Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12616001381471
Ethics application status
Approved
Date submitted
2/09/2016
Date registered
5/10/2016
Date last updated
20/03/2017
Type of registration
Prospectively registered

Titles & IDs
Public title
Albumin mass balance and markers of endothelial injury in pancreatic surgery
Scientific title
An observational study in two patient groups undergoing major pancreatic surgery, for benign and malignant disease respectively, assessing leakage of albumin by mass balance calculation.
Secondary ID [1] 290079 0
Nil
Universal Trial Number (UTN)
U1111-1187-1657
Trial acronym
Albumin 6
Linked study record

Health condition
Health condition(s) or problem(s) studied:
pancreatic cancer 300157 0
endothelial injury 300158 0
Condition category
Condition code
Oral and Gastrointestinal 300040 300040 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon

Intervention/exposure
Study type
Observational
Patient registry
False
Target follow-up duration
Target follow-up type
Description of intervention(s) / exposure
Patients scheduled for pancreatoduodenectomy for malignant or benign disease, respectively, will be investigated during and after surgery. At the day of surgery, baseline blood samples will be taken in the operating room as soon as the first intravascular line is inserted. Anesthesia and surgery will proceed according to unit routines including epidural block and general anesthesia. Intravenous fluids will comprise acetated Ringer’s solution and glucose, but no starch. Blood will be sampled repeatedly during surgery and up to the morning of the third postoperative day for assessment of albumin and hemoglobin balance at a maximum of 15 instances. Albumin and hemoglobin will also be measured in sponges, suction bottles, drains, administrated blood products etc. to keep track of losses and gains. Baseline plasma volume will be calculated by anthropometry.
Plasma and serum will also be sampled repeatedly for assessment of glycocalyx shedding products and markers of inflammation until the morning of the third post-operative day. The sum of all study specific blood sampling will be limited to 75 ml, approximately 1.5% of the blood volume.
Intervention code [1] 295815 0
Not applicable
Comparator / control treatment
The two patient groups (malignant and benign) will be compared regarding cumulative albumin shift from the blood, not explained by bleeding, and thus presumably into the interstitial space. There are two reasons to expect that there can be a difference: 1) capillary patency is impaired in cancer, possibly due to inflammation, causing more rapid transcapillary escape rate for albumin; 2) in the cancer patients surgical excision will be greater comprising lymph glands and vessels, possibly impairing lymphatic return and thus increasing albumin losses i.e. accumulation of albumin in the interstitium.
Control group
Active

Outcomes
Primary outcome [1] 299517 0
cumulative perioperative albumin shift, i.e. loss of albumin from the blood not explained by bleeding
Timepoint [1] 299517 0
end of surgery (compared to baseline prior to surgery when cumulative perioperative albumin shift per definition is zero)
Secondary outcome [1] 327411 0
cumulative perioperative albumin shift, i.e. loss of albumin from the blood not explained by bleeding or losses in drains. By repeated measurements of blood hemoglobin and plasma albumin, combined with meticulous assessment of gained albumin and hemoglobin in infused blood products and losses by bleeding or in drains, it is possible to compare losses of hemoglobin with losses of albumin. In a previous study albumin was lost to a higher amount i.e. the cumulative perioperative albumin shift, presumably to the extracellular space.
Timepoint [1] 327411 0
morning of postoperative day 3 (compared to baseline prior to surgery when cumulative perioperative albumin shift per definition is zero)
Secondary outcome [2] 327412 0
Time course of markers of endothelial injury (such as heparan sulphate, syndecan 1, hyalorone) measured by ELISA of EDTA-plasma samples
Timepoint [2] 327412 0
from baseline before surgery, at start of surgical reconstruction, at end of surgery, at 2-3 hours after end of surgery, in the morning of postoperative day 1, and in the morning of postoperative day 3
Secondary outcome [3] 327413 0
Time course of markers of inflammation (such as IL6, IL8, IL10) measured by ELISA in plasma samples.
Timepoint [3] 327413 0
from baseline before surgery, at start of surgical reconstruction, at end of surgery, at 2-3 hours after end of surgery, in the morning of postoperative day 1, and in the morning of postoperative day 3
Secondary outcome [4] 327414 0
Composite hypothesis generating correleations between albumin kinetic parameters , markers of inflammation and endothelial injury and indices of volume status. Albumin kinetic parameters (P-alb, plasma dilution, and cumulative perioperative albumin shift) are assessed by P-alb, B-Hb, and assessment of gains and losses of albumin and hemoglobin. Markers of inflammation and endothelial injury by ELISA of plasma samples. Volume status is assessed by gain and losses of fluids and by scale, respectively.
Timepoint [4] 327414 0
Changes from baseline until end of surgery, and until the morning of postoperative day 1, respectively
Secondary outcome [5] 327966 0
Fluid balance by keeping track of fluid gains and losses
Timepoint [5] 327966 0
Before surgery, at end of surgery, in the morning of postoperative day 1, in the morning of postoperative day 2, in the morning of postoperative day 3
Secondary outcome [6] 328111 0
Body weight by scale
Timepoint [6] 328111 0
Before surgery, in the morning of postoperative day 1, in the morning of postoperative day 2, in the morning of postoperative day 3
Secondary outcome [7] 328112 0
Plasma volume dilution, by repeated meassures of B-Hb, P-alb and gains and losses of fluids
Timepoint [7] 328112 0
Before surgery, at approximately hourly intervals during surgery and up to 3 hrs after end of surgery, in the morning of each postoperative Day 1-3
Secondary outcome [8] 328113 0
Plasma albumin by nephelometry
Timepoint [8] 328113 0
Before surgery, at approximately hourly intervals during surgery and up to 3 hrs after end of surgery, in the morning of each postoperative Day 1-3

