APPENDIX 1. PROJECT DESCRIPTION.

Version 1. 23/10/17

Author. G Sharp

Title

“A pilot study to investigate the role of thromboelastography in cytoreductive surgery (CRS)

and hyperthermic intraperitoneal chemotherapy (HIPEC) patients”

Project Team Roles & Responsibilities

Names Affiliations Positions Responsibilities of

researcher

Responsibilities of researcher

Dr Gary Sharp IAS SRMO

colorectal

surgery

Lead investigator Ethics proposal, literature

review, database creation, data

collection, data cleansing,

manuscript production,

scientific dissemination

Dr Nabila Ansari IAS Consultant

Peritonectomy

Surgeon

Associate

investigator

Literature review, data

collection, data cleansing,

expert peritonectomy surgical

review of manuscript, scientific

dissemination

Dr Rebecca

McNamara

Anae Consultant

Anaesthetist

Associate

investigator

Database creation, data

collection, expert anaesthetic

review of manuscript

Dr Neil Pillinger Anae Consultant

Anaesthetist

Associate

investigator

Database creation, data

collection, expert anaesthetic


A/Prof Christopher

Young

IAS A/Professor of

Colorectal

Surgery

Associate

investigator

Data cleansing, manuscript

production, scientific

dissemination, expert academic



96

Resources

• Resources necessary for the project to be conducted include;

o Thromboelastography (TEG) machines (already available and used routinely

in the operating theatre during cytoreductive surgery (CRS) and HIPEC

procedures) (figure 1).

o TEG cartridges to carry out the assays (already available) (figure 2)

Figure 1. TEG machine Figure 2. TEG cartridges.

• Funding/support being sought or secured

o Nil.

o TEG is supplied by the anaesthetics department as a routine test.

Background

Cytoreductive surgery (CRS) is a combination of peritonectomy procedures and visceral

resections employed to remove all macroscopic peritoneal disease. This is combined with

hyperthermic intraperitoneal chemotherapy (HIPEC) to address microscopic peritoneal


97

disease. HIPEC involves instillation of a heated chemotherapeutic agent into the abdominal

and pelvic cavities for between 30-60 minutes. HIPEC is used to treat microscopic tumour

deposits whereas surgery removes macroscopic tumour. CRS is a maximally invasive

procedure performed on appropriate patients with surgically resectable malignant disease

which has metastasised within the abdominal cavity to involve the peritoneum. CRS is usually

performed through a large midline incision (a laparotomy) running from the lower sternal edge

to the pubic bone to ensure adequate access to all quadrants of the abdomen (figure 3).

Figure 3. A laparotomy incision

Through this incision, surgeons perform a thorough examination of the peritoneal cavity and

an assessment of the extent of disease is made using the Peritoneal Carcinomatosis Index (PCI).

CRS is then performed with an aim to remove all macroscopic disease using a combination of

peritonectomy procedures and visceral resection where the extent of surgery is determined by

the volume of disease. Following CRS, HIPEC is circulated through the abdominal cavity using

a closed system and a delivery pump via an open colosseum technique (Figure 4, 5). These

procedures can be long lengthy.


98

Figure 4. Schematic of HIPEC set up.

Figure 5. Open abdomen with the HIPEC being administered.

Once CRS and HIPEC is complete, any bowel anastomoses are formed, drains inserted and the

abdomen is closed. Postoperatively, the patient is transferred to intensive care accompanied by

the consultant anaesthetist. During the surgical procedure it is not uncommon for patients to

receive blood product replacement, this has significant morbidity and cost associated.


99

We as the peritonectomy group (anaesthetist and surgeons) have noticed that all of our patients

post operatively have a level of coagulopathy as defined by their INR/PT/aPTT. There is a

great paucity of evidence in CRS and HIPEC as such no research has been carried out to define

why these patients are coagulopathic. There are many suggestions and indeed many possible

causes but as-yet we have failed to define the cause or suggest a reasonable hypothesis. What

we do know through evidence-based medicine is that greater knowledge of coagulopathy and

the benefits of point of care (POC) testing using TEG assays may benefit patients.

What is TEG?

