Anesthesia and Immunological and Oxidative Stress in Relation to Abdominal Cancer Surgery
Conditions: Anesthesia, Colon Cancer, Surgery
Sponsor: University of Copenhagen

Protocol:  
ANIMOX-study: Anesthesia and Immunological and 
Oxidative Stress in relation to Abdominal Cancer 
Surgery 
 
Protocol version: v6_23052019 (approved protocol will be submitted to 
clinicaltrials.org) 
 
Sponsor 
Ismail Gögenur, MD, DMSc2 
Principal investigator 
Rune Børch Hasselager, MD2 
Investigators: 
Ismail Gögenur, MD, DMSc2 
Nicolai Bang Foss, MD, DMSc1 
Steffen Jais Rosenstock, MD, DMSc3 
Michael Valentin Haugaard, MD3 
Thue Bisgaard, MD, DMSc3 
Institutions: 
1Department of Anesthesiology and Intensive Care 
Hvidovre Hospital 
Kettegård Alle 30, DK-2650 Hvidovre, Denmark 
 
2Center for Surgical Science 
Zealand University Hospital 
University of Copenhagen 
Lykkebækvej 1, DK-4600 Køge, Denmark 
 
3Department of Gastrointestinal Surgery 
Hvidovre Hospital 
Kettegård Alle 30, DK-2650 Hvidovre, Denmark 
 

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Correspondance: 
Email: runehasselager@gmail.com 
Phone: +4531104653 
 
Table of Contents 
BACKGROUND AND PURPOSE ...................................................................................................... 3 
OBJECTIVES ....................................................................................................................................................... 3 
METHODS ............................................................................................................................................ 4 
DESIGN AND APPROVALS ................................................................................................................................. 4 
STUDY SETTING ................................................................................................................................................ 4 
INTERVENTION ................................................................................................................................................. 4 
Withdrawal criteria: ..................................................................................................................................... 5 
POPULATION ..................................................................................................................................................... 5 
Study group: The “Hvidovre population”: ........................................................................................... 5 
Eligibility criteria: .......................................................................................................................................... 5 
Control group: The “Zealand University Hospital population” ................................................. 6 
BIOLOGICAL SAMPLES ................................................................................................................................... 67 
Handling of blood samples ......................................................................................................................... 7 
PRIMARY OUTCOME: ........................................................................................................................................ 7 
Blood samples .................................................................................................................................................. 7 
Quality of Recovery – 15 questionnaire ............................................................................................... 7 
GUIDELINES FOR ORAL AND WRITTEN CONSENT AND PARTICIPANT TIMELINE .................................... 7 
SAMPLE SIZE ...................................................................................................................................................... 8 
Study size ............................................................................................................................................................ 8 
RECRUITMENT TIMELINE ............................................................................................................................. 89 
DATA COLLECTION AND MANAGEMENT........................................................................................................ 9 
STATISTICAL ANALYSIS PLAN .................................................................................................................... 910 
Data analysis .................................................................................................................................................. 10 
RISKS, HARMS AND INCONVENIENCES ....................................................................................10 
PERIPHERAL BLOOD SAMPLES..................................................................................................................... 10 
QOR-15 QUESTIONNAIRES .......................................................................................................................... 10 
ETHICAL CONSIDERATIONS .................................................................................................. 1011 
RISK OF RANDOM FINDINGS ......................................................................................................................... 11 
PUBLICATION OF RESULTS ........................................................................................................................... 11 
ECONOMY ..........................................................................................................................................11 
BUDGET ........................................................................................................................................................... 11 
FUNDING .................................................................................................................................................... 1112 
INSURANCE ..................................................................................................................................................... 12 
CONFLICTS OF INTEREST .............................................................................................................12 
REFERENCES .....................................................................................................................................12 
APPENDICES ............................................................................................................................... 1615 
APPENDIX 1: STANDARD OPERATING PROCEDURE FOR ANESTHESIA TO MAJOR ABDOMINAL 
LAPAROTOMY AND LAPAROSCOPIC SURGERY AT HVIDOVRE HOSPITAL .......................................... 1615 
 