Eligibility
Key inclusion criteria
Patient scheduled for pancreatoduodenectomy with benign and malignant diagnosis, respectively
Written informed consent
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Patients scheduled for major vascular surgery during the pancreatoduodenectomy.
Outliers, due to change in surgical procedure or profuse bleeding.

Study design
Purpose
Screening
Duration
Cross-sectional
Selection
Defined population
Timing
Prospective
Statistical methods / analysis
we aim at studying at least 12 evaluable patients in each the two study groups, but up to 40 patients can be recruited to compensate for exclusion of outliers, thus achieving more homogenous patient groups than in our previous study (Norberg et al Criit Care 2016; 20:113) when 24 +/- 17 g albumin was lost at end of surgery in patients undergoing majour abdominal surgery.
There are no published mesurements of albumin shift in the two groups of this study, but in german gynecological patients protein loss under surgery has been reported as 49 and 13 g, in malignant and benign patients, respectively (Rehm et al Acta Anaesthesiol Scand 1998; 42: 39-46).
Assuming a smaller variation, less albumin loss in the benign patient group 18 +/- 15 g and larger loss in the malignant Group 36 +/- 15 g we achieve 96% power to find a significant difference from baseline in the benign group (effect size 1.2 = difference/s.d., n=12) and 80% power to find a difference between groups as presented above (effect size 1.2). Groups will be compared at end of surgery and in the morning of postoperative day 3. If not different, groups will be treated as one group in the further statistical evaluation.
With 24 subjects there is a power of 80% to detect a correlation of 0.54 between two parameters by a 2-sided t-test and a significance level of 5%. The large number of mutual correlations between markers of endothelial injury, inflammation, fluid balance, changes in body weight and parameters of albumin mass balance calculations are exploratory. This part of the study is mainly hypothesis generating.
Normality of data will be assessed by Sharpio-Wilk’s test of normality and parametric or non-parametric analysis applied accordingly. The primary endpoint will be evaluated by t-test or Wilcoxon, as appropriate. Likewise correlations will be reported as Pearson’s correlation coefficient r or Spearman's rank correlation rs.
Demographic preoperative data such as age, height, weight, BMI, gender, routine lab, history of weight loss, diagnoses, and current medications will be presented as numbers, averages and standard deviation, or as median range as applicable.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
2/01/2017
Actual
3/03/2017
Date of last participant enrolment
Anticipated
31/05/2018
Actual
Date of last data collection
Anticipated
31/05/2018
Actual
Sample size
Target
40
Accrual to date
Final
Recruitment outside Australia
Country [1] 8181 0
Sweden
State/province [1] 8181 0