TEG, originally known as “Harterts Instrument”, was produced in 1948 by Hartert. Used

throughout Europe in the 1950’s to identify anticoagulant effects, thrombocytopaenia and

fibrinolysis and later utilised by Americans Swan et al in 1958 during cardiac surgery. Its use

in research then commenced around 1990 and began in earnest with trauma patients and the

evaluation of trauma induced coagulopathy (TIC). TEG is a POC device that analyses clot

production, growth and breakdown. It’s performed on whole blood at the bedside allowing

quicker evaluation of in-vivo haemostasis thus guiding resuscitation. Each element of the

TEG trace correlates to a specific aspect of coagulation (figure 4).

Figure 4. A TEG trace.


100

Once the TEG is complete, clinicians are supplied with a graphical representation and assay

data regarding coagulation allowing rationalised blood product replacement. TEG works by

placing whole blood into a plastic cartridge which contains a cup; extending into the whole

blood from above is a thin torsion wire. The plastic cup then rotates at a set rate and degrees of

motion. This motion continues throughout clot formation and as fibrin strands form onto the

torsion wire it begins to move the torsion wire. These viscoelastic changes in clot property are

registered by an electromagnetic transducer which in turn is interpreted by the TEG software

and a physical trace is produced. The trace made can then be evaluated against set parameters

defined by the manufacturer. As clot lysis occurs the torsion wire is moved less allowing near

real time clot evaluation.

Perioperative analysis of coagulation and haemoglobin is paramount in managing pathological

states arising from haemorrhage. Intraoperative monitoring of patients includes diligently

recording blood loss, organ perfusion, haemoglobin concentration, unwanted effects of blood

product transfusion and coagulopathy. Standard laboratory tests (SLT’s) such as INR/PT and

PTT were originally used to diagnose bleeding disorders and subsequently used to evaluate

anticoagulants. The end-point of these tests is the first detectable fibrin level which equates to

approximately the first 20-60 seconds of clot formation. SLT’s are used routinely within

general surgery but have been shown to poorly correlate with bleeding risk and are a poor

prognosticators for haemorrhage in critically unwell patients. These time-consuming tests lack

real-time evaluation with values derived from plasma, not whole blood. They also lack

information concerning platelet function, fibrin formation, fibrinolysis and importantly

hyperfibrinolysis. Many studies suggest SLT’s are inadequate when used alone to guide

haemorrhagic resuscitation and coagulopathy. Recent evidence proposes the use of more robust


101

assays such as TEG. TEG assays are regarded as POC assays performed on whole blood

which assesses clot formation and breakdown. They are regularly utilised worldwide to guide

allogenic blood product resuscitation and define coagulopathy. Allogenic blood product

transfusion is associated with significant cost, morbidity and mortality. The ability of TEG

assays to rationalise blood product transfusion subsequently lowers transfusion complications

and costs especially in trauma, cardiac and OLT surgery.

• Rationale/Justification

o There is very little current research available of the role of using TEG in

patients undergoing CRS/HIPEC

o There is a need to better to define the extent of perioperative coagulopathy

encountered in patients with peritoneal malignancy undergoing CRS/HIPEC

o This research will hopefully lead to improved practice in CRS/HIPEC through

rationalisation of blood product replacement, by highlighting specific

coagulation issues

o This research will hopefully lead to improved practice in CRS through

rationalisation of blood product replacement, by highlighting specific

coagulation issues

• Research questions

o What is the Thromboelastography (TEG) profile of CRS/HIPEC patients

intraoperatively

• Research aims

o To identify possible patterns in TEG profiles of CRS/HIPEC patients


102

• Research objectives

o To have a greater knowledge of the coagulation profile of CRS/HIPEC

patients to aid allogenic blood product replacement which in turn will reduce

morbidity and cost

• Expected outcomes

o TEG may show a consistent pattern of coagulopathy unique to CRS patients

due to the unique insults experienced by this patient population (HIPEC and

lengthy surgery)

Project Design

• Research project setting

o Physical site – Royal Prince Alfred Hospital, Missenden Road, Camperdown,

NSW 2250.

• Methodological approach

o Patients will be consented as per normal – explanation of surgery and

possibility for blood product transfusion.

o Patients will be anaesthetised as per normal.

o CRS patients will have an arterial line inserted after induction of general

anaesthesia as per normal. Meaning no additional invasive procedures are

required.

o The arterial line will be utilised to draw off 5 mls of blood at defined time

periods from the commencement of knife to skin.