 
 

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Background and Purpose 
Colorectal cancer is a frequent type of cancer accounting for 600,000 deaths annually. 
Surgical resection remains the best treatment for long-term survival. However, studies 
suggest that events in the perioperative period can induce metastasis formation and 
tumor growth1,2,3. Tumor cells are released into the blood stream during surgery and 
the surgical stress may create a favorable environment for dissemination of tumor 
cells into distant tissue4,5,6,7,8. This is done by a cascade of pro-cancerous 
catecholamines, prostaglandins and cytokines combined with an impaired anti-
cancerous cell mediated immune response9,10,11.  
Until recently, focus on the anesthetic management of cancer patients has been 
limited. Relatively small alterations in the perioperative anesthetic management may 
play a tremendous role in tumor progression9. Optimizing anesthesia to reduce the 
surgical stress response could improve recurrence rates and long-term outcomes for 
cancer patients by inhibiting perioperative metastasis formation. Regional anesthesia 
and amide local anesthetics are suspected to calm the immunologic storm of 
prostaglandins, catecholamines and cytokines when used in the perioperative 
phase12,13,14,15,16,17,. Furthermore, volatile inhalational anesthesia is thought to 
modulate the immune system in a pro-cancerous way, while propofol may have 
opposite effects18,19,20,21,22. Many of these recent studies are statistically underpowered 
and susceptible to bias, and experts in cancer treatment and anesthesia have 
emphasized the need for further research within this specific field5,23,24. 
In this study we aim to characterize differences in the immunologic response 
to surgery between inhalational, total intravenous and epidural anesthesia. This will 
be done by analyzing blood samples obtained in the perioperative period in patients 
undergoing different modes of anesthesia. We will furthermore describe the quality of 
recovery for patients anesthetized with the different methods 
Objectives 
We hypothesize that the immunologic response to surgery and metastasis 
progression are influenced by the anesthetic technique. 
 
 

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Methods 
The study is initiated by Center for Surgical Science, Department of Surgery, Zealand 
University Hospital. It will be included in the Ph.D. studies of Rune Hasselager at 
University of Copenhagen. 
Design and approvals 
This study, initiated by Center for Surgical Science, Zealand University Hospital, will 
be a prospective cohort study. Approval from Danish Data Protection Agency and the 
Regional Committee for Health Research and Ethics is required. The study will 
require informed consent from participants.  
Permission to transfer data from the IMOX study will be obtained from the Danish 
Data Protection Agency. The trial protocol will be submitted to clinicaltrials.org 
before initiation of the trial. Manuscripts will be prepared according to the STROBE 
statement25. 
Study setting 
The study will take place at Hvidovre Hospital. This is a Danish university hospital. It 
supports 500,000 people and is one of four main emergency hospitals in Copenhagen 
Denmark. About 300 laparoscopic colon resections are performed at this facility 
every year. 
Intervention 
Participants will undergo laparoscopic colon resection for cancer. They will be 
anaesthetized according to the standard operating procedure at Hvidovre Hospital (see 
appendix 1) with the exception that no dexamethasone is administered as it could 
modulate the immune response. This includes anesthesia induction and maintenance 
with intravenous propofol and remifentanil. Patients will receive 4 mg ondansetron at 
the end of anesthesia. 
A thoracic epidural catheter will be installed preoperatively and kept for up to three 
days. After an initial bolus with bupivacaine, continuous infusion of bupivacaine and 
sufentanil will be used to maintain the epidural analgesic effect. Postoperatively the 
epidural will be paused or discontinued if it is displaced or if side effects occur. It will 
only be re-installed if there is still need of neuraxial analgesia. 
Patients will follow a standard Enhanced Recovery After Surgery (ERAS) protocol 
used at the facility.  