Funding & Sponsors
Funding source category [1] 294449 0
Government body
Name [1] 294449 0
Supported by grants provided by the Stockholm County Council (ALF project), grant #550178
Country [1] 294449 0
Sweden
Primary sponsor type
Individual
Name
Ake Norberg
Address
Perioperative Medicine and Intensive Care, B31
Karolinska University Hospital, Huddinge
SE-141 86 Stockholm
Country
Sweden
Secondary sponsor category [1] 293303 0
None
Name [1] 293303 0
Address [1] 293303 0
Country [1] 293303 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 295881 0
Regional Ethical Board in Stockholm
Ethics committee address [1] 295881 0
Regionala etikprovningsnamnden i Stockholm
FE 289
171 77 STOCKHOLM
Ethics committee country [1] 295881 0
Sweden
Date submitted for ethics approval [1] 295881 0
13/09/2016
Approval date [1] 295881 0
02/11/2016
Ethics approval number [1] 295881 0
Dnr: 2016/1765-31

Summary
Brief summary
Background
Intravenous fluids are regularly used during major abdominal surgery. A vivid debate on infusion rates, guidance, and choice of fluids is ongoing. Colloids are larger molecules that stay longer (hours) in plasma, but long term effects (weeks or more) are poorly investigated. After the recent recommendation against the use of the synthetic colloid hydroxyethyl starch by the European Medical Agency for safety reasons, albumin containing solutions remain the most used colloid in Sweden and at Karolinska University Hospital. However, evidence of any long term beneficial effects of albumin is missing.
Albumin is the main constituent of plasma proteins, contributing to the colloid osmotic pressure in the capillaries. Normally, it leaves the blood stream through the capillary walls at a rate of 4-5% of the intravascular pool per hour, and returns to plasma by the lymph at the same rate. Being an endogenous substance, it carries low risk of adverse effects, but the dosing is controversial, and costs high.
We have previously demonstrated a cumulative perioperative albumin shift of 24 +/- 17 g at the end of major abdominal surgery not explained by bleeding when starch was used as intravenous fluid. We believe that this amount of albumin is displaced to the interstitium, possibly contributing to edema. If capillary leakage is induced by hypervolemia, inflammation or other mechanisms is unclear.
Study purpose
In this observational study we are looking at two patient groups scheduled for pancreaticoduodenectomy because of malignant or benign disease, respectively. The primary purpose is to find if albumin is lost from the blood even when only crystalloids are used during surgery, our present routine. The malignant patients are likely to lose albumin quicker through the capillary walls because they suffer from chronic inflammation and also have a slower lymphatic return because surgery in that case comprises lymphadenectomies and a more extended dissection. We also want to investigate markers of injury to the capillary walls, markers of inflammation, and indices of volume status to generate new hypotheses.
The primary hypothesis is that albumin is lost in both patient groups, but more so in the malignant group, at the end of surgery.
The overall aim of our research program is to define the role of albumin in modern fluid therapy. This observational study is an important step in understanding effects of our present fluid routine in major abdominal surgery, to find when and to what degree albumin is lost from the blood stream, and to generate hypotheses on mechanisms. Future interventional studies will depend heavily on these results.
Trial website
Trial related presentations / publications
Public notes
Attachments [1] 1338 1338 0 0
/AnzctrAttachments/371432-Beslut EPN 161102.pdf (Ethics approval)

Contacts
Principal investigator
Name 68786 0
Dr Ake Norberg
Address 68786 0
Karolinska Institutet, Department of Clinical Science, Intervention and
Technology (CLINTEC)
and
Dept. Perioperative Medicine and Intensive Care, B31
Karolinska University Hospital, Huddinge
SE-141 86 Stockholm
Country 68786 0
Sweden
Phone 68786 0
+46 73 966 11 52
Fax 68786 0
+46 8 779 54 24
Email 68786 0
[email protected]
Contact person for public queries
Name 68787 0
Dr Ake Norberg
Address 68787 0
Karolinska Institutet, Department of Clinical Science, Intervention and
Technology (CLINTEC)
and
Dept. Perioperative Medicine and Intensive Care, B31
Karolinska University Hospital, Huddinge
SE-141 86 Stockholm
Country 68787 0
Sweden
Phone 68787 0
+46 73 966 11 52
Fax 68787 0
+46 8 779 54 24
Email 68787 0
[email protected]
Contact person for scientific queries
Name 68788 0
Dr Ake Norberg
Address 68788 0
Karolinska Institutet, Department of Clinical Science, Intervention and
Technology (CLINTEC)
and
Dept. Perioperative Medicine and Intensive Care, B31
Karolinska University Hospital, Huddinge
SE-141 86 Stockholm
Country 68788 0
Sweden
Phone 68788 0
+46 73 966 11 52
Fax 68788 0
+46 8 779 54 24
Email 68788 0
[email protected]

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