103

o These times will be at the beginning of the operation when we would usually

perform blood gas analysis, immediately pre HIPEC and at HIPEC

completion, again when we would normally perform blood gas analysis. The

final TEG would be at the end of the procedure as the patient’s epidermis is

being sutured.

o If they require additional TEG assays outside of these set times they will be

carried out and acted on appropriately by the consultant anaesthetists as per

normal.

o Routine INR/APTT/PT will be utilised as per normal at the same times as the

four TEG assays stated above.

o Blood product and fluid resuscitation will be guided by routine investigations

(INR/APTT/PT and urine output) as per normal.

o TEG is already carried out as standard in these patients so the only thing to

change will be the standardised times that they will be taken.

o The paper print-out produced by the TEG machine will be filed with the

anaesthetic notes within the confidential medical notes.

o Dr Gary Sharp will collate and enter the details of these assays into an

anonymised Excel spreadsheet which will be held on a computer in the

Anaesthetic department at Royal Prince Alfred Hospital. No information will

be taken off-site by any members of the project team.

o The rationale behind this method is to allow the peritonectomy team to

evaluate the intraoperative and postoperative coagulation profile of

CRS/HIPEC patients. This will better our knowledge of the unique

coagulation profile of these patients which in turn equates to abnormalities

anticipated and acted upon quicker.


104

• Participants

o CRS/HIPEC patients. 15 in total.

o Inclusion criteria. >18 years, CRS/HIPEC patients.

o Exclusion criteria – known deranged liver function tests, known coagulation

disorder.

• Sample size and statistical or power issues

o This is only a pilot study and asuch power issues will not be addressed. This

will of course be acknowledged as a limitation of the study.

• Participant recruitment strategies

o CRS/HIPEC patients.

o TEG is already carried out as standard in this patient population as a known

beneficial adjunct during these procedures. It is likened to taking blood from

their arterial line to check haemoglobin concentration which occurs routinely

at the standardised times defined above. As such consent will be implied.

• Timeframes

o This study will run until 15 participants have been evaluated. We estimate the

study to cease by the end of March 2018.

• Research Activities

o Participant commitment – to have four TEG readings taken at set points

outlined above from an already inserted arterial line.


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o Project duration – roughly 4 months

o Participant follow-up – none.

• Data Collection/Gathering

o We will collect four TEG assays per patient intraoperatively.

o We will collect the TEG assay print outs from the TEG machine. The

anonymised data will be added to a spreadsheet by Dr Gary Sharp. The TEG

assay print outs with be filed along with the anaesthetic charts in the patient’s

confidential medical notes.

o Impact of and response to participant withdrawal – this is a test that is already

carried out as per normal management of CRS/HIPEC patients. If any patients

explicitly refuse TEG assays, we will of course refrain.

• Data Management

o Data will be stored on a private computer owned and housed in the anaesthetic

department of RPA hospital. Data will be entered and analysed on this

computer only.

o Access to the spreadsheet data will only be made available to members of the

project group via a classified password on this single computer.

o We will use the data to produce a scientific manuscript for publication and as

a presentation for a scientific meeting.

o We will destroy the information stored on this computer after seven years.

o The information will be archived on the single computer for seven years.

• Data Analysis


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o We will analyse the data utilising the following information;

▪ Demographic information – age, sex etc

▪ Primary cause of Peritoneal Carcinomatosis (if known)

▪ Past medical history

▪ Past surgical history

▪ CRS uses a scoring system known as Peritoneal Cancer Index (PCI),

this will used to define subgroups.

▪ Duration of surgery (from knife to skin to wound closure)

▪ Organs resected

▪ Surgical complications

▪ Mean temperature

▪ Duration of HIPEC

▪ Type of HIPEC

▪ HIPEC complications

▪ Blood loss

▪ Volume replacement – e.g. albumin, crystalloid

▪ Blood products if any

▪ Haemoglobin

▪ Anaesthetic complications

▪ TEG assay parameters

▪ Date and time extubated

▪ Days in ICU

▪ Normal clotting (INR/APTT/PTT) intraoperative

▪ Calcium, magnesium, phosphate

▪ Fibrinogen level if applicable


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• For research involving an investigational device

o Approved name – Thromboelastography.

o Trade name - TEG

o Manufacturer – Haemonetics USA.

o Known adverse events – none.

o Known contra-indications or warnings – none.

o Approved by - CE marked, ISO certified and FDA approved, European and

British guidelines include TEG in their massive transfusion protocol

Results, Outcomes and Future Plans

• Plans for return of results of research to participants

o They will be made aware of the study and if they wish to be sent a copy of

results once published we will make this available free of charge.