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Blood samples will be obtained before surgery and at four time points postoperatively 
and patient files will be assessed for adverse events within 30 days from surgery. 
Withdrawal criteria: 
Patients can be withdrawn from the study for any of the following reasons: 
 Failure to adhere to the anesthesia intervention described above- including 
failure to install effective continuous epidural anesthesia. 
 Adverse events after surgery 
 Any complication over grade 2 in Clavien-Dindo26 
classification  
 Blood transfusion 
 Deep vein thrombosis or pulmonary embolism 
 Anastomotic leak 
 Acute renal failure 
 Infection (wound infection or systemic infection) during the 
observation period. 
 After consultation patients can be withdrawn due to withdrawal of informed 
consent to participate in the study at the patients’ own request at any time for 
any reason.   
 
Population 
Study group: The “Hvidovre population”: 
We will include patients undergoing laparoscopic hemicolectomy for cancer 
scheduled for anesthesia with total intravenous anesthesia combined with epidural 
anesthesia on Hvidovre Hospital according to the intervention described above. 
 
Eligibility criteria: 
Inclusion criteria: 
1. Patients over 18 years 
2. Patients diagnosed with colorectal cancer (UICC stadium I-III) and scheduled 
for laparoscopic hemicolectomy.  
3. ASA class I-III (Classification of the American Society of Anesthesiology) 

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4. Patients scheduled for anesthesia with propofol, remifentanil and epidural 
anesthesia. 
5. Signed informed consent 
Exclusion criteria: 
1. Known immune-defects 
2. Patients undergoing neoadjuvant chemo or radiotherapy 
3. History of previous cancer 
4. Patients in immunomodulatory treatment within last 6 months 
5. Daily oral or intravenous steroid-use 
6. Patients that have undergone major surgery within one month before planned 
colon resection. 
Control group: The “Zealand University Hospital population” 
The immunological and oxidative stress in relation to abdominal surgery (IMOX) 
study is ongoing at Zealand University Hospital, Roskilde. It is a prospective 
explorative study cohort that consists of 60 patients undergoing laparoscopic 
colorectal cancer surgery. The aim of the study is to characterize the immunological 
and oxidative stress response to surgery. Outcomes similar to the primary and 
secondary outcomes of the ANIMOX-study are included in the IMOX-study. Patients 
are already included in the IMOX-study and blood samples are collected and kept in a 
bio bank.  
We will retrieve data on our main outcomes from the IMOX study in our 
analysis. Only electronic data will be used and no biologic material will be transferred 
from the IMOX project to ANIMOX. The population will be stratified according to 
anesthetic technique, which, according to the standard operating procedure, is either 
total intravenous anesthesia with propofol and remifentanil or volatile anesthesia with 
sevoflurane combined with a fast acting opioid (remifentanil or sufentanil). Patients 
anaesthetized with other techniques including epidural or other regional blocks will be 
excluded from the analysis. 
 
Biological samples 
To characterize the immunological response to surgery we obtain blood samples for 
analysis on postoperative day -1, 1, 2, 3 and 10 (or at the visit on day 10-14 where 
pathology results are given). 

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Handling of blood samples 
Blood samples will be drawn by a trained professional and analyzed immediately at 
the standard lab facilities at Hvidovre Hospital and destroyed immediately hereafter. 
The results will be accessible in Sundhedsplatformen. 
 