• Plans for dissemination and publication of project outcomes

o Publication in a scientific journal.

o Presentation at a scientific conference.

• Other potential uses of the data at the end of the project

o None.

• Plans for sharing and/or future use of data and/or follow-up research

o None.


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APPENDIX 2. PATIENT INFORMATION

A pilot study to investigate the role of thromboelastography in Cytoreductive surgery (CRS)

and Hyperthermic intraperitoneal chemotherapy (HIPEC) patients.

INFORMATION FOR PARTICIPANTS

Introduction

You are invited to take part in a research study if you are about to undergo Cytoreductive

surgery with Hyperthermic intraperitoneal chemotherapy. This study will investigate if there

are any changes in blood clotting whilst you are undergoing the surgery. Blood clotting or

“coagulation” can be altered by many variables during surgery including temperature, blood

loss, fluid replacement and electrolytes. Patients with pre-existing conditions such as cancer

may also have altered coagulation. During a prolonged operation such as CRS, it is common

for your anaesthetist to periodically test how your blood is clotting in order to guide whether

blood products to assist clotting need to be administered. In the past, these blood tests needed

to be sent to the laboratory which took up to an hour to be returned. Now we are able to test

clotting at the bedside using a machine called a Thromboelastograph or TEG machine allowing

results to be available in real time.

Specific Purpose of the Study

The specific purpose of this study is to determine what is the clotting profile of patients

undergoing Cytoreductive surgery and HIPEC Intraoperatively and post operatively .

The study is being conducted by the following investigators:

• Dr Gary Sharp, Lead investigator, Colorectal Surgery

• Professor Christopher Young, Colorectal Surgery

• Dr Neil Pillinger, Department of Anaesthetics

• Dr Rebecca McNamara, Department of Anaesthetics

• Dr Nabila Ansari, Consultant CRS Surgeon

Study Procedures

If you agree to participate in this study, you will be asked to sign the Participant Consent

Form. We will ask you a few questions about your health and about any medications you

might be taking to ensure your blood is suitable for the experiment. During your operation

three blood samples (total 15mL) will be taken from a blood sampling cannula which is

placed routinely in all cases. One blood sample will be taken post operatively in the

Intensive care unit. Your anaesthetic care will then be standard care. You will have donated

blood for testing in the laboratory only, and there will be no alteration to your elective

surgery or anaesthetic at all.

Risks

Since we are taking the blood from the intraarterial cannula you will have for the anaesthetic,

there should be no additional risk or discomfort whatsoever.

Benefits


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While we intend that this research study furthers medical knowledge and may improve our

provision of blood products or transfusion management in the future, it will not be of direct,

additional benefit to you.

Costs

Participation in this study will not cost you anything, nor will you be paid.

Voluntary Participation

Participation in this study is entirely voluntary. You do not have to take part in it. If you do

decide to take part, you can withdraw at any time up until the blood sample is collected from

you without having to give a reason.

Confidentiality

All the information collected from you for the study will be treated confidentially, and only

the researchers named above will have access to it. The study results may be presented at a

conference or in a scientific publication, but individual participants will not be identifiable in

such a presentation.

Further Information

When you have read this information, Dr Pillinger or Dr Sharpe or your anaesthetist will

discuss it with you further and answer any questions you may have. If you would like to

know more at any stage, please feel free to contact Dr Gary Sharp via the hospital

switchboard 02 95156111.

This information sheet is for you to keep.

Ethics Approval and Complaints

This study has been approved by the Ethics Review Committee (RPAH Zone) of the Sydney

Local Health District. Any person with concerns or complaints about the conduct of this study

should contact the Executive Officer on 02 9515 6766 and quote protocol number _______.


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APPENDIX 3. ETHICS APPROVAL

the investigation of clotting abnormalities in

Documents