Primary outcome:  
The primary outcome will be changes in neutrophil to lymphocyte ratio from day 0 to 
day 1. Neutrophil to lymphocyte ratio has been linked to poor outcome after 
colorectal cancer surgery. The ratio will be estimated using absolute numbers from 
differential counts pre and postoperatively.  
Blood samples 
Standard blood samples will be obtained and analyzed immediately at each time 
point. These include Hgb, Leucocytes including a differential count, thrombocytes, 
ALAT, LDH, Alkaline phosphatase, bilirubin, INR, albumin, Na, K, Creatinine, CRP 
and Glucose. 
Quality of Recovery – 15 questionnaire 
At each time point (day -1, 1,2 and 10) the patients are asked to fill in the validated 
Quality of Recovery Questionnaire QoR-1527. The QoR-15 questionnaire results in a 
score of 0–150. These outcome measures will be correlated with changes in 
immunologic outcome measures in the perioperative period.  
Guidelines for oral and written consent and participant timeline 
The first contact with a potential participant will be either during a stable phase of the 
primary admission, during an out-patient visit or during an introduction meeting prior 
to surgery. Patients will receive both oral and written information about the study. 
Patients will be contacted and a meeting where the inclusion will take place will be 
planned. An appropriately trained investigator will give information about the study 
including potential risks, harms and inconveniences. Before this meeting, patients will 
be informed that:  
1. The patients have 24 hours or more to consider their informed consent. 
2. An observer at the meeting can accompany the patient.   

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The meeting will take place in a quiet and undisturbed room. Amended to the patient 
information will be a document from the Central Ethical Committee with the title of 
”Your rights as a test subject in a biomedical research”, which the patient will be 
recommended to read before inclusion.  
Patients will have blood samples taken at four time-points - before surgery, day 1, day 
2, day 3 and at the out-patient visit 10-14 days after surgery, where pathology results 
are given. The patient timeline is outlined in figure 1. 
Participation is voluntary and no financial compensation will be given to participants. 
 
Sample size 
Study size 
Due to the exploratory nature of this study, it is not possible to perform a valid sample 
size estimation. However, based on a pilot study of 45 patients undergoing 
laparoscopic hemicolectomy we found that the neutrophil to lymphocyte ratio 
increased 5.33 neutrophils/lymphocyte from preoperatively to postoperative day 1 
(SD 3.33). With a power of 0.8 and an alpha value of 0.05 we will be able to detect a 
50% smaller increase in neutrophil to lymphocyte ratio with 25 participants. As this 
power calculation is associated with much uncertainty we will include 30 evaluable 
patients (patients completing the study without meeting withdrawal criteria) to avoid a 
type 2 error.  
We estimate that 10-20% of included patients will meet withdrawal criteria before 
completing the study. Therefore we expect that we need to include 36 patients to 
complete the study. 
They will be compared to the patients included in the IMOX-study at Zealand 
University Hospital. 
 
Recruitment timeline 
Patients scheduled for laparoscopic hemicolectomy at Hvidovre Hospital will be 
screened for eligibility. 300 laparoscopic colon resections for cancer are performed at 
this facility each year and most of these are scheduled for total intravenous anesthesia 
with epidural anesthesia. With an inclusion rate of 50% we expect to be able to 

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include 30 participants that completes the study and does not meet the withdrawal 
criteria within 26-52 weeks. 
We expect to begin inclusion in January 2019 and to finish the trial by 31th December 
2019. 
 
 
Data collection and management 
To screen for eligibility to be included in the study we will request and obtain data on 
tumor stage, age, known immune defects, ASA-score, type of surgery, planned 
anaesthesia type and use of steroids. 
After informed consent and inclusion in the study, data on demographics 
(comorbitities, age, sex), disease stage (clinical and pathological tumor histology), 
perioperative management (anesthesia type, medication, surgical procedure) and 
adverse events up to 30 days postoperatively will be obtained from the patient file.  
Nurses at the Surgical Ward will be trained to encourage participants to fill in the 
QoR-15 questionnaires. The questionnaires will be kept with the patient in a folder 
that will be returned at the time of discharge. The patient will bring one QoR-15 
questionnaire home to fill in at day 10. This questionnaire will be returned at the 
pathology result visit at day 10-14. 
Blood samples will be taken and handled by a trained health care professional and 
brought to the laboratory for preparation and analysis within one hour.  
Patients who are discharged before blood samples are taken on day 1,2, and 3 will 
asked if they wish attend the blood sampling as out-patients at the same timepoints. 
Patients who does not show up to, or does not have the final blood samples taken at 
the time of out-patient pathology results will be contacted and encouraged to have the 
final blood samples taken and return the last QoR-15 questionnaire. 
Study data will be stored according to guidelines from the Danish Data Protection 
Agency and “databeskyttelsesforordningen” and “databeskyttelsesloven” will be 
adhered to.  
Statistical analysis plan 
Data will be analyzed using R, SAS institute or SPSS. All tests will be two-sided with 
p<0.05 considered to be significant.  

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Data analysis 
Data from the Hvidovre population and the Zealand University Hospital population 
will be combined to evaluate the effects of inhalational anesthesia (sevoflurane and 
opioid), total intravenous anesthesia (propofol and remifentanil) and total intravenous 
anesthesia (propofol and remifentanil) combined with epidural anesthesia 
(bupivacaine with opioid). Only electronic data will be used from the IMOX project – 
no biologic material will be transferred. 
Baseline and clinical characteristics for patients, stratified for anesthesia type will be 
presented as frequencies for nominal, dichotomous and ordinal variables and medians 
with IQR for continuous variables. Outcome variables will be presented and described 
with appropriate tests. Depending on whether data is normally distributed or not, 
differences between the groups will be assessed using parametric or non-parametric 
statistics, respectively.  
Risks, harms and inconveniences 
 
Patients will receive the standard care at the respective hospital. The study does not 
influence any treatment or intervention related to the hospitalization. 
Peripheral blood samples 
Blood will be drawn from puncture of the cubic vein. The needle can cause minor 
discomfort including hematoma, which will disappear within few days. 
QoR-15 questionnaires 
Filling in the QoR-15 questionnaire will require a short amount of time and effort at 
the four time points. 
Ethical considerations 
Research within this field is until now very limited, but optimization of the anesthetic 
technique used for cancer surgery can benefit millions of people undergoing surgery 
for cancer in the future.  

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Approval from the regional scientific ethical committee is mandatory. Important 
modifications in the protocol will be communicated to the committee and approved 
before implementation. 
Written consent from all participants will be obtained before inclusion as described 
above. Participants can at any time withdraw their consent. 
All personal information about enrolled patients will be collected and protected 
according to Danish Law to ensure confidentiality before, during and after the study. 
Data will only be assessed by participants of the study group according to the 
approval from the Danish Data Protection Agency. 
Risk of random findings 
We do not expect random findings that will affect participants, as the scope of this 
study is to explore mechanisms of the immune system in the short perioperative 
period. We will not perform genome or DNA analysis, which potentially could reveal 
unknown underlying genetic disease. 
Publication of results 
Results of the study will, regardless of the results, be submitted for publication in an 
international peer-reviewed medical journal. No personal data that can be directly 
linked to a participant will be published. 
Economy 
Budget 
 
DKK 
Sample collection incl. test tubes 
66,000 
Presentation of results (travel and conference fees) 
30,000 
Publication fee 
10,000 
6 months salary for Ph.D. student Rune Hasselager 
275,000 
Total 
381,000 
Funding 
The study is initiated and will be funded by Center for Surgical Science, Zealand 
University Hospital. On an ongoing basis we will apply for grants from private or 
public foundations. We have received a grant from Hesse’s Mindefond of 66,000 

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DKK for lab assistance for this project. Financial transactions and bookkeeping will 
be administered by Department of Surgery, Zealand University Hospital. 
Sources of economical support will be declared in manuscripts. 
Insurance 
Patients included in this study are covered by the insurance of Hvidovre Hospital. The 
project is included in “Patienterstatningsordningen”. 
Conflicts of interest 
None of the investigators have any conflicts of interest in this study. 
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Appendices 
Appendix 1: Standard operating procedure for anesthesia to major abdominal 
laparotomy and laparoscopic surgery at Hvidovre Hospital
 
 

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